bluuebunny/crossref_metadata_2025 huggingface dataset:
Intra-clustering analysis reveals tissue-specific mutational patterns
Authors: Choudalakis Stamatis , Kastis George , Dikaios Nikolaos
Published: February 2024

The identification of tissue-specific mutational patterns associated with cancer development is challenging due to the low frequency of certain mutations and the high variability among tumors within the same cancer type. To address the inter-tumoral heterogeneity issue, our study aims to uncover infrequent mutational patterns by leveraging clustering analysis. To that end, a Network Graph of 8303 patients and 198 genes was constructed from single-point-mutation data that were retrieved from The Cancer Genome Atlas (TCGA). Patient-gene groups were retrieved with the parallel use of two separate methodologies based on the: (a) Barber’s modularity index, and (b) network dynamics. An intra-clustering analysis was employed to explore the patterns within smaller patient subgroups, which involved the Fisher’s exact test, multiple correspondence analysis and DISCOVER. This analysis was applied over 24 statistically meaningful groups of 2619 patients spanning 21 cancer types and it recovered 42 mutational patterns that are not reported in the TCGA consortium analysis publications. Notably, our findings: (i) suggest that AMER1 mutations are a putative separative element between colon and rectal adenocarcinomas, (ii) highlight the significant presence of RAC1 in head and neck squamous cell carcinoma (iii) suggest that EP300 mutations in head and neck squamous cell carcinoma are irrelevant of the HPV status of the patients and (iv) show that mutational-based clusters can contain patients with contrasting genetic alterations.

Significance

The submitted paper proposes a novel method to identify infrequent cancer-specific mutational patterns through network graphs and clustering analysis.

This analysis recovered: (a) 3 statistically significant cancer-gene relations that are not reported in the corresponding TCGA consortium analyses, (b) 28 known cancer-gene relations, (c) 39 significant patterns of co-occurrence or of mutual exclusivity that are not reported in current literature and (d) 14 reported significant mutational patterns.
Emo-FilM: A multimodal dataset for affective neuroscience using naturalistic stimuli
Authors: Morgenroth Elenor , Moia Stefano , Vilaclara Laura , Fournier Raphael , Muszynski Michal , Ploumitsakou Maria , Almató-Bellavista Marina , Vuilleumier Patrik , Van De Ville Dimitri
Published: February 2024

The extensive Emo-FilM dataset stands forEmotion research usingFilms and fMRI in healthy participants. This dataset includes detailed emotion annotations by 44 raters for 14 short films with a combined duration of over 2½ hours, as well as recordings of respiration, heart rate, and functional magnetic resonance imaging (fMRI) from a different sample of 30 individuals watching the same films. The detailed annotations of experienced emotion evaluated 50 items including ratings of discrete emotions and emotion components from the domains of appraisal, motivation, motor expression, physiological response, and feeling. Quality assessment for the behavioural data shows a mean inter-rater agreement of 0.38. The parallel fMRI data was acquired at 3 Tesla in four sessions, accompanied with a high-resolution structural (T1) and resting state fMRI scans for each participant. Physiological recordings during fMRI included heart rate, respiration, and electrodermal activity (EDA). Quality assessment indicators confirm acceptable quality of the MRI data. This dataset is designed, but not limited, to studying the dynamic neural processes involved in emotion experience. A particular strength of this data is the high temporal resolution of behavioural annotations, as well as the inclusion of a validation study in the fMRI sample. This high-quality behavioural data in combination with continuous physiological and MRI measurements makes this dataset a treasure trove for researching human emotion in response to naturalistic stimulation in a multimodal framework.
HB-EGF and EGF infusion following CNS demyelination mitigates age-related decline in regeneration of oligodendrocytes from neural precursor cells originating in the ventricular-subventricular zone
Authors: Moradi Kaveh , Mitew Stanislaw , Xing Yao Lulu , Merson Tobias D.
Published: February 2024

In multiple sclerosis (MS), chronic demyelination initiated by immune-mediated destruction of myelin, leads to axonal damage and neuronal cell death, resulting in a progressive decline in neurological function. The development of interventions that potentiate remyelination could hold promise as a novel treatment strategy for MS. To this end, our group has demonstrated that neural precursor cells (NPCs) residing in the ventricular-subventricular zone (V-SVZ) of the adult mouse brain contribute significantly to remyelination in response to central nervous system (CNS) demyelination and can regenerate myelin of normal thickness. However, aging takes its toll on the regenerative potential of NPCs and reduces their contribution to remyelination. In this study, we investigated how aging influences the contribution of NPCs to oligodendrogenesis during the remyelination process and whether the delivery of growth factors into the brains of aged mice could potentiate the oligodendrogenic potential of NPCs. To enable us to map the fate of NPCs in response to demyelination induced at different postnatal ages,Nestin-CreERT2;Rosa26-LSL-eYFPmice were gavaged with tamoxifen at either 8 weeks, 30 weeks or one year of age before being challenged with cuprizone for a period of six weeks. Using osmotic minipumps, we infused heparin-binding EGF-like growth factor (HB-EGF), and/or epidermal growth factor (EGF) into the cisterna magna for a period of two weeks beginning at the peak of cuprizone-induced demyelination (n=6-8 mice per group). Control mice received artificial cerebrospinal fluid (vehicle) alone. Mice were perfused six weeks after cuprizone withdrawal and the contribution of NPCs to oligodendrocyte regeneration in the corpus callosum was assessed. Our data reveal that although NPC-derived oligodendrocyte generation declined dramatically with age, this decline was partially reversed by growth factor infusion. Notably, co-infusion of EGF and HB-EGF increased oligodendrocyte regeneration twofold in some regions of the corpus callosum. Our results shed light on the beneficial effects of EGF and HB-EGF for increasing the contribution of NPCs to remyelination and indicate their therapeutic potential to combat the negative effects of aging upon remyelination efficacy.
The choice-wide behavioral association study: data-driven identification of interpretable behavioral components
Authors: Kastner David B. , Williams Greer , Holobetz Cristofer , Romano Joseph P. , Dayan Peter
Published: February 2024

Behavior contains rich structure across many timescales, but there is a dearth of methods to identify relevant components, especially over the longer periods required for learning and decision-making. Inspired by the goals and techniques of genome-wide association studies, we present a data-driven method—the choice-wide behavioral association study: CBAS—that systematically identifies such behavioral features. CBAS uses a powerful, resampling-based, method of multiple comparisons correction to identify sequences of actions or choices that either differ significantly between groups or significantly correlate with a covariate of interest. We apply CBAS to different tasks and species (flies, rats, and humans) and find, in all instances, that it provides interpretable information about each behavioral task.
Neurons underlying aggressive actions that are shared by both males and females inDrosophila
Authors: Tao Liangyu , Ayembem Deven , Barranca Victor J. , Bhandawat Vikas
Published: February 2024

Aggression involves both sexually monomorphic and dimorphic actions. How the brain implements these two types of actions is poorly understood. We found that a set of neurons, which we call CL062, previously shown to mediate male aggression also mediate female aggression. These neurons elicit aggression acutely and without the presence of a target. Although the same set of actions is elicited in males and females, the overall behavior is sexually dimorphic. The CL062 neurons do not expressfruitless, a gene required for sexual dimorphism in flies, and expressed by most other neurons important for controlling fly aggression. Connectomic analysis suggests that these neurons have limited connections withfruitlessexpressing neurons that have been shown to be important for aggression, and signal to different descending neurons. Thus, CL062 is part of a monomorphic circuit for aggression that functions parallel to the known dimorphic circuits.
Pre-existing visual responses in a projection-defined dopamine population explain individual learning trajectories
Authors: Pan-Vazquez A , Sanchez Araujo Y , McMannon B , Louka M , Bandi A , Haetzel L ,   International Brain Laboratory, Pillow JW , Daw ND , Witten IB
Published: February 2024

Learning a new task is challenging because the world is high dimensional, with only a subset of features being reward-relevant. What neural mechanisms contribute to initial task acquisition, and why do some individuals learn a new task much more quickly than others? To address these questions, we recorded longitudinally from dopamine (DA) axon terminals in mice learning a visual task. Across striatum, DA responses tracked idiosyncratic and side-specific learning trajectories. However, even before any rewards were delivered, contralateral-side-specific visual responses were present in DA terminals only in the dorsomedial striatum (DMS). These pre-existing responses predicted the extent of learning for contralateral stimuli. Moreover, activation of these terminals improved contralateral performance. Thus, the initial conditions of a projection-specific and feature-specific DA signal help explain individual learning trajectories. More broadly, this work implies that functional heterogeneity across DA projections serves to bias target regions towards learning about different subsets of task features, providing a mechanism to address the dimensionality of the initial task learning problem.
Metal mixtures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study
Authors: Jang Dae Gyu , Dou John , Koubek Emily J. , Teener Samuel , Zhao Lili , Bakulski Kelly M. , Mukherjee Bhramar , Batterman Stuart A. , Feldman Eva L. , Goutman Stephen A.
Published: February 2024

Background

The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival, and exposure sources.

Methods

Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. Odds and hazard ratios for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected SNPs.

Results

Plasma and urine samples from 454 ALS and 294 control participants were analyzed. Elevated levels of individual metals, including copper, selenium, and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62,p<0.001; urine, OR=3.10, CI=2.43-3.97,p<0.001) and poorer ALS survival (plasma, HR=1.42, CI=1.24-1.63,p<0.001; urine, HR=1.52, CI=1.31-1.76,p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures associated with measured plasma and urine metals.

Conclusion

Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.
Common and separable neural alterations in adult and adolescent depression – evidence from neuroimaging meta-analyses
Authors: Bore Mercy Chepngetich , Liu Xiqin , Kendrick Keith M , Zhou Bo , Zhang Jie , Klugah-Brown Benjamin , Becker Benjamin
Published: February 2024

Depression is a highly prevalent and debilitating disorder that often begins in adolescence. However, it remains unclear whether adults and adolescents with depression exhibit common or separate brain dysfunctions during reward processing. We aimed to identify common and separable neurofunctional alterations during receipt of rewards and brain structure in adolescents and adults with depression. A coordinate-based meta-analysis was employed using Seed-based d mapping with permutation of subject images (SDM-PSI). Compared with healthy controls, both age groups exhibited common activity decreases in the right striatum (putamen, caudate) and subgenual ACC. Adults with depression showed decreased reactivity in the right putamen and subgenual ACC, while adolescents with depression showed decreased activity in the left mid cingulate, right caudate but increased reactivity in the right post central gyrus. This meta-analysis revealed shared (caudate) and separable (putamen and mid cingulate cortex) reward-related alterations in adults and adolescents with depression. The findings suggest age-specific neurofunctional alterations and stress the importance of adolescent-specific interventions that target social functions.
Aging of the Spine: Characterizing genetic and physiological determinants of spinal curvature
Authors: Wang Frances M. , Ruby J. Graham , Sethi Anurag , Veras Matthew , Telis Natalie , Melamud Eugene
Published: February 2024

Increased spinal curvature is one of the most recognizable aging traits in the human population. However, despite high prevalence, the etiology of this condition remains poorly understood. To gain better insight into the physiological, biochemical, and genetic risk factors involved, we developed a novel machine learning method to automatically derive thoracic kyphosis and lumbar lordosis angles from dual-energy X-ray absorptiometry (DXA) scans in the UK Biobank Imaging cohort. In 41,212 participants, we find that on average males and females gain 2.42° kyphotic and 1.48° lordotic angle per decade of life. Increased spinal curvature was strongly associated with decreased muscle mass and bone mineral density. Adiposity had opposing associations, with decreased kyphosis and increased lordosis. To gain further insight into the molecular mechanisms involved, we carried out a genome-wide association study and identified several risk loci associated with both traits. Using Mendelian randomization, we further show that genes fundamental to the maintenance of musculoskeletal function (COL11A1, PTHLH, ETFA, TWIST1) and cellular homeostasis such as RNA transcription and DNA repair (RAD9A, MMS22L, HIF1A, RAB28) are likely involved in increased spinal curvature.
THE SPREAD OF INFECTIOUS DISEASES IN MIGRATION ROUTES BETWEEN CARAVANS AND RESIDENT COMMUNITIES: MODELLING YELLOW FEVER IN CENTRAL AMERICA
Authors: Simon Sabrina Soares , Amaku Marcos , Massad Eduardo
Published: February 2024

Objectives

To investigate the impact of yellow fever (YF) vaccination in the context of an outbreak and its association with migration, by assessing the effects of herd immunity in endemic communities and caravans, and its potential spread to other subsequent at-risk, disease-free communities in the migratory route.

Methods

We use a SEIRV-SEI compartmental deterministic model for humans and vectors and numerical simulations applied to three coupled populations - caravans, endemic and disease-free communities. Two scenarios are evaluated with different vaccination coverage levels at endemic communities and in caravans.

Results

When communities endemic to YF are the source of migration, herd immunity is critical, but vaccinating caravans is by far the most significant intervention to protect migrants and disease-free communities upwards from the risk of YF introduction.

Conclusion

Preventing outbreaks of climate-sensitive infectious diseases in the context of migration must be a joint effort of common interest. Maintaining vaccination coverage at recommended levels combined with the continued effort to vaccinate people on the move is the only intervention that can prevent a health crisis. Therefore, vaccination against climate-sensitive diseases should be considered climate adaptation.
Extracellular matrix dependent regulation of Septin 7 in focal adhesions promotes mechanosensing and response in fibroblasts
Authors: Sturgess Wesley , Packirisamy Swathi , Geneidy Rodina , Swaminathan Vinay
Published: February 2024

Fibroblasts are contractile adherent cells that maintain tissue homeostasis by sensing a wide array of changes in the extracellular matrix (ECM) and in response, regulate the physical and compositional properties of the ECM. These diverse cues are sensed by focal adhesions (FAs) that differentially couple changes in the ECM to the actomyosin machinery via modulation of integrin activation and the resultant recruitment of several proteins. One such protein is Septin-7 (Sept-7) that belongs to the septin family and has been found in FA proteomics and interactome studies. Sept-7 however, is not considered an FA protein and is thought to regulate and be regulated by actin outside of FAs. To reconcile these differences, here we used total internal reflection microscopy to image Sept-7 localization and dynamics at the cell-ECM interface and found that that ECM-mediated integrin activation in fibroblasts regulates the formation of spatially distinct higher order Sept-7 structures at FA subpopulations. In and around FAs located in the perinuclear regions of the cell, ECM binding resulted in the formation and stabilization of Sept-7 bundles while ECM binding and complete integrin activation promoted the growth of FA-like elongated Sept-7 structures that dynamically associated with the core of peripheral FAs. Functionally, peripheral Sept-7 structures promoted the elongation of peripheral FAs while perinuclear Sept-7 bundles were critical in regulating the maturation and stabilization of perinuclear FAs. Due to this coupling between the ECM, integrin activation and regulation of Sept-7 structures, we found that Sept-7 is required for a wide range of ECM sensing functions in fibroblasts including modulating sensitivity to changes in ECM stiffness and density and in contributing to the cells ability to remodel the ECM. Collectively, our results show that Sept-7 is an FA protein that gets recruited and assembled in diverse higher order structures in an ECM dependent manner to differentially regulate FA subpopulations and promote mechanosensing and ECM remodelling functions in fibroblasts.
Chemically induced senescence prompts functional changes in human microglia-like cells
Authors: Armanville S. , Tocco C. , Haj Mohamad Z. , Clarke D. , Robitaille R. , Drouin-Ouellet J.
Published: February 2024

In response to various stressors, cells can enter a state called cellular senescence which is characterized by irreversible cell cycle arrest and a senescence-associated secretory phenotype (SASP). The progressive accumulation of senescent glial cells in the central nervous system (CNS) with aging suggests a potential role for senescence as driver of aging and inflammation in the brain. As the main immune cell population residing in the CNS, microglia are thought to play a pivotal role in the progression of age-associated neuroinflammation. Furthermore, due to their slow turnover, microglia are highly susceptible to undergoing cellular senescence. However, current understanding of age-related changes in microglia and their impact on brain aging is limited. Due to the challenge in accessing human primary microglia and the lack of models to adequately recapitulate aging, this knowledge is predominantly limited to rodent studies. Here, we chemically induced senescence in a human immortalized microglia cell line with a cocktail of senescence-inducing molecules. We demonstrate that chemically induced senescent microglia adopt a pro-inflammatory phenotype, have reduced phagocytic activity and impaired calcium activity. Our results show that chemically induced senescence can mimic features of cellular aging and can provide insight on the impact of aging and cellular senescence on human microglia.
Single-cell approach dissectingagrquorum sensing dynamics inStaphylococcus aureus
Authors: Bär Julian , Charlton Samuel G. V. , Tarnutzer Andrea , Ugolini Giovanni Stefano , Secchi Eleonora , Zinkernagel Annelies S.
Published: February 2024

Staphylococcus aureusboth colonizes humans and causes severe virulent infections. Virulence is regulated by theagrquorum sensing system and its autoinducing peptide (AIP), with dynamics at the single-cell level across fouragr-types – each defined by distinct AIP sequences and capable of cross-inhibition – remaining elusive. Employing microfluidics, time-lapse microscopy, and deep-learning image analysis, we uncovered significant differences in AIP sensitivity amongagr-types. We observed bimodalagractivation, attributed to intergenerational phenotypic stability and influenced by AIP concentration. Upon AIP stimulation,agr-IIIshowed AIP insensitivity, whileagr-IIexhibited increased sensitivity and prolonged generation time. Beyond expected cross-inhibition ofagr-Iby heterologous AIP-II and -III, the presumably cross-activating AIP-IV also inhibitedagr-I. Community interactions across differentagr-type pairings revealed four main patterns: stable or switched dominance, and delayed or stable dual activation, influenced by community characteristics. These insights underscore the potential of personalized treatment strategies considering virulence and genetic diversity.
Cross-species alignment along the chronological axis reveals evolutionary effect on structural development of human brain
Authors: Li Yue , Sun Qinyao , Zhu Shunli , Chu Congying , Wang Jiaojian
Published: February 2024

Disentangling evolution mysteries of human brain has always been an imperative endeavor in neuroscience. On the one hand, by spatially aligning the brains between human and nonhuman primates (NHPs), previous efforts in comparative studies revealed both correspondence and difference in brain anatomy, e.g., the morphological and the connectomic patterns. On the other hand, brain anatomical development along the temporal axis is evident for both human and NHPs in early life. However, it remains largely unknown whether we can conjugate the brain development phases between human and NHPs, and, especially, what the role played by the brain anatomy in the conjugation will be. Here, we proposed to embed the brain anatomy of human and macaque in the chronological axis for enabling the cross-species comparison on brain development. Specifically, we separately established the prediction models by using the brain anatomical features in gray matter and white matter tracts to predict the chronological age in the human and macaque samples with brain development. We observed that applying the trained models within-species could well predict the chronological age. Interestingly, by conducting the cross-species application of the trained models, e.g., applying the model trained in humans to the data of macaques, we found a significant cross-species imbalance regarding to the model performance, in which the model trained in macaque showed a higher accuracy in predicting the chronological age of human than the model trained in human in predicting the chronological age of macaque. The cross application of the trained model introduced the brain cross-species age gap (BCAP) as an individual index to quantify the cross-species discrepancy along the temporal axis of brain development for each participant. We further showed that BCAP was associated with the behavioral performance in both visual sensitivity test and picture vocabulary test in the human samples. Taken together, our study situated the cross-species brain development along the chronological axis, which highlighted the disproportionately anatomical development in the human brain to extend our understanding of the potential evolutionary effects.
SUMO-mediated regulation of a H3K4me3 reader controls germline development inC. elegans
Authors: Carvalho Cátia A. , Abu-Shach Ulrike Bening , Raju Asha , Vershinin Zlata , Levy Dan , Boxem Mike , Broday Limor
Published: February 2024

ULP-2 is a conserved SUMO protease required for embryonic development inC. elegans. Here we revealed that ULP-2 controls germline development by regulating the PHD-SET domain protein, SET-26. Specifically, theulp-2mutant hermaphrodites exhibit increased sterility and progressive elevation in global protein sumoylation. In the progeny of homozygous animals, meiosis is arrested at the diplotene stage and the cells in the proximal germline acquire a somatic fate. Germline RNAseq analysis revealed the downregulation of numerous germline genes, whereas somatic gene expression is upregulated inulp-2mutant gonads. To determine the key factors that are regulated by ULP-2, we performed a yeast two-hybrid screen and identified the H3K4me3 reader, SET-26. Genetic interaction was observed in double mutantulp-2;set-26resulting in enhanced sterility phenotype to complete sterility in the first generation of homozygous offspring. Consistently, SET-26 is sumoylated and its sumoylation levels are regulated by ULP-2. Moreover, we detected reduction in H3K4me3 levels bound to SET-26 in theulp-2mutant background. A comparative proteomics screen between WT andulp-2loss of activity identified the predicted methyltransferase SET-27 as a ULP-2-dependent SET-26-associated protein. SET-27 knockout genetically interacts with ULP-2 in the germline, but not with SET-26. Taken together, we revealed a ULP-2/SET-26 axis which is required for the maintenance and regulation of germline development.
Stable flies are bonafide reservoirs of mastitis-associated bacteria
Authors: Sommer Andrew J. , Kettner Julia E. , Coon Kerri L.
Published: February 2024

HematophagousStomoxys(stable) fly populations in dairy barns are sustained by a constant availability of cattle hosts and manure, which serve as major reservoirs of both zoonotic and opportunistic bacterial pathogens. However, the overall composition and diversity of bacterial communities associated withStomoxysflies and the ability of biting flies to acquire and transmit potentially pathogenic bacteria present in their surrounding environment remain to be investigated. Here, we present the first culture-independent examination ofStomoxys-associated bacterial communities through longitudinal sampling of fly and manure samples collected from two connected dairy facilities in South Central Wisconsin. High throughput 16S rRNA gene amplicon sequencing was used to characterize and compare bacterial communities present on or within flies and in manure collected from the same facility. Bacterial alpha diversity was overall higher in manure samples as compared to fly samples, with manure-associated bacterial communities being dominated by members of the Bacteroidales, Eubacteriales, and Oscillospirales. In contrast, flies harbored relatively low-complexity communities dominated by members of the Enterobacterales, Staphylococcales, and Lactobacillales. Clinically relevant bacterial strains, includingEscherichiaspp. and other taxa associated with mastitic cows housed in the same facilities, were detected in paired fly and manure samples but exhibited dramatically elevated abundances in fly samples as compared to manure samples. Viable colonies ofEscherichia,Klebsiella, andStaphylococcusspp. were also readily isolated from fly samples, confirming that flies harbor culturable mastitis associated bacteria. This study provides definitive support for a potential role for biting flies in mediating bacterial pathogen transmission in dairy barns and other agricultural settings.

IMPORTANCE

Disease prevention on dairy farms has significant implications for cattle health, food security, and zoonosis. Of particular importance is the control of bovine mastitis, which can be caused by a diverse array of environmental bacterial pathogens, includingKlebsiella,E. coli,Streptococcus, andStaphylococcusspp. Despite being one of the most significant and costly cattle diseases worldwide, the epidemiology of bovine mastitis is not well understood. This study provides the first culture-dependent and culture-independent evidence to support the potential for biting flies to transmit opportunistic bovine and human pathogens in agricultural settings. It also links carriage of specific bacterial taxa in flies to clinical mastitis cases in cows housed in the same facility at the time of sampling. Altogether, these results indicate that biting flies represent an important, yet understudied biosecurity threat to animal husbandry facilities.
Rhesus Cytomegalovirus-encoded Fcγ-binding glycoproteins facilitate viral evasion from IgG-mediated humoral immunity
Authors: Otero Claire E. , Petkova Sophia , Ebermann Martin , Taher Husam , John Nessy , Hoffmann Katja , Davalos Angel , Moström Matilda J. , Gilbride Roxanne M , Papen Courtney R. , Barber-Axthelm Aaron , Scheef Elizabeth A. , Barfield Richard , Sprehe Lesli M. , Kendall Savannah , Manuel Tabitha D. , Vande Burgt Nathan H. , Chan Cliburn , Denton Michael , Streblow Zachary J. , Streblow Daniel N. , Hansen Scott G , Kaur Amitinder , Permar Sallie , Früh Klaus , Hengel Hartmut , Malouli Daniel , Kolb Philipp
Published: February 2024

Human cytomegalovirus (HCMV) encodes four viral Fc-gamma receptors (vFcγRs) that counteract antibody-mediated activationin vitro, but their role in infection and pathogenesis is unknown. To examine thein vivofunction of vFcγRs in animal hosts closely related to humans, we identified and characterized vFcγRs encoded by rhesus CMV (RhCMV). We demonstrate that Rh05, Rh152/151 and Rh173 represent the complete set of RhCMV vFcγRs, each displaying functional similarities to their respective HCMV orthologs with respect to antagonizing host FcγR activationin vitro. When RhCMV-naïve rhesus macaques were infected with vFcγR-deleted RhCMV, peak plasma viremia levels and anti-RhCMV antibody responses were comparable to wildtype infections. However, the duration of plasma viremia was significantly shortened in immunocompetent, but not in CD4+ T cell-depleted animals. Since vFcγRs were not required for superinfection, we conclude that vFcγRs delay control by virus-specific adaptive immune responses, particularly antibodies, during primary infection.
Engineering an Escherichia coli strain for production of long single-stranded DNA
Authors: Shen Konlin , Flood Jake J. , Zhang Zhihuizi , Ha Alvin , Shy Brian R. , Dueber John E. , Douglas Shawn M.
Published: February 2024

Long single-stranded DNA (ssDNA) is a versatile molecular reagent with applications including RNA- guided genome engineering and DNA nanotechnology, yet its production is typically resource-intensive. We introduce a novel method utilizing an engineeredE. coli “helper”strain and phagemid system that simplifies long ssDNA generation to a straightforward transformation and purification procedure. Our method obviates the need for helper plasmids and their associated contamination by integrating M13mp18 genes directly into theE. colichromosome. We achieved ssDNA lengths ranging from 504 to 20,724 nucleotides with titers up to 250 μg/L following alkaline-lysis purification. The efficacy of our system was confirmed through its application in primary T cell genome modifications and DNA origami folding. The reliability, scalability, and ease of our approach promises to unlock new experimental applications requiring large quantities of long ssDNA.
A multi-looping chromatin signature predicts dysregulated gene expression in neurons with familial Alzheimer’s disease mutations
Authors: Chandrashekar Harshini , Simandi Zoltan , Choi Heesun , Ryu Han-Seul , Waldman Abraham J. , Nikish Alexandria , Muppidi Srikar S. , Gong Wanfeng , Paquet Dominik , Phillips-Cremins Jennifer E.
Published: February 2024

Mammalian genomes fold into tens of thousands of long-range loops, but their functional role and physiologic relevance remain poorly understood. Here, using human post-mitotic neurons with rare familial Alzheimer’s disease (FAD) mutations, we identify hundreds of reproducibly dysregulated genes and thousands of miswired loops prior to amyloid accumulation and tau phosphorylation. Single loops do not predict expression changes; however, the severity and direction of change in mRNA levels and single-cell burst frequency strongly correlate with the number of FAD-gained or -lost promoter-enhancer loops. Classic architectural proteins CTCF and cohesin do not change occupancy in FAD-mutant neurons. Instead, we unexpectedly find TAATTA motifs amenable to binding by DLX homeodomain transcription factors and changing noncoding RNAPolII signal at FAD-dynamic promoter-enhancer loops.DLX1/5/6mRNA levels are strongly upregulated in FAD-mutant neurons coincident with a shift in excitatory-to-inhibitory gene expression and miswiring of multi-loops connecting enhancers to neural subtype genes.DLX1overexpression is sufficient for loop miswiring in wildtype neurons, including lost and gained loops at enhancers with tandem TAATTA arrays and singular TAATTA motifs, respectively. Our data uncover a genome structure-function relationship between multi-loop miswiring and dysregulated excitatory and inhibitory transcriptional programs during lineage commitment of human neurons homozygously-engineered with rare FAD mutations.
O-GlcNAcylation of the intellectual disability protein DDX3X exerts proteostatic cell cycle control
Authors: Mitchell Conor W. , Yuan Huijie , Sønderstrup-Jensen Marie , Authier Florence , D’Alessio Alfonso Manuel , Ferenbach Andrew T. , van Aalten Daan M.F.
Published: February 2024

O-GlcNAcylation is an evolutionary conserved post-translational modification implicated in neurodevelopment. Missense variants of O-GlcNAc transferase (OGT) are causal for the intellectual disability syndrome OGT Congenital Disorder of Glycosylation (OGT-CDG). The observation of microcephaly in OGT-CDG patients suggests that dysregulation of the cell cycle and aberrant neurogenesis may contribute to disease aetiology. Here, we identify Ser584 O-GlcNAcylation of DDX3X, a known intellectual disability and microcephaly associated protein, as a key regulator of G1/S-phase transition, inhibiting proteasome-dependent degradation of DDX3X. DDX3X levels are reduced in a mouse model of OGT-CDG, alongside the DDX3X-target gene and synaptogenic regulator cyclin E1. These data reveal how a single DDX3X O-GlcNAc site exerts control of the cell cycle and highlights dysregulation of DDX3X-dependent translation, and concomitant impairments in cortical neurogenesis, as a possible pathway disrupted in OGT-CDG.
Nir1-LNS2 is a novel phosphatidic acid biosensor that reveals mechanisms of lipid production
Authors: Weckerly Claire C. , Rahn Taylor A. , Ehrlich Max , Wills Rachel C. , Pemberton Joshua G. , Airola Michael V. , Hammond Gerald R. V.
Published: February 2024

Despite various roles of phosphatidic acid (PA) in cellular functions such as lipid homeostasis and vesicular trafficking, there is a lack of high-affinity tools to study PA in live cells. After analysis of the predicted structure of the LNS2 domain in the lipid transfer protein Nir1, we suspected that this domain could serve as a novel PA biosensor. We created a fluorescently tagged Nir1-LNS2 construct and then performed liposome binding assays as well as pharmacological and genetic manipulations of HEK293A cells to determine how specific lipids affect the interaction of Nir1-LNS2 with membranes. We found that Nir1-LNS2 bound to both PA and PIP2in vitro. Interestingly, only PA was necessary and sufficient to localize Nir1-LNS2 to membranes in cells. Nir1-LNS2 also showed a heightened responsiveness to PA when compared to biosensors using the Spo20 PA binding domain (PABD). Nir1-LNS2’s high sensitivity revealed a modest but discernible contribution of PLD to PA production downstream of muscarinic receptors, which has not been visualized with previous Spo20-based probes. In summary, Nir1-LNS2 emerges as a versatile and sensitive biosensor, offering researchers a new powerful tool for real-time investigation of PA dynamics in live cells.
Unraveling metastable Markovian open quantum systems
Authors: Brown Calum A. , Macieszczak Katarzyna , Jack Robert L.
Published: February 2024

We analyze the dynamics of metastable Markovian open quantum systems by unraveling their average dynamics into stochastic trajectories. We use quantum reset processes as examples to illustrate metastable phenomenology, including a simple three-state model whose metastability is of classical type, and a two-qubit model that features a metastable decoherence-free subspace. In the three-state model, the trajectories exhibit classical metastable phenomenology: fast relaxation into distinct phases and slow transitions between them. This extends the existing correspondence between classical and quantum metastability. It enables the computation of committors for the quantum phases, and the mechanisms of rare transitions between them. For the two-qubit model, the decoherence-free subspace appears in the unraveled trajectories as a slow manifold on which the quantum state has a continuous slow evolution. This provides a classical (nonmetastable) analog of this quantum effect. We discuss the general implications of these results, and we highlight the useful role of quantum reset processes for analysis of quantum trajectories in metastable systems.

Published by the American Physical Society
2024
Dissipationless Counterflow Currents above
Tc
in Bilayer Superconductors
Authors: Homann Guido , Michael Marios H. , Cosme Jayson G. , Mathey Ludwig
Published: February 2024

We report the existence of dissipationless currents in bilayer superconductors above the critical temperature Tc, assuming that the superconducting phase transition is dominated by phase fluctuations. Using a semiclassical U(1) lattice gauge theory, we show that thermal fluctuations cause a transition from the superconducting state at low temperature to a resistive state above Tc, accompanied by the proliferation of unbound vortices. Remarkably, while the proliferation of vortex excitations causes dissipation of homogeneous in-plane currents, we find that counterflow currents, flowing in the opposite direction within a bilayer, remain dissipationless. The presence of a dissipationless current channel above Tc is attributed to the inhibition of vortex motion by local superconducting coherence within a single bilayer, in the presence of counterflow currents. Our theory presents a possible scenario for the pseudogap phase in bilayer cuprates.

Published by the American Physical Society
2024
Exploring the nontrivial band edge in the bulk of the topological insulators
Bi2Se3
and
Bi2Te3
Authors: Guehne Robin , Chlan Vojtěch
Published: February 2024

Bi2Se3 and related compounds are prototype three-dimensional topological insulators with a single Dirac cone in the surface band structure. While the topological surface states can be characterized with surface-sensitive methods, the underlying bulk energy band inversion has not been investigated in detail. Here, a study is presented that combines density-functional theory and nuclear magnetic resonance to explore the nontrivial band edge of Bi2Se3 and Bi2Te3. It is found that the topological band inversion is not a discrete reversal of the order of the valence and conduction band at the Γ point. Rather, the bands closest to the Fermi level become well mixed and spread evenly below and above the band gap, such that the characters of the valence- and conduction-band edges become indistinguishable. Beside those bands relevant for the band inversion, i.e., Bi and Se pz, also Bi px and py states are involved. As a part of this mixture of states, the band inversion shows no edges in k space.

Published by the American Physical Society
2024
Phase-controlled heat modulation with Aharonov-Bohm interferometers
Authors: Hwang Sun-Yong , Sothmann Björn , López Rosa
Published: February 2024

A heat modulator is proposed based on a voltage-biased Aharonov-Bohm interferometer. Once an electrical bias is applied, Peltier effects give rise to a flow of heat that can be modulated by a magnetic flux. We determine the corresponding temperature changes using a simple thermal model. Our calculations demonstrate that the modulated temperature difference can be as large as 80 mK at base temperature about 600 mK with relative temperature variations reaching 10%. Our model also predicts, quite generally, the emergence of spin-polarized heat flows without any ferromagnetic contacts, if Rashba spin-orbit interaction is combined with the applied magnetic flux, which potentially paves the way towards caloritronic information processing.

Published by the American Physical Society
2024
Observation of weak localization in dual-gated bilayer
MoS2
Authors: Qu Tingyu , Masseroni Michele , Taniguchi Takashi , Watanabe Kenji , Özyilmaz Barbaros , Ihn Thomas , Ensslin Klaus
Published: February 2024

We investigate the magnetoresistance of a dual-gated bilayer MoS2 encapsulated by hexagonal boron nitride. At low magnetic fields (|B|<0.5T), we observe a negative magnetoresistance, which we identify as the weak localization effect. We determine both the phase coherence length and mean free path as a function of electron density and displacement field. Both characteristic lengths show a similar monotonic increase with electron density, while they are not affected by the displacement field. We further investigate the dephasing mechanism by measuring the temperature dependence of the phase coherence length. Our results suggest that when only the lower spin-orbit split bands (K↑, K′↓) contribute to transport is Coulomb scattering the dominant source of decoherence, while intervalley scattering seems not to play a relevant role in this regime. This observation is consistent with the picture of spin-polarized valleys (spin-valley locking), where the intrinsic spin-orbit coupling protects the spin states, rather than introducing an additional dephasing mechanism as in other materials.

Published by the American Physical Society
2024
Sensing of magnetic field effects in radical-pair reactions using a quantum sensor
Authors: Khurana Deepak , Jensen Rasmus H. , Giri Rakshyakar , Bocquel Juanita , Andersen Ulrik L. , Berg-Sørensen Kirstine , Huck Alexander
Published: February 2024

Magnetic field effects (MFE) in certain chemical reactions have been well established in the last five decades and are attributed to the evolution of transient radical pairs whose spin dynamics are determined by local and external magnetic fields. The majority of existing experimental techniques used to probe these reactions only provide ensemble averaged reaction parameters and spin chemistry, hindering the observation of the potential presence of quantum coherent phenomena at the single molecule scale. Here, considering a single nitrogen-vacancy (NV) center as quantum sensor, we investigate the prospects and requirements for the detection of MFEs on the spin dynamics of radical pairs at the scale of a single and small ensembles of molecules. We employ elaborate and realistic models of radical pairs, considering their coupling to the local spin environment and the sensor. For two model systems, we derive signals of MFE detectable even in the weak coupling regime between a radical pair and an NV quantum sensor and observe that the dynamics of certain populations, as well as coherence elements, of the density matrix of the radical pair are directly detectable. Our investigations will provide important guidelines for the potential detection of spin chemistry of biomolecules at the scale of a single and small ensembles of molecules.

Published by the American Physical Society
2024
Spatiotemporal Torquing of Light
Authors: Hancock S. W. , Zahedpour S. , Goffin A. , Milchberg H. M.
Published: February 2024

We demonstrate the controlled spatiotemporal transfer of transverse orbital angular momentum (OAM) to electromagnetic waves: the spatiotemporal torquing of light. This is a radically different situation from OAM transfer to longitudinal, spatially defined OAM light by stationary or slowly varying refractive-index structures such as phase plates or air turbulence. We show that net transverse OAM per photon can be spatiotemporally imparted to a light pulse only if (1) a transient phase perturbation is well overlapped with the pulse in spacetime, or (2) the pulse initially has nonzero transverse OAM density, and the perturbation removes energy from it. Physical insight is provided by the mechanical analogy of torquing a wheel or removing mass as it spins. Our OAM theory for spatiotemporal optical vortex (STOV) pulses [S. W. Hancock ,] correctly quantifies the light-matter interaction of our experiments and provides a spatiotemporal-torque-based explanation for the first measurement of STOVs [N. Jhajj , ].

Published by the American Physical Society
2024
Accessing the effect of smartphone agricultural applications on land transfer: evidence from Sichuan province in China
Authors: Yu Xi , Abdulai Awudu , Li Dongmei
Published: February 2024

Purpose

This study aims to examine farmers' decision to use smartphone agricultural applications (SAAs) and how SAAs adoption impact their land transfer behaviors in terms of the current land transfer-in area (LTA) and the future willingness to renew land transfer-in after it expires (WTR).

Design/methodology/approach

This study provides empirical evidence on the relationship between farmers' use of SAAs and land transfer choice, using a field survey data of 752 rural farm households in 2020 from Sichuan province of China. The endogenous switching models are employed to address potential self-selection bias associated with voluntary SAAs use and to quantitatively examine the impacts of SAAs use on land transfer choice.

Findings

The empirical results reveal that SAAs significantly improves the probability of transfer-in of more land by 39.10%. We find SAAs use has heterogeneous impacts on land transfer-in choice in the groups of agricultural technology, extension service, marketing and credit. Besides, we also find that SAAs use exerts highly positive and significant impact on farmers with less land area transfer-in. Moreover, SAAs can increase the probability of farmers' willingness to renew the land transfer-in by 30%.

Originality/value

To the best of our knowledge, this study is the first to explore the quantitative relationship between the use of SAAs and farm households' land transfer choice. The findings of this work can provide policy-related insights to help government promote the development of digital applications in the agricultural sector.