bluuebunny/crossref_metadata_2025 huggingface dataset:
An in-silico investigation of the effect of changing cycling crank power and cadence on muscle energetics and active muscle volume
Authors: Riveros-Matthey Cristian D. , Carroll Timothy J. , Connick Mark J. , Lichtwark Glen A.
Published: September 2023

This study used musculoskeletal modelling to explore the relationship between cycling conditions (power output and cadence) and muscle activation and metabolic power. We hypothesized that the cadence that minimized the simulated average active muscle volume would be higher than that which minimized the simulated metabolic power. We validated the simulation by comparing predicted muscle activation and fascicle velocities from select muscles with experimental records of electromyography and ultrasound images. We found strong correlations for averaged muscle activations and moderate to good correlations for fascicle dynamics. These correlations tended to weaken when analyzed at the individual participant level. Our study revealed a curvilinear relationship between average active muscle volume and cadence, with the minimum active volume being aligned to the self-selected cadence. The simulated metabolic power was consistent with previous results and was minimized at lower cadences than that which minimized active muscle volume across power outputs. Whilst there are some limitations to the musculoskeletal modelling approach, the findings suggest that minimizing active muscle volume may be a more important factor than minimizing metabolic power for self-selected cycling cadence preferences. Further research is warranted to explore the potential of an active muscle volume based objective function for control schemes across a wider range of cycling conditions.
Embryogenesis in myrmicine ants combines features of short and long germ-band modes of development
Authors: Fang Chi-Chun , Rajakumar Arjuna , Kenny Andrew , Mueller Ulrich G. , Abouheif Ehab , Stein David
Published: September 2023

Ants exhibit complex social organization, morphologically distinct castes with division of labor, and the exploitation of diverse ecological niches. The extent to which these features have influenced embryonic development relative to other insects remains unclear. Insect embryogenesis has been classified into one of three modes: long, short, and intermediate germ-band. In long germ-band development, exemplified by the fruit flyDrosophila melanogaster, segments along the entire anterior-posterior axis of the embryonic primordium are established almost simultaneously, prior to gastrulation, with the initial embryonic primordium surrounding almost the entire volume of the egg. In short and intermediate germ-band modes, the embryonic primordium occupies a smaller proportion of the egg surface, with anterior segments initially specified, and remaining segments being added sequentially from a posterior growth zone. Here, we show a novel pattern of development in three myrmicine ants, the fungus-gardening antsAtta texanaandMycocepurus smithii, and the red imported fire antSolenopsis invicta. Early in embryogenesis, they exhibit features of short germ-band development, while later in development they exhibit a newly-characterized progressive pattern of segmentation that has been associated with some long germ-band-developing insects. Moreover, despite similarities in the size of ant andDrosophilaeggs, the duration of embryogenesis in the three ant species is 10 to 20-fold longer than inDrosophilaand is also significantly longer than in the honeybeeApis melliferaand the jewel waspNasonia vitripennis. In addition, the embryos produced byA. texanafoundress queens develop to first instar larvae 25% faster than embryos produced by mature queens. We discuss these results in the context of the eusocial lifestyle of ants.
Exploring the mechanisms and potential therapeutic targets of Ferroptosis Related Genes in ankylosing spondylitis
Authors: Liu Zhen-Gang , Yang Fan , Chen Bing , Li Peng-Fu , Zhang Bo-Yin
Published: September 2023

Background

Ferroptosis is a novel type of regulated cell death, and there is growing evidence that it is directly associated with the disease. Therefore, this study aimed to investigate the relevance of iron Ferroptosis-related genes to ankylosing spondylitis (AS) to propose a novel targeted therapy for AS patients.

Methods

AS samples were downloaded from the Gene Expression Omnibus (GEO) database (GSE41038). Ferroptosis-related genes were obtained from the FerrDb database, and differential expression analysis was performed using the GEO2R tool. Additionally, we constructed a protein-protein interaction (PPI) network and identified the central genes using Cytoscape. A neural network model was developed utilizing the data mining software Clementine. cMap technology was used to screen potential pharmacological compounds that target the central gene,and a predictive model was built by machine learning methods.

Results

We discovered 786 differentially expressed genes in AS samples compared to normal tissue, including 359 up-regulated and 427 down-regulated genes. The intersection of ferroptosis-related genes and differential genes yielded 20 overlapping genes. We constructed a hub gene co-expression network with 20 nodes and 14 edges and obtained the ten most recommended drugs for AS.

Conclusion

Bioinformatics analysis identified 20 potential genes associated with Ferroptosis in AS. Genes such as CAV1, NOX4, and NQO1 were revealed to influence the development of AS by regulating Ferroptosis. Our study provides new insights into the function of iron Ferroptosis-related genes in AS, suggesting that targeting Ferroptosis may be a potential therapeutic option for AS.
Detecting Differential Alternative Splicing in Mass Spectrometry-based Proteomics Data
Authors: Ammar Constantin , Csaba Gergely , Hadziahmetovic Armin , Vasilopoulou Catherine G. , Gruber Markus , Mann Matthias , Zimmer Ralf
Published: September 2023

Alternative splicing can substantially diversify biological cell states and influence cellular function. The functional impact of splicing has to be estimated at protein level, typically by mass spectrometry (MS) -based proteomics. Although this technology measures increasingly large peptides sets, distinguishing isoform-specific peptides are rare, limiting detection and quantification of splicing. We introduce MS-EmpiReS, a quantification-based computational approach for differential alternative splicing detection in proteomics data. Its core principle is to differentially quantify peptides mapping to different regions of genes. This approach increased the number of testable peptides hundred-fold in a clinical cancer cohort, resulting in a large number of cancer-relevant splicing candidates. Splicing events detected by both MS-EmpiReS and deep RNA sequencing correlated well but also provided complementary information. The proteomics data allowed us to define a per-sample splicing score to separate cancer conditions. Finally, deep brain proteomes from different mice separated strongly by the lower abundance protein splicing isoform.
Cancer immunotherapy response persists after lymph node resection
Authors: Zhou Hengbo , Menzel Lutz , Baish James W. , O’Melia Meghan J. , Darragh Laurel B. , Effiom Derek N. , Specht Emma , Czapla Juliane , Lei Pin-ji , Rajotte Johanna J. , Liu Lingshan , Nikmaneshi Mohammad R. , Razavi Mohammad S. , Vander Heiden Matthew G. , Ubellacker Jessalyn M. , Munn Lance L. , Karam Sana D. , Boland Genevieve M. , Cohen Sonia , Padera Timothy P.
Published: September 2023

Lymphatic transport facilitates the presentation of cancer antigens in tumor-draining lymph nodes (tdLNs), leading to T cell activation and the generation of systemic antitumor immune surveillance. Surgical removal of LNs to control cancer progression is routine in clinical practice. However, whether removing tdLNs impairs immune checkpoint blockade (ICB) is still controversial. Our analysis demonstrates that melanoma patients remain responsive to PD-1 checkpoint blockade after LN dissection. We were able to recapitulate the persistent response to ICB after complete LN resection in murine melanoma and mammary carcinoma models. Mechanistically, soluble antigen and antigen- carrying migratory dendritic cells are diverted to non-directly tumor draining LNs (non-tdLNs) after tdLN dissection. Consistently, robust ICB responses in patients with head and neck cancer after primary tumor and tdLN resection correlated with the presence of reactive LNs in distant areas. These findings indicate that non-tdLNs sufficiently compensate for the removal of direct tdLNs and sustain the response to ICB.
Lung influenza virus specific memory CD4 T cell location and optimal cytokine production are dependent on interactions with lung antigen-presenting cells
Authors: Hargrave Kerrie E , Worrell Julie C , Pirillo Chiara , Brennan Euan , Masdefiol Garriga Andreu , Gray Joshua I , Purnell Thomas , Roberts Edward W , MacLeod Megan KL
Published: September 2023

Influenza A virus (IAV) infection leads to the formation of mucosal memory CD4 T cells that can protect the host. An in-depth understanding of the signals that shape memory cell development is required for more effective vaccine design. We have examined the formation of memory CD4 T cells in the lung following IAV infection of mice, characterising changes to the lung landscape and immune cell composition. IAV-specific CD4 T cells were found throughout the lung at both primary and memory time points. These cells were found near lung airways and in close contact with a range of immune cells including macrophages, dendritic cells, and B cells. Interactions between lung IAV-specific CD4 T cells and MHCII+ cells during the primary immune response were important in shaping the subsequent memory pool. Treatment with an anti-MHCII blocking antibody increased the proportion of memory CD4 T cells found at lung airways but reduced interferon-g expression by IAV-specific immunodominant memory CD4 T cells. The immunodominant CD4 T cells expressed higher levels of PD1 than other IAV-specific CD4 T cells and PD1+ memory CD4 T cells were located further away from MHCII+ cells than their PD1-negative counterparts. This distinction in location was lost in mice treated with anti-MHCII antibody. These data suggest that sustained antigen presentation in the lung impacts on the formation of memory CD4 T cells by regulating their cytokine production and location.
Optimal Sampling Rate for 3D Single Molecule Localization
Authors: Chang Huanzhi , Fu Shuang , Li Yiming
Published: September 2023

Resolution of single molecule localization microscopy (SMLM) depends on the localization accuracy, which can be improved by utilizing engineered point spread functions (PSF) with delicate shapes. However, the intrinsic pixelation effect of the detector sensor will deteriorate PSFs under different sampling rates. The influence of the pixelation effect to the achieved 3D localization accuracy for different PSF shapes under different signal to background ratio (SBR) and pixel dependent readout noise has not been investigated in detail so far. In this work, we proposed a framework to characterize the 3D localization accuracy of pixelated PSF at different sampling rates. Four different PSFs (astigmatic PSF, double helix (DH) PSF, Tetrapod PSF and 4Pi PSF) were evaluated and the pixel size with optimal 3D localization performance were derived. This work provides a theoretical guide for the optimal design of sampling rate for 3D super resolution imaging.
The role of learning in the evolution of status signalling: a modeling approach
Authors: Quiñones Andrés E. , Bshary Redouan , Cadena C. Daniel
Published: September 2023

Adaptive behavioural responses often depend on qualities of the interacting partner of an individual. For example, when competing for resources, an individual might be better off escalating fights with individuals of lower quality, while restraining from fighting individuals of higher quality. Communication systems involving signals of quality allow individuals to reduce uncertainty regarding the fighting ability of their partners and make more adaptive behavioral decisions. However, dishonest individuals can destabilize such communications systems. An open question is whether cognitive mechanisms, such as learning, can maintain the honesty of signals, thus favoring their evolutionary stability. We present evolutionary simulations where individuals can produce a signal proportional to their quality and learn along their lifetime the best response to the signals emitted by their peers. Our simulations replicate previous results where the handicap principle mediates the evolution of signals. In our simulations learning on the receiver side can mediate the evolution of signals of quality on the sender side. When the cost of the signal is proportional to the quality of the sender, all individuals in populations are honest signalers. In contrast to traditional models which predict the absence of signals when the cost is not proportional to the quality of the signaler, our model revealed that learning facilitates the evolution of a polymorphism in which populations comprise both honest and dishonest signalers. We argue that learning may have a role in the evolution and dynamics of a wide range of communication systems and more generally in behavioral responses.
Global regulators facilitate adaptation to a phenotypic trade-off
Authors: Deyell Matthew , Opuu Vaitea , Griffiths Andrew D. , Tans Sander J. , Nghe Philippe
Published: September 2023

Organisms depend on their ability to balance multiple phenotypes by evolutionary adaptation. For instance, cellular growth and movement jointly enable critical processes including microbial colonization and cancer invasiveness. Growth and movement are known to be controlled by local regulators that target single operons, as well as by global regulators that impact hundreds of genes. However, how these different levels of regulation interplay during evolution is unclear. Using Escherichia coli growth and motility as a model system, we show that global regulators enable the adaptation of two phenotypes bound by a trade-off, where improvement in one causes deterioration in the other. We measured how CRISPR-mediated knockdowns of global and local transcription factors impact growth and motility in different environments. We find that local regulators mostly modulate motility, while global regulators jointly modulate growth and motility. Genetic perturbations display complex high order interactions between genes and environments. Nevertheless, gene perturbations display consistent patterns in the growth-motility space when grouped by their position in the regulatory hierarchy. These patterns constrain evolutionary scenarios, where local regulators are typically mutated first to optimize motility, then global regulators allow cells to adjust the trade-off between growth and motility. These findings overall highlight the role of pleiotropic regulators for coordinating phenotypic responses in complex environments.
Divide-and-conquer quantum algorithm for hybridde novogenome assembly of short and long reads
Authors: Fang Jing-Kai , Lin Yue-Feng , Huang Jun-Han , Chen Yibo , Fan Gao-Ming , Sun Yuhui , Feng Guanru , Guo Cong , Meng Tiejun , Zhang Yong , Xu Xun , Xiang Jingen , Li Yuxiang
Published: September 2023

Computational biology holds immense promise as a domain that can leverage quantum advantages due to its involvement in a wide range of challenging computational tasks. Researchers have recently explored the applications of quantum computing in genome assembly implementation. However, the issue of repetitive sequences remains unresolved. In this paper, we propose a hybrid assembly quantum algorithm using high-accuracy short reads and error-prone long reads to deal with sequencing errors and repetitive sequences. The proposed algorithm builds upon the variational quantum eigensolver and utilizes divide-and-conquer strategies to approximate the ground state of larger Hamiltonian while conserving quantum resources. Using simulations of 10-qubit quantum computers, we address problems as large as 140 qubits, yielding optimal assembly results. The convergence speed is significantly improved via the problem-inspired ansatz based on the known information about the assembly problem. Besides, entanglement within quantum circuits is qualitatively verified to notably accelerate the assembly path optimization.
A unifying model that explains the origins of human inverted copy number variants
Authors: Brewer Bonita J. , Dunham Maitreya J. , Raghuraman M. K.
Published: September 2023

With the release of the telomere-to-telomere human genome sequence and the availability of both long-read sequencing and optical genome mapping techniques, the identification of copy number variants and other structural variants is providing new insights into human genetic disease. Different mechanisms have been proposed to account for the novel junctions in these complex architectures, including aberrant forms of DNA replication, non-allelic homologous recombination and various pathways that repair DNA breaks. Here we have focused on a set of structural variants that include an inverted segment and propose that they share a common initiating event: an inverted triplication with long, unstable palindromic junctions. The secondary rearrangement of these palindromes gives rise to the various forms of inverted structural variants. We postulate that this same mechanism (ODIRA: Origin Dependent Inverted Repeat Amplification) that creates the inverted copy number variants in inherited syndromes also generates the palindromes found in cancers.
Disparities in seizure outcomes revealed by large language models
Authors: Xie Kevin , Ojemann William K.S. , Gallagher Ryan S. , Lucas Alfredo , Hill Chloé E. , Hamilton Roy H. , Johnson Kevin B. , Roth Dan , Litt Brian , Ellis Colin A.
Published: September 2023

Objective

Large-language models (LLMs) in healthcare have the potential to propagate existing biases or introduce new ones. For people with epilepsy, social determinants of health are associated with disparities in access to care, but their impact on seizure outcomes among those with access to specialty care remains unclear. Here we (1) evaluated our validated, epilepsy-specific LLM for intrinsic bias, and (2) used LLM-extracted seizure outcomes to test the hypothesis that different demographic groups have different seizure outcomes.

Methods

First, we tested our LLM for intrinsic bias in the form of differential performance in demographic groups by race, ethnicity, sex, income, and health insurance in manually annotated notes. Next, we used LLM-classified seizure freedom at each office visit to test for outcome disparities in the same demographic groups, using univariable and multivariable analyses.

Results

We analyzed 84,675 clinic visits from 25,612 patients seen at our epilepsy center 2005-2022. We found no differences in the accuracy, or positive or negative class balance of outcome classifications across demographic groups. Multivariable analysis indicated worse seizure outcomes for female patients (OR 1.33, p = 3x10-8), those with public insurance (OR 1.53, p = 2x10-13), and those from lower-income zip codes (OR ≥ 1.22, p ≤ 6.6x10-3). Black patients had worse outcomes than White patients in univariable but not multivariable analysis (OR 1.03, p = 0.66).

Significance

We found no evidence that our LLM was intrinsically biased against any demographic group. Seizure freedom extracted by LLM revealed disparities in seizure outcomes across several demographic groups. These findings highlight the critical need to reduce disparities in the care of people with epilepsy.

Key Points

We used large language models (LLMs) and natural language processing to extract seizure outcomes from clinical note text.

We found no evidence of intrinsic bias in the LLM algorithm, in that it performed similarly across all demographic groups.

Using LLM-extracted seizure outcomes, female sex, public insurance, and lower income zip- codes were associated with higher likelihood of seizures at each visit.

Black race was associated with higher likelihood of seizures in univariable but not multivariable analysis.

These findings highlight the critical need to reduce disparities in the care of people with epilepsy.
Peripheral Blood Single-Cell Sequencing Uncovers Common and Specific Immune Aberrations in Fibrotic Lung Diseases
Authors: Zhao Amy Y. , Unterman Avraham , Abu Hussein Nebal , Sharma Prapti , Flint Jasper , Yan Xiting , Adams Taylor S. , Justet Aurelien , Sumida Tomokazu S. , Zhao Jiayi , Schupp Jonas C. , Raredon Micha Sam B. , Ahangari Farida , Zhang Yingze , Buendia-Roldan Ivette , Adegunsoye Ayodeji , Sperling Anne I. , Prasse Antje , Ryu Changwan , Herzog Erica , Selman Moises , Pardo Annie , Kaminski Naftali
Published: September 2023

Rationale and Objectives

The extent and commonality of peripheral blood immune aberrations in fibrotic interstitial lung diseases are not well characterized. In this study, we aimed to identify common and distinct immune aberrations in patients with idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (FHP) using cutting-edge single-cell profiling technologies.

Methods

Single-cell RNA sequencing was performed on patients and healthy controls’ peripheral blood and bronchoalveolar lavage samples using 10X Genomics 5’ gene expression and V(D)J profiling. Cell type composition, transcriptional profiles, cellular trajectories and signaling, and T and B cell receptor repertoires were studied. The standard Seurat R pipeline was followed for cell type composition and differential gene expression analyses. Transcription factor activity was imputed using the DoRothEA-VIPER algorithm. Pseudotime analyses were conducted using Monocle3, while RNA velocity analyses were performed with Velocyto, scVelo, and CellRank. Cell-cell connectomics were assessed using the Connectome R package. V(D)J analyses were conducted using CellRanger and Immcantation frameworks. Across all analyses, disease group differences were assessed using the Wilcoxon rank-sum test.

Measurements and Main Results

327,990 cells from 83 samples were profiled. Overall, changes in monocytes were common to IPF and FHP, whereas lymphocytes exhibited disease-specific aberrations. Both diseases displayed enrichment of CCL3hi/CCL4hiCD14+ monocytes (p<2.2e-16) and S100AhiCD14+ monocytes (p<2.2e-16) versus controls. Trajectory and RNA velocity analysis suggested that pro-fibrotic macrophages observed in BAL originated from peripheral blood monocytes. Lymphocytes exhibited disease-specific aberrations, with CD8+ GZMKhiT cells and activated B cells primarily enriched in FHP patients. V(D)J analyses revealed unique T and B cell receptor complementarity-determining region 3 (CDR3) amino acid compositions (p<0.05) in FHP and significant IgA enrichment in IPF (p<5.2e-7).

Conclusions

We identified common and disease-specific immune mechanisms in IPF and FHP; S100Ahimonocytes and SPP1himacrophages are common to IPF and FHP, whereas GMZKhiT lymphocytes and T and B cell receptor repertoires were unique in FHP. Our findings open novel strategies for the diagnosis and treatment of IPF and FHP.
Phase-separating fusion proteins drive cancer by dysregulating transcription through ectopic condensates
Authors: Farahi Nazanin , Lazar Tamas , Tompa Peter , Mészáros Bálint , Pancsa Rita
Published: September 2023

Numerous cellular processes rely on biomolecular condensates formed through liquid-liquid phase separation (LLPS), thus, perturbations of LLPS underlie various diseases. We found that proteins initiating LLPS are frequently implicated in somatic cancers, even surpassing their involvement in neurodegeneration. Cancer-associated LLPS scaffolds are connected to all cancer hallmarks and tend to be oncogenes with dominant genetic effects lacking therapeutic options. Since most of them act as oncogenic fusion proteins (OFPs), we undertook a systematic analysis of cancer driver OFPs by assessing their module-level molecular functions. We identified both known and novel combinations of molecular functions that are specific to OFPs and thus have a high potential for driving tumorigenesis. Protein regions driving condensate formation show an increased association with DNA- or chromatin-binding domains of transcription regulators within OFPs, indicating a common molecular mechanism underlying several soft tissue sarcomas and hematologic malignancies where phase-separation-prone OFPs form abnormal, ectopic condensates along the DNA, and thereby dysregulate gene expression programs.
Data from Entomological Collections of Aedes (Diptera: Culicidae) in a post-epidemic area of Chikungunya, City of Kinshasa, Democratic Republic of Congo
Authors: Nsabatien Victoire , Zanga Josue , Agossa Fiacre , Mvuama Nono , Bamba Maxwell , Mansiangi Osée , Mbashi Leon , Mvudi Vanessa , Diza Glodie , Kantin Dorcas , Basosila Narcisse , Lukoki Hyacinthe , Bokulu Arsene , Bosulu Christelle , Bukaka Erick , Nagahuedi Jonas , Palata Jean Claude , Metelo Emery
Published: September 2023

Arbovirus epidemics (e.g. Chikungunya, dengue, West Nile, Yellow Fever, and Zika), are a growing threat in Africa in areas whereAedes(Ae.)aegyptiandA. albopictusare present.

The lack of complete sampling of these two vectors limits our ability to understand their propagation dynamics in areas at risk from arboviruses. Here, we describe for the first time the geographical distribution of two arbovirus vectors (Ae. aegyptiandAe. albopictus) in a chikungunya post-epidemic zone in the provincial city of Kinshasa, Democratic Republic of Congo between 2020 and 2022. In total 6,943 observations were reported using larval capture and human capture on landing methods. These data are published in the public domain as a Darwin Core archive in the Global Biodiversity Information Facility. The results of this study potentially provide important information for further basic and advanced studies on the ecology and phenology of these vectors, as well as on vector dynamics after an epidemic period.

Subject Areas

Ecology, Biodiversity, Taxonomy

Data description
Test-retest reliability of spectral parameterization by 1/fcharacterization usingSpecParam
Authors: McKeown Daniel J. , Finley Anna J. , Kelley Nicholas J. , Cavanagh James F. , Keage Hannah A. D. , Baumann Oliver , Schinazi Victor R. , Moustafa Ahmed A. , Angus Douglas J
Published: September 2023

SpecParam(formally known asFOOOF) allows for the refined measurements of electroencephalography periodic and aperiodic activity, and potentially provides a non-invasive measurement of excitation:inhibition balance. However, little is known about the psychometric properties of this technique. This is integral for understanding the usefulness ofSpecParamas a tool to determine differences in measurements of cognitive function, and electroencephalography activity. We used intraclass correlation coefficients (ICC) to examine the test-retest reliability of parameterized activity across three sessions (90 minutes apart and 30 days later) in 49 healthy young adults at rest with eyes open (EO), eyes closed (EC), and during three EC cognitive tasks including subtraction (Math), music recall (Music), and episodic memory (Memory). ICCs were good for the aperiodic exponent and offset (ICCs > .70) and parameterized periodic activity (ICCs > .66 for alpha and beta power, central frequency, and bandwidth) across conditions. Across all three sessions,SpecParamperformed poorly in EO (40% of participants had poor fits over non-central sites) and had poor test-retest reliability for parameterized periodic activity.SpecParammostly provides reliable metrics of individual differences in parameterized neural activity. More work is needed to understand the suitability of EO resting data for parameterization usingSpecParam.
Redox Active Plant Phenolic, Acetosyringone, for Electrogenetic Signaling
Authors: Zakaria Fauziah Rahma , Chen Chen-Yu , Li Jinyang , Wang Sally , Payne Gregory F. , Bentley William E.
Published: September 2023

Redox is a unique, programmable modality capable of bridging communication between biology and electronics. Previous studies have shown that theE. coliredox-responsive OxyRS regulon can be re-wired to accept electrochemically generated hydrogen peroxide (H2O2) as an inducer of gene expression. Here we report that the redox-active phenolic plant signaling molecule acetosyringone (AS) can also induce gene expression from the OxyRS regulon. AS must be oxidized, however, as the reduced state present under normal conditions cannot induce gene expression. Thus, AS serves as a “pro-signaling molecule” that can be activated by its oxidation - in our case by application of oxidizing potential to an electrode. We show that the OxyRS regulon is not induced electrochemically if the imposed electrode potential is in the mid-physiological range. Electronically sliding the applied potential to either oxidative or reductive extremes induces this regulon but through different mechanisms: reduction of O2to form H2O2or oxidation of AS. Fundamentally, this work reinforces the emerging concept that redox signaling depends more on molecular activities than molecular structure. From an applications perspective, the creation of an electronically programmed “pro-signal” dramatically expands the toolbox for electronic control of biological responses in microbes, including in complex environments, cell-based materials, and biomanufacturing.
Flexible 3-D Electrochemical Impedance Spectroscopy Sensors Incorporating Phase Delay for Comprehensive Characterization of Atherosclerosis
Authors: Chen Michael , Neverova Natalia , Xu Shili , Suwannaphoom Krit , Lluri Gentian , Tamboline Mikayla , Duarte Sandra , Fishbein Michael C. , Luo Yuan , Packard René R. Sevag
Published: September 2023

Background

Distinguishing quiescent from rupture-prone atherosclerotic lesions has significant translational and clinical implications. Electrochemical impedance spectroscopy (EIS) characterizes biological tissues by assessing impedance and phase delay responses to alternating current at multiple frequencies.

We evaluated invasive 6-point stretchable EIS sensors over a spectrum of experimental atherosclerosis and compared results with intravascular ultrasound (IVUS), molecular positron emission tomography (PET) imaging, and histology.

Methods

Male New Zealand White rabbits (n=16) were placed on a high-fat diet for 4 or 8 weeks, with or without endothelial denudation via balloon injury of the infrarenal abdominal aorta. Rabbits underwentin vivomicro-PET imaging of the abdominal aorta with68Ga-DOTATATE,18F-NaF, and18F-FDG, followed by invasive interrogation via IVUS and EIS. Background signal corrected values of impedance and phase delay were determined. Abdominal aortic samples were collected for histological analyses. Analyses were performed blindly.

Results

Phase delay correlated with anatomic markers of plaque burden, namely intima/media ratio (r=0.883 at 1 kHz,P=0.004) and %stenosis (r=0.901 at 0.25 kHz,P=0.002), similar to IVUS. Moreover, impedance was associated with markers of plaque activity including macrophage infiltration (r=0.813 at 10 kHz,P=0.008) and macrophage/smooth muscle cell (SMC) ratio (r=0.813 at 25 kHz,P=0.026).68Ga-DOTATATE correlated with intimal macrophage infiltration (r=0.861,P=0.003) and macrophage/SMC ratio (r=0.831,P=0.021),18F-NaF with SMC infiltration (r=-0.842,P=0.018), and18F-FDG correlated with macrophage/SMC ratio (r=0.787,P=0.036).

Conclusions

EIS with phase delay integrates key atherosclerosis features that otherwise require multiple complementary invasive and non-invasive imaging approaches to capture. These findings indicate the potential of invasive EIS as a comprehensive modality for evaluation of human coronary artery disease.

GRAPHICAL ABSTRACT

HIGHLIGHTS

Electrochemical impedance spectroscopy (EIS) characterizes both anatomic features – via phase delay; and inflammatory activity – via impedance profiles, of underlying atherosclerosis.

EIS can serve as an integrated, comprehensive metric for atherosclerosis evaluation by capturing morphological and compositional plaque characteristics that otherwise require multiple imaging modalities to obtain.

Translation of these findings from animal models to human coronary artery disease may provide an additional strategy to help guide clinical management.
A paradigm for regulation at the effector interface with RNA-binding proteins
Authors: Shah Kriti , He Shiyang , Turner David J. , Corbo Joshua , Rebbani Khadija , Bateman Joseph M. , Cheloufi Sihem , Igreja Cátia , Valkov Eugene , Murn Jernej
Published: September 2023

RNA-binding proteins (RBPs) are key regulators of gene expression, but how RBPs convey regulatory instructions to the core effectors of RNA processing is unclear. Here we document the existence and functions of a multivalent RBP–effector interface. We show that the effector interface of a deeply conserved RBP with an essential role in metazoan development, Unkempt, is mediated by a novel type of ‘dual-purpose’ peptide motifs that can contact two different surfaces of interacting proteins. Unexpectedly, we find that the multivalent contacts do not merely serve effector recruitment but are required for the accuracy of RNA recognition by the recruiting RBP. Systems analyses reveal that multivalent RBP–effector contacts can repurpose the principal activity of an effector for a different function, as we demonstrate for reuse of the central eukaryotic mRNA decay factor CCR4-NOT in translational control. Our study establishes the molecular assembly and functional principles of an RBP–effector interface, with implications for the evolution and function of RBP-operated regulatory networks.
Computational design of sequence-specific DNA-binding proteins
Authors: Glasscock Cameron J. , Pecoraro Robert , McHugh Ryan , Doyle Lindsey A. , Chen Wei , Boivin Olivier , Lonnquist Beau , Na Emily , Politanska Yuliya , Haddox Hugh K. , Cox David , Norn Christoffer , Coventry Brian , Goreshnik Inna , Vafeados Dionne , Lee Gyu Rie , Gordan Raluca , Stoddard Barry L. , DiMaio Frank , Baker David
Published: September 2023

Sequence-specific DNA-binding proteins (DBPs) play critical roles in biology and biotechnology, and there has been considerable interest in the engineering of DBPs with new or altered specificities for genome editing and other applications. While there has been some success in reprogramming naturally occurring DBPs using selection methods, the computational design of new DBPs that recognize arbitrary target sites remains an outstanding challenge. We describe a computational method for the design of small DBPs that recognize specific target sequences through interactions with bases in the major groove, and employ this method in conjunction with experimental screening to generate binders for 5 distinct DNA targets. These binders exhibit specificity closely matching the computational models for the target DNA sequences at as many as 6 base positions and affinities as low as 30–100 nM. The crystal structure of a designed DBP-target site complex is in close agreement with the design model, highlighting the accuracy of the design method. The designed DBPs function in bothEscherichia coliand mammalian cells to repress and activate transcription of neighboring genes. Our method is a substantial step towards a general route to small and hence readily deliverable sequence-specific DBPs for gene regulation and editing.
Low Shear in Short-Term Impacts Endothelial Cell Traction and Alignment in Long-Term
Authors: Chandurkar Mohanish K. , Mittal Nikhil , Royer-Weeden Shaina P. , Lehmann Steven D. , Rho Yeonwoo , Han Sangyoon J.
Published: September 2023

Within the vascular system, endothelial cells (ECs) are exposed to fluid shear stress (FSS), a mechanical force exerted by blood flow that is critical for regulating cellular tension and maintaining vascular homeostasis. The way ECs react to FSS varies significantly; while high, laminar FSS supports vasodilation and suppresses inflammation, low or disturbed FSS can lead to endothelial dysfunction and increase the risk of cardiovascular diseases. Yet, the adaptation of ECs to dynamically varying FSS remains poorly understood. This study focuses on the dynamic responses of ECs to brief periods of low FSS, examining its impact on endothelial traction—a measure of cellular tension that plays a crucial role in how endothelial cells respond to mechanical stimuli. By integrating traction force microscopy (TFM) with a custom-built flow chamber, we analyzed how human umbilical vein endothelial cells (HUVECs) adjust their traction in response to shifts from low to high shear stress. We discovered that initial exposure to low FSS prompts a marked increase in traction force, which continues to rise over 10 hours before slowly decreasing. In contrast, immediate exposure to high FSS causes a quick spike in traction followed by a swift reduction, revealing distinct patterns of traction behavior under different shear conditions. Importantly, the direction of traction forces and the resulting cellular alignment under these conditions indicate that the initial shear experience dictates long-term endothelial behavior. Our findings shed light on the critical influence of short-lived low-shear stress experiences in shaping endothelial function, indicating that early exposure to low FSS results in enduring changes in endothelial contractility and alignment, with significant consequences for vascular health and the development of cardiovascular diseases.
Advancing GABA-edited MRS Research through a Reconstruction Challenge
Authors: Berto Rodrigo Pommot , Bugler Hanna , Dias Gabriel , Oliveira Mateus , Ueda Lucas , Dertkigil Sergio , Costa Paula D. P. , Rittner Leticia , Merkofer Julian P. , Sande Dennis M. J. van de , Amirrajab Sina , Drenthen Gerhard S. , Veta Mitko , Jansen Jacobus F. A. , Breeuwer Marcel , Sloun Ruud J. G. van , Qayyum Abdul , Rodero Cristobal , Niederer Steven , Souza Roberto , Harris Ashley D.
Published: September 2023

Purpose

To create a benchmark for the comparison of machine learning-based Gamma-Aminobutyric Acid (GABA)-edited Magnetic Resonance Spectroscopy (MRS) reconstruction models using one quarter of the transients typically acquired during a complete scan.

Methods

The Edited-MRS reconstruction challenge had three tracks with the purpose of evaluating machine learning models trained to reconstruct simulated (Track 1), homogeneousin vivo(Track 2), and heterogeneousin vivo(Track 3) GABA-edited MRS data. Four quantitative metrics were used to evaluate the results: mean squared error (MSE), signal-to-noise ratio (SNR), linewidth, and a shape score metric that we proposed. Challenge participants were given three months to create, train and submit their models. Challenge organizers provided open access to a baseline U-NET model for initial comparison, as well as simulated data,in vivodata, and tutorials and guides for adding synthetic noise to the simulations.

Results

The most successful approach for Track 1 simulated data was a covariance matrix convolutional neural network model, while for Track 2 and Track 3in vivodata, a vision transformer model operating on a spectrogram representation of the data achieved the most success. Deep learning (DL) based reconstructions with reduced transients achieved equivalent or better SNR, linewidth and fit error as conventional reconstructions with the full amount of transients. However, some DL models also showed the ability to optimize the linewidth and SNR values without actually improving overall spectral quality, pointing to the need for more robust metrics.

Conclusion

The edited-MRS reconstruction challenge showed that the top performing DL based edited-MRS reconstruction pipelines can obtain with a reduced number of transients equivalent metrics to conventional reconstruction pipelines using the full amount of transients. The proposed metric shape score was positively correlated with challenge track outcome indicating that it is well-suited to evaluate spectral quality.
Regulatory Mechanisms Orchestrating Cellular Diversity in Cd36+ Olfactory Sensory Neurons Revealed by Single-Cell Multi-omics Analysis
Authors: Yang Jiawen , Shi Peiyu , Li Yiheng , Zuo Yachao , Xu Tao , An Ziyang , Peng Dongjie , Zhang Weixing , Xu Yicong , Tang Zhongjie , Li Anan , Xu Jin
Published: September 2023

The olfactory system relies on the precise expression of olfactory receptor (OR) genes in individual olfactory sensory neurons (OSNs) to detect and discriminate a vast array of odorants. Recent discoveries have revealed remarkable complexity and diversity within OSNs, including the existence of two distinct OSN populations based on high-affinity receptor Cd36 expression. However, the regulatory mechanisms governing this cellular diversity in the same cell type remain elusive.

To address these questions, we conducted single-cell multi-omics analyses of mature OSNs in the mouse olfactory epithelium. Firstly, we systematically revealed the transcriptome diversity and spatial distribution of Cd36+ OSNs and found a specific subset of olfactory receptors co-expressed with Cd36 in a deterministic manner. scATAC-seq profiling of chromatin landscape demonstrated a divergence between Cd36+ OSNs and Cd36- OSNs, including differential accessibility of cis-elements. By integrating transcriptome and epigenome profiling of OSN lineage-associated cell types, we revealed that the processes governing this diversity are initiated at the immature OSNs stage, where cellular diversity was first set by the lineage-specific binding of Lhx2 at Hdac9 enhancer. Hdac9, which is specifically expressed in the Cd36- OSN lineage, functions as a histone deacetylase and may repress the transcription of Mef2-dependent genes that contribute to Cd36+ OSN diversity. By gene regulation network analysis, we revealed Mef2a and Tshz1 as the key transcription factors, orchestrating the transcriptome diversity of Cd36+ OSNs. Remarkably, we identified and confirmed Tshz1 as a critical transcription factor that directly promotes Cd36 expression in OSNs through enhancer binding. Our study unravels the intricate regulatory landscape and principles governing cellular diversity in the olfactory system. These findings provide valuable insights into the regulation principles underlying neuronal heterogeneity and its functional implications.
Amino acid residues for specific binding to ssDNA facilitate topological loading of bacterial condensin MukB
Authors: Akiyama Koichiro , Yano Koichi , Niki Hironori
Published: September 2023

The bacterial condensin MukB facilitates proper chromosome segregation inEscherichia coli. A portion of the MukB proteins localize at a specific chromosome region, binding to DNA in a non-sequence-specific manner. However, it is unclear how MukB localizes at a particular site without sequence specificity. Like other structural maintenance of chromosome (SMC) proteins, MukB topologically loads onto DNA, and It has an intrinsic property of preferential topological loading onto the single-stranded DNA (ssDNA). We consider it crucial for the localization of a specific region. To investigate the property of MukB, we attempted to identify positively charged amino acid residues responsible for ssDNA binding. We created a series of mutated MukB proteins in which a single positively charged amino acid was replaced with a negatively charged one. The results showed that some substitutions located on the inner surface of the MukB head domain impacted ssDNA-binding activity, leading to deficiencies in cell growth and nucleoid segregation. The efficiency of topological loading onto ssDNA was also decreased when the positive charges were replaced with negative ones. These amino acid residues align with and bind to ssDNA when the MukB dimer secures ssDNA within its ring, thereby likely strengthening the ssDNA-binding ability of MukB.
Local endoreduplication of the host is a conserved process during Phytomyxea-host interaction
Authors: Hittorf M , Garvetto A , Magauer M , Kirchmair M , Salvenmoser W , Murúa P , Neuhauser S
Published: September 2023

Endoreduplication is a modified cell cycle in which cells duplicate their DNA without subsequent mitosis. This process is common in plants and can also be found in other organisms like algae and animals. Biotrophic plant pathogens have been shown to induce endoreduplication in their host to gain space and/or nutrients. Phytomyxea (divided into the Plasmodiophorida, the Phagomyxida, and theMarinomyxaclade) are obligate biotrophic parasites of plants, diatoms, brown algae, and oomycetes. Here, we tested if phytomyxids induce local endoreduplication in two distant hosts (plants and brown algae). By combining fluorescent in situ hybridisation (FISH) coupled with nuclear area measurements and flow cytometry, we confirmed that endoreduplication is induced byPlasmodiophora brassicae(Plasmodiophorida) in infected plants and demonstrate this process in combination withMaullinia ectocarpiiandMaullinia braseltonii(Phagomyxida) in brown algae. We identified molecular signatures of endoreduplication in RNA-seq datasets ofP. brassicae-infectedBrassica oleraceaeandM. ectocarpii-infectedEctocarpus siliculosus. Cell cycle switch proteins (CCS52A1 and B in plants and CCS52 in algae) as well as the protein kinase WEE1 (in plants) were identified as genes potentially important for the phytomyxean-induced switch from the mitotic cell cycle to the endocycle. Their expression pattern changed in infected plants and brown algae accordingly. In this study we expand the knowledge on Phytomyxea-host interactions by showing that induced endoreduplication in the host is a conserved feature in phytomyxid infections. The induction of this cellular mechanism by phytomyxid parasites in phylogenetically distant hosts further points at a fundamental importance of endoreduplication in these biotrophic interactions.
PGR5 is required to avoid photosynthetic oscillations during light transitions
Authors: Degen Gustaf E. , Pastorelli Federica , Johnson Matthew P.
Published: September 2023

The production of ATP and NADPH by the light reactions of photosynthesis and their consumption by the Calvin-Benson-Bassham (CBB) cycle and other downstream metabolic reactions requires careful regulation. Environmental shifts perturb this careful balance, leading to photo-oxidative stress and losses in CO2assimilation. Imbalances in the production and consumption of ATP and NADPH manifest themselves as transient instability in the chlorophyll fluorescence, P700, electrochromic shift and CO2uptake signals recorded on leaves. These oscillations can be induced in wild-type plants by sudden shifts in CO2concentration or light intensity, however mutants exhibiting increased oscillatory behaviour have yet to be reported. This has precluded an understanding of the regulatory mechanisms employed by plants to suppress oscillations. Here we show that the Arabidopsispgr5mutant, which is deficient in PGR5-dependent cyclic electron transfer (CET), exhibits increased oscillatory behaviour. In contrast, mutants lacking the NDH-dependent CET are largely unaffected. The absence of oscillations in thehope2mutant, which likepgr5, lacks photosynthetic control and exhibits high ATP synthase conductivity, ruled out loss of these photoprotective mechanisms as causes. Instead, we observed slower formation of proton motive force and by inference ATP synthesis inpgr5following environmental perturbation, leading to the transient reduction of the electron transfer chain and photosynthetic oscillations. PGR5-dependent CET therefore plays a major role in damping the effect of environmental perturbations on photosynthesis to avoid losses in CO2fixation.