bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational ranking-assisted identification of Plexin-B2 in homotypic and heterotypic clustering of circulating tumor cells in breast cancer metastasis
Authors: Schuster Emma , Dashzeveg Nurmaa , Jia Yuzhi , Golam Kibria , Zhang Tong , Hoffman Andrew , Zhang Youbin , Zheng Chunlei , Ramos Erika , Taftaf Rokana , Shennawy Lamiaa El- , Scholten David , Kitata Reta B. , Adorno-Cruz Valery , Reduzzi Carolina , Spahija Sabina , Xu Rong , Siziopikou Kalliopi P. , Platanias Leonidas C. , Shah Ami , Gradishar William J. , Cristofanilli Massimo , Tsai Chia-Feng , Shi Tujin , Liu Huiping
Published: April 2023

Metastasis is the cause of over 90% of all deaths associated with breast cancer, yet the strategies to predict cancer spreading based on primary tumor profiles and therefore prevent metastasis are egregiously limited. As rare precursor cells to metastasis, circulating tumor cells (CTCs) in multicellular clusters in the blood are 20-50 times more likely to produce viable metastasis than single CTCs. However, the molecular mechanisms underlying various CTC clusters, such as homotypic tumor cell clusters and heterotypic tumor-immune cell clusters, are yet to be fully elucidated. Combining machine learning-assisted computational ranking with experimental demonstration to assess cell adhesion candidates, we identified a transmembrane protein Plexin- B2 (PB2) as a new therapeutic target that drives the formation of both homotypic and heterotypic CTC clusters. High PB2 expression in human primary tumors predicts an unfavorable distant metastasis-free survival and is enriched in CTC clusters compared to single CTCs in advanced breast cancers. Loss of PB2 reduces formation of homotypic tumor cell clusters as well as heterotypic tumor-myeloid cell clusters in triple-negative breast cancer. Interactions between PB2 and its ligand Sema4C on tumor cells promote homotypic cluster formation, and PB2 binding with Sema4A on myeloid cells (monocytes) drives heterotypic CTC cluster formation, suggesting that metastasizing tumor cells hijack the PB2/Sema family axis to promote lung metastasis in breast cancer. Additionally, using a global proteomic analysis, we identified novel downstream effectors of the PB2 pathway associated with cancer stemness, cell cycling, and tumor cell clustering in breast cancer. Thus, PB2 is a novel therapeutic target for preventing new metastasis.
An active traveling wave of Eda/NF-kB signaling controls the timing and hexagonal pattern of skin appendages in zebrafish
Authors: Evanitsky Maya N. , Di Talia Stefano
Published: April 2023

Periodic patterns make up a variety of tissues, including skin appendages such as feathers and scales. Skin appendages serve important and diverse functions across vertebrates, yet the mechanisms that regulate their patterning are not fully understood. Here, we have used live imaging to investigate dynamic signals regulating the ontogeny of zebrafish scales. Scales are bony skin appendages which develop sequentially along the anterior-posterior and dorsal-ventral axes to cover the fish in a hexagonal array. We have found that scale development requires cell-cell communication and is coordinated through an active wave mechanism. Using a live transcriptional reporter, we show that a wave of Eda/NF-κB activity precedes scale initiation and is required for scale formation. Experiments decoupling the propagation of the wave from dermal placode formation and osteoblast differentiation demonstrate that the Eda/NF-kB activity wavefront times the sequential patterning of scales. Moreover, this decoupling resulted in defects in scale size and significant deviations in the hexagonal patterning of scales. Thus, our results demonstrate that a biochemical traveling wave coordinates scale initiation and proper hexagonal patterning across the fish body.
A zero-agnostic model for copy number evolution in cancer
Authors: Schmidt Henri , Sashittal Palash , Raphael Benjamin J.
Published: April 2023

Motivation

New low-coverage single-cell DNA sequencing technologies enable the measurement of copy number profiles from thousands of individual cells within tumors. From this data, one can infer the evolutionary history of the tumor by modeling transformations of the genome via copy number aberrations. A widely used model to infer suchcopy number phylogeniesis thecopy number transformation(CNT) model in which a genome is represented by an integer vector and a copy number aberration is an event that either increases or decreases the number of copies of a contiguous segment of the genome. The CNT distance between a pair of copy number profiles is the minimum number of events required to transform one profile to another. While this distance can be computed efficiently, no efficient algorithm has been developed to find the most parsimonious phylogeny under the CNT model.

Results

We introduce thezero-agnostic copy number transformation(ZCNT) model, a simplification of the CNT model that allows the amplification or deletion of regions with zero copies. We derive a closed form expression for the ZCNT distance between two copy number profiles and show that, unlike the CNT distance, the ZCNT distance forms a metric. We leverage the closed-form expression for the ZCNT distance and an alternative characterization of copy number profiles to derive polynomial time algorithms for two natural relaxations of the small parsimony problem on copy number profiles. While the alteration of zero copy number regions allowed under the ZCNT model is not biologically realistic, we show on both simulated and real datasets that the ZCNT distance is a close approximation to the CNT distance. Extending our polynomial time algorithm for the ZCNT small parsimony problem, we develop an algorithm,Lazac, for solving the large parsimony problem on copy number profiles. We demonstrate thatLazacoutperforms existing methods for inferring copy number phylogenies on both simulated and real data.

Availability

Lazacis implemented in C++17 and is freely available at:github.com/raphaelgroup/lazac-copy-number.
A molecular arm: the molecular bending-unbending mechanism of integrin
Authors: Li Zhenhai
Published: April 2023

Integrin conformational change is the key to transmitting signals across the cell membrane. The integrin on the cell surface undergoes bending-unbending cycles while sensing and responding to the mechanical environment. Mechanical force triggers the unbending of integrin. However, how an integrin stably extends and how an extended integrin spontaneously bends back are unclear. I performed molecular dynamics simulations on integrin and its subunits to reveal the bending-unbending mechanism of integrin at the atomic level. According to the simulations, the integrin structure works like a human arm. The integrin α subunit serves as the bones, while the β leg serves as the bicep. Thus, the integrin extension results in the stretching of the β leg, and the extended integrin spontaneously bends as a consequence of the contraction of the β leg. This study provides new insights into the mechanism of how the integrin secures in the bent inactivated state and sheds light on the mechanism of how the integrin could achieve the stable extended state.

Author summary

As a mechanosensitive protein, the integrin is a molecular machine, which converts the mechano-signal to others, or in the opposite way. The reversible conformational change of integrin is the key to the mechanosensing function. It is straightforward that the integrin would extend while it senses pulling force. However, how integrin bends back after releasing the force is not clear. The ability to bend back guarantees that the integrin can be reused in the bending-unbending cycles. With molecular dynamics simulations, this study shows the integrin works as a molecular arm in the bending-unbending working cycles, which answers how the integrin spontaneously bends back. Meanwhile, based on this study, several hypothesized mechanisms for integrin to be stably extended are proposed.
Physiological accuracy in simulating refractory cardiac tissue: the volume-averaged bidomain model vs. the cell-based EMI model
Authors: Reimer Joyce , Domínguez-Rivera Sebastián A. , Sundnes Joakim , Spiteri Raymond J.
Published: April 2023

The refractory period of cardiac tissue can be quantitatively described using strength-interval (SI) curves. The information captured in SI curves is pertinent to the design of anti-arrhythmic devices including pacemakers and implantable cardioverter defibrillators. As computational cardiac modelling becomes more prevalent, it is feasible to consider the generation of computationally derived SI curves as a supplement or precursor to curves that are experimentally derived. It is beneficial, therefore, to examine the profiles of the SI curves produced by different cardiac tissue models to determine whether some models capture the refractory period more accurately than others. In this study, we compare the unipolar SI curves of two tissue models: the current state-of-the-art bidomain model and the recently developed extracellular-membrane-intracellular (EMI) model. The EMI model’s resolution of individual cell structure makes it a more detailed model than the bidomain model, which forgoes the structure of individual cardiac cells in favour of treating them homogeneously as a continuum. We find that the resulting SI curves elucidate differences between the models, including that the behaviour of the EMI model is noticeably closer to the refractory behaviour of experimental data compared to that of the bidomain model. These results hold implications for future computational pacemaker simulations and shed light on the predicted refractory properties of cardiac tissue from each model.

Author summary

Mathematical modelling and computational simulation of cardiac activity have the potential to greatly enhance our understanding of heart function and improve the precision of cardiac medicine. The current state-of-the-art model is the bidomain model, which considers a volume average of cardiac activity. Although the bidomain model has had success in several applications, in other situations, its approach may obscure critical details of heart function. The extracellular-membrane-intracellular (EMI) model is a recently developed model of cardiac tissue that addresses this limitation. It models cardiac cells individually; therefore, it offers significantly greater physiological accuracy than bidomain simulations. This increase in accuracy comes at a higher computational cost, however. To explore the benefits of one model over the other, here we compare the performance of the bidomain and EMI models in a pacing study of cardiac tissue often employed in pacemaker design. We find that the behaviour of the EMI model is noticeably closer to experimental data than the behaviour of the bidomain model.

These results hold implications for future pacemaker design and improve our understanding of the two models in relation to one another.
WormSwin: Instance segmentation of C. elegans using vision transformer
Authors: Deserno Maurice , Bozek Katarzyna
Published: April 2023

The possibility to extract motion of a single organism from video recordings at a large-scale provides means for the quantitative study of its behavior, both individual and collective. This task is particularly difficult for organisms that interact with one another, overlap, and occlude parts of their bodies in the recording. Here we propose WormSwin - an approach to extract single animal postures of Caenorhabditis elegans (C. elegans) from recordings of many organisms in a single microscope well. Based on transformer neural network architecture our method segments individual worms across a range of videos and images generated in different labs. Our solutions offers accuracy of 0.990 average precision (AP0.50) and comparable results on the benchmark image dataset BBBC010. Finally, it allows to segment challenging overlapping postures of mating worms with an accuracy sufficient to track the organisms with a simple tracking heuristic. An accurate and efficient method forC. eleganssegmentation opens up new opportunities for studying of its behaviors previously inaccessible due to the difficulty in the worm extraction from the video frames.
Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination
Authors: Zhou Zhao-Hua , Cortese Margaret M. , Fang Jia-Long , Wood Robert , Hummell Donna S. , Risma Kimberly A. , Norton Allison E. , KuKuruga Mark , Kirshner Susan , Rabin Ronald L. , Agarabi Cyrus , Staat Mary A. , Halasa Natasha , Ware Russell , Stahl Anna , McMahon Maureen , Browning Peter , Maniatis Panagiotis , Bolcen Shanna , Edwards Kathryn M. , Su John R. , Dharmarajan Sai , Forshee Richard , Broder Karen R. , Anderson Steven , Kozlowski Steven
Published: April 2023

Background

The mechanism for anaphylaxis following mRNA COVID-19 vaccination has been widely debated; understanding this serious adverse event is important for future vaccines of similar design. A mechanism proposed is type I hypersensitivity (i.e., IgE-mediated mast cell degranulation) to excipient polyethylene glycol (PEG). Using an assay that, uniquely, had been previously assessed in patients with anaphylaxis to PEG, our objective was to compare anti-PEG IgE in serum from mRNA COVID-19 vaccine anaphylaxis case-patients and persons vaccinated without allergic reactions. Secondarily, we compared anti-PEG IgG and IgM to assess alternative mechanisms.

Methods

Selected anaphylaxis case-patients reported to U.S. Vaccine Adverse Event Reporting System December 14, 2020 – March 25, 2021 were invited to provide a serum sample. mRNA COVID-19 vaccine study participants with residual serum and no allergic reaction post-vaccination (“controls”) were frequency matched to cases 3:1 on vaccine and dose number, sex and 10-year age category. Anti-PEG IgE was measured using a dual cytometric bead assay. Anti-PEG IgG and IgM were measured using two different assays. Laboratorians were blinded to case/control status.

Results

All 20 case-patients were women; 17 had anaphylaxis after dose 1, 3 after dose 2. Thirteen (65%) were hospitalized and 7 (35%) were intubated. Time from vaccination to serum collection was longer for case-patients vs controls (post-dose 1: median 105 vs 21 days). Among Moderna recipients, anti-PEG IgE was detected in 1 of 10 (10%) case-patients vs 8 of 30 (27%) controls (p=0.40); among Pfizer-BioNTech recipients, it was detected in 0 of 10 case-patients (0%) vs 1 of 30 (3%) controls (p>0.99). Anti-PEG IgE quantitative signals followed this same pattern. Neither anti-PEG IgG nor IgM was associated with case status with both assay formats.

Conclusion

Our results support that anti-PEG IgE is not a predominant mechanism for anaphylaxis post-mRNA COVID-19 vaccination.
Abnormal higher-order network interactions in Parkinson’s disease visual hallucinations
Authors: Tan Joshua B. , Müller Eli J. , Orlando Isabella F. , Taylor Natasha L. , Margulies Daniel S. , Szeto Jennifer , Lewis Simon J.G. , Shine James M. , O’Callaghan Claire
Published: April 2023

Visual hallucinations in Parkinson’s disease can be viewed from a systems-level perspective, whereby abnormal communication between brain networks responsible for perception predisposes a person to hallucinate. To this end, abnormal functional interactions between higher-order and primary sensory networks have been implicated in the pathophysiology of visual hallucinations in Parkinson’s disease, however the precise signatures remain to be determined. Dimensionality reduction techniques offer a novel means for simplifying the interpretation of multidimensional brain imaging data, identifying hierarchical patterns in the data that are driven by both within- and between-functional network changes. Here, we applied two complementary non-linear dimensionality reduction techniques – diffusion-map embedding and t-distributed Stochastic Neighbour Embedding (t-SNE) – to resting state fMRI data, in order to characterise the altered functional hierarchy associated with susceptibility to visual hallucinations. Our study involved 77 people with Parkinson’s disease (31 with hallucinations; 46 without hallucinations) and 19 age-matched healthy controls. In patients with visual hallucinations, we found compression of the unimodal-heteromodal gradient consistent with increased functional integration between sensory and higher order networks. This was mirrored in a traditional functional connectivity analysis, which showed increased connectivity between the visual and default-mode networks in the hallucinating group. Together, these results suggest a route by which higher-order regions may have excessive influence over earlier sensory processes, as proposed by theoretical models of hallucinations across disorders. By contrast, the t-SNE analysis identified distinct alterations in prefrontal regions that were not apparent in the functional connectivity analysis, suggesting complex reconfigurations in functional brain network architecture as a function of the disease process. Together, the results confirm abnormal brain organisation associated with the hallucinating phenotype in Parkinson’s disease, and highlight the utility of applying convergent dimensionality reduction techniques to investigate complex clinical symptoms. In addition, the patterns we describe in Parkinson’s disease converge with those seen in other conditions, suggesting that reduced hierarchical differentiation across sensory-perceptual systems may be a common transdiagnostic vulnerability in neuropsychiatric disorders with perceptual disturbances.
Environmental, Socioeconomic, and Health Factors Associated with Gut Microbiome Species and Strains in Isolated Honduras Villages
Authors: Shridhar Shivkumar Vishnempet , Beghini Francesco , Alexander Marcus , Singh Adarsh , Juárez Rigoberto Matute , Brito Ilana L. , Christakis Nicholas A.
Published: April 2023

Despite a growing interest in the gut microbiome of non-industrialized countries, data linking microbiome features from such settings to diverse phenotypes remains uncommon. Using metagenomic data from a community-based cohort of 1,871 people from isolated villages in the Mesoamerican highlands of western Honduras, we report novel associations between bacterial species and phenotypes. We also find an uncharacterizedLachnospiraceaespecies associated with 22 different phenotypes, and little overlap with a prior Dutch Microbiome Project. Furthermore, including strain-phylogenetic information modifies the overall relationship between the gut microbiome and the phenotypes, especially in some phenotypes like household wealth. Coincidentally, wealthier individuals also have a higher number of polymorphic sites. Our analysis suggests new roles that gut microbiome surveillance can play in understanding broad features of individual and public health.
Semiconductor augumented valuable chemical photosynthesis fromRhodospirillum rubrumand mechanism study
Authors: Wang Lin , Shi Shulan , Liang Jun , Wang Bo , Xing Xiwen , Zeng Cuiping
Published: April 2023

Photosynthetic biohybrid systems based on purple bacteria and semiconducting nanomaterials are promising platforms for sustainable solar-powered chemical production. However, these types of biohybrid systems have not been fully developed to date, and their energy utilization and electron transfer mechanisms are not well understood. Herein, aRhodospirillum rubrum-CdS biohybrid system was successfully constructed. The photosynthetic activity and photoelectrochemical properties of biohybrid system were analyzed. Chromatographic and spectroscopic studies confirmed the metabolic activities ofR. rubrumcells were effectively augmented by surface-deposited CdS nanoparticles and validated with increased H2 evolution, polyhydroxybutyric acid (PHB) production, and solid biomass accumulation. Energy consumption and metabolic profiles ofR. rubrum-CdS biohybrid system exhibited a growth phase-dependent behaviour. Photoelectrochemical study confirmed that light-excited electrons from CdS enhanced photosynthetic electron flow ofR. rubrumcells. Monochromatic light modulated photoexcitation of biohybrid system was utilized to explore interfacial electron transfer between CdS andR. rubrumcells, and the results showed that CdS enhanced the utilization of blue light byR. rubrumcells. This work investigated the feasibility and prospect of utilizingR. rubrumin semi-artificial photosynthesis of valuable products, and offered insights into the energy utilization and the electron transfer mechanism between nanomaterials and purple bacteria.
Decoding State-Dependent Cortical-Cerebellar Cellular Functional Connectivity in the Mouse Brain
Authors: Yan Yuhao , Murphy Timothy H
Published: April 2023

ABSTRACT

The cerebellum participates in motor tasks, but also a broad spectrum of cognitive functions. However, cerebellar connections with higher areas such as cortex are not direct and the mechanisms by which the cerebellum integrates and processes diverse information streams are not clear. We investigated the functional connectivity between single cerebellar neurons and population activity of the dorsal cortex using mesoscale imaging. Our findings revealed dynamic coupling between individual cerebellar neurons and diverse cortical networks, and such functional association can be influenced by local excitatory and inhibitory connections. While the cortical representations of individual cerebellar neurons displayed marked changes across different brain states, the overall assignments to specific cortical topographic areas at the population level remained stable. Simple spikes and complex spikes of the same Purkinje cells displayed either similar or distinct cortical functional connectivity patterns. Moreover, the spontaneous functional connectivity patterns aligned with cerebellar neurons’ functional responses to external stimuli in a modality-specific manner. Importantly, the tuning properties of subsets of cerebellar neurons differed between anesthesia and awake states, mirrored by state-dependent changes in their long-range functional connectivity patterns. Collectively, our results provide a comprehensive view of the state-dependent cortical-cerebellar functional connectivity landscape and demonstrate that remapping of long-range functional network association could underlie state-dependent change in sensory processing.
Methane formation driven by light and heat prior to the origin of life
Authors: Ernst Leonard , Barayeu Uladzimir , Hädeler Jonas , Dick Tobias P. , Klatt Judith M. , Keppler Frank , Rebelein Johannes G.
Published: April 2023

Methane is a potent greenhouse gas, which likely enabled the evolution of life by keeping the early Earth warm. Here, we demonstrate new routes towards abiotic methane formation under early-earth conditions from methylated sulfur and nitrogen compounds with prebiotic origin. These compounds are demethylated in Fenton reactions governed by ferrous iron and reactive oxygen species, produced by light and heat in aqueous environments. The reactions generate methyl radicals and ultimately release methane and ethane. Organic iron chelators enhance reaction rates and recycle ferric to ferrous complexes via ligand-to-metal charge transfer, establishing a light-driven iron redox cycle. This abiotic reaction facilitates methane and ethane formation across Earth’s humid realm, thereby shaping the chemical evolution of the atmosphere prior to the origin of life and beyond.

One-Sentence Summary

Under suboxic and anoxic conditions, iron and reactive oxygen species drive the global formation of methane in aqueous environments.
A quantitative model for spatio-temporal dynamics of root gravitropism
Authors: Porat Amir , Rivière Mathieu , Meroz Yasmine
Published: April 2023

Plant organs adapt their morphology according to environmental signals through growth-driven processes called tropisms. While much effort has been directed in the development of mathematical models describing the tropic dynamics of aerial organs, these cannot provide a good description of roots due to intrinsic physiological differences. Here we present a mathematical model informed by gravitropic experiments onArabidopsis thalianaroots, assuming a sub-apical growth profile and apical sensing. The model quantitatively recovers the full spatio-temporal dynamics observed in experiments. An analytical solution of the model enables us to evaluate the gravitropic and proprioceptive sensitivities of roots, while also allowing us to corroborate the requirement of proprioception in describing root dynamics. Lastly, we find that the dynamics are analogous to a damped harmonic oscillator, providing intuition regarding the source of the observed oscillatory behavior. In all, the model not only provides a quantitative description of root tropic dynamics, but also provides a mathematical framework for the future investigation of roots in complex media.
Oligodendrocyte calcium signaling sculpts myelin sheath morphology
Authors: Iyer Manasi , Kantarci Husniye , Ambiel Nicholas , Novak Sammy W. , Andrade Leonardo R. , Lam Mable , Münch Alexandra E. , Yu Xinzhu , Khakh Baljit S. , Manor Uri , Zuchero J. Bradley
Published: April 2023

Myelin is essential for rapid nerve signaling and is increasingly found to play important roles in learning and in diverse diseases of the CNS. Morphological parameters of myelin such as sheath length and thickness are regulated by neuronal activity and can precisely tune conduction velocity, but the mechanisms controlling sheath morphology are poorly understood. Local calcium signaling has been observed in nascent myelin sheaths and can be modulated by neuronal activity. However, the role of calcium signaling in sheath formation and remodeling is unknown. Here, we used genetic tools to attenuate oligodendrocyte calcium signaling during active myelination in the developing mouse CNS. Surprisingly, we found that genetic calcium attenuation did not grossly affect the number of myelinated axons or myelin thickness. Instead, calcium attenuation caused striking myelination defects resulting in shorter, dysmorphic sheaths. Mechanistically, calcium attenuation reduced actin filaments in oligodendrocytes, and an intact actin cytoskeleton was necessary and sufficient to achieve accurate myelin morphology. Together, our work reveals a novel cellular mechanism required for accurate CNS myelin formation and provides mechanistic insight into how oligodendrocytes may respond to neuronal activity to sculpt myelin sheaths throughout the nervous system.
Somatic Calcium Signals from Layer II/III Motor Cortex for Continuous Neural Decoding
Authors: Wang Ruixue , Han Jiawei , Hu Xiaoling , You Heecheon , Zhang Shaomin
Published: April 2023

The latest research shows that calcium signals can provide a new signal source for brain-machine interfaces (BMI). However, it remains a question whether the calcium signals from layer 2/3 motor cortex can be used for continuous neural decoding. And how they are involved in movement coding is also worth investigating. Here we collect the somatic signals in M1 layer 2/3 while mice performed a lever-press task under the one-photon imaging. We first present the potential of somatic calcium signals from layer 2/3 in continuous neural decoding through an improved recurrent neural network. Layer 2/3 neurons exhibit three types of calcium dynamics with distinct spatiotemporal coding patterns involved in the movement. Pre-pressing and pressing neurons enable sparse coding of movement through complementary spatiotemporal information. While post-pressing neurons predict the lever movement most accurately through the calcium dynamics with higher fidelity. These results demonstrate the capability of calcium signals from layer 2/3 neurons as a motor BMI driver and underscore their diversity in motor coding, opening a new avenue for studying the motor cortex and designing optical BMIs.
Strong purifying selection in haploid tissue-specific genes of Scots pine supports the masking theory
Authors: Cervantes Sandra , Kesälahti Robert , Kumpula Timo A. , Mattila Tiina M. , Helanterä Heikki , Pyhäjärvi Tanja
Published: April 2023

The masking theory states that genes expressed in haploid stage will be under more efficient selection. In contrast, selection will be less efficient in genes expressed in diploid stage, where the fitness effects of recessive deleterious or beneficial mutations can be hidden from selection in heterozygous form. This difference can influence several evolutionary processes such as maintenance of genetic variation, adaptation rate, and genetic load. Masking theory expectations have been confirmed in single-cell haploid and diploid organisms. However, in multicellular organisms, such as plants, the effects of haploid selection are not clear-cut. In plants, the great majority of studies indicating haploid selection have been carried out using male haploid tissues in angiosperms. Hence, evidence in these systems is confounded with the effects of sexual selection and intra-specific competition. Evidence from other plant groups is scarce and results show no support for the masking theory.

Here we have used a gymnosperm Scots pine megagametophyte, a maternally-derived seed haploid tissue, and four diploid tissues to test the strength of purifying selection on a set of genes with tissue-specific expression. By using targeted resequencing data of those genes, we obtained estimates of genetic diversity, the site frequency spectrum of 0-fold and 4-fold sites, and inferred the distribution of fitness effects (DFE) of new mutations in haploid and diploid tissue-specific genes. Our results show that purifying selection is stronger for tissue-specific genes expressed in the haploid megagametophyte tissue, and that this signal of strong selection is not an artifact driven by high expression levels
Activation of peroxisome proliferator-activated receptor-γ prevents monocrotaline-induced pulmonary arterial hypertension by suppressing of nuclear factor-kappa B mediated autophagy
Authors: Zhang Peng , Shi Congcong , Song Juntao , Dong Tongbao , Zhang Kaixiao
Published: April 2023

To investigate the molecular mechanisms underlying autophagy inducing pulmonary vascular remodeling and rosiglitazone inhibiting pulmonary arterial hypertension (PAH). Monocrotaline (MCT) was intraperitoneally injection to induce the rat PAH model. The right ventricular hypertrophy index (RVHI), right ventricle systolic pressure (RVSP), percentage of medial wall thickness (%MT) and histomorphologic analyses were performed to evaluate the development of PAH. The translocation of nuclear factor-kappa B (NF-κB) p65 subunit from cytosol to nucleus, the protein expression levels of LC3B, Beclin 1 and RND3 were determined by western blot. Furthermore, NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC) and peroxisome proliferator-activated receptor-γ (PPARγ) activator, rosiglitazone, were used to inhibit the activation of NF-κB and activate PPARγ signaling, respectively. MCT injection dramatically induced PAH models in rats as manifested by the increased RVSP, RVHI, and %MT. In addition, the activation of NF-κB and autophagy were significantly enhanced and the RND3 were markedly decreased in MCT-induced PAH in rat. However, these effects could be significantly suppressed either by the supplementation of PDTC or rosiglitazone. NF-κB promotes the development of PAH by activation of autophagy and consequent down-regulation of RND3 expression. Activation of PPARγ suppresses autophagy by inhibiting NF-κB in MCT-induced PAH. Our results not only uncovered the mechanisms of PPARγ activator in the protection of PAH but also provided potential therapeutic target for PAH treatment.
An in vitro model for vitamin A transport across the human blood-brain barrier
Authors: Est Chandler B. , Murphy Regina M.
Published: April 2023

Vitamin A, supplied by the diet, is critical for brain health, but little is known about its delivery across the blood-brain barrier (BBB). Brain microvascular endothelial-like cells (BMECs) differentiated from human-derived induced pluripotent stem cells (iPSC) form a tight barrier that recapitulates many of the properties of the human BBB. We paired iPSC-derived BMECs with recombinant vitamin A serum transport proteins, retinol binding protein (RBP) and transthyretin (TTR), to create anin vitromodel for the study of vitamin A (retinol) delivery across the human BBB. iPSC-derived BMECs display a strong barrier phenotype, express key vitamin A metabolism markers and can be used for quantitative modeling of retinol accumulation and permeation. Manipulation of retinol, RBP and TTR concentrations, and the use of mutant RBP and TTR, yielded novel insights into the patterns of retinol accumulation in, and permeation across, the BBB. The results described herein provide a platform for deeper exploration of the regulatory mechanisms of retinol trafficking to the human brain.
“Shin in the eye”: Au-CS@FNDs as contact lens additives for blocking UV irradiation, bacterial keratitis, and corneal neovascularization therapies
Authors: Nie Linyan , Hu Xiaowen , Zhao Yunxiao , Wu Fan , Wang Yaran , Chen Lei , Wang Yi , Liu Yong
Published: April 2023

Ophthalmic disease treatment remains a significant problem globally, resulting in poor vision and blindness. UV irradiation and bacterial infection may cause severe damage to the corneal, leading to vision loss within a few days. Corneal neovascular abnormally growth that bock lights reach to eyes, causes low vision. Thus it requires urgent and efficient clinical treatment. Contact lenses play an essential role in treating ophthalmic issues. In this work, we synthesized the chitosan-stabilized Au nanoparticles with a simple method. The Au nanoparticles were further physically adsorbed with negatively charged fluorescent nanodiamonds, yielding Au-CS@FNDs. These Au-CS@FNDs particles were proven with excellent UV adsorption, antibacterial properties, and photothermal conversation ability. Furthermore, we embedded Au-CS@FNDs particles into contact lenses to prevent corneal damage from UV light and bacterial infection. Moreover, the Au-CS@FNDs embedded contact lenses were used to inhibit the neovascularization in the Human Vascular Endothelial Cells via the photodynamic effect of Au nanoparticles. To the best of our knowledge, it is the first time that gold and diamond nanoparticles were used as additives in contact lenses, aiming at clinically corneal neovascular. Our results suggest that the controllable photothermal effect of Au-CS@FNDs embedded contact lenses may provide a unique way to intervene the neovascular-induced vision loss.

Abstract Figure
A potential patient stratification biomarker for Parkinso’s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells
Authors: Naaldijk Yahaira , Fernández Belén , Fasiczka Rachel , Fdez Elena , Leghay Coline , Croitoru Ioana , Kwok John B. , Boulesnane Yanisse , Vizeneux Amelie , Mutez Eugenie , Calvez Camille , Destée Alain , Taymans Jean-Marc , Aragon Ana Vinagre , Yarza Alberto Bergareche , Padmanabhan Shalini , Delgado Mario , Alcalay Roy N. , Chatterton Zac , Dzamko Nicolas , Halliday Glenda , Ruiz-Martínez Javier , Chartier-Harlin Marie-Christine , Hilfiker Sabine
Published: April 2023

Parkinso’s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes fromG2019S-LRRK2PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected inR1441G-LRRK2andG2019S-LRRK2PD patients and in non-manifestingLRRK2mutation carriers, indicating that they acumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate PD patients who will benefit from LRRK2-related therapeutics.

One-sentence summary

Peripheral blood-derived cells can be employed to stratify Parkinso’s disease patients most likely to respond to LRRK2-related therapeutics.
CK2α-dependent regulation of Wnt activity governs white matter development and repair
Authors: Wang Chih-Yen , Zuo Zhongyuan , Kim Kyoung In , Bellen Hugo J. , Lee Hyun Kyoung
Published: April 2023

Wnt signaling plays an essential role in developmental and regenerative myelination in the CNS. The Wnt signaling pathway is comprised of multiple regulatory layers; thus, how these processes are coordinated to orchestrate oligodendrocyte development remains unclear. Here we show CK2α, a Wnt/β-catenin signaling Ser/Thr kinase, phosphorylates Daam2, inhibiting its function and Wnt-activity during oligodendrocyte development. Intriguingly, we found Daam2 phosphorylation differentially impacts distinct stages of oligodendrocyte development, accelerating early differentiation followed by decelerating maturation and myelination. Application towards white matter injury revealed CK2α-mediated Daam2 phosphorylation plays a protective role for developmental and behavioral recovery after neonatal hypoxia, while promoting myelin repair following adult demyelination. Together, our findings identify a novel regulatory node in the Wnt pathway that regulates oligodendrocyte development via protein phosphorylation-induced signaling complex instability and highlights a new biological mechanism for myelin restoration.

Significance

Wnt signaling plays a vital role in OL development and has been implicated as an adverse event for myelin repair after white matter injury. Emerging studies have shed light on multi-modal roles of Wnt effectors in the OL lineage, but the underlying molecular mechanisms and modifiable targets in OL remyelination remain unclear. Using genetic mouse development and injury model systems, we delineate a novel stage-specific function of Daam2 in Wnt signaling and OL development via a S704/T7-5 phosphorylation mechanism, and determine a new role of the kinase CK2α in contributing to OL development. In-depth understanding of CK2α-Daam2 pathway regulation will allow us to precisely modulate its activity in conjunction with Wnt signaling and harness its biology for white matter pathology.
Flowers are leakier than leaves but cheaper to build
Authors: Roddy Adam B. , Guilliams C. Matt , Fine Paul V.A. , Mambelli Stefania , Dawson Todd E. , Simonin Kevin A.
Published: April 2023

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Producing and maintaining flowers is essential for reproduction in most angiosperms, underpinning population persistence and speciation. Although the physiological costs of flowers often oppose pollinator selection, these physiological costs have rarely been quantified.

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We measured a suite of physiological traits quantifying the water and carbon costs and drought tolerance on flowers and leaves of over 100 phylogenetically diverse species, including water and dry mass contents, minimum epidermal conductance to water vapor (gmin), vein density, and dry mass per area.

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Although there was substantial variation among species, flowers had significantly highergminand water content per unit area than leaves, but significantly lower vein density and dry mass per area than leaves. Both leaves and flowers exhibited similarly strong scaling between dry mass investment and water content.

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The highergminof flowers offset their higher water content, suggesting that flowers may desiccate more rapidly than leaves during drought. The coordination between dry mass and water investment suggests that flowers rely on a hydrostatic skeleton to remain upright rather than on a carbon-based skeleton. For short-lived structures like flowers, water may be relatively cheaper than carbon, particularly given the relatively high amount of water loss per unit of carbon synthesized in photosynthesis.
Improved interpretability of bacterial genome-wide associations using gene cluster centric k-mers
Authors: Neubauer Hannes , Galardini Marco
Published: April 2023

The wide adoption of bacterial genome sequencing and encoding both core and accessory genome variation using k-mers has allowed bacterial genome wide association studies (GWAS) to identify genetic variants associated with relevant phenotypes such as those linked to infection. Significant limitations still remain as far as the interpretation of association results is concerned, which affects the wider adoption of GWAS methods on microbial data sets. We have developed a simple computational method (panfeed) that explicitly links each k-mer to their gene cluster at base resolution level, which allows us to avoid biases introduced by a global de Bruijn graph as well as more easily map and annotate associated variants. We tested panfeed on two independent data sets, correctly identifying previously characterized causal variants, which demonstrates the precision of the method, as well as its scalable performance. panfeed is a command line tool written in the python programming language and available athttps://github.com/microbial-pangenomes-lab/panfeed.
In situ structures from relaxed cardiac myofibrils reveal the organization of the muscle thick filament
Authors: Tamborrini Davide , Wang Zhexin , Wagner Thorsten , Tacke Sebastian , Stabrin Markus , Grange Michael , Kho Ay Lin , Rees Martin , Bennett Pauline , Gautel Mathias , Raunser Stefan
Published: April 2023

The thick filament is a key component of sarcomeres, the basic force-generating and load-bearing unit of striated muscle1. Mutations in thick filament proteins are associated with familial hypertrophic cardiomyopathy and other heart and muscle diseases2, 3. Despite this central importance for sarcomere force generation, it remains unclear how thick filaments are structurally organized and how its components interact with each other and with thin filaments to enable highly regulated muscle contraction. Here, we present the molecular architecture of native cardiac sarcomeres in the relaxed state, determined by electron cryo-tomography. Our reconstruction of the thick filament reveals the three-dimensional organization of myosin heads and tails, myosin-binding protein C (MyBP-C) and titin, elucidating the structural basis for their interaction during muscle contraction. The arrangement of myosin heads is variable depending on their position along the filament, suggesting that they have different capacities in terms of strain susceptibility and activation. Myosin tails exhibit a distinct arrangement and pattern of interactions. These are likely orchestrated by three alpha and three beta titin chains that are arranged like a spring, suggesting the existence of specialized roles of thick filament segments in length-dependent activation and contraction. Surprisingly, while the three titin alpha chains run along the entire length of the thick filament, titin beta does not. The structure also demonstrates that the C-terminal region of MyBP-C binds myosin tails and unexpectedly also directly interacts with the myosin heads, suggesting a previously undescribed direct role in the preservation of the myosin OFF state. Furthermore, we visualize how MyBP-C forms links between thin and thick filaments. These findings establish a robust groundwork for forthcoming research endeavors aiming to explore muscle disorders that involve sarcomeric structural components.
Identification of 1600 replication origins inS. cerevisiae
Authors: Foss Eric J. , Lichauco Carmina , Gatbonton-Schwager Tonibelle , Gonske Sara J. , Lofts Brandon , Lao Uyen , Bedalov Antonio
Published: April 2023

There are approximately 500 known origins of replication in the yeast genome, and the process by which DNA replication initiates at these locations is well understood. In particular, these sites are made competent to initiate replication by loading of the Mcm replicative helicase prior to the start of S phase; thus, “a site to which MCM is bound in G1” might be considered to provide an operational definition of a replication origin. By fusing a subunit of Mcm to micrococcal nuclease, a technique referred to as “Chromatin Endogenous Cleavage”, we previously showed that known origins are typically bound by a single Mcm double hexamer, loaded adjacent to the ARS consensus sequence (ACS). Here we extend this analysis from known origins to the entire genome, identifying candidate Mcm binding sites whose signal intensity varies over at least 3 orders of magnitude. Published data quantifying the production of ssDNA during S phase showed clear evidence of replication initiation among the most abundant 1600 of these sites, with replication activity decreasing in concert with Mcm abundance and disappearing at the limit of detection of ssDNA. Three other hallmarks of replication origins were apparent among the most abundant 5,500 sites. Specifically, these sites (1) appeared in intergenic nucleosome-free regions that were flanked on one or both sides by well-positioned nucleosomes; (2) were flanked by ACSs; and (3) exhibited a pattern of GC skew characteristic of replication initiation. Furthermore, the high resolution of this technique allowed us to demonstrate a strong bias for detecting Mcm double-hexamers downstream rather than upstream of the ACS, which is consistent with the directionality of Mcm loading by Orc that has been observedin vitro. We conclude that, if sites at which Mcm double-hexamers are loaded can function as replication origins, then DNA replication origins are at least 3-fold more abundant than previously assumed, and we suggest that replication may occasionally initiate in essentially every intergenic region. These results shed light on recent reports that as many as 15% of replication events initiate outside of known origins, and this broader distribution of replication origins suggest that S phase in yeast may be less distinct from that in humans than is widely assumed.
Adhesion-induced cortical flows pattern E-cadherin-mediated cell contacts
Authors: Arslan Feyza Nur , Hannezo Édouard , Merrin Jack , Loose Martin , Heisenberg Carl-Philipp
Published: April 2023

Metazoan development relies on the formation and remodeling of cell-cell contacts. Dynamic reorganization of adhesion receptors and the actomyosin cell cortex in space and time play a central role in cell-cell contact formation and maturation. Yet, how this process is mechanistically achieved remains unclear. Here, by building a biomimetic assay composed of progenitor cells adhering to supported lipid bilayers functionalized with E-cadherin ectodomains, we show that cortical Actin flows, driven by the depletion of Myosin-2 at the cell contact center, mediate the dynamic reorganization of adhesion receptors and cell cortex at the contact. E-cadherin-dependent downregulation of the small GTPase RhoA at the forming contact leads to both a depletion of Myosin-2 and a decrease of F-actin at the contact center. This depletion of Myosin-2 causes centrifugal F-actin flows, leading to further accumulation of F-actin at the contact rim and the progressive redistribution of E-cadherin from the contact center to the rim. Eventually, this combination of actomyosin downregulation and flows at the contact determine the characteristic molecular organization, with E-cadherin and F-actin accumulating at the contact rim, where they are needed to mechanically link the contractile cortices of the adhering cells.