bluuebunny/crossref_metadata_2025 huggingface dataset:
A live-cell image-based machine learning strategy for reducing variability in PSC differentiation systems
Authors: Yang Xiaochun , Chen Daichao , Sun Qiushi , Wang Yao , Xia Yu , Yang Jinyu , Lin Chang , Dang Xin , Cen Zimu , Liang Dongdong , Wei Rong , Xu Ze , Xi Guangyin , Xue Gang , Ye Can , Wang Li-Peng , Zou Peng , Wang Shi-Qiang , Rivera-Fuentes Pablo , Püntener Salome , Chen Zhixing , Liu Yi , Zhang Jue , Zhao Yang
Published: June 2023

The differentiation of pluripotent stem cells (PSCs) into diverse functional cell types provides a promising solution to support drug discovery, disease modeling, and regenerative medicine. However, functional cell differentiation is currently limited by the substantial line-to-line and batch-to-batch variabilities, which severely impede the progress of scientific research and the manufacturing of cell products. For instance, PSC-to-cardiomyocyte (CM) differentiation is vulnerable to inappropriate doses of CHIR99021 (CHIR) that are applied in the initial stage of mesoderm differentiation. Here, by harnessing live-cell bright-field imaging and machine learning (ML), we realize real-time cell recognition in the entire differentiation process, e.g., CMs, cardiac progenitor cells (CPCs), PSC clones, and even misdifferentiated cells. This enables non-invasive prediction of differentiation efficiency, purification of ML-recognized CMs and CPCs for reducing cell contamination, early assessment of the CHIR dose for correcting the misdifferentiation trajectory, and evaluation of initial PSC colonies for controlling the start point of differentiation, all of which provide a more invulnerable differentiation method with resistance to variability. Moreover, with the established ML models as a readout for the chemical screen, we identify a CDK8 inhibitor that can further improve the cell resistance to the overdose of CHIR. Together, this study indicates that artificial intelligence is able to guide and iteratively optimize PSC differentiation to achieve consistently high efficiency across cell lines and batches, providing a better understanding and rational modulation of the differentiation process for functional cell manufacturing in biomedical applications.
Assessment of the technological viability of photoelectrochemical devices for oxygen and fuel production on Moon and Mars
Authors: Ross Byron , Haussener Sophia , Brinkert Katharina
Published: June 2023

Human deep space exploration is presented with multiple challenges, such as the reliable, efficient and sustainable operation of life support systems. The production and recycling of oxygen, carbon dioxide (CO2) and fuels are hereby key, as a resource resupply will not be possible. Photoelectrochemical (PEC) devices are investigated for the light-assisted production of hydrogen and carbon-based fuels from CO2 within the green energy transition on Earth. Their monolithic design and the sole reliance on solar energy makes them attractive for applications in space. Here, we establish the framework to evaluate PEC device performances on Moon and Mars. We present a refined Martian solar irradiance spectrum and establish the thermodynamic and realistic efficiency limits of solar-driven lunar water-splitting and Martian carbon dioxide reduction (CO2R) devices. Finally, we discuss the technological viability of PEC devices in space by assessing the performance combined with solar concentrator devices and explore their fabrication via in-situ resource utilization.
Durable contraception in the female domestic cat using viral-vectored delivery of a feline anti-Müllerian hormone transgene
Authors: Vansandt Lindsey M. , Meinsohn Marie-Charlotte , Godin Philippe , Nagykery Nicholas , Sicher Natalie , Kano Motohiro , Kashiwagi Aki , Chauvin Maeva , Saatcioglu Hatice D. , Barnes Julie L. , Miller Amy G. , Thompson Amy K. , Bateman Helen L. , Donelan Elizabeth M. , González Raquel , Newsom Jackie , Gao Guangping , Donahoe Patricia K. , Wang Dan , Swanson William F. , Pépin David
Published: June 2023

Eighty percent of the estimated 600 million domestic cats in the world are free-roaming. These cats typically experience suboptimal welfare and inflict high levels of predation on wildlife. Additionally, euthanasia of healthy animals in overpopulated shelters raises ethical considerations. While surgical sterilization is the mainstay of pet population control, there is a need for efficient, safe, and cost-effective permanent contraception alternatives. Herein, we report evidence that a single intramuscular treatment with an adeno-associated viral vector delivering an anti-Müllerian hormone transgene produces long-term contraception in the domestic cat. Treated females are followed for over two years, during which transgene expression, anti-transgene antibodies, and reproductive hormones are monitored. Mating behavior and reproductive success are measured during two mating studies. Here we show that ectopic expression of anti-Müllerian hormone does not impair sex steroids nor estrous cycling, but prevents breeding-induced ovulation, resulting in safe and durable contraception in the female domestic cat.
NERNST: a genetically-encoded ratiometric non-destructive sensing tool to estimate NADP(H) redox status in bacterial, plant and animal systems
Authors: Molinari Pamela E. , Krapp Adriana R. , Weiner Andrea , Beyer Hannes M. , Kondadi Arun Kumar , Blomeier Tim , López Melina , Bustos-Sanmamed Pilar , Tevere Evelyn , Weber Wilfried , Reichert Andreas S. , Calcaterra Nora B. , Beller Mathias , Carrillo Nestor , Zurbriggen Matias D.
Published: June 2023

NADP(H) is a central metabolic hub providing reducing equivalents to multiple biosynthetic, regulatory and antioxidative pathways in all living organisms. While biosensors are available to determine NADP+ or NADPH levels in vivo, no probe exists to estimate the NADP(H) redox status, a determinant of the cell energy availability. We describe herein the design and characterization of a genetically-encoded ratiometric biosensor, termed NERNST, able to interact with NADP(H) and estimate ENADP(H). NERNST consists of a redox-sensitive green fluorescent protein (roGFP2) fused to an NADPH-thioredoxin reductase C module which selectively monitors NADP(H) redox states via oxido-reduction of the roGFP2 moiety. NERNST is functional in bacterial, plant and animal cells, and organelles such as chloroplasts and mitochondria. Using NERNST, we monitor NADP(H) dynamics during bacterial growth, environmental stresses in plants, metabolic challenges to mammalian cells, and wounding in zebrafish. NERNST estimates the NADP(H) redox poise in living organisms, with various potential applications in biochemical, biotechnological and biomedical research.
Whistler-mode chorus waves at Mars
Authors: Teng Shangchun , Wu Yifan , Harada Yuki , Bortnik Jacob , Zonca Fulvio , Chen Liu , Tao Xin
Published: June 2023

Chorus waves are naturally occurring electromagnetic emissions in space and are known to produce highly energetic electrons in the hazardous radiation belt. The characteristic feature of chorus is its fast frequency chirping, whose mechanism remains a long-standing problem. While many theories agree on its nonlinear nature, they differ on whether or how the background magnetic field inhomogeneity plays a key role. Here, using observations of chorus at Mars and Earth, we report direct evidence showing that the chorus chirping rate is consistently related to the background magnetic field inhomogeneity, despite orders of magnitude difference in a key parameter quantifying the inhomogeneity at the two planets. Our results show an extreme test of a recently proposed chorus generation model and confirm the connection between the chirping rate and magnetic field inhomogeneity, opening the door to controlled plasma wave excitation in the laboratory and space.
LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways
Authors: Kshirsagar Aditya , Doroshev Svetlana Maslov , Gorelik Anna , Olender Tsviya , Sapir Tamar , Tsuboi Daisuke , Rosenhek-Goldian Irit , Malitsky Sergey , Itkin Maxim , Argoetti Amir , Mandel-Gutfreund Yael , Cohen Sidney R. , Hanna Jacob H. , Ulitsky Igor , Kaibuchi Kozo , Reiner Orly
Published: June 2023

Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the molecular motor cytoplasmic dynein activity. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it governs the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the extracellular matrix (ECM) expression and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post-transcriptional regulation underlying development and mechanosensitive processes.
Revealing CO2 dissociation pathways at vicinal copper (997) interfaces
Authors: Kim Jeongjin , Yu Youngseok , Go Tae Won , Gallet Jean-Jacques , Bournel Fabrice , Mun Bongjin Simon , Park Jeong Young
Published: June 2023

Size- and shape-tailored copper (Cu) nanocrystals can offer vicinal planes for facile carbon dioxide (CO2) activation. Despite extensive reactivity benchmarks, a correlation between CO2 conversion and morphology structure has not yet been established at vicinal Cu interfaces. Herein, ambient pressure scanning tunneling microscopy reveals step-broken Cu nanocluster evolutions on the Cu(997) surface under 1 mbar CO2(g). The CO2 dissociation reaction produces carbon monoxide (CO) adsorbate and atomic oxygen (O) at Cu step-edges, inducing complicated restructuring of the Cu atoms to compensate for increased surface chemical potential energy at ambient pressure. The CO molecules bound at under-coordinated Cu atoms contribute to the reversible Cu clustering with the pressure gap effect, whereas the dissociated oxygen leads to irreversible Cu faceting geometries. Synchrotron-based ambient pressure X-ray photoelectron spectroscopy identifies the chemical binding energy changes in CO-Cu complexes, which proves the characterized real-space evidence for the step-broken Cu nanoclusters under CO(g) environments. Our in situ surface observations provide a more realistic insight into Cu nanocatalyst designs for efficient CO2 conversion to renewable energy sources during C1 chemical reactions.
Neoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors
Authors: Schmidt Julien , Chiffelle Johanna , Perez Marta A. S. , Magnin Morgane , Bobisse Sara , Arnaud Marion , Genolet Raphael , Cesbron Julien , Barras David , Navarro Rodrigo Blanca , Benedetti Fabrizio , Michel Alexandra , Queiroz Lise , Baumgaertner Petra , Guillaume Philippe , Hebeisen Michael , Michielin Olivier , Nguyen-Ngoc Tu , Huber Florian , Irving Melita , Tissot-Renaud Stéphanie , Stevenson Brian J. , Rusakiewicz Sylvie , Dangaj Laniti Denarda , Bassani-Sternberg Michal , Rufer Nathalie , Gfeller David , Kandalaft Lana E. , Speiser Daniel E. , Zoete Vincent , Coukos George , Harari Alexandre
Published: June 2023

The success of cancer immunotherapy depends in part on the strength of antigen recognition by T cells. Here, we characterize the T cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities of 371 CD8 T cell clones specific for neoantigens, tumor-associated antigens (TAAs) or viral antigens isolated from tumors or blood of patients and healthy donors. T cells from tumors exhibit stronger functional and structural avidity than their blood counterparts. Relative to TAA, neoantigen-specific T cells are of higher structural avidity and, consistently, are preferentially detected in tumors. Effective tumor infiltration in mice models is associated with high structural avidity and CXCR3 expression. Based on TCR biophysicochemical properties, we derive and apply an in silico model predicting TCR structural avidity and validate the enrichment in high avidity T cells in patients’ tumors. These observations indicate a direct relationship between neoantigen recognition, T cell functionality and tumor infiltration. These results delineate a rational approach to identify potent T cells for personalized cancer immunotherapy.
Rare phenomena of central rhythm and pattern generation in a case of complete spinal cord injury
Authors: Minassian Karen , Bayart Aymeric , Lackner Peter , Binder Heinrich , Freundl Brigitta , Hofstoetter Ursula S.
Published: June 2023

Lumbar central pattern generators (CPGs) control the basic rhythm and coordinate muscle activation underlying hindlimb locomotion in quadrupedal mammals. The existence and function of CPGs in humans have remained controversial. Here, we investigated a case of a male individual with complete thoracic spinal cord injury who presented with a rare form of self-sustained rhythmic spinal myoclonus in the legs and rhythmic activities induced by epidural electrical stimulation (EES). Analysis of muscle activation patterns suggested that the myoclonus tapped into spinal circuits that generate muscle spasms, rather than reflecting locomotor CPG activity as previously thought. The EES-induced patterns were fundamentally different in that they included flexor-extensor and left-right alternations, hallmarks of locomotor CPGs, and showed spontaneous errors in rhythmicity. These motor deletions, with preserved cycle frequency and period when rhythmic activity resumed, were previously reported only in animal studies and suggest a separation between rhythm generation and pattern formation. Spinal myoclonus and the EES-induced activity demonstrate that the human lumbar spinal cord contains distinct mechanisms for generating rhythmic multi-muscle patterns.
PIE-seq: identifying RNA-binding protein targets by dual RNA-deaminase editing and sequencing
Authors: Ruan Xiangbin , Hu Kaining , Zhang Xiaochang
Published: June 2023

RNA-binding proteins (RBPs) are essential for gene regulation, but it remains a challenge to identify their RNA targets across cell types. Here we present PIE-Seq to investigate Protein-RNA Interaction with dual-deaminase Editing and Sequencing by conjugating C-to-U and A-to-I base editors to RBPs. We benchmark PIE-Seq and demonstrate its sensitivity in single cells, its application in the developing brain, and its scalability with 25 human RBPs. Bulk PIE-Seq identifies canonical binding features for RBPs such as PUM2 and NOVA1, and nominates additional target genes for most tested RBPs such as SRSF1 and TDP-43/TARDBP. Homologous RBPs frequently edit similar sequences and gene sets in PIE-Seq while different RBP families show distinct targets. Single-cell PIE-PUM2 uncovers comparable targets to bulk samples and applying PIE-PUM2 to the developing mouse neocortex identifies neural-progenitor- and neuron-specific target genes such as App. In summary, PIE-Seq provides an orthogonal approach and resource to uncover RBP targets in mice and human cells.
Estimating the impact of COVID-19 vaccine inequities: a modeling study
Authors: Gozzi Nicolò , Chinazzi Matteo , Dean Natalie E. , Longini Jr Ira M. , Halloran M. Elizabeth , Perra Nicola , Vespignani Alessandro
Published: June 2023

Access to COVID-19 vaccines on the global scale has been drastically hindered by structural socio-economic disparities. Here, we develop a data-driven, age-stratified epidemic model to evaluate the effects of COVID-19 vaccine inequities in twenty lower middle and low income countries (LMIC) selected from all WHO regions. We investigate and quantify the potential effects of higher or earlier doses availability. In doing so, we focus on the crucial initial months of vaccine distribution and administration, exploring counterfactual scenarios where we assume the same per capita daily vaccination rate reported in selected high income countries. We estimate that more than 50% of deaths (min-max range: [54−94%]) that occurred in the analyzed countries could have been averted. We further consider scenarios where LMIC had similarly early access to vaccine doses as high income countries. Even without increasing the number of doses, we estimate an important fraction of deaths (min-max range: [6−50%]) could have been averted. In the absence of the availability of high-income countries, the model suggests that additional non-pharmaceutical interventions inducing a considerable relative decrease of transmissibility (min-max range: [15−70%]) would have been required to offset the lack of vaccines. Overall, our results quantify the negative impacts of vaccine inequities and underscore the need for intensified global efforts devoted to provide faster access to vaccine programs in low and lower-middle-income countries.
Coherent dynamics of strongly interacting electronic spin defects in hexagonal boron nitride
Authors: Gong Ruotian , He Guanghui , Gao Xingyu , Ju Peng , Liu Zhongyuan , Ye Bingtian , Henriksen Erik A. , Li Tongcang , Zu Chong
Published: June 2023

Optically active spin defects in van der Waals materials are promising platforms for modern quantum technologies. Here we investigate the coherent dynamics of strongly interacting ensembles of negatively charged boron-vacancy ($${{{{{{{{\rm{V}}}}}}}}}_{{{{{{{{\rm{B}}}}}}}}}^{-}$$VB−) centers in hexagonal boron nitride (hBN) with varying defect density. By employing advanced dynamical decoupling sequences to selectively isolate different dephasing sources, we observe more than 5-fold improvement in the measured coherence times across all hBN samples. Crucially, we identify that the many-body interaction within the$${{{{{{{{\rm{V}}}}}}}}}_{{{{{{{{\rm{B}}}}}}}}}^{-}$$VB−ensemble plays a substantial role in the coherent dynamics, which is then used to directly estimate the concentration of$${{{{{{{{\rm{V}}}}}}}}}_{{{{{{{{\rm{B}}}}}}}}}^{-}$$VB−. We find that at high ion implantation dosage, only a small portion of the created boron vacancy defects are in the desired negatively charged state. Finally, we investigate the spin response of$${{{{{{{{\rm{V}}}}}}}}}_{{{{{{{{\rm{B}}}}}}}}}^{-}$$VB−to the local charged defects induced electric field signals, and estimate its ground state transverse electric field susceptibility. Our results provide new insights on the spin and charge properties of$${{{{{{{{\rm{V}}}}}}}}}_{{{{{{{{\rm{B}}}}}}}}}^{-}$$VB−, which are important for future use of defects in hBN as quantum sensors and simulators.
Limosilactobacillus mucosae-derived extracellular vesicles modulates macrophage phenotype and orchestrates gut homeostasis in a diarrheal piglet model
Authors: Li Jingjing , Feng Shuaifei , Wang Zhenyu , He Jinhui , Zhang Zeyue , Zou Huicong , Wu Zhifeng , Liu Xiangdong , Wei Hong , Tao Shiyu
Published: June 2023

The diarrheal disease causes high mortality, especially in children and young animals. The gut microbiome is strongly associated with diarrheal disease, and some specific strains of bacteria have demonstrated antidiarrheal effects. However, the antidiarrheal mechanisms of probiotic strains have not been elucidated. Here, we used neonatal piglets as a translational model and found that gut microbiota dysbiosis observed in diarrheal piglets was mainly characterized by a deficiency of Lactobacillus, an abundance of Escherichia coli, and enriched lipopolysaccharide biosynthesis. Limosilactobacillus mucosae and Limosilactobacillus reuteri were a signature bacterium that differentiated healthy and diarrheal piglets. Germ-free (GF) mice transplanted with fecal microbiota from diarrheal piglets reproduced diarrheal disease symptoms. Administration of Limosilactobacillus mucosae but not Limosilactobacillus reuteri alleviated diarrheal disease symptoms induced by fecal microbiota of diarrheal piglets and by ETEC K88 challenge. Notably, Limosilactobacillus mucosae-derived extracellular vesicles alleviated diarrheal disease symptoms caused by ETEC K88 by regulating macrophage phenotypes. Macrophage elimination experiments demonstrated that the extracellular vesicles alleviated diarrheal disease symptoms in a macrophage-dependent manner. Our findings provide insights into the pathogenesis of diarrheal disease from the perspective of intestinal microbiota and the development of probiotic-based antidiarrheal therapeutic strategies.
Realizing all-to-all couplings among detachable quantum modules using a microwave quantum state router
Authors: Zhou Chao , Lu Pinlei , Praquin Matthieu , Chien Tzu-Chiao , Kaufman Ryan , Cao Xi , Xia Mingkang , Mong Roger S. K. , Pfaff Wolfgang , Pekker David , Hatridge Michael
Published: June 2023

One of the primary challenges in realizing large-scale quantum processors is the realization of qubit couplings that balance interaction strength, connectivity, and mode confinement. Moreover, it is very desirable for the device elements to be detachable, allowing components to be built, tested, and replaced independently. In this work, we present a microwave quantum state router, centered on parametrically driven, Josephson-junction based three-wave mixing, that realizes all-to-all couplings among four detachable quantum modules. We demonstrate coherent exchange among all four communication modes, with an average full-iSWAP time of 764 ns and average inferred inter-module exchange fidelity of 0.969, limited by mode coherence. We also demonstrate photon transfer and pairwise entanglement between module qubits, and parallel operation of simultaneousiSWAP exchange across the router. Our router-module architecture serves as a prototype of modular quantum computer that has great potential for enabling flexible, demountable, large-scale quantum networks of superconducting qubits and cavities.
Computational modeling of DLBCL predicts response to BH3-mimetics
Authors: Cloete Ielyaas , Smith Victoria M. , Jackson Ross A. , Pepper Andrea , Pepper Chris , Vogler Meike , Dyer Martin J. S. , Mitchell Simon
Published: June 2023

In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. Variability in the expression and sequestration of these proteins in Diffuse Large B cell Lymphoma (DLBCL) likely contributes to variability in response to BH3-mimetics. Successful deployment of BH3-mimetics in DLBCL requires reliable predictions of which lymphoma cells will respond. Here we show that a computational systems biology approach enables accurate prediction of the sensitivity of DLBCL cells to BH3-mimetics. We found that fractional killing of DLBCL, can be explained by cell-to-cell variability in the molecular abundances of signaling proteins. Importantly, by combining protein interaction data with a knowledge of genetic lesions in DLBCL cells, our in silico models accurately predict in vitro response to BH3-mimetics. Furthermore, through virtual DLBCL cells we predict synergistic combinations of BH3-mimetics, which we then experimentally validated. These results show that computational systems biology models of apoptotic signaling, when constrained by experimental data, can facilitate the rational assignment of efficacious targeted inhibitors in B cell malignancies, paving the way for development of more personalized approaches to treatment.
Meta-analysis of single-cell and single-nucleus transcriptomics reveals kidney cell type consensus signatures
Authors: Quatredeniers Marceau , Serafin Alice S. , Benmerah Alexandre , Rausell Antonio , Saunier Sophie , Viau Amandine
Published: June 2023

While the amount of studies involving single-cell or single-nucleus RNA-sequencing technologies grows exponentially within the biomedical research area, the kidney field requires reference transcriptomic signatures to allocate each cluster its matching cell type. The present meta-analysis of 39 previously published datasets, from 7 independent studies, involving healthy human adult kidney samples, offers a set of 24 distinct consensus kidney cell type signatures. The use of these signatures may help to assure the reliability of cell type identification in future studies involving single-cell and single-nucleus transcriptomics while improving the reproducibility in cell type allocation.
ICESat-2 river surface slope (IRIS): A global reach-scale water surface slope dataset
Authors: Scherer Daniel , Schwatke Christian , Dettmering Denise , Seitz Florian
Published: June 2023

The global reach-scale “ICESat-2 River Surface Slope” (IRIS) dataset comprises average and extreme water surface slopes (WSS) derived from ICESat-2 observations between October 2018 and August 2022 as a supplement to 121,583 reaches from the “SWOT Mission River Database” (SWORD). To gain full advantage of ICESat-2’s unique measurement geometry with six parallel lidar beams, the WSS is determined across pairs of beams or along individual beams, depending on the intersection angle of spacecraft orbit and river centerline. Combining both approaches maximizes spatial and temporal coverage. IRIS can be used to research river dynamics, estimate river discharge, and correct water level time series from satellite altimetry for shifting ground tracks. Additionally, by referencing SWORD as a common database, IRIS may be used in combination with observations from the recently launched SWOT mission.
Gap-free genome assembly of anadromous Coilia nasus
Authors: Ma Fengjiao , Wang Yinping , Su Bixiu , Zhao Chenxi , Yin Denghua , Chen Chunhai , Yang Yanping , Wang Chenhe , Luo Bei , Wang Hongqi , Deng Yanmin , Xu Pao , Yin Guojun , Jian Jianbo , Liu Kai
Published: June 2023

The Chinese tapertail anchovy,Coilia nasus, is a socioeconomically important anadromous fish that migrates from near ocean waters to freshwater to spawn every spring. The analysis of genomic architecture and information ofC. nasuswere hindered by the previously released versions of reference genomes with gaps. Here, we report the assembly of a chromosome-level gap-free genome ofC. nasusby incorporating high-coverage and accurate long-read sequence data with multiple assembly strategies. All 24 chromosomes were assembled without gaps, representing the highest completeness and assembly quality. We assembled the genome with a size of 851.67 Mb and used BUSCO to estimate the completeness of the assembly as 92.5%. Using a combination ofde novoprediction, protein homology and RNA-seq annotation, 21,900 genes were functionally annotated, representing 99.68% of the total predicted protein-coding genes. The availability of gap-free reference genomes forC. nasuswill provide the opportunity for understanding genome structure and function, and will also lay a solid foundation for further management and conservation of this important species.
Face mask is an efficient tool to fight the Covid-19 pandemic and some factors increase the probability of its adoption
Authors: Damette Olivier , Huynh Toan Luu Duc
Published: June 2023

This study examines the dynamic impact of face mask use on both infected cases and fatalities at a global scale by using a rich set of panel data econometrics. An increase of 100% of the proportion of people declaring wearing a mask (multiply by two) over the studied period lead to a reduction of around 12 and 13.5% of the number of Covid-19 infected cases (per capita) after 7 and 14 days respectively. The delay of action varies from around 7 days to 28 days concerning infected cases but is more longer concerning fatalities. Our results hold when using the rigorous controlling approach. We also document the increasing adoption of mask use over time and the drivers of mask adoption. In addition, population density and pollution levels are significant determinants of heterogeneity regarding mask adoption across countries, while altruism, trust in government and demographics are not. However, individualism index is negatively correlated with mask adoption. Finally, strict government policies against Covid-19 have a strong significant effect on mask use.
Perivascular network segmentations derived from high-field MRI and their implications for perivascular and parenchymal mass transport in the rat brain
Authors: Rey Julian A. , Farid Uzair M. , Najjoum Christopher M. , Brown Alec , Magdoom Kulam Najmudeen , Mareci Thomas H. , Sarntinoranont Malisa
Published: June 2023

A custom segmentation workflow was applied to ex vivo high-field MR images of rat brains acquired following in vivo intraventricular contrast agent infusion to generate maps of the perivascular spaces (PVS). The resulting perivascular network segmentations enabled analysis of perivascular connections to the ventricles, parenchymal solute clearance, and dispersive solute transport within PVS. Numerous perivascular connections between the brain surface and the ventricles suggest the ventricles integrate into a PVS-mediated clearance system and raise the possibility of cerebrospinal fluid (CSF) return from the subarachnoid space to the ventricles via PVS. Assuming rapid solute exchange between the PVS and CSF spaces primarily by advection, the extensive perivascular network decreased the mean clearance distance from parenchyma to the nearest CSF compartment resulting in an over 21-fold reduction in the estimated diffusive clearance time scale, irrespective of solute diffusivity. This corresponds to an estimated diffusive clearance time scale under 10 min for amyloid-beta which suggests that the widespread distribution of PVS may render diffusion an effective parenchymal clearance mechanism. Additional analysis of oscillatory solute dispersion within PVS indicates that advection rather than dispersion is likely the primary transport mechanism for dissolved compounds greater than 66 kDa in the long (> 2 mm) perivascular segments identified here, although dispersion may be significant for smaller compounds in shorter perivascular segments.
Site-directed mutagenesis of Mycobacterium tuberculosis and functional validation to investigate potential bedaquiline resistance-causing mutations
Authors: Otum Christian C. , Rivière Emmanuel , Barnard Monique , Loubser Johannes , Williams Monique J. , Streicher Elizabeth M. , Van Rie Annelies , Warren Robin M. , Klopper Marisa
Published: June 2023

Molecular detection of bedaquiline resistant tuberculosis is challenging as only a small proportion of mutations in candidate bedaquiline resistance genes have been statistically associated with phenotypic resistance. We introduced two mutations, atpE Ile66Val and Rv0678 Thr33Ala, in the Mycobacterium tuberculosis H37Rv reference strain using homologous recombineering or recombination to investigate the phenotypic effect of these mutations. The genotype of the resulting strains was confirmed by Sanger- and whole genome sequencing, and bedaquiline susceptibility was assessed by minimal inhibitory concentration (MIC) assays. The impact of the mutations on protein stability and interactions was predicted using mutation Cutoff Scanning Matrix (mCSM) tools. The atpE Ile66Val mutation did not elevate the MIC above the critical concentration (MIC 0.25–0.5 µg/ml), while the MIC of the Rv0678 Thr33Ala mutant strains (> 1.0 µg/ml) classifies the strain as resistant, confirming clinical findings. In silico analyses confirmed that the atpE Ile66Val mutation minimally disrupts the bedaquiline-ATP synthase interaction, while the Rv0678 Thr33Ala mutation substantially affects the DNA binding affinity of the MmpR transcriptional repressor. Based on a combination of wet-lab and computational methods, our results suggest that the Rv0678 Thr33Ala mutation confers resistance to BDQ, while the atpE Ile66Val mutation does not, but definite proof can only be provided by complementation studies given the presence of secondary mutations.
Ebselen derivatives inhibit SARS-CoV-2 replication by inhibition of its essential proteins: PLpro and Mpro proteases, and nsp14 guanine N7-methyltransferase
Authors: Zmudzinski Mikolaj , Rut Wioletta , Olech Kamila , Granda Jarosław , Giurg Mirosław , Burda-Grabowska Małgorzata , Kaleta Rafał , Zgarbova Michala , Kasprzyk Renata , Zhang Linlin , Sun Xinyuanyuan , Lv Zongyang , Nayak Digant , Kesik-Brodacka Malgorzata , Olsen Shaun K. , Weber Jan , Hilgenfeld Rolf , Jemielity Jacek , Drag Marcin
Published: June 2023

Proteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (Mpro, 3CLpro) and papain-like protease (PLpro) are responsible for viral polyprotein cleavage—a process crucial for viral survival and replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2H)-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is a potent, covalent inhibitor of both the proteases and its potency was evaluated in enzymatic and antiviral assays. In this study, we screened a collection of 34 ebselen and ebselen diselenide derivatives for SARS-CoV-2 PLpro and Mpro inhibitors. Our studies revealed that ebselen derivatives are potent inhibitors of both the proteases. We identified three PLpro and four Mpro inhibitors superior to ebselen. Independently, ebselen was shown to inhibit the N7-methyltransferase activity of SARS-CoV-2 nsp14 protein involved in viral RNA cap modification. Hence, selected compounds were also evaluated as nsp14 inhibitors. In the second part of our work, we employed 11 ebselen analogues—bis(2-carbamoylaryl)phenyl diselenides—in biological assays to evaluate their anti-SARS-CoV-2 activity in Vero E6 cells. We present their antiviral and cytoprotective activity and also low cytotoxicity. Our work shows that ebselen, its derivatives, and diselenide analogues constitute a promising platform for development of new antivirals targeting the SARS-CoV-2 virus.
Self-regulation of visual word form area activation with real-time fMRI neurofeedback
Authors: Haugg Amelie , Frei Nada , Menghini Milena , Stutz Felizia , Steinegger Sara , Röthlisberger Martina , Brem Silvia
Published: June 2023

The Visual Word Form Area (VWFA) is a key region of the brain’s reading network and its activation has been shown to be strongly associated with reading skills. Here, for the first time, we investigated whether voluntary regulation of VWFA activation is feasible using real-time fMRI neurofeedback. 40 adults with typical reading skills were instructed to either upregulate (UP group, N = 20) or downregulate (DOWN group, N = 20) their own VWFA activation during six neurofeedback training runs. The VWFA target region was individually defined based on a functional localizer task. Before and after training, also regulation runs without feedback (“no-feedback runs”) were performed. When comparing the two groups, we found stronger activation across the reading network for the UP than the DOWN group. Further, activation in the VWFA was significantly stronger in the UP group than the DOWN group. Crucially, we observed a significant interaction of group and time (pre, post) for the no-feedback runs: The two groups did not differ significantly in their VWFA activation before neurofeedback training, but the UP group showed significantly stronger activation than the DOWN group after neurofeedback training. Our results indicate that upregulation of VWFA activation is feasible and that, once learned, successful upregulation can even be performed in the absence of feedback. These results are a crucial first step toward the development of a potential therapeutic support to improve reading skills in individuals with reading impairments.
Preferential rabbit antibody responses to C-termini of NOTCH3 peptide immunogens
Authors: Lee Soo Jung , Gasche Mitchell B. , Burrows Connor J. , Kondepudi Akhil , Zhang Xiaojie , Wang Michael M.
Published: June 2023

Antibodies raised in peptide-immunized rabbits have been used in biological research for decades. Although there has been wide implementation of this approach, specific proteins are occasionally difficult to target for multiple reasons. One consideration that was noted in mice is that humoral responses may preferentially target the carboxyl terminus of the peptide sequence which is not present in the intact protein. To shed light on the frequency of preferential rabbit antibody responses to C-termini of peptide immunogens, we present our experience with generation of rabbit antibodies to human NOTCH3. A total of 23 antibodies were raised against 10 peptide sequences of human NOTCH3. Over 70% (16 of 23) of these polyclonal antibodies were determined to be C-terminal preferring: NOTCH3 peptide-reactive antibodies largely targeted the terminating free carboxyl group of the immunizing peptide. The antibodies that preferred C-terminal epitopes reacted weakly or not at all with recombinant target sequences with extension the C-terminus that eliminated the free carboxyl group of the immunogen structure; furthermore, each of these antisera revealed no antibody reactivity to proteins truncated before the C-terminus of the immunogen. In immunocytochemical applications of these anti-peptide antibodies, we similarly found reactivity to recombinant targets that best binding to cells expressing the free C-terminus of the immunizing sequence. In aggregate, our experience demonstrates a strong propensity for rabbits to mount antibody responses to C-terminal epitopes of NOTCH3-derived peptides which is predicted to limit their use against the native protein. We discuss some potential approaches to overcome this bias that could improve the efficiency of generation of antibodies in this commonly utilized experimental paradigm.
Integrated ultrasonographic approach to evaluate fluid responsiveness in critically ill patients
Authors: Innocenti Francesca , Savinelli Caterina , Coppa Alessandro , Tassinari Irene , Pini Riccardo
Published: June 2023

In patients with acute circulatory failure, we tested the feasibility of the evaluation of the fluid-responsiveness (FR) by a combined approach with echocardiography and lung ultrasound. We enrolled 113 consecutive patients admitted to the Emergency Department High-Dependency Unit of Careggi University-Hospital from January 2015 to June 2020. We assessed: (1) inferior vena cava collapsibility index (IVCCI); (2) the variation of aortic flow (VTIAo) during the passive leg raising test (PLR); (3) the presence of interstitial syndrome by lung ultrasound. FR was defined as an increase in the VTIAo > 10% during PLR or IVCCI ≥ 40%. FR patients were treated with fluid and those non-FR with diuretics or vasopressors. The therapeutic strategy was reassessed after 12 h. The goal was to maintain the initial strategy. Among 56 FR patients, at lung ultrasound, 15 patients showed basal interstitial syndrome and 4 all-lung involvement. One fluid bolus was given to 51 patients. Among 57 non-FR patients, 26 patients showed interstitial syndrome at lung ultrasound (basal fields in 14, all lungs in 12). We administered diuretics to 21 patients and vasopressors to 4 subjects. We had to change the initial treatment plan in 9% non-FR patients and in 12% FR patients (p = NS). In the first 12 h after the evaluation, non-FR patients received significantly less fluids compared to those FR (1119 ± 410 vs 2010 ± 1254 ml, p < 0.001). The evaluation of the FR based on echocardiography and lung ultrasound was associated with the reduction in fluid administration for non-FR patients compared with those FR.
Opposite modulation of functional recovery following contusive spinal cord injury in mice with oligodendrocyte-selective deletions of Atf4 and Chop/Ddit3
Authors: Gao Yonglin , Wei George Z. , Forston Michael D. , Rood Benjamin , Hodges Emily R. , Burke Darlene , Andres Kariena , Morehouse Johnny , Armstrong Christine , Glover Charles , Slomnicki Lukasz P. , Ding Jixiang , Chariker Julia H. , Rouchka Eric C. , Saraswat Ohri Sujata , Whittemore Scott R. , Hetman Michal
Published: June 2023

The integrated stress response (ISR)-activated transcription factors ATF4 and CHOP/DDIT3 may regulate oligodendrocyte (OL) survival, tissue damage and functional impairment/recovery in white matter pathologies, including traumatic spinal cord injury (SCI). Accordingly, in OLs of OL-specific RiboTag mice, Atf4, Chop/Ddit3 and their downstream target gene transcripts were acutely upregulated at 2, but not 10, days post-contusive T9 SCI coinciding with maximal loss of spinal cord tissue. Unexpectedly, another, OL-specific upregulation of Atf4/Chop followed at 42 days post-injury. However, wild type versus OL-specific Atf4−/− or Chop−/− mice showed similar white matter sparing and OL loss at the injury epicenter, as well as unaffected hindlimb function recovery as determined by the Basso mouse scale. In contrast, the horizontal ladder test revealed persistent worsening or improvement of fine locomotor control in OL-Atf4−/− or OL-Chop−/− mice, respectively. Moreover, chronically, OL-Atf−/− mice showed decreased walking speed during plantar stepping despite greater compensatory forelimb usage. Therefore, ATF4 supports, while CHOP antagonizes, fine locomotor control during post-SCI recovery. No correlation between those effects and white matter sparing together with chronic activation of the OL ISR suggest that in OLs, ATF4 and CHOP regulate function of spinal cord circuitries that mediate fine locomotor control during post-SCI recovery.
Platelets from patients with myeloproliferative neoplasms have increased numbers of mitochondria that are hypersensitive to depolarization by thrombin
Authors: Ross David M. , Liang Hai Po Helena , Iqra Zeenet , Whittaker Shane , Tan Chuen Wen , Dale Brian J. , Chen Vivien M.
Published: June 2023

Thrombosis is one of the cardinal manifestations of myeloproliferative neoplasms (MPN). The mechanisms leading to a prothrombotic state in MPN are complex and remain poorly understood. Platelet mitochondria play a role in platelet activation, but their number and function have not been extensively explored in MPN to date. We observed an increased number of mitochondria in platelets from MPN patients compared with healthy donors. MPN patients had an increased proportion of dysfunctional platelet mitochondria. The fraction of platelets with depolarized mitochondria at rest was increased in essential thrombocythemia (ET) patients and the mitochondria were hypersensitive to depolarization following thrombin agonist stimulation. Live microscopy showed a stochastic process in which a higher proportion of individual ET platelets underwent mitochondrial depolarization and after a shorter agonist exposure compared to healthy donors. Depolarization was immediately followed by ballooning of the platelet membrane, which is a feature of procoagulant platelets. We also noted that the mitochondria of MPN patients were on average located nearer the platelet surface and we observed extrusion of mitochondria from the platelet surface as microparticles. These data implicate platelet mitochondria in a number of prothrombotic phenomena. Further studies are warranted to assess whether these findings correlate with clinical thrombotic events.
Improvement of retinal function in Alzheimer disease-associated retinopathy by dietary lysophosphatidylcholine-EPA/DHA
Authors: Sugasini Dhavamani , Park Jason C. , McAnany J. Jason , Kim Tae-Hoon , Ma Guangying , Yao Xincheng , Antharavally Babu , Oroskar Anil , Oroskar Asha A. , Layden Brian T. , Subbaiah Papasani V.
Published: June 2023

Alzheimer disease (AD) is the most prevalent cause of dementia in the elderly. Although impaired cognition and memory are the most prominent features of AD, abnormalities in visual functions often precede them, and are increasingly being used as diagnostic and prognostic markers for the disease. Retina contains the highest concentration of the essential fatty acid docosahexaenoic acid (DHA) in the body, and its deficiency is associated with several retinal diseases including diabetic retinopathy and age related macular degeneration. In this study, we tested the hypothesis that enriching retinal DHA through a novel dietary approach could ameliorate symptoms of retinopathy in 5XFAD mice, a widely employed model of AD. The results show that 5XFAD mice have significantly lower retinal DHA compared to their wild type littermates, and feeding the lysophosphatidylcholine (LPC) form of DHA and eicosapentaenoic acid (EPA) rapidly normalizes the DHA levels, and increases retinal EPA by several-fold. On the other hand, feeding similar amounts of DHA and EPA in the form of triacylglycerol had only modest effects on retinal DHA and EPA. Electroretinography measurements after 2 months of feeding the experimental diets showed a significant improvement in a-wave and b-wave functions by the LPC-diet, whereas the TAG-diet had only a modest benefit. Retinal amyloid β levels were decreased by about 50% by the LPC-DHA/EPA diet, and by about 17% with the TAG-DHA/EPA diet. These results show that enriching retinal DHA and EPA through dietary LPC could potentially improve visual abnormalities associated with AD.
Reconfigurable biconcave lens antenna based on plasma technology
Authors: Sadeghikia Fatemeh , Zafari Kazem , Dorbin Mohammad-Reza , Himdi Mohamed , Horestani Ali Karami
Published: June 2023

This article is focused on the application of plasma technology for the development of microwave lens antennas with electronically controllable radiation gain. With this aim, the analytical background and design procedure for designing a biconcave lens based on plasma dielectric material are presented. The procedure is used to design a plasma lens antenna with a pyramidal horn feed. The effect of switching the designed lens ON and OFF on the radiation gain of the lens antenna is investigated. It is also shown that the plasma frequency of the lens can be used to dynamically adjust the radiation gain. A one-dimensional version of the proposed plasma lens operating at 10 GHz has been developed to validate the concept. Experimentally measured characteristics of a fabricated prototype of the lens antenna based on commercially available fluorescent lamps confirm the presented design procedure and numerical results. The results also show that changing the plasma frequency of the lens can be used to adjust the radiation gain of the proposed lens antenna.
Longitudinal torsional vibrations of the chain drive system of mine scraper conveyor
Authors: Lu Jinnan , Yang Runkun , Mao Jun , Xie Chunxue
Published: June 2023

To deeply analyse the dynamic characteristics of the scraper conveyor during operation, the mechanical characteristics of the coupled longitudinal and torsional vibrational modes under excitation by cargo loading are studied. Based on the Kelvin‒Voigt model and the point-by-point tension method, a model of the coupled longitudinal and torsional vibrations of the scraper chain drive system is established. Then the functional program is constructed and the numerical simulation is carried out. Finally, the correctness of the model is verified by comparison with experiments. The research results reveal the torsional vibration characteristics of the scraper chain drive system under two different working conditions, light load and medium load, and determine the influence area of the torsional vibration of the scraper. The results of this analysis provide a theoretical basis for the subsequent optimization of the scraper parameters, the prediction of scraper chain drive system failure, and the calculation to give an early warning before failure occurs.