bluuebunny/crossref_metadata_2025 huggingface dataset:
Denoising diffusion weighted imaging data using convolutional neural networks
Authors: Cheng Hu , Vinci-Booher Sophia , Wang Jian , Caron Bradley , Wen Qiuting , Newman Sharlene , Pestilli Franco
Published: January 2022

Diffusion weighted imaging (DWI) with multiple, high b-values is critical for extracting tissue microstructure measurements; however, high b-value DWI images contain high noise levels that can overwhelm the signal of interest and bias microstructural measurements. Here, we propose a simple denoising method that can be applied to any dataset, provided a low-noise, single-subject dataset is acquired using the same DWI sequence. The denoising method uses a one-dimensional convolutional neural network (1D-CNN) and deep learning to learn from a low-noise dataset, voxel-by-voxel. The trained model can then be applied to high-noise datasets from other subjects. We validated the 1D-CNN denoising method by first demonstrating that 1D-CNN denoising resulted in DWI images that were more similar to the noise-free ground truth than comparable denoising methods, e.g., MP-PCA, using simulated DWI data. Using the same DWI acquisition but reconstructed with two common reconstruction methods, i.e. SENSE1 and sum-of-square, to generate a pair of low-noise and high-noise datasets, we then demonstrated that 1D-CNN denoising of high-noise DWI data collected from human subjects showed promising results in three domains: DWI images, diffusion metrics, and tractography. In particular, the denoised images were very similar to a low-noise reference image of that subject, more than the similarity between repeated low-noise images (i.e. computational reproducibility). Finally, we demonstrated the use of the 1D-CNN method in two practical examples to reduce noise from parallel imaging and simultaneous multi-slice acquisition. We conclude that the 1D-CNN denoising method is a simple, effective denoising method for DWI images that overcomes some of the limitations of current state-of-the-art denoising methods, such as the need for a large number of subjects for training and accounting for the rectified noise floor.
Prevalence of multimorbidity combinations and their association with medical costs and poor health: a population-based study of U.S. adults
Authors: Schiltz Nicholas K.
Published: January 2022

BACKGROUND

Multimorbidity is common, but the prevalence and burden of the specific combinations of coexisting disease has not been systematically examined in the general U.S. adult population.

OBJECTIVE

To identify and estimate the burden of highly prevalent combinations of chronic conditions that are treated among one million or more adults in the United States.

METHODS

Cross-sectional analysis of U.S. households in the Medical Expenditure Panel Survey (MEPS), 2016–2019, a large nationally-representative sample of the community-dwelling population. Association rule mining was used to identify the most common combinations of 20 chronic conditions that have high relevance, impact, and prevalence in primary care. The main measures and outcomes were annual treated prevalence, total medical expenditures, and perceived poor health. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals.

RESULTS

Frequent pattern mining yielded 223 unique combinations of chronic disease, including 74 two-way (dyad), 115 three-way (triad), and 34 four-way combinations that are treated in one million or more U.S. adults. Hypertension-hyperlipidemia was the most common two-way combination occurring in 30.8 million adults. The combination of diabetes-arthritis-cardiovascular disease was associated with the highest median annual medical expenditures ($23,850, [Interquartile range: $11,593 – $44,616]), and the combination of diabetes-arthritis-asthma/COPD} had the highest age-race-sex adjusted odds ratio of poor self-rated health (adjusted odd ratio: 6.9, [95%CI: 5.4 – 8.8]).

CONCLUSION

This study demonstrates that many multimorbidity combinations are highly prevalent among U.S. adults, yet most research and practice-guidelines remain single disease focused. Highly prevalent and burdensome multimorbidity combinations could be prioritized for evidence-based research on optimal prevention and treatment strategies.
CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
Authors: Allouch Awatef , Voisin Laurent , Zhang Yanyan , Syed Raza , Lecluse Yann , Calvo Julien , Sélimoglu-Buet Dorothée , De Botton Stéphane , Louache Fawzia , Pflumio Françoise , Solary Eric , Perfettini Jean-Luc
Published: January 2022

Most tumor-associated macrophages (TAMs), which are abundant in the tumor microenvironment, demonstrate an immunosuppressive phenotype and contribute to tumor progression, treatment resistance and poor clinical outcomes1,2. Due to their functional plasticity, these cells could be reprogrammed to acquire a pro-inflammatory phenotype and promote tumor clearance1. Several therapeutic approaches targeting TAMs to alleviate their immunosuppressive properties or to harness their tumoricidal capacities have been developed3,4. Inhibition of interactions between phagocytic inhibitor receptors on macrophages and “don’t eat me signals” on cancer cells, which promotes cancer cell engulfment, showed therapeutic benefits for several tumor types4–6. Investigating mechanisms involved in macrophage-mediated phagocytosis of tumor cells, we demonstrate here a key role for the cyclin-dependent kinase inhibitor CDKN1A (p21). Through transcriptional repression of SIRPα (Signal-Regularity Protein α), which encodes a phagocytic inhibitor, CDKN1A promotes the ability of monocyte-derived macrophages (MDMs) to engulf leukemic cells. In turn, these MDMs acquire a pro-inflammatory phenotype that extends to surrounding MDMs in an Interferon γ (IFNγ)-dependent manner. Human monocytes genetically engineered to overexpress p21 (p21TD-Mo) differentiate into anti-inflammatory MDMs that are primed for leukemic cell phagocytosis when transferred into mice xenografted with patient-derived T-cell acute lymphoblastic leukemia (T-ALL) cells. After leukemic cell engulfment, engineered macrophages undergo a pro-inflammatory activation, reducing leukemic burden and substantially prolonging survival of mice. These results reveal p21 as a trigger of phagocytosis-guided pro-inflammatory reprogramming of TAMs and demonstrate the potential for p21TD-Mo-based cell therapy in cancer immunotherapy.
Age of the bone marrow dictates clonality of smooth muscle-derived cells in the atherosclerotic plaque
Authors: Kabir Inamul , Zhang Xinbo , Dave Jui M. , Chakraborty Raja , Qu Rihao , Chandran Rachana R. , Ntokou Aglaia , Gallardo-Vara Eunate , Aryal Binod , Rotllan Noemi , Garcia-Milian Rolando , Hwa John , Kluger Yuval , Martin Kathleen A. , Fernández-Hernando Carlos , Greif Daniel M.
Published: January 2022

Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cell (SMC) progenitors clonally expand giving rise to up to ∼70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aged bone marrow (BM)-derived cells non-cell autonomously induce SMC polyclonality and worsen atherosclerosis. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin β3 resulting in increased tumor necrosis factor [TNF]-α signaling. In turn, TNFα signals through TNF receptor 1 on SMCs to promote proliferation and induces recruitment and expansion of multiple SMC progenitors into the atherosclerotic plaque. Notably, integrin β3 overexpression in aged BM preserves dominance of the lineage of a single SMC progenitor and attenuates plaque burden. Our results demonstrate a molecular mechanism of aged macrophage-induced SMC polyclonality and atherogenesis and suggest novel therapeutic strategies.

Graphical abstract

Age of BM-derived monocytes/macrophages determines clonality of SMC lineage in the atherosclerotic plaque.Atherogenesis is depicted in a young (a) or aged (b) host. Aged monocytes/macrophages have decreased levels of the epigenetic regulator TET2, leading to reduction of the 5-hydroxymethylcytosine (5hmC) mark on theItgb3promoter. The resulting low integrin β3 levels in aged monocytes/macrophages induces high TNF-α levels, facilitating recruitment and expansion of multiple SMC progenitors (polyclonality) in the atherosclerotic plaque and worse disease burden. In contrast, the young control is characterized by mono/oligoclonal SMC expansion in a smaller plaque.
Nucleosome topology and DNA sequence modulate the engagement of pioneer factors SOX2 and OCT4
Authors: Gadea Fabiana C. Malaga , Nikolova Evgenia N.
Published: January 2022

Nucleosomes in eukaryotic genomes present a barrier to the competent binding of many regulatory proteins. Pioneer transcription factors (pTFs) can bind their target sites on nucleosomal DNA and collaborate with other factors to locally open chromatin and promote transcription. While the interaction of pluripotency pioneer factors and functional partners Sox2 and Oct4 with nucleosomes has been widely studied, molecular details about their engagement in different nucleosome contexts remain elusive. Here, using high-resolution nuclear magnetic resonance (NMR) spectroscopy and biochemical studies, we reveal site-specific structural and dynamic information about pTF interaction with nucleosomes. We find that the affinity of Sox2 and Oct4 to the nucleosome and their synergistic binding correlates with solvent-exposed sites but is highly position and DNA sequence dependent and linked to distinct pTF conformation and dynamics. Sox2 alone forms a super-stable complex near superhelical location 5 (SHL5) with similar affinity and conformation to that of naked DNA but shows elevated dynamics at suboptimal positions. Oct4 strongly favors positions near SHL5.5 and SHL6.5 and both of its DNA binding modules, POUSor POUHD, are required for stable complex formation. A ternary complex forms efficiently on canonical Sox2-Oct4 composite motifs (no spacing) near nucleosome ends but is sparse at spaced motifs and absent at internal sites. Moreover, the ability of Sox2 to fold and bend DNA plays a key role in the formation of a stable nucleosome complex and cooperative Oct4 binding. Collectively, our findings describe diverse binding modes of Sox2 and Oct4 on nucleosomes that could guide their site selection and potential interaction with other chromatin factorsin vivo.
Cold Tolerance is Governed by Diverse Genetic Mechanisms Including Those Regulated by NB-LRR-type Receptor Proteins in Arabidopsis
Authors: Sahoo Dipak K. , Hegde Chinmay , Bhattacharyya Madan K.
Published: January 2022

Cold stress adversely affects the growth and development of plants and limits the geographical distribution of crop plants. Accumulation of spontaneous mutations shapes the adaptation of plant species to diverse climatic conditions. Genome-wide association study of the phenotypic variation gathered by a newly designed phenomic platform with that of the single nucleotide polymorphic (SNP) loci across the genomes of 417 Arabidopsis natural variants collected from various geographical regions revealed 33 candidate genes for cold tolerance. Investigation of at least two independent mutants for 29 of these genes identified 16 cold tolerance genes controlling diverse genetic mechanisms. This study identified five genes encoding novel leucine-rich repeat domain-containing proteins, including three nucleotide-binding site leucine-rich repeat (NBS-LRR) proteins. Among the 16 identified cold tolerance genes, ADS2 and ACD6 are the only two cold tolerance genes identified earlier. The comparatively little overlap between the genes identified in this genome-wide association study of natural variants with those discovered previously through forward and reverse genetic approaches suggests that cold tolerance is a complex physiological process governed by a large number of genetic mechanisms.

Short Summary

Cold stress adversely affects the growth and development of plants and limits the geographical distribution of crop plants. Genome-wide association study of the phenotypic variation of Arabidopsis natural variants with that of the single nucleotide polymorphic loci followed by T-DNA insertion mutant analyses of 29 candidate genes led to assigning cold tolerance function for the first time to 14 genes including three nucleotide-binding sites leucine repeat region (NB-LRR) protein genes. The comparatively little overlap between the genes identified in this study with those discovered previously suggests that cold tolerance is governed by a complex network of multiple genetic mechanisms.
Optimus: a general purpose adaptive optimisation engine in R
Authors: Johnson Nicholas A. G. , Tamon Liezel , Liu Xin , Sahakyan Aleksandr B.
Published: January 2022

Motivation

Many calculations in computational biology necessitate a use of a probabilistic optimisation protocol to determine a set of parameters that capture the system at a desired state in the configurational space. Here, we developed a flexible optimisation engine in R that can be plugged to any, simple or complex, modelling initiative through a few lucid interfacing functions, to perform a seamless optimisation with rigorous parameter sampling.

Results

Optimus features an acceptance ratio simulated annealing, acceptance ratio replica exchange, and adaptive thermoregulation, thus driving a Monte Carlo optimisation process in a flexible manner, through constrained acceptance frequency but unconstrained adaptive pseudo temperature regiments. We show the applicability of our R optimiser to a wide variety of problems spanning data analyses and computational biology tasks.

Availability and Implementation

Optimus is written and implemented in R, and is freely available from the http://github.com/SahakyanLab/Optimus repository.

Contact

aleksandr.sahakyan@imm.ox.ac.uk

Supplementary Information

Supplementary information with more details, tutorials, and developer instructions is available.

Graphical Abstract

The Optimus software logo depicting two gears (“Op”) that drag the system “s”, trapped in a “u” minimum, through a rough solution landscape into a more favourable solution with a deeper pseudo-energy minimum (“p”).
Complex genetic architecture underlying the plasticity of maize agronomic traits
Authors: Jin Minliang , Liu Haijun , Liu Xiangguo , Guo Tingting , Guo Jia , Yin Yuejia , Ji Yan , Li Zhenxian , Zhang Jinhong , Wang Xiaqing , Qiao Feng , Xiao Yingjie , Zan Yanjun , Yan Jianbing
Published: January 2022

Phenotypic plasticity is the property of a given genotype to produce multiple phenotypes in response to changing environmental conditions. Understanding the genetic basis of phenotypic plasticity and establishing a predictive model is highly relevant for future agriculture under changing climate. Here, we report findings on the genetic basis of phenotypic plasticity for 23 complex traits using a maize diverse population, planted at five sites with distinct environmental conditions and genotyped with ~ 6.60 million SNPs. We found that altitude-related environmental factors were main drivers for across site variation in flowering time traits but not plant architecture and yield traits. For 23 traits, we detected 109 QTLs, of which 29 was for mean, 66 was for plasticity, and 14 for both parameters, besides, 80% of the QTLs were interreacted with the environment. The effects of several QTLs changed in magnitude or sign, driving variation in phenotype plasticity, and we further experimentally validated one plastic gene ZmTPS14.1 whose effect was likely mediated by the compensation effect of ZmSPL6 which was from the downstream pathway probably. By integrating genetic diversity, environmental variation, and their interaction in a joint model, we could provide site-specific predictions with increased accuracy by as much as 15.5%, 3.8%, and 4.4% for DTT, PH, and EW, respectively. Overall, we revealed a complex genetic architecture involving multiallelic, pleiotropy, and genotype by environment interaction underlying maize complex trait mean and plasticity variation. Our study thus provided novel insights into the dynamic genetic architectures of agronomic traits in response to changing environments, paving a practical route to precision agriculture.
Understanding the development of oral epithelial organs through single cell transcriptomic analysis
Authors: Ye Qianlin , Bhojwani Arshia , Hu Jimmy K.
Published: January 2022

During vertebrate craniofacial development, the oral epithelium begins as a simple and morphologically homogeneous tissue. It then gives rise to locally complex structures, including the developing teeth, salivary glands, and taste buds. While there is significant knowledge about the molecular mechanisms regulating the morphogenesis of these organs at later stages, how the epithelium is initially patterned and specified to generate diverse cell types and organs remains largely unknown. To elucidate the genetic programs that direct the formation of distinct oral epithelial populations, we mapped the transcriptional landscape of embryonic day (E) 12 mouse mandibular epithelia at single cell resolution. Our analysis identified key transcription factors and gene regulatory networks that define different epithelial cell types as well as regions patterned along the oral-aboral axis. By examining the spatiotemporal expression of region-specific markers in embryonic mandibles, our results pointed to a model where the dental field is progressively confined to its position by the formation of the aboral epithelium anteriorly and the non-dental oral epithelium posteriorly. Using our data, we also identifiedNtrk2as a promoter of cell proliferation in the forming incisor, contributing to its invagination. Together, our results provide a detailed transcriptional atlas of the developing mandibular epithelium and unveil new genetic markers and regulators that are present during the specification of various oral epithelial structures.
Development of a core outcome set on traditional Chinese medicine (COS-TCM) for rheumatic heart disease (RHD): study protocol
Authors: Sheng Xiaodi , Chen Chao , Ji Zhaochen , Hu Haiyin , Zhang Mingyan , Wang Hui , Pang Bo , Zhang Dong , Zhang Junhua , Guo Liping
Published: January 2022

Introduction

Rheumatic heart disease (RHD) is an important cause of acquired heart disease in children and adolescents globally. Clinical trials on RHD treatment with traditional Chinese medicine (TCM) are gradually increasing in China. However, because clinical trials are heterogeneous and report outcomes selectively, similar studies cannot be merged and compared, complicating assessing the effectiveness and safety of TCM, diminishes the value of clinical trials, and results in a waste of research resources. Therefore, there is an urgent need to develop a core outcome set of traditional Chinese medicine for rheumatic heart disease (COS-TCM-RHD). This study will report the protocol development process for COS-TCM-RHD.

Methods and analysis

A multidisciplinary Steering Committee will lead the development of this protocol through four stages (1). Establishing a comprehensive and systematic outcomes checklist through a systematic review of previously published research, retrieval of clinical trial registration centers, patient’s semi-structured interviews, and clinician’s questionnaire surveys; (2). Screen stakeholder groups from various fields to participate in the Delphi survey; (3). Two rounds of e-Delphi surveys will be conducted to determine the outcomes of various concerned stakeholder groups; (4). Hold a face-to-face consensus meeting to develop the COS-TCM-RHD.

Ethics and dissemination

Ethical approval has been granted by the Tianjin university of Traditional Chinese Medicine Ethics Committee. The findings will be published in peer-reviewed journals and the website of Chinese Clinical Trials for Core Outcome Set.

Trial registration

This study protocol has been prospectively registered with the Core Outcome Measures in Effectiveness Trials (COMET):

http://www.comet-initiative.org/Studies/Details/1743.

Strengths and limitations of this study

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This protocol is the first core outcomes set registered on the Core Outcome Measures in Effectiveness Trials (COMET) website for the treatment of rheumatic heart disease by Traditional Chinese medicine.

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This study is guided by the Core Outcome Set-STAndards for Development and Core Outcome Set-Standardized Protocol Items, with recommendations of the COMET.

▪

A multidisciplinary Steering Committee will supervise this research, and stakeholders from different fields including clinicians, patients, methodologists, and COS developers will be engaged.

▪

Systematic reviews, qualitative research (patient’s semi-structured interviews and clinician’s questionnaire surveys), Delphi surveys, and consensus meetings will be used for core outcome set development.

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Traditional Chinese medicine is mainly used in China. Thus, the geographical distribution of stakeholders will be a limitation.
One vaccine to counter many diseases? Modelling the economics of oral polio vaccine against child mortality and COVID-19
Authors: Chang Angela Y. , Aaby Peter , Avidan Michael S. , Benn Christine S. , Bertozzi Stefano M. , Blatt Lawrence , Chumakov Konstantin , Khader Shabaana A. , Kottilil Shyam , Nekkar Madhav , Netea Mihai G. , Sparrow Annie , Jamison Dean T.
Published: January 2022

Background

Recent reviews summarize evidence that some vaccines have heterologous or non-specific effects (NSE), potentially offering protection against multiple pathogens. Numerous economic evaluations examine vaccines’ pathogen-specific effects, but we have found only two economic evaluations of NSE. This paper starts to fill this gap by reporting economic evaluations of the NSE of oral polio vaccine (OPV) against under-five mortality and COVID-19.

Methods

We studied two settings: (1) reducing child mortality in a high-mortality setting (Guinea-Bissau) and (2) preventing COVID-19 in India. In the former, the intervention involves three annual campaigns in which children receive OPV incremental to routine immunization. In the latter, a susceptible-exposed-infectious-recovered model was developed to estimate the population benefits of two scenarios, in which OPV would be co-administered alongside COVID-19 vaccines. Incremental cost-effectiveness and benefit-cost ratios were modelled for ranges of intervention effectiveness estimates to supplement the headline numbers and account for heterogeneity and uncertainty.

Results

For child mortality, headline cost-effectiveness was $650 per child death averted. For COVID-19, assuming OPV had 20% effectiveness, incremental cost per death averted was $23,000-65,000 if it were administered simultaneously with a COVID-19 vaccine less than 200 days into a wave of the epidemic. If the COVID-19 vaccine availability were delayed, the cost per averted death would decrease to $2600-6100. Estimated benefit-to-cost ratios vary but are consistently high.

Conclusion

Economic evaluation suggests the potential of OPV to efficiently reduce child mortality in high mortality environments. Likewise, within a broad range of assumed effect sizes OPV could play an economically attractive role against COVID-19.
Whole-exome Sequencing Study of Hypospadias
Authors: Chen Zhongzhong , Lei Yunping , Finnell Richard H. , Su Zhixi , Wang Yaping , Xie Hua , Chen Fang
Published: January 2022

While hypospadias is one of the most common male congenital disorders, the missing heritability contributed by rare variants with larger effects is poorly understood. To systematically explore the variant patterns in the developing of hypospadias, we performed whole exome sequencing (WES) in 191 severe hypospadias cohort and three trios. Subsequent RNA sequencing of 12 severe hypospadiac foreskins and 6 non-hypospadiac foreskins were conducted. Among previous reported hypospadias risk associated genes, we found thatNR5A1, SRD5A2andARgenes are mutational hotspots in the etiology of severe hypospadias. Additionally, rare damaging variants in novel identified outer dynein arm heavy chain (ODNAH) genes (DNAH5, DNAH8, DNAH9, DNAH11, andDNAH17) (p= 4.8×10−17) were significantly enriched in 191 sporadic severe hypospadias compared with 208 controls. The following transcriptomic analysis further demonstrated that the mutations in theDNAH8andDNAH17genes might affect the network regulation of testosterone (T)-dihydrotestosterone-androgen receptor (T-DHT-AR) signaling. We also identified a novel rare damaging variant ofDNAH8in a severe hypospadias case which was transmitted from the mother. Overall, a panel ofODNAHgenes with rare damaging variants were identified in 22.5% of severe hypospadias patients. This study provides unequivocal evidence for association ofODNAHgenes and hypospadias. This knowledge may guide the genetic counseling for hypospadias.

One Sentence Summary

Rare damaging variants in outer DNAH genes were identified in 22.5% of severe hypospadias patients, which may guide the genetic counseling of families facing familial hypospadias.
Joinpoint Regression to Determine the Impact of COVID-19 on Mortality in Europe: A Longitudinal Analysis From 2000 to 2020 in 27 Countries
Authors: Rovetta Alessandro
Published: January 2022

The novel coronavirus disease 2019 (COVID-19) represented the most extensive health emergency in human history. However, to date, there is still a lot of uncertainty about the exact death toll the pandemic has claimed. In particular, the number of official deaths could be vastly underestimated. Despite this, many conspirationists speculate that COVID-19 is not a dangerous disease. Therefore, in this manuscript, we use joinpoint regression analysis to estimate the impact of COVID-19 in 27 European countries by comparing annual mortality trends from 2000 to 2020. Furthermore, we provide accessible evidence even for a non-expert audience. Siegel (A1) and Holm-Bonferroni (A2) approaches were employed to assess the significance of the results separately. In conclusion, these results estimate that COVID-19 increased the overall mortality in Europe by 10% (A1: P < .001, A2: Adjusted P = .001). In 16 out of 27 countries (59.3%), the excess mortality ranged from 7.4% to 18.5% (A1: P < .003, A2: Adjusted P < .040). Comparison of the excess mortalities’ distribution to the null counterfactual showed that the mortality increase was highly significant across Europe (Adjusted P < .001).
High Hedgehog signaling is transduced by a multikinase-dependent switch controling the apico-basal distribution of the GPCR Smoothened
Authors: Gonçalves-Antunes Marina , Sanial Matthieu , Contremoulins Vincent , Carvalho Sandra , Plessis Anne , Bécam et Isabelle
Published: January 2022

The oncogenic GPCR Smoothened is a key transducer of the Hedgehog morphogen, which plays essential roles in the patterning of epithelial structures. Here, we examine how Hedgehog controls Smoothened subcellular localization and activity in a polarized epithelium using the Drosophila wing imaginal disc as a model. We provide evidence that Hedgehog promotes the stabilization of Smoothened by switching its fate after endocytosis toward recycling. This effect involves the sequential and additive action of Protein Kinase A, Casein Kinase I and the Fused kinase. Moreover, in the presence of very high levels of Hedgehog, a second effect of Fused leads to the local enrichment of Smoothened in the most basal domain of the cell membrane. Together, these results link the morphogenetic effects of Hedgehog to the apico-basal distribution of Smoothened and provide a novel mechanism for regulation of a GPCR by plasma membrane subcompartimentalisation.
Alternative splicing changes are associated with pre-birth adaptation during lung development
Authors: Fidalgo Marta F. , Fonseca Catarina G. , Caldas Paulo , Raposo Alexandre A. S. F. , Balboni Tania , Grosso Ana R. , Vasconcelos Francisca F. , Franco Cláudio A.
Published: January 2022

Gas exchanges are ensured by lung alveoli, which are mainly composed by epithelial alveolar type 1 (AT1), alveolar type 2 (AT2) and capillary endothelial cells (ECs). Alveologenesis starts during late embryonic development and continues after birth and relies on extensive biochemical crosstalk between these cell types. How this crosstalk is modulated to anticipate and accommodate the radical changes occurring at birth is still unclear.

We investigated the alternative splicing (AS) changes occurring during lung development at the embryonic to postnatal transition by performing RNAseq of mouse lungs at distinct developmental stages. We found that most of the AS changes occur at the embryonic to postnatal transition. In addition, we identified hnRNP A1, Cpeb4 and Elavl2/HuB as putative splicing regulators of this transition. We show that the AS of a major pro- angiogenic chemokine, vascular endothelial growth factor A (VEGFA), is differentially regulated at this transition. Remarkably, we found that there is a switch from the predominance of Vegfa 164 to Vegfa 188 just before birth specifically in AT1 cells, whilst in other cell populations Vegfa does not undergo AS changes. Moreover, we identified a novel Vegfa isoform generated by the retention of intron 5, Vegfa i5.

Our results reveal a cell type-specific regulation of Vegfa AS that may constitute a pre- birth adaptation mechanism of the epithelial-endothelial crosstalk, which may be fundamental for the adaptation to breathing and may have implications for pathological conditions.
Lysosomes are Required for Early Dorsal Signaling in theXenopusEmbryo
Authors: Tejeda-Muñoz Nydia , De Robertis Edward M.
Published: January 2022

Lysosomes are the digestive center of the cell and play important roles in human disease, including cancer. Previous work has suggested that late endosomes, also known as multivesicular bodies (MVBs), and lysosomes are essential for canonical Wnt pathway signaling. Sequestration of Glycogen Synthase 3 (GSK3) and of β□catenin destruction complex components in MVBs is required for sustained canonical Wnt signaling. Little is known about the role of lysosomes during early development. In theXenopusegg, a Wnt-like cytoplasmic determinant signal initiates formation of the body axis following a cortical rotation triggered by sperm entry. Here we report that cathepsin D was activated in lysosomes specifically on the dorsal marginal zone of the embryo at 64-cell stage, long before zygotic transcription starts. Expansion of the multivesicular body (MVB) compartment with low-dose Hydroxychloroquine (HCQ) greatly potentiated the dorsalizing effects of the Wnt agonist Lithium chloride (LiCl) in embryos, and this effect required macropinocytosis. Formation of the dorsal axis required lysosomes, as indicated by brief treatments with the vacuolar ATPase (V-ATPase) Bafilomycin A1 inhibitor at the 32-cell stage. Inhibiting the MVB-forming machinery with a dominant-negative point mutation in Vacuolar Protein Sorting 4 (Vps4-EQ) also interfered with the endogenous dorsal axis. The Wnt-like activity of the dorsal cytoplasmic determinant Huluwa (Hwa), and that of microinjected xWnt8 mRNA, also required lysosome acidification and the MVB-forming machinery. We conclude that lysosome function is essential for early dorsal axis development inXenopus. The results highlight the intertwining between membrane trafficking, lysosomes, and vertebrate axis formation.

Significance

The dorsal axis of the vertebrate Xenopus embryo is established by an early Wnt signal generated by a rotation of the cortex of the egg towards the opposite side of the sperm entry point. In this study, we report that lysosomal Cathepsin D becomes activated on the dorsal marginal zone of the embryo already at the 64-cell stage, and that this asymmetry is enhanced by increasing Wnt signaling levels. We present experiments showing that lysosome activity, macropinocytosis, and multivesicular body formation are required for the dorsal signal provided maternally in the egg, and for twinning by microinjectedhuluwaandWnt8mRNA. The results indicate that the cell biology of lysosomes plays a fundamental role in vertebrate development.
Overlapping transcriptional programs promote survival and axonal regeneration of injured retinal ganglion cells
Authors: Jacobi Anne , Tran Nicholas M , Yan Wenjun , Benhar Inbal , Tian Feng , Schaffer Rebecca , He Zhigang , Sanes Joshua
Published: January 2022

Injured neurons in the adult mammalian central nervous system often die and seldom regenerate axons. To uncover transcriptional pathways that could ameliorate these disappointing responses we analyzed three interventions that increase survival and regeneration of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC) injury, albeit not to a clinically useful extent. We assessed gene expression in each of 46 RGC types by single cell transcriptomics following ONC and treatment. We also compared RGCs that regenerated to those that survived but did not regenerate. Each intervention enhanced survival of most RGC types, but type-independent axon regeneration required manipulation of multiple pathways. Distinct computational methods converged on separate sets of genes selectively expressed by RGCs likely to be dying, surviving, or regenerating. Overexpression of genes associated with the regeneration program enhanced axon regeneration in vivo, indicating that mechanistic analysis can be used to identify novel methods for promoting regeneration of injured neurons.
Cell atlas of the human ocular anterior segment: Tissue-specific and shared cell types
Authors: van Zyl Tavé , Yan Wenjun , McAdams Alexi , Monavarfeshani Aboozar , Hageman Gregory S. , Sanes Joshua R.
Published: January 2022

The anterior segment of the eye consists of the cornea, iris, ciliary body, crystalline lens and aqueous humor outflow pathways. Together, these tissues are essential for the proper functioning of the eye. Disorders of vision have been ascribed to defects in all of them; some, including glaucoma and cataract, are among the most prevalent causes of blindness in the world. To characterize the cell types that comprise these tissues, we generated an anterior segment cell atlas of the human eye using high throughput single-nucleus RNA sequencing (snRNAseq). We profiled 191,992 nuclei from non-diseased anterior segment tissues from 6 human donors, identifying >60 cell types. Many of these cell types were discrete, whereas others, especially in lens and cornea, formed continua corresponding to known developmental transitions that persist in adulthood. Having profiled each tissue separately, we performed an integrated analysis of the entire anterior segment revealing that some cell types are unique to single structure whereas others are shared across tissues. The integrated cell atlas was then used to investigate cell type-specific expression patterns of more than 900 human ocular disease genes identified either through Mendelian inheritance patterns or genome-wide association studies (GWAS).

SIGNIFICANCE STATEMENT

Several of the most prevalent blinding ocular conditions worldwide, including glaucoma, cataract and uncorrected refractive error, involve structures of the anterior segment of the human eye, which consists of the cornea, iris, ciliary body, crystalline lens and aqueous humor outflow pathways. In addition to providing transcriptomic profiles of the cell types within individual tissues, this work contributes to our understanding of the relatedness and diversity of these cell types across contiguous tissues by generating an integrated anterior segment cell atlas and documenting the expression of over 900 disease-associated genes in each cell type. By allowing simultaneous interrogation of cell-type specific expression of genes across multiple tissues, the atlas may yield broad insight into normal and disease-associated anterior segment functions.
Computation of Antigenicity Predicts SARS-CoV-2 Vaccine Breakthrough Variants
Authors: Hu Ye-fan , Hu Jing-chu , Gong Hua-rui , Danchin Antoine , Sun Ren , Chu Hin , Hung Ivan Fan-Ngai , Yuen Kwok Yung , To Kelvin Kai-Wang , Zhang Bao-zhong , Yau Thomas , Huang Jian-Dong
Published: January 2022

It has been reported that multiple SARS-CoV-2 variants of concerns (VOCs) including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) can reduce neutralisation by antibodies, resulting in vaccine breakthrough infections. Virus-antiserum neutralisation assays are typically performed to monitor potential vaccine breakthrough strains. However, such experimental-based methods are slow and cannot instantly validate whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone and in real time. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralisation titres. Based on this correlation, we obtained a computational model for the receptor binding domain (RBD) of the spike protein to predict the fold decrease in virus-antiserum neutralisation titres with high accuracy (~0.79). Our predicted results were comparable with experimental neutralisation titres of variants, including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), B.1.429 (Epsilon), P.1 (Gamma), B.1.526 (Iota), B.1.617.1 (Kappa), and C.37 (Lambda), as well as SARS-CoV. Here, we firstly predicted the fold of decrease of B.1.1.529 (Omicron) as 17.4-fold less susceptible to neutralisation. We visualised all 1521 SARS-CoV-2 lineages to indicate variants including B.1.621 (Mu), B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed athttp://jdlab.online.
Pathogenicity of SARS-CoV-2 Omicron in Syrian hamsters and its neutralization with different Variants of Concern
Authors: Mohandas Sreelekshmy , Yadav Pragya D. , Sapkal Gajanan , Shete Anita M. , Deshpande Gururaj , Nyayanit Dimpal A. , Patil Deepak , Kadam Manoj , Kumar Abhimanyu , Mote Chandrashekhar , Jain Rajlaxmi
Published: January 2022

SARS-CoV-2 Omicron variant is rampantly spreading across the globe. Animal models are useful in understanding the disease characteristics as well as properties of emerging SARS-CoV-2 variants. We assessed the pathogenicity and immune response generated by BA.1 sub-lineage of SARS-CoV-2 Omicron variant with R346K mutation in 5 to 6-week old Syrian hamsters. Virus shedding, organ viral load, lung disease and immune response generated were sequentially assessed. The disease characteristics of Omicron were found to be similar to that of other SARS-CoV-2 variants of concerns in hamsters like high viral replication in the respiratory tract and interstitial pneumonia. The infected hamsters demonstrated lesser body weight gain in comparison to the uninfected control hamsters. Viral RNA could be detected in nasal washes and respiratory organs (nasal turbinate, trachea, bronchi and lungs) till 10 and 14 days respectively. The clearance of the virus was observed from nasal washes and lungs by day 7. Neutralizing antibody response against Omicron variant was detected from day 5 with rising antibody titers till 14 days. However, the cross-neutralization titre of the sera against other variants showed severe reduction ie., 7 fold reduction against Alpha and no titers against B.1, Beta and Delta. This preliminary data shows that Omicron variant infection can produce moderate to severe lung disease and the neutralizing antibodies produced in response to Omicron variant infection shows poor neutralizing ability against other co-circulating SARS-CoV-2 variants like Delta which necessitates caution as it may lead to increased cases of reinfection.
Neurodevelopmental oscillatory basis of speech processing in noise
Authors: Bertels Julie , Niesen Maxime , Destoky Florian , Coolen Tim , Ghinst Marc Vander , Wens Vincent , Rovai Antonin , Trotta Nicola , Baart Martijn , Molinaro Nicola , Tiège Xavier De , Bourguignon Mathieu
Published: January 2022

Humans’ extraordinary ability to understand speech in noise relies on multiple processes that develop with age. Using magnetoencephalography (MEG), we characterize the underlying neuromaturational basis by quantifying how cortical oscillations in 144 participants (aged 5 to 27 years) track phrasal and syllabic structures in connected speech mixed with different types of noise. While the extraction of prosodic cues from clear speech was stable during development, its maintenance in a multi-talker background matured rapidly up to age 9 and was associated with speech comprehension. Furthermore, while the extraction of subtler information provided by syllables matured at age 9, its maintenance in noisy backgrounds progressively matured until adulthood. Altogether, these results highlight distinct behaviorally relevant maturational trajectories for the neuronal signatures of speech perception. In accordance with grain-size proposals, neuromaturational milestones are reached increasingly late for linguistic units of decreasing size, with further delays incurred by noise.

Teaser

The neural signature of speech processing in silence and noise features multiple behaviorally relevant developmental milestones
A molecular dynamics study of antimicrobial peptide translocation across the outer membrane of Gram-negative bacteria
Authors: Sharma Pradyumn , Ganapathy Ayappa K.
Published: January 2022

With rising bacterial resistance, antimicrobial peptides (AMPs) have been widely investigated as potential antibacterial molecules to replace conventional antibiotics. Our understanding of the molecular mechanism for membrane disruption are largely based on AMP interactions with the inner phospholipid bilayers of both Gram-negative and Grampositive bacteria. Mechanisms for AMP translocation across the outer membrane of Gram-negative bacteria composed of lipopolysaccharides and the asymmetric lipid bilayer are incompletely understood. In the current study, we have employed atomistic molecular dynamics and umbrella sampling simulations with an aggregate duration of ~ 8 microseconds to understand the free energy landscape of CM15 peptide within the OM of Gram-negative bacteria, E. coli. The peptide has a favourable binding free energy (−130 kJ mol−1) in the O-antigen region with a large barrier (150 kJ mol−1) at the interface between the anionic coresaccharides and upper bilayer leaflet made up of lipid A molecules. We have analyzed the peptide and membrane properties at each of the 100 ns duration umbrella sampling windows to study variations in the membrane and the peptide structure during the translocation through the OM. Interestingly the peptide is seen to elongate, adopting a membrane perpendicular orientation in the phospholipid region resulting in the formation of a transient water channel during it’s translocation through the bilayer. The presence of the peptide at the lipid A and core-saccharide interface results in a 11% increase in the membrane area with the peptide adopting a predominantly membrane parallel orientation in this cation rich region. Additionally, the lateral displacement of the peptide is significantly reduced in this region, and increases toward the inner phospholipid leaflet and the outer O-antigen regions of the membrane. The peptide is found to be sufficiently hydrated across both the hydrophilic as well as hydrophobic regions of the membrane and remains unstructured without any gain in helical content. Our study unravels the complex free energy landscape for the translocation of the AMP CM15 across the outer membrane of Gram-negative bacteria and we discuss the implications of our findings with the broader question of how AMPs overcome this barrier during antimicrobial activity.
Microtubule-Inspired Functionalization of Carbon Nanotubes: A Biomimetic Carrier Design
Authors: de Almeida Barcelos Karina , Alisaraie Laleh
Published: January 2022

We propose a bioinspired, non-covalent carbon nanotubes (CNTs) functionalization strategy to augment their bioavailability and alleviate their biotoxicity. For functionalization, select amphiphilic peptides from a cytoskeletal biopolymer, microtubule (MT), were used. The peptides are involved in the MT polymerization by maintaining the essential lateral interactions among the MT’s α- and β-tubulin subunits. They also participate in forming the MT-binding sites for hosting several MT-targeting antimitotics. Utilizing in silico methods, this study showed the peptides influenced CNT’s diffusivity and aqueous solubility. The hydrodynamic shield formed by the peptides from β-tubulin was more widespread on the CNT than the α-tubulin peptides’; however, the latter created a broader hydrophobic CNT coating than those from the β-tubulin. In particular, the peptides consisting of the H1-B2, H10, H1-B2, and the M-loop, demonstrated structural features that serve to augment CNTs’ water solubility and dispersibility. The performance of the peptide-functionalized CNTs as drug carriers was examined by studying seventeen antimitotics. The CNT-peptides structural composition was identified as a suitable carrier for phomopsin A, laulimalide, epothilone A, epothilone D, discodermolide, eribulin, and docetaxel. The peptides played dual roles displaying affinities to the antimitotics and the CNT; in particular, the peptides from the H1-B2 and H2-B3 loops of β-tubulin exhibited exceptional binding properties. Specific mutations on the wildtype peptides, including those from the α-tubulin M-loop and H2-B3, or the β-tubulin H1-B2, are proposed to refine their hydrophobicity, eliminate unfavorable inter-peptides electrostatic interactions or the spatial hindrance at certain regions, to enhance their conformational steadiness and exposure to the tube surface. A combination of the select amphiphilic peptides from both tubulin subunits is suggested to improve CNTs bioavailability and efficiency for carrying insoluble hydrophobic cargos.
Phase transitions and (p–T–X) behaviour of centrosymmetric perovskites: modelling with transformed crystallographic data
Authors: Thomas Noel W.
Published: January 2022

A reversible transformation of the unit-cell parameters and atomic coordinates of centrosymmetric perovskites ABX
3 into a Cartesian space is defined. Analytical expressions for the three vectors for the pseudocubic cell and three vectors for a BX
6 octahedron are derived for space groups Pbmn, Cmcm, Ibmm, P4/mbm, P4/nmc, I4/mcm and R
3
c. The following structural parameters may be derived from these vectors: up to six pseudocubic parameters defining octahedral geometry; length- and angle-based octahedral distortion parameters λ and σ; inclination angles of tilted octahedra, θ1, θ2 and θ3; angles of tilt of octahedra; AX
12:BX
6 polyhedral volume ratio, V

A
/V

B
; parameters η
A
and η
B
defining the relative contraction of inner AX
8 polyhedra and expansion of BX
6 octahedra due to octahedral tilting. The application of these parameters is demonstrated by reference to published crystal structures. The variation of η
A
and η
B
with temperature in the compositional series Sr
x
Ba1–x
SnO3 and Sr
x
Ba1–x
HfO3, as well as the temperature series of BaPbO3 and CaTiO3, is related to the sequence of phases Pbmn → Ibmm→ Pm
3
m. Stabilization of the Cmcm phase is likewise interpreted in terms of these two parameters for NaTaO3 and NaNbO3. The pressure evolution of the structures of MgSiO3, YAlO3, (La1–x
Nd
x
)GaO3 (0 ≤ x ≤ 1) and YAl0.25Cr0.75O3 is modelled with the appropriate structural parameters, thereby also addressing the characteristics of the Pbmn → R
3
c transition. Simulation of MgSiO3 up to 125 GPa and of YAlO3 up to 52 GPa in space group Pbnm is carried out by using the Birch–Murnaghan equation of state. In both cases, full sets of oxygen coordinates assuming regular octahedra are generated. Octahedral distortion is also modelled in the latter system and predicted to have a key influence on structural evolution and the sequence of phase transitions. The core modelling procedures are made available as a Microsoft Excel file.