bluuebunny/crossref_metadata_2025 huggingface dataset:
Capturing the distribution as it shifts: chile pepper (Capsicum annuumL.) domestication gradient meets geography
Authors: Martínez-Ainsworth NE , Scheppler H , Moreno-Letelier A , Bernau V , Kantar MB , Mercer KL , Jardón-Barbolla L
Published: December 2022

Aim

Domestication is an ongoing well-described process. However, while many have studied the changes domestication causes in the genetic landscape, few have explored the way domestication changes the geographic landscape in which the plants exist. Therefore, the goal of this study was to understand how the domestication status changed the suitable geographic space of chile pepper in its center of origin.

Methods

Capsicum annuumis a major crop species globally whose domestication center, Mexico, has been well studied. This provides a unique opportunity to explore the degree to which ranges of different domestication classes diverged and how these ranges might be altered by climate change. To this end, we created ecological niche models for four domestication classes (wild, semiwild, landrace, modern cultivar) based on present climate and future climate scenarios for 2050, 2070, and 2090.

Results

Considering present environment, we found substantial overlap in the geographic niches of all the domestication gradient categories. Yet, there were also clear unique environmental and geographic aspects to the current ranges. Wild and commercial varieties were at ease in desert conditions as opposed to landraces. With projections into the future, habitat was lost asymmetrically, with wild, semiwild and landraces at far greater risk than modern cultivars. Further, we identified areas where future suitability overlap between landraces and wilds is expected to decouple.

Main conclusions

While range expansion is widely associated with domestication, there is little support of a constant niche expansion (either in environmental or geographical space) throughout the domestication gradient. However, a shift to higher altitudes with cooler climate was identified for landraces. The clear differences in environmental adaptation, such as higher mean diurnal range and precipitation seasonality along the domestication gradient classes and their future potential range shifts show the need to increase conservation efforts, particularly to preserve landraces and semiwild genotypes.
Administration of amniotic fluid stem cell extracellular vesicles promotes development of fetal hypoplastic lungs by immunomodulating lung macrophages
Authors: Antounians Lina , Figueira Rebeca Lopes , Kukreja Bharti , Zani-Ruttenstock Elke , Khalaj Kasra , Montalva Louise , Doktor Fabian , Obed Mikal , Blundell Matisse , Wu Taiyi , Chan Cadia , Wagner Richard , Lacher Martin , Wilson Michael D. , Kalish Brian T. , Zani Augusto
Published: December 2022

Congenital diaphragmatic hernia (CDH) is a devastating condition characterized by incomplete closure of the diaphragm and herniation of abdominal organs into the chest. As a result, fetuses have pulmonary hypoplasia, whose severity is the main determinant of poor outcome. The pathogenesis of pulmonary hypoplasia secondary to CDH is at least in part explained by lack or dysregulation of miRNAs that are known to regulate lung developmental processes. Herein, we report that intra-amniotic administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs) rescues lung growth and maturation in a fetal rat model of CDH. To understand which fetal lung cells and biological pathways are affected by AFSC-EVs, we conducted whole lung single nucleus RNA-sequencing. We discovered that CDH lungs have a multilineage inflammatory signature with macrophage enrichment, and confirmed these findings in autopsy samples of lungs from human fetuses with CDH. Transcriptomic analysis of CDH fetal rat lungs also showed that AFSC-EV treatment reduced macrophage density and inflammation to normal levels. Analyzing the miRNAs contained in the AFSC-EV cargo with validated mRNA targets, we found that the downregulated genes in AFSC-EV treated CDH lungs were involved in inflammatory response and immune system processes. This study reports a single cell atlas of normal and hypoplastic CDH fetal rat lungs and provides evidence that AFSC-EVs restore lung development by addressing multiple pathophysiological aspects of CDH.

One Sentence Summary

Amniotic fluid stem cell extracellular vesicle treatment for fetal lung macrophage modulation
DEFECTIVE KERNEL1 (DEK1) regulates cellulose synthesis and affects primary cell wall mechanics
Authors: Novaković Lazar , Yakubov Gleb E. , Ma Yingxuan , Bacic Antony , Blank Kerstin G. , Sampathkumar Arun , Johnson Kim L.
Published: December 2022

The cell wall is one of the defining features of plants, controlling cell shape, regulating growth dynamics and hydraulic conductivity, as well as mediating plants interactions with both the external and internal environments. Here we report that a putative mechanosensitive Cys-protease DEFECTIVE KERNEL1 (DEK1) interacts with cell wall integrity (CWI) pathways and regulation of cellulose synthesis. Our results indicate that DEK1 is an important regulator of cellulose synthesis in epidermal tissue ofArabidopsis thalianacotyledons during early post-embryonic development. DEK1 is involved in regulation of cellulose synthase complexes (CSCs) by modifying their biosynthetic properties, possibly through interactions with various cellulose synthase regulatory proteins. Mechanical properties of the primary cell wall are altered inDEK1modulated lines supporting a role in maintenance of CWI. DEK1 affects stiffness of the cell wall and thickness of the cellulose microfibrils bundles in epidermal cell walls of cotyledons.
ACR TI-RADS®SCORE ULTRASOUND – PICTORIAL ESSAY OF ULTRASOUND / ELASTOSONOGRAPHY / ANATOMY / CYTOLOGY and HISTOLOGY
Authors: Andrade Luís Jesuíno De Oliveira , De Oliveira Luis Matos , Vinhaes Bittencourt Alcina Maria , De Carvalho Lourenço Letícia Góes , Matos De Oliveira Gabriela Correia
Published: December 2022

Introduction

Thyroid Imaging Reporting and Data System (TI-RADS®) is a system for classifying thyroid nodules detected at ultrasonography, aiming at a descriptive standardization as well as to classify their risk of malignancy based on sonographic findings.

Aium

To present a pictorial essay by composing anatomical, histological, ultrasound and elastography images of the TI-RADS®score.

Method

Using software for image composition, based on the ultrasound image of the various types of thyroid nodules, we adapt to the anatomical image, the elastosonography, and histological corresponding TI-RADS®and present a pictorial essay.

Results

The correlation between the sonographic, elastography, anatomical, cytology and histological images corresponding to the TI-RADS®score are demonstrated.

Conclusion

Ultrasonographic features, elastosonography, anatomical, and histological in evaluation of thyroid nodules can correlate with features TI-RADS® score.
Massively parallel characterization of insulator activity across the genome
Authors: Hong Clarice KY , Erickson Alyssa A , Li Jie , Federico Arnold J , Cohen Barak A
Published: December 2022

Insulators arecis-regulatory sequences (CRSs) that can block enhancers from activating target promoters or act as barriers to block the spread of heterochromatin. Their name derives from their ability to ‘insulate’ transgenes from genomic position effects, an important function in gene therapy and biotechnology applications that require high levels of sustained transgene expression. In theory, flanking transgenes with insulators protects them from position effects, but in practice, efforts to insulate transgenes meet with mixed success because the contextual requirements for insulator function in the genome are not well understood. A key question is whether insulators are modular elements that can function anywhere in the genome or whether they are adapted to function only in certain genomic locations. To distinguish between these two possibilities we developed MPIRE (MassivelyParallel IntegratedRegulatoryElements) and used it to measure the effects of three insulators (A2, cHS4, ALOXE3) and their mutants at thousands of locations across the genome. Our results show that each insulator functions in only a small number of genomic locations, and that insulator function depends on the sequence motifs that comprise each insulator. All three insulators can block enhancers in the genome, but specificity arises because each insulator blocks enhancers that are bound by different sets of transcription factors. All three insulators can block enhancers in the genome, but only ALOXE3 can act as a heterochromatin barrier. We conclude that insulator function is highly context dependent and that MPIRE is a robust and systematic method for revealing the context dependencies of insulators and othercis-regulatory elements across the genome.
High SARS-CoV-2 seroprevalence in Lagos, Nigeria with robust antibody and cellular responses
Authors: Akanmu Sulaimon , Herrera Bobby Brooke , Chaplin Beth , Ogunsola Sade , Osibogun Akin , Onawoga Fatima , John-Olabode Sarah , Akase Iorhen E. , Nwosu Augustina , Hamel Donald J , Chang Charlotte A , Kanki Phyllis J
Published: December 2022

Background

Early evidence suggested that the impact of the COVID-19 pandemic was less severe in Africa compared to other parts of the world. However, more recent studies indicate higher SARS-CoV-2 infection and COVID-19 mortality rates on the continent than previously documented. Research is needed to better understand SARS-CoV-2 seroprevalence and immunity in Africa.

Methods

Our collaboration with the Lagos State COVID-19 Taskforce, enabled secondary analyses of immune responses in healthcare workers (HCWs) and Oxford/AstraZeneca COVID-19 vaccine recipients from the general population across 5 local government areas (LGAs) in Lagos State, Nigeria. Western blots were used to simultaneously detect SARS-CoV-2 spike and nucleocapsid (N) antibodies and stimulation of peripheral blood mononuclear cells with N followed by an IFN-γ ELISA was used to examine T cell responses.

Findings

Antibody data demonstrated high SARS-CoV-2 seroprevalence of 71.6% (96/134) in HCWs and 54.8% (63/115) in the general population. Antibodies directed to only SARS-CoV-2 N, suggesting pre-existing coronavirus immunity, were seen in 10.4% (14/134) of HCWs and 20.0% (23/115) of the general population. T cell data showed that IFN-γ responses against SARS-CoV-2 N were robust in detecting exposure to the virus, demonstrating 87.5% sensitivity and 92.3% specificity.

Interpretation

These results have important implications for understanding the paradoxical high SARS-CoV-2 infection with low mortality rate in Africa as compared to other parts of the world, as well as for the development of T cell-based diagnostics and vaccines.

Funding

Harvard University, Motsepe Presidential Research Accelerator Fund for Africa
Development and validation of AI-based pre-screening of large bowel biopsies
Authors: Bilal Mohsin , Tsang Yee Wah , Ali Mahmoud , Graham Simon , Hero Emily , Wahab Noorul , Dodd Katherine , Sahota Harvir , Wu Shaobin , Lu Wenqi , Jahanifar Mostafa , Robinson Andrew , Azam Ayesha , Benes Ksenija , Nimir Mohammed , Hewitt Katherine , Bhalerao Abhir , Eldaly Hesham , Ahmed Raza Shan E , Gopalakrishnan Kishore , Minhas Fayyaz , Snead David , Rajpoot Nasir
Published: December 2022

Background

Histopathological examination is a pivotal step in the diagnosis and treatment planning of many major diseases. With the aims of facilitating diagnostic decision-making and improving the use of pathologists’ time, we developed an AI-based pre-screening tool that analyses whole slide images (WSIs) of large bowel biopsies to identify normal, inflammatory, and neoplastic biopsies.

Methods

To learn the differential histological patterns from digitised WSIs of large bowel biopsy slides stained with Haematoxylin and Eosin (H&E), our proposed weakly supervised deep learning method uses only slide-level diagnostic labels and no detailed cell or region-level annotations. The proposed method was developed on an internal cohort of biopsy slides (n=5054) from a single laboratory labelled with corresponding diagnostic categories assigned by pathologists. Performance of the tool was evaluated on the internal development cohort (n=5054) in a cross-validation setting, and three external unseen cohorts (n=1536) for independent validation.

Findings

The proposed tool demonstrates high degree of accuracy to assist with the pre-screening of large bowel biopsies, being able to identify neoplastic biopsies (AUROC = 0·993), inflammatory biopsies (AUROC = 0·966) and all abnormal biopsies (AUROC = 0·979). On the three independent validation cohorts, it achieves AUROC values of 0·943, 0·958 and 0·964 for the detection of abnormal biopsies. Analysis of saliency maps confirms the representation of disease heterogeneity in model predictions and their association with relevant histological features. Interestingly, after examining diagnostic discrepancies between the proposed AI tool and original diagnostic labels, a panel of pathologists found that the proposed tool correctly identified a number of abnormal slides that had been initially reported as normal.

Interpretations

The proposed tool with its high sensitivity of detecting abnormal colorectal biopsies promises significant improvements in clinical workflow efficiency and assistance in diagnostic decision-making through pre-screening of normal biopsies.

Funding

Innovate UK on behalf of UK Research and Innovation.
Integrated fragmentomic profile and 5-Hydroxymethylcytosine of capture-based low-pass sequencing data enables pan-cancer detection via cfDNA
Authors: Zhang Zhidong , Pi Xuenan , Gao Chang , Zhang Jun , Xia Lin , Yan Xiaoqin , Hu Xinlei , Yan Ziyue , Zhang Shuxin , Wei Ailin , Guo Yuer , Liu Jingfeng , Li Ang , Liu Xiaolong , Zhang Wei , Liu Yanhui , Xie Dan
Published: December 2022

Using epigenetic markers and fragmentomics of cell-free DNA for cancer detection has been proven applicable. We further combine the two features and explore the diagnostic potential of the features on pan-cancer detection. We extracted cfDNA fragmentomic features from 191 whole-genome sequencing data and investigated them in 396 low-pass 5hmC sequencing data from four common cancer types and controls. We identified aberrant ultra-long fragments (220-500bp) of cancer samples in 5hmC sequencing data, both in size and coverage profile, and showed its dominant role in cancer prediction. Since cfDNA hydroxymethylation and fragmentomic markers can be detected simultaneously in low-pass 5hmC sequencing data, we built an integrated model including 63 features of both fragmentomic features and hydroxymethylation signatures for pan-cancer detection with high sensitivity and specificity (88.52% and 82.35%, respectively). We showed that fragmentomic information in 5hmC sequencing data is an ideal marker for cancer detection and that it shows high performance in low-pass sequencing data.
Computational modeling reveals latent components of mouse behavior in the sucrose preference test
Authors: Verharen Jeroen P H , de Jong Johannes W , Zhu Yichen , Lammel Stephan
Published: December 2022

The sucrose preference test (SPT) measures the relative preference of a sucrose solution over water to assess hedonic behaviors in rodents. The SPT involves numerous complex behaviors, including learning, motivation, and choice. Yet, it remains uncertain whether its main outcome measure, sucrose preference, can reflect these behavioral subcomponents. Here, we conducted an experimental and computational decomposition of mouse behavior in the SPT and discovered previously unrecognized behavioral subcomponents associated with changes in sucrose preference. While both acute and chronic stress reduced sucrose preference, only chronic stress evoked anhedonia. Additionally, reduced sucrose preference induced by optogenetics is not always indicative of anhedonia but can also reflect learning deficits. Even small variations in experimental conditions influence behavior, task outcome and interpretation. Thus, an ostensibly simple behavioral task can entail high levels of complexity, demonstrating the need for careful dissection of behavior into its subcomponents when studying the underlying neurobiology.
Unraveling the viral dark matter of the rumen microbiome with a new global virome database
Authors: Yan Ming , Pratama Akbar Adjie , Li Zongjun , Jiang Yu , Sullivan Matthew B. , Yu Zhongtang
Published: December 2022

Like in the human gut and other environments, viruses are probably also diverse and modulate the microbiome (both population and function) in the rumen of ruminants, but it remains largely unknown. Here we mined 975 published rumen metagenomes for viral sequences, created the first rumen virome database (RVD), and perform ecogenomic meta-analyses of these data. This identified 397,180 species-level viral operational taxonomic units (vOTUs) and allowed for a 10-fold increase in classification rate of rumen viral sequences compared with other databases. Most of the classified vOTUs belong to the orderCaudovirales, but distinct from those in the human gut. Rumen viruses likely have ecosystem impacts as they were predicted to infect dominant fiber degraders and methane producers, and they carry diverse auxiliary metabolic genes and antibiotic resistance genes. Together, the RVD database and these findings provide a baseline framework for future research on how viruses may impact the rumen ecosystem.
Impact of early insect herbivory on the invasive oak lace bug (Corythucha arcuataSay, 1832) in different oak species
Authors: Valdés-Correcher Elena , de Groot Maarten , Schillé Laura , Stemmelen Alex , Mellerin Yannick , Bonnard Olivier , Castagneyrol Bastien
Published: December 2022

Insect herbivores co-occurring on the same host plant interact in various ways. In particular, early-season insect herbivory triggers a wide range of plant responses that can determine the performance of herbivores colonizing the plant later in the course of the season. But the strength and direction of such effects are debated, and virtually unknown in the case of novel interactions involving exotic insects in their introduction range. We conducted an observational field study in SW France, a region recently invaded by the Oak Lace Bug (OLB,Corythucha arcuataSay). We measured early chewing damage and subsequent OLB damage in four oak species (Quercus robur, Q. pubescens, Q. cerrisandQ. ilex). We set up a complementary non-choice experiment in the laboratory, feeding OLB with leaves with or without prior herbivory. The four oak species differed in their sensitivity to OLB damage,Q. ilexbeing broadly resistant. Prior herbivory promoted OLB damage in the laboratory experiment, but not in the field. However, prior herbivory did not alter the rank of oak resistance to the OLB. Our results suggest possible synergistic effects between spring defoliators and the OLB. This study brings insight into herbivore-herbivore interactions and their possible implications for forest management.
Spontaneous body wall contractions stabilize the fluid microenvironment that shapes host-microbe associations
Authors: Nawroth JC , Giez C , Klimovich A , Kanso E , Bosch TCG
Published: December 2022

The freshwater polyp Hydra is a popular biological model system; however, we still do not understand one of its most salient behaviours, the generation of spontaneous body wall contractions. Here, by applying experimental fluid dynamics analysis and mathematical modelling, we provide functional evidence that spontaneous contractions of body walls enhance the transport of chemical compounds from and to the tissue surface where symbiotic bacteria reside. Experimentally, a reduction in the frequency of spontaneous body wall contractions is associated with a changed composition of the colonizing microbiota. Together, our findings suggest that spontaneous body wall contractions create an important fluid transport mechanism that (1) may shape and stabilize specific host-microbe associations and (2) create fluid microhabitats that may modulate the spatial distribution of the colonizing microbes. This mechanism may be more broadly applicable to animal-microbe interactions since research has shown that rhythmic spontaneous contractions in the gastrointestinal tracts are essential for maintaining normal microbiota.
The host phylogeny determines viral infectivity and replication acrossStaphylococcushost species
Authors: Walsh Sarah K , Imrie Ryan M , Matuszewska Marta , Paterson Gavin K , Weinert Lucy A , Hadfield Jarrod D , Buckling Angus , Longdon Ben
Published: December 2022

Genetic similarity between eukaryotic host species is an important determinant of the outcome of virus host shifts, where a pathogen infects a novel host species. However, it is less clear if this is the case for prokaryotes where anti-virus defences can be transmitted by horizontal gene transfer and evolve rapidly. Understanding the patterns and determinants of cross-species transmissions may provide insights into the processes underlying pathogen emergence. Here, we measure the susceptibility of 64 strains ofStaphylococcusbacteria (48 strains ofS. aureusand 16 non-aureusspecies) to the bacteriophage ISP, which is currently under investigation for use in phage therapy. Using three methods – plaque assays, optical density (OD) assays, and quantitative (q)PCR – we find that the host phylogeny explains a large proportion of the variation in susceptibility to ISP across the host panel. These patterns were consistent in models of onlyS. aureusstrains and models with a single representative from eachStaphylococcusspecies, suggesting that these phylogenetic effects are conserved both within and among host species. We find positive correlations between susceptibility assessed using a binary measure of plaque assay, OD, and qPCR, but not between the continuous component of plaque assay and any other method, suggesting that plaque assays alone may be inadequate to assess host range. Together, our results demonstrate the ability of bacterial host evolutionary relatedness to explain differences in susceptibility to phage infection, with implications for the development of ISP both as a phage therapy treatment and as an experimental system for the study of virus host shifts.
A small-correlation expansion to quantify information in noisy sensory systems
Authors: Mahuas Gabriel , Marre Olivier , Mora Thierry , Ferrari Ulisse
Published: December 2022

Neural networks encode information through their collective spiking activity in response to external stimuli. This population response is noisy and strongly correlated, with complex interplay between correlations induced by the stimulus, and correlations caused by shared noise. Understanding how these correlations affect information transmission has so far been limited to pairs or small groups of neurons, because the curse of dimensionality impedes the evaluation of mutual information in larger populations. Here we develop a small-correlation expansion to compute the stimulus information carried by a large population of neurons, yielding interpretable analytical expressions in terms of the neurons’ firing rates and pairwise correlations. We validate the approximation on synthetic data and demonstrate its applicability to electrophysiological recordings in the vertebrate retina, allowing us to quantify the effects of noise correlations between neurons and of memory in single neurons.
Transcription factor fluctuations underlie cell-to-cell variability in a signaling pathway response
Authors: Ramu Avinash , Cohen Barak
Published: December 2022

Stochastic differences among clonal cells can initiate cell fate decisions in development or cause cell-to-cell differences in the responses to drugs or extracellular ligands. We hypothesize that some of this phenotypic variability is caused by stochastic fluctuations in the activities of transcription factors. We tested this hypothesis in NIH3T3-CG cells using the response to Hedgehog signaling as a model cellular response. Here we present evidence for the existence of distinct fast and slow responding substates of NIH3T3-CG cells. These two substates have distinct expression profiles, and fluctuations in the activity of thePrrx1transcription factor (TF) underlie some of the differences in expression and responsiveness between fast and slow cells. We speculate that similar variability in other TFs may underlie other phenotypic differences among genetically identical cells.
Internal Normal Mode Analysis applied to RNA flexibility and conformational changes
Authors: Sabei Afra , Caldas Baia Talissa Gabriele , Saffar Raphaël , Martin Juliette , Frezza Elisa
Published: December 2022

We investigated the capability of internal normal modes to reproduce RNA dynamics and predict observed RNA conformational changes, and, notably, those induced by the formation of RNA-protein and RNA-ligand complexes. Here, we extended our iNMA approach developed for proteins to study RNA molecules using a simplified representation of RNA structure and its potential energy. Three datasets were also created to investigate different aspects. Despite all the approximations, our study shows that iNMA is a suitable method to take into account RNA flexibility and describe its conformational changes opening the route to its applicability in any integrative approach where these properties are crucial.
Pilot Study Demonstrates Benefits of Nursing Home Air Purification on COVID-19 Outcomes
Authors: Jutkowitz Eric , Shewmaker Peter , Reddy Ann , Braun Joseph M. , Baier Rosa R.
Published: December 2022

Improving indoor air quality is one potential strategy to reduce the transmission of SARS-CoV-2 in any setting, including nursing homes, where staff and residents have been disproportionately and negatively affected by the COVID-19 pandemic. We used an interrupted time series design to compare trends in weekly COVID-19 cases and deaths before and after installation of ultraviolet air purification in 84 nursing homes in Florida, Georgia, North Carolina, and South Carolina from September 31, 2020 to December 27, 2020. Compared to pre-installation, weekly COVID-19 cases per 1,000 residents (−1.69, 95%CI: -4.32, 0.95) and the weekly probability of reporting any COVID-19 case (−0.02, 95%CI: -0.04, 0.00) declined in the post-installation period. We did not find any difference pre- and post-installation in COVID-19-related mortality (0.00 95%CI: -0.01, 0.02). Our findings from this small number of nursing homes in the southern US demonstrate the potential benefits of air purification in nursing homes on COVID-19 outcomes. We recommend a stronger experimental design to estimate the causal effect of installing air purification devices like this one on improving COVID-19 outcomes in nursing homes.

Practical Implications

Improving indoor air quality is one potential strategy to reduce the burden of COVID-19 in nursing homes and nursing homes are eligible to receive Civil Monetary Penalty funding for purchases that improve air quality. Intervening on air quality may have a wide impact without placing significant burden on individuals to modify their behavior. In this pilot evaluation, we found that installing ultraviolet air purification may be an effective strategy to reduce COVID-19 cases in nursing homes. We recommend a stronger experimental design to determine the causal effect of indoor air interventions, such as air purification, on COVID-19 in this setting.
Potent Immunogenicity and Broad-Spectrum Protection Potential of Microneedle Array Patch-Based COVID-19 DNA Vaccine Candidates Encoding Dimeric RBD Chimera of SARS-CoV and SARS-CoV-2 Variants
Authors: Fan Feng , Zhang Xin , Zhang Zhiyu , Ding Yuan , Wang Limei , Xu Xin , Pan Yaying , Gong Fang-Yuan , Jiang Lin , Kang Lingyu , Kou Zhihua , Zhao Gan , Wang Bin , Gao Xiao-Ming
Published: December 2022

Breakthrough infections by SARS-CoV-2 variants pose a global challenge to pandemic control, and the development of more effective vaccines of broadspectrum protection is needed. In this study, we constructed pVAX1-based plasmids encoding heterodimeric receptor-binding domain (RBD) chimera of SARS-CoV and SARS-CoV-2 Omicron BA.1 (RBDSARS/BA1), SARS-CoV and SARS-CoV-2 Beta (RBDSARS/Beta), or Omicron BA.1 and Beta (RBDBA1/Beta) in secreted form. When i.m. injected in mice, RBDSARS/BA1and RBDSARS/Betaencoding plasmids (pAD1002 and pAD131, respectively) were by far more immunogenic than RBDBA1/Betaplasmid (pAD1003). Dissolvable microneedle array patches (MAP) laden with these DNA plasmids were fabricated. All 3 resulting MAP-based vaccine candidates, namely MAP-1002, MAP1003 and MAP-131, were comparable to i.m. inoculated plasmids with electroporation assistance in eliciting strong and durable IgG responses in BALB/c and C57BL/6 mice as well as rabbits, while MAP-1002 was comparatively the most immunogenic. More importantly, MAP-1002 significantly outperformed inactivated SARS-CoV-2 virus vaccine in inducing RBD-specific IFN-γ+T cells. Moreover, MAP-1002 antisera effectively neutralized pseudoviruses displaying spike proteins of SARS-CoV, prototype SARS-CoV-2 or Beta, Delta, Omicron BA1, BA2 and BA4/5 variants. Collectively, MAP-based DNA constructs encoding chimeric RBDs of SARS-CoV and SARS-CoV-2 variants, as represented by MAP-1002, are potential COVID-19 vaccine candidates worthy further translational study.
Assembly of 43 diverse human Y chromosomes reveals extensive complexity and variation
Authors: Hallast Pille , Ebert Peter , Loftus Mark , Yilmaz Feyza , Audano Peter A. , Logsdon Glennis A. , Bonder Marc Jan , Zhou Weichen , Höps Wolfram , Kim Kwondo , Li Chong , Hoyt Savannah J. , Dishuck Philip C. , Porubsky David , Tsetsos Fotios , Kwon Jee Young , Zhu Qihui , Munson Katherine M. , Hasenfeld Patrick , Harvey William T. , Lewis Alexandra P. , Kordosky Jennifer , Hoekzema Kendra ,   Human Genome Structural Variation Consortium (HGSVC), O’Neill Rachel J. , Korbel Jan O. , Tyler-Smith Chris , Eichler Evan E. , Shi Xinghua , Beck Christine R. , Marschall Tobias , Konkel Miriam K. , Lee Charles
Published: December 2022

The prevalence of highly repetitive sequences within the human Y chromosome has led to its incomplete assembly and systematic omission from genomic analyses. Here, we present long-readde novoassemblies of 43 diverse Y chromosomes spanning 180,000 years of human evolution, including two from deep-rooted African Y lineages, and report remarkable complexity and diversity in chromosome size and structure, in contrast with its low level of base substitution variation. The size of the Y chromosome assemblies varies extensively from 45.2 to 84.9 Mbp and include, on average, 81 kbp of novel sequence per Y chromosome. Half of the male-specific euchromatic region is subject to large inversions with a >2-fold higher recurrence rate compared to inversions in the rest of the human genome. Ampliconic sequences associated with these inversions further show differing mutation rates that are sequence context-dependent and some ampliconic genes show evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, the Yq12, is composed of alternating arrays ofDYZ1andDYZ2repeat units that show extensive variation in the number, size and distribution of these arrays, but retain a 1:1 copy number ratio of the monomer repeats, consistent with the notion that functional or evolutionary forces are acting on this chromosomal region. Finally, our data suggests that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kbp distal to the currently established boundary. The availability of sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of specific traits with Y-chromosomal variants and garnering novel insights into the evolution and function of complex regions of the human genome.
Tail-tape-fused virion and non-virion RNA polymerases of a thermophilic virus with an extremely long tail
Authors: Chaban Anastasiia , Minakhin Leonid , Goldobina Ekaterina , Bae Brain , Hao Yue , Borukhov Sergei , Putzeys Leena , Boon Maarten , Lavigne Rob , Makarova Kira S. , Koonin Eugene V. , Nair Satish K. , Tagami Shunsuke , Severinov Konstantin , Sokolova Maria L.
Published: December 2022

Thermus thermophilusbacteriophage P23-45 encodes a giant 5,002-residue tail tape measure protein (TMP)1that defines the length of its extraordinarily long 800 nm tail2,3. We found that the N-terminal portion of P23-45 TMP is an unusual RNA polymerase (RNAP) homologous to cellular and viral ‘two-barrel’ RNAPs. The TMP-fused virion RNAP transcribes pre-early phage genes, including a gene that encodes another, non-virion RNAP, that transcribes early and some middle phage genes. We determined the crystal structures of both P23-45 RNAPs. The non-virion RNAP has a crab claw-like architecture similar to previously reported two-barrel RNAPs. The virion RNAP adopts a unique flat structure without a clamp, which likely reflects the requirement for its extrusion through the narrow channel in the phage tail for delivery into the cell. Structure and sequence comparisons of the P23-45 RNAPs with other phage and cellular RNAPs suggest that, despite the extensive functional differences, the two P23-45 RNAPs originate from an ancient gene duplication in an ancestral phage. Our findings demonstrate remarkable adaptability of two-barrel RNAPs that can be attained within a single virus species.
Evidence for HARKing in mouse behavioural tests of anxiety
Authors: Rosso Marianna , Herrera Adrian , Würbel Hanno , Voelkl Bernhard
Published: December 2022

Anxiety disorders are among the most common mental health conditions needing new and better treatments. Research and development of anxiolytic drugs using animal models heavily rely on behavioural tests, most of which measure anxiolytic effects by increased exploratory activity in potentially threatening environments. However, interpretation of such tests is ambiguous because reduced exploratory activity can reflect either anxiety or sedation by the compound. Based on a systematic review of the sensitivity of mouse behavioural tests of anxiety to anxiolytic drugs, we analysed outcomes of 206 studies testing the effect of diazepam in either the open-field test or the hole-board test, as outcomes of these tests showed substantial variation in both direction and strength of the drug effect. Surprisingly, we found that both the rationale given for using the test, whether to detect anxiolytic or sedative effects, and the predicted effect of diazepam, anxiolytic or sedative, strongly depended on the reported test results. The most likely explanation for such strong dependency is post-hoc reasoning, also called hypothesizing after the results are known (HARKing). HARKing can invalidate study outcomes and hampers evidence synthesis by inflating effect sizes. It may also lead researchers into blind alleys, put patients in clinical trials at risk, and waste animals, time, and resources for inconclusive research.
Joint Multi-Ancestry and Admixed GWAS Reveals the Complex Genetics behind Human Cranial Vault Shape
Authors: Goovaerts Seppe , Hoskens Hanne , Eller Ryan J , Herrick Noah , Musolf Anthony M , Justice Cristina M , Yuan Meng , Naqvi Sahin , Lee Myoung Keun , Vandermeulen Dirk , Szabo-Rogers Heather L , Romitti Paul A , Boyadjiev Simeon A , Marazita Mary L , Shaffer John R , Shriver Mark D , Wysocka Joanna , Walsh Susan , Weinberg Seth M , Claes Peter
Published: December 2022

The cranial vault – the portion of the skull surrounding the brain and cerebellum – is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conducted a joint multi-ancestry and admixed multivariate GWAS on 3D cranial vault shape extracted from magnetic resonance images of 6,772 children from the ABCD study cohort, identifying 30 genome-wide significant genetic loci and replicating 20 of these signals in 16,947 additional individuals of the UK Biobank. This joint multi-ancestry GWAS was enriched for genetic components of cranial vault shape shared across ancestral groups and yielded a greater discovery than a European-only GWAS. We present supporting evidence for parietal versus frontal bone localization for several of the identified genes based on expression patterns in E15.5 mice. Collectively, our GWAS loci were enriched for processes related to skeletal development and showed elevated activity in cranial neural crest cells, suggesting a role during early craniofacial development. Among the identified genes, wereRUNX2and several of its upstream and downstream actors, highlighting the prominent role of intramembranous ossification – which takes place at the cranial sutures – in influencing cranial vault shape. We found that mutations in many genes associated with craniosynostosis exert their pathogenicity by modulating the same pathways involved in normal cranial vault development. This was further demonstrated in a non-syndromic sagittal craniosynostosis case-parent trio dataset of 63 probands (n = 189), where our GWAS signals nearBMP2, BBS9, andZIC2contributed significantly to disease risk. Moreover, we found strong evidence of overlap with genes influencing the morphology of the face and the brain, suggesting a common genetic architecture connecting these developmentally adjacent structures. Overall, our study provides a comprehensive overview of the genetics underlying normal cranial vault shape and its relevance for understanding modern human craniofacial diversity and the etiology of congenital malformations.
The secretome of irradiated peripheral mononuclear cells attenuates hypertrophic skin scarring
Authors: Vorstandlechner Vera , Copic Dragan , Klas Katharina , Direder Martin , Golabi  , Radtke Christine , Ankersmit Hendrik J. , Mildner Michael
Published: December 2022

Background

Hypertrophic scars can cause pain, movement restrictions, and reduction of quality of life. Despite numerous options to tackle hypertrophic scarring, efficient therapies are still scarce, and cellular mechanisms are not well understood. Secreted factors from peripheral blood mononuclear cells (PBMCsec) were previously described for their beneficial effects in tissue regeneration. Here, we investigated the effects of PBMCsec on skin scarring in mouse models and human scar explant cultures at single cell resolution (scRNAseq).

Methods

Mouse wounds and scars were treated with PBMCsec either intradermally or topically. Human mature scars were treated with PBMCsec ex vivo in explant cultures. All experimental settings were analyzed by single cell RNA sequencing (scRNAseq). A variety of bioinformatics approaches were used to decipher gene regulation in the scRNAseq data sets. Components of the extracellular matrix (ECM) were investigated in situ by immunofluorescence. The effect of PBMCsec on myofibroblast differentiation and elastin expression was investigated by stimulating human primary fibroblasts with TGFβ.

Findings

Topical and intradermal application of PBMCsec regulated the expression of a variety of genes involved in pro-fibrotic processes and tissue remodeling. Our bioinformatics approach identified elastin as a common linchpin of antifibrotic action in both, the mouse and human experimental setting.In vitro, we found that PBMCsec prevents TGFβ-mediated myofibroblast-differentiation and attenuates abundant elastin expression through non-canonical signaling inhibition. Furthermore, TGFβ-induced breakdown of elastic fibers was strongly inhibited by addition of PBMCsec.

Interpretation

Together, we showed anti-fibrotic effect of PBMCsec on cutaneous scars in mouse and human experimental settings, suggesting PBMCsec as a novel therapeutic option to treat skin scarring.

Research in context

Evidence before this study

Paracrine factors secreted from irradiated peripheral mononuclear cells (PBMCsec) show strong tissue regenerative properties in a variety of organs and are shown to enhance cutaneous wound healing. Whether PBMCsec shows anti-fibrotic properties on scar formation has not been investigated so far.

Added value of this study

In the present study, we were able to demonstrate that PBMCsec improves quality of developing and mature scars in mouse and human scar tissue. We found that PBMCsec is able to attenuate the expression of various genes, promoting scar formation and inhibit TGFβ-induced myofibroblast differentiation. Elastin and TXNIP were identified as a common linchpin of its anti-fibrotic action.

Implications of all the available evidence

Usingin vivo, ex vivo, andin vitromodels and analyses on a single-cell level, our study paves the way for clinical studies evaluating the use of PBMCsec for the treatment of human cutaneous scars.
Employee sensemaking of CSR: on micro-discourses of corporate social responsibility
Authors: Miller Katharine E.
Published: December 2022

Purpose

Recently, scholars are pushing for an internal corporate social responsibility (CSR) view through employee perspectives regarding CSR efforts, particularly in considering how organizations can act responsibly toward internal stakeholders (May, 2011). Thus, research has begun taking a “micro-turn” in analyzing CSR (Aguinis and Glavas, 2012), focused on individual analysis of such practices within organizations. The purpose of this study is to uncover the organizational sensemaking of CSR by an important yet less understood stakeholder group, employees.

Design/methodology/approach

This study takes a primarily qualitative, micro-approach via interviews (n = 42) to understanding the internal sensemaking of various organizations' CSR efforts from the perspective of employees. Organizational discourse analysis is utilized.

Findings

At the individual level, findings from over 40 one-on-one interviews highlighted how this stakeholder group rationalizes, perceives and identifies with their employers' socially responsible efforts. Findings uncover both macro- and micro-level understandings of CSR, as well as the reality of CSR within particular organizations from an operational standpoint.

Research limitations/implications

This study provides important theoretical and methodological implications, particularly in its explicitly interpretive and qualitative approach. Specifically, this work contributes to the micro-foundations and limited internal view of CSR by interviewing over 40 employees.

Practical implications

This study provides important pragmatic implications, particularly when considering how CSR is communicated to (internal) stakeholders. Additionally, CSR must be seen as strategic and embedded in core business practices, rather than a one-off campaign.

Social implications

On a societal level, there is an expectation that corporations take care of their employees in terms of emotional and physical well-being, equity, work–life balance, among others. This study suggests a move to more inward-facing CSR practices—specifically those benefiting internal members.

Originality/value

This work contributes to research on the micro-foundations and limited internal view of CSR and provides important pragmatic implications. Specifically, the use of interviews of employees in gaining access to an important stakeholder group is a significant contribution to CSR scholarship.
Board characteristics and CEO turnover–performance relationship: evidence from India
Authors: Jatana Chhavi
Published: December 2022

Purpose

This paper aims to investigate the impact of board characteristics on CEO turnover performance relationship (TPR) in Indian listed firms.

Design/methodology/approach

A subset of the Standard and Poor’s Bombay Stock Exchange 500 (S&P BSE 500) Index companies was analyzed over the period 2015–2019 using the logistic (fixed-effects) regression model.

Findings

It was found that a weak relationship exists between CEO turnover and firm performance. With respect to board characteristics, board size was found to have a significant role in strengthening the TPR. However, other characteristics, such as board independence, multiple directors, board meetings and board gender diversity, played no role in influencing the TPR.

Research limitations/implications

First, the study period is limited to five years, during which several sample firms did not face any CEO turnover event leading to small sample size. Second, this study considers only the board’s gender diversity, whereas other types of diversity are omitted. Third, this study does not differentiate between insider and professional CEOs.

Practical implications

The findings suggest that regulators should focus on the effective enforcement of laws to strengthen the TPR and improve the monitoring role of boards, particularly in emerging economies like India, which face type II agency problems in addition to traditional principal–agent conflict. The results also offer implications for corporations, investors and academic researchers, highlighting areas that need considerable attention pertaining to corporate governance.

Originality/value

This study discerns the impact of several board-related characteristics on the TPR, particularly after the introduction of the new Companies Act 2013 in the emerging economy of India, where it has not been explored extensively.
The impact of interpersonal interaction factors on consumers’ purchase intention in social commerce: a relationship quality perspective
Authors: Zhou Wangyue , Dong Jincai , Zhang Wenyu
Published: December 2022

Purpose

Interpersonal interaction can influence consumers’ purchase intention in social commerce (s-commerce). This paper aims to identify interpersonal interaction factors as well as the mediating effect of relationship quality between interpersonal interaction factors and consumers’ purchase intention in s-commerce.

Design/methodology/approach

This study explores new dimensions of interpersonal interaction in s-commerce by integrating interaction between consumers and online vendors and that between consumers and online recommenders in s-commerce. An online questionnaire was used to collect the data, and partial least squares structural equation modeling (PLS-SEM) was employed for data analysis.

Findings

The results indicate that interpersonal interaction factors of both online vendors and online recommenders positively affect swift guanxi and initial trust between consumers and online vendors. Swift guanxi and initial trust positively affect consumers’ purchase intention. Initial trust partially mediates between interpersonal interaction factors and purchase intention while swift guanxi does not mediate between perceived similarity of online recommenders and purchase intention.

Practical implications

The findings can be used to guide vendors in s-commerce platforms to make good use of platform features to improve interpersonal interaction. Meanwhile, s-commerce platforms should be enhanced with efficient interaction tools to help cultivate relationship quality between consumers and online vendors.

Originality/value

This study combines social exchange theory, trust transfer theory and relationship quality theory to investigate the factors that influence swift guanxi and initial trust between consumers and online vendors, which extends the study of interpersonal interaction and enriches the dimensions of relationship quality in the context of s-commerce.