bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of Potent and Effective Synthetic SARS-CoV-2 Neutralizing Nanobodies
Authors: Stefan Maxwell A. , Light Yooli K. , Schwedler Jennifer L. , McIlroy Peter R. , Courtney Colleen M. , Saada Edwin A. , Thatcher Christine E. , Phillips Ashlee M. , Bourguet Feliza A. , Mageeney Catherine M. , McCloy Summer A. , Collette Nicole M. , Negrete Oscar A. , Schoeniger Joseph S. , Weilhammer Dina R. , Harmon Brooke
Published: May 2021

The respiratory virus responsible for Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-2), has impacted nearly every aspect of life worldwide, claiming the lives of over 2.5 million people globally, at the time of this publication. Neutralizing nanobodies (VHH) represent a promising therapeutic intervention strategy to address the current SARS-2 pandemic and provide a powerful toolkit to address future virus outbreaks. Using a synthetic, high-diversity VHH bacteriophage library, several potent neutralizing VHH antibodies were identified and evaluated for their capacity to tightly bind to the SARS-2 receptor-binding domain (RBD), to prevent binding of SARS-2 spike (S) to the cellular receptor Angiotensin-converting enzyme 2 (ACE2), and to neutralize viral infection. Preliminary preclinical evaluation of multiple nanobody candidates demonstrate that they are prophylactically and therapeutically effectivein vivoagainstwildtypeSARS-2. The identified and characterized nanobodies described herein represent viable candidates for further preclinical evaluation and another tool to add to our therapeutic arsenal to address the COVID-19 pandemic.

Author Summary

To fully address the on-going pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-2), it will be important to have both vaccines and therapeutic strategies to prevent and mitigate the effects of SARS-2. In this study, we describe the identification and characterization of potently neutralizing humanized single domain heavy chain (VHH) antibodies that have binding affinity for both the original Wuhan strain and widely circulating B.1.1.7/UK strain. VHH antibodies have the same therapeutic potential as conventional antibodies in half the size and with greater stability and solubility. Using a synthetic humanized high-diversity VHH phage library we identified several candidates with strong affinity for the SARS-2 spike that block the interaction of SARS-2 spike with the cellular receptor ACE2, and effectively neutralize infection with SARS-2in vitro. By sequencing viral escape mutants generated in the presence of each VHH we mapped the binding sites of the VHH antibodies and assessed their affinity against newly emerging SARS-2 variants. Finally, we demonstrate that two of these VHH antibodies show prophylactic and therapeutic efficacyin vivoagainst challenge with SARS-2. This study establishes that screening highly diverse VHH phage libraries against viral threats can yield highly effective therapeutic agents in real time.
Identification of DAXX As A Restriction Factor Of SARS-CoV-2 Through A CRISPR/Cas9 Screen
Authors: Mac Kain Alice , Maarifi Ghizlane , Aicher Sophie-Marie , Arhel Nathalie , Baidaliuk Artem , Munier Sandie , Donati Flora , Vallet Thomas , Tran Quang Dinh , Hardy Alexandra , Chazal Maxime , Porrot Françoise , OhAinle Molly , Carlson-Stevermer Jared , Oki Jennifer , Holden Kevin , Simon-Lorière Etienne , Bruel Timothée , Schwartz Olivier , van der Werf Sylvie , Jouvenet Nolwenn , Nisole Sébastien , Vignuzzi Marco , Roesch Ferdinand
Published: May 2021

Interferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identified DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 and SARS-CoV replication in human cells. Basal expression of DAXX was sufficient to limit the replication of SARS-CoV-2, and DAXX over-expression further restricted infection. In contrast with most of its previously described antiviral activities, DAXX-mediated restriction of SARS-CoV-2 was independent of the SUMOylation pathway. SARS-CoV-2 infection triggered the re-localization of DAXX to cytoplasmic sites and promoted its degradation. Mechanistically, this process was mediated by the viral papain-like protease (PLpro) and the proteasome. Together, these results demonstrate that DAXX restricts SARS-CoV-2, which in turn has evolved a mechanism to counteract its action.
Bioinformatics analyses of significant genes, related pathways and candidate prognostic biomarkers in Alzheimer’s disease
Authors: Vastrad Basavaraj , Vastrad Chanabasayya
Published: May 2021

Alzheimer’s disease (AD) is one of the most common causes of dementia and frailty. This study aimed to use bioinformatics analysis to identify differentially expressed genes (DEGs) in AD. The Expression profiling by high throughput sequencing dataset GSE125583 was downloaded from the Gene Expression Omnibus (GEO) database and DEGs were identified. After assessment of Gene Ontology (GO) terms and pathway enrichment for DEGs, a protein–protein interaction (PPI) network, module analysis, miRNA-hub gene regulatory network construction and TF-hub gene regulatory network were conducted via comprehensive target prediction and network analyses. Finally, we validated hub genes by receiver operating characteristic curve (ROC). In total, 956 DEGs were identified in the AD samples, including 479 up regulated genes and 477 down regulated genes. Functional enrichment analysis showed that these DEGs are mainly involved in the neuronal system, GPCR ligand binding, regulation of biological quality and cell communication. The hub genes of PAK1, ELAVL2, NSF, HTR2C, TERT, UBD, MKI67, HSPB1, PYHIN1 and TES might be associated with AD. The diagnostic value and expression levels of these hub genes in AD were further confirmed by ROC analysis. In conclusion, we identified pathways and crucial candidate genes that affect the outcomes of patients with AD, and these genes might serve as potential therapeutic targets.
Eusociality and the evolution of aging in superorganisms
Authors: Kramer Boris H. , van Doorn G. Sander , Arani Babak M. S. , Pen Ido
Published: May 2021

Eusocial insects – ants, bees, wasps and termites – are being recognized as model organisms to unravel the evolutionary paradox of aging for two reasons: (1) queens (and kings, in termites) of social insects outlive similar sized solitary insects by up to several orders of magnitude; (2) all eusocial taxa show a divergence of long queen and shorter worker lifespans, despite their shared genomes and even under risk-free laboratory environments. Traditionally, these observations have been explained by invoking classical evolutionary aging theory: well-protected inside their nests, queens are much less exposed to external hazards than foraging workers, and this provides natural selection the opportunity to favor queens that perform well at advanced ages. Although quite plausible, these verbal arguments have not been backed up by mathematical analysis. Here, for the first time, we provide quantitative models for the evolution of caste-specific aging patterns. We show that caste-specific mortality risks are in general neither sufficient nor necessary to explain the evolutionary divergence in lifespan between queens and workers and the extraordinary queen lifespans. Reproductive monopolization and the delayed production of sexual offspring in highly social colonies lead natural selection to inherently favor queens that live much longer than workers, even when exposed to the same external hazards. Factors that reduce a colony’s reproductive skew, such as polygyny and worker reproduction, tend to reduce the evolutionary divergence in lifespan between queens and workers. Caste-specific extrinsic hazards also affect lifespan divergence but to a much smaller extent than reproductive monopolization.
Towards Novel Herbicide Modes of Action by Inhibiting Lysine Biosynthesis in Plants
Authors: Soares da Costa Tatiana P. , Hall Cody J. , Panjikar Santosh , Wyllie Jessica A. , Christoff Rebecca M. , Bayat Saadi , Hulett Mark D. , Abbott Belinda M. , Gendall Anthony R. , Perugini Matthew A.
Published: May 2021

Weeds are becoming increasingly resistant to our current herbicides, posing a significant threat to agricultural production. Therefore, new herbicides are urgently needed. In this study, we exploited a novel herbicide target, dihydrodipicolinate synthase (DHDPS), which catalyses the first and rate-limiting step in lysine biosynthesis. Using a high throughput chemical screen, we identified the first class of plant DHDPS inhibitors that have micromolar potency againstArabidopsis thalianaDHDPS isoforms. Employing X-ray crystallography, we determined that this class of inhibitors binds to a novel and unexplored pocket within DHDPS, which is highly conserved across plant species. We also demonstrated that the inhibitors attenuated the germination and growth ofA. thalianaseedlings and confirmed their pre-emergence herbicidal activity in soil-grown plants. These results provide proof-of-concept that lysine biosynthesis represents a promising target for the development of herbicides with a novel mode of action to tackle the global rise of herbicide resistant weeds.
SPT6 loss Permits the Transdifferentiation of Keratinocytes into an Intestinal Fate that Recapitulates Barrett’s Metaplasia
Authors: Vo Daniella T. , Fuller MacKenzie R. , Tindle Courtney , Anandachar Mahitha Shree , Das Soumita , Sahoo Debashis , Ghosh Pradipta
Published: May 2021

Transient depletion of the transcription elongation factor SPT6 in the keratinocyte has been recently shown to inhibit epidermal differentiation and stratification; instead, they transdifferentiate into a gut-like lineage. We show here that this phenomenon oftransdifferentiationrecapitulates Barrett’s metaplasia, the only human pathophysiologic condition in which a stratified squamous epithelium that is injured due to chronic acid reflux is trans-committed into an intestinal fate. The evidence we present here not only lend support to the notion that the keratinocytes are the cell of origin of Barrett’s metaplasia, but also provide mechanistic insights linking transient acid exposure, downregulation of SPT6, stalled transcription of the master regulator of epidermal fate TP63, loss of epidermal fate and metaplastic progression. Because Barrett’s metaplasia in the esophagus (BE) is a pre-neoplastic condition with no preclinical human models, these findings have a profound impact on the modeling Barrett’s metaplasia-in-a-dish.

GRAPHIC ABSTRACT

HIGHLIGHTS

Keratinocytes transdifferentiate into the gut lineage upon depletion of SPT6

Such transdifferentiation recapitulates Barrett’s metaplasia, not the healthy gut

Acid downregulates SPT6, which derails the expression and functions of TP63

Such downregulation precedes the metaplasia-dysplasia-neoplasia cascade
massNet: integrated processing and classification of spatially resolved mass spectrometry data using deep learning for rapid tumor delineation
Authors: Abdelmoula Walid M. , Stopka Sylwia , Randall Elizabeth C. , Regan Michael , Agar Jeffrey N. , Sarkaria Jann N. , Wells William M. , Kapur Tina , Agar Nathalie Y.R.
Published: May 2021

Motivation

Mass spectrometry imaging (MSI) provides rich biochemical information in a label-free manner and therefore holds promise to substantially impact current practice in disease diagnosis. However, the complex nature of MSI data poses computational challenges in its analysis. The complexity of the data arises from its large size, high dimensionality, and spectral non-linearity. Preprocessing, including peak picking, has been used to reduce raw data complexity, however peak picking is sensitive to parameter selection that, perhaps prematurely, shapes the downstream analysis for tissue classification and ensuing biological interpretation.

Results

We propose a deep learning model, massNet, that provides the desired qualities of scalability, non-linearity, and speed in MSI data analysis. This deep learning model was used, without prior preprocessing and peak picking, to classify MSI data from a mouse brain harboring a patient-derived tumor. The massNet architecture established automatically learning of predictive features, and automated methods were incorporated to identify peaks with potential for tumor delineation. The model’s performance was assessed using cross-validation, and the results demonstrate higher accuracy and a 174-fold gain in speed compared to the established classical machine learning method, support vector machine.

Availability and Implementation

The code is publicly available on GitHub.
Photonic chip-based multimodal super-resolution microscopy for histopathological assessment of cryopreserved tissue sections
Authors: Villegas-Hernández Luis E. , Dubey Vishesh , Nystad Mona , Tinguely Jean-Claude , Coucheron David A. , Dullo Firehun T. , Priyadarshi Anish , Acuña Sebastian , Mateos Jose M. , Barmettler Gery , Ziegler Urs , Hovd Aud-Malin Karlsson , Fenton Kristin Andreassen , Acharya Ganesh , Agarwal Krishna , Ahluwalia Balpreet Singh
Published: May 2021

1.

Histopathological assessment involves the identification of anatomical variations in tissues that are associated with diseases. While diffraction-limited optical microscopes assist in the diagnosis of a wide variety of pathologies, their resolving capabilities are insufficient to visualize some anomalies at subcellular level. Although a novel set of super-resolution optical microscopy techniques can fulfill the resolution demands in such cases, the system complexity, high operating cost, lack of multimodality, and low-throughput imaging of these methods limit their wide adoption in clinical settings. In this study, we interrogate the photonic chip as an attractive high-throughput super-resolution microscopy platform for histopathology. Using cryopreserved ultrathin tissue sections of human placenta, mouse kidney, and zebrafish eye retina prepared by the Tokuyasu method, we validate the photonic chip as a multi-modal imaging tool for histo-anatomical analysis. We demonstrate that photonic-chip platform can deliver multi-modal imaging capabilities such as total internal reflection fluorescence microscopy, intensity fluctuation-based optical nanoscopy, single-molecule localization microscopy, and correlative light-electron microscopy. Our results demonstrate that the photonic chip-based super-resolution microscopy platform has the potential to deliver high-throughput multimodal histopathological analysis of cryopreserved tissue samples.
Axons-on-a-Chip for Mimicking Non-Disruptive Diffuse Axonal Injury underlying Traumatic Brain Injury
Authors: Li Wei , Wang Haofei , Pan Xiaorong , Gagoski Dejan , Durisic Nela , Li Zhiyong , Zhao Chun-Xia , Wang Tong
Published: May 2021

Diffuse axonal injury (DAI) is the most severe pathological feature of traumatic brain injury. However, how primary axonal injury is induced by mechanical stress and whether it could be mitigated remain unknown, largely due to the resolution limits of medical imaging approaches. Here we established an Axon-on-a-Chip (AoC) model for mimicking DAI and investigating its early cellular responses. By integrating computational fluid dynamics and microfluidic techniques, DAI was observed for the first time during mechanical stress, and a clear correlation between stress intensity and severity of DAI was elucidated. This AoC was further used to investigate the dynamic intracellular changes occurring simultaneously with stress, and identified delayed local Ca2+surges escorted rapid disruption of periodic axonal cytoskeleton during the early stage of DAI. Compatible with high-resolution live-microscopy, this model hereby provides a versatile system to identify early mechanisms underlying DAI, offering a platform for screening effective treatments to alleviate brain injuries.
Phenotyping stomatal closure by thermal imaging for GWAS and TWAS of water use efficiency-related genes
Authors: Pignon Charles P. , Fernandes Samuel B. , Valluru Ravi , Bandillo Nonoy , Lozano Roberto , Buckler Edward , Gore Michael A. , Long Stephen P. , Brown Patrick J. , Leakey Andrew D. B.
Published: May 2021

Stomata allow CO2uptake by leaves for photosynthetic assimilation at the cost of water vapor loss to the atmosphere. The opening and closing of stomata in response to fluctuations in light intensity regulate CO2and water fluxes and are essential to maintenance of water-use efficiency (WUE). However, little is known about the genetic basis for natural variation in stomatal movement, especially in C4crops. This is partly because the stomatal response to a change in light intensity is difficult to measure at the scale required for association studies. High-throughput thermal imaging was used to bypass the phenotyping bottleneck and assess 10 traits describing stomatal conductance (gs) before, during and after a stepwise decrease in light intensity for a diversity panel of 659 sorghum accessions. Results from thermal imaging significantly correlated with photosynthetic gas-exchange measurements.gstraits varied substantially across the population and were moderately heritable (h2up to 0.72). An integrated genome-wide and transcriptome-wide association study (GWAS/TWAS) identified candidate genes putatively driving variation in stomatal conductance traits. Of the 239 unique candidate genes identified with greatest confidence, 77 were orthologs of Arabidopsis genes related to functions implicated in WUE, including stomatal opening/closing (24 genes), stomatal/epidermal cell development (35 genes), leaf/vasculature development (12 genes), or chlorophyll metabolism/photosynthesis (8 genes). These findings demonstrate an approach to finding genotype-to-phenotype relationships for a challenging trait as well as candidate genes for further investigation of the genetic basis of WUE in a model C4grass for bioenergy, food, and forage production.

One sentence summary

Rapid phenotyping of 659 accessions ofSorghum bicolorrevealed heritable stomatal responses to a decrease in light. GWAS/TWAS was used to identify candidate genes influencing traits important to WUE.
A metagenomic view of novel microbial and metabolic diversity found within the deep terrestrial biosphere
Authors: Momper Lily , Casar Caitlin P. , Osburn Magdalena R.
Published: May 2021

The deep terrestrial subsurface is a large and diverse microbial habitat and a vast repository of biomass. However, in relation to its size and physical heterogeneity we have limited understanding of taxonomic and metabolic diversity in this realm. Here we present a detailed metagenomic analysis of samples from the Deep Mine Microbial Observatory (DeMMO) spanning depths from the surface to 1.5 km deep in the crust. From these eight geochemically and spatially distinct fluid samples we reconstructed ∼600 metagenome assembled genomes (MAGs), representing 50 distinct phyla and including 18 candidate phyla. These novel clades include many members of the Patescibacteria superphylum and two new MAGs from candidate phylum OLB16, a phylum originally identified in DeMMO fluids and for which only one other MAG is currently available. We find that microbes spanning this expansive phylogenetic diversity and physical space are often capable of numerous dissimilatory energy metabolisms and are poised to take advantage of nutrients as they become available in relatively isolated fracture fluids. This metagenomic dataset is contextualized within a four-year geochemical and 16S rRNA time series, adding another invaluable piece to our knowledge of deep subsurface microbial ecology.
Theta phase mediates deliberate action switching in human Supplementary Motor Areas
Authors: Maffei Giovanni , Zucca Riccardo , Puigbò Jordi-Ysard , Santos-Pata Diogo , Galli Marco , Campo Adrià Tauste , Rocamora Rodrigo , Verschure Paul
Published: May 2021

The ability to deliberately overwrite ongoing automatic actions is a necessary feature of adaptive behavior. It has been proposed that the supplementary motor areas (SMAs) operate as a controller that orchestrates the switching between automatic and deliberate processes by inhibiting ongoing behaviors and so facilitating the execution of alternative ones. In addition, previous studies support the involvement of SMAs theta waves (4-9 Hz) in cognitive control. However, the exact role of such oscillatory dynamics and their contribution to the control of action are not fully understood. To investigate the mechanisms by which the SMAs support direct control of deliberate behavior, we recorded intracranial electroencephalography (iEEG) activity in humans performing a motor sequence task. Subjects had to perform a “change of plans” motor task requiring habitual movements to be overwritten at unpredictable moments. We found that SMAs were exclusively active during trials that demand action reprogramming in response to the unexpected cue but were silent during automatic action execution. Importantly, SMAs activity was characterized by a distinct temporal pattern, expressed in a stereotypical phase alignment of theta oscillations. More specifically, single trial motor performance was correlated with the trial contribution to the global inter-trial phase coherence, with higher coherence associated with faster trials. In addition, theta phase modulated the amplitude of gamma oscillations, with higher cross-frequency coupling in faster trials. Our results suggest that within frontal cortical networks, theta oscillations could encode a control signal that promotes the execution of deliberate actions.
Robust IgM responses following vaccination are associated with prevention ofMycobacterium tuberculosisinfection in macaques
Authors: Irvine Edward B. , O’Neil Anthony , Darrah Patricia A. , Shin Sally , Choudhary Alok , Li Wenjun , Honnen William , Mehra Smriti , Kaushal Deepak , Gideon Hannah Priyadarshini , Flynn JoAnne L. , Roederer Mario , Seder Robert A. , Pinter Abraham , Fortune Sarah , Alter Galit
Published: May 2021

Development of an effective tuberculosis (TB) vaccine has suffered from an incomplete understanding of the correlates of protection againstMycobacterium tuberculosis(Mtb). However, recent work has shown that compared to standard intradermal Bacille Calmette-Guerin (BCG) vaccination, intravenous (IV) BCG vaccination provides nearly complete protection against TB in rhesus macaques. While studies have focused on cellular immunity in this setting, the antibody response elicited by IV BCG vaccination remains incompletely defined. Using an agnostic antibody profiling approach, here we show that IV BCG drives superior antibody responses in the plasma and the bronchoalveolar lavage fluid (BAL). While IV BCG immunization resulted in the broad expansion of antibody titers and effector functions, surprisingly, IgM titers were among the strongest markers of reduced bacterial burden in the plasma and BAL of BCG immunized animals. Moreover, IgM immunity was also enriched among animals receiving protective vaccination with an attenuatedMtbstrain. Finally, a LAM-specific IgM monoclonal antibody reducedMtbsurvivalin vitro. Collectively, these data highlight the potential importance of IgM responses as a marker and as a functional mediator of protection against TB.
Dendritic spine morphology regulates calcium-dependent synaptic weight change
Authors: Bell M. K. , Holst M. V. , Lee C. T. , Rangamani P.
Published: May 2021

Dendritic spines act as biochemical computational units and must adapt their responses according to their activation history. Calcium influx acts as the first signaling step during post-synaptic activation and is a determinant of synaptic weight change. Dendritic spines also come in a variety of sizes and shapes. To probe the relationship between calcium dynamics and spine morphology, we used a stochastic reaction-diffusion model of calcium dynamics in idealized and realistic geometries. We show that despite the stochastic nature of the various calcium channels, receptors, and pumps, spine size and shape can modulate calcium dynamics and subsequently synaptic weight updates in a deterministic manner. Through a series of exhaustive simulations, we find that the calcium dynamics and synaptic weight change depend on the volume-to-surface area of the spine. The relationships between calcium dynamics and spine morphology identified in idealized geometries also hold in realistic geometries suggesting that there are geometrically determined deterministic relationships that may modulate synaptic weight change.
KAI2 regulates seedling development by mediating light-induced remodelling of auxin transport
Authors: Hamon-Josse Maxime , Villaecija-Aguilar Jose Antonio , Ljung Karin , Leyser Ottoline , Gutjahr Caroline , Bennett Tom
Published: May 2021

The photomorphogenic remodelling of seedling growth upon exposure to light is a key developmental transition in the plant life cycle. The α/β-hydrolase signalling protein KARRIKIN-INSENSITIVE2 (KAI2), a close homologue of the strigolactone receptor DWARF14 (D14), is involved in this process, andkai2mutants have strongly altered seedling growth as a result1. KAI2 and D14 both act through the MAX2 (MORE AXILLARY BRANCHING2) F-box protein to target proteins of the SMAX1-LIKE (SUPPRESSOR OF MAX2 1) (SMXL) family for degradation, but the signalling events downstream of this step are unclear in both pathways2. Here, we show thatkai2phenotypes arise because of a failure to downregulate auxin transport from the seedling shoot apex towards the root system, rather than a failure to respond to lightper se. We demonstrate that KAI2 controls the light-induced remodelling of the PIN-mediated auxin transport system in seedlings, promoting the reduction of PIN3, PIN4, and PIN7 abundance in older tissues, and the increase of PIN1, PIN2, PIN3, and PIN7 abundance in the root meristem, consistent with transition from elongation-mediated growth in the dark to meristematically-mediated growth in the light. We show that removing PIN3, PIN4 and PIN7 fromkai2mutants, or pharmacological inhibition of auxin transport and synthesis, is sufficient to suppress mostkai2seedling phenotypes. KAI2 is not required for the light-mediated changes in PIN gene expression but is required for the changes in PIN protein abundance at the plasma membrane; we thus propose that KAI2 acts to promote vesicle trafficking, consistent with previous suggestions about D14-mediated signalling in the shoot3.
Spatial control of cell division by GA-OsGRF7/8 module in a leaf explains the leaf length variation between cultivated and wild rice
Authors: Jathar Vikram , Saini Kumud , Chauhan Ashish , Rani Ruchi , Ichihashi Yasunori , Ranjan Aashish
Published: May 2021

Cellular and genetic understanding of rice leaf size regulation is limited, despite rice being the staple food of more than half of the global population. We investigated the mechanism controlling the rice leaf length using cultivated and wild rice accessions that remarkably differed for leaf size.

Comparative transcriptomics, Gibberellic Acid (GA) quantification, and leaf kinematics of the contrasting accessions suggested the involvement of GA, cell cycle, and Growth-Regulating Factors (GRFs) in the rice leaf size regulation. Zone-specific expression analysis and VIGS established the functions of specific GRFs in the process.

The leaf length of the selected accessions was strongly correlated with GA levels. Higher GA content in wild rice accessions with longer leaves and GA-induced increase in the leaf length via an increase in cell division confirmed a GA-mediated regulation of division zone in rice. Downstream to GA,OsGRF7andOsGRF8function for controlling cell division to determine the rice leaf length.

Spatial control of cell division to determine the division zone size mediated by GA and downstream OsGRF7 and OsGRF8 explains the leaf length differences between the cultivated and wild rice. This mechanism to control rice leaf length might have contributed to optimizing leaf size during domestication.
iProMix: A decomposition model for studying the function of ACE2 based on bulk proteogenomic data for coronavirus pathogenesis
Authors: Song Xiaoyu , Ji Jiayi , Wang Pei
Published: May 2021

Both SARS-CoV and SARS-CoV-2 use ACE2 receptors to enter epithelial cells in lung and many other tissues to cause human diseases. Genes and pathways that regulate ACE2 may facilitate/inhibit viral entry and replication, and genes and pathways that are controlled by ACE2 may be perturbed during infection, both affecting disease severity and outcomes. It is critical to understand how genes and pathways are associated with ACE2 in epithelial cells by leveraging proteomic data, but an accurate large-scale proteomic profiling at cellular resolution is not feasible at current stage. Therefore, we propose iProMix, a novel framework that decomposes bulk tissue proteomic data to identify epithelial cell component specific associations between ACE2 and other proteins. Unlike existing decomposition based association analyses, iProMix allows both predictors and outcomes to be impacted by cell type composition of the tissue and accounts for the impacts of decomposition variations and errors on hypothesis tests. It also builds in the functions to improve cell type estimation if estimates from existing literature are unsatisfactory. Simulations demonstrated that iProMix has well-controlled false discovery rate and large power in non-asymptotic settings with both correctly and mis-specified cell-type composition. We applied iProMix to the 110 adjacent normal tissue samples of patients with lung adenocarcinoma from Clinical Proteomic Tumor Analysis Consortium, and identified that interferon α and γ pathways were most significantly associated with ACE2 protein abundances in epithelial cells. Interestingly, the associations were sex-specific that the positive associations were only observed in men, while in women the associations were negative.
A hybrid PDE–ABM model for viral dynamics with application to SARS–CoV–2 and influenza
Authors: Marzban Sadegh , Han Renji , Juhász Nóra , Röst Gergely
Published: May 2021

We propose a hybrid partial differential equation – agent-based (PDE–ABM) model to describe the spatio-temporal viral dynamics in a cell population. The virus concentration is considered as a continuous variable and virus movement is modelled by diffusion, while changes in the states of cells (i.e. healthy, infected, dead) are represented by a stochastic agent-based model. The two subsystems are intertwined: the probability of an agent getting infected in the ABM depends on the local viral concentration, and the source term of viral production in the PDE is determined by the cells that are infected.

We develop a computational tool that allows us to study the hybrid system and the generated spatial patterns in detail. We systematically compare the outputs with a classical ODE system of viral dynamics, and find that the ODE model is a good approximation only if the diffusion coefficient is large.

We demonstrate that the model is able to predict SARS–CoV–2 infection dynamics, and replicate the output ofin vitroexperiments. Applying the model to influenza as well, we can gain insight into why the outcomes of these two infections are different.
Subtle differences in the pathogenicity of SARS-CoV-2 variants of concern B.1.1.7 and B.1.351 in rhesus macaques
Authors: Munster Vincent J. , Flagg Meaghan , Singh Manmeet , Williamson Brandi N. , Feldmann Friederike , Pérez-Pérez Lizzette , Brumbaugh Beniah , Holbrook Myndi G. , Adney Danielle R. , Okumura Atsushi , Hanley Patrick W. , Smith Brian J. , Lovaglio Jamie , Anzick Sarah L. , Martens Craig , van Doremalen Neeltje , Saturday Greg , de Wit Emmie
Published: May 2021

The emergence of several SARS-CoV-2 variants has caused global concerns about increased transmissibility, increased pathogenicity, and decreased efficacy of medical countermeasures. Animal models can be used to assess phenotypical changes in the absence of confounding factors that affect observed pathogenicity and transmissibility data in the human population. Here, we studied the pathogenicity of variants of concern (VOC) B.1.1.7 and B.1.351 in rhesus macaques and compared it to a recent clade B.1 SARS-CoV-2 isolate containing the D614G substitution in the spike protein. The B.1.1.7 VOC behaved similarly to the D614G with respect to clinical disease, virus shedding and virus replication in the respiratory tract. Inoculation with the B.1.351 isolate resulted in lower clinical scores in rhesus macaques that correlated with lower virus titers in the lungs, less severe histologic lung lesions and less viral antigen detected in the lungs. We observed differences in the local innate immune response to infection. In bronchoalveolar lavages, cytokines and chemokines were upregulated on day 4 in animals inoculated with D614G and B.1.1.7 but not in those inoculated with B.1.351. In nasal samples, we did not detect upregulation of cytokines and chemokines in D614G or B.1.351-inoculated animals. However, cytokines and chemokines were upregulated in the noses of B.1.1.7-inoculated animals. Taken together, our comparative pathogenicity study suggests that ongoing circulation under diverse evolutionary pressure favors transmissibility and immune evasion rather than an increase in intrinsic pathogenicity.
Crystal structures of Aspergillus oryzae Rib2 deaminase: the functional mechanism involved in riboflavin biosynthesis
Authors: Chen Sheng-Chia , Ye Li-Ci , Yen Te-Ming , Zhu Ruei-Xin , Li Cheng-Yu , Chang San-Chi , Liaw Shwu-Huey , Hsu Chun-Hua
Published: May 2021

Riboflavin serves as the direct precursor of the FAD/FMN coenzymes and is biosynthesized in most prokaryotes, fungi and plants. Fungal Rib2 possesses a deaminase domain for deamination of pyrimidine in the third step of riboflavin biosynthesis. Here, four high-resolution crystal structures of a Rib2 deaminase from Aspergillus oryzae (AoRib2) are reported which display three distinct occluded, open and complex forms that are involved in substrate binding and catalysis. In addition to the deaminase domain, AoRib2 contains a unique C-terminal segment which is rich in charged residues. Deletion of this unique segment has no effect on either enzyme activity or protein stability. Nevertheless, the C-terminal αF helix preceding the segment plays a role in maintaining protein stability and activity. Unexpectedly, AoRib2 is the first mononucleotide deaminase found to exist as a monomer, perhaps due to the assistance of its unique longer loops (Lβ1–β2, LαB–β3 and LαC–β4). These results form the basis for a molecular understanding of riboflavin biosynthesis in fungi and might assist in the development of antibiotics.
Putative hexameric glycosyltransferase functional unit revealed by the crystal structure of Acinetobacter baumannii MurG
Authors: Jung Kyoung Ho , Kwon Sunghark , Kim Chang Min , Lee Jun Hyuck , Park Hyun Ho
Published: May 2021

Lipid II, the main component of the bacterial cell wall, is synthesized by the addition of UDP-N-acetylglucosamine to the UDP-N-acetylmuramic acid pentapeptide catalyzed by the glycosyltransferase MurG. Owing to its critical role in cell-wall biosynthesis, MurG is considered to be an attractive target for antibacterial agents. Although the Mur family ligases have been extensively studied, the molecular mechanism of the oligomeric scaffolding assembly of MurG remains unclear. In this study, MurG from Acinetobacter baumannii (abMurG), a human pathogen, was characterized and its hexameric crystal structure was unveiled; this is the first homo-oligomeric structure to be described in the MurG family and the Mur family. Homogeneous protein samples were produced for structural studies using size-exclusion chromatography, the absolute molecular mass was calculated via multi-angle light scattering, and protein–protein interactions were analyzed using the PDBePISA server. abMurG was found to form homo-oligomeric complexes in solution, which might serve as functional units for the scaffolding activity of MurG. Furthermore, analysis of this structure revealed the molecular assembly mechanism of MurG. This structural and biochemical study elucidated the homo-oligomerization mechanism of MurG and suggests a new potential antibiotic target on MurG.
Distinct pathways of solid-to-solid phase transitions induced by defects: the case of DL-methionine
Authors: Shi Genpei , Li Si , Shi Peng , Gong Junbo , Zhang Mingtao , Tang Weiwei
Published: May 2021

Understanding of solid-to-solid phase transition mechanisms in polymorphic systems is of critical importance for rigorous control over polymorph purity in the pharmaceutical industry to achieve the desired bioavailability and efficacy of drugs. Ubiquitous defects in crystals may play an important role in the pathways of phase transitions. However, such effects remain poorly understood. Here, the effects of crystal defects on the solid-to-solid phase transformations between DL-methionine polymorphs α and β are investigated by means of experimental and computational approaches. Thermal analyses of polycrystalline powders show two endothermic peaks in the α-to-β phase transition (and two exothermic peaks for the reverse transition), in contrast with one thermal event observed for single crystals. Variable-temperature 1D and 2D Raman spectra, as well as powder X-ray diffraction patterns, reveal the appearance of two peaks that can attributed to a two-step phase transition, and the extent of the second-step phase transition increases with milling time (or defect density). Quantification of transition kinetics unveils a remarkably higher energy barrier in the second-step phase transition than in the first, proceeding by the cooperative molecular motion pathway. The good linear fitting on the kinetic data by the Jeziorny model suggests that the second-step transition follows the nucleation and growth mechanism. Molecular dynamics simulations were also conducted to understand the role of crystal defects in the solid-state phase transition by tracking the atomic distribution and hydrogen bond lifetime during the transition. It was found that the increasing defect density hinders the propagation of cooperative molecular motion, leading to a combined transition mechanism involving both cooperative motion and nucleation and growth. This study highlights the significant impact of crystal defects on solid-state phase transitions, and the two-step transition mechanism postulated may be universal given the ubiquitous presence of defects in crystalline materials.
Electrochemical behaviour of some commercial stainless steel alloys in simulated body fluid electrolytes
Authors: Bahrawy A. , El-Rabiei Mohamed , Elfiky Hesham , Elsayed Nady , Arafa Mohammed , Negem Mosaad
Published: May 2021

Purpose

The commercial stainless steels have been used extensively in the biomedicine application and their electrochemical behaviour in the simulated body fluid (SBF) are not uncovered obviously. In this research, the corrosion resistance of the commercial stainless steel of Fe–17Cr–xNi alloys (x = 4, 8, 10 and 14) has been studied. This study aims to evaluate the rate of corrosion and corrosion resistance of some Fe–Cr–Ni alloys in SBF at 37°C.

Design/methodology/approach

In this research, the corrosion resistance of the commercial stainless steel of Fe–17Cr–xNi alloys has been studied using open circuit potential, electrochemical impedance spectroscopy and potentiodynamic polarization in the SBF at 37°C and pH 7.4 for a week. Also, the surface morphology of the four alloys was investigated using scanning electron microscopy, elemental composition was obtained via energy dispersive spectroscopy and the crystal lattice structure of Fe–17Cr–xNi alloys was obtained using X-ray diffraction technique. The chemical structure of the protective oxide film has been examined by X-ray photoelectron spectroscopy (XPS) and metals ions released into the solution have been detected after different immersion time using atomic absorption spectroscopy.

Findings

The results revealed that the increase of the Ni content leads to the formation of the stable protective film on the alloys such as the Fe–17Cr–10Ni and Fe–17Cr–14Ni alloys which possess solid solution properties. The Fe–17Cr–14Ni alloy displayed highest resistance of corrosion, notable resistance for localized corrosion and the low corrosion rate in SBF because of the formation of a homogenously protective oxide film on the surface. The XPS analysis showed that the elemental Fe, Cr and Ni react with the electrolyte medium and the passive film is mainly composed of Cr2O3 with some amounts of Fe(II) hydroxide at pH 7.4.

Originality/value

This work includes important investigation to use commercial stainless steel alloys for biomedical application.
The impact of hedonic dining experiences on word of mouth, switching intentions and willingness to pay
Authors: Sukhu Anupama , Bilgihan Anil
Published: May 2021

Purpose

When customers decide to dine out, they choose a restaurant for both physiological and psychological reasons. The psychological reasons include the hedonic/enjoyment goal of the consumer. The purpose of this paper is to investigate whether dining experiences that provide a positive or negative hedonic value will influence positive word of mouth (PWOM), switching intentions (SI) and willingness to pay (WTP).

Design/methodology/approach

Two survey-based experiments using student (N = 112) and general restaurant consumer samples (N = 270) were conducted to test the proposed theoretical model. The student sample provided internal validity, whereas the general consumer sample provided external validity for the study. Two types of manipulations were used to manipulate positive and negative restaurant service encounters. The second study randomly assigned participants into positive or negative scenarios.

Findings

The results suggest that positive (negative) service encounters lead to higher (lower) hedonic value. Higher hedonic value leads to PWOM, WTP and reduced SI. The findings of this study would assist restaurant managers and service scholars by bridging the gap between experiential and relationship marketing.

Originality/value

The current research investigates the dining out experience with a holistic lens.
Determination of the time-dependent convection coefficient in two-dimensional free boundary problems
Authors: Huntul Mousa , Lesnic Daniel
Published: May 2021

Purpose

The purpose of the study is to solve numerically the inverse problem of determining the time-dependent convection coefficient and the free boundary, along with the temperature in the two-dimensional convection-diffusion equation with initial and boundary conditions supplemented by non-local integral observations. From the literature, there is already known that this inverse problem has a unique solution. However, the problem is still ill-posed by being unstable to noise in the input data.

Design/methodology

For the numerical discretization, this paper applies the alternating direction explicit finite-difference method along with the Tikhonov regularization to find a stable and accurate numerical solution. The resulting nonlinear minimization problem is solved computationally using the MATLAB routine lsqnonlin. Both exact and numerically simulated noisy input data are inverted.

Findings

The numerical results demonstrate that accurate and stable solutions are obtained.

Originality/value

The inverse problem presented in this paper was already showed to be locally uniquely solvable, but no numerical solution has been realized so far; hence, the main originality of this work is to attempt this task.
Dhanashree Agro: transforming a “Farmer First” model
Authors: Pingali Srinivas Rao , Korem Jyothi Rani
Published: May 2021

Learning outcomes

The learning outcomes are as follows: to understand the management styles and motivations of SME founders; to understand how SMEs innovate with limited resources; to develop and evaluate technology and platform options to solve operational and business model issues; to build a transforming strategy by leveraging technology; and to understand the agricultural industry and its significance to emerging economies.

Case overview/synopsis

The case is about a Small and Medium Enterprise in India that focussed on the agricultural sector. The company was owner operated and highly successful. As a result, the owner decided to maintain status quo till the COVID-19 crisis forced the company to relook at its strategy and innovate for the second time in its history.

Complexity academic level

MBA.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 11: Strategy.
Imaging Goa’s B2B sales dilemma: provoke or justify
Authors: Kar Pravat Surya , Dasgupta Meeta
Published: May 2021

Learning outcomes

Appreciate changing contours of business to business (B2B) purchase and how sellers should adapt their selling style and promotions.

Case overview/synopsis

In the past two decades, imaging Goa (IG) and Azim Shaikh had weathered many business crises. However, as the COVID 19 pandemic unfolded, he became aware of critical fault lines in his B2B selling model. IG offered customised digital display solutions, but its primary source of revenue was B2B selling of interactive flat panel display (IFPD) devices. It, respectively, controlled about 35% and 3% of the market share of IFPD sales, respectively, in Goa and western India. IG’s success in the B2B segment was because of Shaikh’s ability to build strong relationships and customised solutions in an emerging market context. To deal with the COVID pandemic, the Indian Government had imposed a country-wide lockdown, which forced organisations to adopt work from home. This, in turn, created a pull for IFPDs. Yet, very soon Shaikh realised, in the new normal, there was a growing mismatch between his selling efforts and outcomes. Though overall revenue had not fallen much, but the veteran seller had started doubting his tried and tested relational solution selling model. Case dilemma involves the selection of appropriate selling approaches e.g. solution, insight or tiebreaker selling for different situations. This case also offers an opportunity to discuss, how to use online channels to complement B2B selling.

Complexity Academic Level

This teaching case study is suitable for the graduate-level programme in marketing management.

Supplementary materials

Teaching Notes are available for educators only.

Subject code

CSS 8: Marketing
Intern to employee conversion via person–organization fit
Authors: Rose Philip S. , Teo Stephen T.T. , Nguyen Diep , Nguyen Nguyen Phong
Published: May 2021

Purpose

Internships are utilized globally to recruit graduate employees. However, there is a limited understanding of the process by which interns convert into regular employees, particularly in non-Western research contexts. Integrating attraction–selection–attrition (ASA) theory and proactive career behaviors, this study identifies the mechanisms influencing interns' intentions to convert into regular employment in host organizations in Vietnam.

Design/methodology/approach

Time lagged, questionnaire data were collected from 669 final-year undergraduate business and economics students who participated in internship programs in a large metropolitan city in Vietnam.

Findings

The results indicate that the interns who exhibit proactive career behaviors are more likely to foster high-quality reciprocal relationships with their supervisors and work colleagues during internships. These positive relations magnify interns' intentions to become regular employees via their perceived person–organization fit.

Practical implications

This study has implications for higher education institutions and host organizations when designing internship programs to maximize employment outcomes via conversion of interns into regular employees.

Originality/value

Previous studies have not tested the critical aspect of ASA theory regarding the personalities of the interns when building work-related relationships that result in the person–organization fit before accepting job offers from host organizations.