bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunogenicity of heterologous BNT162b2 booster in fully vaccinated individuals with CoronaVac against SARS-CoV-2 variants Delta and Omicron: the Dominican Republic Experience
Authors: Pérez-Then Eddy , Lucas Carolina , Monteiro Valter Silva , Miric Marija , Brache Vivian , Cochon Leila , Vogels Chantal B. F. , De la Cruz Elena , Jorge Aidelis , De los Santos Margarita , Leon Patricia , Breban Mallery I. , Billig Kendall , Yildirim Inci , Pearson Claire , Downing Randy , Gagnon Emily , Muyombwe Anthony , Razeq Jafar , Campbell Melissa , Ko Albert , Omer Saad B. , Grubaugh Nathan D. , Vermund Sten H. , Iwasaki Akiko
Published: December 2021

The recent emergence of the SARS-CoV-2 Omicron variant is raising concerns because of its increased transmissibility and by its numerous spike mutations with potential to evade neutralizing antibodies elicited by COVID-19 vaccines. The Dominican Republic was among the first countries in recommending the administration of a third dose COVID-19 vaccine to address potential waning immunity and reduced effectiveness against variants. Here, we evaluated the effects of a heterologous BNT162b2 mRNA vaccine booster on the humoral immunity of participants that had received a two-dose regimen of CoronaVac, an inactivated vaccine used globally. We found that heterologous CoronaVac prime followed by BNT162b2 booster regimen induces elevated virus-specific antibody levels and potent neutralization activity against the ancestral virus and Delta variant, resembling the titers obtained after two doses of mRNA vaccines. While neutralization of Omicron was undetectable in participants that had received a two-dose regimen of CoronaVac vaccine, BNT162b2 booster resulted in a 1.4-fold increase in neutralization activity against Omicron, compared to two-dose mRNA vaccine. Despite this increase, neutralizing antibody titers were reduced by 6.3-fold and 2.7-fold for Omicron compared to ancestral and Delta variant, respectively. Surprisingly, previous SARS-CoV-2 infection did not affect the neutralizing titers for Omicron in participants that received the heterologous regimen. Our findings have immediate implications for multiples countries that previously used a two-dose regimen of CoronaVac and reinforce the notion that the Omicron variant is associated with immune escape from vaccines or infection-induced immunity, highlighting the global need for vaccine boosters to combat the impact of emerging variants.
Structures of the Omicron spike trimer with ACE2 and an anti-Omicron antibody: mechanisms for the high infectivity, immune evasion and antibody drug discovery
Authors: Yin Wanchao , Xu Youwei , Xu Peiyu , Cao Xiaodan , Wu Canrong , Gu Chunyin , He Xinheng , Wang Xiaoxi , Huang Sijie , Yuan Qingning , Wu Kai , Hu Wen , Huang Zifu , Liu Jia , Wang Zongda , Jia Fangfang , Xia Kaiwen , Liu Peipei , Wang Xueping , Song Bin , Zheng Jie , Jiang Hualiang , Cheng Xi , Jiang Yi , Deng Su-Jun , Xu H. Eric
Published: December 2021

The Omicron variant of SARS-CoV-2 has rapidly become the dominant infective strain and the focus efforts against the ongoing COVID-19 pandemic. Here we report an extensive set of structures of the Omicron spike trimer by its own or in complex with ACE2 and an anti-Omicron antibody. These structures reveal that most Omicron mutations are located on the surface of the spike protein, which confer stronger ACE2 binding by nearly 10 folds but become inactive epitopes resistant to many therapeutic antibodies. Importantly, both RBD and the closed conformation of the Omicron spike trimer are thermodynamically unstable, with the melting temperature of the Omicron RBD decreased by as much as 7°C, making the spiker trimer prone to random open conformations. An unusual RBD-RBD interaction in the ACE2-spike complex unique to Omicron is observed to support the open conformation and ACE2 binding, serving the basis for the higher infectivity of Omicron. A broad-spectrum therapeutic antibody JMB2002, which has completed Phase 1 clinical trial, is found to interact with the same two RBDs to inhibit ACE2 binding, in a mode that is distinguished from all previous antibodies, thus providing the structural basis for the potent inhibition of Omicron by this antibody. Together with biochemical data, our structures provide crucial insights into higher infectivity, antibody evasion and inhibition of Omicron.
Testing for genetic assimilation with phylogenetic comparative analysis: Conceptual, methodological, and statistical considerations
Authors: Gunderson Alex R. , Revell Liam J.
Published: December 2021

Genetic assimilation is a process that leads to reduced phenotypic plasticity during adaptation to novel conditions, a potentially important phenomenon under global environmental change. Null expectations when testing for genetic assimilation, however, are not always clear. For instance, the statistical artifact of regression to the mean could bias us towards detecting genetic assimilation when it has not occurred. Likewise, the specific mechanism underlying plasticity expression may affect null expectations under neutral evolution. We used macroevolutionary numerical simulations to examine both of these important issues and their interaction, varying whether or not plasticity evolves, the evolutionary mechanism, trait measurement error, and experimental design. We also modified an existing reaction norm correction method to account for phylogenetic non-independence. We found: 1) regression to the mean is pervasive and can generate spurious support for genetic assimilation; 2) experimental design and post-hoc correction can minimize this spurious effect; and 3) neutral evolution can produce patterns consistent with genetic assimilation without constraint or selection, depending on the mechanism of plasticity expression. Additionally, we re-analyzed published macroevolutionary data supporting genetic assimilation, and found that support was lost after proper correction. Considerable caution is thus required whenever investigating genetic assimilation and reaction norm evolution at macroevolutionary scales.
A meta-analysis of task-based differences in bilingual L1 and L2 language networks
Authors: Comstock Lindy , Oliver Bruce
Published: December 2021

The functional organization of first (L1) and second (L2) language processing in bilinguals remains a topic of great interest to the neurolinguistics community. Functional magnetic resonance imaging (fMRI) studies report meaningful differences in the location and extent of hemodynamic changes between tasks performed in the L1 and L2, yet there is no consensus on whether these networks can be considered truly distinct. In part, this may be due to the multiplicity of task designs implemented in such studies, which complicates the interpretation of their findings. This paper compares the results of previous bilingual meta-analyses to a new ALE meta-analysis that categorizes neuroimaging studies by task design. Factors such as the age of L2 acquisition (AoA) and the L2 language proficiency level of participants are also considered. The findings support previous accounts of the effect of participant characteristics on linguistic processing, while at the same time revealing dissociable differences in fMRI activation for L1 and L2 networks within and across tasks that appear independent of these external factors.
Screening of Chimeric GAA Variants in a Preclinical Study of Pompe Disease Results in Candidate Vector for Hematopoietic Stem Cell Gene Therapy
Authors: Dogan Yildirim , Barese Cecilia N. , Schindler Jeffrey W. , Yoon John K. , Unnisa Zeenath , Guda Swaroopa , Jacobs Mary E. , Oborski Christine , Clarke Diana L. , Schambach Axel , Pfeifer Richard , Harper Claudia , Mason Chris , van Til Niek P.
Published: December 2021

Pompe disease is a rare genetic neuromuscular disorder caused by acid alpha-glucosidase (GAA) deficiency resulting in lysosomal glycogen accumulation and progressive myopathy. Enzyme replacement therapy (ERT) is the current standard of care, which prolongs the quality of life for Pompe patients. However, ERT has limitations due to lack of enzyme penetration into the central nervous system (CNS) and skeletal muscles, immunogenicity against the recombinant enzyme, and requires life-long biweekly infusions. In a preclinical mouse model, a clinically relevant promoter to drive lentiviral vector-mediated expression of engineered GAA in autologous hematopoietic stem and progenitor cells (HSPC) was tested with nine unique human chimeric GAA coding sequences incorporating distinct peptide tags and codon-optimization iterations. Vectors including glycosylation independent lysosomal targeting (GILT) tags resulted in effective GAA enzyme delivery into key disease tissues with enhanced reduction of glycogen, myofiber and CNS vacuolation, compared to non-tagged GAA in Gaa knockout mice, a model of Pompe disease. Genetically modified microglial cells in brains were detected at low levels, but provided robust correction. Furthermore, an aminoacid substitution in the tag added to reduced capacity to induce insulin signaling and there was no evidence of off-target effects. This study demonstrated the therapeutic potential of lentiviral HSPC gene therapy exploiting optimized GAA tagged coding sequences to reverse Pompe disease pathology in a preclinical mouse model providing a promising vector candidate for further investigation.

One Sentence Summary

A candidate vector for hematopoietic stem cell gene therapy of Pompe disease.
Evidence of learning walks related to scorpion home burrow navigation
Authors: Gaffin Douglas D. , Muñoz Maria G. , Hoefnagels Mariëlle
Published: December 2021

TheNavigation by Chemotextural Familiarity Hypothesis(NCFH) suggests that scorpions use their midventral pectines to gather chemical and textural information near their burrows and use this information as they subsequently return home. For NCFH to be viable, animals must somehow acquire home-directed “tastes” of the substrate, such as through path integration (PI) and/or learning walks. We conducted laboratory behavioral trials using desert grassland scorpions (Paruroctonus utahensis). Animals reliably formed burrows in small mounds of sand we provided in the middle of circular, sandlined behavioral arenas. We processed overnight infrared video recordings with a MATLAB script that tracked animal movements at 1-2 s intervals. In all, we analyzed the movements of 23 animals, representing nearly 1500 hours of video recording. We found that once animals established their home burrows, they immediately made one to several short, looping excursions away from and back to their burrows before walking greater distances. We also observed similar excursions when animals made burrows in level sand in the middle of the arena (i.e., no mound provided). These putative learning walks, together with recently reported PI in scorpions, may provide the crucial home-directed information requisite for NCFH.
A single cell transcriptional roadmap for human pacemaker cell differentiation
Authors: Wiesinger Alexandra , Li Jiuru , Fokkert Lianne , Bakker Priscilla , Verkerk Arie O. , Christoffels Vincent M. , Boink Gerard J.J. , Devalla Harsha D.
Published: December 2021

Each heartbeat is triggered by the sinoatrial node, the natural pacemaker of the heart. Animal models have revealed that pacemaker cells share a common progenitor with the (pro)epicardium, and that the pacemaker cardiomyocytes further diversify into “transitional”, “tail” and “head” subtypes. However, the underlying molecular mechanisms are poorly understood. Here, we studied the differentiation of human induced pluripotent stem cells into pacemaker cardiomyocytes. Single cell RNA sequencing identified the presence of myocardial populations resembling subtypes present in the formed sinoatrial node, and in addition revealed a side population of (pro)epicardial cells. Time-course trajectory analysis uncovered a role for WNT signaling in determining myocardial versus proepicardial cell fate. We experimentally demonstrate that presence of WNT signaling prior to the branching point of a common progenitor enhances proepicardial cell differentiation at the expense of myocardial pacemaker cells. Furthermore, we uncover a role for TGFβ and WNT signaling in differentiation towards transitional and head pacemaker subtypes, respectively. Our findings provide new biological insights into human pacemaker differentiation, open avenues for complex disease modeling and inform regenerative approaches.
Interleukin 4 controls the role of macrophages in pulmonary metastatic tumor cell seeding and growth
Authors: Rodriguez-Tirado Carolina , Entenberg David , Li Jiufeng , Qian Bin-Zhi , Condeelis John S. , Pollard Jeffrey W
Published: December 2021

Metastasis is the systemic manifestation of cancer and the main cause of death from breast cancer. In mouse models of lung metastases, recruitment of classical monocytes from blood to the lung and their differentiation to metastasis-associated macrophages (MAMs) facilitate cancer cell extravasation, survival, and growth. Ablation of MAMs or their monocytic progenitors inhibits metastasis. We hypothesized that factors controlling macrophage polarization modulate tumor cell extravasation in the lung. We evaluated whether signaling by Th1 or Th2 cytokines in macrophages affected trans-endothelial migration of tumor cells in vitro. Interferon γ and LPS inhibited macrophage-dependent tumor cell extravasation while the Th2 cytokine interleukin-4 (IL4) enhanced this process. We demonstrated that IL4 receptor (IL4rα)null mice develop fewer and smaller lung metastasis. Adoptive transfer of wild type monocytes toIL4rαdeficient mice rescued this phenotype. IL4 signaling in macrophages controls the expression of the chemokine receptor CXCR2, necessary for IL4-mediated tumor cell extravasation in vitro. Furthermore, IL4 signaling in macrophages transcriptionally regulates several other genes already causally associated with lung metastasis including CCL2, CSF1, CCR1, HGF and FLT1. The central role for IL4 signaling in MAMs was confirmed by high-resolution intravital imaging of the lung in mice at the time of metastatic seeding, which showed reduced physical interaction between tumor cells andIL4rα-deficient macrophages. This interaction enhances tumor cell survival. These data indicate that IL4 signaling in monocytes and macrophages is key during seeding and growth of breast metastasis in the lung as it regulates pro-tumoral paracrine signaling between cancer cells and macrophages.
Evaluation of chest X-Ray with automated interpretation algorithms for mass tuberculosis screening in prisons
Authors: Soares Thiego Ramon , de Oliveira Roberto Dias , Liu Yiran E. , Silva Santos Andrea da , Santos Paulo Cesar Pereira dos , Monte Luma Ravena Soares , Oliveira Lissandra Maia de , Park Chang Min , Hwang Eui Jin , Andrews Jason R. , Croda Julio
Published: December 2021

Rationale

The World Health Organization (WHO) recommends systematic tuberculosis (TB) screening in prisons. Evidence is lacking for accurate and scalable screening approaches in this setting.

Objectives

To assess the diagnostic accuracy of artificial intelligence-based chest x-ray interpretation algorithms for TB screening in prisons.

Methods

Prospective TB screening study in three prisons in Brazil from October 2017 to December 2019. We administered a standardized questionnaire, performed chest x-ray in a mobile unit, and collected sputum for confirmatory testing using Xpert MTB/RIF and culture. We evaluated x-ray images using three algorithms (CAD4TB version 6, LunitTB and qXR) and compared their diagnostic accuracy. We utilized multivariable logistic regression to assess the effect of demographic and clinical characteristics on algorithm accuracy. Finally, we investigated the relationship between abnormality scores and Xpert semi-quantitative results.

Measurements and Main Results

Among 2,075 incarcerated individuals, 259 (12.5%) had confirmed TB. All three algorithms performed similarly overall with AUCs of 0.87-0.91. At 90% sensitivity, only LunitTB and qXR met the WHO Target Product Profile requirements for a triage test, with specificity of 84% and 74%, respectively. All algorithms had variable performance by age, prior TB, smoking, and presence of TB symptoms. LunitTB was the most robust to this heterogeneity, but nonetheless failed to meet the TPP for individuals with previous TB. Abnormality scores of all three algorithms were significantly correlated with sputum bacillary load.

Conclusions

Automated x-ray interpretation algorithms can be an effective triage tool for TB screening in prisons. However, their specificity is insufficient in individuals with previous TB.
AtERF60,negatively regulatesABR1to modulate basal resistance response in Arabidopsis
Authors: Joshi Ashutosh , Phukan Ujjal J , Singh Neeti , Jeena Gajendra Singh , Kumar Sunil , Pandey Durgesh Kumar , Pandey Alok , Tripathi Vineeta , Shukla Rakesh Kumar
Published: December 2021

APETALA2 (AP2)/ERF family transcription factors (TFs) contribute an important function against various external cues. Our study reportsAtERF60, an AP2/ERF TF, which plays a key role in regulating theABR1gene, leading to an altered basal resistance response in Arabidopsis.AtERF60is induced in response to drought, salt, abscisic acid (ABA), salicylic acid (SA), and bacterial pathogenPstDC3000 infection.AtERF60interacts with DEHYDRATION RESPONSE ELEMENTS and GCC box, indicating its ability to regulate multiple responses. The overexpressing lines ofAtERF60demonstrated increased resistance toPstDC3000 infection, whereaserf60mutant lines showed increased susceptibility. Complementation of theerf60mutant background exhibits no significant difference towardsPstDC3000 infection compared with the WT Col-0. Microarray and qRT-PCR analysis of overexpression and mutant lines indicated thatAtERF60regulates stress-inducible genes. The induction of these differentially expressed transcripts was significantly increased inerf60mutant lines, whereas it was reversed in wild-type lines whenAtERF60was complemented.ABR1was one of the differentially expressed transcripts, and we discovered thatAtERF60interacts with the DREcis-elements in theABR1promoter. Further, qRT-PCR expression analysis after infection withPstDC3000 inAtERF60-OX,erf60and its complementation background suggest that the mutation inAtERF60upregulatesABR1activity, leading to the enhanced susceptibility towardsPstDC3000. Conversely,AtERF60overexpression suppressesABR1activity, strengthening the basal resistance responses of Arabidopsis.
Biomechanical and biochemical assessment of YB-1 expression in melanoma cells
Authors: Cykowska Anna , Hofmann Ulf Krister , Tiwari Aadhya , Kosnopfel Corinna , Riester Rosa , Danalache Marina
Published: December 2021

Malignant melanoma is the most lethal form of skin cancer; its incidence has increased over the last five decades. Y-box binding protein 1 (YB-1) plays a prominent role in mediating metastatic behavior by promoting epithelial-to-mesenchymal transition (EMT) processes. Migratory melanoma cells exhibit two major phenotypes: elongated mesenchymal or rounded amoeboid. The actomyosin cytoskeleton is key in both phenotypes, but intermediate filaments also undergo a significant rearrangement process, switching from cytokeratin-rich to vimentin and nestin-rich network. In this study, we aimed to investigate to what extent YB-1 impacts the biomechanical (cell stiffness) and biochemical aspects of melanoma cells and their cytoskeleton. To this end, we subjected A375 YB-1 knock-out and parental cells to atomic force microscopy investigations (stiffness determination), immunolabelling, and proteome analysis. We found that YB-1 expressing cells were significantly stiffer compared to the corresponding YB-1 knock-out cell line. Proteomic analysis revealed that expression of YB-1 results in a strong co-expression of nestin, vimentin, fascin-1, and septin-9. In the YB-1 knock-out nestin was completely depleted, but zyxin was strongly upregulated. Collectively, our results showed that YB-1 knock-out acquires some characteristics of mesenchymal phenotype but lacks important markers of malignancy and invasiveness such as nestin or vimentin. We posit that there is an association of YB-1 expression with an amoeboid phenotype, which would explain the increased migratory capacity.
Subcellular dynamics and functional activity of the cleaved Na+channel β1 subunit intracellular domain
Authors: Haworth Alexander S. , Hodges Samantha L. , Capatina Alina L. , Isom Lori L. , Baumann Christoph G. , Brackenbury William J.
Published: December 2021

The voltage-gated Na+channel β1 subunit, encoded bySCN1B, regulates cell surface expression and gating of α subunits, and participates in cell adhesion. β1 is cleaved by α/β and γ-secretases, releasing an extracellular domain and intracellular domain (ICD) respectively. AbnormalSCN1Bexpression/function is linked to pathologies including epilepsy, cardiac arrhythmia, and cancer. In this study, we sought to determine the effect of secretase cleavage on β1 function in breast cancer cells. Using a series of GFP-tagged β1 constructs, we show that β1-GFP is mainly retained intracellularly, particularly in the endoplasmic reticulum and endolysosomal pathway, and accumulates in the nucleus. Reduction in endosomal β1-GFP levels occurred following γ-secretase inhibition, implicating endosomes, and/or the preceding plasma membrane, as important sites for secretase processing. Using live-cell imaging, we report β1ICD-GFP accumulation in the nucleus. Furthermore, β1-GFP and β1ICD-GFP both increased Na+current, whereas β1STOP-GFP, which lacks the ICD, did not, thus highlighting that the β1-ICD was necessary and sufficient to increase Na+current measured at the plasma membrane. Importantly, although the endogenous Na+current expressed in MDA-MB-231 cells is TTX-resistant (carried by Nav1.5), the Na+current increased by β1-GFP or β1ICD-GFP was TTX-sensitive. In addition, β1-GFP increased mRNA levels of the TTX-sensitive α subunitsSCN1A/Nav1.1 andSCN9A/Nav1.7. Taken together, this work suggests that the β1-ICD is a critical regulator of α subunit function in cancer cells. Our data further highlight that γ-secretase may play a key role in regulating β1 function in breast cancer.
Biogenesis of mature piRNAs in Caenorhabditis elegans is dependent on orchestration between multiple ribonucleases and PRG-1
Authors: Samajdar Aniruddha , Chowdhury Tamoghna , Chatterjee Saibal
Published: December 2021

Piwi-interacting RNAs (piRNAs) are an animal-specific class of germline-enriched small non-coding RNAs that shape transcriptome, as well as ensure genomic integrity and fertility by regulating transposons and other selfish genetic elements. In Caenorhabditis elegans mature piRNAs are 21-nucleotides long, begin with a monophosphorylated uridine, and they associate with PRG-1 to form piRISCs that scan the transcriptome for ‘non-self’ sequences. However, these piRNAs are born as longer 5’-capped transcripts, where PARN-1, a 3’-5’ exoribonuclease, contributes to the formation of the mature 3’-end. But, till date, the 5’-processing events remain elusive. We demonstrate that the recently identified endoribonuclease activity of XRN-2 is involved in the processing of the 5’-end of precursor piRNAs in worms. Depletion of XRN-2 results in reduced mature piRNA levels, with concomitant increase in levels of the 5’-capped precursors. We also reveal that the piRNAs born as longer precursor molecules (≥60 nt), prior to 5’-end processing, undergo ENDU-1-mediated endoribonucleolytic processing of their 3’-ends. Our in vitro RNA-protein interaction studies unravel the mechanistic interactions between XRN-2 and PRG-1 towards the formation of mature 5’-ends of piRNAs. In vivo experiments employing prg-1 mutant worms indicate that XRN-2 has the potential to perform clearance of precursors that are not bound and protected by PRG-1. Finally, we also demonstrate that XRN-2 is not only important for the generation of mature piRNAs and piRNA-dependent endo-siRNAs, but through yet unknown pathways, it also affects piRNA-independent endo-siRNAs that shape transcriptome, as well as contribute to genomic integrity via regulation of transposable elements.
Transcription Profile And Pathway Analysis Of The Endocannabinoid Receptor Inverse Agonist AM630 In The Core And Infiltrative Boundary Of Human Glioblastoma Cells
Authors: Williams Gareth , Chambers David , Rahman Ruman , Molina-Holgado Francisco
Published: December 2021

Background

We have previously reported that the endocannabinoid receptor inverse agonist AM630 is a potent inhibitor of isocitrade dehydrogenase-1 wild-type glioblastoma (GBM) core tumor cell proliferation. To uncover the mechanism behind the anti-tumour effects we have performed a transcriptional analysis of AM630 activity both in the tumour core cells (U87) and the invasive margin cells (GIN-8), the latter representing a better proxy of post-surgical residual disease.

Results

The core and invasive margin cells exhibited markedly different gene expression profiles and only the core cells had high expression of a potential AM630 target, the CB1 receptor. Both cell types had moderate expression of the HTR2B serotonin receptor, a reported AM630 target. We found that the AM630 driven transcriptional response was substantially higher in the central cells than in the invasive margin cells, with the former driving the up regulation of immune response and the down regulation of cell cycle and metastatic pathways and correlating with transcriptional responses driven by established anti-neoplastics as well as serotonin receptor antagonists.

Conclusion

Our results highlight the different responsiveness of the core and invasive margin cells. Taken together, whilst our findings identify AM630 as an anti-neoplastic drug, showing a high correlation with known anti-proliferative drugs, we find distinct drug sensitivies of the infiltrative margin relative to contrast-enhanced core regions of GBM upon which failed molecular targeted therapies to date have been predicated.
Shrimp draft genome contains independent clusters of ancient and current endogenous viral elements (EVE) of the parvovirus IHHNV
Authors: Taengchaiyaphum Suparat , Wongkhaluang Prapatsorn , Flegel Timothy W. , Sritunyalucksana Kallaya
Published: December 2021

Background

Shrimp have the ability to accommodate viruses in long term, persistent infections without signs of disease. Endogenous viral elements (EVE) play a role in this process probably via production of negative-sense Piwi-interacting RNA (piRNA)-like fragments. These bind with Piwi proteins to dampen viral replication via the RNA interference (RNAi) pathway. We searched a draft genome of the giant tiger shrimp (Penaeus monodon)(GenBank record JABERT000000000) for the presence of EVE related to a shrimp parvovirus originally named infectious hypodermal and hematopoietic necrosis virus (IHHNV).

Results

The shrimp draft genome contained 3 piRNA-like gene clusters containing scrambled IHHNV EVE. Two clusters were located distant from one another in linkage group 35 (LG35). Both LG35 clusters contained multiple DNA fragments with high homology (99%) to GenBank records DQ228358 and EU675312 that were both called “ non-infectious IHHNV Type A” (IHHNV-A) when originally discovered. However, our results and those from a recent Australian P. monodon genome assembly indicate that the relevant GenBank records for IHHNV-A are sequence-assembly artifacts derived from scrambled and fragmental IHHNV-EVE. Although the EVE in the two LG35 clusters showed high homology only to IHHNV-A, the clusters were separate and distinct with respect to the arrangement (i.e., order and reading direction) and proportional content of the IHHNV-A GenBank records. We conjecture that these 2 clusters may constitute independent allele-like clusters on a pair of homologous chromosomes. The third EVE cluster was found in linkage group 7 (LG7). It contained EVE with high homology (99%) only to GenBank record AF218266 with the potential to protect shrimp against infectious IHHNV.

Conclusions

Our results suggested the possibility of viral-type specificity in EVE clusters. Specificity is important because whole EVE clusters for one viral type would be transmitted to offspring as collective hereditary units. This would be advantageous if one or more of the EVE within the cluster were protective against disease caused by the cognate virus. It would also facilitate gene editing for removal of non-protective EVE clusters or for transfer of protective EVE clusters to genetically improve existing shrimp breeding stocks that might lack them.
Regulation of Kidney Mitochondrial Function by Caloric Restriction
Authors: Serna Julian D. C. , Amaral Andressa G. , Caldeira da Silva Camille C. , Munhoz Ana C. , Menezes-Filho Sergio L. , Kowaltowski Alicia J.
Published: December 2021

Caloric restriction (CR) prevents obesity, promotes healthy aging, and increases resilience against several pathological stimuli in laboratory rodents. At the mitochondrial level, protection promoted by CR in the brain and liver is related to higher calcium uptake rates and capacities, avoiding Ca2+-induced mitochondrial permeability transition. Dietary restriction has also been shown to increase kidney resistance against damaging stimuli such as ischemia/reperfusion, but if these effects are related to similar mitochondrial adaptations had not yet been uncovered. Here, we characterized changes in mitochondrial function in response to six months of CR in rats, measuring bioenergetic parameters, redox balance and calcium homeostasis. CR promoted an increase in mitochondrial oxygen consumption rates under non-phosphorylating and uncoupled conditions. While CR prevents mitochondrial reactive oxygen species production in many tissues, in kidney we found that mitochondrial H2O2 release was enhanced, although levels of carbonylated proteins and methionine sulfoxide were unchanged. Surprisingly, and opposite to the effects observed in brain and liver, mitochondria from CR animals are more prone to Ca2+-induced mitochondrial permeability transition. CR mitochondria also displayed higher calcium uptake rates, which were not accompanied by changes in calcium efflux rates, nor related to altered inner mitochondrial membrane potentials or the amounts of the mitochondrial calcium uniporter (MCU). Instead, increased mitochondrial calcium uptake rates in CR kidneys correlate with a loss of MICU2, an MCU modulator. Interestingly, MICU2 is also modulated by CR in liver, suggesting it has a broader diet-sensitive regulatory role controlling mitochondrial calcium homeostasis. Together, our results highlight the organ-specific bioenergetic, redox, and ionic transport effects of CR. Specifically, we describe the regulation of the expression of MICU2 and its effects on mitochondrial calcium transport as a novel and interesting aspect of the metabolic responses to dietary interventions.
Investigating the in vivo biodistribution of extracellular vesicles isolated from various human cell sources using positron emission tomography
Authors: Rosenkrans Zachary T. , Thickens Anna S. , Kink John A. , Aluicio-Sarduy Eduardo , Engle Jonathan W. , Hematti Peiman , Hernandez Reinier
Published: December 2021

Noninvasive imaging is a powerful tool for understanding the in vivo behavior of drug delivery systems and successfully translating promising platforms into the clinic. Extracellular vesicles (EVs), nano-sized vesicles with a lipid bilayer produced by nearly all cell types, are emerging platforms for drug delivery. To date, the biodistribution of EVs has been insufficiently investigated, particularly using nuclear imaging-based modalities such as positron emission tomography (PET). Herein, we developed positron-emitting radiotracers to investigate the biodistribution of EVs isolated from various human cell sources using PET imaging. Chelator conjugation did not impact EVs size and subsequent radiolabeling was found to be highly efficient and stable with Zr-89 (t1/2 = 78.4 h). In vivo tracking of EVs isolated from bone marrow-derived mesenchymal stromal cells (BMSCs EVs), primary human macrophages (Mϕ EVs), and a melanoma cell line (A375 EVs) were performed in immunocompetent ICR mice. Imaging studies revealed excellent in vivo circulation for all EVs, with a half-life of approximately 12 h. Significantly higher liver uptake was observed for Mϕ EVs, evidencing the tissue tropism of EV and highlighting the importance of carefully choosing EVs cell sources for drug delivery applications. Conversely, the liver, spleen, and lung uptake of the BMSC EVs and A375 EVs was relatively low. We also investigated the impact of immunodeficiency on the biodistribution of BMSC EVs using NSG mice. The spleen uptake drastically increased in NSG mice, which could confound results of therapeutic studies employing this mouse models. Lastly, PET imaging studies in a melanoma tumor model demonstrated efficient tumor uptake of BMSC EVs following intravenous injection. Overall, these imaging studies evidenced the potential of EVs as carriers to treat a variety of diseases, such as cancer or in regenerative medicine applications, and the necessity to understand EVs tropism to optimize their therapeutic deployment.
Subgenomic SARS-CoV-2 replicon and reporter replicon cell lines enable ultrahigh throughput antiviral screening and mechanistic studies with antivirals, viral mutations or host factors that affect COVID-19 replication
Authors: Lan Shuiyun , Tedbury Philip R. , Ong Yee Tsuey , Shah Raven , Slack Ryan L. , Cilento Maria E. , Zhang Huanchun , Du Haijuan , Lulkin Nicole , Le Uyen , Kirby Karen A. , Melcak Ivo , Cantara William A. , Boggs Emerson A. , Sarafianos Stefan G.
Published: December 2021

Replicon-based technologies were used to develop reagents and assays for advanced drug discovery efforts against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and for examining all facets of the SARS-CoV-2 replication cycle at reduced biocontainment level. Specifically: a) 21 replicons were cloned in bacterial artificial chromosomes (BACs) and delivered as transfectable plasmid DNA or transcribed RNA in various cell types. Replicons carrying mutations that affect the activity or antiviral susceptibility of SARS-CoV-2 enzymes were used to establish utility for mechanistic studies while reducing the community risks associated with gain-of-function studies in fully infectious virus. b) A BHK-21 stable cell line harboring SARS-CoV-2 replicon was generated and characterized in robust high/ultra-high throughput assays of antiviral efficacy with orthogonal SARS-CoV-2 replication reporter genes (Nano luciferase and enhanced green fluorescent protein-eGFP); the estimated antiviral potencies in the fully infectious SARS-CoV-2 system and in the transient or stable replicon systems were similar. HEK293 and Calu1 stable cell lines expressing SARS-CoV-2 replicon have also been prepared. Finally, c) we generated trans-encapsidated replicons by co-expression with SARS-CoV-2 structural proteins, thus producing single-round infectious SARS-CoV-2 virus-like particles that are able to transduce susceptible cell types and have expanded utility to enable study of virion assembly and entry into target cells. Hence, these SARS-CoV-2 replicon-based reagents include a novel approach to replicon-harboring cell line generation and are valuable tools that can be used at lower biosafety level (BSL2) for drug discovery efforts, characterization of SARS-CoV-2 and variant evolution in the COVID-19 pandemic, mechanisms of inhibition and resistance, and studies on the role of SARS-CoV-2 genes and host dependency factors.
Short-term Projections based on Early Omicron Variant Dynamics in England
Authors: Keeling Matt J. , Brooks-Pollock Ellen , Challen Rob , Danon Leon , Dyson Louise , Gog Julia R. , Guzmán Rincón Laura , Hill Edward M. , Pellis Lorenzo , Read Jonathan M. , Tildesley Michael J.
Published: December 2021

Throughout the ongoing COVID-19 pandemic, the worldwide transmission and replication of SARS-COV-2, the causative agent of COVID-19 disease, has resulted in the opportunity for multiple mutations to occur that may alter the virus transmission characteristics, the effectiveness of vaccines and the severity of disease upon infection. The Omicron variant (B.1.1.529) was first reported to the WHO by South Africa on 24 November 2021 and was declared a variant of concern by the WHO on 26 November 2021. The variant was first detected in the UK on 27 November 2021 and has since been reported in a number of countries globally where it is frequently associated with rapid increase in cases. Here we present analyses of UK data showing the earliest signatures of the Omicron variant and mathematical modelling that uses the UK data to simulate the potential impact of this variant in the UK. In order to account for the uncertainty in transmission advantage, vaccine escape and severity at the time of writing, we carry out a sensitivity analysis to assess the impact of these variant characteristics on future risk.
Information flow, Gating, and Energetics in dimeric molecular motors
Authors: Takaki Ryota , Mugnai Mauro L. , Thirumalai D.
Published: December 2021

Molecular motors belonging to the kinesin and myosin super family hydrolyze ATP by cycling through a sequence of chemical states. These cytoplasmic motors are dimers made up of two linked identical monomeric globular proteins. Fueled by the free energy generated by ATP hydrolysis, the motors walk on polar tracks (microtubule or filamentous actin) processively, which means that only one head detaches and executes a mechanical step while the other stays bound to the track. Thus, the one motor head must regulate chemical state of the other, referred to as “gating”, a concept that is not fully understood. Inspired by experiments, showing that only a fraction of the energy from ATP hydrolysis is used to advance the kinesin motors against load, we demonstrate that additional energy is used for coordinating the chemical cycles of the two heads in the dimer - a feature that characterizes gating. To this end, we develop a general framework based on information theory and stochastic thermodynamics, and establish that gating could be quantified in terms of information flow between the motor heads. Applications of the theory to kinesin-1 and Myosin V show that information flow occurs, with positive cooperativity, at external resistive loads that are less than a critical value, Fc. When force exceeds Fc, effective information flow ceases. Interestingly, Fc, which is independent of the input energy generated through ATP hydrolysis, coincides with force at which the probability of backward steps starts to increase. Our findings suggest that transport efficiency is optimal only at forces less than Fc, which implies that these motors must operate at low loads under in vivo conditions.
Research on robust adaptive sliding film fault-tolerant control under nonlinear distortion of signal transmission in amorphous flat air-to-ground wireless ad-hoc network system
Authors: Wang Zhifang , Yu Jianguo , Lin Shangjing
Published: December 2021

Purpose

To solve the above problems and ensure the stability of the ad hoc network node topology in the process of wireless signal transmission, this paper aims to design a robust adaptive sliding film fault-tolerant controller under the nonlinear distortion of signal transmission in an amorphous flat air-to-ground wireless ad hoc network system.

Design/methodology/approach

This paper designs a robust adaptive sliding film fault-tolerant controller under the nonlinear distortion of signal transmission in an amorphous flat air-to-ground wireless ad hoc network system.

Findings

The simulation results show that the amorphous flat wireless self-organizing network system has good nonlinear distortion fault-tolerant correction ability under the feedback control of the designed controller, and the system has the asymptotically stable convergence ability; the test results show: the node topology of the self-organizing network structural stability is significantly improved, which provides a foundation for the subsequent realization of long-distance transmission of ad hoc network nodes.

Research limitations/implications

Because of the chosen research approach, the research results may lack generalizability. Therefore, researchers are encouraged to test the proposed propositions further.

Originality/value

The controller can extract the fault information caused by nonlinear distortion in the wireless signal transmission process, and at the same time, its feedback matrix K can gradually converge the generated wireless signal error to zero, to realize the stable transmission of the wireless signal.
Conformal transformation of Douglas space of second kind with special (α, β)-metric
Authors: Ranjan Rishabh , Pandey P.N. , Paul Ajit
Published: December 2021

Purpose

In this paper, the authors prove that the Douglas space of second kind with a generalised form of special (α, β)-metric F, is conformally invariant.

Design/methodology/approach

For, the authors have used the notion of conformal transformation and Douglas space.

Findings

The authors found some results to show that the Douglas space of second kind with certain (α, β)-metrics such as Randers metric, first approximate Matsumoto metric along with some special (α, β)-metrics, is invariant under a conformal change.

Originality/value

The authors introduced Douglas space of second kind and established conditions under which it can be transformed to a Douglas space of second kind.
RE-engineered factory acceptance testing under the new normal
Authors: Peiris Sanduni , De Silva Nayanthara
Published: December 2021

Purpose

Factory acceptance testing (FAT) in the construction industry has been severely hampered due to restrictions in cross-border travel resulting from the COVID-19 pandemic. Consequently, virtual FAT (vFAT) became a popular substitute for physical FAT. However, the credibility of vFAT is being questioned because it was adopted without much scrutiny. Hence, this study is aimed at investigating vFATs and re-engineering the FAT process to suit an effective vFAT environment.

Design/methodology/approach

A comprehensive literature search on FAT procedures was followed by two stages of expert interviews with eight leading subject experts and a case study. The findings were analysed using code-based content analysis on NVivo software.

Findings

Strengths of vFATs include “reduction in cost and time consumed”, “flexibility for more participants” and “faster orders”. Most emphasized weaknesses include “lack of reliability” and “lack of technology transfer”. vFAT has mostly increased test reliability by “improving accessibility” and has decreased reliability by “restricting physical touch and feel observation of the equipment”. A four-step vFAT process was developed with a noteworthy additional step called “Pre-FAT Meeting”.

Research limitations/implications

The scope of this study is limited to the Sri Lankan construction industry. Expansion of the geographical area of focus is recommended for future studies.

Originality/value

The findings of this study unveil a vFAT process, which is timely and beneficial for construction practitioners to optimize and enhance the effectiveness of vFATs which are currently conducted in a disarranged manner.
Identifying the key success factors of F&B sharing services: new insights from a multiple-phase decision-making model
Authors: Chang Ya-Yuan , Wu Hung-Che , Cheng Ching-Chan , Chen Cheng-Ta
Published: December 2021

Purpose

In the tide of the sharing economy, food and beverage sharing services (FBSS) are gradually drawing public attention. Many comments about FBSS are posted and discussed online, and this information may suggest the key factors in the operation of FBSS. This study aims to identify the key success factors (KSFs) of FBSS from online communities and media, potential consumers, customers and experts.

Design/methodology/approach

This study utilizes Internet big data analytics (IBDA) to identify the key FBSS factors and then examines the KSFs of FBSS through conducting an analysis of the importance of key factors for potential consumers, confirmatory factor analysis of customer satisfaction of key factors, multiple regression analysis of customer satisfaction of key factors influencing the customers' intentions to continue participating in FBSS and a decision-making trial and evaluation laboratory of experts' opinions.

Findings

The results showed that the 15 key FBSS factors through IBDA were screened out. Among them, four KSFs that influence the operation of FBSS were identified. These four KSFs are discussed in detail in the text.

Originality/value

The findings of this study provide references for FBSS providers in the future to enhance customer value, service quality and business competitive advantages of FBSS.
Modeling cost overrun in building construction projects using the interpretive structural modeling approach: a developing country perspective
Authors: Shoar Shahab , Yiu Tak Wing , Payan Shamsi , Parchamijalal Majid
Published: December 2021

Purpose

Although several studies have been conducted on the causes of cost overrun, they have mainly assumed that the causes of cost overrun are independent of each other, and few of them scrutinized the complex interrelationships between the causes. To fill the gap, this study aims to investigate the mutual interactions between the causes of cost overrun using interpretive structural modeling (ISM) and proposing strategies to tackle the causes considering their interactions.

Design/methodology/approach

Critical causes of cost overrun were identified through a comprehensive literature review. In total, 22 key causes are then refined based on the opinions of relevant experts involved in the Iranian building and construction sector. Using the nominal group technique, the causes' interactions were examined and represented via the ISM diagram. The causes were also classified using “matrix cross-reference multiplication applied to a classification (MICMAC)” technique.

Findings

The results showed that price fluctuation, claims, execution delay, delay in payment and change order positioned at the highest level of the obtained model can directly result in cost overrun, and corruption and poor contract management located at the base of the model are two major root causes of cost overruns. It was also concluded that more attention should be paid to the precontract phase of the project to address and prevent corruption and managerial issues deeply rooted in this stage.

Originality/value

The findings of this study provide a clear understanding of how different causes of cost overrun are related to each other and can ultimately assist project managers of different parties in choosing strategies to mitigate cost overrun in building construction projects.