bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetically proxied inhibition of L-2-hydroxyglutarate dehydrogenase and the risk of coronary artery disease: A Mendelian randomization study
Authors: Song Euijun
Published: January 2023

Background

L-2-hydroxyglutarate dehydrogenase (L2HGDH) deletion-induced L-2-hydroxyglutarate accumulation plays a cardioprotective role in hypoxic conditions. However, there has been no causal evidence in real-world clinical data. We aimed to examine the causal effects ofL2HGDHinhibition on coronary artery disease (CAD) and myocardial infarction (MI) using Mendelian randomization (MR) analysis.

Methods

We used nineL2HGDH-proxied genetic variants associated with blood 2-hydroxyglutarate levels as genetic instruments, and performed two-sample MR analysis using the CARDIoGRAMplusC4D meta-analysis datasets of CAD (60,801 CAD cases and 123,504 controls) and MI (34,541 MI cases and 261,984 controls).

Results

Genetically proxied inhibition ofL2HGDHassociated with 2-hydroxyglutarate levels potentially decreased the risk of CAD (odds ratio [OR] 0.486, 95% confidence interval [CI] 0.242–0.977, P=0.043) but was not associated with the risk of MI (OR 0.676, 95% CI 0.312–1.463, P=0.320). This potentially causal association betweenL2HGDHinhibition and CAD was unlikely to be biased by horizontal pleiotropy, whereas there might be a weak instrument bias.

Conclusion

Our MR analysis suggests the potential association between genetically proxied inhibition ofL2HGDHand CAD. Our findings may have therapeutic implications for L2HGDH inhibitors in CAD, and further large-scale clinical studies are needed.
G3DC: a Gene-Graph-Guided selective Deep Clustering method for single cell RNA-seq data
Authors: He Shuqing , Fan Jicong , Yu Tianwei
Published: January 2023

Single-Cell RNA sequencing (scRNA-seq) technology measures the expression of thousands of genes at the cellular level. Analyzing single cell transcriptome allows the identification of heterogeneous cell groups, cellular-level regulations, and the trajectory of cell development. An important aspect in the analyses of scRNA-seq data is the clustering of cells, which is hampered by issues such as high dimensionality, cell type imbalance, redundancy, and dropout. Given cells of each type are functionally consistent, incorporating biological relations between genes may improve the clustering results. Here, we develop a deep embedded clustering method, G3DC, that incorporates a graph loss based on existing gene network, together with a reconstruction loss to achieve both discriminative and informative embedding. The involvement of the gene network strengthens clustering performance, while helping the selection of functionally coherent genes that contribute to the clustering results. In addition, this method is well adapted to the sparse and zero-inflated scRNA-seq data with theℓ2,1-norm involved. Extensive experiments have shown that G3DC offers high clustering accuracy with regard to agreement with true cell types, outperforming other leading single-cell clustering methods. In addition, G3DC selects biologically relevant genes that contribute to the clustering, providing insight into biological functionality that differentiate cell groups.
Deciphering drug response and phenotypic heterogeneity of cancer cells using gene ensembles of regulatory units defined by chromatin domains
Authors: Pandey Neetesh , Sharma Madhu , Mathur Arpit , Anene-Nzel Chukwuemeka George , Hakimullah Muhammad , Patel Priyanka , Jha Indra Prakash , Chandra Omkar , Mishra Shreya , Bhattacharya Jui , Sharma Ankur , Foo Roger , Sandhu Kuljeet , Mandoli Amit , DasGupta Ramanuj , Kumar Vibhor
Published: January 2023

The effect of co-localization of genes in the topologically associated domains (TADs) and their activity as a regulatory unit in cancer samples and cells, together with drug-response, needs comprehensive analysis. Here, we analyzed the activity of TADs using cancer-cell transcriptomes along with chromatin-interaction and epigenome profiles to understand their relationship with drug-response. Our analysis of 819 cancer cell-line transcriptomes revealed that their response to multiple drugs was more correlated with the activity of individual TADs than genes. Applying our approach to 9014 cancer patients’ data (20 different cancer types) also revealed a higher association between survival and the activity of thousands of individual TADs in comparison to their genes. CRISPR-mediated knock-out of regulatory sites inside a TAD associated with cisplatin-response of oral cancer cells and discovery of primate-specific gain of synteny of genes within a TAD containing EGFR gene and its contribution towards cancer malignancy demonstrate greater utility of TAD-activity based analysis.
EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis
Authors: Chakraborty Sukanya , Bhat Aaqib M. , Mushtaq Insha , Luan Haitao , Kalluchi Achyuth , Mirza Sameer , Storck Matthew D. , Chaturvedi Nagendra , Lopez- Guerrero Jose Antonio , Llombart-Bosch Antonio , Machado Isidro , Scotlandi Katia , Meza Jane L. , Ghosal Gargi , Coulter Donald W. , Rowley M Jordan , Band Vimla , Mohapatra Bhopal C. , Band Hamid
Published: January 2023

Overexpression of EPS15 Homology Domain containing 1 (EHD1) has been linked to tumorigenesis but whether its core function as a regulator of intracellular traffic of cell surface receptors plays a role in oncogenesis remains unknown. We establish that EHD1 is overexpressed in Ewing sarcoma (EWS), with high EHD mRNA expression specifying shorter patient survival. ShRNA and CRISPR-knockout with mouseEhd1rescue established a requirement of EHD1 for tumorigenesis and metastasis. RTK antibody arrays identified the IGF-1R as a target of EHD1 regulation in EWS. Mechanistically, we demonstrate a requirement of EHD1 for endocytic recycling and Golgi to plasma membrane traffic of IGF-1R to maintain its surface expression and downstream signaling. Conversely, EHD1 overexpression-dependent exaggerated oncogenic traits require IGF-1R expression and kinase activity. Our findings define the RTK traffic regulation as a proximal mechanism of EHD1 overexpression-dependent oncogenesis that impinges on IGF-1R in EWS, supporting the potential of IGF-1R and EHD1 co-targeting.
Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2
Authors: Ma Yong , Li Pengbin , Hu Yunqi , Qiu Tianyi , Wang Lixiang , Lu Hongjie , Lv Kexin , Xu Mengxin , Zhuang Jiaxin , Liu Xue , He Suhua , He Bing , Liu Shuning , Liu Lin , Wang Yuanyuan , Yue Xinyu , Zhai Yanmei , Luo Wanyu , Mai Haoting , Zhao Wenjing , Chen Jun , Chen Shoudeng , Xiong Xiaoli , Shi Mang , Pan Ji-An , Chen Yao-Qing
Published: January 2023

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to Serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploringSarbecovirus’ evolution.

Author Summary

The Spike strain of SARS-CoV-2 has accumulated many mutations during its time in circulation, most of which have occurred in the S1 region, and more specifically in the RBD, in an effort to either improve the virus’s affinity for the receptor ACE2 or to enhance its ability to evade the immune system. Mutations in the Spike S2 region have more far-reaching effects than those in the S1 region because it is more conserved across sarbecoviruses. By comparing SARS and SARS2, we found that an important substitution at amino acid position 813 in the S2 region (T813S) disrupts the utilization of TMPRSS2 and can significantly influence viral entry into cells. This discovery deepens our knowledge of S proteins and provides new prospects for tracing the evolution of Sarbecoviruses.
Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimer’s Disease
Authors: Wang Yixuan , Huang Jinghan , Ang Ting Fang Alvin , Zhu Yibo , Tao Qiushan , Mez Jesse , Alosco Michael , Denis Gerald V. , Belkina Anna , Gurnani Ashita , Ross Mark , Gong Bin , Han Jingyan , Lunetta Kathryn L. , Stein Thor D. , Au Rhoda , Farrer Lindsay A. , Zhang Xiaoling , Qiu Wei Qiao
Published: January 2023

Cerebrovascular damage coexists with Alzheimer’s disease (AD) pathology and increases AD risk. However, it is unclear whether endothelial progenitor cells reduce AD risk via cerebrovascular repair. By using the Framingham Heart Study (FHS) offspring cohort, which includes data on different progenitor cells, the incidence of AD dementia, peripheral and cerebrovascular pathologies, and genetic data (n = 1,566), we found that elevated numbers of circulating endothelial progenitor cells with CD34+CD133+ co-expressions had a dose-dependent association with decreased AD risk (HR = 0.67, 95% CI: 0.46-0.96, p = 0.03) after adjusting for age, sex, years of education, andAPOEε4. With stratification, this relationship was only significant among those individuals who had vascular pathologies, especially hypertension (HTN) and cerebral microbleeds (CMB), but not among those individuals who had neither peripheral nor central vascular pathologies. We applied a genome-wide association study (GWAS) and found that the number of CD34+CD133+ cells impacted AD risk depending on the homozygous genotypes of two genes:KIRREL3rs580382 CC carriers (HR = 0.31, 95% CI: 0.17-0.57, p<0.001),KIRREL3rs4144611 TT carriers (HR = 0.29, 95% CI: 0.15-0.57, p<0.001), andEXOC6Brs61619102 CC carriers (HR = 0.49, 95% CI: 0.31-0.75, p<0.001) after adjusting for confounders. In contrast, the relationship did not exist in their counterpart genotypes, e.g.KIRREL3TT/CT or GG/GT carriers andEXOC6BGG/GC carriers. Our findings suggest that circulating CD34+CD133+ endothelial progenitor cells can be therapeutic in reducing AD risk in the presence of cerebrovascular pathology, especially inKIRREL3andEXOC6Bgenotype carriers.
First GWAS on Alzheimer’s Disease in Argentina and Chile populations
Authors: Dalmasso Maria Carolina , de Rojas Itziar , Olivar Natividad , Muchnik Carolina , Angel Bárbara , Gloger Sergio , Sanchez Abalos Mariana Soledad , Chacón M.Victoria , Aránguiz Rafael , Orellana Paulina , Cuesta Carolina , Galeano Pablo , Campanelli Lorenzo , Novack Gisela Vanina , Martinez Luis Eduardo , Medel Nancy , Lisso Julieta , Sevillano Zulma , Irureta Nicolás , Castaño Eduardo Miguel , Montrreal Laura , Thoenes Michaela , Hanses Claudia , Heilmann-Heimbach Stefanie , Kairiyama Claudia , Mintz Ines , Villella Ivana , Rueda Fabiana , Romero Amanda , Wukitsevits Nancy , Quiroga Ivana , Gona Cristina ,   EADB, Lambert Jean-Charles , Solis Patricia , Politis Daniel Gustavo , Mangone Carlos Alberto , Gonzalez-Billault Christian , Boada Mercè , Tàrraga Lluís , Slachevsky Andrea , Albala Cecilia , Fuentes Patricio , Kochen Silvia , Brusco Luis Ignacio , Ruiz Agustín , Morelli Laura , Ramírez Alfredo
Published: January 2023

INTRODUCTION

Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities.

METHODS

we performed a GWAS on sporadic Alzheimer’s disease (AD) including 540 patients and 852 controls from Argentina and Chile. We explored the variants associated with AD in European GWAS from European Alzheimer’s and Dementia Biobank (EADB) and tested their genetic risk score (GRS) performance in this admixed population.

RESULTS

we detectedAPOE4as single genome-wide significant signal (OR=2.93[2.37-3.63], p=2.6×10−23), and fifteen additional suggestive signals previously undetected. Nine of the 83 variants reported by EADB in Europeans were replicated, and the AD-GRS presented similar performance in this Latin population, despite the score diminishes when the Native American ancestry rises.

DISCUSSION

we report the first GWAS on AD in a population from South America. It shows shared genetics that modulate AD risk between the European and the Latin American populations.
Enhanced physician performance when using an artificial intelligence model to detect ischemic stroke on computed tomography
Authors: Hillis James M , Bizzo Bernardo C , Gauriau Romane , Bridge Christopher P , Chin John K , Hakamy Buthaina , Mercaldo Sarah , Conklin John , Dutta Sayon , Mehan William A , Regenhardt Robert W , Singh Ajay , Singhal Aneesh B , Sonis Jonathan D , Succi Marc D , Zhang Tianhao , Xing Bin , Kalafut John F , Dreyer Keith J , Lev Michael H , González R Gilberto
Published: January 2023

Acute ischemic stroke can be subtle to detect on non-contrast computed tomography imaging. We show that a novel artificial intelligence model significantly improves the performance of physicians, including ED physicians, neurologists and radiologists, in identifying and quantifying the volume of acute ischemic stroke lesions. This model may lead to improved clinical decision-making for stroke patients.
Post-pandemic modeling of COVID-19: Waning immunity determines recurrence frequency
Authors: Calvetti D , Somersalo E
Published: January 2023

There are many factors in the current phase of the COVID-19 pandemic that signal the need for new modeling ideas. In fact, most traditional infectious disease models do not address adequately the waning immunity, in particular as new emerging variants have been able to brake the immune shield acquired either by previous infection by a different strain of the virus, or by inoculation of vaccines not effective for the current variant. Furthermore, in a post-pandemic landscape in which reporting is no longer a default, it is impossible to have reliable quantitative data at the population level. Our contribution to COVID-19 post-pandemic modeling is a simple mathematical predictive model along the age-distributed population framework, that can take into account the waning immunity in a transparent and easily controllable manner. Numerical simulations show that under static conditions, the model produces periodic solutions that are qualitatively similar to the reported data, with the period determined by the immunity waning profile. Evidence from the mathematical model indicates that the immunity dynamics is the main factor in the recurrence of infection spikes, however, irregular perturbation of the transmission rate, due to either mutations of the pathogen or human behavior, may result in suppression of recurrent spikes, and irregular time intervals between consecutive peaks. The spike amplitudes are sensitive to the transmission rate and vaccination strategies, but also to the skewness of the profile describing the waning immunity, suggesting that these factors should be taken into consideration when making predictions about future outbreaks.
Combinatorial gene inactivation of aldehyde dehydrogenases mitigates aldehyde oxidation catalyzed by resting cells ofE. coliRARE strains
Authors: Butler Neil D. , Anderson Shelby R. , Dickey Roman M. , Nain Priyanka , Kunjapur Aditya M.
Published: January 2023

Aldehydes are attractive chemical targets given applications as end products in the flavors and fragrances industry and as intermediates due to their propensity for C-C bond formation. While biosynthetic routes to diverse aldehydes have been designed, a common challenge is the stability of these aldehydes in the presence of microbial hosts of engineered pathways. Here, we identify and address unexpected oxidation of a model collection of aromatic aldehydes, including many that originate from biomass degradation, in the presence ofEscherichia colistrains that were engineered to minimize aldehyde reduction. Of heightened interest to us were resting cell conditions as they offer numerous advantages for the bioconversion of toxic metabolites. Surprisingly, when diverse aldehydes are supplemented toE. coliRARE cells grown under aerobic conditions, they remain stabilized on the timescale of days, whereas when these same aldehydes are supplemented to resting cell preparations ofE. coliRARE that had been grown under the same conditions, we observe substantial oxidation. By performing combinatorial inactivation of six candidate aldehyde dehydrogenase genes in theE. coligenome using multiplexed automatable genome engineering (MAGE), we demonstrate that this oxidation can be substantially slowed, with greater than 50% retention of 6 out of 8 aldehydes when assayed 4 hours after their addition. Given that our newly engineered strain exhibitsReducedOxidationAndReduction of aromatic aldehydes, we dubbed it theE. coliROAR strain. Seeking to apply this new strain to resting cell biocatalysis, we compared the capability to synthesis the aldehyde furfural from 2-furoic acid via the carboxylic acid reductase enzyme fromNocardia iowensis. Here, we found that use of ROAR resting cells achieved 2-fold enhancement in furfural titer after 4 h and nearly 9-fold enhancement after 20 h as compared to resting cells of the RARE strain. Moving forward, the use of this strain to generate resting cells should allow aldehyde product isolation, further enzymatic conversion, or chemical reactivity under cellular contexts that better accommodate aldehyde toxicity.

Highlights

When genes that encode aldehyde reductases are knocked out inEscherichia colistrains, supplemented aldehydes can experience oxidation instead of reduction, which is catalyzed by a different set of endogenous enzymes.

Interestingly, we show for a collection of aromatic aldehydes that this oxidation is far more substantial when using resting cell preparations than during aerobic fermentation.

We investigate the identity of the responsible genes by performing combinatorial gene inactivation using multiplex automatable genome engineering.

The strain that we engineer exhibits Reduced Oxidation And Reduction (theE. coliROAR strain) and thereby enables design of more efficient aldehyde bioconversion processes under diverse formats.
Development, validation, and usage of metrics to evaluate the quality of clinical research hypotheses
Authors: Jing Xia , Zhou Yuchun , Cimino James J. , Shubrook Jay H. , Patel Vimla L. , De Lacalle Sonsoles , Weaver Aneesa , Liu Chang
Published: January 2023

Objectives

Metrics and instruments can provide guidance for clinical researchers to assess their potential research projects at an early stage before significant investment. Furthermore, metrics can also provide structured criteria for peer reviewers to assess others’ clinical research manuscripts or grant proposals. This study aimed to develop, test, validate, and use evaluation metrics and instruments to accurately, consistently, and conveniently assess the quality of scientific hypotheses for clinical research projects.

Materials and Methods

Metrics development went through iterative stages, including literature review, metrics and instrument development, internal and external testing and validation, and continuous revisions in each stage based on feedback. Furthermore, two experiments were conducted to determine brief and comprehensive versions of the instrument.

Results

The brief version of the instrument contained three dimensions: validity, significance, and feasibility. The comprehensive version of metrics included novelty, clinical relevance, potential benefits and risks, ethicality, testability, clarity, interestingness, and the three dimensions of the brief version. Each evaluation dimension included 2 to 5 subitems to evaluate the specific aspects of each dimension. For example, validity included clinical validity and scientific validity. The brief and comprehensive versions of the instruments included 12 and 39 subitems, respectively. Each subitem used a 5-point Likert scale.

Conclusion

The validated brief and comprehensive versions of metrics can provide standardized, consistent, and generic measurements for clinical research hypotheses, allow clinical researchers to prioritize their research ideas systematically, objectively, and consistently, and can be used as a tool for quality assessment during the peer review process.
Design and Retrospective Cohort Validation of an Algorithm for Surgical Site Infection Surveillance after Hip Replacement Surgery Using Natural Language Processing and Extreme Gradient Boosting
Authors: Flores-Balado Alvaro , Méndez Carlos Castresana , González Antonio Herrero , Gutierrez Raúl Mesón , Arcos Javier , Martín-Ríos María Dolores
Published: January 2023

Background

Surgical site infection (SSI) surveillance is a labor-intensive endeavor. We present the design and retrospective cohort validation of a multivariable algorithm to screen for SSI in patients undergoing hip replacement surgery, permitting real-time case detection, and reducing the number of clinical records to be reviewed manually.

Methods

We designed a multivariable algorithm using extreme gradient-boosting (XGBoost) to screen for SSI in patients undergoing hip replacement surgery. The development and validation cohort included all healthcare episodes dating from the initial hospital admission for surgery until 90 days after joint replacement (n=19661) between January 2014 and December 2021 from four hospitals in Madrid, Spain. A NLP pipeline was implemented to obtain text variables from free-text fields of the EHR. Clinical, prescription, microbiology, and laboratory variables were also collected. Episodes were split randomly into training (70%) and testing (30%) datasets. Hyperparameters were adjusted to penalize false negatives.

Findings

The presence of positive microbiological cultures, the text variable “infection”, and the prescription of clindamycin were strong markers of SSI. Statistical analysis of the final model indicated a high sensitivity (99·18%) and specificity (91·01%) with an F1-score of 0·32, AUC of 0·989 and accuracy of 91·27%. The model correctly classified 5129 episodes as negative for SSI, with only one case of SSI escaping detection (NPV 99·98%).

Interpretation

We conclude that the combination of NLP and extreme gradient boosting is a sensitive tool for SSI surveillance in hip replacement surgery, permitting real-time, semi-automatic surveillance. In practice, our results translate as an 88·95% reduction in the total volume of clinical records to be reviewed manually. To the best of our knowledge, this is the first time that an algorithm incorporating data from multiple sources using NLP and extreme gradient boosting has been developed for orthopedic SSI surveillance.

Funding

This study did not receive any funding.
Autophagy mediates cancer cell resistance to doxorubicin induced by the Programmed Death 1/Programmed Death Ligand 1 immune checkpoint axis
Authors: Minassian Lori , Sanwalka Daniel , Paré Jean-François , Macdonald-Goodfellow Shannyn , Sutherland R. Liam , Ghaffari Abdi , Margerum Chelsea L. , Koti Madhuri , Craig Andrew W.B. , Cotechini Tiziana , Siemens D. Robert , Chan Edmond , Graham Charles H.
Published: January 2023

Background

While the Programmed Death 1/Programmed Death Ligand 1 (PD-1/PD-L1) immune checkpoint is an important mechanism of immune evasion in cancer, recent studies have shown that it can also lead to resistance to chemotherapy in cancer cells via reverse signaling. Here we describe a novel mechanism by which autophagy mediates cancer cell drug resistance induced by PD-1/PD-L1 signaling.

Methods

Human and mouse breast cancer cells were treated with recombinant PD-1 (rPD-1) to stimulate PD-1/PD-L1 signaling. Activation of autophagy was assessed by immunoblot analysis of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II and Beclin 1 protein levels, two important markers of autophagy. Moreover, autophagosome formation was assessed in human breast cancer cells using green fluorescence protein (GFP)-tagged LC3. Cells were either treated with Beclin 1 or Atg7 shRNA to assess the role of autophagy on resistance to doxorubicin mediated by PD-1/PD-L1 signalling. We then investigated signaling mechanisms upstream of PD-1/PD-L1 induced autophagy by assessing phosphorylation of extracellular signal-related kinase (ERK).

Results

Treatment of cells with rPD-1 resulted in a time-dependent increase in LC3-II as well as Beclin 1, and an increase in autophagosome formation. Knockdown of Beclin 1 or Atg7 prevented drug resistance induced by PD-1/PD-L1 signaling. Exposure of breast cancer cells to rPD-1 resulted in increased ERK phosphorylation and inhibition of ERK activation abolished autophagy induced by PD-1/PD-L1 signaling.

Conclusions

These studies provide a rationale for the use of PD-1/PD-L1 immune checkpoint blockers and autophagy inhibitors as potential chemosensitizers in cancer therapy.
Establishment of aMycoplasma hyorhinischallenge model in five-week-old piglets
Authors: Földi Dorottya , Nagy Zsófia Eszter , Belecz Nikolett , Szeredi Levente , Földi József , Kollár Anna , Tenk Miklós , Kreizinger Zsuzsa , Gyuranecz Miklós
Published: January 2023

Mycoplasma hyorhinisis an emerging swine pathogen bacterium with high prevalence worldwide. The main lesions caused are arthritis and polyserositis and the clinical manifestation of the disease may result in significant economic losses due to the decreased weight gain and enhanced medical costs.

Our aim was to compare two challenge routes to induceM. hyorhinisinfection using the same clinical isolate. Five-week-old, Choice hybrid pigs were inoculated on two consecutive days by intravenous route (Group IV-IV) or by intravenous and intraperitoneal route (Group IV-IP). Mock infected animals were used as control (Control Group). After challenge, the clinical signs were recorded for 28 days, after which the animals were euthanized. Gross pathological and histopathological examinations, PCR detection, isolation and genotyping of the re-isolatedMycoplasmasp. and culture of bacteria other thanMycoplasmasp. were carried out. ELISA test was used to detect anti-M. hyorhinisimmunoglobulins in the sera of all animals. Pericarditis and polyarthritis were observed in both challenge groups, however the serositis was more severe in Group IV-IV. Statistically significant differences were detected between the challenged groups and the control group regarding the average daily weight gain, pathological scores and ELISA titres. Additionally, histopathological scores in Group IV-IV differed significantly from the scores in the Control Group. All re-isolated strains were the same or a close genetic variant of the original challenge strain. Our results indicate that both challenge routes are suitable for modelling the disease. However, due to the more severe pathological lesions and the more natural-like route of infection in Group IV-IV, the two-dose intravenous challenge is recommended by the authors to induce serositis and arthritis associated withM. hyorhinisinfection.
Activation-induced cytidine deaminase-basedin vivocontinuous evolution system enables rapid protein engineering
Authors: Zhang Xinyu , Liu Zhanzhi , Xu Ying , Rao Deming , Chen Xiaoqian , Li Zhigang , Huang Yan , Wu Jing
Published: January 2023

Directed evolution is a powerful tool to modify the properties of proteins. However, due to multi-round and stage combinations, directed evolution usually requires time- and labor-intensive manual intervention, which limits the efficiency of protein modification to some extent. Therefore,in vivocontinuous evolution system is highly preferred because it can couple the multiple rounds and steps of direction evolution with the host growth cycle, leading to the advantages of effort-saving and accuracy. However, the existing types of this kind of systems can not meet the booming demand. Herein, this paper describes promotedEscherichia coli-assisted continuous evolution (PEACE) that allows forin vivocontinuous evolution of target genes. This system polymorphisms the target gene by activation-induced cytidine deaminase-T7 RNA polymerase (AID-T7 PNAP) fusion protein, then it couples the enzymatic properties of desired variants with the expression of antitoxins to achieve efficient growth-coupled screen using the toxin-antitoxin system (TAS). In this study, T7 RNAP was finally employed for validation of PEACE system, and its specificity to the promoter was successfully altered. These results demonstrated the feasibility and further application potential of PEACE.
Primate superior colliculus is engaged in abstract higher-order cognition
Authors: Peysakhovich Barbara , Tetrick Stephanie M. , Silva Alessandra A. , Li Sihai , Zhu Ou , Ibos Guilhem , Johnston W. Jeffrey , Freedman David J.
Published: January 2023

Categorization is a fundamental cognitive process by which the brain assigns stimuli to behaviorally meaningful groups. Investigations of visual categorization in primates have identified a hierarchy of cortical areas that are involved in the transformation of sensory information into abstract category representations. However, categorization behaviors are ubiquitous across diverse animal species, even those without a neocortex, motivating the possibility that subcortical regions may contribute to abstract cognition in primates. One candidate structure is the superior colliculus (SC), an evolutionarily conserved midbrain region that, although traditionally thought to mediate only reflexive spatial orienting, is involved in cognitive tasks that require spatial orienting. Here, we reveal a novel role of the primate SC in abstract, higher-order visual cognition. We compared neural activity in the SC and the posterior parietal cortex (PPC), a region previously shown to causally contribute to category decisions, while monkeys performed a visual categorization task in which they report their decisions with a hand movement. The SC exhibits stronger and shorter-latency category encoding than the PPC, and inactivation of the SC markedly impairs monkeys’ category decisions. These results extend SC’s established role in spatial orienting to abstract, non-spatial cognition.
A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease
Authors: Geng Zhi Zachary , Atla Sandeep , Shaabani Namir , Vulupala Veerabhadra R. , Yang Kai S. , Alugubelli Yugendar R. , Khatua Kaustav , Chen Peng-Hsun Chase , Xiao Jing , Blankenship Lauren R. , Ma Xinyu R. , Vatansever Erol C. , Cho Chia-Chuan , Ma Yuying , Allen Robert , Ji Henry , Xu Shiqing , Liu Wenshe Ray
Published: January 2023

SARS-CoV-2 is the coronavirus pathogen of the currently prevailing COVID-19 pandemic. It relies on its main protease (MPro) for replication and pathogenesis. MProis a demonstrated target for the development of antivirals for SARS-CoV-2. Past studies have systematically explored tripeptidyl inhibitors such as nirmatrelvir as MProinhibitors. However, dipeptidyl inhibitors especially those with a spiro residue at their P2 position have not been systematically investigated. In this work, we synthesized about 30 reversibly covalent dipeptidyl MProinhibitors and characterized them onin vitroenzymatic inhibition potency, structures of their complexes with MPro, cellular MProinhibition potency, antiviral potency, cytotoxicity, andin vitrometabolic stability. Our results indicated that MProhas a flexible S2 pocket that accommodates dipeptidyl inhibitors with a large P2 residue and revealed that dipeptidyl inhibitors with a large P2 spiro residue such as (S)-2-azaspiro[4,4]nonane-3-carboxylate and (S)-2-azaspiro[4,5]decane-3-carboxylate have optimal characteristics. One compound MPI60 containing a P2 (S)-2-azaspiro[4,4]nonane-3-carboxylate displayed high antiviral potency, low cellular cytotoxicity, and highin vitrometabolic stability and can be potentially advanced to further preclinical tests.
The spirit of the fruit: contextual and transituational motives for consumption
Authors: Arboleda Ana M. , Manfredi Luciana C. , Marcazzo Giuseppina , Arroyo Christian
Published: January 2023

Purpose

This research aims to reach meaningful insights into fruit consumption motives. The study articulates contextual motives observed through inherent fruit characteristics (i.e. attributes and benefits) with personal motives that transcend the situation (i.e. emotions and cultural values).

Design/methodology/approach

This qualitative study used the focus group technique comprising eight groups of eight to 10 subjects (n = 94). The participants were frequent fresh-fruit consumers.

Findings

The analysis differentiates contextual motives from transituational ones. Older participants are motivated by taking care of health matters. They value fruit as an expression of their determination to take action and care for others. Younger participants are motivated by the experience of pleasure. Fruits have a hedonic value related to joy, being refreshing and tasteful.

Practical implications

Results serve marketers and decision-makers to better target motivations for fruit consumption enhancement. These motivations could be implemented by communicating specific fruit attributes that respond to short-term needs. In the long run, marketers could create fruit consumption campaigns that respond to deeper consumer values.

Social implications

Designing fruit consumption campaigns aligned with individuals' motives could effectively strengthen the adoption of a healthy lifestyle. This study is helpful from the aspect of a public-policy approach expected to improve public health.

Originality/value

Consumers' fruit preference transcends tangible product characteristics to motives aligned with their goals, emotions and human values. This path merges two approaches: contextual motivations and the Means-end chain model. The first approach recognises short-term observable product characteristics, whereas the latter works on long-term values.
Health-related misinformation and public governance of COVID-19 in South Africa
Authors: Kariuki Paul , Ofusori Lizzy Oluwatoyin , Goyayi Maria Lauda , Subramaniam Prabhakar Rontala
Published: January 2023

Purpose

The purpose of this paper was to examine health-related misinformation proliferation during COVID-19 pandemic and its implications on public governance in South Africa.

Design/methodology/approach

Because of COVID-19 related restrictions, this study conducted a systematic review. The researchers searched several search engines which include PubMed, Web of Science and Scopus to identify relevant studies. A total of 252 peer reviewed research papers were identified. These research papers were furthered filtered, and a total of 44 relevant papers were eventually selected

Findings

There is a relationship between the spread of health-related misinformation and public governance. Government coordination and institutional coherence across the different spheres of governance is affected when there are multiple sources of information that are unverified and uncoordinated.

Research limitations/implications

This study was limited to a systematic review because of COVID-19 restrictions, and therefore, actual data could not be collected. Moreover, this study was limited to health-related communication, and therefore, its findings can only be generalized to the health sector.

Practical implications

Future research in this subject should consider actual data collection from the departments of health and communications to gain an in-depth understanding of misinformation and its implications on public governance from their perspective as frontline departments as far as government communication is concerned.

Social implications

Misinformation is an impediment to any fight against a public health emergency. Institutions which regulate communications technology and monitor misinformation should work harder in enforcing the law to deter information peddlers from their practice. This calls for reviewing existing regulation so that online spaces are safer for communicating health-related information.

Originality/value

Effective health communication remains a priority for the South African Government during COVID-19. However, with health-related misinformation on the increase, it is imperative to mitigate the spread to ensure it does not impede effective public governance. Government departments in South Africa are yet to develop policies that mitigate the spread of misinformation, and this paper may assist them in doing so.
Meritocracy or aristocracy? Appraising the performance appraisal systems
Authors: Akhtar Junaid , Abdullah Iqra
Published: January 2023

Learning outcomes

The aim of the case is to understand the performance management system of academic staff members in higher education institution. Furthermore, students would be able to compare two performance appraisal policies and analyze which one could better serve the purpose considering the context of educational institution. The case would help students understand the performance dynamics of the academic staff and how the performance management system in place affect employees.

Case overview/synopsis

The case study presents a troubling situation faced by Asim Khan, a newly appointed director of the Midland University, regarding retention of the faculty. Upon joining Midland, Khan noticed a trend that faculty who was serving the university from many years are leaving the organization one after the other. He decided to revise the faculty policies that he believed was the root cause of faculty turnover in Midland. He formulated a committee to review the existing policies and revamp if required. The committee identified some flaws in the faculty appraisal policy in place at that time and formulated a new one with the consultation of top management. However, when the new appraisal policy was presented to the faculty, few faculty members raised their eyes over a few aspects of the proposed policy. As the new academic year was approaching, Khan had to make an important decision after critically analyzing the pros and cons of both policies that which of the two should be followed for the upcoming year’s appraisals.

Complexity academic level

The case can potentially be used in the post-graduate courses in MBA programs offering a major in human resource management.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 6: Human resource management.
The role of country of origin image, brand image and eWOM in the intention to receive the Sinopharm vaccine
Authors: Ghorbanzadeh Davood , Shabbir Muhammad Salman
Published: January 2023

Purpose

This study aims to explain the factors associated with receiving a specific brand of Covid-19 vaccine within the framework of the theory of reasoned action. The study extends the theory of reasoned action with the country of origin image, brand image and electronic word of mouth (e-WOM) variables.

Design/methodology/approach

The study is based on a cross-sectional survey conducted among 460 people who received the Sinofarm vaccine. Participants were selected using an online convenience sampling method. The structural equation modeling (SEM) technique tests the proposed hypotheses.

Findings

The results showed that the essential factor associated with the intent to get the Chinese Sinopharm vaccine is the attitude toward the Signopharm vaccine. Also, WOM, subjective norms and brand image are the most critical factors that play a role in forming a favorable attitude toward the Sinopharm vaccine. Finally, the country-of-origin image does not affect attitudes toward the Sinopharm vaccine.

Originality/value

The area of vaccine marketing has been given limited attention in academic literature. This study addresses this area with little research and is greatly attractive to many brands targeting the consumer market. The study results can form a foundation for creating the branding strategy of this product category and assessing its demand in various markets.
Financial inclusion in Egypt: the road ahead
Authors: Hassouba Taghreed Abdelaziz
Published: January 2023

Purpose

The literature review stated that financial inclusion (FI) influences economic growth through different channels. Hence, this paper aims to investigate the underlying process of FI in Egypt theoretically, and to derive some policy implications for promoting the process and achieving more improvement in different financial and economic aspects, that is basically through discussing the opinions of FI's main stockholders in Egypt.

Design/methodology/approach

The analysis used secondary data from the Global Findex and FAS Database, namely, automated teller machines, outstanding deposits and loans with commercial banks, debit and credit cards ownership. The research particularly used scientific methods as method of deduction, methods of graphical and tabular representation of data, comparative analysis and synthesis of partial knowledge. The paper is also based on a descriptive approach in addition to in-depth interviews with the main stakeholders of the financial inclusion process in Egypt.

Findings

The analyzed results of interviews revealed that new FI vision should have a deep understanding of the financial lives of the poor and low-income groups, including how they acquire, manage and use their money. However, the impact is becoming more prominent for the efficiency of the banking system and hence economic growth rather a regulatory and sound institutional framework enhances it. This finding supported the fact that Egypt can design an appropriate FI strategy, but the main challenge is how to implement it with the required speed and outreach capacity, especially in underprivileged communities.

Research limitations/implications

The result of this study has interesting implications for Egypt's ability to attain effective FI initiatives that promote sound financial choices and behavior which in turn help to stimulate financial and economic growth.

Originality/value

The study contributes to the literature by assessing the FI level in Egypt, its implications and how it should be enhanced for better performance and results in the future. It addresses the deep fact of this process through inclusive surveys and interviews that help in determining the road ahead.
Real‐world effectiveness and safety of bosentan in Japanese patients with systemic sclerosis: A single‐center retrospective study
Authors: Ishikawa Mai , Endo Yukie , Yamazaki Sahori , Sekiguchi Akiko , Uchiyama Akihiko , Motegi Sei‐ichiro
Published: January 2023

Patients with systemic sclerosis (SSc) develop various vascular disorders, including digital ulcers (DUs), which are sometimes intractable. Bosentan is a dual endothelin receptor antagonist expected to suppress the development of new DUs. The objective of this study was to analyze retrospectively Japanese SSc patients treated with bosentan and investigate its efficacy and safety. We analyzed 40 patients who visited our department from 2009 to 2022 and were treated with bosentan. Of the 25 patients who were able to continue bosentan, 64% (16 patients) were cured by 16 weeks . New DUs occurred in 5.9% (2/34) of patients and the number of new DUs per person was 0.1. Adverse events occurred in 45% (18/40), and hepatic dysfunction was occurred most frequently at 32.5% (13/40). In univariate analysis, hepatic dysfunction was significantly high in patients with low modified Rodnan total skin thickness score. Antimitochondria‐antibody‐positive patients were more likely to develop liver dysfunction. Hepatic dysfunction was improved without the reduction or discontinuation, dose reduction, discontinuation, or concomitant use of ursodeoxycholic acid. These results suggest that bosentan can be selected as an additional treatment for DU, which is difficult to treat with existing therapies, while carefully monitoring hepatic function.
Non‐native fish facilitate non‐native snails and alter food web structure in experimental pond communities
Authors: Crone Erin R. , Sauer Erin L. , Preston Daniel L.
Published: January 2023

Contemporary ecosystems commonly support multiple non‐native species, which can alter community structure and directly or indirectly interact with one another. Novel interactions between invasive species can result in the facilitation or suppression of one or both invaders, making it important to understand the underlying mechanisms that affect invasion outcomes.

Goldfish Carassius auratus and Chinese mystery snails Cipangopaludina chinensis have been introduced widely through the aquarium trade and co‐occur in their non‐native ranges. We used an outdoor mesocosm experiment to assess separate and combined effects of goldfish and mystery snails on urban pond community structure and to investigate whether goldfish and mystery snails affected one another positively, neutrally or negatively. We predicted that the distinct trophic levels of each species and the anti‐predator traits of mystery snails would lead to positive interactions between invaders and synergistic effects on the aquatic community.

Goldfish directly increased turbidity and decreased filamentous algae, zooplankton, juvenile native snails and survival of amphibians via consumptive effects. Goldfish indirectly increased periphyton, phytoplankton and body size of surviving native green frogs Lithobates clamitans through trophic cascades and/or release from competition. Mystery snails had more subtle effects including reducing growth rates of native grey tree frogs Hyla versicolor, likely through competitive interactions.

With goldfish present, mystery snails showed increased reproductive success (higher biomass of juveniles), likely due to indirect competitive release from other herbivores. In contrast to their effects on native snails, goldfish did not consume juvenile mystery snails, likely due to their unique traits (e.g. large size and shell thickness). Mystery snails slightly reduced goldfish growth but did not affect their survival.

These results suggest unidirectional facilitation between invaders via indirect changes in the food web. Overall, our study found strong direct and indirect effects of invasive aquarium species, particularly goldfish, and provides experimental support for the invasional meltdown hypothesis within urban waterbodies, which are especially prone to invasions.

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