bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-1/LAG-3 bispecific antibody potentiates T cell activation and increases antitumor efficacy
Authors: Shi Ning , Zhou Yangyihua , Liu Yujun , Zhang Ran , Jiang Xingjun , Ren Caiping , Gao Xiang , Luo Longlong
Published: November 2022

Several clinical studies demonstrate that there exist other immune checkpoints overexpressed in some PD-1 inhibitor-resistant tumor patients. Among them, Lymphocyte-activation gene 3 (LAG-3) is one of the important immune checkpoint molecules and has been clinically demonstrated to have synergistic anti-tumor effects in combination with PD-1 antibody. In this study, we designed a novel ‘knob-in-hole’ PD-1/LAG-3 bispecific antibody (BsAb) YG-003D3. In conclusion, the BsAb maintained the similar affinity and thermal stability to the parental antibody, and the BsAb structure can be independent of each other in the process of double-target recognition, and the recognition activity will not be affected. Moreover, the BsAb can not only target PD-1 and LAG-3 on single cell simultaneously, but also bridge the two kinds of cells expressing PD-1 and LAG-3, so as to release the ‘brake system of immune checkpoints’ and activate immune cells to exert anti-tumor effects more effectively. Especially in the PBMCs activation assay, YG-003D3 induced stronger IFN-γ, IL-6, and TNF-α secretion compared to anti-PD-1 or anti-LAG-3 single drug group or even combined drug group. In the tumor killing experiment of PBMC in vitro, YG-003D3 has a better ability to activate PBMC to kill tumor cells than anti-PD-1 or anti-LAG-3 single drug group or even combined drug group, and the killing rate is as high as 20%. In a humanized PD-1/LAG-3 transgenic mouse subcutaneous tumor-bearing model, YG-003D3 showed good anti-tumor activity, even better than that of the combination group at the same molar concentration. Further studies have shown that YG-003D3 could significantly alter the proportion of immune cells in the tumor microenvironment. In particular, the proportion of CD45+, CD3+ T, CD8+ T cells in tumor tissue and the proportion of CD3+ T, CD8+ T, CD4+ T cells in peripheral blood were significantly increased. These results suggest that YG-003D3 exerts a potent antitumor effect by activating the body ‘s immune system. In summary, the BsAb YG-003D3 has good anti-tumor activity, which is expected to become a novel drug candidate for cancer immunotherapy.
Developmental endothelial locus-1 in cardiovascular and metabolic diseases: A promising biomarker and therapeutic target
Authors: Zhao Mengmeng , Zheng Zihui , Li Chenfei , Wan Jun , Wang Menglong
Published: November 2022

Cardiovascular and metabolic diseases (CVMDs) are a leading cause of death worldwide and impose a major socioeconomic burden on individuals and healthcare systems, underscoring the urgent need to develop new drug therapies. Developmental endothelial locus-1 (DEL-1) is a secreted multifunctional domain protein that can bind to integrins and play an important role in the occurrence and development of various diseases. Recently, DEL-1 has attracted increased interest for its pharmacological role in the treatment and/or management of CVMDs. In this review, we present the current knowledge on the predictive and therapeutic role of DEL-1 in a variety of CVMDs, such as atherosclerosis, hypertension, cardiac remodeling, ischemic heart disease, obesity, and insulin resistance. Collectively, DEL-1 is a promising biomarker and therapeutic target for CVMDs.
The atypical chemokine receptor-2 fine-tunes the immune response in herpes stromal keratitis
Authors: Yu Tian , Schuette Fabian , Christofi Maria , Forrester John V. , Graham Gerard J. , Kuffova Lucia
Published: November 2022

Herpes stromal keratitis (HSK) is a blinding corneal disease caused by herpes simplex virus-1 (HSV-1), a common pathogen infecting most of the world’s population. Inflammation in HSK is chemokine-dependent, particularly CXCL10 and less so the CC chemokines. The atypical chemokine receptor-2 (ACKR2) is a decoy receptor predominantly for pro-inflammatory CC chemokines, which regulates the inflammatory response by scavenging inflammatory chemokines thereby modulating leukocyte infiltration. Deletion of ACKR2 exacerbates and delays the resolution of the inflammatory response in most models. ACKR2 also regulates lymphangiogenesis and mammary duct development through the recruitment of tissue-remodeling macrophages. Here, we demonstrate a dose-dependent upregulation of ACKR2 during corneal HSV-1 infection. At an HSV inoculum dose of 5.4 x 105pfu, but not at higher dose, ACKR2 deficient mice showed prolonged clinical signs of HSK, increased infiltration of leukocytes and persistent corneal neovascularization. Viral clearance and T cell activation were similar in ACKR2-/-and wild type mice, despite a transient diminished expression of CD40 and CD86 in dendritic cells. The data suggest that ACKR2 fine-tunes the inflammatory response and the level of neovascularization in the HSK.
Effects of diurnal temperature fluctuations on growth performance, energy metabolism, stress response, and gut microbes of juvenile mud crab Scylla paramamosain
Authors: Liu Jiahao , Chen Shujian , Ren Zhiming , Ye Yangfang , Wang Chunlin , Mu Changkao , Wu Qingyang , Shi Ce
Published: November 2022

A 51-day experiment was conducted to investigate the effects of diurnal temperature fluctuations (DTF) on growth performance, energy metabolism, stress response and gut microbiota of juvenile mud crab Scylla paramamosain. One control and three fluctuation groups were set up, i.e., constant (28 ± 0°C) (CT), slight (SF) (28 ± 2°C), medium (MF) (28 ± 4°C), and large (LF) (28 ± 6°C) DTF. The survival rate tended to decrease with the intensification of DTF, the survival of rate of CT, SF, MF and LF were 80.6 ± 3.9%, 75.0 ± 6.8%, 33.3 ± 6.8%, and 30.6 ± 10.4% respectively. The crab in SF and MF had a shorter, but LF had a longer molt interval compared with the crab in the CT group. Cortisol, blood glucose (GLU), total cholesterol (T-CHO) and triglyceride (TG) levels peaked in the LF group. The exacerbation of DTF caused a dramatic increase in reactive oxygen species (ROS) levels and impacted the antioxidant capacity of juvenile crabs. The relative expression of AMP-activated protein kinase (ampk), heat shock protein 70 (hsp70) and heat shock protein 90 (hsp90) genes was significantly increased in MF group. The expression of Ribosomal protein S6 kinase (s6k) and Mechanistic target of rapamycin (tor) genes was significantly up-regulated in the SF group (P< 0.05) but large DTF caused a decrease in the relative expression of a large number of functional genes. DTF affected the structure and function of gut microbes. The bacterial community changed with the intensification of DTF and alpha diversity continued to rise. Five biomarkers were identified, where Rhodobacterales and Rhodobacterac were significantly more abundant in the CT group, Campylobacterales,Vibrionales and erysipelotrichales were more abundant in the SF, MF and LF groups. In addition, SF also enhanced gut microbes interactions compared with other treatments. These results suggest that drastic environmental DTF reduced the growth and survival of young mud crabs, and the effect was mediated by energy metabolism, antioxidant pathways and gut microbes.
Diagnosis of giant cell arteritis by temporal artery biopsy is associated with biopsy length
Authors: Ruediger Carlee , Ninan Jem , Dyer Kathryn , Lyne Suellen , Tieu Joanna , Black Rachel J. , Dodd Thomas , Lester Susan , Hill Catherine L.
Published: November 2022

Aims

Temporal artery biopsy (TAB) is a widely used method for establishing a diagnosis of Giant Cell Arteritis (GCA). The optimal TAB length for accurate histological GCA diagnosis has been suggested as 15 mm post-fixation (15–20 mm pre-fixation). The aim of this study was to determine the relationship between a histological GCA diagnosis and optimal TAB length in the South Australian (SA) population.

Materials and methods

Pre-fixation TAB length (mm) was reported in 825/859 of all samples submitted to SA Pathology between 2014 and 2020 from people aged 50 and over. When more than one biopsy was taken, the longest length was recorded. Analyses of both TAB length and TAB positive proportions were performed by multivariable linear and logistic regression analysis, including covariates sex, age, and calendar year.

Results

The median age of participants was 72 (IQR 65, 79) years, 549 (66%) were female. The TAB positive proportion was 172/825 (21%) with a median biopsy length of 14 mm (IQR 9, 18). Biopsy length (mm) was shorter in females (p = 0.001), increased with age (p = 0.006), and a small positive linear trend with calendar year was observed (p = 0.015). The TAB positive proportion was related to older age (slope/decade: 6, 95% CI 3.6, 8.3, p < 0.001) and to TAB length (slope/mm 0.6, 95% CI 0.2, 0.9, p = 0.002), but not sex or calendar year. Comparison of models with TAB length cut-points at 5, 10, 15, 20 mm in terms of diagnostic yield, receiver operating characteristics and Akaike Information Criteria confirmed ≥ 15 mm as an appropriate, recommended TAB length. However, only 383 (46%) of the biopsies in our study met this criteria. The diagnostic yield at this cut-point was estimated as 25% which equates to an expected additional 30 histologically diagnosed GCA patients.

Conclusion

This study confirms that TAB biopsy length is a determinant of a histological diagnosis of temporal arteritis, and confirms that a TAB length ≥ 15 mm is optimal. Approximately half the biopsies in this study were shorter than this optimal length, which has likely led to under-diagnosis of biopsy-proven GCA in SA. Further work is needed to ensure appropriate TAB biopsy length.
Advances in experimental and computational methodologies for the study of microbial-surface interactions at different omics levels
Authors: González-Plaza Juan José , Furlan Cristina , Rijavec Tomaž , Lapanje Aleš , Barros Rocío , Tamayo-Ramos Juan Antonio , Suarez-Diez Maria
Published: November 2022

The study of the biological response of microbial cells interacting with natural and synthetic interfaces has acquired a new dimension with the development and constant progress of advanced omics technologies. New methods allow the isolation and analysis of nucleic acids, proteins and metabolites from complex samples, of interest in diverse research areas, such as materials sciences, biomedical sciences, forensic sciences, biotechnology and archeology, among others. The study of the bacterial recognition and response to surface contact or the diagnosis and evolution of ancient pathogens contained in archeological tissues require, in many cases, the availability of specialized methods and tools. The current review describes advances in in vitro and in silico approaches to tackle existing challenges (e.g., low-quality sample, low amount, presence of inhibitors, chelators, etc.) in the isolation of high-quality samples and in the analysis of microbial cells at genomic, transcriptomic, proteomic and metabolomic levels, when present in complex interfaces. From the experimental point of view, tailored manual and automatized methodologies, commercial and in-house developed protocols, are described. The computational level focuses on the discussion of novel tools and approaches designed to solve associated issues, such as sample contamination, low quality reads, low coverage, etc. Finally, approaches to obtain a systems level understanding of these complex interactions by integrating multi omics datasets are presented.
Characteristics of gut microbiota and fecal metabolomes in patients with celiac disease in Northwest China
Authors: Shi Tian , Feng Yan , Liu Weidong , Liu Huan , Li Ting , Wang Man , Li Ziqiong , Lu Jiajie , Abudurexiti Adilai , Maimaitireyimu Ayinuer , Hu Jiali , Gao Feng
Published: November 2022

Celiac disease (CD) is an autoimmune small bowel disease. The pattern of gut microbiota is closely related to dietary habits, genetic background, and geographical factors. There is a lack of research on CD-related gut microbiota in China. This study aimed to use 16S rDNA sequencing and metabolomics to analyze the fecal microbial composition and metabolome characteristics in patients diagnosed with CD in Northwest China, and to screen potential biomarkers that could be used for its diagnosis. A significant difference in the gut microbiota composition was observed between the CD and healthy controls groups. At the genus level, the abundance of Streptococcus, Lactobacillus, Veillonella, and Allisonella communities in the CD group were increased (Q < 0.05). Furthermore, the abundance of Ruminococcus, Faecalibacterium, Blautia, Gemmiger, and Anaerostipes community in this group were decreased (Q < 0.05). A total of 222 different fecal metabolites were identified in the two groups, suggesting that CD patients have a one-carbon metabolism defect. Four species of bacteria and six metabolites were selected as potential biomarkers using a random forest model. Correlation analysis showed that changes in the gut microbiota were significantly correlated with changes in fecal metabolite levels. In conclusion, the patterns of distribution of gut microbiota and metabolomics in patients with CD in Northwest China were found to be unique to these individuals. This has opened up a new way to explore potential beneficial effects of supplementing specific nutrients and potential diagnostic and therapeutic targets in the future.
An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection
Authors: Devaux Christian A. , Camoin-Jau Laurence
Published: November 2022

It has been known for many years that the angiotensin-converting enzyme 2 (ACE2) is a cell surface enzyme involved in the regulation of blood pressure. More recently, it was proven that the severe acute respiratory syndrome coronavirus (SARS-CoV-2) interacts with ACE2 to enter susceptible human cells. This functional duality of ACE2 tends to explain why this molecule plays such an important role in the clinical manifestations of coronavirus disease 2019 (COVID-19). At the very start of the pandemic, a publication from our Institute (entitled “ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome”), was one of the first reviews linking COVID-19 to the duplicitous nature of ACE2. However, even given that COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin system (RAS), we were still far from understanding the complexity of the mechanisms which are controlled by ACE2 in different cell types. To gain insight into the physiopathology of SARS-CoV-2 infection, it is essential to consider the polymorphism and expression levels of the ACE2 gene (including its alternative isoforms). Over the past 2 years, an impressive amount of new results have come to shed light on the role of ACE2 in the pathophysiology of COVID-19, requiring us to update our analysis. Genetic linkage studies have been reported that highlight a relationship between ACE2 genetic variants and the risk of developing hypertension. Currently, many research efforts are being undertaken to understand the links between ACE2 polymorphism and the severity of COVID-19. In this review, we update the state of knowledge on the polymorphism of ACE2 and its consequences on the susceptibility of individuals to SARS-CoV-2. We also discuss the link between the increase of angiotensin II levels among SARS-CoV-2-infected patients and the development of a cytokine storm associated microvascular injury and obstructive thrombo-inflammatory syndrome, which represent the primary causes of severe forms of COVID-19 and lethality. Finally, we summarize the therapeutic strategies aimed at preventing the severe forms of COVID-19 that target ACE2. Changing paradigms may help improve patients’ therapy.
Hypothetical protein FoDbp40 influences the growth and virulence of Fusarium oxysporum by regulating the expression of isocitrate lyase
Authors: Zhao Busi , He Dan , Gao Song , Zhang Yan , Wang Li
Published: November 2022

Fungal growth is closely related to virulence. Finding the key genes and pathways that regulate growth can help elucidate the regulatory mechanisms of fungal growth and virulence in efforts to locate new drug targets. Fusarium oxysporum is an important plant pathogen and human opportunistic pathogen that has research value in agricultural and medicinal fields. A mutant of F. oxysporum with reduced growth was obtained by Agrobacterium tumefaciens-mediated transformation, the transferred DNA (T-DNA) interrupted gene in this mutant coded a hypothetical protein that we named FoDbp40. FoDbp40 has an unknown function, but we chose to explore its possible functions as it may play a role in fungal growth regulatory mechanisms. Results showed that F. oxysporum growth and virulence decreased after FoDbp40 deletion. FOXG_05529 (NCBI Gene ID, isocitrate lyase, ICL) was identified as a key gene that involved in the reduced growth of this mutant. Deletion of FoDbp40 results in a decrease of more than 80% in ICL expression and activity, succinate level, and energy level, plus a decrease in phosphorylated mammalian target of rapamycin level and an increase in phosphorylated 5′-adenosine monophosphate activated protein kinase level. In summary, our study found that the FoDbp40 regulates the expression of ICL at a transcriptional level and affects energy levels and downstream related pathways, thereby regulating the growth and virulence of F. oxysporum.
Characterization of a virulence-modifying protein of Leptospira interrogans identified by shotgun phage display
Authors: Lauretti-Ferreira Fabiana , Teixeira André Azevedo Reis , Giordano Ricardo José , da Silva Josefa Bezerra , Abreu Patricia Antonia Estima , Barbosa Angela Silva , Akamatsu Milena Apetito , Ho Paulo Lee
Published: November 2022

Pathogenic species of Leptospira are etiologic agents of leptospirosis, an emerging zoonotic disease of worldwide extent and endemic in tropical regions. The growing number of identified leptospiral species sheds light to their genetic diversity and unique virulence mechanisms, many of them still remain unknown. Toxins and adhesins are important virulence factors in several pathogens, constituting promising antigens for the development of vaccines with cross-protection and long-lasting effect against leptospirosis. For this aim, we used the shotgun phage display technique to unravel new proteins with adhesive properties. A shotgun library was constructed using fragmented genomic DNA from Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130 and pG8SAET phagemid vector. Selection of phages bearing new possible cell-binding antigens was performed against VERO cells, using BRASIL biopanning methodology. Analysis of selected clones revealed the hypothetical protein LIC10778, a potentially exposed virulence factor that belongs to the virulence-modifying (VM) protein family (PF07598), composed of 13 members in the leptospiral strain Fiocruz L1-130. Prediction of LIC10778 tertiary structure indicates that the protein contains a cellular-binding domain (N-terminal portion) and an unknown domain of no assigned activity (C-terminal portion). The predicted N-terminal domain shared structural similarities with the cell-binding and internalization domain of toxins like Ricin and Abrin, as well as to the Community-Acquired Respiratory Distress Syndrome (CARDS) toxin in Mycoplasma pneumoniae. Interestingly, recombinant portions of the N-terminal region of LIC10778 protein showed binding to laminin, collagens I and IV, vitronectin, and plasma and cell fibronectins using overlay blotting technique, especially regarding the binding site identified by phage display. These data validate our preliminary phage display biopanning and support the predicted three-dimensional models of LIC10778 protein and other members of PF07598 protein family, confirming the identification of the N-terminal cell-binding domains that are similar to ricin-like toxins. Moreover, fluorescent fused proteins also confirmed that N-terminal region of LIC10778 is capable of binding to VERO and A549 cell lines, further highlighting its virulence role during host-pathogen interaction in leptospirosis probably mediated by its C-terminal domain. Indeed, recent results in the literature confirmed this assumption by demonstrating the cytotoxicity of a closely related PF07598 member.
The plethora of Tubeufiaceae in lakes of the northwestern Yunnan plateau, China
Authors: Li Long-Li , Shen Hong-Wei , Bao Dan-Feng , Wanasinghe Dhanushka N. , Lu Yong-Zhong , Feng Yuan , Luo Zong-Long
Published: November 2022

The diversity of lignicolous freshwater fungi in northwestern Yunnan, China, has been studied for several years in the College of Agriculture and Biological Science, at Dali University. Over the last 5 years, we published two new genera and nine new species of Tubeufiaceae from northwestern Yunnan. This study focused on introducing tubeufia-like hyphomycetous fungi found in freshwater lakes in the northwestern Yunnan plateau. Eleven fresh collections of tubeufiaceous taxa were gathered and identified. Among them, a new genus, Neomanoharachariella, is introduced to accommodate Neomanoharachariella aquatica, which is characterized by a light brown to dark brown color, dictyoseptate, and broadly oval to ellipsoid and well-developed conidiophores. Two new species, viz., Neohelicosporium suae and Parahelicomyces suae, one new record, Helicoma rufum, and three new collections, namely, H. rugosum, P. hyalosporus, and Tubeufia cylindrothecia are introduced based on morphological evidence and molecular phylogenetic analysis of combined ITS, LSU, tef 1-α, and RPB2 sequence data. Detailed descriptions and illustrations of these species are provided, and a morphological comparison with similar taxa is discussed.
Fermentation quality, bacterial community, and predicted functional profiles in silage prepared with alfalfa, perennial ryegrass and their mixture in the karst region
Authors: Fan Xueying , Xie Zhiming , Cheng Qiming , Li Maoya , Long Jianhua , Lei Yao , Jia Yushan , Chen Yulian , Chen Chao , Wang Zhijun
Published: November 2022

There is little information regarding the dynamics of fermentation products and the bacterial community in silage prepared with alfalfa (MS), perennial ryegrass (LP), and their mixture in the karst region. In this study, we explored the effects of combining MS with LP in different ratios (100% MS, 70% MS + 30% LP, 50% MS + 50% LP, 30% MS + 70% LP and 100% LP; fresh matter basis) on silage chemical composition, fermentation quality, bacterial communities and predicted functions during the ensiling process. Each treatment was prepared in triplicate and stored at room temperature (22–25°C) for 7, 15, and 45 days. The dry matter (DM) and water-soluble carbohydrate content of the silages increased as the LP proportion in the mixed silage increased; at 45 days, the 70% MS + 30% LP, 50% MS + 50% LP and 30% MS + 70% LP silages contained higher (p < 0.05) CP content than the 100% MS and 100% LP silages. The 30% MS + 70% LP and 100% LP silages exhibited lower (p < 0.05) pH and higher (p < 0.05) LA content than the other silages; at 45 days, none of the silages contained PA or BA. As fermentation proceeded, the abundance of harmful (Enterobacteriaceae and Sphingomonas) and beneficial (Lentilactobacillus, Lactiplantibacillus, Secundilactobacillus, and Levilactobacillus) microorganisms decreased and increased, respectively, as the LP proportion in the mixed silage increased. The predicted functional distribution of microbial communities and metabolic pathways revealed that the 30% MS + 70% LP and 100% LP silages had a stronger capacity for fermentation and a weaker capacity for nitrate reduction than the other silages. Moreover, as the fermentation proceeded, the 30% MS + 70% LP and 100% LP treatments enhanced the functions of “Metabolism,” “Genetic information processing” and “Organismal systems” at level 1, the functions of “Amino acid metabolism” and “Nucleotide metabolism” at level 2, and the functions of “Metabolic pathways,” “Biosynthesis of secondary metabolites,” “Biosynthesis of antibiotics” and “Purine metabolism” at level 3. Thus, adding LP could improve the fermentation quality of MS silage by changing the composition and metabolic function of microbes; furthermore, ensiling 30% alfalfa with 70% ryegrass can produce high-quality silage in the karst region.
Interaction between chicken TRIM25 and MDA5 and their role in mediated antiviral activity against IBDV infection
Authors: Diaz-Beneitez Elisabet , Cubas-Gaona Liliana Lilibeth , Candelas-Rivera Oscar , Benito-Zafra Ana , Sánchez-Aparicio Maria Teresa , Miorin Lisa , Rodríguez José F. , García-Sastre Adolfo , Rodríguez Dolores
Published: November 2022

Infectious Bursal Disease Virus (IBDV) is the causative agent of an immunosuppressive disease that affects domestic chickens (Gallus gallus) severely affecting poultry industry worldwide. IBDV infection is characterized by a rapid depletion of the bursal B cell population by apoptosis and the atrophy of this chief lymphoid organ. Previous results from our laboratory have shown that exposure of infected cells to type I IFN leads to an exacerbated apoptosis, indicating an important role of IFN in IBDV pathogenesis. It has been described that recognition of the dsRNA IBDV genome by MDA5, the only known cytoplasmic pattern recognition receptor for viral RNA in chickens, leads to type I IFN production. Here, we confirm that TRIM25, an E3 ubiquitin ligase that leads to RIG-I activation in mammalian cells, significantly contributes to positively regulate MDA5-mediated activation of the IFN-inducing pathway in chicken DF-1 cells. Ectopic expression of chTRIM25 together with chMDA5 or a deletion mutant version exclusively harboring the CARD domains (chMDA5 2CARD) enhances IFN-β and NF-ĸB promoter activation. Using co-immunoprecipitation assays, we show that chMDA5 interacts with chTRIM25 through the CARD domains. Moreover, chTRIM25 co-localizes with both chMDA5 and chMDA5 2CARD, but not with chMDA5 mutant proteins partially or totally lacking these domains. On the other hand, ablation of endogenous chTRIM25 expression reduces chMDA5-induced IFN-β and NF-ĸB promoter activation. Interestingly, ectopic expression of either wild-type chTRIM25, or a mutant version (chTRIM25 C59S/C62S) lacking the E3 ubiquitin ligase activity, restores the co-stimulatory effect of chMDA5 in chTRIM25 knockout cells, suggesting that the E3-ubiquitin ligase activity of chTRIM25 is not required for its downstream IFN-β and NF-ĸB activating function. Also, IBDV-induced expression of IFN-β, Mx and OAS genes was reduced in chTRIM25 knockout as compared to wild-type cells, hence contributing to the enhancement of IBDV replication. Enhanced permissiveness to replication of other viruses, such as avian reovirus, Newcastle disease virus and vesicular stomatitis virus was also observed in chTRIM25 knockout cells. Additionally, chTRIM25 knockout also results in reduced MAVS-induced IFN-β promoter stimulation. Nonetheless, similarly to its mammalian counterpart, chTRIM25 overexpression in wild-type DF-1 cells causes the degradation of ectopically expressed chMAVS.
Male-killing mechanisms vary between Spiroplasma species
Authors: Arai Hiroshi , Inoue Maki N. , Kageyama Daisuke
Published: November 2022

Male-killing, a male-specific death of arthropod hosts during development, is induced by Spiroplasma (Mollicutes) endosymbionts of the Citri–Poulsonii and the Ixodetis groups, which are phylogenetically distant groups. Spiroplasma poulsonii induces male-killing in Drosophila melanogaster (Diptera) using the Spaid toxin that harbors ankyrin repeats, whereas little is known about the origin and mechanisms of male-killing induced by Spiroplasma ixodetis. Here, we analyzed the genome and the biological characteristics of a male-killing S. ixodetis strain sHm in the moth Homona magnanima (Tortricidae, Lepidoptera). Strain sHm harbored a 2.1 Mb chromosome and two potential plasmids encoding Type IV effectors, putatively involved in virulence and host–symbiont interactions. Moreover, sHm did not harbor the spaid gene but harbored 10 ankyrin genes that were homologous to those in other S. ixodetis strains. In contrast to the predominant existence of S. poulsonii in hemolymph, our quantitative PCR assays revealed a systemic distribution of strain sHm in H. magnanima, with particularly high titers in Malpighian tubules but low titers in hemolymph. Furthermore, transinfection assays confirmed that strain sHm can infect cultured cells derived from distantly related insects, namely Aedes albopictus (Diptera) and Bombyx mori (Lepidoptera). These results suggest different origins and characteristics of S. ixodetis- and S. poulsonii-induced male-killing.
Differentiating acute from chronic insomnia with machine learning from actigraphy time series data
Authors: Rani S. , Shelyag S. , Karmakar C. , Zhu Ye , Fossion R. , Ellis J. G. , Drummond S. P. A. , Angelova M.
Published: November 2022

Acute and chronic insomnia have different causes and may require different treatments. They are investigated with multi-night nocturnal actigraphy data from two sleep studies. Two different wrist-worn actigraphy devices were used to measure physical activities. This required data pre-processing and transformations to smooth the differences between devices. Statistical, power spectrum, fractal and entropy analyses were used to derive features from the actigraphy data. Sleep parameters were also extracted from the signals. The features were then submitted to four machine learning algorithms. The best performing model was able to distinguish acute from chronic insomnia with an accuracy of 81%. The algorithms were then used to evaluate the acute and chronic groups compared to healthy sleepers. The differences between acute insomnia and healthy sleep were more prominent than between chronic insomnia and healthy sleep. This may be associated with the adaptation of the physiology to prolonged periods of disturbed sleep for individuals with chronic insomnia. The new model is a powerful addition to our suite of machine learning models aiming to pre-screen insomnia at home with wearable devices.
Cochlear resident macrophage mediates development of ribbon synapses via CX3CR1/CX3CL1 axis
Authors: Song Xinyu , Li Yang , Guo Rui , Yu Qianru , Liu Shan , Teng Qi , Chen Zhong-Rui , Xie Jing , Gong Shusheng , Liu Ke
Published: November 2022

Cochlear ribbon synapses formed between spiral ganglion neurons and inner hair cells in postnatal mice must undergo significant morphological and functional development to reach auditory maturation. However, the mechanisms underlying cochlear ribbon synapse remodeling remain unclear. This study found that cochlear resident macrophages are essential for cochlear ribbon synapse development and maturation in mice via the CX3CR1/CX3CL1 axis. CX3CR1 expression (a macrophage surface-specific receptor) and macrophage count in the cochlea were significantly increased from postnatal day 7 then decreased from days 14 to 28. Seven-day treatment with CX3CR1 inhibitors and artificial upregulation of CX3CL1 levels in the inner ear environment using the semicircular canal injection technique were initiated on day 7, and this resulted in a significant increase in hearing threshold on day 28. Additionally, abnormalities in the morphology and number of cochlear ribbon synapses were detected on day P14, which may be associated with hearing impairment. In conclusion, macrophage regulation of cochlear ribbon synapse remodeling via the CX3CR1/CX3CL1 axis is required during hearing development and offers a new perspective on immune-related hearing loss throughout auditory development. Importantly, it could be a new treatment target for sensorineural hearing loss.
Development and external validation of a radiomics combined with clinical nomogram for preoperative prediction prognosis of resectable pancreatic ductal adenocarcinoma patients
Authors: Wang Fangqing , Zhao Yuxuan , Xu Jianwei , Shao Sai , Yu Dexin
Published: November 2022

Purpose

To develop and externally validate a prognosis nomogram based on contrast-enhanced computed tomography (CECT) combined clinical for preoperative prognosis prediction of patients with pancreatic ductal adenocarcinoma (PDAC).

Methods

184 patients from Center A with histopathologically confirmed PDAC who underwent CECT were included and allocated to training cohort (n=111) and internal validation cohort (n=28). The radiomic score (Rad - score) for predicting overall survival (OS) was constructed by using the least absolute shrinkage and selection operator (LASSO). Univariate and multivariable Cox regression analysis was used to construct clinic-pathologic features. Finally, a radiomics nomogram incorporating the Rad - score and clinical features was established. External validation was performed using Center B dataset (n = 45). The validation of nomogram was evaluated by calibration curve, Harrell’s concordance index (C-index) and decision curve analysis (DCA). The Kaplan-Meier (K-M) method was used for OS analysis.

Results

Univariate and multivariate analysis indicated that Rad – score, preoperative CA 19-9 and postoperative American Joint Committee on Cancer (AJCC) TNM stage were significant prognostic factors. The nomogram based on Rad - score and preoperative CA19-9 was found to exhibit excellent prediction ability: in the training cohort, C-index was superior to that of the preoperative CA19-9 (0.713 vs 0.616, P< 0.001) and AJCC TNM stage (0.713 vs 0.614, P< 0.001); the C-index was also had good performance in the validation cohort compared with CA19-9 (internal validation cohort: 0.694 vs 0.555, P< 0.001; external validation cohort: 0.684 vs 0.607, P< 0.001) and AJCC TNM stage (internal validation cohort: 0.694 vs 0.563, P< 0.001; external validation cohort: 0.684 vs 0.596, P< 0.001). The calibration plot and DCA showed excellent predictive accuracy in the validation cohort.

Conclusion

We established a well-designed nomogram to accurately predict OS of PDAC preoperatively. The nomogram showed a satisfactory prediction effect and was worthy of further evaluation in the future.
Comparative efficacy and safety of prophylactic norepinephrine and phenylephrine in spinal anesthesia for cesarean section: A systematic review and meta-analysis with trial sequential analysis
Authors: Liu Peng , He Hong , Zhang Shan-Shan , Liang Yun , Gao Zi-Jun , Yuan Hui , Dong Bu-Huai
Published: November 2022

Background: Phenylephrine is the first-line drug used to maintain blood pressure in cesarean delivery. However, it poses a high risk of bradycardia and depression of cardiac activity in pregnant women. Consequently, norepinephrine has gained popularity over the recent years, as an alternative to Phenylephrine because it is thought that prophylactic use of vasopressors may reduce the incidence of hypotension after spinal anesthesia. This systematic review compared the efficacy of both treatments.

Methods: We searched the following databases; CNKI, PubMed, Embase, Web of science, clinicaltrials.gov, Medline and Cochrane Library, for randomized controlled trials comparing the prophylactic efficacy of norepinephrine and phenylephrine on elective cesarean delivery under spinal anesthesia. The search period was from inception to July 2022, and the primary outcome indicator was incidence of bradycardia. Statistical analysis was conducted on Rev manager 5.4, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to evaluate the quality of evidence from each main finding.

Results: A total of 12 papers were included in the analysis. The incidence of bradycardia (RR = 0.37, 95% CI: 0.28 to 0.49, p < 0.00001) and reactive hypertension (RR = 0.58, 95% CI 0.40 to 0.83, p = 0.003) was significantly lower in the norepinephrine (NE) group compared with the phenylephrine (PE) category. In contrast, there were no statistical differences in the umbilical cord blood gas analysis pH values between the groups (arterial: MD = 0.00, 95% CI −0.00 to 0.01, p = 0.22, vein: MD = 0.01, 95% CI −0.00 to 0.02, p = 0.06). The incidence of hypotension, nausea, and vomiting did not differ significantly between the NE and PE groups (hypotension: 23% vs. 18%; nausea: 14% vs. 18%; vomiting: 5% vs. 7%, respectively).

Conclusion: Prophylactic use of norepinephrine is safe and effective in maintaining maternal hemodynamics without causing adverse events to either the pregnant woman or fetus.

Systematic Review Registration: website https://www.crd.york.ac.uk/prospero/, identifier CRD42022347095
Drug-induced liver injury in COVID-19 treatment: Incidence, mechanisms and clinical management
Authors: Li Xichuan , Wang Wanting , Yan Suying , Zhao Weipeng , Xiong Hui , Bao Cuiping , Chen Jinqian , Yue Yuan , Su Yanjun , Zhang Chunze
Published: November 2022

The COVID-19 outbreak triggered a serious and potentially lethal pandemic, resulting in massive health and economic losses worldwide. The most common clinical manifestations of COVID-19 patients are pneumonia and acute respiratory distress syndrome, with a variety of complications. Multiple organ failure and damage, ultimately leading to patient death, are possible as a result of medication combinations, and this is exemplified by DILI. We hope to summarize DILI caused by the antiviral drugs favipiravir, remdesivir, lopinavir/ritonavir, and hydroxychloroquine in COVID-19 patients in this review. The incidence of liver injury in the treatment of COVID-19 patients was searched on PubMed to investigate DILI cases. The cumulative prevalence of acute liver injury was 23.7% (16.1%–33.1%). We discuss the frequency of these events, potential mechanisms, and new insights into surveillance strategies. Furthermore, we also describe medication recommendations aimed at preserving DILI caused by treatment in COVID-19 patients.
A risk model developed based on necroptosis to assess progression for ischemic cardiomyopathy and identify possible therapeutic drugs
Authors: Lu Yang , Wang Dashuai , Zhu Yaoxi , Du Yimei , Zhang Jinying , Yang Han
Published: November 2022

Object: Ischemic cardiomyopathy (ICM), with high morbidity and mortality, is the most common cause of heart failure. Cardiovascular remodeling secondary to chronic myocardial ischemia is the main cause of its progression. A recently identified type of programmed cell death called necroptosis is crucial in the development of various cardiovascular diseases. However, the function role of necroptosis in cardiac remodeling of ICM has not been elucidated. Our study aimed to screen for genes associated with necroptosis and construct a risk score to assess the progression and evaluate the prognosis of ICM patients, and further to search for potentially therapeutic drugs.

Methods: The gene expression profiling was obtained from the GEO database. LASSO regression analysis was used to construct necroptosis-related gene signatures associated with ICM progression and prognosis. TF-gene and miRNA-gene networks were constructed to identify the regulatory targets of potential necroptosis-related signature genes. Pathway alterations in patients with high necroptosis-related score (NRS) were analyzed by GO, KEGG, GSEA analysis, and immune cell infiltration was estimated by ImmuCellAI analysis. CMap analysis was performed to screen potential small molecule compounds targeting patients with high NRS. Independent risk analyses were performed using nomograms.

Results: Six necroptosis-related signature genes (STAT4, TNFSF10, CHMP5, CHMP18, JAK1, and CFLAR) were used to define the NRS, with areas under the ROC curves of 0.833, 0.765, and 0.75 for training test, test set, and validation set, respectively. Transcription factors FOXC1 and hsa-miR-124-3p miRNA may be regulators of signature genes. Patients with higher NRS have pathway enriched in fibrosis and metabolism and elevated nTreg cells. AZD-7762 may be an effective drug to improve the prognosis of patients with high NRS. A feature-based nomogram was constructed from which patients could derive clinical benefit.

Conclusion: Our results reveal 6 necroptosis gene signatures that can evaluate the progression and prognosis of ICM with high clinical value, and identify potential targets that could help improve cardiovascular remodeling.
Community pharmacists’ views and experiences toward over-the-counter medicines misuse and abuse in Saudi Arabia: A qualitative study
Authors: Algarni Mohammad , Jalal Zahraa , Hadi Muhammad Abdul , Alghamdi Saleh
Published: November 2022

Background: Community pharmacists are uniquely positioned to identify and address the issue of misuse and abuse of over-the-counter (OTC) medicines. To date, no study has explored the Saudi community pharmacists’ views and experiences regarding aspects of OTC medicines’ misuse and abuse.

Objective: To explore the views and experiences of the Saudi community pharmacists towards OTC medicines misuse and abuse. Furthermore, we aimed to identify frequently misused and abused medicines, the reasons and contributing factors, the role of pharmacists, and potential risk-mitigating strategies.

Methods: Semi-structured interviews were conducted with a convenient sample of sixteen community pharmacists recruited from community pharmacies across the AL-Baha region, Saudi Arabia. Interviews were conducted using a pilot-tested interview guide in the Arabic language. All interviews were audio-recorded, transcribed verbatim, translated from Arabic into English, and then thematically analysed.

Results: Analysis of interviews generated five main themes, including the commonly misused and abused OTC medicines, reasons and factors contributing to misuse and abuse of OTC medicines, pharmacists’ interventions to manage misuse and abuse, challenges and barriers to pharmacists’ interventions in misuse and abuse issues; and potential strategies to reduce the risk of OTC medicines misuse and abuse and improve pharmacists’ practice. Sedative antihistamines, cough products containing dextromethorphan, codeine-based analgesics, and non-codeine-based analgesics were commonly misused and abused OTC medicines. Managing ongoing medical conditions was the main reason for misusing OTC analgesics while recreational use and inducing sleep were the common reasons for abuse. Several factors contributing to misuse and abuse were reported, including unprofessional advice sought from other people, lack of awareness about medicines, and commercial advertisement of OTC products. Community pharmacists identified misuse and abuse among customers by judging their behaviours and attitudes and using structured questioning techniques. Counselling customers on the appropriate use of medicines, providing safe alternatives, and refusing to sell products were among the commonly used actions of pharmacists to address misuse/abuse. Pharmacists proposed several strategies to reduce the risk of OTC medicines misuse/abuse but believed that rescheduling OTC medicines with abuse potential to prescription-only medicine was the best option.

Conclusion: Community pharmacists believed that the misuse and abuse of OTC medicines amongst pharmacy customers was common. A multidimensional strategy consisting of upskilling community pharmacists, a comprehensive review of OTC medicines sale regulations, and patient education to limit the risks of OTC medicines misuse/abuse is required.
Potential physiological responses contributing to the ergogenic effects of acute ischemic preconditioning during exercise: A narrative review
Authors: O’Brien Liam , Jacobs Ira
Published: November 2022

Ischemic preconditioning (IPC) has been reported to augment exercise performance, but there is considerable heterogeneity in the magnitude and frequency of performance improvements. Despite a burgeoning interest in IPC as an ergogenic aid, much is still unknown about the physiological mechanisms that mediate the observed performance enhancing effects. This narrative review collates those physiological responses to IPC reported in the IPC literature and discusses how these responses may contribute to the ergogenic effects of IPC. Specifically, this review discusses documented central and peripheral cardiovascular responses, as well as selected metabolic, neurological, and perceptual effects of IPC that have been reported in the literature.
Data assimilation on mechanistic models of glucose metabolism predicts glycemic states in adolescents following bariatric surgery
Authors: Richter Lauren R. , Albert Benjamin I. , Zhang Linying , Ostropolets Anna , Zitsman Jeffrey L. , Fennoy Ilene , Albers David J. , Hripcsak George
Published: November 2022

Type 2 diabetes mellitus is a complex and under-treated disorder closely intertwined with obesity. Adolescents with severe obesity and type 2 diabetes have a more aggressive disease compared to adults, with a rapid decline in pancreatic β cell function and increased incidence of comorbidities. Given the relative paucity of pharmacotherapies, bariatric surgery has become increasingly used as a therapeutic option. However, subsets of this population have sub-optimal outcomes with either inadequate weight loss or little improvement in disease. Predicting which patients will benefit from surgery is a difficult task and detailed physiological characteristics of patients who do not respond to treatment are generally unknown. Identifying physiological predictors of surgical response therefore has the potential to reveal both novel phenotypes of disease as well as therapeutic targets. We leverage data assimilation paired with mechanistic models of glucose metabolism to estimate pre-operative physiological states of bariatric surgery patients, thereby identifying latent phenotypes of impaired glucose metabolism. Specifically, maximal insulin secretion capacity, σ, and insulin sensitivity, SI, differentiate aberrations in glucose metabolism underlying an individual’s disease. Using multivariable logistic regression, we combine clinical data with data assimilation to predict post-operative glycemic outcomes at 12 months. Models using data assimilation sans insulin had comparable performance to models using oral glucose tolerance test glucose and insulin. Our best performing models used data assimilation and had an area under the receiver operating characteristic curve of 0.77 (95% confidence interval 0.7665, 0.7734) and mean average precision of 0.6258 (0.6206, 0.6311). We show that data assimilation extracts knowledge from mechanistic models of glucose metabolism to infer future glycemic states from limited clinical data. This method can provide a pathway to predict long-term, post-surgical glycemic states by estimating the contributions of insulin resistance and limitations of insulin secretion to pre-operative glucose metabolism.