bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence of Down Syndrome by maternal age in Chinese population
Authors: Song Yi , Jieping Song , Tianshu Zhou , Zhijun Zhang , Jingxuan Zhang , Bo Wang
Published: August 2022

Objective: This study aims to estimate the maternal age-related risk of Down syndrome in an Asian population.

Methods: We performed a retrospective data analysis including a total of 206,295 pregnant women who presented for second-trimester maternal serum screening for Down syndrome at Hubei Maternal and Child Health Hospital for the years 2008–2017. Cases were assigned to three groups: ≤26 years of age, 27–33 years of age, and ≥34 years of age. The incidence of Down Syndrome was calculated for each age group. The differences between groups were tested using the chi-square (χ2) test.

Results: The incidence of Down syndrome in women ≤26 years of age, 27–33 years of age, and ≥34 years of age was 0.67‰, 0.29‰, and 2.07‰ respectively. Statistically significant difference was found between the three age groups (χ2 = 79.748, p < 0.05).

Conclusion: Down syndrome rate was significantly higher in women ≥34 years of age. Younger women (≤26 years of age) had a significantly higher risk for Down’s syndrome, compared to women aged 27–33.
Long noncoding RNA profiling reveals that LncRNA BTN3A2 inhibits the host inflammatory response to Eimeria tenella infection in chickens
Authors: Yu Hailiang , Mi Changhao , Wang Qi , Dai Guojun , Zhang Tao , Zhang Genxi , Xie Kaizhou , Zhao Zhenhua
Published: August 2022

Coccidiosis is a widespread parasitic disease that causes serious economic losses to the poultry industry every year. Long noncoding RNAs (lncRNAs) play important roles in transcriptional regulation and are involved in a variety of diseases and immune responses. However, the lncRNAs associated with Eimeria tenella (E. tenella) resistance have not been identified in chickens. In addition, the expression profiles and functions of lncRNAs during E. tenella infection remain unclear. In the present study, high-throughput sequencing was applied to identify lncRNAs in chicken cecal tissues from control (JC), resistant (JR), and susceptible (JS) groups on day 4.5 post-infection (pi), and functional tests were performed. A total of 564 lncRNAs were differentially expressed, including 263 lncRNAs between the JS and JC groups, 192 between the JR and JS groups, and 109 between the JR and JC groups. Functional analyses indicated that these differentially expressed lncRNAs were involved in pathways related to E. tenella infection, including the NF-kappa B signaling, B cell receptor signaling and natural killer cell-mediated cytotoxicity pathways. Moreover, through cis regulation network analysis of the differentially expressed lncRNAs, we found that a novel lncRNA termed lncRNA BTN3A2 was significantly increased in both cecum tissue and DF-1 cells after coccidia infection or sporozoite stimulation. Functional test data showed that the overexpression of lncRNA BTN3A2 reduced the production of inflammatory cytokines, including IL-6, IL-1β, TNF-α and IL-8, while lncRNA BTN3A2 knockdown promoted the production of these inflammatory cytokines. Taken together, this study identify the differentially expressed lncRNAs during E. tenella infection in chickens for the first time and provide the direct evidence that lncRNA BTN3A2 regulates the host immune response to coccidia infection.
Serum cytokine levels are associated with tumor progression during FOLFIRINOX chemotherapy and overall survival in pancreatic cancer patients
Authors: van der Sijde Fleur , Dik Willem A. , Mustafa Dana A. M. , Vietsch Eveline E. , Besselink Marc G. , Debets Reno , Koerkamp Bas Groot , Haberkorn Brigitte C. M. , Homs Marjolein Y. V. , Janssen Quisette P. , Luelmo Saskia A. C. , Mekenkamp Leonie J. M. , Oostvogels Astrid A. M. , Smits-te Nijenhuis Marja A. W. , Wilmink Johanna W. , van Eijck Casper H. J. ,   the Dutch Pancreatic Cancer Group
Published: August 2022

Background

Biomarkers predicting treatment response may be used to stratify patients with pancreatic ductal adenocarcinoma (PDAC) for available therapies. The aim of this study was to evaluate the association of circulating cytokines with FOLFIRINOX response and with overall survival (OS).

Methods

Serum samples were collected before start and after the first cycle of FOLFIRINOX from patients with PDAC (n=83) of all disease stages. Overall, 34 circulating cytokines were analyzed with a multiplex immunoassay. In addition, changes in peripheral blood immune cell counts were determined by flow cytometry to correlate with differences in cytokine levels. Chemotherapy response was determined by CT scans with the RECIST 1.1 criteria, as disease control (n=64) or progressive disease (n=19) within eight cycles of FOLFIRINOX.

Results

Patients with high serum IL-1RA concentrations after one cycle of chemotherapy were less likely to have tumor progression during FOLFIRINOX (OR 0.25,P=0.040). Increase of circulating IL-1RA concentrations correlated with increase of total, classical (CD14+CD16-), and non-classical monocytes (CD14-CD16+), and dendritic cells. In multivariable cox regression, including the variables chemotherapy response outcome and baseline CA19-9 level, serum concentrations of IL-7 (HR 2.14,P=0.010), IL-18 (HR 2.00,P=0.020), and MIP-1β (HR 0.51,P=0.025) after one cycle of FOLFIRINOX showed correlations with OS.

Conclusions

Circulating IL-1RA, IL-7, IL-18, and MIP-1β concentrations are biomarkers associated with FOLFIRINOX response in PDAC patients, suggesting an important role for specific immune cells in chemotherapy response and PDAC progression. Cytokine-based treatment might improve patient outcome and should be evaluated in future studies.
Regulated necrosis in COVID-19: A double-edged sword
Authors: Sun Chen , Han Yunze , Zhang Ruoyu , Liu Simon , Wang Jing , Zhang Yuqing , Chen Xuemei , Jiang Chao , Wang Junmin , Fan Xiaochong , Wang Jian
Published: August 2022

COVID-19 caused by SARS-CoV-2 can cause various systemic diseases such as acute pneumonia with cytokine storm. Constituted of necroptosis, pyroptosis, and ferroptosis, regulated necrosis constitutes the cell death patterns under the low apoptosis condition commonly observed in COVID-19. Regulated necrosis is involved in the release of cytokines like TNF-α, IL-1 β, and IL-6 and cell contents such as alarmins, PAMPs, and DAMPs, leading to more severe inflammation. Uncontrolled regulated necrosis may explain the poor prognosis and cytokine storm observed in COVID-19. In this review, the pathophysiology and mechanism of regulated necrosis with the double-edged sword effect in COVID-19 are thoroughly discussed in detail. Furthermore, this review also focuses on the biomarkers and potential therapeutic targets of the regulated necrosis pathway in COVID-19, providing practical guidance to judge the severity, prognosis, and clinical treatment of COVID-19 and guiding the development of clinical anti-SARS-CoV-2 drugs.
MMKP: A mind mapping knowledgebase prototyping tool for precision medicine
Authors: Liang Siliang , Li Yun , Dong Qingling , Chen Xin
Published: August 2022

Background

With significant advancements in the area of precision medicine, the breadth and complexity of the relevant knowledge in the field has increased significantly. However, the difficulty associated with dynamic modelling and the disorganization of such knowledge hinders its rapid development potential.

Results

To overcome the difficulty in using the relational database model for dynamic modelling, and to aid in the organization of precision medicine knowledge, we developed the Mind Mapping Knowledgebase Prototyping (MMKP) tool. The MMKP implements a novel design that we call a “polymorphic foreign key”, which allows the establishment of a logical linkage between a single table field and a record from any table. This design has advantages in supporting dynamic changes to the structural relationships in precision medicine knowledge. Knowledge stored in MMKP is presented as a mind map to facilitate human interaction. When using this tool, medical experts may curate the structure and content of the precision knowledge in a flow that is similar to the human thinking process.

Conclusions

The design of polymorphic foreign keys natively supports knowledge modelling in the form of mind mapping, which avoids the hard-coding of medical logic into a rigid database schema and significantly reduces the workload that is required for adapting a relational data model to future changes to the medical logic. The MMKP tool provides a graphical user interface for both data management and knowledgebase prototyping. It supports the flexible customization of the data field constraints and annotations. MMKP is available as open-source code on GitHub: https://github.com/ZjuLiangsl/mmkp.
Fibrosis in fat: From other diseases to Crohn’s disease
Authors: Xiong Shanshan , Tan Jinyu , Wang Yu , He Jinshen , Hu Fan , Wu Xiaomin , Liu Zishan , Lin Sinan , Li Xuehua , Chen Zhihui , Mao Ren
Published: August 2022

Creeping fat is a specific feature of Crohn’s disease (CD) and is characterized by mesenteric fat wrapping around the intestine. It highly correlates with intestinal transmural inflammation, muscular hypertrophy, fibrosis, and stricture formation. However, the pathogenesis of creeping fat remains unclear. Molecular crosstalk exists between mesenteric fat and the intestine. Indeed, creeping fat contains different types of cells, including adipocytes and immune cells. These cell types can produce various cytokines, fatty acids, and growth factors, which affect the mesenteric fat function and modulate intestinal inflammation and immunity. Moreover, adipocyte progenitors can produce extracellular matrix to adapt to fat expansion. Previous studies have shown that fat fibrosis is an important feature of adipose tissue malfunction and exists in other diseases, including metabolic disorders, cancer, atrial fibrillation, and osteoarthritis. Furthermore, histological sections of CD showed fibrosis in the creeping fat. However, the role of fibrosis in the mesenteric fat of CD is not well understood. In this review, we summarized the possible mechanisms of fat fibrosis and its impact on other diseases. More specifically, we illustrated the role of various cells (adipocyte progenitors, macrophages, mast cells, and group 1 innate lymphoid cells) and molecules (including hypoxia-inducible factor 1-alpha, transforming growth factor-beta, platelet-derived growth factor, and peroxisome proliferator-activated receptor-gamma) in the pathogenesis of fat fibrosis in other diseases to understand the role of creeping fat fibrosis in CD pathogenesis. Future research will provide key information to decipher the role of fat fibrosis in creeping fat formation and intestinal damage, thereby helping us identify novel targets for the diagnosis and treatment of CD.
Identification and validation of an anoikis-associated gene signature to predict clinical character, stemness, IDH mutation, and immune filtration in glioblastoma
Authors: Sun Zhongzheng , Zhao Yongquan , Wei Yan , Ding Xuan , Tan Chenyang , Wang Chengwei
Published: August 2022

Background

Glioblastoma (GBM) is the most prominent and aggressive primary brain tumor in adults. Anoikis is a specific form of programmed cell death that plays a key role in tumor invasion and metastasis. The presence of anti-anoikis factors is associated with tumor aggressiveness and drug resistance.

Methods

The non-negative matrix factorization algorithm was used for effective dimension reduction for integrated datasets. Differences in the tumor microenvironment (TME), stemness indices, and clinical characteristics between the two clusters were analyzed. Difference analysis, weighted gene coexpression network analysis (WGCNA), univariate Cox regression, and least absolute shrinkage and selection operator regression were leveraged to screen prognosis-related genes and construct a risk score model. Immunohistochemistry was performed to evaluate the expression of representative genes in clinical specimens. The relationship between the risk score and the TME, stemness, clinical traits, and immunotherapy response was assessed in GBM and pancancer.

Results

Two definite clusters were identified on the basis of anoikis-related gene expression. Patients with GBM assigned to C1 were characterized by shortened overall survival, higher suppressive immune infiltration levels, and lower stemness indices. We further constructed a risk scoring model to quantify the regulatory patterns of anoikis-related genes. The higher risk score group was characterized by a poor prognosis, the infiltration of suppressive immune cells and a differentiated phenotype, whereas the lower risk score group exhibited the opposite effects. In addition, patients in the lower risk score group exhibited a higher frequency of isocitrate dehydrogenase (IDH) mutations and a more sensitive response to immunotherapy. Drug sensitivity analysis was performed, revealing that the higher risk group may benefit more from drugs targeting the PI3K/mTOR signaling pathway.

Conclusion

We revealed potential relationships between anoikis-related genes and clinical features, TME, stemness, IDH mutation, and immunotherapy and elucidated their therapeutic value.
Mucosal immune and stress responses of Neoparamoeba perurans-infected Atlantic salmon (Salmo salar) treated with peracetic acid shed light on the host-parasite-oxidant interactions
Authors: Lazado Carlo C. , Strand David A. , Breiland Mette W. , Furtado Francisco , Timmerhaus Gerrit , Gjessing Mona C. , Hytterød Sigurd , Merkin Grigory V. , Pedersen Lars-Flemming , Pittman Karin A. , Krasnov Aleksei
Published: August 2022

Treatment development for parasitic infestation is often limited to disease resolution as an endpoint response, and physiological and immunological consequences are not thoroughly considered. Here, we report the impact of exposing Atlantic salmon affected with amoebic gill disease (AGD) to peracetic acid (PAA), an oxidative chemotherapeutic. AGD-affected fish were treated with PAA either by exposing them to 5 ppm for 30 min or 10 ppm for 15 min. Unexposed fish from both infected and uninfected groups were also included. Samples for molecular, biochemical, and histological evaluations were collected at 24 h, 2 weeks, and 4 weeks post-treatment. Behavioral changes were observed during PAA exposure, and post-treatment mortality was higher in the infected and PAA treated groups, especially in 10 ppm for 15 min. Plasma indicators showed that liver health was affected by AGD, though PAA treatment did not exacerbate the infection-related changes. Transcriptome profiling in the gills showed significant changes, triggered by AGD and PAA treatments, and the effects of PAA were more notable 24 h after treatment. Genes related to immune pathways of B- and T- cells and protein synthesis and metabolism were downregulated, where the magnitude was more remarkable in 10 ppm for 15 min group. Even though treatment did not fully resolve the pathologies associated with AGD, 5 ppm for 30 min group showed lower parasite load at 4 weeks post-treatment. Mucous cell parameters (i.e., size and density) increased within 24 h post-treatment and were significantly higher at termination, especially in AGD-affected fish, with some treatment effects influenced by the dose of PAA. Infection and treatments resulted in oxidative stress—in the early phase in the gill mucosa, while systemic reactive oxygen species (ROS) dysregulation was evident at the later stage. Infected fish responded to elevated circulating ROS by increasing antioxidant production. Exposing the fish to a crowding stress revealed the interference in the post-stress responses. Lower cortisol response was displayed by AGD-affected groups. Collectively, the study established that PAA, within the evaluated treatment protocols, could not provide a convincing treatment resolution and, thus, requires further optimization. Nonetheless, PAA treatment altered the mucosal immune and stress responses of AGD-affected Atlantic salmon, shedding light on the host-parasite-treatment interactions.
Comprehensive analysis of a novel signature incorporating lipid metabolism and immune-related genes for assessing prognosis and immune landscape in lung adenocarcinoma
Authors: Wang Yuli , Xu Jing , Fang Yuan , Gu Jiefei , Zhao Fanchen , Tang Yu , Xu Rongzhong , Zhang Bo , Wu Jianchun , Fang Zhihong , Li Yan
Published: August 2022

Background

As the crosstalk between metabolism and antitumor immunity continues to be unraveled, we aim to develop a prognostic gene signature that integrates lipid metabolism and immune features for patients with lung adenocarcinoma (LUAD).

Methods

First, differentially expressed genes (DEGs) related to lipid metabolism in LUAD were detected, and subgroups of LUAD patients were identified via the unsupervised clustering method. Based on lipid metabolism and immune-related DEGs, variables were determined by the univariate Cox and LASSO regression, and a prognostic signature was established. The prognostic value of the signature was evaluated by the Kaplan–Meier method, time-dependent ROC, and univariate and multivariate analyses. Five independent GEO datasets were employed for external validation. Gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analysis were performed to investigate the underlying mechanisms. The sensitivity to common chemotherapeutic drugs was estimated based on the GDSC database. Finally, we selected PSMC1 involved in the signature, which has not been reported in LUAD, for further experimental validation.

Results

LUAD patients with different lipid metabolism patterns exhibited significant differences in overall survival and immune infiltration levels. The prognostic signature incorporated 10 genes and stratified patients into high- and low-risk groups by median value splitting. The areas under the ROC curves were 0.69 (1-year), 0.72 (3-year), 0.74 (5-year), and 0.74 (10-year). The Kaplan–Meier survival analysis revealed a significantly poorer overall survival in the high-risk group in the TCGA cohort (p < 0.001). In addition, both univariate and multivariate Cox regression analyses indicated that the prognostic model was the individual factor affecting the overall survival of LUAD patients. Through GSEA and GSVA, we found that tumor progression and inflammatory and immune-related pathways were enriched in the high-risk group. Additionally, patients with high-risk scores showed higher sensitivity to chemotherapeutic drugs. The in vitro experiments further confirmed that PSMC1 could promote the proliferation and migration of LUAD cells.

Conclusions

We developed and validated a novel signature incorporating both lipid metabolism and immune-related genes for all-stage LUAD patients. This signature can be applied not only for survival prediction but also for guiding personalized chemotherapy and immunotherapy regimens.
The association between peritraumatic distress, perceived stress, depression in pregnancy, and NR3C1 DNA methylation among Chinese pregnant women who experienced COVID-19 lockdown
Authors: Wei Liqing , Ying Xiaohong , Zhai Mengxi , Li Jiayu , Liu Dan , Liu Xin , Yu Bin , Yan Hong
Published: August 2022

Prenatal stress can affect pregnant women in an epigenetic way during the critical period of conception of their offspring. The study aims to investigate the relationship between peritraumatic distress, prenatal perceived stress, depression, and glucocorticoid receptor (NR3C1) DNA methylation among pregnant women who experienced COVID-19 lockdown in China. Study data were collected from 30 pregnant women in Wuhan and Huanggang, China. The Peritraumatic Distress Inventory was used to measure peritraumatic distress, the Edinburgh Postnatal Depression Scale was used to measure depressive symptoms, and the Perceived Stress Scale was used to measure perceived stress. DNA methylation in the exon 1F promoter region of NR3C1 gene from the venous blood mononuclear cell genome was characterized by bisulfite sequencing. Correlation and linear regression were used for data analysis. The mean level of peritraumatic distress, perceived stress, and depression was 6.30 (SD = 5.09), 6.50 (SD = 5.41), and 6.60 (SD = 4.85), respectively, with 23.33% of pregnant women being depressed. The mean NR3C1 methylation was 0.65 (SD = 0.22). Prenatal depression was positively correlated with the degree of methylation in venous blood from the mother (r = 0.59, p = 0.001), and depression predicted methylation of NR3C1 gene at the CpG 8 site (β = 0.05, p = 0.03). No association was found between peritraumatic distress as well as perceived stress and methylation of NR3C1. NR3C1 gene was susceptible to epigenetic modification of DNA methylation in the context of prenatal stress, and maternal depression was associated with increased NR3C1 methylation among women who experienced COVID-19 lockdown.
The gamble between oncolytic virus therapy and IFN
Authors: Li Qingbo , Tan Fengxian , Wang Yuanyuan , Liu Xiaohui , Kong Xianbin , Meng Jingyan , Yang Long , Cen Shan
Published: August 2022

Various studies are being conducted on oncolytic virotherapy which one of the mechanisms is mediating interferon (IFN) production by it exerts antitumor effects. The antiviral effect of IFN itself has a negative impact on the inhibition of oncolytic virus or tumor eradication. Therefore, it is very critical to understand the mechanism of IFN regulation by oncolytic viruses, and to define its mechanism is of great significance for improving the antitumor effect of oncolytic viruses. This review focuses on the regulatory mechanisms of IFNs by various oncolytic viruses and their combination therapies. In addition, the exerting and the producing pathways of IFNs are briefly summarized, and some current issues are put forward.
Distinct plasma chemokines and cytokines signatures in Leishmania guyanensis-infected patients with cutaneous leishmaniasis
Authors: Mesquita Tirza Gabrielle Ramos de , Junior José do Espírito Santo , Silva Luan Diego Oliveira da , Silva George Allan Villarouco , Araújo Felipe Jules de , Pinheiro Suzana Kanawati , Kerr Herllon Karllos Athaydes , Silva Lener Santos da , Souza Luciane Macedo de , Almeida Samir Assad de , Queiroz Krys Layane Guimarães Duarte , Souza Josué Lacerda de , Silva Cilana Chagas da , Sequera Héctor David Graterol , Souza Mara Lúcia Gomes de , Barbosa Anderson Nogueira , Pontes Gemilson Soares , Guerra Marcus Vinitius de Farias , Ramasawmy Rajendranath
Published: August 2022

The immunopathology associated with Leishmaniasis is a consequence of inflammation. Upon infection with Leishmania, the type of host-immune response is determinant for the clinical manifestations that can lead to either self-healing or chronic disease. Multiple pathways may determine disease severity. A comparison of systemic immune profiles in patients with cutaneous leishmaniasis caused by L. guyanensis and healthy individuals with the same socio-epidemiological characteristics coming from the same endemic areas as the patients is performed to identify particular immune profile and pathways associated with the progression of disease development. Twenty-seven plasma soluble circulating factors were evaluated between the groups by univariate and multivariate analysis. The following biomarkers pairs IL-17/IL-9 (ρ=0,829), IL-17/IL-12 (ρ=0,786), IL-6/IL-1ra (ρ=0,785), IL-6/IL-12 (ρ=0,780), IL-1β/G-CSF (ρ=0,758) and IL-17/MIP-1β (ρ=0,754) showed the highest correlation mean among the patient while only INF-γ/IL-4 (ρ=0.740), 17/MIP-1β (ρ=0,712) and IL-17/IL-9 (ρ=0,707) exhibited positive correlation among the control group. The cytokine IL-17 and IL1β presented the greater number of positive pair correlation among the patients. The linear combinations of biomarkers displayed IP-10, IL-2 and RANTES as the variables with the higher discriminatory activity in the patient group compared to PDGF, IL-1ra and eotaxin among the control subjects. IP-10, IL-2, IL-1β, RANTES and IL-17 seem to be predictive value of progression to the development of disease among the Lg-infected individuals.
A newly identified secreted larval antigen elicits basophil-dependent protective immunity against N. brasiliensis infection
Authors: Thuma Natalie , Döhler Daniela , Mielenz Dirk , Sticht Heinrich , Radtke Daniel , Reimann Lena , Warscheid Bettina , Voehringer David
Published: August 2022

Hookworms infect more that 400 million people and cause significant socio-economic burden on endemic countries. The lack of efficient vaccines and the emergence of anthelminthic drug resistance are of major concern. Free-living hookworm larvae infect their hostsviathe skin and live as adult worms in the small intestine where they feed on host tissue and blood. Excretory/secretory (E/S) products, released by helminths as they migrate through their host, are thought to play a key role in facilitating infection and successful establishment of parasitism. However, E/S products can also elicit protective immune responses that might be harnessed for vaccine development. By performing Western blots with serum ofNippostrongylus brasiliensis(Nb) infected mice as a model for human hookworm infection, we identified a largely overlapping set of IgG1- and IgE-reactive antigens in E/S from infective L3 stage larvae. Mass spectrometry analysis led to the identification of a new protein family with 6 paralogues in the Nb genome which we termed Nb-LSA1 for “Nippostrongylus brasiliensislarval secreted protein 1”. The recombinantly expressed 17 kDa family member Nb-LSA1a was recognized by antibodies in the serum of Nb immune mice. Immunization of mice with Nb-LSA1a in alum elicited a strong IgG1 response but no detectable antigen-specific IgE. Most importantly, immunized mice were largely protected against a challenge Nb infection. This effect was dependent on the presence of basophils and occurred before the parasites reached the intestine. Therefore, basophils appear to play a critical role for rapid control of infection with L3 stage larvae in mice immunized with a single secreted larval protein. A better understanding of basophil-mediated protective immunity and identification of potent larval antigens of human hookworms could help to develop promising vaccination strategies.
Deciphering genome-wide transcriptomic changes in grapevines heavily infested by spotted lanternflies
Authors: Islam Md Tariqul , Kudla-Williams Crosley , Kar Suraj , Londo Jason P. , Centinari Michela , Rosa Cristina
Published: August 2022

The spotted lanternfly, a newly invasive insect in the U.S. that is a great concern for the grapevine industry, produces damage on its host plants through aggressive feeding, using a piercing and sucking method to feed on the phloem of plants. In the eastern US, adult SLF can invade vineyards through fruit ripening until the end of the growing season; however, it is still unclear how prolonged late-season SLF feeding can affect the health of grapevines, as well as the host responses to this extensive damage. Thus, we have performed a comprehensive genome-wide transcriptome analysis in grapevines heavily infested by the spotted lanternfly, as it occurs in Pennsylvania vineyards, and compared it to other relevant transcriptomes in grapes with different degrees to susceptibility to similar pests. Among a variety of plant responses, we highlight here a subset of relevant biological pathways that distinguish or are common to the spotted lanternfly and other phloem feeders in grapevine. The molecular interaction between spotted lanternfly and the vine begins with activation of signal transduction cascades mediated mainly by protein kinase genes. It also induces the expression of transcription factors in the nucleus, of other signaling molecules like phytohormones and secondary metabolites, and their downstream target genes responsible for defense and physiological functions, such as detoxification and photosynthesis. Grapevine responses furthermore include the activation of genes for cell wall strengthening via biosynthesis of major structural components. With this study, we hope to provide the regulatory network to explain effects that the invasive spotted lanternfly has on grapevine health with the goal to improve its susceptibility.
Data-driven integrated care pathways: Standardization of delivering patient-centered care
Authors: Han Shasha , Ma Libing
Published: August 2022

Health care delivery in China is in transition from reactive and doctor-centered to preventative and patient-centered. The challenge for the reform is to account for the needs of unique individuals and local communities while ensuring efficiency and equity. This Viewpoint presents data-driven integrated care pathways as a potential solution to standardize patient-centered care delivery, highlighting five core aspects of the entire care journey for personalization by using real-time data and digital technology, and identifying three capabilities to support the uptake of data-driven design.
Effect of atorvastatin on skeletal muscles of patients with knee osteoarthritis: Post-hoc analysis of a randomised controlled trial
Authors: Lim Yuan Z. , Cicuttini Flavia M. , Wluka Anita E. , Jones Graeme , Hill Catherine L. , Forbes Andrew B. , Tonkin Andrew , Berezovskaya Sofia , Tan Lynn , Ding Changhai , Wang Yuanyuan
Published: August 2022

Objective

Populations with knee osteoarthritis (KOA) are at increased risk of cardiovascular disease, due to higher prevalence of risk factors including dyslipidaemia, where statins are commonly prescribed. However, the effect of statins on muscles and symptoms in this population is unknown. Thus, this study examined the effect of atorvastatin on muscle properties in patients with symptomatic KOA.

Design

Post-hoc analysis of a 2-year multicentre randomised, double-blind, placebo-controlled trial.

Setting

Australian community.

Participants

Participants aged 40–70 years (mean age 55.7 years, 55.6% female) with KOA who met the American College of Rheumatology clinical criteria received atorvastatin 40 mg daily (n = 151) or placebo (n = 153).

Main outcome measures

Levels of creatinine kinase (CK), aspartate transaminase (AST), and alanine transaminase (ALT) at 1, 6, 12, and 24 months; muscle strength (by dynamometry) at 12 and 24 months; vastus medialis cross-sectional area (CSA) on magnetic resonance imaging at 24 months; and self-reported myalgia.

Results

There were no significant between-group differences in CK and AST at all timespoints. The atorvastatin group had higher ALT than placebo group at 1 (median 26 vs. 21, p = 0.004) and 6 (25 vs. 22, p = 0.007) months without significant between-group differences at 12 and 24 months. Muscle strength increased in both groups at 24 months without between-group differences [mean 8.2 (95% CI 3.5, 12.9) vs. 5.9 (1.3, 10.4), p = 0.49]. Change in vastus medialis CSA at 24 months favoured the atorvastatin group [0.11 (−0.10, 0.31) vs. −0.23 (−0.43, −0.03), p = 0.02] but of uncertain clinical significance. There was a trend for more myalgia in the atorvastatin group (8/151 vs. 2/153, p = 0.06) over 2 years, mostly occurring within 6 months (7/151 vs. 1/153, p = 0.04).

Conclusions

In those with symptomatic KOA, despite a trend for more myalgia, there was no clear evidence of an adverse effect of atorvastatin on muscles, including those most relevant to knee joint health.
COL17A1 editing via homology-directed repair in junctional epidermolysis bullosa
Authors: Petković Igor , Bischof Johannes , Kocher Thomas , March Oliver Patrick , Liemberger Bernadette , Hainzl Stefan , Strunk Dirk , Raninger Anna Maria , Binder Heide-Marie , Reichelt Julia , Guttmann-Gruber Christina , Wally Verena , Piñón Hofbauer Josefina , Bauer Johann Wolfgang , Koller Ulrich
Published: August 2022

Background

Epidermolysis bullosa (EB), a severe genetic disorder characterized by blister formation in skin, is caused by mutations in genes encoding dermal-epidermal junction proteins that function to hold the skin layers together. CRISPR/Cas9-induced homology-directed repair (HDR) represents a promising tool for editing causal mutations in COL17A1 in the treatment of junctional epidermolysis bullosa (JEB).

Methods

In this study, we treated primary type XVII collagen (C17)-deficient JEB keratinocytes with either Cas9 nuclease or nickase (Cas9n) ribonucleoproteins (RNP) and a single-stranded oligonucleotide (ssODN) HDR template in order to correct a causal pathogenic frameshift mutation within the COL17A1 gene.

Results

As analyzed by next-generation sequencing of RNP-nucleofected keratinocytes, we observed an HDR efficiency of ∼38% when cells were treated with the high-fidelity Cas9 nuclease, a mutation-specific sgRNA, and an ssODN template. The combined induction of end-joining repair and HDR-mediated pathways resulted in a C17 restoration efficiency of up to 60% as assessed by flow cytometry. Furthermore, corrected JEB keratinocytes showed a significantly increased adhesive strength to laminin-332 and an accurate deposition of C17 along the basement membrane zone (BMZ) upon differentiation into skin equivalents.

Conclusion

Here we present a gene editing approach capable of reducing end joining-generated repair products while increasing the level of seamless HDR-mediated gene repair outcomes, thereby providing a promising CRISPR/Cas9-based gene editing approach for JEB.
RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2
Authors: Vesuna Farhad , Akhrymuk Ivan , Smith Amy , Winnard Paul T. , Lin Shih-Chao , Panny Lauren , Scharpf Robert , Kehn-Hall Kylene , Raman Venu
Published: August 2022

SARS-CoV-2, the virus behind the deadly COVID-19 pandemic, continues to spread globally even as vaccine strategies are proving effective in preventing hospitalizations and deaths. However, evolving variants of the virus appear to be more transmissive and vaccine efficacy toward them is waning. As a result, SARS-CoV-2 will continue to have a deadly impact on public health into the foreseeable future. One strategy to bypass the continuing problem of newer variants is to target host proteins required for viral replication. We have used this host-targeted antiviral (HTA) strategy that targets DDX3X (DDX3), a host DEAD-box RNA helicase that is usurped by SARS-CoV-2 for virus production. We demonstrated that targeting DDX3 with RK-33, a small molecule inhibitor, reduced the viral load in four isolates of SARS-CoV-2 (Lineage A, and Lineage B Alpha, Beta, and Delta variants) by one to three log orders in Calu-3 cells. Furthermore, proteomics and RNA-seq analyses indicated that most SARS-CoV-2 genes were downregulated by RK-33 treatment. Also, we show that the use of RK-33 decreases TMPRSS2 expression, which may be due to DDX3s ability to unwind G-quadraplex structures present in the TMPRSS2 promoter. The data presented support the use of RK-33 as an HTA strategy to control SARS-CoV-2 infection, irrespective of its mutational status, in humans.
Metabolic engineering of Halomonas elongata: Ectoine secretion is increased by demand and supply driven approaches
Authors: Hobmeier Karina , Oppermann Martin , Stasinski Natalie , Kremling Andreas , Pflüger-Grau Katharina , Kunte Hans Jörg , Marin-Sanguino Alberto
Published: August 2022

The application of naturally-derived biomolecules in everyday products, replacing conventional synthetic manufacturing, is an ever-increasing market. An example of this is the compatible solute ectoine, which is contained in a plethora of treatment formulations for medicinal products and cosmetics. As of today, ectoine is produced in a scale of tons each year by the natural producer Halomonas elongata. In this work, we explore two complementary approaches to obtain genetically improved producer strains for ectoine production. We explore the effect of increased precursor supply (oxaloacetate) on ectoine production, as well as an implementation of increased ectoine demand through the overexpression of a transporter. Both approaches were implemented on an already genetically modified ectoine-excreting strain H. elongata KB2.13 (ΔteaABC ΔdoeA) and both led to new strains with higher ectoine excretion. The supply driven approach led to a 45% increase in ectoine titers in two different strains. This increase was attributed to the removal of phosphoenolpyruvate carboxykinase (PEPCK), which allowed the conversion of 17.9% of the glucose substrate to ectoine. For the demand driven approach, we investigated the potential of the TeaBC transmembrane proteins from the ectoine-specific Tripartite ATP-Independent Periplasmic (TRAP) transporter as export channels to improve ectoine excretion. In the absence of the substrate-binding protein TeaA, an overexpression of both subunits TeaBC facilitated a three-fold increased excretion rate of ectoine. Individually, the large subunit TeaC showed an approximately five times higher extracellular ectoine concentration per dry weight compared to TeaBC shortly after its expression was induced. However, the detrimental effect on growth and ectoine titer at the end of the process hints toward a negative impact of TeaC overexpression on membrane integrity and possibly leads to cell lysis. By using either strategy, the ectoine synthesis and excretion in H. elongata could be boosted drastically. The inherent complementary nature of these approaches point at a coordinated implementation of both as a promising strategy for future projects in Metabolic Engineering. Moreover, a wide variation of intracelllular ectoine levels was observed between the strains, which points at a major disruption of mechanisms responsible for ectoine regulation in strain KB2.13.
Influence of revegetation on soil microbial community and its assembly process in the open-pit mining area of the Loess Plateau, China
Authors: Chang Yuanyuan , Chen Fu , Zhu Yanfeng , You Yunnan , Cheng Yanjun , Ma Jing
Published: August 2022

Vegetation recovery is an important marker of ecosystem health in the mining area. Clarifying the influence of vegetation recovery on the characteristics of soil microbial community and its assembly process can improve our understanding of the ecological resilience and self-maintaining mechanism in the open-pit mining area. For this purpose, we employed MiSeq high-throughput sequencing coupled with null model analysis to determine the composition, molecular ecological network characteristics, key bacterial and fungal clusters, and the assembly mechanism of the soil microbial communities in shrubs (BL), coniferous forest (CF), broad-leaved forests (BF), mixed forest (MF), and the control plot (CK, the poplar plantation nearby that had been continuously grown for over 30 a without disturbance). The results showed that the vegetation restoration model had a significant influence on the α-diversity of the microbial community (p < 0.05). Compared with CK, Sobs and Shannon index of MF and CF have increased by 35.29, 3.50, and 25.18%, 1.05%, respectively, whereas there was no significant difference in the α-diversity of fungal community among different vegetation restoration types, Actinobacteria, Chloroflexi, Proteobacteria, and Acidobacteria were the dominant phyla. The diversity of the first two phyla was significantly higher than those of CK. However, the diversity of the last two phyla was dramatically lower than those of CK (p < 0.05). Ascomycota and Basidiomycota were dominant phyla in the fungal community. The abundance and diversity of Ascomycota were significantly higher than those of CK, while the abundance and diversity of the latter were considerably lower than those of CK (p < 0.05). The stochastic process governed the assembly of the soil microbial community, and the contribution rate to the bacterial community construction of CK, CF, BF, and MF was 100.0%. Except for MF, where the soil fungal community assembly was governed by the deterministic process, all other fungal communities were governed by the stochastic process. Proteobacteria and Acidobacteria are key taxa of the bacterial network, while Mortierellales, Thelebolales, Chaetothyriales, and Hypocreales are the key taxa of the fungal network. All these results might provide the theoretical foundation for restoring the fragile ecosystem in the global mining region.
A Fe2+-dependent self-inhibited state influences the druggability of human collagen lysyl hydroxylase (LH/PLOD) enzymes
Authors: Scietti Luigi , Moroni Elisabetta , Mattoteia Daiana , Fumagalli Marco , De Marco Matteo , Negro Lisa , Chiapparino Antonella , Serapian Stefano A. , De Giorgi Francesca , Faravelli Silvia , Colombo Giorgio , Forneris Federico
Published: August 2022

Multifunctional human collagen lysyl hydroxylase (LH/PLOD) enzymes catalyze post-translational hydroxylation and subsequent glycosylation of collagens, enabling their maturation and supramolecular organization in the extracellular matrix (ECM). Recently, the overexpression of LH/PLODs in the tumor microenvironment results in abnormal accumulation of these collagen post-translational modifications, which has been correlated with increased metastatic progression of a wide variety of solid tumors. These observations make LH/PLODs excellent candidates for prospective treatment of aggressive cancers. The recent years have witnessed significant research efforts to facilitate drug discovery on LH/PLODs, including molecular structure characterizations and development of reliable high-throughput enzymatic assays. Using a combination of biochemistry and in silico studies, we characterized the dual role of Fe2+ as simultaneous cofactor and inhibitor of lysyl hydroxylase activity and studied the effect of a promiscuous Fe2+ chelating agent, 2,2’-bipyridil, broadly considered a lysyl hydroxylase inhibitor. We found that at low concentrations, 2,2’-bipyridil unexpectedly enhances the LH enzymatic activity by reducing the inhibitory effect of excess Fe2+. Together, our results show a fine balance between Fe2+-dependent enzymatic activity and Fe2+-induced self-inhibited states, highlighting exquisite differences between LH/PLODs and related Fe2+, 2-oxoglutarate dioxygenases and suggesting that conventional structure-based approaches may not be suited for successful inhibitor development. These insights address outstanding questions regarding druggability of LH/PLOD lysyl hydroxylase catalytic site and provide a solid ground for upcoming drug discovery and screening campaigns.
Using CRISPR/Cas9 genome editing in human iPSCs for deciphering the pathogenicity of a novel CCM1 transcription start site deletion
Authors: Pilz Robin A. , Skowronek Dariush , Hamed Motaz , Weise Anja , Mangold Elisabeth , Radbruch Alexander , Pietsch Torsten , Felbor Ute , Rath Matthias
Published: August 2022

Cerebral cavernous malformations are clusters of aberrant vessels that can lead to severe neurological complications. Pathogenic loss-of-function variants in the CCM1, CCM2, or CCM3 gene are associated with the autosomal dominant form of the disease. While interpretation of variants in protein-coding regions of the genes is relatively straightforward, functional analyses are often required to evaluate the impact of non-coding variants. Because of multiple alternatively spliced transcripts and different transcription start points, interpretation of variants in the 5′ untranslated and upstream regions of CCM1 is particularly challenging. Here, we identified a novel deletion of the non-coding exon 1 of CCM1 in a proband with multiple CCMs which was initially classified as a variant of unknown clinical significance. Using CRISPR/Cas9 genome editing in human iPSCs, we show that the deletion leads to loss of CCM1 protein and deregulation of KLF2, THBS1, NOS3, and HEY2 expression in iPSC-derived endothelial cells. Based on these results, the variant could be reclassified as likely pathogenic. Taken together, variants in regulatory regions need to be considered in genetic CCM analyses. Our study also demonstrates that modeling variants of unknown clinical significance in an iPSC-based system can help to come to a final diagnosis.
Asparagine, colorectal cancer, and the role of sex, genes, microbes, and diet: A narrative review
Authors: Shen Xinyi , Jain Abhishek , Aladelokun Oladimeji , Yan Hong , Gilbride Austin , Ferrucci Leah M. , Lu Lingeng , Khan Sajid A. , Johnson Caroline H.
Published: August 2022

Asparagine (Asn) and enzymes that catalyze the metabolism of Asn have been linked to the regulation and propagation of colorectal cancer (CRC). Increased Asn and asparagine synthetase (ASNS) expression, both contribute to CRC progression and metastasis. In contradistinction, L-asparaginase (ASNase) which breaks down Asn, exhibits an anti-tumor effect. Metabolic pathways such as KRAS/PI3K/AKT/mTORC1 signaling and high SOX12 expression can positively regulate endogenous Asn production. Conversely, the tumor suppressor, TP53, negatively impacts ASNS, thus limiting Asn synthesis and reducing tumor burden. Asn abundance can be altered by factors extrinsic to the cancer cell such as diet, the microbiome, and therapeutic use of ASNase. Recent studies have shown that sex-related factors can also influence the regulation of Asn, and high Asn production results in poorer prognosis for female CRC patients but not males. In this narrative review, we critically review studies that have examined endogenous and exogenous modulators of Asn bioavailability and summarize the key metabolic networks that regulate Asn metabolism. We also provide new hypotheses regarding sex-related influences on Asn, including the involvement of the sex-steroid hormone estrogen and estrogen receptors. Further, we hypothesize that sex-specific factors that influence Asn metabolism can influence clinical outcomes in CRC patients.
Drug affinity-responsive target stability unveils filamins as biological targets for artemetin, an anti-cancer flavonoid
Authors: Ferraro Giusy , Belvedere Raffaella , Petrella Antonello , Tosco Alessandra , Stork Björn , Salamone Stefano , Minassi Alberto , Pollastro Federica , Morretta Elva , Monti Maria Chiara
Published: August 2022

Artemetin is a valuable 5-hydroxy-3,6,7,3′,4′-pentamethoxyflavone present in many different medicinal plants with very good oral bioavailability and drug-likeness values, owing to numerous bioactivities, such as anti-inflammatory and anti-cancer ones. Here, a multi-disciplinary plan has been settled and applied for identifying the artemetin target(s) to inspect its mechanism of action, based on drug affinity-responsive target stability and targeted limited proteolysis. Both approaches point to the disclosure of filamins A and B as direct artemetin targets in HeLa cell lysates, also giving detailed insights into the ligand/protein-binding sites. Interestingly, also 8-prenyl-artemetin, which is an artemetin more permeable semisynthetic analog, directly interacts with filamins A and B. Both compounds alter filamin conformation in living HeLa cells with an effect on cytoskeleton disassembly and on the disorganization of the F-actin filaments. Both the natural compound and its derivative are able to block cell migration, expectantly acting on tumor metastasis occurrence and development.