bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of CAR T cell exhaustion and current counteraction strategies
Authors: Zhu Xiaoying , Li Qing , Zhu Xiaojian
Published: December 2022

The functional state of chimeric antigen receptor T (CAR T) cells determines their efficacy in vivo. Exhausted CAR T cells exhibit decreased proliferative capacity, impaired anti-tumor activity, and attenuated persistence. CAR T cell exhaustion has been recognized as a vital cause of nonresponse and relapse after CAR T cell therapy. However, the triggers and mechanisms leading to CAR T cell exhaustion remain blurry and complicated. Therefore, it is essential to clear the regulation network of CAR T cell exhaustion and explore potent solutions. Here, we review the diverse inducers of CAR T cell exhaustion in terms of manufacture process and immunosuppressive tumor microenvironment. In addition to the admitted immune checkpoint blockade, we also describe promising strategies that may reverse CAR T cell exhaustion including targeting the tumor microenvironment, epigenetics and transcriptomics.
Integrated genomic analysis identifies novel low-frequency cis-regulatory variant rs2279658 associated with VSD risk in Chinese children
Authors: Jin Lihui , Han Zhenyuan , Jiang Zhongli , Lu Jieru , Wu Yizhuo , Yan Bingqian , Zhang Weibin , Lin Xuedong , Jiang Lvyan , Zhao Pengjun , Sun Kun
Published: December 2022

VSD combined with other cardiac or extracardiac malformations (defined as “complex VSD” by us) is one of the major causes of perinatal morbidity and mortality. Functional non-coding SNPs (cis-regulatory SNPs) have not been systematically studied in CHDs, including complex VSD. Here we report an exome-wide association analysis using WES data of 60 PA/VSD cases, 20 TOF cases and 100 controls in Chinese children. We identify 93 low-frequency non-coding SNPs associated with complex VSD risk. A functional genomics pipeline integrating ATAC-seq, ChIP-seq and promoter CHi-C recognizes the rs2279658 variant as a candidate cis-regulatory SNP. Specifically, rs2279658 resides in a cardiac-specific enhancer bound by FOXH1 and PITX2, and would abrogate binding of these two transcription factors to the identified enhancer during cardiac morphogenesis. COQ2 and FAM175A are predicted to be target genes for “rs2279658-FOXH1 or PITX2” pairs in the heart. These findings highlight the importance of cis-regulatory SNPs in the pathogenesis of complex VSD and broaden our understanding of this disease.
Loss of ARHGAP15 affects the directional control of migrating interneurons in the embryonic cortex and increases susceptibility to epilepsy
Authors: Liaci Carla , Camera Mattia , Zamboni Valentina , Sarò Gabriella , Ammoni Alessandra , Parmigiani Elena , Ponzoni Luisa , Hidisoglu Enis , Chiantia Giuseppe , Marcantoni Andrea , Giustetto Maurizio , Tomagra Giulia , Carabelli Valentina , Torelli Federico , Sala Mariaelvina , Yanagawa Yuchio , Obata Kunihiko , Hirsch Emilio , Merlo Giorgio R.
Published: December 2022

GTPases of the Rho family are components of signaling pathways linking extracellular signals to the control of cytoskeleton dynamics. Among these, RAC1 plays key roles during brain development, ranging from neuronal migration to neuritogenesis, synaptogenesis, and plasticity. RAC1 activity is positively and negatively controlled by guanine nucleotide exchange factors (GEFs), guanosine nucleotide dissociation inhibitors (GDIs), and GTPase-activating proteins (GAPs), but the specific role of each regulator in vivo is poorly known. ARHGAP15 is a RAC1-specific GAP expressed during development in a fraction of migrating cortical interneurons (CINs) and in the majority of adult CINs. During development, loss of ARHGAP15 causes altered directionality of the leading process of tangentially migrating CINs, along with altered morphology in vitro. Likewise, time-lapse imaging of embryonic CINs revealed a poorly coordinated directional control during radial migration, possibly due to a hyper-exploratory behavior. In the adult cortex, the observed defects lead to subtle alteration in the distribution of CALB2-, SST-, and VIP-positive interneurons. Adult Arhgap15-knock-out mice also show reduced CINs intrinsic excitability, spontaneous subclinical seizures, and increased susceptibility to the pro-epileptic drug pilocarpine. These results indicate that ARHGAP15 imposes a fine negative regulation on RAC1 that is required for morphological maturation and directional control during CIN migration, with consequences on their laminar distribution and inhibitory function.
Perovskite LaNiO3/Ag3PO4 heterojunction photocatalyst for the degradation of dyes
Authors: Ameen Shahzad , Murtaza Maida , Arshad Muhammad , Alhodaib Aiyeshah , Waseem Amir
Published: December 2022

Pristine lanthanum nickelate (LaNiO3), silver phosphate (Ag3PO4) and perovskite lanthanum nickelate silver phosphate composites (LaNiO3/Ag3PO4) were prepared using the facile hydrothermal method. Three composites were synthesized by varying the percentage of LaNiO3 in Ag3PO4. The physical properties of as-prepared samples were studied by powder X-ray diffraction (pXRD), Fourier-transform infrared (FT-IR), Scanning electron microscopy (SEM) and Energy-dispersive X-ray (EDX). Among all synthesized photocatalysts, 5%LaNiO3/Ag3PO4 composite has been proved to be an excellent visible light photocatalyst for the degradation of dyes i.e., rhodamine B (RhB) and methyl orange (MO). The photocatalytic activity and stability of Ag3PO4 were also enhanced by introducing LaNiO3 in Ag3PO4 heterojunction formation. Complete photodegradation of 50 mg/L of RhB and MO solutions using 25 mg of 5%LaNiO3/Ag3PO4 photocatalyst was observed in just 20 min. Photodegradation of RhB and MO using 5%LaNiO3/Ag3PO4 catalyst follows first-order kinetics with rate constants of 0.213 and 0.1804 min−1, respectively. Perovskite LaNiO3/Ag3PO4 photocatalyst showed the highest stability up to five cycles. The photodegradation mechanism suggests that the holes (h+) and superoxide anion radicals O2 •− plays a main role in the dye degradation of RhB and MO.
Gut brain interaction theory reveals gut microbiota mediated neurogenesis and traditional Chinese medicine research strategies
Authors: Zhang Chenxi , Xue Peng , Zhang Haiyan , Tan Chenxi , Zhao Shiyao , Li Xudong , Sun Lihui , Zheng Huihui , Wang Jun , Zhang Baoling , Lang Weiya
Published: December 2022

Adult neurogenesis is the process of differentiation of neural stem cells (NSCs) into neurons and glial cells in certain areas of the adult brain. Defects in neurogenesis can lead to neurodegenerative diseases, mental disorders, and other maladies. This process is directionally regulated by transcription factors, the Wnt and Notch pathway, the extracellular matrix, and various growth factors. External factors like stress, physical exercise, diet, medications, etc., affect neurogenesis and the gut microbiota. The gut microbiota may affect NSCs through vagal, immune and chemical pathways, and other pathways. Traditional Chinese medicine (TCM) has been proven to affect NSCs proliferation and differentiation and can regulate the abundance and metabolites produced by intestinal microorganisms. However, the underlying mechanisms by which these factors regulate neurogenesis through the gut microbiota are not fully understood. In this review, we describe the recent evidence on the role of the gut microbiota in neurogenesis. Moreover, we hypothesize on the characteristics of the microbiota-gut-brain axis based on bacterial phyla, including microbiota’s metabolites, and neuronal and immune pathways while providing an outlook on TCM’s potential effects on adult neurogenesis by regulating gut microbiota.
Pharmaco-invasive therapy: Early implementation of statins and proprotein convertase subtilisin/kexin type 9 inhibitors after acute coronary syndrome
Authors: Mensink F. B. , Los J. , Ten Cate T. J. F. , Oemrawsingh R. M. , Brouwer M. A. , El Messaoudi S. , van Royen N. , Cornel J. H. , Riksen N. P. , van Geuns R. J. M.
Published: December 2022

Elevated LDL-cholesterol (LDL-C) plays a major role in atheroma formation and inflammation. Medical therapy to lower elevated LDL-C is the cornerstone for reducing the progression of atherosclerotic cardiovascular disease. Statin therapy, and more recently, other drugs such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven efficacy in long-term lowering of LDL-C and therefore diminish cardiovascular risk. During an acute coronary syndrome (ACS), a systemic inflammatory response can destabilize other non-culprit atherosclerotic plaques. Patients with these vulnerable plaques are at high risk of experiencing recurrent cardiovascular events in the first few years post-ACS. Initiating intensive LDL-C lowering therapy in these patients with statins or PCSK9 inhibitors can be beneficial via several pathways. High-intensity statin therapy can reduce inflammation by directly lowering LDL-C, but also through its pleiotropic effects. PCSK9 inhibitors can directly lower LDL-C to recommended guideline thresholds, and could have additional effects on inflammation and plaque stability. We discuss the potential role of early implementation of statins combined with PCSK9 inhibitors to influence these cascades and to mediate the associated cardiovascular risk, over and above the well-known long-term beneficial effects of chronic LDL-C lowering.
Simplified acute physiology score III is excellent for predicting in-hospital mortality in coronary care unit patients with acute myocardial infarction: A retrospective study
Authors: Zheng Xiaoyu , Hu Tianyang , Liu Tingrong , Wang Wei
Published: December 2022

Background

Coronary care unit (CCU) patients with acute myocardial infarction (AMI) lack effective predictors of in-hospital mortality. This study aimed to investigate the performance of four scoring systems in predicting in-hospital mortality in CCU patients with AMI.

Methods

The baseline data, the logistic organ dysfunction system (LODS), the Oxford acute severity of illness score (OASIS), the simplified acute physiology score II (SAPS II), and the simplified acute physiology score III (SAPS III) scores of the patients were extracted from the fourth edition of the Medical Information Mart for Critical Care (MIMIC-IV) database. Independent risk factors for in-hospital mortality were identified by regression analysis. We performed receiver operating characteristic (ROC) curves and compared the area under the curve (AUC) to clarify the predictive value of the four scoring systems. Meanwhile, Kaplan–Meier curves and decision curve analysis (DCA) were performed to determine the optimal scoring system for predicting in-hospital mortality.

Results

A total of 1,098 patients were included. The SAPS III was an independent risk factor for predicting in-hospital mortality in CCU patients with AMI before and after the propensity score matching (PSM) analysis. The discrimination of in-hospital mortality by SAPS III was superior to that of LODS, OASIS, and SAPS II. The AUC of the SAPS III scoring system was the highest among the four scoring systems, at 0.901 (before PSM) and 0.736 (after PSM). Survival analysis showed that significantly more in-hospital mortality occurred in the high-score SAPS III group compared to the low-score SAPS III group before PSM (HR 7.636, P < 0.001) and after PSM (HR 2.077, P = 0.005). The DCA curve of SAPS III had the greatest benefit score across the largest threshold range compared to the other three scoring systems.

Conclusion

The SAPS III was an independent risk factor for predicting in-hospital mortality in CCU patients with AMI. The predictive value for in-hospital mortality with SAPS III is superior to that of LODS, OASIS, and SAPS II. The results of the DCA analysis suggest that SAPS III may provide a better clinical benefit for patients. We demonstrated that SAPS III is an excellent scoring system for predicting in-hospital mortality for CCU patients with AMI.
Zingiber officinale (Ginger) as a treatment for inflammatory bowel disease: A review of current literature
Authors: Sadeghi Poor Ranjbar Fatemeh , Mohammadyari Fatemeh , Omidvar Atharzahra , Nikzad Farhad , Doozandeh Nargesi Nooria , Varmazyar Majid , Dehghankar Soroush , Vosoughian Fatemeh , Olangian-Tehrani Sepehr , Nanbakhsh Sepehr , Mansourian Tina , Deravi Niloofar , Tutunchian Zohreh , Salahi Mehrnaz , Poudineh Mohadeseh , Ghayyem Hani
Published: December 2022

Inflammatory bowel disease (IBD) is a term used for a variety of conditions involving persistent inflammation of the digestive system. Ulcerative colitis (UC) and Crohn’s disease (CD) are examples of IBD. There were some treatments like Amino salicylates, glucocorticoids, immunosuppressants, antibiotics, and surgery which have been used for treating IBD. However, the short and long-term disabling adverse effects, like nausea, pancreatitis, elevated liver enzymes, allergic reactions, and other life-threatening complications remain a significant clinical problem. On the other hand, herbal medicine, believed to be safer, cheaper, and easily available, has gained popularity for treating IBD. Nowadays, Ginger, the Rizhome of Z. officinale from the Zingiberaceae family, one of the most commonly used fresh spices and herbs, has been proposed as a potential option for IBD treatment. According to upper issues, IBD treatment has become one of the society’s concerns. So, this review aims to summarize the data on the yin and yang of ginger use in IBD treatment.
Elevated circulating GPHB5 levels in women with insulin resistance and polycystic ovary syndrome: A cross-sectional study and multiple intervention studies
Authors: Wang Yanping , Xiang Ting , Xia Xuyun , Zhang Hongmin , Geng Shan , Yang Gangyi , Qiu Sheng , He Yirui , Liu Rui , Li Ling , Liu Hua , Li Ke , Zhang Lili , Liang Zerong , He Jianguo
Published: December 2022

Objective

GPHB5 has been found to be associated with glucose and lipid metabolism in animal studies. However, the association of GPHB5 with IR and metabolic disorders remains unknown, and there is a lack of research in humans. Our aim in this study was to investigate the relationship between circulating GPHB5 and metabolic disorders in humans.

Methods

Bioinformatics analysis was performed to understand the relationship between GPHB5 and metabolic disorders. GPHB5 mRNA expression in mice and rats was determined using RT-qPCR. Circulating GPHB5 concentrations were measured with an ELISA kit. EHC and OGTT were performed in humans.

Results

Bioinformatics analysis shows that GPHB5 is associated with metabolic disorders and PCOS. GPHB5 mRNA expression levels in the metabolic-related tissues of HFD-fed mice, db/db and ob/ob mice, and PCOS rats were significantly higher than those of WT mice or rats. In human studies, we find that circulating GPHB5 levels were significantly higher in women with IR and PCOS. GPHB5 levels were positively correlated with age, BMI, WHR, BP, FBG, 2 h-BG, FIns, 2 h-Ins, TC, LDL-C, HbA1c, and FFA, but negatively correlated with adiponectin. Furthermore, GPHB5 was positively correlated with DHEAS and FAI, while negatively correlated with SHBG, FSH, SHBG and FSH. The increased GPHB5 concentration was related to IR and PCOS. After the treatment of metformin, GLP-1RA (Lira), and TZDs, circulating GPHB5 levels were decreased.

Conclusions

Our results reveal that circulating GPHB5 could be a biomarker and potential therapeutic target for IR and PCOS in women.
Influence of BPA exposure, measured in saliva, on childhood weight
Authors: Heras-González Leticia , Espino Diana , Jimenez-Casquet Maria Jose , Lopez-Moro Alejandro , Olea-Serrano Fatima , Mariscal-Arcas Miguel
Published: December 2022

Introduction

Endocrine disruptors such as bisphenol A (BPA), BPA glycidyl methacrylate, and other BPA acrylate–based derivatives have been related to type 2 diabetes, the metabolic syndrome, and obesity, among other metabolic disorders. The objective of this study is to examine the influence of BPA exposure by saliva analysis and daily physical activity on the risk of overweight/obesity in schoolchildren from southern Spain.

Methods

The study included 300 children (53.5% girls) aged 7–10 years. Participants completed a questionnaire with four sections: participant data, including demographic information and life and family habits; semi-quantitative food frequency questionnaire; anthropometric variables; and physical activity variables. All participants underwent dental examination, when the presence of sealants/composites in each tooth and other dental alterations was recorded, and samples of whole saliva were collected for UHPLC-MS/MS analyses.

Results

Risk of overweight/obesity was significantly influenced by body fat composition (OR = 10.77), not walking to and from school (OR = 1.38), lesser energy expenditure in sedentary activities (OR = 12.71), greater energy expenditure in sports (OR =1.62), and exposure to BPA from dental sealants/composites (OR = 1.38; p = 0.058).

Discussion

Further research is warranted on this issue in children, who may be especially vulnerable to the negative health effects of endocrine disruption.
Association between triglyceride-glucose index and atrial fibrillation: A retrospective observational study
Authors: Chen Shengnan , Mei Qiao , Guo Li , Yang Xiaoli , Luo Wenbin , Qu Xuemei , Li Xiaoping , Zhou Bingqing , Chen Ken , Zeng Chunyu
Published: December 2022

Background

Insulin resistance is associated with atrial remodeling as well as atrial fibrillation (AF). However, there was limited evidence on the relationship of triglyceride-glucose index (TyG) index, a simple, valuable marker of insulin resistance, with AF. Thus, we aimed to investigate the association between TyG index and AF among hospitalized patients.

Methods

A retrospective observational study was conducted in Daping Hospital, which included 356 hospitalized patients from the Department of Cardiology. Clinical and biochemical parameters were collected from electronic medical records and AF was diagnosed from electrocardiogram (ECG) findings.

Results

We found that the TyG index was significantly higher in the AF group than in the group without AF. Multivariate logistic regression revealed that hypertension (OR = 1.756, 95%CI 1.135-2.717, P = 0.011) and TyG index (OR = 2.092, 95%CI 1.412-3.100, P<0.001) were positively associated with AF. The analysis of the area under the ROC curve was performed and revealed that area under curve (AUC) of TyG index was 0.600 (95%CI, 0.542-0.659, P = 0.001), the optimal critical value was 8.35, the sensitivity was 65.4%, and the specificity was 52.0%. Additional subgroup analyses of diabetic and non-diabetic subjects were also performed and found the TyG index was increased in non-diabetic subjects with AF. Furthermore, a logistic regression analysis showed TyG index was associated with AF (OR = 3.065, 95% CI, 1.819-5.166, P<0.001) in non-diabetic subjects. However, TyG index was not associated with AF in diabetic subjects.

Conclusion

Elevated TyG index is an independent risk factor for AF among non-diabetic hospitalized patients.
The potential mechanisms and application prospects of non-coding RNAs in intervertebral disc degeneration
Authors: Jiang Chao , Chen Zhe , Wang Xiaohui , Zhang Yongyuan , Guo Xinyu , Xu Zhengwei , Yang Hao , Hao Dingjun
Published: December 2022

Low back pain (LBP) is one of the most common musculoskeletal symptoms and severely affects patient quality of life. The majority of people may suffer from LBP during their life-span, which leading to huge economic burdens to family and society. According to the series of the previous studies, intervertebral disc degeneration (IDD) is considered as the major contributor resulting in LBP. Furthermore, non-coding RNAs (ncRNAs), mainly including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), can regulate diverse cellular processes, which have been found to play pivotal roles in the development of IDD. However, the potential mechanisms of action for ncRNAs in the processes of IDD are still completely unrevealed. Therefore, it is challenging to consider ncRNAs to be used as the potential therapeutic targets for IDD. In this paper, we reviewed the current research progress and findings on ncRNAs in IDD: i). ncRNAs mainly participate in the process of IDD through regulating apoptosis of nucleus pulposus (NP) cells, metabolism of extracellular matrix (ECM) and inflammatory response; ii). the roles of miRNAs/lncRNAs/circRNAs are cross-talk in IDD development, which is similar to the network and can modulate each other; iii). ncRNAs have been attempted to combat the degenerative processes and may be promising as an efficient bio-therapeutic strategy in the future. Hence, this review systematically summarizes the principal pathomechanisms of IDD and shed light on the therapeutic potentials of ncRNAs in IDD.
Pathways for the carbon peak of resource-based cities under an energy-water coupling relationship: A case study of Taiyuan, Shanxi Province
Authors: Lin Gang , Jiang Dong , Fu Jingying , Yin Yitong
Published: December 2022

The “dual carbon” goal proposes new requirements for urban development, and the contradiction between high-speed urban development and environmental problems is becoming increasingly critical. The path of green and low-carbon development urgently needs to be investigated. In this paper, a simulation system of urban carbon emission based on system dynamics is built from four perspectives of population, economy, water resources and energy, aiming at building a method system for carbon peak path that is universally applicable to resource-based cities from a systematic perspective. This paper designs five scenarios: business as unusual scenario (BAU), adjustment of industrial structure (CPA1), adjustment of energy structure (CPA2), reduce energy consumption per unit of GDP (CPA3) and comprehensive management (CPAcomprehensive). Compared with the other four scenarios, the comprehensive scenario had the best coordination benefit for the coupling system, which took into account economic development, resource consumption and carbon emission reduction and could promote the realization of a carbon peak in Taiyuan city in 2029, and the comprehensive scenario will reduce CO2 by 17.14 million tons, water consumption by 158 million m3, energy consumption by 5.58 million tons of standard coal and economic growth by 175.21 billion yuan in 2029.
Endogenous rhythm variation and adaptation to the tidal environment in the freshwater snail, Semisulcospira reiniana
Authors: Yokomizo Takumi , Takahashi Yuma
Published: December 2022

Organisms have endogenous timekeeping system(s) to coordinate their biological processes with environmental cycles, allowing adaptation to external rhythmic changes in their environment. The change in endogenous rhythms could contribute to range expansion in a novel rhythmic environment. We hypothesized that populations of the freshwater snail near estuaries show a circatidal rhythm to synchronize with the tidal cycle. We compared the behavioral and gene expression rhythms between non-tidal and tidal populations of the freshwater snail, Semisulcospira reiniana. Individuals inhabiting tidal areas exhibited a rhythmic activity pattern coordinated with the tidal cycle under both field and laboratory conditions, but individuals inhabiting upstream non-tidal areas showed a circadian activity pattern. The proportion of circadian oscillating genes was greater in non-tidal than in tidal individuals, while that of circatidal oscillating genes was greater in tidal than in non-tidal individuals. Additionally, transcriptome-wide population genetic analyses revealed that these two adjacent populations can be clearly distinguished genetically, though the genetic distance was very small. Our results provide evidence of the shift in an endogenous rhythm via range expansion to a novel rhythmic environment. The changes in a small number of genes and/or phenotypic plasticity may contribute to the difference in the endogenous rhythms between non-tidal and tidal populations.
Modeling Pinus radiata D. Don growth and pasture production under different land uses and climate scenarios
Authors: Ferreiro-Domínguez N. , Rigueiro-Rodríguez A. , Mosquera-Losada M. R.
Published: December 2022

Yield-SAFE is a biophysical model to predict long-term production according to light and water availability in agricultural, forest, and agroforestry systems. The Yield-SAFE model should be calibrated and validated for the highest number of tree species and crops to be used as a management tool that takes into account climate change. This study aimed to calibrate and validate the Yield-SAFE model for Pinus radiata D. Don and sown pasture (Dactylis glomerata L.) to estimate the production in (1) forest systems, (2) agricultural systems, and (3) silvopastoral systems established in Galicia (NW Spain) under different conditions of climate: (i) reference “current” climate from 1961 to 1990, (ii) climate from 2021 to 2050, and (iii) climate from 2051 to 2080. The Yield-SAFE model can now be used to assess the long-term productivity of P. radiata D. Don and D. glomerata L. under different land uses and climate conditions. The Yield-SAFE model simulated similar tree and pasture growth in all scenarios of climate because the inter-annual variation of climate was small. However, tree growth estimated with the Yield-SAFE model was higher in the silvopastoral systems than in the forest systems, indicating that land use had more impact on land productivity than climate. Therefore, in regions such as Galicia, the Yield-SAFE model could be used as a tool to support the land use change in an agroforestry context, whilst also including climate scenarios which is considered a valuable solution to mitigate the effect of climate change.
Wood borer detection rates on wood packaging materials entering the United States during different phases of ISPM 15 implementation and regulatory changes
Authors: Haack Robert A. , Hardin Jesse A. , Caton Barney P. , Petrice Toby R.
Published: December 2022

Wood packaging material (WPM) used in international trade, such as crating and pallets, is recognized as a high-risk pathway for the introduction of bark- and wood-infesting insects (borers). The International Standards for Phytosanitary Measures No. 15 (ISPM 15), which sets treatment requirements for WPM, was adopted in 2002. The United States (US) implemented ISPM 15 during 2005–2006. We used 2003–2020 AQIM (Agriculture Quarantine Inspection Monitoring, conducted by USDA APHIS) data, based on standard random sampling, to compare pre-ISPM 15 borer detection rates in WPM entering the US (2003–2004) to detection rates during 2005–2006 (implementation phase), 2007–2009 (post-ISPM 15 when bark was not regulated) and 2010–2020 (post-ISPM 15 when bark was regulated). We examined borer detection rates overall for all AQIM WPM records and individually for the three main cargo survey programs within AQIM [Italian tiles, perishables, and general WPM (GWPM) for any WPM associated with containerized maritime imports], and individually for three major US trading partners (China, Italy, and Mexico). During 2003–2020, wood borers were detected in 180 of 87,571 consignments with WPM (0.21%). When compared to 2003–2004 (detection rate of 0.34%), detection rates fell 61% during 2005–2006, 47% during 2007–2009, and 36% during 2010–2020. Similar declines occurred for WPM associated with Italian tiles and perishables. However, for GWPM there was no significant reduction post-ISPM 15. WPM infestation rates were reduced significantly during various post-ISPM 15 periods for Italy and Mexico, but not for China. Seven families or subfamilies of borers were recorded in WPM with Cerambycidae and Scolytinae being most frequent. The incidence of WPM with bark fell significantly after the 2009 change to ISPM 15 that required debarked WPM. We discuss several factors that could influence the apparent effectiveness of ISPM 15.
An immune infiltration-related long non-coding RNAs signature predicts prognosis for hepatocellular carcinoma
Authors: Li Gen , Xu Shaodian , Yang Shuai , Wu Cong , Zhang Liangliang , Wang Hongbing
Published: December 2022

Background: With a high incidence and dismal survival rate, hepatocellular carcinoma (HCC) tops the list of the world’s most frequent malignant tumors. Immunotherapy is a new approach to cancer treatment, and its effect on prolonging overall survival (OS) varies from patient to patient. For a more effective prognosis and treatment of HCC, we are committed to identifying immune infiltration-related long non-coding RNAs (IIRLs) with prognostic value in hepatocellular carcinoma.

Methods: In our study, we calculated immune scores of 369 hepatocellular carcinoma samples from the Cancer Genome Atlas (TCGA) database by using an estimation algorithm, and obtained long non-coding RNAs (lncRNAs) associated with immune infiltration by using Weighted Gene Co-expression Network analysis (WGCNA). For training cohort, univariate Cox, least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analysis were used to determine prognostic IIRLs, we established a prognostic IIRLs signature. By testing cohort and entire cohort, we confirmed that the signature is practical. The prognosis of people with different clinicopathological stages and risk scores were predicted by the nomogram we constructed. In addition, Immune cell infiltration analysis and prediction of therapeutic drugs were performed.

Results: 93 IIRLs were obtained by WGCNA. Furthermore, the prognostic value of these IIRLs were evaluated by using univariate Cox, Lasso and multivariate Cox analysis. Four IIRLs were used to create a signature with a prognosis. Time-related receiver operating characteristic (ROC) curve revealed that this model had an acceptable prognostic value for HCC patients. By using univariate and multivariate Cox regression analysis, this risk score has been shown to be an independent prognostic factor for HCC. The nomogram we made showed good predictions. Except for that, the treatment with immune checkpoint inhibitors (ICI) was likely to be more effective for low-risk patients.

Conclusion: Based on four IIRLs, a prognostic signature was created in this research showed good accuracy in predicting OS. This study also provided valuable references for Immunotherapy of hepatocellular carcinoma.
Opportunities and challenges for newborn screening and early diagnosis of rare diseases in Latin America
Authors: Giugliani Roberto , Castillo Taucher Silvia , Hafez Sylvia , Oliveira Joao Bosco , Rico-Restrepo Mariana , Rozenfeld Paula , Zarante Ignacio , Gonzaga-Jauregui Claudia
Published: December 2022

Rare diseases (RDs) cause considerable death and disability in Latin America. Still, there is no consensus on their definition across the region. Patients with RDs face a diagnostic odyssey to find a correct diagnosis, which may last many years and creates a burden for caregivers, healthcare systems, and society. These diagnostic delays have repercussions on the health and economic burden created by RDs and continue to represent an unmet medical need. This review analyzes barriers to the widespread adoption of newborn screening (NBS) programs and early diagnostic methods for RDs in Latin America and provides recommendations to achieve this critical objective. Increasing the adoption of NBS programs and promoting early diagnosis of RDs are the first steps to improving health outcomes for patients living with RDs. A coordinated, multistakeholder effort from leaders of patient organizations, government, industry, medical societies, academia, and healthcare services is required to increase the adoption of NBS programs. Patients’ best interests should remain the guiding principle for decisions regarding NBS implementation and early diagnosis for RDs.
Pasture intake protects against commercial diet-induced lipopolysaccharide production facilitated by gut microbiota through activating intestinal alkaline phosphatase enzyme in meat geese
Authors: Ali Qasim , Ma Sen , Farooq Umar , Niu Jiakuan , Li Fen , Li Defeng , Wang Zhichang , Sun Hao , Cui Yalei , Shi Yinghua
Published: December 2022

Introduction

Diet strongly affects gut microbiota composition, and gut bacteria can influence the intestinal barrier functions and systemic inflammation through metabolic endotoxemia. In-house feeding system (IHF, a low dietary fiber source) may cause altered cecal microbiota composition and inflammatory responses in meat geese via increased endotoxemia (lipopolysaccharides) with reduced intestinal alkaline phosphatase (ALP) production. The effects of artificial pasture grazing system (AGF, a high dietary fiber source) on modulating gut microbiota architecture and gut barrier functions have not been investigated in meat geese. Therefore, this study aimed to investigate whether intestinal ALP could play a critical role in attenuating reactive oxygen species (ROS) generation and ROS facilitating NF-κB pathway-induced systemic inflammation in meat geese.

Methods

The impacts of IHF and AGF systems on gut microbial composition via 16 sRNA sequencing were assessed in meat geese. The host markers analysis through protein expression of serum and cecal tissues, hematoxylin and eosin (H&E) staining, localization of NF-қB and Nrf2 by immunofluorescence analysis, western blotting analysis of ALP, and quantitative PCR of cecal tissues was evaluated.

Results and Discussion

In the gut microbiota analysis, meat geese supplemented with pasture showed a significant increase in commensal microbial richness and diversity compared to IHF meat geese demonstrating the antimicrobial, antioxidant, and anti-inflammatory ability of the AGF system. A significant increase in intestinal ALP-induced Nrf2 signaling pathway was confirmed representing LPS dephosphorylation mediated TLR4/MyD88 induced ROS reduction mechanisms in AGF meat geese. Further, the correlation analysis of top 44 host markers with gut microbiota showed that artificial pasture intake protected gut barrier functions via reducing ROS-mediated NF-κB pathway-induced gut permeability, systemic inflammation, and aging phenotypes. In conclusion, the intestinal ALP functions to regulate gut microbial homeostasis and barrier function appear to inhibit pro-inflammatory cytokines by reducing LPS-induced ROS production in AGF meat geese. The AGF system may represent a novel therapy to counteract the chronic inflammatory state leading to low dietary fiber-related diseases in animals.
Circulating plasmablasts and follicular helper T-cell subsets are associated with antibody-positive autoimmune epilepsy
Authors: Hara Atsushi , Chihara Norio , Akatani Ritsu , Nishigori Ryusei , Tsuji Asato , Yoshimura Hajime , Kawamoto Michi , Otsuka Yoshihisa , Kageyama Yasufumi , Kondo Takayuki , Leypoldt Frank , Wandinger Klaus-Peter , Matsumoto Riki
Published: December 2022

Autoimmune epilepsy (AE) is an inflammatory disease of the central nervous system with symptoms that have seizures that are refractory to antiepileptic drugs. Since the diagnosis of AE tends to rely on a limited number of anti-neuronal antibody tests, a more comprehensive analysis of the immune background could achieve better diagnostic accuracy. This study aimed to compare the characteristics of anti-neuronal antibody-positive autoimmune epilepsy (AE/Ab(+)) and antibody-negative suspected autoimmune epilepsy (AE/Ab(-)) groups. A total of 23 patients who met the diagnostic criteria for autoimmune encephalitis with seizures and 11 healthy controls (HC) were enrolled. All patients were comprehensively analyzed for anti-neuronal antibodies; 13 patients were identified in the AE/Ab(+) group and 10 in the AE/Ab(-) group. Differences in clinical characteristics, including laboratory and imaging findings, were evaluated between the groups. In addition, the immunophenotype of peripheral blood mononuclear cells (PBMCs) and CSF mononuclear cells, particularly B cells and circulating Tfh (cTfh) subsets, and multiplex assays of serum and CSF were analyzed using flow cytometry. Patients with AE/Ab(+) did not show any differences in clinical parameters compared to patients with AE/Ab(-). However, the frequency of plasmablasts within PBMCs and CSF in patients with AE/Ab(+) was higher than that in patients with AE/Ab(-) and HC, and the frequency of cTfh17 cells and inducible T-cell co-stimulator (ICOS) expressing cTfh17 cells within cTfh subsets was higher than that in patients with AE/Ab(-). Furthermore, the frequency of ICOShighcTfh17 cells was positively correlated with that of the unswitched memory B cells. We also found that IL-12, IL-23, IL-6, IL-17A, and IFN-γ levels were elevated in the serum and IL-17A and IL-6 levels were elevated in the CSF of patients with AE/Ab(+). Our findings indicate that patients with AE/Ab(+) showed increased differentiation of B cells and cTfh subsets associated with antibody production. The elevated frequency of plasmablasts and ICOS expressing cTfh17 shift in PBMCs may be indicative of the presence of antibodies in patients with AE.
Neoadjuvant immunotherapy for resectable esophageal cancer: A review
Authors: Li Qing , Liu Ting , Ding Zhenyu
Published: December 2022

Esophageal cancer (EC) is one of the most common cancers worldwide, especially in China. Despite therapeutic advances, the 5-year survival rate of EC is still dismal. For patients with resectable disease, neoadjuvant chemoradiotherapy (nCRT) in combination with esophagectomy is the mainstay of treatment. However, the pathological complete response (pCR) rate to nCRT of 29.2% to 43.2% is not satisfactory, and approximately half of the patients will develop either a locoregional recurrence or distant metastasis. It is, therefore, necessary to explore novel and effective treatment strategies to improve the clinical efficacy of treatment. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) has significantly changed the treatment paradigm for a wide variety of advanced cancers, including EC. More recently, increasing clinical evidence has demonstrated that neoadjuvant immunotherapy can potentially improve the survival of patients with resectable cancers. Furthermore, accumulating findings support the idea that chemotherapy and/or radiotherapy can activate the immune system through a variety of mechanisms, so a combination of chemotherapy and/or radiotherapy with immunotherapy can have a synergistic antitumor effect. Therefore, it is reasonable to evaluate the role of neoadjuvant immunotherapy for patients with surgically resectable EC. In this review, we discuss the rationale for neoadjuvant immunotherapy in patients with EC, summarize the current results of utilizing this strategy, review the planned and ongoing studies, and highlight the challenges and future research needs.
Age of onset correlates with clinical characteristics and prognostic outcomes in neuromyelitis optica spectrum disorder
Authors: Hu Yacen , Sun Qiying , Yi Fang , Yao Lingyan , Tian Yun , Tang Haiyun , Luo Mengchuan , Xie Nina , Wang Zhiqin , Liao Xinxin , Zhou Lin , Xu Hongwei , Zhou Yafang
Published: December 2022

Objective

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease preferentially affects the optic nerve and the spinal cord. The first attack usually occurs in the third or fourth decade, though patients with disease onset in the fifties or later are not uncommon. This study aimed to investigate the clinical characteristics and prognosis in patients with different age of onset and to explore the correlations between age of onset and clinical characteristics and prognostic outcomes.

Method

We retrospectively reviewed the medical records of 298 NMOSD patients diagnosed according to the 2015 updated version of diagnostic criteria. Patients were divided into early-onset NMOSD (EO-NMOSD) (<50 years at disease onset) and late-onset NMOSD (LO-NMOSD) (≥50 years at disease onset) based on the age of disease onset. LO-NMOSD patients were divided into two subgroups: relative-late-onset NMOSD (RLO-NMOSD) (50~70 years at disease onset) and very-late-onset NMOSD (≥70 years at disease onset). Clinical characteristics, laboratory findings, neuroimaging features, and prognostic outcomes were investigated.

Results

Compared to EO-NMOSD patients, patients with LO-NMOSD showed more frequent transverse myelitis (TM) (58.20% vs. 36.00%, p = 0.007) while less frequent optic neuritis (ON) (23.10% vs. 34.80%, p = 0.031) and brainstem/cerebral attacks (7.50% vs. 18.30%, p = 0.006) as the first attack. Patients with LO-NMOSD showed less frequent relapses, higher Expanded Disability Status Scale (EDSS) score at the last follow-up, fewer NMOSD-typical brain lesions, and longer segments of spinal cord lesions. Patients with older onset age showed a higher proportion of increased protein levels in cerebrospinal fluid during the acute phase of attacks. Age at disease onset positively correlated with length of spinal cord lesions at first attack and at last follow-up, negatively correlated with ARR-1 (ARR excluding the first attack, calculated from disease onset to final follow-up), irrespective of AQP4-IgG serostatus. Patients with older age at disease onset progressed to severe motor disability sooner, and age of onset positively correlated with EDSS score at the last follow-up, irrespective of AQP4-IgG serostatus.

Conclusion

Age of disease onset affects clinical characteristics and prognosis outcomes of patients with NMOSD.
Lipoxin A4 attenuates MSU-crystal-induced NLRP3 inflammasome activation through suppressing Nrf2 thereby increasing TXNRD2
Authors: Zhou You , Chen Yongjun , Zhong Xiaowu , Xia Hongtao , Zhao Mingcai , Zhao Mengyuan , Xu Lei , Guo Xiaolan , You Chong-Ge
Published: December 2022

Gout is a common inflammatory disease. The activation of NLRP3 inflammasome induced by monosodium urate (MSU) crystals has a critical role in gout, and its prevention is beneficial for patients. Lipoxin A4 (LXA4) is an endogenous lipoxygenase-derived eicosanoid mediator with powerful anti-inflammatory properties. However, whether LXA4 can suppress NLRP3 inflammasome activation induced by MSU crystals remains unclear. This study aimed to investigate the protective effect of LXA4 on MSU-crystal-induced NLRP3 inflammasome activation and its underlying molecular mechanisms. We found that LXA4 inhibited MSU-crystal-induced NLRP3 inflammasome activation, interleukin (IL)-1β maturation, and pyroptosis. More specifically, LXA4 suppressed the assembly of the NLRP3 inflammasome, including oligomerization and speck formation of ASC, and ASC-NLRP3 interaction. Furthermore, LXA4 suppressed oxidative stress, the upstream events for NLRP3 inflammasome activation, as evidenced by the fact that LXA4 eliminated total reactive oxygen species (ROS) generation and alleviated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and mitochondrial dysfunction. However, LXA4 also depressed the Nrf2 activation, a critical molecule in the antioxidant pathway, and then exerted an inhibitory impact on Klf9 expression and promotional impact on TXNRD2 expression, two molecules located downstream of Nrf2 in sequence. Knockdown of TXNRD2 reversed the LXA4-induced depression of ROS and NLRP3 inflammasome. Moreover, LXA4 alleviated joint inflammation and decreased the production of cleaved caspase-1 and matured IL-1β in gouty arthritis rats. Taken together, our findings demonstrate that LXA4 can attenuate MSU-crystal-induced NLRP3 inflammasome activation, probably through suppressing Nrf2 activation to increase TXNRD2 expression. The present study highlights the potential of LXA4 as an attractive new gout treatment candidate.
Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen
Authors: Unger Lukas W. , Muckenhuber Moritz , Mahr Benedikt , Schwarz Christoph , Pilat Nina , Granofszky Nicolas , Regele Heinz , Wekerle Thomas
Published: December 2022

Introduction

Inde-novokidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model.

Methods

Naïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period.

Results and Discussion

Administering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L-/-recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically.
Preclinical evaluation of safety and immunogenicity of a primary series intranasal COVID-19 vaccine candidate (BBV154) and humoral immunogenicity evaluation of a heterologous prime-boost strategy with COVAXIN (BBV152)
Authors: Sunagar Raju , Prasad Sai D. , Ella Raches , Vadrevu Krishna Mohan
Published: December 2022

Most if not all vaccine candidates developed to combat COVID-19 due to SARS-CoV-2 infection are administered parenterally. As SARS-CoV-2 is transmitted through infectious respiratory fluids, vaccine-induced mucosal immunity could provide an important contribution to control this pandemic. ChAd-SARS-CoV-2-S (BBV154), a replication-defective chimpanzee adenovirus (ChAd)-vectored intranasal (IN) COVID-19 vaccine candidate, encodes a prefusion-stabilized version of the SARS-CoV-2 spike protein containing two proline substitutions in the S2 subunit. We performed preclinical evaluations of BBV154 in mice, rats, hamsters and rabbits. Repeated dose toxicity studies presented excellent safety profiles in terms of pathology and biochemical analysis. IN administration of BBV154 elicited robust mucosal and systemic humoral immune responses coupled with Th1 cell-mediated immune responses. BBV154 IN vaccination also elicited potent variant (omicron) cross neutralization antibodies. Assessment of anti-vector (ChAd36) neutralizing antibodies following repeated doses of BBV154 IN administration showed insignificant titers of ChAd36 neutralizing antibodies. However, the immune sera derived from the same animals displayed significantly higher levels of SARS-CoV-2 virus neutralization (p<0.003). We also evaluated the safety and immunogenicity of heterologous prime-boost vaccination with intramuscular (IM) COVAXIN-prime followed by BBV154 IN administration. COVAXIN priming followed by BBV154 IN-booster showed an acceptable reactogenicity profile comparable to the homologous COVAXIN/COVAXIN or BBV154/BBV154 vaccination model. Heterologous vaccination of COVAXIN-prime and BBV154 booster also elicited superior (p<0.005) and cross variant (omicron) protective immune responses (p<0.013) compared with the homologous COVAXIN/COVAXIN schedule. BBV154 has successfully completed both homologous and heterologous combination schedules of human phase 3 clinical trials and received the restricted emergency use approval (in those aged above 18 years) from the Drugs Controller General of India (DCGI).