bluuebunny/crossref_metadata_2025 huggingface dataset:
Ferrets as a model for tuberculosis transmission
Authors: Gupta Tuhina , Somanna Naveen , Rowe Thomas , LaGatta Monica , Helms Shelly , Owino Simon Odera , Jelesijevic Tomislav , Harvey Stephen , Jacobs Wayne , Voss Thomas , Sakamoto Kaori , Day Cheryl , Whalen Christopher , Karls Russell , He Biao , Tompkins S. Mark , Bakre Abhijeet , Ross Ted , Quinn Frederick D.
Published: August 2022

Even with the COVID-19 pandemic, tuberculosis remains a leading cause of human death due to a single infectious agent. Until successfully treated, infected individuals may continue to transmit Mycobacterium tuberculosis bacilli to contacts. As with other respiratory pathogens, such as SARS-CoV-2, modeling the process of person-to-person transmission will inform efforts to develop vaccines and therapies that specifically impede disease transmission. The ferret (Mustela furo), a relatively inexpensive, small animal has been successfully employed to model transmissibility, pathogenicity, and tropism of influenza and other respiratory disease agents. Ferrets can become naturally infected with Mycobacterium bovis and are closely related to badgers, well known in Great Britain and elsewhere as a natural transmission vehicle for bovine tuberculosis. Herein, we report results of a study demonstrating that within 7 weeks of intratracheal infection with a high dose (>5 x 103 CFU) of M. tuberculosis bacilli, ferrets develop clinical signs and pathological features similar to acute disease reported in larger animals, and ferrets infected with very-high doses (>5 x 104 CFU) develop severe signs within two to four weeks, with loss of body weight as high as 30%. Natural transmission of this pathogen was also examined. Acutely-infected ferrets transmitted M. tuberculosis bacilli to co-housed naïve sentinels; most of the sentinels tested positive for M. tuberculosis in nasal washes, while several developed variable disease symptomologies similar to those reported for humans exposed to an active tuberculosis patient in a closed setting. Transmission was more efficient when the transmitting animal had a well-established acute infection. The findings support further assessment of this model system for tuberculosis transmission including the testing of prevention measures and vaccine efficacy.
Prognostic value of myocardial salvage index assessed by cardiovascular magnetic resonance in reperfused ST-segment elevation myocardial infarction
Authors: Zhang Shiru , Ma Quanmei , Jiao Yundi , Wu Jiake , Yu Tongtong , Hou Yang , Sun Zhijun , Zheng Liqiang , Sun Zhaoqing
Published: August 2022

Aims

Cardiovascular magnetic resonance (CMR) is a powerful tool to quantify the myocardial area at risk (AAR) and infarct size (IS), and evaluate the extent of myocardial salvage in acute ST-segment elevation myocardial infarction (STEMI). This study aimed to assess the prognostic value of myocardial salvage index (MSI) assessed by CMR in reperfused STEMI and investigate whether MSI could improve the predictive efficacy of the Global Registry of Acute Coronary Events (GRACE) risk score.

Methods and results:

About 104 consecutive patients who were hospitalized with first-time STEMI and received reperfusion therapy were prospectively enrolled. The primary endpoint was the incident of major adverse cardiovascular event (MACE) including all-cause mortality, non-fatal myocardial reinfarction and congestive heart failure within 36 months after the index event. Cox regression analysis was used to evaluate the prognostic association of MSI with MACE risk. About 21 (20.2%) patients developed MACE during the 3-year follow-up period, and patients with MSI < median had a higher incidence of MACE than those with MSI ≥ median [16 (30.8%) vs. 5 (9.6%), P = 0.007]. After adjusting all the parameters associated with MACE in univariate Cox analysis, MSI assessed by CMR remained independently significant as a predictor of MACE in multivariate Cox analysis (hazard ratio 0.963, 95% CI: 0.943–0.983; P < 0.001). Adding MSI to the GRACE risk score significantly increased the prognostic accuracy of the GRACE risk score (area under the curve: 0.833 vs. 0.773; P = 0.044), with a net reclassification improvement of 0.635 (P = 0.009) and an integrated discrimination improvement of 0.101 (P = 0.002).

Conclusion

This study confirmed that MSI assessed by CMR had a good long-term prognostic value in reperfused STEMI and improve the prognostic performance of the GRACE risk score.
Rockburst intensity prediction in underground buildings based on improved spectral clustering algorithm
Authors: Xia Zhenzhao , Mao Jingyin , He Yao
Published: August 2022

Rockbursts occur in many deep underground excavations and have caused non-negligible casualties or property losses in deep underground building activities over the past hundreds of years. Effective early warning approaches to judge the practical situation of a rock mass during excavation are one of the best ways to avoid rockbursts, while proposing high demands for monitoring data and computational methods. In this study, a data-driven method based on spectral clustering to predict rockburst intensity was proposed. Considering the fact that the original spectral clustering has some defects, an improvement strategy that selects K-medoids, or an improved variant of K-medoids to replace the original K-means clustering as the latter clustering process, was executed. First, the hyperparameters and selections of the latter clustering algorithms were determined, and improved K-medoids with related hyperparameters were determined by 65 rockburst samples collected in underground engineering cases. Based on the previous configurations of flow and hyperparameters, the remaining 17 samples were labeled using a concise labeling flow, which was also based on spectral processes in spectral clustering. The results of the control experiments show that the proposed method has certain feasibility and superiority (82.40% accuracy performance) in rockburst intensity prediction for underground construction.
Increased risk of testosterone deficiency is associated with the systemic immune-inflammation index: a population-based cohort study
Authors: Li Yongchao , Liu Minghui , Cui Yu , Zhu Zewu , Chen Jinbo , Zeng Feng , Gao Meng , Li Yang , Huang Fang , Chen Hequn
Published: August 2022

Purpose

This study aimed to explore the relationship between serum testosterone levels and systemic immune-inflammation index (SII).

Methods

Complete SII and serum testosterone data of men over 20 years of age were retrieved from the 2011–2016 National Health and Nutrition Examination Survey to conduct a prevalence survey. To calculate SII, the platelet count was multiplied by the neutrophil-to-lymphocyte count ratio. Isotope dilution liquid chromatography and tandem mass spectrometry were employed to measure serum testosterone concentration. Testosterone deficiency (TD) was defined as a serum testosterone level ≤ 300ng/dl. Weighted proportions and multivariable regression analyses were used to analyze the association between SII and TD.

Results

Overall, the data of 7389 participants were analyzed, The SII ranged from 1.53 - 6297.60. Of the participants, 28.42% had a low serum testosterone level (≤ 300 ng/dl). In the fully adjusted multivariable logistic model, the second quartile (OR: 1.27, p = 0.0737), the third quartile (OR: 1.43, p = 0.0090), and the fourth quartile (OR:1.48, p = 0.0042) of SII significantly increased the TD incidence rate, with the lowest quartile of the SII as a reference. For subgroup analysis, statistically significant associations were observed in participants aged 20-40, obese, non-hypertensive, and non-diabetic. The interaction test revealed no significant effect on this connection.

Conclusions

There was a positive relationship between a high SII and an increased prevalence of TD in a nationwide sample of adult men in the United States. Further prospective studies on a larger scale are warranted to confirm the causality between SII and TD.
Signaling pathways activated by sea bass gonadotropin-inhibitory hormone peptides in COS-7 cells transfected with their cognate receptor
Authors: Wang Bin , Paullada-Salmerón José A. , Vergès-Castillo Alba , Gómez Ana , Muñoz-Cueto José A.
Published: August 2022

Results of previous studies provided evidence for the existence of a functional gonadotropin-inhibitory hormone (GnIH) system in the European sea bass, Dicentrarchus labrax, which exerted an inhibitory action on the brain-pituitary-gonadal axis of this species. Herein, we further elucidated the intracellular signaling pathways mediating in sea bass GnIH actions and the potential interactions with sea bass kisspeptin (Kiss) signaling. Although GnIH1 and GnIH2 had no effect on basal CRE-luc activity, they significantly decreased forskolin-elicited CRE-luc activity in COS-7 cells transfected with their cognate receptor GnIHR. Moreover, an evident increase in SRE-luc activity was noticed when COS-7 cells expressing GnIHR were challenged with both GnIH peptides, and this stimulatory action was significantly reduced by two inhibitors of the PKC pathway. Notably, GnIH2 antagonized Kiss2-evoked CRE-luc activity in COS-7 cells expressing GnIHR and Kiss2 receptor (Kiss2R). However, GnIH peptides did not alter NFAT-RE-luc activity and ERK phosphorylation levels. These data indicate that sea bass GnIHR signals can be transduced through the PKA and PKC pathways, and GnIH can interfere with kisspeptin actions by reducing its signaling. Our results provide additional evidence for the understanding of signaling pathways activated by GnIH peptides in teleosts, and represent a starting point for the study of interactions with multiple neuroendocrine factors on cell signaling.
Computationally Inexpensive 1D-CNN for the Prediction of Noisy Data of NOx Emissions From 500 MW Coal-Fired Power Plant
Authors: Saif-Ul-Allah Muhammad Waqas , Khan Javed , Ahmed Faisal , Salman Chaudhary Awais , Gillani Zeeshan , Hussain Arif , Yasin Muhammad , Ul-Haq Noaman , Khan Asad Ullah , Bazmi Aqeel Ahmed , Ahmad Zubair , Hasan Mudassir
Published: August 2022

Coal-fired power plants have been used to meet the energy requirements in countries where coal reserves are abundant and are the key source of NOx emissions. Owing to the serious environmental and health concerns associated with NOx emissions, much work has been carried out to reduce NOx emissions. Sophisticated artificial intelligence (AI) techniques have been employed during the past few decades, such as least-squares support vector machine (LSSVM), artificial neural networks (ANN), long short-term memory (LSTM), and gated recurrent unit (GRU), to develop the NOx prediction model. Several studies have investigated deep neural networks (DNN) models for accurate NOx emission prediction. However, there is a need to investigate a DNN-based NOx prediction model that is accurate and computationally inexpensive. Recently, a new AI technique, convolutional neural network (CNN), has been introduced and proven superior for image class prediction accuracy. According to the best of the author’s knowledge, not much work has been done on the utilization of CNN on NOx emissions from coal-fired power plants. Therefore, this study investigated the prediction performance and computational time of one-dimensional CNN (1D-CNN) on NOx emissions data from a 500 MW coal-fired power plant. The variations of hyperparameters of LSTM, GRU, and 1D-CNN were investigated, and the performance metrics such as RMSE and computational time were recorded to obtain optimal hyperparameters. The obtained optimal values of hyperparameters of LSTM, GRU, and 1D-CNN were then employed for models’ development, and consequently, the models were tested on test data. The 1D-CNN NOx emission model improved the training efficiency in terms of RMSE by 70.6% and 60.1% compared to LSTM and GRU, respectively. Furthermore, the testing efficiency for 1D-CNN improved by 10.2% and 15.7% compared to LSTM and GRU, respectively. Moreover, 1D-CNN (26 s) reduced the training time by 83.8% and 50% compared to LSTM (160 s) and GRU (52 s), respectively. Results reveal that 1D-CNN is more accurate, more stable, and computationally inexpensive compared to LSTM and GRU on NOx emission data from the 500 MW power plant.
The size-distribution of earth’s lakes and ponds: Limits to power-law behavior
Authors: Cael B. B. , Biggs Jeremy , Seekell D. A.
Published: August 2022

Global-scale characterizations of Earth’s lakes and ponds assume their surface areas are power-law distributed across the full size range. However, empirical power-laws only hold across finite ranges of scales. In this paper, we synthesize evidence for upper and lower limits to power-law behavior in lake and pond size-distributions. We find support for the power-law assumption in general. We also find strong evidence for a lower limit to this power-law behavior, although the specific value for this limit is highly variable (0.001–1 km2), corresponding to orders of magnitude differences of the total number of lakes and ponds. The exact mechanisms that break the power-law at this limit are unknown. The power-law extends to the size of Earth’s largest lake. There is inconsistent evidence for an upper limit at regional-scales. Explaining variations in these limits stands to improve the accuracy of global lake characterizations and shed light on the specific mechanism responsible for forming and breaking lake power-law distributions.
Holocene wildfire and vegetation dynamics in Central Yakutia, Siberia, reconstructed from lake-sediment proxies
Authors: Glückler Ramesh , Geng Rongwei , Grimm Lennart , Baisheva Izabella , Herzschuh Ulrike , Stoof-Leichsenring Kathleen R. , Kruse Stefan , Andreev Andrei , Pestryakova Luidmila , Dietze Elisabeth
Published: August 2022

Wildfires play an essential role in the ecology of boreal forests. In eastern Siberia, fire activity has been increasing in recent years, challenging the livelihoods of local communities. Intensifying fire regimes also increase disturbance pressure on the boreal forests, which currently protect the permafrost beneath from accelerated degradation. However, long-term relationships between changes in fire regime and forest structure remain largely unknown. We assess past fire-vegetation feedbacks using sedimentary proxy records from Lake Satagay, Central Yakutia, Siberia, covering the past c. 10,800 years. Results from macroscopic and microscopic charcoal analyses indicate high amounts of burnt biomass during the Early Holocene, and that the present-day, low-severity surface fire regime has been in place since c. 4,500 years before present. A pollen-based quantitative reconstruction of vegetation cover and a terrestrial plant record based on sedimentary ancient DNA metabarcoding suggest a pronounced shift in forest structure toward the Late Holocene. Whereas the Early Holocene was characterized by postglacial open larch-birch woodlands, forest structure changed toward the modern, mixed larch-dominated closed-canopy forest during the Mid-Holocene. We propose a potential relationship between open woodlands and high amounts of burnt biomass, as well as a mediating effect of dense larch forest on the climate-driven intensification of fire regimes. Considering the anticipated increase in forest disturbances (droughts, insect invasions, and wildfires), higher tree mortality may force the modern state of the forest to shift toward an open woodland state comparable to the Early Holocene. Such a shift in forest structure may result in a positive feedback on currently intensifying wildfires. These new long-term data improve our understanding of millennial-scale fire regime changes and their relationships to changes of vegetation in Central Yakutia, where the local population is already being confronted with intensifying wildfire seasons.
Alpine wetland degradation reduces carbon sequestration in the Zoige Plateau, China
Authors: Yang Ao , Kang Xiaoming , Li Yong , Zhang Xiaodong , Zhang Kerou , Kang Enze , Yan Zhongqing , Li Meng , Wang Xiaodong , Niu Yuechuan , Yan Liang
Published: August 2022

Alpine wetland plays an important role in the global carbon balance but are experiencing severe degradation under climate change and human activities. With the aim to clarify the effect of alpine wetland degradation on carbon fluxes (including net ecosystem CO2 exchange, NEE; ecosystem respiration, ER; gross ecosystem productivity, GEP, and CH4 flux), we investigated 12 sites and measured carbon fluxes using the static chamber method in the Zoige alpine wetland during August 2018, including undegraded wetland (UD), lightly degraded wetland (LD), moderately degraded wetland (MD), and severely degraded wetland (SD). The results showed that carbon sink strengths differ among the Zoige wetlands with different degradation stages during the growing season. From UD to LD, the rate of carbon sequestration (mean value of NEE) increased by 25.70%; however, from LD to SD, it decreased by 81.67%. Wetland degradation significantly reduced soil water content (SWC), soil organic carbon (SOC), microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN). NEE was significantly correlated with MBC and MBN, while ER was positively correlated with ST but negatively correlated with SOC (P < 0.01). Among all measured environmental factors, GEP was positively correlated with pH (P < 0.01), while CH4 flux was most closely correlated with SOC, SWC, MBC, MBN, and ST (P < 0.001), and was also affected by pH and NO3– content (P < 0.01). These results suggest that the capacity of carbon sequestration in the Zoige wetlands reduced with intensification of the degradation. This study provides a reference for sustainably managing and utilizing degraded wetlands under climate change.
Herding pattern among Bronze Age steppe communities: An ethnographic approach to mapping pasture in the Southeastern Ural Mountains, Russia
Authors: Ng Chuenyan , Wei Weiyan , Yu Chong , Zheng Junlei
Published: August 2022

Recent ethnographic data can assist with the examination of Bronze Age pastoralist herding patterns, however, there are still missing links between the archeological record and available ethnographic data from the Southeastern Ural Mountains regions. One way to explore the answer to this question is to use archaeobotanical data to understand the herding pattern in prehistory, which in many ways act as a bridge between pastoralist subsistence economy and plant exploitation strategy in the microenvironment. Compared with previous research, this ethnographic study was undertaken through field research based on the analysis results of the archaeobotanical record recovered from the Bronze Age Stepnoye settlement. The archaeobotanical sampling associated with the excavation of the Stepnoye settlement indicated a significant pattern of local wild resource exploitation for humans and livestock. Therefore, regional ethnographic study and pasture mapping in local catchment zone provide essential comparative data to interpret the herding-related plant remains and further discussion of herding patterns among Bronze Age pastoralist communities in this area.
Cranberry polyphenols and agave agavins impact gut immune response and microbiota composition while improving gut barrier function, inflammation, and glucose metabolism in mice fed an obesogenic diet
Authors: Medina-Larqué Ana-Sofía , Rodríguez-Daza María-Carolina , Roquim Marcela , Dudonné Stéphanie , Pilon Geneviève , Levy Émile , Marette André , Roy Denis , Jacques Hélène , Desjardins Yves
Published: August 2022

The consumption of plant-based bioactive compounds modulates the gut microbiota and interacts with the innate and adaptive immune responses associated with metabolic disorders. The present study aimed to evaluate the effect of cranberry polyphenols (CP), rich in flavonoids, and agavins (AG), a highly branched agave-derived neo-fructans, on cardiometabolic response, gut microbiota composition, metabolic endotoxemia, and mucosal immunomodulation of C57BL6 male mice fed an obesogenic high-fat and high-sucrose (HFHS) diet for 9 weeks. Interestingly, CP+AG-fed mice had improved glucose homeostasis. Oral supplementation with CP selectively and robustly (five-fold) increases the relative abundance of Akkermansia muciniphila, a beneficial bacteria associated with metabolic health. AG, either alone or combined with CP (CP+AG), mainly stimulated the glycan-degrading bacteria Muribaculum intestinale, Faecalibaculum rodentium, Bacteroides uniformis, and Bacteroides acidifaciens. This increase of glycan-degrading bacteria was consistent with a significantly increased level of butyrate in obese mice receiving AG, as compared to untreated counterparts. CP+AG-supplemented HFHS-fed mice had significantly lower levels of plasma LBP than HFHS-fed controls, suggesting blunted metabolic endotoxemia and improved intestinal barrier function. Gut microbiota and derived metabolites interact with the immunological factors to improve intestinal epithelium barrier function. Oral administration of CP and AG to obese mice contributed to dampen the pro-inflammatory immune response through different signaling pathways. CP and AG, alone or combined, increased toll-like receptor (TLR)-2 (Tlr2) expression, while decreasing the expression of interleukin 1ß (ILß1) in obese mice. Moreover, AG selectively promoted the anti-inflammatory marker Foxp3, while CP increased the expression of NOD-like receptor family pyrin domain containing 6 (Nlrp6) inflammasome. The intestinal immune system was also shaped by dietary factor recognition. Indeed, the combination of CP+AG significantly increased the expression of aryl hydrocarbon receptors (Ahr). Altogether, both CP and AG can shape gut microbiota composition and regulate key mucosal markers involved in the repair of epithelial barrier integrity, thereby attenuating obesity-associated gut dysbiosis and metabolic inflammation and improving glucose homeostasis.
Advanced Cell Therapies for Glioblastoma
Authors: Wang Guangwen , Wang Wenshi
Published: August 2022

The sheer ubiquity of Gioblastoma (GBM) cases would lead you to believe that there should have been many opportunities for the discovery of treatments to successfully render it into remission. Unfortunately, its persistent commonality is due in large part to the fact that it is the most treatment-resistant tumors in adults. That completely changes the treatment plan of attack. Long established and accepted treatment therapies such as surgical resection, radiation, and aggressive chemotherapy, (and any combination thereof) have only confirmed that the disease lives up to its treatment-resistant reputation. To add to the seemingly insurmountable task of finding a cure, GBM has also proven to be a very stubborn and formidable opponent to newer immunotherapies. Across the board, regardless of the therapy combination, the five-year survival rate of GBM patients is still very poor at a heartbreaking 5.6%. Obviously, the present situation cannot be tolerated or deemed acceptable. The grave situation calls for researchers to be more innovative and find more efficient strategies to discover new and successful strategies to treat GBM. Inspired by researchers worldwide attempting to control GBM, we provide in this review a comprehensive overview of the many diverse cell therapies currently being used to treat GBM. An overview of the treatments include: CAR T cells, CAR NK cells, gamma-delta T cells, NKT cells, dendritic cells, macrophages, as well stem cell-based strategies. To give you the complete picture, we will discuss the efficacy, safety, and developmental stages, the mechanisms of action and the challenges of each of these therapies and detail their potential to be the next-generation immunotherapeutic to eliminate this dreadful disease.
Targeted treatment of autoimmune cytopenias in primary immunodeficiencies
Authors: Pacillo Lucia , Giardino Giuliana , Amodio Donato , Giancotta Carmela , Rivalta Beatrice , Rotulo Gioacchino Andrea , Manno Emma Concetta , Cifaldi Cristina , Palumbo Giuseppe , Pignata Claudio , Palma Paolo , Rossi Paolo , Finocchi Andrea , Cancrini Caterina
Published: August 2022

Primary Immunodeficiencies (PID) are a group of rare congenital disorders of the immune system. Autoimmune cytopenia (AIC) represents the most common autoimmune manifestation in PID patients. Treatment of AIC in PID patients can be really challenging, since they are often chronic, relapsing and refractory to first line therapies, thus requiring a broad variety of alternative therapeutic options. Moreover, immunosuppression should be fine balanced considering the increased susceptibility to infections in these patients. Specific therapeutic guidelines for AIC in PID patients are lacking. Treatment choice should be guided by the underlying disease. The study of the pathogenic mechanisms involved in the genesis of AIC in PID and our growing ability to define the molecular underpinnings of immune dysregulation has paved the way for the development of novel targeted treatments. Ideally, targeted therapy is directed against an overexpressed or overactive gene product or substitutes a defective protein, restoring the impaired pathway. Actually, the molecular diagnosis or a specific drug is not always available. However, defining the category of PID or the immunological phenotype can help to choose a semi-targeted therapy directed towards the suspected pathogenic mechanism. In this review we overview all the therapeutic interventions available for AIC in PID patients, according to different immunologic targets. In particular, we focus on T and/or B cells targeting therapies. To support decision making in the future, prospective studies to define treatment response and predicting/stratifying biomarkers for patients with AIC and PID are needed.
Mining the multifunction of mucosal-associated invariant T cells in hematological malignancies and transplantation immunity: A promising hexagon soldier in immunomodulatory
Authors: Gao Meng-Ge , Zhao Xiao-Su
Published: August 2022

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved innate-like T cells capable of recognizing bacterial and fungal ligands derived from vitamin B biosynthesis. Under different stimulation conditions, MAIT cells can display different immune effector phenotypes, exerting immune regulation and anti-/protumor responses. Based on basic biological characteristics, including the enrichment of mucosal tissue, the secretion of mucosal repair protective factors (interleukin-17, etc.), and the activation of riboflavin metabolites by intestinal flora, MAIT cells may play an important role in the immune regulation effect of mucosal lesions or inflammation. At the same time, activated MAIT cells secrete granzyme B, perforin, interferon γ, and other toxic cytokines, which can mediate anti-tumor effects. In addition, since a variety of hematological malignancies express the targets of MAIT cell-specific effector molecules, MAIT cells are also a potentially attractive target for cell therapy or immunotherapy for hematological malignancies. In this review, we will provide an overview of MAIT research related to blood system diseases and discuss the possible immunomodulatory or anti-tumor roles that unique biological characteristics or effector phenotypes may play in hematological diseases.
Predictive value of drug efficacy by M6A modification patterns in rheumatoid arthritis patients
Authors: Song Shan , Zhao Rong , Qiao Jun , Liu Jia , Cheng Ting , Zhang Sheng-Xiao , Li Xiao-Feng
Published: August 2022

Background

Rheumatoid arthritis is a highly heterogeneous autoimmune disease characterized by unpredictable disease flares and significant differences in therapeutic response to available treatments. One possible reason for poor efficacy is that it cannot be treated accurately due to no optimal stratification for RA patients.

Objective

This study aims to construct an RA classification model by m6A characters and further predict response to medication.

Methods

Twenty m6A regulators were used to construct a random forest diagnosis model, and RNA-seq analysis was employed for external validation. The RNA modification patterns mediated by 20 m6A regulators were systematically evaluated in 1191 RA samples and explored different molecular clusters associated with other immune microenvironment characteristics and biological pathways. Then, we established an m6A score model to quantify the m6A modification patterns. The model was applied to patients at baseline to test the association between m6Ascore and infliximab responsiveness.

Results

The m6A diagnosis model showed good discriminatory ability in distinguishing RA. Patients with RA were classified into three clusters with distinct molecular and cellular signatures. Cluster A displayed strongly activated inflammatory cells and pathways. Specific innate lymphocytes occupied cluster B. Cluster C was mainly enriched in prominent adaptive lymphocytes and NK-mediated cytotoxicity signatures with the highest m6A score. Patients with a low m6Ascore exhibited significantly infliximab therapeutic benefits compared with those with a high m6Ascore (p< 0.05).

Conclusion

Our study is the first to provide a comprehensive analysis of m6A modifications in RA, which provides an innovative patient stratification framework and potentially enables improved therapeutic decisions.
Bile acids in immunity: Bidirectional mediators between the host and the microbiota
Authors: Godlewska Urszula , Bulanda Edyta , Wypych Tomasz P.
Published: August 2022

Host-microbiota interactions are bidirectional. On one hand, ecological pressures exerted by the host shape the composition and function of the microbiota. On the other, resident microbes trigger multiple pathways that influence the immunity of the host. Bile acids participate in both parts of this interplay. As host-derived compounds, they display bacteriostatic properties and affect the survival and growth of the members of the microbial community. As microbiota-modified metabolites, they further influence the microbiota composition and, in parallel, modulate the immunity of the host. Here, we provide a comprehensive overview of the mechanisms behind this unique dialogue and discuss how we can harness bile acids to treat intestinal inflammation.
Spatial biology analysis reveals B cell follicles in secondary lymphoid structures may regulate anti-tumor responses at initial melanoma diagnosis
Authors: Therien Aaron D. , Beasley Georgia M. , Rhodin Kristen E. , Farrow Norma E. , Tyler Douglas S. , Boczkowski David , Al-Rohil Rami N. , Holl Eda K. , Nair Smita K.
Published: August 2022

Introduction

B cells are key regulators of immune responses in melanoma. We aimed to explore differences in the histologic location and activation status of B cell follicles in sentinel lymph nodes (SLN) of melanoma patients.

Methods

Flow cytometry was performed on fresh tumor draining lymph nodes (LN). Paraffin slides from a separate cohort underwent NanoString Digital Spatial Profiling (DSP)®. After staining with fluorescent markers for CD20 (B cells), CD3 (T cells), CD11c (antigen presenting cells) and a nuclear marker (tumor) was performed, regions of interest (ROI) were selected based on the location of B cell regions (B cell follicles). A panel of 68 proteins was then analyzed from the ROIs.

Results

B cell percentage trended higher in patients with tumor in LN (n=3) compared to patients with nSLN (n=10) by flow cytometry. B cell regions from a separate cohort of patients with tumor in the (pSLN) (n=8) vs. no tumor (nSLN) (n=16) were examined with DSP. Within B cell regions of the SLN, patients with pSLN had significantly higher expression of multiple activation markers including Ki-67 compared to nSLN patients. Among 4 patients with pSLN, we noted variability in arrangement of B cell follicles which were either surrounding the tumor deposit or appeared to be infiltrating the tumor. The B cell follicle infiltrative pattern was associated with prolonged recurrence free survival.

Conclusion

These data suggest a role for B cell follicles in coordinating effective adaptive immune responses in melanoma when low volume metastatic disease is present in tumor draining LN.
Single-cell sequencing reveals heterogeneity between pancreatic adenosquamous carcinoma and pancreatic ductal adenocarcinoma with prognostic value
Authors: Zhang Deyu , Wu Suna , Pan Shubo , Wang Meiqi , Wang Zhen , He Zixuan , Zhang Guanghao , Cui Fang , Song Yihang , Li Wanshun , Shi Xiaohua , Huang Haojie , Xu Huanhai
Published: August 2022

Pancreatic adenosquamous carcinoma (ASPC) is a rare subtype of pancreatic cancer with lethal malignancy, and few studies have focused on the heterogeneity of ASPC. Here, we performed a single-cell sequencing procedure on pancreatic tumor tissue from an ASPC patient and a patient with high-grade intraductal papillary mucinous neoplasm (IPMN). Through the combined analysis of single-cell sequencing data from five pancreatic ductal adenocarcinoma (PDAC) patients, one IPMN patient, and one ASPC patient in a public database, we identified 11 main types of cells, including macrophages, B cells, cancer stem cells, ductal cells, fibroblasts, endo/stellate cells, neutrophils, acinar cells, T cells, natural killer (NK) cells, dendritic cells, and mast cells. Then, the different characteristics and differentiation paths of the immune microenvironment among IPMN, ASPC, and PDAC in macrophages, T cells, and cancer-associated fibroblasts (CAFs) were identified through multiple bioinformatics analyses. Two novel special cancer-associated fibroblasts were identified as nCAFs and imCAFs. Then, cancer cells in duct cells were identified using the infercnv software. Two ASPC-specific subgroups of cancer cells with squamous cell features were identified. Finally, the identified specific CAFs and cancer cells were mapped to TCGA-PAAD cohort through the cibersoftx software. All of these identified subgroups were calculated to have a significant prognostic value in pancreatic cancer patients. These findings will promote the clinical application of single-cell sequencing data of pancreatic cancer and deepen our understanding of ASPC.
Phylogenetic relationship and soil salinity shape intraspecific trait variability of Phragmites australis in the Yellow River Delta
Authors: Wu Yiming , Liu Lele , Yin Meiqi , Guo Weihua
Published: August 2022

Soil salinization has been one of the main causes of ecosystem degradation in many estuarine wetlands under global climate changes, but it remains unclear how salinization shifts the phenotypic variability and genetic diversity of the foundation plant species in estuarine wetlands. To reveal the effects of salinization on natural populations of foundation plant species, we investigated the intraspecific variation of Phragmites australis using five functional traits (shoot height, leaf length, panicle length, seed number per panicle, and mass per seed) and ten microsatellite markers in the five sites across the Yellow River Delta. The salinity was indicated by electrical conductivity, and the reproductive strategy was estimated by the ratio of panicle length to shoot height. The linear models showed that the shoot height, leaf length, and panicle length had significantly negative correlations to soil salinity, while the mass per seed had a significantly positive correlation to soil salinity. However, there were no significant relationships between the seed number per panicle or reproductive ratio and soil salinity. The genetic diversity within populations was high in all sites (He > 0.5), but the genetic differentiation between populations was very weak (FST from 0.0074 to 0.0212), which suggested that there was a strong genetic flow among populations. Genetic structure analyses showed two phylogenetic groups of P. australis distributed in four of five surveyed sites across the Yellow River Delta. Our study also found significant phylogenetic signals in the leaf length and mass per seed, suggesting a substantial role of phylogenetic relationship (technically, neutral genetic relatedness) in intraspecific variation and salt adaptation of P. australis. Our study provides novel insight into the adaptative responses of the foundation plant species to soil salinization from individual traits to population genetics and offers significant implications for ecological restoration and adaptive management of saline lands in estuarine wetlands.
Ditangquan exercises based on safe-landing strategies prevent falls and injury among older individuals with sarcopenia
Authors: Li Zhen-rui , Ma Yun-jing , Zhuang Jie , Tao Xun-chen , Guo Chao-yang , Liu Shu-ting , Zhu Ran-ran , Wang Jin-xiang , Fang Lei
Published: August 2022

Background

Sarcopenia is the age-related loss of skeletal muscle mass and function; it is a risk factor for falls among older individuals. Few studies have focused on training such individuals to adopt a safe-landing strategy that would protect them from fall-related injuries. Ditangquan is a traditional Chinese martial art comprising movements that conform to the principles of safe landing. This study aims to investigate the effectiveness of Ditangquan in preventing fall-related injuries among older individuals with sarcopenia.

Methods

A total of 70 participants (21 males and 49 females with sarcopenia) between 60 and 80 years of age were recruited from three local communities and randomly assigned to the Ditangquan exercise group (DG) or the control group (CG) in a 1:1 ratio. Three times a week for 24 weeks, both the DG and CG received an hour of conventional exercise and an hour of Ditangquan exercise based on safe landing. Primary outcomes were the modified falls efficacy scale (MFES), the number of falls, and fall injuries; the secondary outcome was the Timed Up & Go (TUG) test.

Results

The DG had significantly fewer falls (1 vs. 8, P = 0.028) and fall injuries (0 vs. 6, P = 0.025) than the CG. Furthermore, at the end of the study, the DG had a significantly improved MFES (mean difference: 32.17 scores; 95% CI: 21.32, 43.02; P <0.001) and TUGT (mean difference: −4.94 s; 95% CI: −7.95, −1.93; P = 0.002) as compared with the CG.

Conclusion

Ditangquan exercise based on the safe-landing strategy effectively improves the functional mobility of the elderly, reduces the occurrence of falls and injuries, and increases the individual's confidence in preventing falls.
Patients with seronegative rheumatoid arthritis have a different phenotype than seropositive patients: A clinical and ultrasound study
Authors: Carbonell-Bobadilla Natalia , Soto-Fajardo Carina , Amezcua-Guerra Luis M. , Batres-Marroquín Ana Beatriz , Vargas Tania , Hernández-Diazcouder Adrian , Jiménez-Rojas Valentin , Medina-García Ana Cristina , Pineda Carlos , Silveira Luis H.
Published: August 2022

Introduction

Rheumatoid arthritis (RA) is an inflammatory disease whose clinical phenotype largely depends on the presence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). Seronegative RA appears to be a less severe disease, but this remains controversial. This study aimed to assess whether seronegative patients show a less severe disease than seropositive patients.

Methods

A cross-sectional study was conducted on RA outpatients from a single center. Clinical activity scales, laboratory evaluations, and cardiovascular risk scores were assessed. Musculoskeletal ultrasound (US) examinations were performed.

Results

One hundred and fourteen patients were enrolled. Eighty-five were seropositive (76% women) and 29 seronegative (93% women). Seropositive patients had a younger age at disease onset (43 ± 14 vs. 54 ± 11; p = 0.001) and used sulfasalazine (47 vs. 17%; p = 0.004) and glucocorticoids (36 vs. 10%; p = 0.007) more frequently. No differences in clinical activity scales and in 10-year cardiovascular risk were observed. Pathological US data were found more frequently in seropositive patients in the 2nd metacarpophalangeal (MCP) joint, both in grayscale (71 vs. 38%; p = 0.008) and in power Doppler (PD; 53 vs. 9%; p < 0.001); erosions (36 vs. 9%; p = 0.020) were also more frequent. We found greater severity of PD signals in the 2nd MCP and 3rd MCP joints of the seropositive patients, while synovitis severity was higher only in the 2nd MCP joints. The percentage of total joints with erosions (9 vs. 1%; p < 0.001) and 2nd MCP joints with erosions (25 vs. 7%; p < 0.001) was higher in seropositive patients.

Conclusion

RA patients show a differentiated phenotype according to their ACPA and RF status. In seronegative patients, RA begins later in life and has a lower requirement for antirheumatic therapies. On US evaluation, seropositive patients show more joint damage, especially in MCP joints. Despite this, long-term cardiovascular risk is similar among RA patients, regardless of their RF and ACPA status.
Monoamine oxidase inhibition in cigarette smokers: From preclinical studies to tobacco product regulation
Authors: Sved Alan F. , Weeks Jillian J. , Grace Anthony A. , Smith Tracy T. , Donny Eric C.
Published: August 2022

Monoamine oxidase (MAO) activity is reduced in cigarette smokers and this may promote the reinforcing actions of nicotine, thereby enhancing the addictive properties of cigarettes. At present, it is unclear how cigarette smoking leads to MAO inhibition, but preclinical studies in rodents show that MAO inhibition increases nicotine self-administration, especially at low doses of nicotine. This effect of MAO inhibition develops slowly, likely due to plasticity of brain monoamine systems; studies relying on acute MAO inhibition are unlikely to replicate what happens with smoking. Given that MAO inhibition may reduce the threshold level at which nicotine becomes reinforcing, it is important to consider this in the context of very low nicotine content (VLNC) cigarettes and potential tobacco product regulation. It is also important to consider how this interaction between MAO inhibition and the reinforcing actions of nicotine may be modified in populations that are particularly vulnerable to nicotine dependence. In the context of these issues, we show that the MAO-inhibiting action of cigarette smoke extract (CSE) is similar in VLNC cigarettes and cigarettes with a standard nicotine content. In addition, we present evidence that in a rodent model of schizophrenia the effect of MAO inhibition to enhance nicotine self-administration is absent, and speculate how this may relate to brain serotonin systems. These issues are relevant to the MAO-inhibiting effect of cigarette smoking and its implications to tobacco product regulation.
Historical efforts to develop 99mTc-based amyloid plaque targeting radiotracers
Authors: Takalloobanafshi Ghazaleh , Kukreja Aditi , Hicks Justin W.
Published: August 2022

Imaging biomarkers have changed the way we study Alzheimer's disease and related dementias, develop new therapeutics to treat the disease, and stratify patient populations in clinical trials. With respect to protein aggregates comprised of amyloid-β plaques and tau neurofibrillary tangles, Positron Emission Tomography (PET) has become the gold standard imaging modality for quantitative visualization. Due to high infrastructural costs, the availability of PET remains limited to large urban areas within high income nations. This limits access to leading edge medical imaging, and potentially access to new treatments, by millions of rural and remote residents in those regions as well as billions of people in middle- and low-income countries. Single Photon Emission Computed Tomography (SPECT) is a more widely available imaging alternative with lower infrastructural costs and decades of familiarity amongst nuclear medicine professionals. Recent technological advances have closed the gap in spatial resolution and quantitation between SPECT and PET. If effective SPECT radiotracers were available to visualize amyloid-β plaques, geographic barriers to imaging could be circumvented. In this review, we will discuss past efforts to develop SPECT radiotracers targeting amyloid-β plaques which incorporate the most used radionuclide in nuclear medicine: technetium-99m (99mTc; t1/2 = 6.01 h; γ = 140 keV). While reviewing the various chemical scaffolds and chelates employed, the focus will be upon the impact to the pharmacological properties of putative 99mTc-based amyloid-targeting radiotracers.
Portulaca oleracea L. extracts alleviate 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice
Authors: Lv Wei-jie , Huang Jie-yi , Li Shu-peng , Gong Xiao-pei , Sun Jing-bo , Mao Wei , Guo Shi-ning
Published: August 2022

Atopic dermatitis (AD) is a common chronic allergic skin disease characterized clinically by severe skin lesions and pruritus. Portulaca oleracea L. (PO) is a resourceful plant with homologous properties in medicine and food. In this study, we used two different methods to extract PO, and compared the therapeutic effects of PO aqueous extract (POAE) and PO ultrasound-assisted ethanol extract (POEE) on 2,4-dinitrochlorobenzene (DNCB)-induced AD mice. The results showed that in POAE and POEE, the extraction rates of polysaccharides were 16.95% and 9.85%, while the extraction rates of total flavonoids were 3.15% and 3.25%, respectively. Compared with AD mice, clinical symptoms such as erythema, edema, dryness and ulceration in the back and left ear were alleviated, and pruritus behavior was reduced after POAE and POEE treatments. The thickness of the skin epidermis was thinned, the density of skin nerve fibers labeled with protein gene product 9.5 (PGP9.5) was decreased, and mast cell infiltration was reduced. There was a decrease in blood lymphocytes, eosinophils and basophils, a significant decrease in spleen index and a noticeable decrease in serum immunoglobulin E (Ig E). POEE significantly reduced the concentration of the skin pruritic factor interleukin (Il)-31. POAE and POEE reduced the concentration of skin histamine (His), down-regulated mRNA expression levels of interferon-γ (Ifnγ), tumor necrosis factor-α (Tnf-α), thymic stromal lymphopoietin (Tslp) and Il-4, with an increase of Filaggrin (Flg) and Loricrin (Lor) in skin lesions. These results suggested that POAE and POEE may inhibit atopic response and alleviate the clinical symptoms of AD by inhibiting the expression of immune cells, inflammatory mediators and cytokines. PO may be a potential effective drug for AD-like diseases.
ASNS can predict the poor prognosis of clear cell renal cell carcinoma
Authors: Gan Xinqiang , Liu Ruiji , Cheng Hong , Mao Weipu , Feng Ninghan , Chen Ming
Published: August 2022

Purpose

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies of the urinary system. This study was conducted to discover a new target that can predict the prognosis and promote the treatment of ccRCC.

Methods

The raw data were downloaded from the TCGA database, and the predictive value of ASNS for various clinicopathological features was verified in the following analysis. Then, we analyzed the potential involvement of ASNS in tumor immunity and obtained the possible pathways involving ASNS through GO/KEGG enrichment analysis and GSEA. We also further verified our findings in pathological specimens of ccRCC patients.

Results

ASNS expression was significantly increased in ccRCC, which was associated with advanced clinicopathological characteristics. It was an independent prognostic factor for overall survival in 535 patients with ccRCC. Immune cell infiltration analysis revealed that ASNS expression was related to T lymphocyte infiltration of tumors and poor prognosis. Moreover, we performed relevant functional enrichment analyses of ASNS.

Conclusions

ASNS might play a significant role in the development and immune cell infiltration of ccRCC and serve as a valuable clinical prognostic biomarker.