bluuebunny/crossref_metadata_2025 huggingface dataset:
Research on the Regional Environmental Impact and Risk Assessment Affected by Mineral Resource Development: A Case Study of the Taojia River Watershed in Hunan
Authors: Cao Hongying , Wang Ziwei , Liao Xiaoyong , Li You , Zhu Yongbing
Published: June 2022

The mining and production of mineral resources can directly lead to soil and water pollution, posing a serious threat to human health. In this study, the Taojia River basin, a tributary of the Xiangjiang River, was selected as the study area. Based on the concentrations of heavy metals (As, Cd, Pb, and Zn) in 653 soil/substrate samples collected from 342 points in the study area in 2013 and 2021, the changes in soil heavy metal concentrations in the region were systematically analyzed to assess their environmental risks and impacts on regional environmental quality. The results showed that from 2013 to 2021, the As, Pb, and Zn pollution in regional soil, tailing sand, and surface water was reduced, while the Cd pollution increased. The average soil As, Pb, and Zn concentrations decreased from 3,750, 2,340, and 1,180 mg/kg to 457, 373, and 387mg/kg, respectively, while the Cd concentration increased from 0.11to 1.91 mg/kg; additionally, the overall distribution trend of heavy metal concentrations was high in the south, low in the north, and gradually decreased from upstream to downstream. The single evaluation index of heavy metal pollution risk showed that the percentages of medium to heavy pollution points in the soil As, Pb, and Zn were 84, 57, and 28%, respectively, in 2013, and this index decreased to 38, 37, and 25%, respectively, in 2021. The regional environmental quality was closely related to the intensity of mineral resource development. From 2000 to 2010, frequent mining development activities led to an increase in the area of construction land and a continuous decrease in the area of arable land, grassland, and vegetation cover in the region. During 2010–2020, the area of construction land decreased, and the vegetation coverage increased. The comprehensive evaluation index showed that the overall soil pollution risk in the watershed decreased, and the proportion of heavily polluted points decreased from 80 to 65%. It was shown by principal component analysis and factor analysis that mining development activities were the largest source of heavy metal pollution, in addition to mixed sources of tailings, solid waste, agriculture, and traffic emission sources. The results provide a scientific basis for the management and risk control of heavy metal pollution in the Taojia River basin.
A New Jurassic Kempynine Species With Notes on Historical Distributions of Kempyninae Integrated Both Fossil and Extant Taxa (Neuroptera: Osmylidae)
Authors: Ma Yiming , Shih Chungkun , Ren Dong , Wang Yongjie
Published: June 2022

The extant kempynines, a strict “southern group,” are confined to South America and Australia, while their most fossil relatives are abundantly recorded in the Northern Hemisphere. This pattern of the biogeographic distribution implies the complicated evolutionary scenario of Kempyninae. Herein, a new northern species Arbusella platyptera Ma et Wang, sp. nov. is described from the Jiulongshan Formation in Daohugou, Inner Mongolia, China. Additionally, a key to the extinct species and extant genera of Kempyninae is provided. Integrating all extant and most fossil genera of Kempyninae, we conducted phylogenetic analyses to explore the inner relationships of Kempyninae for the first time. The results corroborate the monophyly of Kempyninae and retrieve three clades within the subfamily, namely, two northern fossil genera (†Arbusellla + †Jurakempynus), constituting the basalmost clade and three other northern fossil genera (†Sauktangida + †Mirokempynus + †Ponomarenkius), forming a monophylic clade, which is sister to the third clade that includes all extant southern genera and the southern fossil genus of †Euporismites. Also, the extant kempynines were hypothesized to evolve independently from their northern Mesozoic relatives. The Dispersal-vicariance (DIVA) analysis revealed a northern and prepangean origin of Kempyninae, and the northern ancestral kempynines first colonized the Southern Hemisphere before the split of Pangea. Our results expose a more complicated evolutionary scenario of the insects with a long evolutionary history and provide new insights into the formation of distribution patterns in current relictual insects.
Case Report: Balanced Reciprocal Translocation t (17; 22) (p11.2; q11.2) and 10q23.31 Microduplication in an Infertile Male Patient Suffering From Teratozoospermia
Authors: Huang Shan , Wu Huiling , Qi Yunwei , Wei Liqiang , Lv Xiaodan , He Yu
Published: June 2022

Two chromosomal abnormalities are described in an infertile man suffering from teratozoospermia: balanced reciprocal translocation t (17; 22) (p11.2; q11.2) and a microduplication in the region 10q23.31. Twenty genes located on the breakpoints of translocation (e.g., ALKBH5, TOP3A, SPECC1L, and CDC45) are selected due to their high expression in testicular tissues and might be influenced by chromosome translocation. Four genes located on the breakpoints of microduplication including FLJ37201, KIF20B, LINC00865, and PANK1 result in an increased dosage of genes, representing an imbalance in the genome. These genes have been reported to be associated with developmental disorders/retardation and might be risk factors affecting spermatogenesis. Bioinformatics analysis is carried out on these key genes, intending to find the pathogenic process of reproduction in the context of the translocation and microduplication encountered in the male patient. The combination of the two chromosomal abnormalities carries additional risks for gametogenesis and genomic instability and is apparently harmful to male fertility. Overall, our findings could contribute to the knowledge of male infertility caused by genetic factors.
N6-Methyladenosine-Related Long Non-Coding RNAs Are Identified as a Potential Prognostic Biomarker for Lung Squamous Cell Carcinoma and Validated by Real-Time PCR
Authors: Zhang Wei , Zhang Qian , Xie Zhefan , Che Li , Xia Tingting , Cai Xingdong , Liu Shengming
Published: June 2022

Currently, the precise mechanism by which N6-methyladenosine (m6A) modification of long non-coding RNAs (lncRNAs) promotes the occurrence and development of lung squamous cell carcinoma (LUSC) and influences tumor microenvironment (TME) remains unclear. Therefore, we studied the prognostic value of m6A-related lncRNAs and their relationship with TME in 495 LUSC samples from The Cancer Genome Atlas (TCGA) database. Pearson’s correlation and univariate Cox regression analysis identified 6 m6A-related lncRNAs with prognostic values for LUSC patients. LUSC patients were divided into two subgroups (clusters 1 and 2) using principal component analysis. The expression of PD-L1 was lower in tumor tissues and cluster 2 of LUSC patients. Cluster 2 of LUSC patients had a high immune score, stromal score, and unique immune cell infiltration. The focal adhesion kinase (FAK) pathway and cytokine receptor pathways are enriched in cluster 1. The m6A-related lncRNA prognostic markers (m6A-LPMs) were established using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. The risk score was calculated by 4 m6A-LPMs and associated with OS, TME, clinicopathological characteristics of LUSC patients. After adjusting for age, gender, and stage, the risk score was also an independent prognostic factor for LUSC patients. Real-time PCR results showed that the expression of 4 m6A-LPMs was consistent with our prediction results. Our study found that 4 m6A-LPMs (AC138035.1, AC243919.2, HORMAD2-AS1, and AL122125.1) are closely associated with LUSC prognosis, in future, they may as novel diagnostic biomarkers for LUSC and provide new immunotherapy targets for LUSC patients.
A General-Purpose Machine Learning R Library for Sparse Kernels Methods With an Application for Genome-Based Prediction
Authors: Montesinos López Osval Antonio , Mosqueda González Brandon Alejandro , Palafox González Abel , Montesinos López Abelardo , Crossa José
Published: June 2022

The adoption of machine learning frameworks in areas beyond computer science have been facilitated by the development of user-friendly software tools that do not require an advanced understanding of computer programming. In this paper, we present a new package (sparse kernel methods, SKM) software developed in R language for implementing six (generalized boosted machines, generalized linear models, support vector machines, random forest, Bayesian regression models and deep neural networks) of the most popular supervised machine learning algorithms with the optional use of sparse kernels. The SKM focuses on user simplicity, as it does not try to include all the available machine learning algorithms, but rather the most important aspects of these six algorithms in an easy-to-understand format. Another relevant contribution of this package is a function for the computation of seven different kernels. These are Linear, Polynomial, Sigmoid, Gaussian, Exponential, Arc-Cosine 1 and Arc-Cosine L (with L = 2, 3, … ) and their sparse versions, which allow users to create kernel machines without modifying the statistical machine learning algorithm. It is important to point out that the main contribution of our package resides in the functionality for the computation of the sparse version of seven basic kernels, which is indispensable for reducing computational resources to implement kernel machine learning methods without a significant loss in prediction performance. Performance of the SKM is evaluated in a genome-based prediction framework using both a maize and wheat data set. As such, the use of this package is not restricted to genome prediction problems, and can be used in many different applications.
Case Report: Optic Atrophy and Nephropathy With m.13513G>A/MT-ND5 mtDNA Pathogenic Variant
Authors: Barone Valentina , La Morgia Chiara , Caporali Leonardo , Fiorini Claudio , Carbonelli Michele , Gramegna Laura Ludovica , Bartiromo Fiorina , Tonon Caterina , Morandi Luca , Liguori Rocco , Petrini Aurelia , Brugnano Rachele , Del Sordo Rachele , Covarelli Carla , Morroni Manrico , Lodi Raffaele , Carelli Valerio
Published: June 2022

Isolated complex I deficiency represents the most common mitochondrial respiratory chain defect involved in mitochondrial disorders. Among these, the mitochondrial DNA (mtDNA) m.13513G>A pathogenic variant in the NADH dehydrogenase 5 subunit gene (MT-ND5) has been associated with heterogenous manifestations, including phenotypic overlaps of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, Leigh syndrome, and Leber’s hereditary optic neuropathy (LHON). Interestingly, this specific mutation has been recently described in patients with adult-onset nephropathy. We, here, report the unique combination of LHON, nephropathy, sensorineural deafness, and subcortical and cerebellar atrophy in association with the m.13513G>A variant.
Representation Learning: Recommendation With Knowledge Graph via Triple-Autoencoder
Authors: Geng Yishuai , Xiao Xiao , Sun Xiaobing , Zhu Yi
Published: June 2022

The last decades have witnessed a vast amount of interest and research in feature representation learning from multiple disciplines, such as biology and bioinformatics. Among all the real-world application scenarios, feature extraction from knowledge graph (KG) for personalized recommendation has achieved substantial performance for addressing the problem of information overload. However, the rating matrix of recommendations is usually sparse, which may result in significant performance degradation. The crucial problem is how to extract and extend features from additional side information. To address these issues, we propose a novel feature representation learning method for the recommendation in this paper that extends item features with knowledge graph via triple-autoencoder. More specifically, the comment information between users and items is first encoded as sentiment classification. These features are then applied as the input to the autoencoder for generating the auxiliary information of items. Second, the item-based rating, the side information, and the generated comment representations are incorporated into the semi-autoencoder for reconstructed output. The low-dimensional representations of this extended information are learned with the semi-autoencoder. Finally, the reconstructed output generated by the semi-autoencoder is input into a third autoencoder. A serial connection between the semi-autoencoder and the autoencoder is designed here to learn more abstract and higher-level feature representations for personalized recommendation. Extensive experiments conducted on several real-world datasets validate the effectiveness of the proposed method compared to several state-of-the-art models.
Honey Bee Genetic Stock Determines Deformed Wing Virus Symptom Severity but not Viral Load or Dissemination Following Pupal Exposure
Authors: Penn Hannah J. , Simone-Finstrom Michael D. , Chen Yanping , Healy Kristen B.
Published: June 2022

Honey bees exposed to Varroa mites incur substantial physical damage in addition to potential exposure to vectored viruses such as Deformed wing virus (DWV) that exists as three master variants (DWV-A, DWV-B, and DWV-C) and recombinants. Although mite-resistant bees have been primarily bred to mitigate the impacts of Varroa mites, mite resistance may be associated with increased tolerance or resistance to the vectored viruses. The goal of our study is to determine if five honey bee stocks (Carniolan, Italian, Pol-Line, Russian, and Saskatraz) differ in their resistance or tolerance to DWV based on prior breeding for mite resistance. We injected white-eyed pupae with a sublethal dose (105) of DWV or exposed them to mites and then evaluated DWV levels and dissemination and morphological symptoms upon adult emergence. While we found no evidence of DWV resistance across stocks (i.e., similar rates of viral replication and dissemination), we observed that some stocks exhibited reduced symptom severity suggestive of differential tolerance. However, DWV tolerance was not consistent across mite-resistant stocks as Russian bees were most tolerant, while Pol-Line exhibited the most severe symptoms. DWV variants A and B exhibited differential dissemination patterns that interacted significantly with the treatment group but not bee stock. Furthermore, elevated DWV-B levels reduced adult emergence time, while both DWV variants were associated with symptom likelihood and severity. These data indicate that the genetic differences underlying bee resistance to Varroa mites are not necessarily correlated with DWV tolerance and may interact differentially with DWV variants, highlighting the need for further work on mechanisms of tolerance and bee stock–specific physiological interactions with pathogen variants.
Client Experiences in a Mobile-Phone Counseling Intervention for Enhancing Access to Prevention of Mother To-Child Transmission (PMTCT) Services in Kenya
Authors: Okal Jerry Okoth , Sarna Avina , Lango Daniel , Matheka James , Owuor Danmark , Kinywa Eunice Auma , Kalibala Sam
Published: June 2022

Background

The prevention of mother-to-child transmission (PMTCT) is considered one of the most successful HIV prevention strategies in detecting and reducing HIV acquisition in utero or at birth. It is anticipated that with the increasing growth of digital technologies mobile phones can be utilized to enhance PMTCT services by improving provider-client interactions, expanding access to counseling services, and assisting in counteracting social and structural barriers to uptake of PMTCT services. Understanding the subjective experiences of women accessing PMTCT services in different settings has the potential to inform the development and promotion of such methods. This paper explores the perspectives of HIV-positive pregnant women attending maternal and neonatal clinic services in Kisumu, Kenya.

Methods

Data are reported from in-depth interviews with women, following a longitudinal study investigating the impact of a structured, counselor-delivered, mobile phone counseling intervention to promote retention in care and adherence to ARV prophylaxis/treatment, for HIV-positive pregnant women. Thematic content analysis was conducted.

Results

Discussions indicated that mobile-phone counseling provided useful health-related information, enhanced agency, and assisted mothers access critical PMTCT services across the cascade of care. Similarly, mobile-phone counseling offered personalized one-to-one contact with trained health providers including facilitating discussion of personal issues that likely affect access to services. Findings also identified barriers to the uptake of services, including a lack of partner support, poor health, poverty, facility-related factors, and provider attitudes.

Discussion

Overall, findings show that mobile-phone counseling is feasible, acceptable, and can enhance access to PMTCT services by overcoming some of the individual and facility-level barriers. Although mobile-phone counseling has not been routinized in most health facilities, future work is needed to assess whether mobile-phone counseling can be scaled-up to aid in the effective use of HIV and PMTCT services, as well as improving other related outcomes for mother and child dyad.
B Cells Are Required to Generate Optimal Anti-Melanoma Immunity in Response to Checkpoint Blockade
Authors: Singh Shubhra , Roszik Jason , Saini Neeraj , Singh Vipul Kumar , Bavisi Karishma , Wang Zhiqiang , Vien Long T. , Yang Zixi , Kundu Suprateek , Davis Richard E. , Bover Laura , Diab Adi , Neelapu Sattva S. , Overwijk Willem W. , Rai Kunal , Singh Manisha
Published: June 2022

Immunotherapies such as checkpoint blockade therapies are known to enhance anti-melanoma CD8+ T cell immunity, but only a fraction of patients treated with these therapies achieve durable immune response and disease control. It may be that CD8+ T cells need help from other immune cells to generate effective and long-lasting anti-tumor immunity or that CD8+ T cells alone are insufficient for complete tumor regression and cure. Melanoma contains significant numbers of B cells; however, the role of B cells in anti-melanoma immunity is controversial. In this study, B16 melanoma mouse models were used to determine the role of B cells in anti-melanoma immunity. C57BL/6 mice, B cell knockout (KO) C57BL/6 mice, anti-CD19, and anti-CXCL13 antibody-treated C57BL/6 mice were used to determine treatment efficacy and generation of tumor-specific CD8+ T cells in response to PD-L1 blockade alone or combination with TLR-7/8 activation. Whole transcriptome analysis was performed on the tumors from B cell depleted and WT mice, untreated or treated with anti-PD-L1. Both CD40-positive and CD40-negative B cells were isolated from tumors of TLR-7/8 agonist-treated wild-type mice and adoptively transferred into tumor-bearing B cell KO mice, which were treated with anti-PD-L1 and TLR-7/8 agonist. Therapeutic efficacy was determined in the presence of activated or inactivated B cells. Microarray analysis was performed on TLR-7/8-treated tumors to look for the B cell signatures. We found B cells were required to enhance the therapeutic efficacy of monotherapy with anti-PD-L1 antibody and combination therapy with anti-PD-L1 antibody plus TLR-7/8 agonist. However, B cells were not essential for anti-CTLA-4 antibody activity. Interestingly, CD40-positive but not CD40-negative B cells contributed to anti-melanoma immunity. In addition, melanoma patients’ TCGA data showed that the presence of B cell chemokine CXCL13 and B cells together with CD8+ T cells in tumors were strongly associated with improved overall survival. Our transcriptome data suggest that the absence of B cells enhances immune checkpoints expression in the tumors microenvironment. These results revealed the importance of B cells in the generation of effective anti-melanoma immunity in response to PD-1-PD-L1 blockade immunotherapy. Our findings may facilitate the design of more effective anti-melanoma immunotherapy.
Granulocyte-Macrophage Colony-Stimulating Factor Modulates Myeloid-Derived Suppressor Cells and Treg Activity in Decompensated Cirrhotic Patients With Sepsis
Authors: Sehgal Rashi , Maiwall Rakhi , Rajan Vijayaraghavan , Islam Mojahidul , Baweja Sukriti , Kaur Navkiran , Kumar Guresh , Ramakrishna Gayatri , Sarin Shiv K. , Trehanpati Nirupma
Published: June 2022

Background

Decompensated cirrhosis patients are more prone to bacterial infections. Myeloid-derived suppressor cells (MDSCs) expand in sepsis patients and disrupt immune cell functions. Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy helps in restoring immune cell functions and resolving infections. Its role in MDSC modulation in cirrhosis with sepsis is not well understood.

Methods

A total of 164 decompensated cirrhotic—62 without (w/o), 72 with sepsis, and 30 with sepsis treated with GM-CSF—and 15 healthy were studied. High-dimensional flow cytometry was performed to analyze MDSCs, monocytes, neutrophils, CD4 T cells, and Tregs at admission and on days 3 and day 7. Ex vivo co-cultured MDSCs with T cells were assessed for proliferation and apoptosis of T cells and differentiation to Tregs. Plasma factors and mRNA levels were analyzed by cytokine-bead assay and qRT-PCR.

Results

Frequencies of MDSCs and Tregs were significantly increased (p = 0.011 and p = 0.02) with decreased CD4 T cells (p = 0.01) in sepsis than w/o sepsis and healthy controls (HCs) (p = 0.000, p = 0.07, and p = 0.01) at day 0 and day 7. In sepsis patients, MDSCs had increased IL-10, Arg1, and iNOS mRNA levels (p = 0.016, p = 0.043, and p = 0.045). Ex vivo co-cultured MDSCs with T cells drove T-cell apoptosis (p = 0.03, p = 0.03) with decreased T-cell proliferation and enhanced FOXP3+ expression (p = 0.044 and p = 0.043) in sepsis compared to w/o sepsis at day 0. Moreover, blocking the MDSCs with inhibitors suppressed FOXP3 expression. GM-CSF treatment in sepsis patients significantly decreased MDSCs and FOXP3+ Tregs but increased CD4 T-cell functionality and improved survival.

Conclusion

MDSCs have an immunosuppressive function by expanding FOXP3+ Tregs and inhibiting CD4+ T-cell proliferation in sepsis. GM-CSF treatment suppressed MDSCs, improved T-cell functionality, and reduced Tregs in circulation.
Bioenergetic Failure Drives Functional Exhaustion of Monocytes in Acute-on-Chronic Liver Failure
Authors: Maheshwari Deepanshu , Kumar Dhananjay , Jagdish Rakesh Kumar , Nautiyal Nidhi , Hidam Ashinikumar , Kumari Rekha , Sehgal Rashi , Trehanpati Nirupama , Baweja Sukriti , Kumar Guresh , Sinha Swati , Bajpai Meenu , Pamecha Viniyendra , Bihari Chhagan , Maiwall Rakhi , Sarin Shiv Kumar , Kumar Anupam
Published: June 2022

Objective

The monocyte–macrophage system is central to the host’s innate immune defense and in resolving injury. It is reported to be dysfunctional in acute-on-chronic liver failure (ACLF). The disease-associated alterations in ACLF monocytes are not fully understood. We investigated the mechanism of monocytes’ functional exhaustion and the role of umbilical cord mesenchymal stem cells (ucMSCs) in re-energizing monocytes in ACLF.

Design

Monocytes were isolated from the peripheral blood of ACLF patients (n = 34) and matched healthy controls (n = 7) and patients with compensated cirrhosis (n = 7); phagocytic function, oxidative burst, and bioenergetics were analyzed. In the ACLF mouse model, ucMSCs were infused intravenously, and animals were sacrificed at 24 h and day 11 to assess changes in monocyte function, liver injury, and regeneration.

Results

Patients with ACLF (alcohol 64%) compared with healthy controls and those with compensated cirrhosis had an increased number of peripheral blood monocytes (p < 0.0001) which displayed significant defects in phagocytic (p < 0.0001) and oxidative burst capacity (p < 0.0001). ACLF patients also showed a significant increase in the number of liver macrophages as compared with healthy controls (p < 0.001). Bioenergetic analysis showed markedly reduced oxidative phosphorylation (p < 0.0001) and glycolysis (p < 0.001) in ACLF monocytes. Patients with monocytes having maximum mitochondrial respiration of <37.9 pmol/min [AUC = 0.822, hazard ratio (HR) = 4.5] and baseline glycolysis of ≤42.7 mpH/min (AUC = 0.901, HR = 9.1) showed increased 28-day mortality (p < 0.001). Co-culturing ACLF monocytes with ucMSC showed improved mitochondrial respiration (p < 0.01) and phagocytosis (p < 0.0001). Furthermore, ucMSC therapy increased monocyte energy (p < 0.01) and phagocytosis (p < 0.001), reduced hepatic injury, and enhanced hepatocyte regeneration in ACLF animals.

Conclusion

Bioenergetic failure drives the functional exhaustion of monocytes in ACLF. ucMSCs resuscitate monocyte energy and prevent its exhaustion. Restoring monocyte function can ameliorate hepatic injury and promote liver regeneration in the animal model of ACLF.
Immunoinformatic Design of a Multivalent Peptide Vaccine Against Mucormycosis: Targeting FTR1 Protein of Major Causative Fungi
Authors: Araf Yusha , Moin Abu Tayab , Timofeev Vladimir I. , Faruqui Nairita Ahsan , Saiara Syeda Afra , Ahmed Nafisa , Parvez Md. Sorwer Alam , Rahaman Tanjim Ishraq , Sarkar Bishajit , Ullah Md. Asad , Hosen Mohammad Jakir , Zheng Chunfu
Published: June 2022

Mucormycosis is a potentially fatal illness that arises in immunocompromised people due to diabetic ketoacidosis, neutropenia, organ transplantation, and elevated serum levels of accessible iron. The sudden spread of mucormycosis in COVID-19 patients engendered massive concern worldwide. Comorbidities including diabetes, cancer, steroid-based medications, long-term ventilation, and increased ferritin serum concentration in COVID-19 patients trigger favorable fungi growth that in turn effectuate mucormycosis. The necessity of FTR1 gene-encoded ferrous permease for host iron acquisition by fungi has been found in different studies recently. Thus, targeting the transit component could be a potential solution. Unfortunately, no appropriate antifungal vaccine has been constructed as of yet. To date, mucormycosis has been treated with antiviral therapy and surgical treatment only. Thus, in this study, the FTR1 protein has been targeted to design a convenient and novel epitope-based vaccine with the help of immunoinformatics against four different virulent fungal species. Furthermore, the vaccine was constructed using 8 CTL, 2 HTL, and 1 LBL epitopes that were found to be highly antigenic, non-allergenic, non-toxic, and fully conserved among the fungi under consideration. The vaccine has very reassuring stability due to its high pI value of 9.97, conclusive of a basic range. The vaccine was then subjected to molecular docking, molecular dynamics, and immune simulation studies to confirm the biological environment’s safety, efficacy, and stability. The vaccine constructs were found to be safe in addition to being effective. Finally, we used in-silico cloning to develop an effective strategy for vaccine mass production. The designed vaccine will be a potential therapeutic not only to control mucormycosis in COVID-19 patients but also be effective in general mucormycosis events. However, further in vitro, and in vivo testing is needed to confirm the vaccine’s safety and efficacy in controlling fungal infections. If successful, this vaccine could provide a low-cost and effective method of preventing the spread of mucormycosis worldwide.
Adiponectin Ameliorates GMH-Induced Brain Injury by Regulating Microglia M1/M2 Polarization Via AdipoR1/APPL1/AMPK/PPARγ Signaling Pathway in Neonatal Rats
Authors: Xu Ningbo , Li Xifeng , Weng Jun , Wei Chunhua , He Zhenyan , Doycheva Desislava Met , Lenahan Cameron , Tang Wenhui , Zhou Jian , Liu Yanchao , Xu Qiang , Liu Yahong , He Xuying , Tang Jiping , Zhang John H. , Duan Chuanzhi
Published: June 2022

Adiponectin (APN), a fat-derived plasma hormone, is a classic anti-inflammatory agent. Multiple studies have demonstrated the beneficial role of APN in acute brain injury, but the effect of APN in germinal matrix hemorrhage (GMH) is unclear, and the underlying molecular mechanisms remain largely undefined. In the current study, we used a GMH rat model with rh-APN treatment, and we observed that APN demonstrated a protective effect on neurological function and an inhibitory effect on neuroinflammation after GMH. To further explore the underlying mechanisms of these effects, we found that the expression of Adiponectin receptor 1 (AdipoR1) primarily colocalized with microglia and neurons in the brain. Moreover, AdiopR1, but not AdipoR2, was largely increased in GMH rats. Meanwhile, further investigation showed that APN treatment promoted AdipoR1/APPL1-mediated AMPK phosphorylation, further increased peroxisome proliferator-activated receptor gamma (PPARγ) expression, and induced microglial M2 polarization to reduce the neuroinflammation and enhance hematoma resolution in GMH rats. Importantly, either knockdown of AdipoR1, APPL1, or LKB1, or specific inhibition of AMPK/PPARγ signaling in microglia abrogated the protective effect of APN after GMH in rats. In all, we propose that APN works as a potential therapeutic agent to ameliorate the inflammatory response following GMH by enhancing the M2 polarization of microglia via AdipoR1/APPL1/AMPK/PPARγ signaling pathway, ultimately attenuating inflammatory brain injury induced by hemorrhage.
Impact of Diminished Expression of circRNA on Multiple Sclerosis Pathomechanisms
Authors: Mycko Marcin P. , Zurawska Anna E. , Selmaj Igor , Selmaj Krzysztof W.
Published: June 2022

Circular RNA (circRNA) molecules represent a novel and unique class of endogenous non-coding RNAs controlling the expression and function of microRNA (miRNA) and post-transcriptional regulation. Recent studies implicated circRNA in the pathomechanism of multiple sclerosis (MS). Hybridization microarray was used to define the circRNA profile in the peripheral blood mononuclear cells (PBMCs) from 20 untreated patients with relapsing–remitting MS (RRMS: 10 in relapse, 10 in remission) and 10 healthy controls (HCs). We analyzed close to 14,000 individual circRNAs per sample. The discovery set data were validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) with an independent cohort of 45 RRMS patients (18 in relapse, 27 in remission) and 27 HCs. Microarray analysis revealed 246 circRNAs differentially downregulated (P < 0.05) in RRMS patients versus HCs. We validated two circRNAs of the three showing the lowest levels of differential expression in the RRMS remission group versus the HC group: hsa_circRNA_101145 and hsa_circRNA_001896. Their expression was significantly decreased during remission in RRMS (P = 0.0000332, FC = 0.385 and P = 0.0455, FC = 0.591, respectively) and in patients showing a lower level of disability (hsa_circRNA_101145, P = 0.0695; hsa_circRNA_001896, P = 0.0008). Bioinformatic analysis revealed 10 miRNAs interacting with these circRNAs in a complementary manner and led to the discovery of three protein-coding mRNAs downregulated in patients with RRMS during remission. These transcripts have been previously implicated in oxidative stress, blood–brain barrier permeability, microglia function, and extracellular matrix molecules altering the microenvironment and inhibiting oligodendrocyte progenitor cells. circRNAs displayed a distinct profile in PBMCs from patients with RRMS, and our results may implicate circRNAs with low expression in important mechanistic pathways of RRMS.
Single-Cell RNA and ATAC Sequencing Reveal Hemodialysis-Related Immune Dysregulation of Circulating Immune Cell Subpopulations
Authors: Wu Hongwei , Dong Jingjing , Yu Haiyan , Wang Kang , Dai Weier , Zhang Xinzhou , Hu Nan , Yin Lianghong , Tang Donge , Liu Fanna , Dai Yong
Published: June 2022

Background

An increased risk of infection, malignancy, and cardiovascular diseases in maintenance hemodialysis patients is associated with hemodialysis-related immunity disturbances. Although defects in T-lymphocyte-dependent immune responses and preactivation of antigen-presenting cells have been documented in hemodialysis patients, the effects of long-term hemodialysis on the transcriptional program and chromosomal accessibility of circulating immune cell subpopulations remain poorly defined.

Methods

We integrated single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to characterize the transcriptome profiles of peripheral mononuclear cells (PBMCs) from healthy controls and maintenance hemodialysis patients. Validation of differentially expressed genes in CD4+ T cells and monocytes were performed by magnetic bead separation and quantitative real-time PCR.

Results

We identified 16 and 15 PBMC subgroups in scRNA-seq and scATAC-seq datasets, respectively. Hemodialysis significantly suppressed the expression levels of T cell receptor (TCR) genes in CD4+ T cell subsets (e.g., TRAV4, CD45, CD3G, CD3D, CD3E) and major histocompatibility complex II (MHC-II) pathway-related genes in monocytes (HLA-DRB1, HLA-DQA2, HLA-DQA1, HLA-DPB1). Downstream pathways of TCR signaling, including PI3K-Akt-mTOR, MAPK, TNF, and NF-κB pathways, were also inhibited in CD4+ T cell subpopulations during the hemodialysis procedure. Hemodialysis altered cellular communication patterns between PBMC subgroups, particularly TGF-TGFBR, HVEM-BTLA, and IL16-CD4 signalings between CD4+ T cells and monocytes. Additionally, we found that hemodialysis inhibited the expression of AP-1 family transcription factors (JUN, JUND, FOS, FOSB) by interfering with the chromatin accessibility profile.

Conclusions

Our study provides a valuable framework for future investigations of hemodialysis-related immune dysregulation and identifies potential therapeutic targets for reconstituting the circulating immune system in maintenance hemodialysis patients.
A Global Regulatory Network for Dysregulated Gene Expression and Abnormal Metabolic Signaling in Immune Cells in the Microenvironment of Graves’ Disease and Hashimoto’s Thyroiditis
Authors: Zheng Haitao , Xu Jie , Chu Yongli , Jiang Wenzhou , Yao Wenjie , Mo Shaowen , Song Xicheng , Zhou Jin
Published: June 2022

Background

Although the pathogenetic mechanisms of Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) have been elucidated, the molecular mechanisms by which the abnormal immune function of cellular subpopulations trigger an autoimmune attack on thyroid tissue largely remains unexplained.

Methods

The study included 2 HT patients, 2 GD patients, and 1 control donor. The thyroid samples were extracted for single-cell RNA sequencing, whole transcriptome, full-length transcriptome (Oxford Nanopore Technologies), and metabolome sequencing. Identification of immune cells with dysregulated gene expression and abnormal metabolic signaling was performed in the microenvironment, both at the bulk and single-cell levels. Based on functional enrichment analysis, the biological processes and pathways involved in abnormal immune cells were further explored. Finally, according to cell communication analysis, the global regulatory network of immune cells was constructed.

Results

CD4+ T cells, CD8+ T cells, and macrophages were abnormally increased in patients with HT and GD. The differentially expressed genes of these cells were significantly involved in signaling pathways, including Th1 and Th2 cell differentiation, Th17 cell differentiation, cytokine–cytokine receptor interaction, and NF-kappa B signaling pathway. Moreover, in HT, CD4+ T cells interact with macrophages via the IL16-CCR5/FGF10-FGFR1/CXCL13-CXCR3 axis, and macrophages interact with CD8+ T cells via the CD70-CD27 axis, thereby activating the T-cell receptor signaling pathway and NF-kappa B signaling pathway. In GD, CD4+ T cells interact with macrophages via the CXCR3-CXCL10/PKM-CD44/MHCII-NFKBIE axis, and macrophages interact with CD8+ T cells via the IFNG-IFNGR1/CCR7-CCL21 axis, thereby activating T-cell receptor signaling pathway, Th1 and Th2 cell differentiation, and chemokine signaling pathway.

Conclusion

In HT and GD, immune dysregulated cells interact and activate relevant immune pathways and further aggravate the immune response. This may trigger the immune cells to target the thyroid tissue and influence the development of the disease.
Relationship Between a Vitamin D Genetic Risk Score and Autoantibodies Among First-Degree Relatives of Probands With Rheumatoid Arthritis and Systemic Lupus Erythematosus
Authors: Vanderlinden Lauren A. , Bemis Elizabeth A. , Seifert Jennifer , Guthridge Joel M. , Young Kendra A. , Demoruelle Mary Kristen , Feser Marie , DeJager Wade , Macwana Susan , Mikuls Ted R. , O’Dell James R. , Weisman Michael H. , Buckner Jane , Keating Richard M. , Gaffney Patrick M. , Kelly Jennifer A. , Langefeld Carl D. , Deane Kevin D. , James Judith A. , Holers Vernon Michael , Norris Jill M.
Published: June 2022

Objective

Higher 25-hydroxyvitamin D (25(OH)D) levels have been associated with reduced risk for autoimmune diseases and are influenced by vitamin D metabolism genes. We estimated genetically-determined vitamin D levels by calculating a genetic risk score (GRS) and investigated whether the vitamin D GRS was associated with the presence of autoantibodies related to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in those at increased risk for developing RA and SLE, respectively.

Methods

In this cross-sectional study, we selected autoantibody positive (aAb+) and autoantibody negative (aAb-) individuals from the Studies of the Etiologies of Rheumatoid Arthritis (SERA), a cohort study of first-degree relatives (FDRs) of individuals with RA (189 RA aAb+, 181 RA aAb-), and the Lupus Family Registry and Repository (LFRR), a cohort study of FDRs of individuals with SLE (157 SLE aAb+, 185 SLE aAb-). Five SNPs known to be associated with serum 25(OH)D levels were analyzed individually as well as in a GRS: rs4588 (GC), rs12785878 (NADSYN1), rs10741657 (CYP2R1), rs6538691 (AMDHD1), and rs8018720 (SEC23A).

Results

Both cohorts had similar demographic characteristics, with significantly older and a higher proportion of males in the aAb+ FDRs. The vitamin D GRS was inversely associated with RA aAb+ (OR = 0.85, 95% CI = 0.74-0.99), suggesting a possible protective factor for RA aAb positivity in FDRs of RA probands. The vitamin D GRS was not associated with SLE aAb+ in the LFRR (OR = 1.09, 95% CI = 0.94-1.27). The SEC23A SNP was associated with RA aAb+ in SERA (OR = 0.65, 95% CI = 0.43-0.99); this SNP was not associated with SLE aAb+ in LFRR (OR = 1.41, 95% CI = 0.90 – 2.19).

Conclusion

Genes associated with vitamin D levels may play a protective role in the development of RA aAbs in FDRs of RA probands, perhaps through affecting lifelong vitamin D status. The GRS and the SEC23A SNP may be of interest for future investigation in pre-clinical RA. In contrast, these results do not support a similar association in SLE FDRs, suggesting other mechanisms involved in the relationship between vitamin D and SLE aAbs not assessed in this study.
Case Report: Comorbid Hyper-IgD Syndrome and Hidradenitis Suppurativa – A New Syndromic Form of HS? A Report of Two Cases
Authors: Guillem Philippe , Mintoff Dillon , Kabbani Mariam , Cogan Elie , Vlaeminck-Guillem Virginie , Duquesne Agnes , Benhadou Farida
Published: June 2022

Hidradenitis Suppurativa (HS) is a chronic suppurative disease of the pilosebaceous unit. The current model of HS pathophysiology describes the condition as the product of hyperkeratinisation and inflammation at the hair follicular unit. Environmental factors (such as smoking and obesity), gender, genetic predisposition, and skin dysbiosis are considered the main pathogenic drivers of the disease. Autoinflammatory syndromes associated with HS are rare but may help to highlight the potential roles of autoinflammation and dysregulated innate immune system in HS. Therefore, it is of major relevance to increase the awareness about these diseases in order to improve the understanding of the disease and to optimize the management of the patients. Herein, we report for the first time, to our knowledge, two clinical cases of Hyper-IgD syndrome-associated HS. Hyper-IgD is an autoinflammatory syndrome caused by a mevalonate kinase deficiency (MKD), a key kinase in the sterol and isoprenoid production pathway. We describe the potentially shared pathophysiological mechanisms underpinning comorbid MKD-HS and propose therapeutic options for the management of these patients.
Global Trends in Research of Lipid Metabolism in T lymphocytes From 1985 to 2022: A Bibliometric Analysis
Authors: Chen Peng , Zhong Cheng , Jin Shengxi , Zhang Yiyin , Li Yirun , Xia Qiming , Cheng Jiaxi , Fan Xiaoxiao , Lin Hui
Published: June 2022

Lipids are involved in both energy metabolism and signaling transduction. Abnormal lipid metabolism in T cells is associated with the differentiation, longevity and activity of T cells, which has received increasing concern since its firstly reported in 1985. To evaluate the trends of lipid metabolism in T cells and map knowledge structure, we employed bibliometric analysis. A total of 286 related publications obtained from the Web of Science Core Collection published between 1985 and 2022 were analyzed using indicators of publication and citation metrics, countries, institutes, authors, cited references and key words. The present research status, the global trends and the future development directions in lipid metabolism and T cells were visualized and discussed. In summary, this study provides a comprehensive display on the field of lipid metabolism in T cells, which will help researchers explore lipid metabolism in T cells more effectively and intuitively.
Clinical Features, Treatment, and Prognostic Factors in Neuronal Surface Antibody-Mediated Severe Autoimmune Encephalitis
Authors: Wang Baojie , Wang Chunjuan , Feng Jianli , Hao Maolin , Guo Shougang
Published: June 2022

Objective

This study aimed to determine the clinical characteristics and evaluate the efficacy of immunotherapy and the long-term prognosis of severe autoimmune encephalitis (AE) in China.

Methods

Clinical features, laboratory or radiological findings, and treatment outcomes of 60 severe patients with AE from January 1, 2014, to December 31, 2020, were collected. Continuous variables were compared using the t-test and the nonparametric Mann–Whitney U test, as appropriate. Univariate and multivariable logistic regression analyses were performed to assess the correlations between factors, treatment responses, and prognosis of severe AE.

Results

The median age of symptom onset was 35 years. Tumors were identified in 23.3% of patients, and 36/60 (60%) patients responded to first-line immunotherapy. Second-line immunotherapy was implemented in 26/60 (43.3%) patients. A significant clinical benefit was observed in 19/26 (73.1%) patients treated with lower dosage rituximab; seven patients were still refractory and received bortezomib as an add-on therapy. During the last follow-up, 48/60 (80%) patients achieved good outcomes (mRS, 0–2), and 10 died. Seventeen patients experienced relapses. A high CD19+ B-cell count (OR, 1.197; 95% CI [1.043–1.496]; p = 0.041) and a lower neutrophil-to-lymphocyte ratio (NLR; OR, 0.686; 95% CI [0.472–0.884]; p = 0.015) predict the response to first-line treatment and good prognosis, respectively.

Conclusions

Patients with severe AE were in critical condition at baseline but could be salvaged after effective rescue immunotherapy. A lower dosage of rituximab could be an optimal option for severe AE. CD19+ B-cell count and NLR may provide prognostic information for predicting treatment response and outcome of severe AE.
TIGIT as a Promising Therapeutic Target in Autoimmune Diseases
Authors: Yue Chenran , Gao Sheng , Li Shuting , Xing Zhouhang , Qian Hengrong , Hu Ying , Wang Wenqian , Hua Chunyan
Published: June 2022

Co-inhibitory receptors (IRs) are molecules that protect host against autoimmune reactions and maintain peripheral self-tolerance, playing an essential role in maintaining immune homeostasis. In view of the substantial clinical progresses of negative immune checkpoint blockade in cancer treatment, the role of IRs in autoimmune diseases is also obvious. Several advances highlighted the substantial impacts of T cell immunoglobulin and ITIM domain (TIGIT), a novel IR, in autoimmunity. Blockade of TIGIT pathway exacerbates multiple autoimmune diseases, whereas enhancement of TIGIT function has been shown to alleviate autoimmune settings in mice. These data suggested that TIGIT pathway can be manipulated to achieve durable tolerance to treat autoimmune disorders. In this review, we provide an overview of characteristics of TIGIT and its role in autoimmunity. We then discuss recent approaches and future directions to leverage our knowledge of TIGIT as therapeutic target in autoimmune diseases.
From CD16a Biology to Antibody-Dependent Cell-Mediated Cytotoxicity Improvement
Authors: Coënon Loïs , Villalba Martin
Published: June 2022

Antibody-dependent cell-mediated cytotoxicity (ADCC) is a potent cytotoxic mechanism that is mainly mediated in humans by natural killer (NK) cells. ADCC mediates the clinical benefit of several widely used cytolytic monoclonal antibodies (mAbs), and increasing its efficacy would improve cancer immunotherapy. CD16a is a receptor for the Fc portion of IgGs and is responsible to trigger NK cell-mediated ADCC. The knowledge of the mechanism of action of CD16a gave rise to several strategies to improve ADCC, by working on either the mAbs or the NK cell. In this review, we give an overview of CD16a biology and describe the latest strategies employed to improve antibody-dependent NK cell cytotoxicity.
Development of Human ILCs and Impact of Unconventional Cytotoxic Subsets in the Pathophysiology of Inflammatory Diseases and Cancer
Authors: Calvi Michela , Di Vito Clara , Frigo Alessandro , Trabanelli Sara , Jandus Camilla , Mavilio Domenico
Published: June 2022

Innate lymphoid cells (ILCs) were firstly described by different independent laboratories in 2008 as tissue-resident innate lymphocytes mirroring the phenotype and function of T helper cells. ILCs have been subdivided into three distinct subgroups, ILC1, ILC2 and ILC3, according to their cytokine and transcriptional profiles. Subsequently, also Natural Killer (NK) cells, that are considered the innate counterpart of cytotoxic CD8 T cells, were attributed to ILC1 subfamily, while lymphoid tissue inducer (LTi) cells were attributed to ILC3 subgroup. Starting from their discovery, significant advances have been made in our understanding of ILC impact in the maintenance of tissue homeostasis, in the protection against pathogens and in tumor immune-surveillance. However, there is still much to learn about ILC ontogenesis especially in humans. In this regard, NK cell developmental intermediates which have been well studied and characterized prior to the discovery of helper ILCs, have been used to shape a model of ILC ontogenesis. Herein, we will provide an overview of the current knowledge about NK cells and helper ILC ontogenesis in humans. We will also focus on the newly disclosed circulating ILC subsets with killing properties, namely unconventional CD56dimNK cells and cytotoxic helper ILCs, by discussing their possible role in ILC ontogenesis and their contribution in both physiological and pathological conditions.