bluuebunny/crossref_metadata_2025 huggingface dataset:
Aire and Fezf2, two regulators in medullary thymic epithelial cells, control autoimmune diseases by regulating TSAs: Partner or complementer?
Authors: Qi Yanfei , Zhang Rongchao , Lu Yaoping , Zou Xueyang , Yang Wei
Published: August 2022

The expression of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs) is believed to be responsible for the elimination of autoreactive T cells, a critical process in the maintenance of central immune tolerance. The transcription factor autoimmune regulator (Aire) and FEZ family zinc finger 2(Fezf2) play an essential role in driving the expression of TSAs in mTECs, while their deficiency in humans and mice causes a range of autoimmune manifestations, such as type 1 diabetes, Sjögren’s syndrome and rheumatoid arthritis. However, because of their regulatory mechanisms, the expression profile of TSAs and their relationship with special autoimmune diseases are still in dispute. In this review, we compare the roles of Aire and Fezf2 in regulating TSAs, with an emphasis on their molecular mechanisms in autoimmune diseases, which provides the foundation for devising improved diagnostic and therapeutic approaches for patients.
The multifaceted roles of NLRP3-modulating proteins in virus infection
Authors: Harris James , Borg Natalie A.
Published: August 2022

The innate immune response to viruses is critical for the correct establishment of protective adaptive immunity. Amongst the many pathways involved, the NLRP3 [nucleotide-binding oligomerisation domain (NOD)-like receptor protein 3 (NLRP3)] inflammasome has received considerable attention, particularly in the context of immunity and pathogenesis during infection with influenza A (IAV) and SARS-CoV-2, the causative agent of COVID-19. Activation of the NLRP3 inflammasome results in the secretion of the proinflammatory cytokines IL-1β and IL-18, commonly coupled with pyroptotic cell death. While this mechanism is protective and key to host defense, aberrant NLRP3 inflammasome activation causes a hyperinflammatory response and excessive release of cytokines, both locally and systemically. Here, we discuss key molecules in the NLRP3 pathway that have also been shown to have significant roles in innate and adaptive immunity to viruses, including DEAD box helicase X-linked (DDX3X), vimentin and macrophage migration inhibitory factor (MIF). We also discuss the clinical opportunities to suppress NLRP3-mediated inflammation and reduce disease severity.
The role of B cells in COVID-19 infection and vaccination
Authors: Chen Shiru , Guan Fei , Candotti Fabio , Benlagha Kamel , Camara Niels Olsen Saraiva , Herrada Andres A. , James Louisa K. , Lei Jiahui , Miller Heather , Kubo Masato , Ning Qin , Liu Chaohong
Published: August 2022

B cells secrete antibodies and mediate the humoral immune response, making them extremely important in protective immunity against SARS-CoV-2, which caused the coronavirus disease 2019 (COVID-19) pandemic. In this review, we summarize the positive function and pathological response of B cells in SARS-CoV-2 infection and re-infection. Then, we structure the immunity responses that B cells mediated in peripheral tissues. Furthermore, we discuss the role of B cells during vaccination including the effectiveness of antibodies and memory B cells, viral evolution mechanisms, and future vaccine development. This review might help medical workers and researchers to have a better understanding of the interaction between B cells and SARS-CoV-2 and broaden their vision for future investigations.
Immunosuppression and apoptosis activation mediated by p53-Bcl2/Bax signaling pathway -The potential mechanism of goldfish (Carassius auratus Linnaeus) gill disease caused by Myxobolus ampullicapsulatus
Authors: Liu Senyue , Luo Lin , Zuo Fengyuan , Geng Yi , Ou Yangping , Chen Defang , Yang Shiyong , Luo Wei , Wang Yan , Wang Jun , Huang Xiaoli
Published: August 2022

Myxobolus, a major harmful type of myxospora, is one of the main parasitic pathogens of freshwater fish. Once myxoboliosis occurs, treatment can be extremely difficult. Therefore, clear understandings of the etiology of myxoboliosis and its pathological mechanism are keys for prevention and control. Here, histology, transmission electron microscopy, transcriptome study, tunel assay, and immunohistochemistry were carried out, revealing the morphology, pathological effects as well as host response mechanism of goldfish gill to Myxobolus ampullicapsulatus. Histological studies showed that the mature spores of Myxobolus ampullicapsulatus were composed of three parts, the spore shell, sporoplasm and bottle shaped polar capsule containing double S-shaped polar filaments. Transcriptome analysis revealed that Myxobolus ampullicapsulatus -infected (Myx) goldfish gills were characterized by apoptosis activation mediated by “p53 signaling pathway” with significantly up-regulated apoptosis-related differential genes dominated by p53-Bcl2/Bax signaling pathway. In addition, tunel assay revealed severe gill apoptosis in the Myx group. Transcriptome analysis also revealed that Myx group showed changes in immune response and significantly down-regulated immune-related differential genes. Beyond that, immunohistochemistry showed that there was no significant increase in the number of gill lymphocyte after parasite infection. These results suggest that the pathological mechanism of Myxobolus ampullicapsulatus infection on gills of goldfish may be related to apoptosis and immunosuppression. Subsequent qRT-PCR showed that apoptosis-related genes (Caspase3,Bad, Bax) and anti-inflammatory gene IL-10 were significantly increased, while immune-related pro-inflammatory genes (IL-1β, IL-8) were markedly down-regulated, further verifying the transcriptome results. Based on the above results, we concluded that p53-Bcl2/Bax related networks that dominant the expression of apoptosis genes were activated while immunity was suppressed in the gills of Myxobolus ampullicapsulatus infected goldfish. Our study is not only of benefit to enrich the taxonomy of Myxobolus but also clarifies its pathogenic mechanism, thus providing targets for prevention and control of myxoboliosis.
Future changes in the seasonal habitat suitability for anchovy (Engraulis japonicus) in Korean waters projected by a maximum entropy model
Authors: Bang Minkyoung , Sohn Dongwha , Kim Jung Jin , Choi Wonkeun , Jang Chan Joo , Kim Changsin
Published: August 2022

Anchovy (Engraulis japonicus), a commercially and biologically important fish species in Korean waters, is a small pelagic fish sensitive to environmental change. Future changes in its distribution in Korean waters with significant environmental change remain poorly understood. In this study, we examined the projected changes in the seasonal anchovy habitat in Korean waters in the 2050s under three representative concentration pathways (RCPs; RCP 2.6, RCP 4.5, and RCP 8.5) by using a maximum entropy model (MaxEnt). The MaxEnt was constructed by anchovy presence points and five environmental variables (sea surface temperature, sea surface salinity, sea surface current speed, mixed layer depth, and chlorophyll-a concentration) from 2000–2015. Future changes in the anchovy habitat in Korean waters showed variation with seasonality: in the 2050s, during winter and spring, the anchovy habitat area is projected to increase by 19.4–38.4%, while in summer and fall, the habitat area is projected to decrease by up to 19.4% compared with the historical period (2000–2015) under the three different RCPs. A substantial decline (16.5–60.8%) is expected in summer in the East China Sea and the Yellow Sea—main spawning habitat. This considerable decrease in the spawning habitat may contribute to a decline in the anchovy biomass, relocation of the spawning area, and changes in the reproduction timing in Korean waters. Our findings suggest that seasonal variation of the anchovy habitat should be considered to ensure effective future management strategies for the effect of climate change on fisheries resources, particularly for environmentally sensitive species, such as anchovy.
Satellite retrieval of oceanic particulate organic nitrogen concentration
Authors: Wang Yongquan , Liu Huizeng , Wu Guofeng
Published: August 2022

Over the past several decades, satellite ocean color remote sensing has greatly improved our understanding of the biogeochemical properties of the global ocean. Particulate organic nitrogen (PON) refers to the nitrogen contained in biological or other debris particles, and it plays important roles in the ecosystem functions and biogeochemical processes of the marine biology. However, few studies have focused on the satellite retrieval of oceanic PON concentrations. With an attempt to fill the gap, this study aimed to explore the feasibility of retrieving oceanic PON concentrations from remote sensing data, determine the bio-optical proxies for satellite PON retrievals, and develop satellite oceanic PON retrieval models for the global ocean. In situ PON data collected over the global ocean and Moderate-resolution Imaging Spectroradiometer (MODIS) Level-3 products were used. Three different types of models were tested: (1) apparent optical property (AOP)-based models, 2) inherent optical property (IOP)-based models, and 3) biological property-based models. Results showed that ocean color remote sensing could be used for oceanic PON concentration retrieval in the global ocean, and AOP-based models calibrated produced better fitting performance than the other two types; models based on blue-to-green band ratio (BG) and normalized difference nitrogen index (NDNI) produced comparable and better fitting and validation performance; and IOP-based and biological property-based models produced lower but also acceptable performance. With the PON models developed, the monthly variations of PON concentrations in the global ocean were also explored. In further studies, PON models will be used to explore oceanic PON spatiotemporal variations and the underlying driving forces.
Implemented occupational health surveillance limits the spread of SARS-CoV-2 Omicron at the workplace
Authors: Gesto João Silveira Moledo , Cabanelas Adriana , Farjun Bruna , dos Santos Monique Cristina , Fidalgo-Neto Antonio A. , Kuriyama Sergio N. , Souza Thiago Moreno L.
Published: August 2022

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has put an enormous pressure on human societies, at both health and economic levels. Early diagnosis of SARS-CoV-2, the causative agent of 2019 coronavirus disease (COVID-19), has proved an efficient method to rapidly isolate positive individuals and reduce transmission rates, thus alleviating its negative impact on society’s well-being and economic growth. In this work, through a coordinated and centralized effort to monitor SARS-CoV-2 circulation in companies from the State of Rio de Janeiro, Brazil, we have detected and linked an early rise of infection rates in January 2022 to the introduction of the Omicron variant of concern (VoC) (BA.1). Interestingly, when the Omicron genomic isolates were compared to correlates from public datasets, it was revealed that introduction events were multiple, with possible migration routes mapping to: Mali; Oman and United States; and Italy, Latin America, and United States. In addition, we have built a haplotype network with our genomic dataset and found no strong evidence of transmission chains, between and within companies. Considering Omicron’s particularly high transmissibility, and that most of our samples (>87%) arose from 3 out of 10 companies, these findings suggest that workers from such environments were exposed to SARS-CoV-2 outside their company boundaries. Thus, using a mixed strategy in which quick molecular diagnosis finds support in comprehensive genomic analysis, we have shown that a successfully implemented occupational health program should contribute to document emerging VoC and to limit the spread of SARS-CoV-2 at the workplace.
Identification of a novel variant in N-cadherin associated with dilated cardiomyopathy
Authors: Chen Yuanying , Sun Qiqing , Hao Chanjuan , Guo Ruolan , Wang Chentong , Yang Weili , Zhang Yaodong , Wang Fangjie , Li Wei , Guo Jun
Published: August 2022

Background

Dilated cardiomyopathy (DCM), which is a major cause of heart failure, is a primary cardiac muscle disease with high morbidity and mortality rates. DCM is a genetically heritable disease and more than 10 gene ontologies have been implicated in DCM. CDH2 encodes N-cadherin and belongs to a superfamily of transmembrane proteins that mediate cell–cell adhesion in a calcium-dependent manner. Deficiency of CDH2 is associated with arrhythmogenic right ventricular cardiomyopathy (OMIM: 618920) and agenesis of the corpus callosum, cardiac, ocular, and genital syndrome (OMIM: 618929). However, there have been no reports of isolated DCM associated with CDH2 deficiency.

Methods

We performed whole exome sequencing in a 12-year-old girl with non-syndromic DCM and her unaffected parents. Variants in both known DCM-related genes and novel candidate genes were analyzed and pathogenicity confirmation experiments were performed.

Results

No pathogenic/likely pathogenic variant in known DCM-related genes was identified in the patient. We found a de novo variant in a candidate gene CDH2 in the patient, namely, c.474G>C/p.Lys158Asn (NM_001792.5). This variant has not been reported in the ClinVar or Human Gene Mutation Database (HGMD). CDH2 p.Lys158Asn was found in the conserved domain of N-cadherin, which is associated with the hydrolysis of the precursor segment and interference with adhesiveness. Furthermore, we tested the expression and efficiency of cell–cell adhesion while overexpressing the CDH2 Lys158Asn mutant and two previously reported variants in CDH2 as positive controls. The adhesion efficiency was considerably reduced in the presence of the mutated CDH2 protein compared with wild-type CDH2 protein, which suggested that the mutated CDH2 protein's adhesion capacity was impaired. The variant was probably pathogenic after integrating clinical manifestations, genetic analysis, and functional tests.

Conclusion

We identified a CDH2 variant in DCM. We observed a new clinical symptom associated with N-cadherin deficiency and broadened the genetic spectra of DCM.
B cells in systemic lupus erythematosus: Targets of new therapies and surveillance tools
Authors: Parodis Ioannis , Gatto Mariele , Sjöwall Christopher
Published: August 2022

B cell hyperactivity is a hallmark of the complex autoimmune disease systemic lupus erythematosus (SLE), which has justified drug development focusing on B cell altering agents during the last decades, as well as the off-label use of B cell targeting biologics. About a decade ago, the anti-B cell activating factor (BAFF) belimumab was the first biological agent to be licensed for the treatment of adult patients with active yet non-renal and non-neuropsychiatric SLE, to later be expanded to include treatment of pediatric SLE and, recently, lupus nephritis. B cell depletion is recommended as an off-label option in refractory cases, with the anti-CD20 rituximab having been the most used B cell depleting agent to date while agents with a slightly different binding specificity to CD20 such as obinutuzumab have also shown promise, forming a part of the current pipeline. In addition, terminally differentiated B cells have also been the targets of experimental therapies, with the proteasome inhibitor bortezomib being one example. Apart from being promising drug targets, B and plasma cells have also shown promise in the surveillance of patients with SLE, especially for monitoring B cell depleting or B cell altering therapies. Inadequate B cell depletion may signify poor expected clinical response to rituximab, for example, while prominent reductions in certain B cell subsets may signify a protection against flare development in patients treated with belimumab. Toward an era with a richer therapeutic armamentarium in SLE, including to a large extent B cell altering treatments, the challenge that emerges is to determine diagnostic means for evidence-based therapeutic decision-making, that uses clinical information, serological markers, and gene expression patterns to guide individualized precision strategies.
Distinct stages of the intestinal bacterial community of Ampullaceana balthica after salinization
Authors: Kivistik Carmen , Käiro Kairi , Tammert Helen , Sokolova Inna M. , Kisand Veljo , Herlemann Daniel P. R.
Published: August 2022

Environmental disturbances influence bacterial community structure and functioning. To investigate the effect of environmental disturbance caused by changes in salinity on host-protected bacterial communities, we analyzed the microbiome within the gastrointestinal tract ofAmpullaceana balthicain different salinities.A. balthicais a benthic gastropod found in fresh- and mesohaline waters. Whereas the total energy reserves ofA. balthicawere unaffected by an increase of salinity to 3, a high mortality rate was detected after a shift from freshwater to salinity 6 suggesting a major disruption of energy homeostasis. The shift to salinity 6 also caused a change in the gastrointestinal bacterial community composition. At salinity 3, the bacterial community composition of different host individuals was related either to the freshwater or salinity 6 gastrointestinal bacterial community, indicating an ambivalent nature of salinity 3. Since salinity 3 represents the range where aquatic gastropods are able to regulate their osmolarity, this may be an important tipping point during salinization. The change in the intestinal microbiome was uncoupled from the change in the water bacterial community and unrelated to the food source microbiome. Our study shows that environmental disturbance caused by salinity acts also on the host-protected microbiome. In light of the sea-level rise, our findings indicate that salinization of the near-shore freshwater bodies will cause changes in organisms’ intestinal microbiomes if a critical salinity threshold (presumably ∼3) is exceeded.
Bromate reduction by Shewanella oneidensis MR-1 is mediated by dimethylsulfoxide reductase
Authors: Wang Yicheng , Fan Jiale , Shen Yonglin , Ye Fan , Feng Zhiying , Yang Qianning , Wang Dan , Cai Xunchao , Mao Yanping
Published: August 2022

Microbial bromate reduction plays an important role in remediating bromate-contaminated waters as well as biogeochemical cycling of bromine. However, little is known about the molecular mechanism of microbial bromate reduction so far. Since the model strain Shewanella oneidensis MR-1 is capable of reducing a variety of oxyanions such as iodate, which has a high similarity to bromate, we hypothesize that S. oneidensis MR-1 can reduce bromate. Here, we conducted an experiment to investigate whether S. oneidensis MR-1 can reduce bromate, and report bromate reduction mediated by a dimethylsulfoxide reductase encoded with dmsA. S. oneidensis MR-1 is not a bromate-respiring bacterium but can reduce bromate to bromide under microaerobic conditions. When exposed to 0.15, 0.2, 0.25, 0.5, and 1 mM bromate, S. oneidensis MR-1 reduced bromate by around 100, 75, 64, 48, and 23%, respectively, within 12 h. In vivo evidence from gene deletion mutants and complemented strains of S. oneidensis MR-1 indicates that MtrB, MtrC, CymA, GspD, and DmsA are involved in bromate reduction, but not NapA, FccA, or SYE4. Based on our results as well as previous findings, a proposed molecular mechanism for bromate reduction is presented in this study. Moreover, a genomic survey indicates that 9 of the other 56 reported Shewanella species encode proteins highly homologous to CymA, GspD, and DmsA of S. oneidensis MR-1 by sequence alignment. The results of this study contribute to understanding a pathway for microbial bromate reduction.
Toxicity and modulation of silver nanoparticles synthesized using abalone viscera hydrolysates on bacterial community in aquatic environment
Authors: Zhang Yue , Yang Zhuan , Ni Jing , Ma Ying , Xiong Hejian , Jian Wenjie
Published: August 2022

Polysaccharide decorated silver nanoparticles (AgNPs) are a new type of antibacterial agent in aquaculture, but their effects on the bacterial community structure in aquaculture water are still unknown. In this study, the primary hydrolysate from abalone (Haliotis discus hannai) viscera (AVH) was used to biosynthesize AVH-AgNPs by in situ reduction, and the crystallinity nature, size, morphology, and chemical composition were analyzed by high-resolution characterization techniques such as Ultraviolet–visible spectroscopy (UV–vis), X-rays diffraction (XRD), Transmission Electron Microscope (TEM), Dynamic light scattering (DLS), Zeta potential, inductively coupled plasma-optical emission spectrometry (ICP-OES) and Turbiscan stability index (TSI) values. Furthermore, the acute toxicity of AVH-AgNPs to zebrafish (Danio rerio) and their effects on bacterial community structure in fish culture water at low concentrations were studied. The results showed that the spherical AVH-AgNPs with an average diameter of 54.57 ± 12.96 nm had good stability, low toxicity, and good in vitro antibacterial activity. Within the experimental concentration range, all AVH-AgNPs treatments had decreased the bacterial diversity in zebrafish culture water to varying degrees. The bacteria with significantly decreased abundances were pathogenic or potential pathogenic, such as Aeromonas veronii, Flavobacterium columnare, and genera Flectobacillus and Bosea. The abundance of Haliscomenobacter sp. JS224, which might cause sludge swelling, also decreased significantly. On the other hand, the relative abundance of some bacterial taxa could remove xenobiotics (e.g., Runella defluvii and Phenylobacterium), control water eutrophication (Sediminibacterium), and reduce toxic algae proliferation (Candidatus Intestinusbacter nucleariae and Candidatus Finniella), increased significantly. Thus, the application of AVH-AgNPs in aquaculture water at low concentrations is relatively safe and has positive significance for improving the aquaculture environment. Also, AVH-AgNPs have good prospects in aquaculture.
Toosendanin suppresses African swine fever virus replication through upregulating interferon regulatory factor 1 in porcine alveolar macrophage cultures
Authors: Liu Yuanjia , Zhang Xinheng , Liu Zexin , Huang Li , Jia Weixin , Lian Xinlei , Weng Changjiang , Zhang Guihong , Qi Wenbao , Chen Jianxin
Published: August 2022

African swine fever virus (ASFV) is a highly infectious and lethal swine pathogen that causes severe socio-economic consequences in affected countries. Unfortunately, effective vaccine for combating ASF is unavailable so far, and the prevention and control strategies for ASFV are still very limited. Toosendanin (TSN), a triterpenoid saponin extracted from the medicinal herb Melia toosendan Sieb. Et Zucc, has been demonstrated to possess analgesic, anti-inflammatory, anti-botulism and anti-microbial activities, and was used clinically as an anthelmintic, while the antiviral effect of TSN on ASFV has not been reported. In this study, we revealed that TSN exhibited a potent inhibitory effect on ASFV GZ201801-38 strain in porcine alveolar macrophages (PAMs; EC50 = 0.085 μM, SI = 365) in a dose-dependent manner. TSN showed robust antiviral activity in different doses of ASFV infection and reduced the transcription and translation levels of ASFV p30 protein, viral genomic DNA quantity as well as viral titer at 24 and 48 h post-infection. In addition, TSN did not affect virion attachment and release but intervened in its internalization in PAMs. Further investigations disclosed that TSN played its antiviral role by upregulating the host IFN-stimulated gene (ISG) IRF1 rather than by directly inactivating the virus particles. Overall, our results suggest that TSN is an effective antiviral agent against ASFV replication in vitro and may have the potential for clinical use.
Unravelling the pharmacokinetics of aflatoxin B1: In vitro determination of Michaelis–Menten constants, intrinsic clearance and the metabolic contribution of CYP1A2 and CYP3A4 in pooled human liver microsomes
Authors: Lootens Orphélie , De Boevre Marthe , Gasthuys Elke , Van Bocxlaer Jan , Vermeulen An , De Saeger Sarah
Published: August 2022

Mycotoxins, fungal secondary metabolites, are ubiquitously present in food commodities. Acute exposure to high levels or chronic exposure to low levels has an impact on the human body. The phase I metabolism in the human liver, performed by cytochrome P450 (CYP450) enzymes, is accountable for more than 80% of the overall metabolism of exogenous and endogenous compounds. Mycotoxins are (partially) metabolized by CYP450 enzymes. In this study, in vitro research was performed on CYP450 probes and aflatoxin B1 (AFB1), a carcinogenic mycotoxin, to obtain pharmacokinetic data on AFB1, required for further experimental work. The CYP450 probes of choice were a CYP3A4 substrate, midazolam (MDZ) and a CYP1A2 substrate, phenacetin (PH) since these are the main metabolizing phase I enzymes of AFB1. Linearity experiments were performed on the three substrates indicating that linear conditions were achieved at a microsomal protein concentration and incubation time of 0.25 mg/ml and 5 min, 0.50 mg/ml and 20 min and 0.25 mg/ml and 5 min for MDZ, PH and AFB1, respectively. The Km was determined in human liver microsomes and was estimated at 2.15 μM for MDZ, 40.0 μM for PH and 40.9 μM for AFB1. The associated Vmax values were 956 pmol/(mg.min) (MDZ), 856 pmol/(mg.min) (PH) and 11,536 pmol/(mg.min) (AFB1). Recombinant CYP systems were used to determine CYP450-specific Michaelis–Menten values for AFB1, leading to a CYP3A4 Km of 49.6 μM and an intersystem extrapolation factor (ISEF) corrected Vmax of 43.6 pmol/min/pmol P450 and a CYP1A2 Km of 58.2 μM and an ISEF corrected Vmax of 283 pmol/min/pmol P450. An activity adjustment factor (AAF) was calculated to account for differences between microsome batches and was used as a correction factor in the determination of the human in vivo hepatic clearance for MDZ, PH and AFB1. The hepatic blood clearance corrected for the AAF CLH,B,MDZ,AAF, CLH,B,PH,AAF CLH,B,AFB1,AAF(CYP3A4) and CLH,B,AFB1,AAF(CYP1A2) were determined in HLM at 44.1 L/h, 21.7 L/h, 40.0 L/h and 38.5 L/h. Finally, inhibition assays in HLM showed that 45% of the AFB1 metabolism was performed by CYP3A4/3A5 enzymes and 49% by CYP1A2 enzymes.
Genetic tagging of the adenosine A2A receptor reveals its heterogeneous expression in brain regions
Authors: Wang Muran , Li Zewen , Song Yue , Sun Qiuqin , Deng Lu , Lin Zhiqing , Zeng Yang , Qiu Chunhong , Lin Jingjing , Guo Hui , Chen Jiangfan , Guo Wei
Published: August 2022

The adenosine A2A receptor (A2AR), a G protein-coupled receptor, is involved in numerous and varied physiological and pathological processes, including inflammation, immune responses, blood flow, and neurotransmission. Accordingly, it has become an important drug target for the treatment of neuropsychiatric disorders. However, the exact brain distribution of A2AR in regions outside the striatum that display relatively low levels of endogenous A2AR expression has hampered the exploration of A2AR functions under both physiological and pathological conditions. To further study the detailed distribution of the A2AR in low-expression regions, we have generated A2AR knock-in mice in which the 3xHA-2xMyc epitope tag sequence was fused to the C-terminus of A2AR (A2AR-tag mice) via CRISPR/Cas9 technology. Here, using CRISPR/Cas9 technology, we have generated A2AR knock-in mice in which the 3xHA-2xMyc epitope tag sequence was fused to the C-terminus of A2AR (A2AR-tag mice). The A2AR-tag mice exhibited normal locomotor activity and emotional state. Consistent with previous studies, A2AR fluorescence was widely detected in the striatum, nucleus accumbens, and olfactory tubercles, with numerous labeled cells being evident in these regions in the A2AR-tag mouse. Importantly, we also identified the presence of a few but clearly labeled cells in heterogeneous brain regions where A2AR expression has not previously been unambiguously detected, including the lateral septum, hippocampus, amygdala, cerebral cortex, and gigantocellular reticular nucleus. The A2AR-tag mouse represents a novel useful genetic tool for monitoring the expression of A2AR and dissecting its functions in brain regions other than the striatum.
Phase I/II trial of local interstitial chemotherapy with arsenic trioxide in patients with newly diagnosed glioma
Authors: Han Dayong , Teng Lei , Wang Xiaoxiong , Zhen Yunbo , Chen Xiaofeng , Yang Mingchun , Gao Ming , Yang Guang , Han Mingyang , Wang Ligang , Xu Jiajun , Li Yue , Shumadalova Alina , Zhao Shiguang
Published: August 2022

Background

Glioma is the most common primary brain tumor in adults with poor prognosis. The glioma patients benefit from STUPP strategy, including maximum and safe resection and adjuvant radiotherapy and chemotherapy. Arsenic trioxide could inhibit various tumors. However, it is a challenge to evaluate the efficiency and safety of srsenic trioxide in glioma patients.

Objective

The arsenic trioxide has the potent therapeutic effect on glioma. However, the safety and efficacy of local interstitial chemotherapy with arsenic trioxide in newly diagnosed glioma patients is unclear.

Methods

All patients received partial or complete tumor resection and intraoperative implantation of Ommaya reservoirs followed by standard radiotherapy. Arsenic trioxide with the starting dose 0.3 mg was administered via an Ommaya reservoir catheter inserted into the tumor cavity for 5 consecutive days every 3 months for a total of eight cycles unless tumor progression or excessive toxicity was observed.

Results

No hematological or grade 4 non-hematological toxicity was observed in any patient during arsenic trioxide treatment. The maximum tolerated dose of 1.5 mg of arsenic trioxide was safe and well tolerated. The median overall survival for WHO grade 3 glioma was 33.6 months, and for glioblastoma was 13.9 months. The median progression-free survival for WHO grade 2 glioma was 40.3 months, for grade 3 glioma was 21.5 months, and for glioblastoma was 9.5 months.

Conclusion

These results suggest that arsenic trioxide is safe and well tolerated with local delivery into the tumor cavity of the brain, and the dose recommended for a phase II trial is 1.5 mg.
Positive emotions foster spontaneous synchronisation in a group movement improvisation task
Authors: Smykovskyi Andrii , Bieńkiewicz Marta M. N. , Pla Simon , Janaqi Stefan , Bardy Benoît G.
Published: August 2022

Emotions are a natural vector for acting together with others and are witnessed in human behaviour, perception and body functions. For this reason, studies of human-to-human interaction, such as multi-person motor synchronisation, are a perfect setting to disentangle the linkage of emotion with socio-motor interaction. And yet, the majority of joint action studies aiming at understanding the impact of emotions on multi-person performance resort to enacted emotions, the ones that are emulated based on the previous experience of such emotions, and almost exclusively focus on dyadic interaction. In addition, tasks chosen to study emotion in joint action are frequently characterised by a reduced number of physical dimensions to gain experimental control and subsequent facilitation in data analysis. Therefore, it is not clear how naturalistically induced emotions diffuse in more ecological interactions with other people and how emotions affect the process of interpersonal synchronisation. Here, we show that positive and negative emotions differently alter spontaneous human synchronous behaviour during a multi-person improvisation task. The study involved 39 participants organised in triads who self-reported liking improvisational activities (e.g., dancing). The task involved producing improvisational movements with the right hand. Participants were emotionally induced by manipulated social feedback involving a personal ranking score. Three-dimensional spatio-temporal data and cardiac activity were extracted and transformed into oscillatory signals (phases) to compute behavioural and physiological synchrony. Our results demonstrate that individuals induced with positive emotions, as opposed to negative emotions or a neutral state, maintained behavioural synchrony with other group members for a longer period of time. These findings contribute to the emerging shift of neuroscience of emotion and affective sciences towards the environment  of social significance where emotions appear the most—in interaction with others. Our study showcases a method of quantification of synchrony in an improvisational and interactive task based on a well-established Kuramoto model.
Maternal low-protein diet reduces skeletal muscle protein synthesis and mass via Akt-mTOR pathway in adult rats
Authors: de Vasconcelos Diogo Antonio Alves , Nachbar Renato Tadeu , Pinheiro Carlos Hermano , do Amaral Cátia Lira , Crisma Amanda Rabello , Vitzel Kaio Fernando , Abreu Phablo , Alonso-Vale Maria Isabel , Lopes Andressa Bolsoni , Bento-Santos Adriano , Falcão-Tebas Filippe , de Santana David Filipe , do Nascimento Elizabeth , Curi Rui , Pithon-Curi Tania Cristina , Hirabara Sandro Massao , Leandro Carol Góis
Published: August 2022

Several studies have demonstrated that a maternal low-protein diet induces long-term metabolic disorders, but the involved mechanisms are unclear. This study investigated the molecular effects of a low-protein diet during pregnancy and lactation on glucose and protein metabolism in soleus muscle isolated from adult male rats. Female rats were fed either a normal protein diet or low-protein diet during gestation and lactation. After weaning, all pups were fed a normal protein diet until the 210th day postpartum. In the 7th month of life, mass, contractile function, protein and glucose metabolism, and the Akt-mTOR pathway were measured in the soleus muscles of male pups. Dry weight and contractile function of soleus muscle in the low-protein diet group rats were found to be lower compared to the control group. Lipid synthesis was evaluated by measuring palmitate incorporation in white adipose tissue. Palmitate incorporation was higher in the white adipose tissue of the low-protein diet group. When incubated soleus muscles were stimulated with insulin, protein synthesis, total amino acid incorporation and free amino acid content, glucose incorporation and uptake, and glycogen synthesis were found to be reduced in low-protein diet group rats. Fasting glycemia was higher in the low-protein diet group. These metabolic changes were associated with a decrease in Akt and GSK-3β signaling responses to insulin and a reduction in RPS6 in the absence of the hormone. There was also notably lower expression of Akt in the isolated soleus muscle of low-protein diet group rats. This study is the first to demonstrate how maternal diet restriction can reduce skeletal muscle protein and mass by downregulating the Akt-mTOR pathway in adulthood.
Stage-dependent prognostic shift in mismatch repair-deficient tumors: Assessing patient outcomes in stage II and III colon cancer
Authors: Hestetun Kjersti Elvestad , Rosenlund Nina Benedikte , Stanisavljević Luka , Dahl Olav , Myklebust Mette Pernille
Published: August 2022

Introduction

Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) is associated with an improved prognosis in colon cancer stage II but poor prognosis in stage IV colon cancer. The clinical significance of dMMR in colon cancer stage III is not established.

Methods

Tissue microarrays (TMAs) from 544 patients with colon cancer stage II and III with clinicopathological and survival data were stained for mismatch repair (MMR) proteins, CD3, CD8, and programmed death ligand-1 (PD-L1), and programmed death ligand- 1 (PD-L1). Patient outcomes were reviewed.

Results

In stage III colon cancer, dMMR was a marker of poor disease-free survival (DFS) (Kaplan–Meier, mean survival in months: dMMR: 28.76 (95% CI 18.46–39.05) vs. pMMR 40.91 (37.20–44.63), p=0.014, multivariate Cox regression: hazard ratio (HR) 4.17 (95% CI 2.02–8.61), p<0.001). In stage II colon cancer, there was a tendency toward improved DFS for dMMR patients (dMMR: 57.14 (95% CI 54.66–59.62) vs. pMMR 53.54 (95% CI 51.48–55.60), p=0.015, multivariate Cox regression HR 0.24 (95% CI 0.06-1.04), p=0.057). CD3, CD8, and PD-L1 expression was not associated with prognosis of dMMR patients. Multivariate Cox regression analysis showed a significant interaction between the MMR phenotype and stage (p=0.001).

Conclusion

dMMR is associated with an improved prognosis in stage II colon cancer but is no longer associated with a favorable prognosis in stage III colon cancer.
Pseudo-progression with osimertinib after definitive chemoradiation in unresectable epidermal growth factor receptor mutation positive of stage III non-small cell lung cancer: A case report
Authors: Ren Fei , Wang Yao , Gao Yongsheng , Meng Xiangjiao
Published: August 2022

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been widely used in the treatment of locally advanced non-small cell lung cancer (NSCLC). The phenomenon of pseudoprogression in targeted therapy in EGFR-mutation NSCLC patients is rare. Here, we reported an EGFR-mutation-positive lung adenocarcinoma patient who was admitted to a hospital for cough and chest distress accompanied by shortness of breath. He underwent four cycles of chemotherapy with pemetrexed combined with carboplatin and concurrent radiotherapy in the third and fourth cycles. Then, he was treated by osimertinib maintenance therapy. After 11.5 months of osimertinib treatment, he was assessed to progressive disease by computed tomography. He underwent fiber bronchoscopy, and the biopsy pathology showed extensive necrosis without tumor cells. Until now, the patient has continued on osimertinib for 7 months without relapse or metastasis. As far as we know, we are the first to report pseudoprogression in osimertinib maintenance after definitive chemoradiation. This study reminds the clinicians to distinguish pseudoprogression from osimertinib-induced progression and avoid abandoning effective treatments.
Clinical and economic impact of changing reimbursement criteria for statin treatment among patients with type 2 diabetes mellitus in South Korea
Authors: Kim Siin , Choi Kyungseon , Kim Ji-yool , Suh Hae Sun
Published: August 2022

Aim: Patients with type 2 diabetes mellitus (T2DM) in South Korea can be reimbursed for statins if they have a low-density lipoprotein cholesterol (LDL-C) level of ≥100 mg/dL. We aimed to explore the clinical and economic benefit received by T2DM patients when easing the current criteria for statin treatment by lowering the LDL-C threshold from 100 mg/dL to 70 mg/dL.

Methods: We used a static course model with a 5-year period to compare the following two scenarios in T2DM patients with no history of cardiovascular (CV) events: the current criteria covering LDL-C ≥100 mg/dL and the revised criteria covering LDL-C ≥70 mg/dL. The number of target patients was estimated based on previous Korean studies on patients with T2DM. The current mix of treatments used for T2DM and costs involving CV events were estimated using the National Health Insurance Service–National Health Screening Cohort database. The baseline CV event rates and case fatality were estimated using NHIS Customized database, including 50% patients who were prescribed atorvastatin and 100% who were not prescribed statins between 2009 and 2012 among patients with T2DM in the entire Korean population. After propensity score matching, patients with T2DM not prescribed statins were followed up until 2018 to estimate the incidence rates of coronary heart disease (CHD) and stroke. The efficacy of atorvastatin for the primary prevention of CV events in patients with T2DM was derived from a pivotal clinical trial. The outcome measures were the number of CV events prevented after the change in criteria and the consequent cost savings.

Results: In South Korea, the current and revised criteria covered 2,434,379 and 3,446,149 patients with T2DM, respectively. The change in criteria resulted in the prevention of 726 CV events and cost savings of US dollars (USD) 5.5 million at the national level and USD 0.0089 per member per month in the fifth year.

Conclusion: Easing the reimbursement criteria for statin treatment among patients with T2DM was associated with a reduction in CV events and their related costs; therefore, changing the reimbursement criteria is worth further consideration to mitigate the burden of CV disease.
Maca (Lepidium meyenii Walp.) on semen quality parameters: A systematic review and meta-analysis
Authors: Lee Hye Won , Lee Myeong Soo , Qu Fan , Lee Je-Won , Kim Eunseop
Published: August 2022

Background: This study aimed to examine the evidence for the effect of Lepidium meyenii Walp. [Brassicaceae] (L. meyenii W.), known as maca, on improving semen quality.

Methods: Nine databases were searched for randomized controlled trials (RCTs) that examined the parameters for improvements in semen quality, regardless of the type of L. meyenii W. The risk of bias (ROB) among the studies was evaluated according to the Cochrane ROB tool.

Results: Five RCTs met all of the inclusion criteria. Three RCTs showed mixed efficacy of maca in improving semen quality parameters, including sperm concentration and sperm motility, in men experiencing infertility. The meta-analysis also failed to show the efficacy of maca in increasing the sperm concentration compared to the placebo (weighted mean difference, 2.22, 95% confidence interval −2.94 to 7.37, p = 0.4). Two other RCTs also showed mixed effects of maca on several semen quality parameters in healthy men.

Conclusion: The evidence from the included studies suggests unclear effects of maca on semen quality parameters in both men experiencing infertility and healthy men. However, the total number of RCTs and the total sample size were too small to draw firm conclusions.
Pulmonary adverse events associated with hypertension in non-small cell lung cancer patients receiving PD-1/PD-L1 inhibitors
Authors: Chen Jianing , Wen Yaokai , Chu Xiangling , Liu Yuzhi , Su Chunxia
Published: August 2022

Introduction: Non-small cell lung cancer patients have gained therapeutic benefits from immune checkpoint inhibitors, although immune-related adverse events (irAEs) could be inevitable. Whether irAEs are associated with chronic diseases is still unclear, our study aims to clarify the distinct adverse events in NSCLC patients with concomitant hypertension.

Methods: Adverse event cases were searched and collected in the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database from January 2015 to December 2021. We performed disproportionality analysis to detect safety signals by calculating reporting odds ratios (ROR) and corresponding 95% confidence intervals (95% CIs), information component (IC), and the lower bound of the information component 95% credibility interval (IC025).

Results: Among 17,163 NSCLC patients under treatment with single-agent anti-programmed death-1/programmed death ligand-1 (PD-1/PD-L1) inhibitor (nivolumab, pembrolizumab, cemiplimab, durvalumab, atezolizumab, and avelumab), 497 patients had hypertension while 16,666 patients had no hypertension. 4,283 pulmonary AEs were reported, including 166 patients with hypertension and 4,117 patients without hypertension. Compared with patients without hypertension, patients with hypertension were positively associated with increased reporting of interstitial lung disease (ROR = 3.62, 95%CI 2.68–4.89, IC = 1.54, IC025 = 0.57) among patients receiving anti-PD-1 treatment. The median duration of onset from the time of initiation of anti-PD-1 administration was 28 days (IQR, 12.00–84.25).

Conclusion: Our pharmacovigilance analysis showed the profile of pulmonary toxicities in NSCLC patients with hypertension caused by anti-PD-1/PD-L1 inhibitors. Interstitial lung disease was the statistically significant reporting adverse event in patients with hypertension receiving anti-PD-1 treatment.
Inflammation aggravated the hepatotoxicity of triptolide by oxidative stress, lipid metabolism disorder, autophagy, and apoptosis in zebrafish
Authors: Li Chenqinyao , Zhang Changqing , Zhu Chengyue , Zhang Jie , Xia Qing , Liu Kechun , Zhang Yun
Published: August 2022

Triptolide is a major compound isolated from the Tripterygium wilfordii Hook that is mainly used for the treatment of autoimmune disorders and inflammatory diseases. Though triptolide-induced hepatotoxicity has been widely reported, the hepatic effects when the patients are in an inflammatory state are not clear. In this study, we used low-dose Lipopolysaccharides (LPS) to disrupt the inflammation homeostasis in the liver of zebrafish and explored the hepatotoxicity of triptolide under an inflammatory state. Compared with the Triptolide group, LPS-Triptolide cotreatment exacerbate the liver injury with a remarkable decrease of liver size and liver-specific fluorescence intensity, accompanied by significant elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Liver cell damages were further demonstrated by histological staining and scanning electron microscopy observation. Lipid metabolism was severely impaired as indicated by delayed yolk sac absorption, accumulated triglycerides in the liver, and dysregulation of the related genes, such as ppar-α, cpt-1, mgst, srebf1/2, and fasn. Oxidative stress could be involved in the molecular mechanism as the Nrf2/keap1 antioxidant pathways were down-regulated when the zebrafish in an inflammatory state. Moreover, the expression of autophagy-related genes such as beclin, atg5, map1lc3b, and atg3 was also dysregulated. Finally, apoptosis was significantly induced in responses to LPS-Triptolide co-treatment. We speculate that triptolide could exacerbate the immune response and impair lipid metabolism, resulting in enhanced sensitivity of the zebrafish liver to triptolide-induced toxic effects through disruption of the antioxidant system and induction of apoptosis.
Exploring the mechanisms of neurotoxicity caused by fuzi using network pharmacology and molecular docking
Authors: An Junsha , Fan Huali , Han Mingyu , Peng Cheng , Xie Jie , Peng Fu
Published: August 2022

Safety has always been an important issue affecting the development of traditional Chinese medicine industry, especially for toxic medicinal materials, the establishment of risk prevention and control measures for toxic herbs is of great significance to improving the use of traditional Chinese medicine in clinical. Fuzi is a kind of traditional Chinese medicine and its toxicity has become the most important obstacle of limit in clinical using. In this paper, network pharmacology and molecular docking technology were used to analyze the main toxic components of Fuzi, the key targets and the mechanism of neurotoxicity. We carried out CCK-8 and WB assays, and detected LDH release and SDH activity. It was verified that aconitine caused neurotoxicity through a variety of pathways, including MAPK signaling pathway, pathways related to Akt protein, destruction of cell membrane integrity, damage of mitochondrial function affecting energy metabolism and apoptosis. What’s more, this study confirmed that aconitine could produce neurotoxicity by promoting apoptosis of hippocampus neuron and decreasing its quantity through Nissl Staining and TUNEL assay. This paper found and confirmed multiple targets and various pathways causing neurotoxicity of Fuzi, in order to provide reference for clinical application and related research.