bluuebunny/crossref_metadata_2025 huggingface dataset:
Current progress and future perspectives of neoadjuvant anti-PD-1/PD-L1 therapy for colorectal cancer
Authors: Yang Zhengyang , Wu Guocong , Zhang Xiao , Gao Jiale , Meng Cong , Liu Yishan , Wei Qi , Sun Liting , Wei Pengyu , Bai Zhigang , Yao Hongwei , Zhang Zhongtao
Published: September 2022

Immunotherapies, especially the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors, have revolutionized the therapeutic strategies of various cancers. As for colorectal cancer (CRC), the current clinical application of PD-1/PD-L1 inhibitors are mainly used according to the mutation pattern, which is categorized into deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H) and proficient mismatch repair (pMMR), or non-high levels of microsatellite instability (non-MSI-H). PD-1/PD-L1 inhibitors have been proven to have favorable outcomes against dMMR/MSI-H CRC because of more T-cell infiltration into tumor tissues. Nevertheless, the effectiveness of PD-1/PD-L1 inhibitors in pMMR/non-MSI-H CRC is still uncertain. Because of the quite-lower proportion of dMMR/MSI-H in CRC, PD-1/PD-L1 inhibitors have been reported to combine with other antitumor treatments including chemotherapy, radiotherapy, and targeted therapy for better therapeutic effect in recent clinical trials. Neoadjuvant therapy, mainly including chemotherapy and radiotherapy, not only can reduce clinical stage but also benefit from local control, which can improve clinical symptoms and the quality of life. Adding immunotherapy into neoadjuvant therapy may change the treatment strategy of primary resectable or some metastatic CRC. In this review, we focus on the development of neoadjuvant anti-PD-1/PD-L1 therapy and discuss the future perspectives in CRC.
Partial human Janus kinase 1 deficiency predominantly impairs responses to interferon gamma and intracellular control of mycobacteria
Authors: Daza-Cajigal Vanessa , Albuquerque Adriana S. , Young Dan F. , Ciancanelli Michael J. , Moulding Dale , Angulo Ivan , Jeanne-Julien Valentine , Rosain Jérémie , Minskaia Ekaterina , Casanova Jean-Laurent , Boisson-Dupuis Stéphanie , Bustamante Jacinta , Randall Richard E. , McHugh Timothy D. , Thrasher Adrian J. , Burns Siobhan O.
Published: September 2022

Purpose

Janus kinase-1 (JAK1) tyrosine kinase mediates signaling from multiple cytokine receptors, including interferon alpha/beta and gamma (IFN-α/β and IFN-γ), which are important for viral and mycobacterial protection respectively. We previously reported autosomal recessive (AR) hypomorphic JAK1 mutations in a patient with recurrent atypical mycobacterial infections and relatively minor viral infections. This study tests the impact of partial JAK1 deficiency on cellular responses to IFNs and pathogen control.

Methods

We investigated the role of partial JAK1 deficiency using patient cells and cell models generated with lentiviral vectors expressing shRNA.

Results

Partial JAK1 deficiency impairs IFN-γ-dependent responses in multiple cell types including THP-1 macrophages, Epstein-Barr Virus (EBV)-transformed B cells and primary dermal fibroblasts. In THP-1 myeloid cells, partial JAK1 deficiency reduced phagosome acidification and apoptosis and resulted in defective control of mycobacterial infection with enhanced intracellular survival. Although both EBV-B cells and primary dermal fibroblasts with partial JAK1 deficiency demonstrate reduced IFN-α responses, control of viral infection was impaired only in patient EBV-B cells and surprisingly intact in patient primary dermal fibroblasts.

Conclusion

Our data suggests that partial JAK1 deficiency predominantly affects susceptibility to mycobacterial infection through impact on the IFN-γ responsive pathway in myeloid cells. Susceptibility to viral infections as a result of reduced IFN-α responses is variable depending on cell type. Description of additional patients with inherited JAK1 deficiency will further clarify the spectrum of bacterial and viral susceptibility in this condition. Our results have broader relevance for anticipating infectious complications from the increasing use of selective JAK1 inhibitors.
Hepatic iNKT cells produce type 2 cytokines and restrain antiviral T cells during acute hepacivirus infection
Authors: Raus Svjetlana , Lopez-Scarim Jarrett , Luthy Joshua , Billerbeck Eva
Published: September 2022

Chronic hepatitis C virus (HCV) infection is a curable disease, but the absence of a vaccine remains a major problem in infection prevention. The lack of small animal models and limited access to human liver tissue impede the study of hepatic antiviral immunity and the development of new vaccine strategies. We recently developed an immune-competent mouse model using an HCV-related rodent hepacivirus which shares immunological features with human viral hepatitis. In this study, we used this new model to investigate the role of invariant natural killer T (iNKT) cells during hepacivirus infection in vivo. These cells are enriched in the liver, however their role in viral hepatitis is not well defined. Using high-dimensional flow cytometry and NKT cell deficient mice we analyzed a potential role of iNKT cells in mediating viral clearance, liver pathology or immune-regulation during hepacivirus infection. In addition, we identified new immune-dominant MHC class I restricted viral epitopes and analyzed the impact of iNKT cells on virus-specific CD8+ T cells. We found that rodent hepacivirus infection induced the activation of iNKT cell subsets with a mixed NKT1/NKT2 signature and significant production of type 2 cytokines (IL-4 and IL-13) during acute infection. While iNKT cells were dispensable for viral clearance, the lack of these cells caused higher levels of liver injury during infection. In addition, the absence of iNKT cells resulted in increased effector functions of hepatic antiviral T cells. In conclusion, our study reports a regulatory role of hepatic iNKT cells during hepacivirus infection in vivo. Specifically, our data suggest that iNKT cells skewed towards type 2 immunity limit liver injury during acute infection by mechanisms that include the regulation of effector functions of virus-specific T cells.
Factors associated with neutralizing antibody levels induced by two inactivated COVID-19 vaccines for 12 months after primary series vaccination
Authors: Wang Fuzhen , Huang Baoying , Lv Huakun , Feng Lizhong , Ren Weihong , Wang Xiaoqi , Tang Lin , Liu Qianqian , Wu Dan , Zheng Hui , An Zhijie , Deng Yao , Zhao Li , Ye Fei , Wang Wenling , Zhang Hangjie , Chang Shaoying , Liao Yuting , Chen Fengyang , Rodewald Lance E. , Gao George F. , Yin Zundong , Tan Wenjie
Published: September 2022

Background

BBIBP-CorV and CoronaVac inactivated COVID-19 vaccines are widely-used, World Health Organization-emergency-listed vaccines. Understanding antibody level changes over time after vaccination is important for booster dose policies. We evaluated neutralizing antibody (nAb) titers and associated factors for the first 12 months after primary-series vaccination with BBIBP-CorV and CoronaVac.

Methods

Our study consisted of a set of cross-sectional sero-surveys in Zhejiang and Shanxi provinces, China. In 2021, we enrolled 1,527 consenting 18-59-year-olds who received two doses of BBIBP-CorV or CoronaVac 1, 3, 6, 9, or 12 months earlier and obtained blood samples and demographic and medical data. We obtained 6-month convalescent sera from 62 individuals in Hebei province. Serum nAb titers were measured by standard micro-neutralization cytopathic effect assay in Vero cells with ancestral SARS-CoV-2 strain HB01. We used the first WHO International Standard (IS) for anti-SARS-CoV-2 immunoglobulin (NIBSC code 20/136) to standardized geometric mean concentrations (IU/mL) derived from the nAb geometric mean titers (GMT over 1:4 was considered seropositive). We analyzed nAb titer trends using Chi-square and factors related to nAb titers with logistic regression and linear models.

Results

Numbers of subjects in each of the five month-groupings ranged from 100 to 200 for each vaccine and met group-specific target sample sizes. Seropositivity rates from BBIBP-CorV were 98.0% at 1 month and 53.5% at 12 months, and GMTs were 25.0 and 4.0. Respective seropositivity rates from CoronaVac were 90.0% and 62.5%, and GMTs were 20.2 and 4.1. One-, three-, six-, nine-, and twelve-month GMCs were 217.2, 84.1, 85.7, 44.6, and 10.9 IU/mL in BBIBP-CorV recipients and 195.7, 94.6, 51.7, 27.6, and 13.4 IU/mL in CoronaVac recipients. Six-month convalescent seropositivity was 95.2%; GMC was 108.9 IU/mL. Seropositivity and GMCs were associated with age, sex, and time since vaccination.

Conclusions

Neutralizing Ab levels against ancestral SARS-CoV-2 from BBIBP-CorV or CoronaVac vaccination were similar and decreased with increasing time since vaccination; over half of 12-month post-vaccination subjects were seropositive. Seropositivity and GMCs from BBIBP-CorV and CoronaVac six and nine months after vaccination were similar to or slightly lower than in six-month convalescent sera. These real-world data suggest necessity of six-month booster doses.
The efficacy of immune checkpoint inhibitors in advanced EGFR-Mutated non-small cell lung cancer after resistance to EGFR-TKIs: Real-World evidence from a multicenter retrospective study
Authors: Hu Jia , Huang Di , Wang Yanrong , Li Donghui , Yang Xuejiao , Fu Yan , Du Nan , Zhao Yan , Li Xiaosong , Ma Junxun , Hu Yi
Published: September 2022

Background

The efficacy of immune checkpoint inhibitors (ICIs) in pretreated EGFR-mutated non-small cell lung cancer (NSCLC) patients is controversial. We conducted this multicenter retrospective study to examine the efficacy of ICIs in a real world setting.

Patients and methods

We collected 116 consecutive NSCLC patients with sensitive EGFR mutations who received ICIs alone or in combination after failure to respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and 99 patients were included for final analysis. The impacts of ICIs on the patients’ objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. The relationships between outcomes and clinical characteristics were analyzed.

Results

The ORR in patients with target lesions was 31.25% (95% CI: 22.18-41.52), and the DCR in all patients was 65.66% (95% CI: 55.44-74.91). The overall median PFS was 5.0 months (95% CI: 3.0-6.6), and the median OS was 15.9 months (95% CI: 10.8-23.8). The outcomes were better in patients receiving combination therapy with ECOG scores of 0-1 and no more than 2 lines of prior therapy, with a median PFS of 7.4 months (95% CI: 3.0-13.3) and a median OS of 29.0 months (95% CI: 11.7-NE). Primary EGFR mutation type and treatment mode were found to have a notable impact on clinical outcomes. Both median PFS and OS in patients with EGFR L858R mutation were significantly shorter than those in patients with EGFR exon 19 deletion (19del) (PFS: 2.5 versus 6.7 months, HR: 1.80, log-rank P=0.011; OS: 9.8 versus 26.9 months, HR: 2.48, log-rank P=0.002). Patients receiving combination therapy had notably longer median PFS and OS than those receiving monotherapy (PFS: 5.2 versus 3.0 months, HR: 0.54, log-rank P=0.020; OS: 19.0 versus 7.4 months, HR: 0.46, log-rank P=0.009).

Conclusions

Our study suggests that ICI-based combination therapy is a potential strategy for EGFR-mutated NSCLC patients after EGFR-TKI failure. The efficacy may differ according to EGFR subtypes.
CARD9 deficiency predisposing chromoblastomycosis: A case report and comparative transcriptome study
Authors: Huang Chen , Deng Weiwei , Zhang Yi , Zhang Kai , Ma Yubo , Song Yinggai , Wan Zhe , Wang Xiaowen , Li Ruoyu
Published: September 2022

CARD9 mutations are known to predispose patients to phaeohyphomycosis caused by different dematiaceous fungal species. In this study, we report for the first time a patient of chromoblastomycosis caused by Phialophora expanda, who harbored CARD9 mutation. Through a series of in vivo and in vitro studies, especially a comparative transcriptome study, we compared this case with our former patient suffering from phaeohyphomycosis caused by Phialophora americana. We showed that P. expanda is prone to forming sclerotic bodies both in vitro and in Card9 knockout mice, and has a stronger immunogenicity than P. americana. These data preliminary demonstrated that besides host defense, fungal specificity also contributed to the clinical phenotype in CARD9 deficient patients with dematiaceous fungal infections.
Predictive models for thromboembolic events in giant cell arteritis: A US veterans health administration population-based study
Authors: Michailidou Despina , Zhang Tianyu , Kuderer Nicole M. , Lyman Gary H. , Diamantopoulos Andreas P. , Stamatis Pavlos , Ng Bernard
Published: September 2022

Giant cell arteritis (GCA) that affects older patients is an independent risk factor for thromboembolic events. The objective of this study was to identify predictive factors for thromboembolic events in patients with GCA and develop quantitative predictive tools (prognostic nomograms) for pulmonary embolism (PE) and deep venous thrombosis (DVT). A total of 13,029 patients with a GCA diagnosis were included in this retrospective study. We investigated potential predictors of PE and DVT using univariable and multivariable Cox regression models. Nomograms were then constructed based on the results of our Cox models. We also assessed the accuracy and predictive ability of our models by using calibration curves and cross-validation concordance index. Age, inpatient status at the time of initial diagnosis of GCA, number of admissions before diagnosis of GCA, and Charlson comorbidity index were each found to be independent predictive factors of thromboembolic events. Prognostic nomograms were then prepared based on these predictors with promising prognostic ability. The probability of developing thromboembolic events over an observation period of 5 years was estimated by with time-to-event analysis using the method of Kaplan and Meier, after stratifying patients based on predicted risk. The concordance index of the time-to-event analysis for both PE and DVT was > 0.61, indicating a good predictive performance. The proposed nomograms, based on specific predictive factors, can accurately estimate the probability of developing PE or DVT among patients with GCA.
Spatiotemporal variability and climate teleconnections of global ocean wave power
Authors: Cao Chuanchuan , Chen Ge , Qian Chengcheng , Shang Jie
Published: September 2022

Climate change impacts have driven a transformation of the global energy system. The utilization of renewable energies is required to meet energy demands while protecting the environment. Wind-generated waves, carrying energy from the atmosphere, are a possible energy supply. However, global and long-term variability in wave resources due to the effects of climate change remain uncertain. This study quantified the spatiotemporal patterns and availability of global wave power (GWP) based on the ERA5 hourly and monthly reanalysis products, spanning from 1979 to 2020. The most promising wave resources appeared centralized in the westerlies of both hemispheres, and the wave power exhibited a “rich-get-richer” trend in the Southern Ocean, dominating the overall distribution and variability of GWP. Significant seasonal and interannual oscillation trends in GWP were observed, but with little variations on daily and hourly time scales. We found the average GWP in ERA5 products increased by 12.89% suddenly in 1991, mainly caused by the beginning of altimeter assimilation. This also implies the potential underestimation of wave fields in the modeling results before the advent of altimeter. In the altimeter era, annual GWP exhibits (quasi-) decadal oscillation (variation near ±4%), which differed from the monotonous increases previously reported. An analysis and source tracing based on the climate teleconnections indexes revealed that the primary climate driver of the variability was the Southern Annual Mode (r = 0.84). This study provides scientific guidance for wave power utilization and helps deepen our understanding of air-sea interactions.
A new technique of quantifying protoporphyrin IX in microbial cells in seawater
Authors: Gu Lide , Yue Xinli , Zhong Haowen , Mei Kang , Wang Deli
Published: September 2022

Protoporphyrin IX (PPIX), a fundamental precursor in the synthesis of heme and chlorophyll, plays a vital role in the biological metabolism and biogeochemical cycling in the ocean. PPIX has previously been identified in humans, animals, and plants, while so far as we know, there is no measurements until now regarding its contents in microbes, and especially in marine phytoplankton and bacteria. Here, for the first time, we reported a method of determining PPIX in marine microbial cells via acetone extraction followed by reversed phase high-performance liquid chromatography quantification, in which acetone-acetonitrile/water-formic acid buffer was used as a gradient elution solvent. The method was optimized with the detection limit of 3.8 ± 1.0 pM, and recovery rate of 97.5 ± 1.9%. The structure of the extracted PPIX was further confirmed using tandem mass spectrometry as positively associated with specific protonated molecules [M + H]+. The method was then successfully applied in the determination of PPIX in microbial cells in the water samples collected from a median-sized subtropical estuary (the Jiulong River Estuary, China). The results showed that PPIX existed widely and ranged from 20 – 170 ng/L in cells in the water samples. In the whole estuary, cellular PPIX generally decreased linearly with increasing salinity. A positive correlation of PPIX with particulate organic matter in the estuary suggested of sediment suspension and dissolution as its possible source. In addition, a general hyperbolic fitting pattern was observed for PPIX against dissolved inorganic nitrogen, PO43−, and the bacterial abundance (104 – 106 cells/mL) in the estuary. Such results indicated that PPIX played a crucial role in linking nutrients and the microbial productivity. In summary, we developed a new technique of quantifying cellular PPIX in water samples and confirmed the wide existence of cellular PPIX in natural waters. The data from Jiulong River estuary further suggest that the contents of cellular PPIX be enhanced with the nutrient supply from riverine inputs and sediment suspensions, which thereafter dictate the productivity of phytoplankton and bacteria in coastal waters.
A 3D-printed Sn-doped calcium phosphate scaffold for bone tissue engineering
Authors: Liang Hong , Fu Gaosheng , Liu Jinrui , Tang Yueting , Wang Yujue , Chen Shan , Zhang Yanjie , Zhang Chen
Published: September 2022

Recent developments in 3D printing technology have been applied in the field of tissue engineering to fabricate customized bone repair scaffolds. β-tricalcium phosphate (β-TCP) is a bioceramic material with excellent potential as a scaffold foundation. Doping metallic ions with β-TCP will significantly enhance the mechanical property and bone regeneration performance compared with pure β-TCP specimens. In this study, we proposed a protocol for the fabrication of a Sn-doped β-TCP (Sn@TCP) scaffold using 3D printing technology, and the effect of Sn-doping on the physicochemical properties of the material and its in vitro bioactivity were investigated. Polyethylene glycol and polyvinyl alcohol were used as binder to construct Sn@TCP scaffolds which have good biocompability and can break down into H2O and CO2 after scaffolds sintering. The appearance of the scaffold constructed by 3D printing technology closely matched the computer design. The incorporation of Sn into β-TCP improved the compressive strength of the scaffold. Moreover, the Sn@TCP scaffold retained the inherently good biocompatibility of β-TCP and exhibited better osteoinduction capability than pure β-TCP scaffolds. Notably, the osteoinduction ability of Sn@TCP scaffolds were dependent on the Sn content. In conclusion, the 3D printing of Sn@TCP scaffolds with enhanced mechanical properties and osteoblast-inducing activity show great promise as scaffold materials in bone tissue engineering applications.
Modeling the effect of temperature and notch root radius on fracture toughness
Authors: Deng Yong , Zhang Chao , Shao Jiaxing , Li Weiguo
Published: September 2022

In this work, a physics-based analytical model without any fitting parameters for fracture toughness depending on temperature was proposed. The quantitative relationship between fracture toughness, melting point, Young’s modulus, Poisson’s ratio, and temperature was established. Furthermore, the effect of notch root radius on fracture toughness was investigated, and then we developed a simple theoretical model to characterize the combined effect of temperature and notch root radius on the fracture toughness. Satisfactory agreement between the available experimental measurements and our model predictions was achieved. This study not only advances our in-depth understanding of the quantitative relationship between the temperature and fracture toughness but also provides a powerful and convenient tool to predict the temperature-dependent fracture toughness at different notch root radius.
Influences of exocrine pancreatic insufficiency on nutrient digestibility, growth parameters as well as anatomical and histological morphology of the intestine in a juvenile pig model
Authors: Schubert Dana Carina , Mößeler Anne , Ahlfänger Bianca , Langeheine Marion , Brehm Ralph , Visscher Christian , Abd El-Wahab Amr , Kamphues Josef
Published: September 2022

In a pig model, pancreatic duct ligation (PL) leads to a complete loss of exocrine function, causing an exocrine pancreatic insufficiency (EPI) without affecting endocrine function, allowing research of clinical effects and therapy options. This study aimed to investigate effects of experimentally induced EPI in juvenile pigs on digestion and intestinal morphology. Eight female juvenile cross-bred pigs (BW 54.8 kg at the start of the study) were included. Three animals were considered as a control (CON group), and in five animals the ductus pancreaticus accessorius was ligated (PL group). During the 10-week trial period, body weight and body measurements were recorded regularly. At the end of the trial, gastrointestinal tract (GIT) was investigated macroscopically and histologically and weight and digesta samples of individual segments were obtained. The pigs in the CON showed a significantly higher apparent total tract digestibility of crude protein and crude fat (87.8 and 79.9%, respectively) compared to PL (52.4 and 16.6%, respectively). Significant differences were noted in relative weights of duodenum, jejunum and colon (with and without digesta) and also in absolute weights of jejunum and colon. The mean number of nuclei in the transverse section in stratum circulare were significantly higher in all intestinal segments in CON compared to PL. Overall, EPI results in impaired nutrient digestibility with a greater filling of the GIT with digesta. The elongation of the small intestine does not represent “stretching” of the intestine, but rather increased synthesis of intestinal tissue.
New formulation of a recombinant anthrax vaccine stabilised with structurally modified plant viruses
Authors: Granovskiy Dmitriy L. , Ryabchevskaya Ekaterina M. , Evtushenko Ekaterina A. , Kondakova Olga A. , Arkhipenko Marina V. , Kravchenko Tatiana B. , Bakhteeva Irina V. , Timofeev Vitalii S. , Nikitin Nikolai A. , Karpova Olga V.
Published: September 2022

Anthrax is a disease caused by Bacillus anthracis. The most promising approach to the development of anthrax vaccine is use of the anthrax protective antigen (PA). At the same time, recombinant PA is a very unstable protein. Previously, the authors have designed a stable modified recombinant anthrax protective antigen with inactivated proteolytic sites and substituted deamidation sites (rPA83m). As a second approach to recombinant PA stabilisation, plant virus spherical particles (SPs) were used as a stabiliser. The combination of these two approaches was shown to be the most effective. Here, the authors report the results of a detailed study of the stability, immunogenicity and protectiveness of rPA83m + SPs compositions. These compositions were shown to be stable, provided high anti-rPA83m antibody titres in guinea pigs and were able to protect them from a fully virulent 81/1 Bacillus anthracis strain. Given these facts, the formulation of rPA83m + SPs compositions is considered to be a prospective anthrax vaccine candidate.
A novel hydrophobin encoded by hgfII from Grifola frondosa exhibiting excellent self-assembly ability
Authors: Yang Jiuxia , Ge Lu , Song Bo , Ma Zhongqiang , Yang Xiaotian , Wang Bo , Dai Yixin , Xu Haijin , Qiao Mingqiang
Published: September 2022

Hydrophobins are small proteins from filamentous fungi, which have remarkable self-assembly properties of great potential, e.g., as drug carriers and as anti-bacterial agents, but different hydrophobins, with improved properties, are needed. HGFI (a hydrophobin from Grifola frondosa) is a class I hydrophobin, which can self-assemble into rodlet structures with a length range 100–150 nm. In this study, we identified a new hydrophobin gene (hgfII) from the mycelium of G. frondosa with a much higher transcriptional level than hgfI. Heterologous expression of hgfII was accomplished in the Pichia pastoris. X-ray photoelectron spectroscopy and water contact angle assay measurements revealed that HGFII can self-assemble into a protein film at the air–solid interface, with circular dichroism and thioflavin T fluorescence studies showing that this effect was accompanied by a decrease in α-helix content and an increase in β-sheet content. Using atomic force microscopy, it was shown that HGFII self-assembled into rodlet-like structures with a diameter of 15–30 nm, showing that it was a class I hydrophobin, with self-assembly behavior different from HGFI. The surface hydrophobicity of HGFII was stronger than that of HGFI, meanwhile, in emulsification trials, HGFII displayed better dispersive capacity to the soybean oil than HGFI, producing a more stable and durable emulsion.
Effects of simulated acid rain on rhizosphere microorganisms of invasive Alternanthera philoxeroides and native Alternanthera sessilis
Authors: He Mengying , Hua Zexun , Chen Hanying , Liu Yao , Li Yue , Zhang Zhen
Published: September 2022

Acid rain not only has serious harm to the environment, but also has the same threat to plants, but the invasive plant Alternanthera philoxeroides still grows well compared to the native plant Alternanthera sessilis under acid rain stress. However, the underlying mechanism of resistance to the acid rain environment in invasive Alternanthera philoxeroides remains unclear. In the current study, we comparatively analyzed the plant physiological characteristics, soil physicochemical properties, and rhizosphere microbial communities of invasive A. philoxeroides and native A. sessilis under different pH condition. The simulated acid rain had a significant inhibitory effect on the morphological and physiological traits of A. philoxeroides and A. sessilis and reduced the soil nutrient content. However, A. philoxeroides was more tolerant of acid rain. Compared with CK, simulated acid rain treatment at pH 2.5 significantly increased the Chao1, ACE, and Shannon indexes of A. philoxeroides microorganisms. Under simulated acid rain treatment at pH 2.5, the fungal flora Chao1, ACE and Shannon index were significantly higher than those of CK by 14.5%, 12.4%, and 30.4%, respectively. The dominant bacterial phyla of soil bacteria were Proteobacteria, Actinobacteria, Bacteroidota, Actinobacteria, Firmicutes, Myxococcota, Chloroflexi, Patescibacteria, Gemmatimonadota, Verrucomicrobiota, and Armatimonadota. The dominant fungi were Ascomycota, Basidiomycota, Rozellomycota, and Olpidiomycota. The bacterial and fungal diversity and structure of A. philoxeroides and A. sessilis showed the greatest difference between the pH 2.5 treatment and CK. Redundancy analysis showed that electrical conductivity (EC) and total phosphorus (TP) were the main factors changing the bacterial communities, and available phosphorus (AP), organic matter (OM), EC, and pH were the main factors changing the fungal communities. This study contributes to the microbial community structure of the invasive plant A. philoxeroides and provides a theoretical basis for studying the invasion mechanism of invasive plants under acid rain.
The combination of diethyldithiocarbamate and copper ions is active against Staphylococcus aureus and Staphylococcus epidermidis biofilms in vitro and in vivo
Authors: Kaul Laurine , Abdo Adrian I. , Coenye Tom , Krom Bastiaan P. , Hoogenkamp Michel A. , Zannettino Andrew C. W. , Süss Regine , Richter Katharina
Published: September 2022

Staphylococcus aureus and Staphylococcus epidermidis are associated with life-threatening infections. Despite the best medical care, these infections frequently occur due to antibiotic resistance and the formation of biofilms of these two bacteria (i.e., clusters of bacteria embedded in a matrix). As a consequence, there is an urgent need for effective anti-biofilm treatments. Here, we describe the antibacterial properties of a combination treatment of diethyldithiocarbamate (DDC) and copper ions (Cu2+) and their low toxicity in vitro and in vivo. The antibacterial activity of DDC and Cu2+ was assessed in vitro against both planktonic and biofilm cultures of S. aureus and S. epidermidis using viability assays, microscopy, and attachment assays. Cytotoxicity of DDC and Cu2+ (DDC-Cu2+) was determined using a human fibroblast cell line. In vivo antimicrobial activity and toxicity were monitored in Galleria mellonella larvae. DDC-Cu2+ concentrations of 8 μg/ml DDC and 32 μg/ml Cu2+ resulted in over 80% MRSA and S. epidermidis biofilm killing, showed synergistic and additive effects in both planktonic and biofilm cultures of S. aureus and S. epidermidis, and synergized multiple antibiotics. DDC-Cu2+ inhibited MRSA and S. epidermidis attachment and biofilm formation in the xCELLigence and Bioflux systems. In vitro and in vivo toxicity of DDC, Cu2+ and DDC-Cu2+ resulted in > 70% fibroblast viability and > 90% G. mellonella survival. Treatment with DDC-Cu2+ significantly increased the survival of infected larvae (87% survival of infected, treated larvae vs. 47% survival of infected, untreated larvae, p < 0.001). Therefore, DDC-Cu2+ is a promising new antimicrobial with activity against planktonic and biofilm cultures of S. epidermidis and S. aureus and low cytotoxicity in vitro. This gives us high confidence to progress to mammalian animal studies, testing the antimicrobial efficacy and safety of DDC-Cu2+.
A neuro-inspired computational model of life-long learning and catastrophic interference, mimicking hippocampus novelty-based dopamine modulation and lateral inhibitory plasticity
Authors: Afferni Pierangelo , Cascino-Milani Federico , Mattera Andrea , Baldassarre Gianluca
Published: September 2022

The human brain has a remarkable lifelong learning capability to acquire new experiences while retaining previously acquired information. Several hypotheses have been proposed to explain this capability, but the underlying mechanisms are still unclear. Here, we propose a neuro-inspired firing-rate computational model involving the hippocampus and surrounding areas, that encompasses two key mechanisms possibly underlying this capability. The first is based on signals encoded by the neuromodulator dopamine, which is released by novel stimuli and enhances plasticity only when needed. The second is based on a homeostatic plasticity mechanism that involves the lateral inhibitory connections of the pyramidal neurons of the hippocampus. These mechanisms tend to protect neurons that have already been heavily employed in encoding previous experiences. The model was tested with images from the MNIST machine learning dataset, and with more naturalistic images, for its ability to mitigate catastrophic interference in lifelong learning. The results show that the proposed biologically grounded mechanisms can effectively enhance the learning of new stimuli while protecting previously acquired knowledge. The proposed mechanisms could be investigated in future empirical animal experiments and inspire machine learning models.
Leflunomide combined with low-dose prednisone inhibits proinflammatory T cells responses in myasthenia gravis patients
Authors: Huang Xin , Ran Hao , Li Yingkai , Ma Qian , Ou Changyi , Qiu Li , Feng Huiyu , Liu Weibin
Published: September 2022

We previously found that leflunomide combined with low-dose prednisone rapidly improved the clinical symptoms of myasthenia gravis (MG), but we had not investigated the mechanism of this phenomenon. This study documents the effect of leflunomide combined with low-dose prednisone on pro-inflammatory T cells in MG patients. We compared 32 treated MG patients with 18 controls. We collected peripheral blood before treatment and 4, 8, and 12 weeks after treatment. We extracted peripheral blood mononuclear cells (PBMCs) and stimulated them with phorbol 12-myristate 13-acetate (PMA) + ionomycin and quantified IFN-γ, IL-4, IL-17, and IL-9 secretion through ELISA. We quantified T helper (Th) cells Th1 (CD3+CD4+IFN-γ+), Th2 (CD3+CD4+IL-4+), Th17 (CD3+CD4+IL-17A+) and Th9 (CD3+CD4+IL-9+) among PBMCs. The treatment significantly reduced IL-17 and IL-9 secretion in peripheral blood but did not affect IFN-γ levels. Significant decreases in IL-17 and IL-9 appeared at week 12, and the trend of change was similar to that of the MG composite score. Flow cytometry indicated that leflunomide combined with low-dose prednisone significantly reduced the frequency of Th1 and Th17 cells. These findings demonstrate the potential of this treatment as an alternative immunosuppressive therapy for MG.
Visually driven functional MRI techniques for characterization of optic neuropathy
Authors: Sujanthan Sujeevini , Shmuel Amir , Mendola Janine Dale
Published: September 2022

Optic neuropathies are conditions that cause disease to the optic nerve, and can result in loss of visual acuity and/or visual field defects. An improved understanding of how these conditions affect the entire visual system is warranted, to better predict and/or restore the visual loss. In this article, we review visually-driven functional magnetic resonance imaging (fMRI) studies of optic neuropathies, including glaucoma and optic neuritis (ON); we also discuss traumatic optic neuropathy (TON). Optic neuropathy-related vision loss results in fMRI deficit within the visual cortex, and is often strongly correlated with clinical severity measures. Using predominantly flickering checkerboard stimuli, glaucoma studies indicated retinotopic-specific cortical alteration with more prominent deficits in advanced than in early glaucoma. Some glaucoma studies indicate a reorganized visual cortex. ON studies have indicated that the impacted cortical areas are briefly hyperactive. For ON, brain deficits are greater in the acute stages of the disease, followed by (near) normalization of responses of the LGN, visual cortex, and the dorsal visual stream, but not the ventral extrastriate cortex. Visually-driven fMRI is sensitive, at least in ON, in discriminating patients from controls, as well as the affected eye from the fellow eye within patients. The use of a greater variety of stimuli beyond checkerboards (e.g., visual motion and object recognition) in recent ON studies is encouraging, and needs to continue to disentangle the results in terms of change over time. Finally, visually-driven fMRI has not yet been applied in TON, although preliminary efforts suggest it may be feasible. Future fMRI studies of optic neuropathies should consider using more complex visual stimuli, and inter-regional analysis methods including functional connectivity. We suggest that a more systematic longitudinal comparison of optic neuropathies with advanced fMRI would provide improved diagnostic and prognostic information.
The attention-emotion interaction in healthy female participants on oral contraceptives during 1-week escitalopram intake
Authors: Beinhölzl Nathalie , Molloy Eóin N. , Zsido Rachel G. , Richter Thalia , Piecha Fabian A. , Zheleva Gergana , Scharrer Ulrike , Regenthal Ralf , Villringer Arno , Okon-Singer Hadas , Sacher Julia
Published: September 2022

Previous findings in healthy humans suggest that selective serotonin reuptake inhibitors (SSRIs) modulate emotional processing via earlier changes in attention. However, many previous studies have provided inconsistent findings. One possible reason for such inconsistencies is that these studies did not control for the influence of either sex or sex hormone fluctuations. To address this inconsistency, we administered 20 mg escitalopram or placebo for seven consecutive days in a randomized, double-blind, placebo-controlled design to sixty healthy female participants with a minimum of 3 months oral contraceptive (OC) intake. Participants performed a modified version of an emotional flanker task before drug administration, after a single dose, after 1 week of SSRI intake, and after a 1-month wash-out period. Supported by Bayesian analyses, our results do not suggest a modulatory effect of escitalopram on behavioral measures of early attentional-emotional interaction in female individuals with regular OC use. While the specific conditions of our task may be a contributing factor, it is also possible that a practice effect in a healthy sample may mask the effects of escitalopram on the attentional-emotional interplay. Consequently, 1 week of escitalopram administration may not modulate attention toward negative emotional distractors outside the focus of attention in healthy female participants taking OCs. While further research in naturally cycling females and patient samples is needed, our results represent a valuable contribution toward the preclinical investigation of antidepressant treatment.
The plasticity of cardiac sympathetic nerves and its clinical implication in cardiovascular disease
Authors: Kanazawa Hideaki , Fukuda Keiichi
Published: September 2022

The heart is electrically and mechanically controlled by the autonomic nervous system, which consists of both the sympathetic and parasympathetic systems. It has been considered that the sympathetic and parasympathetic nerves regulate the cardiomyocytes’ performance independently; however, recent molecular biology approaches have provided a new concept to our understanding of the mechanisms controlling the diseased heart through the plasticity of the autonomic nervous system. Studies have found that cardiac sympathetic nerve fibers in hypertrophic ventricles strongly express an immature neuron marker and simultaneously cause deterioration of neuronal cellular function. This phenomenon was explained by the rejuvenation of cardiac sympathetic nerves. Moreover, heart failure and myocardial infarction have been shown to cause cholinergic trans-differentiation of cardiac sympathetic nerve fibersviagp130-signaling cytokines secreted from the failing myocardium, affecting cardiac performance and prognosis. This phenomenon is thought to be one of the adaptations that prevent the progression of heart disease. Recently, the concept of using device-based neuromodulation therapies to attenuate sympathetic activity and increase parasympathetic (vagal) activity to treat cardiovascular disease, including heart failure, was developed. Although several promising preclinical and pilot clinical studies using these strategies have been conducted, the results of clinical efficacy vary. In this review, we summarize the current literature on the plasticity of cardiac sympathetic nerves and propose potential new therapeutic targets for heart disease.
Arbutin improves gut development and serum lipids via Lactobacillus intestinalis
Authors: Ma Jie , Chen Shuai , Li Yuying , Wu Xin , Song Zehe
Published: September 2022

Arbutin has been widely studied in whitening, anti-inflammatory, and antioxidant. However, the interaction between arbutin and intestinal microbes has been rarely studied. Thus, mice were treated with arbutin concentrations of 0, 0.1, 0.2, 0.4, and 1 mg/ml. We found that arbutin promoted gut development such as villus length, villus areas, and villus length/crypt depth (L/D). Total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were significantly reduced by low concentrations of arbutin. Importantly, we analyzed the microbial composition in the control and 0.4 mg/ml arbutin group and found that the abundance of Lactobacillus intestinalis (L. intestinalis) was highest and enhanced in arbutin. Further, mice were fed with oral antibiotics and antibiotics + 0.4 mg/ml arbutin and then we transplanted fecal microbes from oral 0.4 mg/ml arbutin mice to mice pretreated with antibiotics. Our results showed that arbutin improves gut development, such as villus width, villus length, L/D, and villus areas. In addition, L. intestinalis monocolonization was carried out after a week of oral antibiotics and increased villus length, crypt depth, and villus areas. Finally, in vitro arbutin and L. intestinalis co-culture showed that arbutin promoted the growth and proliferation of L. intestinalis. Taken together, our results suggest that arbutin improves gut development and health of L. intestinalis. Future studies are needed to explore the function and mechanism of L. intestinalis affecting gut development.
The causal association of polyunsaturated fatty acids with allergic disease: A two-sample Mendelian randomization study
Authors: Li Yajia , Li Qiangxiang , Cao Ziqin , Wu Jianhuang
Published: September 2022

Objectives

Previous studies have reported a potential association of polyunsaturated fatty acids (PUFAs) levels with allergic disease risk and the possible benefit of PUFAs supplementation on allergic disease prevention. This study was performed to estimate the genetic association between PUFAs and allergic diseases using the method of both univariable and multivariable two-sample Mendelian randomization (MR).

Methods

As indicators of the PUFAs levels, we included the omega-3, omega-6, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), linoleic acid (LA), and the ratio of omega-6 to omega-3 (omega-6:3). Summarized statistics of genome-wide association studies (GWASs) for these PUFAs were obtained from the United Kingdom Biobank and the Twins United Kingdom cohort. Genetic data relating to allergic diseases, including atopic dermatitis (AD), allergic rhinitis (AR), allergic conjunctivitis (AC), allergic urticaria (AU) and asthma, were accessed from the FinnGen biobank analysis. Odds ratios and 95% CIs were used to express the impact.

Results

The MR results denoted a genetic association between the genetically determined increase in omega-3 levels and the decreased risk of some allergic diseases including AD (OR: 0.863; 95% CI: 0.785 to 0.949; p = 3.86E-03), AC (OR:0.720; 95% CI: 0.547 to 0.947; p = 1.87E-02) and AU (OR:0.821; 95% CI: 0.684 to 0.985; p = 3.42E-02), while omega-6 and DHA level was only found to have negatively correlation with risk of AC with ORs of 0.655 (95% CI: 0.445 to 0.964; p = 3.18E-02) and 0.671 (95% CI 0.490 to 0.918; p = 1.25E-02), respectively. Omega-6:3 were causally significantly associated with the increased risk of AD (OR:1.171; 95% CI: 1.045 to 1.312; p = 6.46E-03) and AC (IVW: OR:1.341; 95% CI: 1.032 to 1.743; p = 2.83E-02). After adjustment of age, economic level, BMI, smoking and alcohol behaviors in the multivariable MR analysis, a direct causal protective effect of omega-3 on AD and AC, as well as a direct causal association between DHA and AD were observed. Omega-6:3 was also found to be directly associated with an increased risk of AD and AC. No association was found of EPA or LA with allergic diseases.

Conclusion

Higher PUFA concentrations (omega-3, omega-6, DHA) and lower omega-6:3 ratios were genetically associated with a lower risk of some allergic diseases.
Effects of various logistics packaging on the quality and microbial variation of bigeye tuna (Thunnus obesus)
Authors: Cheng Zhizhen , Pan Weicong , Xian Wendong , Yu Jin , Weng Xudong , Benjakul Soottawat , Guidi Alessandra , Ying Xiaoguo , Deng Shanggui
Published: September 2022

Bigeye tuna (Thunnus obesus) is an economically valuable ocean fish species. It is susceptible to contamination during storage and transportation. Having proper transportation packaging and stable temperature during transportation are critical to prevent quality deterioration. However, the influence of packaging on retaining freshness in transit remains unknown. Here, the impact of different transportation packaging on the quality and microbiological variation of bigeye tuna during the logistics process was investigated by measuring physical-chemical indexes and microbial diversity. It turned out that aluminum foil paper (AFP) group had minimum temperature fluctuation, exhibited preferable water retaining capacity and color protection effect. AFP packaging could efficiently prevent TVB-N increase and microbial growth. After 40 h, the TVB-N value was 21.28 mg/100 g and microbial total plate count was 3.53 lg CFU/g, which was within the acceptable range. Temperature fluctuations and packaging materials had a major effect on the microbial community structure of bigeye tuna. Chitinophagaceae, Acinetobacter, and Knoellia were dominant in the AFP group, while Pseudomonas, Acinetobacter, and Macrococcus were dominant in the expanded polystyrene foam (EPSF) and European logistics (EUL) groups. AFP packaging could effectively slow down the growth and reproduction of Pseudomonas, restraining the growth of microorganisms and preserve the quality of bigeye tuna. This study provides insights into understanding the effects of packaging material on maintaining quality during logistics transportation.
Sintilimab maintenance therapy post first-line cytokine-induced killer cells plus chemotherapy for extensive-stage small cell lung cancer
Authors: Ma Baozhen , Zhou Yu , Shang Yiman , Zhang Yong , Xu Benling , Fu Xiaomin , Guo Jindong , Yang Yonghao , Zhang Fang , Zhou Mengyuan , Huang Hao , Li Fanghui , Lin Hongwei , Zhao Lingdi , Wang Zibing , Gao Quanli
Published: September 2022

Despite recent progress in treating advanced non-small cell lung cancer, clinical intervention in extensive-stage small-cell lung cancer (ES-SCLC) remains stagnant. The purpose of this study was to evaluate the clinical efficacy of cytokine-induced killer (CIK) cells combined with cytotoxic chemotherapy, followed by anti-programmed death 1 antibody (sintilimab) maintenance, in ES-SCLC patients. To explore a new method for safe treatment of ES-SCLC patients, thirteen ES-SCLC patients were enrolled between June 2019 and December 2021. All patients received first-line chemotherapy (etoposide plus platinum) combined with CIK cell therapy. Patients who reached a stable disease state or responded well to treatment received sintilimab maintenance treatment. The primary objective of this study was to determine the median overall survival (OS); the secondary objective was to assess the objective response rate (ORR), progression-free survival 1 and 2 (PFS1 was defined as the duration from the signing of informed consent to the date of tumor progression, or death, or the last follow-up. PFS2 was defined as the duration from the first day of sintilimab treatment to the date of tumor progression, death, or the last follow-up.), and adverse reactions. At a 24.1-month follow-up, the median OS was 11.8 (95% confidence interval [CI]: 10.6–13.0) months, median PFS1 was 5.5 (95% CI: 5.0–6.0) months, and the median PFS2 was 2.3 (95% CI: 0.5–4.1) months. The ORR was 76.9% (10/13), the disease control rate was 100% (13/13), and the 20-month survival rate was 41.7%. Eight participants exhibited grade 3 or 4 adverse events after combination therapy. During maintenance treatment with sintilimab, level 3 adverse events occurred in 1 patient (1/9). In conclusion, adding CIK cells to standard chemotherapy regimens, followed by maintenance therapy with sintilimab, may represent a new safe and effective treatment strategy.

Clinical trial registration

ClinicalTrials.gov (NCT03983759)