bluuebunny/crossref_metadata_2025 huggingface dataset:
Glioma-derived CCL2 and CCL7 mediate migration of immune suppressive CCR2+/CX3CR1+ M-MDSCs into the tumor microenvironment in a redundant manner
Authors: Takacs Gregory P. , Kreiger Christian J. , Luo Defang , Tian Guimei , Garcia Julia S. , Deleyrolle Loic P. , Mitchell Duane A. , Harrison Jeffrey K.
Published: January 2023

Glioblastoma (GBM) is the most common and malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized in part by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive, hematopoietic cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a potent subset of myeloid cells, expressing monocytic (M)-MDSC markers, distinguished by dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate into the TME. This study evaluated the T cell suppressive function and migratory properties of CCR2+/CX3CR1+ MDSCs. Bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Recombinant and glioma-derived CCL2 and CCL7 induce the migration of CCR2+/CX3CR1+ MDSCs with similar efficacy. KR158B-CCL2 and -CCL7 knockdown murine gliomas contain equivalent percentages of CCR2+/CX3CR1+ MDSCs compared to KR158B gliomas. Combined neutralization of CCL2 and CCL7 completely blocks CCR2-expressing cell migration to KR158B cell conditioned media. CCR2+/CX3CR1+ cells are also reduced within KR158B gliomas upon combination targeting of CCL2 and CCL7. High levels of CCL2 and CCL7 are also associated with negative prognostic outcomes in GBM patients. These data provide a more comprehensive understanding of the function of CCR2+/CX3CR1+ MDSCs and the role of CCL2 and CCL7 in the recruitment of these immune suppressive cells and further support the significance of targeting this chemokine axis in GBM.
Macrobenthic functional group analysis of ecological health of the intertidal artificial oyster reefs in the Yangtze Estuary, China
Authors: Zhang Yinan , Wan Hang , Zhao Yunlong , Ding Jiafeng , Zhu Zhenchang , Zhang Hangjun , Liu Zhiquan
Published: January 2023

The functional groups and the ecological health of a constructed oyster reef were investigated during April 2016 to October 2017 in the Yangtze estuary. The data of the long-term monitoring program (14 years) confirmed the feasibility of creating an artificial oyster reef in Yangtze estuary. One or two functional groups were absent from moderate salinity conditions (5.17% - 8.73%), while macrobenthos functional group species richness, abundance, and biomass were greatest under high salinity conditions. The feeding evenness index (jFD) showed that 14 years after construction, the ecosystem health of the artificial oyster reefs were good or high, and was better under high salinity conditions. Ecological health was lower under moderate levels of salinity, possibly due to the absence of some functional groups. Redundancy analysis indicated ecosystem health was associated with changes in salinity and substrate factors. Our study confirmed artificial oyster reef construction is feasible and has a positive effect on estuarine ecosystem health.
Global hotspots of shark interactions with industrial longline fisheries
Authors: Burns Echelle S. , Bradley Darcy , Thomas Lennon R.
Published: January 2023

Sharks are susceptible to industrial longline fishing due to their slow life histories and association with targeted tuna stocks. Identifying fished areas with high shark interaction risk is vital to protect threatened species. We harmonize shark catch records from global tuna Regional Fisheries Management Organizations (tRFMOs) from 2012–2020 and use machine learning to identify where sharks are most threatened by longline fishing. We find shark catch risk hotspots in all ocean basins, with notable high-risk areas off Southwest Africa and in the Eastern Tropical Pacific. These patterns are mostly driven by more common species such as blue sharks, though risk areas for less common, Endangered and Critically Endangered species are also identified. Clear spatial patterns of shark fishing risk identified here can be leveraged to develop spatial management strategies for threatened populations. Our results also highlight the need for coordination in data collection and dissemination by tRFMOs for effective shark management.
Sediment matters as a route of microplastic exposure: A call for more research on the benthic compartment
Authors: Sandgaard Monica Hamann , Palmqvist Annemette , Bour Agathe , Grønlund Sara Nicoline , Hooge Asta , Selck Henriette , Thit Amalie , Syberg Kristian
Published: January 2023

Microplastics (MPs) are ubiquitous in the marine environment. Here, most MPs are expected to sink, either due to polymer density or environmental processes, such as biofouling, leading to sediment being proposed to act as a final sink for marine MPs. There is a discrepancy between the anticipated accumulation of MPs in the sediment compartment and the MP experiments conducted, since most MP effect studies have been conducted with pelagic species using water-only exposures. Here we address fundamental questions in relation to MP pollution to close the knowledge gap related hereto. A systematic literature search was performed to address these questions. We found that benthic invertebrates ingest MPs and that, even though these organisms evolutionary are adapted to handle particles, adverse effects may be observed upon ingestion of MPs. The analysis further revealed that there is a major knowledge gap on the impacts of sediment-associated MPs in marine, benthic invertebrates. To facilitate further and structured research within this topic, we recommend more studies with emphasis on the sediment as an important exposure pathway, and to focus on sediment-associated MP effects on benthic invertebrates. We recommend studies with ecological relevant exposure concentrations and ecological relevant exposure durations with emphasis on impacts on population- and community-level to reduce the knowledge gap within this central area of MP pollution research.
Emulating quantum dynamics with neural networks via knowledge distillation
Authors: Yao Yu , Cao Chao , Haas Stephan , Agarwal Mahak , Khanna Divyam , Abram Marcin
Published: January 2023

We introduce an efficient training framework for constructing machine learning-based emulators and demonstrate its capability by training an artificial neural network to predict the time evolution of quantum wave packets propagating through a potential landscape. This approach is based on the idea of knowledge distillation and uses elements of curriculum learning. It works by constructing a set of simple, but rich-in-physics training examples (a curriculum). These examples are used by the emulator to learn the general rules describing the time evolution of a quantum system (knowledge distillation). We show that this emulator is capable of learning the rules of quantum dynamics from a curriculum of simple training examples (wave packet interacting with a single rectangular potential barrier), and subsequently generalizes this knowledge to solve more challenging cases (propagation through an arbitrarily complex potential landscape). Furthermore, we demonstrate, that using this framework we can not only make high-fidelity predictions, but we can also learn new facts about the underlying physical system, detect symmetries, and measure relative importance of the contributing physical processes.
Effect of residual pore structure on the performance of TRISO particle fuel
Authors: Liu Shichao , Li Yuanming , Chen Ping , Zhou Yi , Tang Changbing
Published: January 2023

The thermal-mechanical performance of tri-isotropic (TRISO) particles with residual pores used in light water reactors (LWRs) was investigated. The effect of residual pore structure on the stress distribution of the inner dense pyrolytic carbon (IPyC) layer, SiC layer, and outer dense pyrolytic carbon (OPyC) layer was studied. The dimensional changes and fission gas release of the fuel particle layers were calculated. Residual pores on the SiC layer can affect the stress distribution of the coated layers. The residual pores, especially the tetrahedrons, may be the source of cracks in the SiC layer, which can break or cause the loss of the capacity of the SiC layer. Residual pores have little influence on the stress distribution of the IPyC and OPyC layers.
Tertiary lymphoid structures in the primary tumor site of patients with cancer-associated myositis: A case–control study
Authors: Kadota Hiroko , Gono Takahisa , Kunugi Shinobu , Ota Yuko , Takeno Mitsuhiro , Seike Masahiro , Shimizu Akira , Kuwana Masataka
Published: January 2023

Objective

To investigate histologic features of immunological components in the primary tumor site of patients with cancer-associated myositis (CAM) by focusing on tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs), which play major roles in antitumor immunity.

Methods

Cancer-associated myositis patients were selected from the single-center idiopathic inflammatory myopathy cohort based on the availability of primary tumor specimens obtained before the introduction of immunomodulatory agents. Control cancer subjects without CAM were selected from the cancer tissue repository at a ratio of 1:2 matched for demographics and cancer characteristics of CAM cases. A series of immunohistochemical analyses was conducted using sequential tumor sections. TLS was defined as an ectopic lymphoid-like structure composed of DC-LAMP+ mature dendritic cells, CD23+ follicular dendritic cells (FDCs) and PNAd+ high endothelial venules. TLS distribution was classified into the tumor center, invasive margin, and peritumoral area.

Results

Six CAM patients and 12 matched non-CAM controls were eligible for the study. There was no apparent difference in the density or distribution of TILs between the groups. TLSs were found in 3 CAM patients (50%) and 4 non-CAM controls (33%). TLSs were exclusively located at the tumor center or invasive margin in CAM cases but were mainly found in the peritumoral area in non-CAM controls. FDCs and class-switched B cells colocalized with follicular helper T cells were abundantly found in the germinal center-like area of TLSs from CAM patients compared with those from non-CAM controls.

Conclusion

The adaptive immune response within TLSs in the primary tumor site might contribute to the pathogenic process of CAM.
Managing ulcerative colitis after surgery
Authors: Calvino-Suarez Cristina , Ferreiro-Iglesias Rocío , Baston Rey Iria , Barreiro-de Acosta Manuel
Published: January 2023

Management of ulcerative colitis after surgery suggested by guidelines (total proctocolectomy with ileal-pouch anal anastomosis) is a big challenge for physicians because patients who believed that their disease had been cured started experiencing very uncomfortable symptoms repeatedly. A high number of patients develop episodes of pouchitis, which is a non-specific inflammation of the pouch whose etiology is unknown. Antibiotics are the elective treatment for acute pouchitis, but regarding chronic pouchitis, this condition is very complicated to treat due to the absence of well-designed specific studies for this group of patients. Antibiotics, budesonide, and biological therapies are some of the recommended drugs for these patients, but despite their use, some need a permanent ileostomy.
Older veterans associated with reduced risk of cancer: Retrospective nationwide matched cohort study in Taiwan
Authors: Pan Li-Fei , Chang Renin , Hsu Chung Y. , Tsui Kuan-Hao
Published: January 2023

Importance

It remains unknown whether Taiwanese veterans have a lower risk of subsequent cancer compared with non-veterans.

Objective

To examine whether veterans are associated with reduced cancer risk.

Methods

From January 2004 to December 2017, this study included 957 veterans and 957 civilians who were propensity score (PS) matched by years of birth, sex, residence, index year, days in the hospital, frequency of outpatient visits, and relevant comorbidities at baseline. Multivariate Cox proportional hazards regression analysis was applied to compare the risks of cancer, overall and by subgroup, and mortality. All the participants were cancer free at the baseline.

Exposures

Veterans retrieved from Taiwan National Health Insurance Research Database (NHIRD).

Main outcome

Cancer extracted from the Registry for Catastrophic Illness Patients Database (RCIPD).

Results

Overall, 1,914 participants were included, and 957 veterans with a mean (SD) age of 75.9 (6.79) years and 946 men (98.9%). The mean follow-up was about 10.5 (±4.51) years. Cancer was recorded in 6.68% (N = 64) and 12.12% (N = 116) of veterans and non-veterans, respectively. Veterans were associated with decreased risk [adjusted hazard ratio (aHR), 0.57; 95% CI: 0.41–0.78; P < 0.001] of cancer compared with civilians after controlling for age, sex, urbanization, hypertension, diabetes, hyperlipidemia, cardiovascular event, COPD, asthma, chronic liver disease, alcohol-related illness, and Parkinson’s disease. Cancer subgroup analyses verified this finding (HRs <1.0). The decreased incidence rate was predominantly for liver cancer (aHR, 0.18; 95% CI: 0.05–0.72; P < 0.05).

Conclusion

Taiwanese older veterans are associated with reduced overall cancer risk than individuals without veteran status.
Severe hypoglycemia in patients with liver cirrhosis and type 2 diabetes
Authors: Yen Fu-Shun , Hou Ming-Chih , Liu Jia-Sin , Hsu Chih-Cheng , Hwu Chii-Min
Published: January 2023

Introduction

Advanced liver disease with massive liver damage may affect the metabolism of hypoglycemic agents and increase the risk of hypoglycemia. We conduct this research to compare the risk of severe hypoglycemia between patients with type 2 diabetes, with and without compensated liver cirrhosis.

Methods

From Taiwan’s National Health Insurance Research Database, we identified persons with type 2 diabetes with cirrhosis (n = 18,209) and without cirrhosis (n = 538,510) from January 1, 2000, to December 31, 2010. Cox proportional hazards models were adopted to assess risks of all-cause mortality and severe hypoglycemia.

Results

The mean follow-up period of this study was 3.7 years. The incidence rates of death during follow-up were 26.54 and 2.75 per 1,000 patient-years [aHR 7.63 (6.70–8.70)] for patients with cirrhosis and without cirrhosis, respectively. The incidence rates of severe hypoglycemia during follow-up were 0.53 and 0.14 per 1,000 patient-years [aHR 2.74 (1.52–4.92)] for patients with and without cirrhosis, respectively. The subgroup analysis of hypoglycemia risks in patients with and without cirrhosis disclosed no significant interaction for variables such as age, sex, chronic kidney disease, sulfonylurea use, number of oral antidiabetic drugs, insulin, b-blocker, and fibrate.

Conclusion

This cohort study demonstrated that patients with type 2 diabetes and compensated cirrhosis showed a higher risk of mortality and severe hypoglycemia than those without liver cirrhosis.
Metabolomics in hepatocellular carcinoma: From biomarker discovery to precision medicine
Authors: Wu Xingyun , Wang Zihao , Luo Li , Shu Dan , Wang Kui
Published: January 2023

Hepatocellular carcinoma (HCC) remains a global health burden, and is mostly diagnosed at late and advanced stages. Currently, limited and insensitive diagnostic modalities continue to be the bottleneck of effective and tailored therapy for HCC patients. Moreover, the complex reprogramming of metabolic patterns during HCC initiation and progression has been obstructing the precision medicine in clinical practice. As a noninvasive and global screening approach, metabolomics serves as a powerful tool to dynamically monitor metabolic patterns and identify promising metabolite biomarkers, therefore holds a great potential for the development of tailored therapy for HCC patients. In this review, we summarize the recent advances in HCC metabolomics studies, including metabolic alterations associated with HCC progression, as well as novel metabolite biomarkers for HCC diagnosis, monitor, and prognostic evaluation. Moreover, we highlight the application of multi-omics strategies containing metabolomics in biomarker discovery for HCC. Notably, we also discuss the opportunities and challenges of metabolomics in nowadays HCC precision medicine. As technologies improving and metabolite biomarkers discovering, metabolomics has made a major step toward more timely and effective precision medicine for HCC patients.
Colistin potentiation in multidrug-resistant Acinetobacter baumannii by a non-cytotoxic guanidine derivative of silver
Authors: Kumar Deepak , Singhal Chaitali , Yadav Manisha , Joshi Pooja , Patra Priyanka , Tanwar Subhash , Das Amitava , Kumar Pramanik Sumit , Chaudhuri Susmita
Published: January 2023

A novel nano-formulation (NF) that sensitizes Acinetobacter baumannii (AB) to otherwise ineffective colistin is described in the present study. Infections due to multidrug resistant (MDR) AB represent a major therapeutic challenge, especially in situations of pre-existing colistin resistance (colR). Subsequently, boosting the effectiveness of colistin would be a better alternative tactic to treat AB infections rather than discovering a new class of antibiotics. We have previously demonstrated an NF comprising self-assembled guanidinium and ionic silver nanoparticles [AD-L@Ag(0)] to have anti-biofilm and bactericidal activity. We report NF AD-L@Ag(0) for the very first time for the potentiation of colistin in Gram-negative colistin-resistant bacteria. Our results implied that a combination of clinically relevant concentrations of colistin and AD-L@Ag(0) significantly decreased colistin-resistant AB bacterial growth and viability, which otherwise was elevated in the presence of only colistin. In this study, we have described various combinations of minimum inhibitory concentration (MIC) of colistin (MICcol, 1/2 MICcol, and 1/4 MICcol) and that of AD-L@Ag(0) [MICAD-L@Ag(0), 1/2 MICAD-L@Ag(0), and 1/4 MICAD-L@Ag(0)] and tested them against MDR AB culture. The results (in broth as well as in solid media) signified that AD-L@Ag(0) was able to potentiate the anti-microbial activity of colistin at sub-MIC concentrations. Furthermore, the viability and metabolic activity of bacterial cells were also measured by CTC fluorescence assay and ATP bioluminescence assay. The results of these assays were in perfect concordance with the scores of cultures (colony forming unit and culture turbidity). In addition, quantitative real-time PCR (qRT-PCR) was performed to unveil the expression of selected genes, DNAgyrA, DNAgyrB, and dac. These genes introduce negative supercoiling in the DNA, and hence are important for basic cellular processes. These genes, due to mutation, modified the Lipid A of bacteria, further resisting the uptake of colistin. Therefore, the expression of these genes was upregulated when AB was treated with only colistin, substantiating that AB is resistant to colistin, whereas the combinations of MICcol + MICAD-L@Ag(0) downregulated the expression of these genes, implying that the developed formulation can potentiate the efficiency of colistin. In conclusion, AD-L@Ag(0) can potentiate the proficiency of colistin, further enhancing colistin-mediated death of AB by putatively disrupting the outer membrane (OM) and facilitating bacterial death.
Spread of the mcr-1 colistin-resistance gene in Escherichia coli through plasmid transmission and chromosomal transposition in French goats
Authors: Treilles Michaël , Châtre Pierre , Drapeau Antoine , Madec Jean-Yves , Haenni Marisa
Published: January 2023

Introduction

Colistin-resistance widely disseminated in food-producing animals due to decades of colistin use to treat diarrhea. The plasmid-borne mcr-1 gene has been extensively reported from bovine, swine and chicken worldwide, but smaller productions such as the goat farming sector were much less surveyed.

Methods

We looked for colistin-resistant isolates presenting plasmid-borne genes of the mcr family in both breeding (n=80) and fattening farms (n=5). Localization of the mcr-1 gene was performed using Southern blot analysis coupled to short-read and long-read sequencing.

Results

Only the mcr-1 gene was identified in 10% (8/80) of the breeding farms and four over the five fattening farms. In total, 4.2% (65/1561) of the animals tested in breeding farms and 60.0% (84/140) of those tested in fattening farms presented a mcr-1-positive E. coli. The mcr-1 gene was located either on the chromosome (32.2%) or on IncX4 (38.9%) and IncHI2 (26.8%) plasmids. As expected, both clonal expansion and plasmidic transfers were observed in farms where the mcr-1 gene was carried by plasmids. Tn6330 transposition was observed in the chromosome of diverse E. coli sequence types within the same farm.

Discussion

Our results show that the mcr-1 gene is circulating in goat production and is located either on plasmids or on the chromosome. Evidence of Tn6330 transposition highlighted the fact that chromosomal insertion does not impair the transmission capability of the mcr-1 gene. Only strict hygiene and biosecurity procedures in breeding farms, as well as a prudent use of antibiotics in fattening farms, can avoid such complex contamination pathways.
Diversity and prevalence of type VI secretion system effectors in clinical Pseudomonas aeruginosa isolates
Authors: Robinson Luca A. , Collins Alice C. Z. , Murphy Ronan A. , Davies Jane C. , Allsopp Luke P.
Published: January 2023

Pseudomonas aeruginosa is an opportunistic pathogen and a major driver of morbidity and mortality in people with Cystic Fibrosis (CF). The Type VI secretion system (T6SS) is a molecular nanomachine that translocates effectors across the bacterial membrane into target cells or the extracellular environment enabling intermicrobial interaction. P. aeruginosa encodes three T6SS clusters, the H1-, H2- and H3-T6SS, and numerous orphan islands. Genetic diversity of T6SS-associated effectors in P. aeruginosa has been noted in reference strains but has yet to be explored in clinical isolates. Here, we perform a comprehensive bioinformatic analysis of the pangenome and T6SS effector genes in 52 high-quality clinical P. aeruginosa genomes isolated from CF patients and housed in the Personalised Approach to P. aeruginosa strain repository. We confirm that the clinical CF isolate pangenome is open and principally made up of accessory and unique genes that may provide strain-specific advantages. We observed genetic variability in some effector/immunity encoding genes and show that several well-characterised vgrG and PAAR islands are absent from numerous isolates. Our analysis shows clear evidence of disruption to T6SS genomic loci through transposon, prophage, and mobile genetic element insertions. We identified an orphan vgrG island in P. aeruginosa strain PAK and five clinical isolates using in silico analysis which we denote vgrG7, predicting a gene within this cluster to encode a Tle2 lipase family effector. Close comparison of T6SS loci in clinical isolates compared to reference P. aeruginosa strain PAO1 revealed the presence of genes encoding eight new T6SS effectors with the following putative functions: cytidine deaminase, lipase, metallopeptidase, NADase, and pyocin. Finally, the prevalence of characterised and putative T6SS effectors were assessed in 532 publicly available P. aeruginosa genomes, which suggests the existence of accessory effectors. Our in silico study of the P. aeruginosa T6SS exposes a level of genetic diversity at T6SS genomic loci not seen to date within P. aeruginosa, particularly in CF isolates. As understanding the effector repertoire is key to identifying the targets of T6SSs and its efficacy, this comprehensive analysis provides a path for future experimental characterisation of these mediators of intermicrobial competition and host manipulation.
Plant genotype influence the structure of cereal seed fungal microbiome
Authors: Malacrinò Antonino , Abdelfattah Ahmed , Belgacem Imen , Schena Leonardo
Published: January 2023

Plant genotype is a crucial factor for the assembly of the plant-associated microbial communities. However, we still know little about the variation of diversity and structure of plant microbiomes across host species and genotypes. Here, we used six species of cereals (Avena sativa, Hordeum vulgare, Secale cereale, Triticum aestivum, Triticum polonicum, and Triticum turgidum) to test whether the plant fungal microbiome varies across species, and whether plant species use different mechanisms for microbiome assembly focusing on the plant ears. Using ITS2 amplicon metagenomics, we found that host species influences the diversity and structure of the seed-associated fungal communities. Then, we tested whether plant genotype influences the structure of seed fungal communities across different cultivars of T. aestivum (Aristato, Bologna, Rosia, and Vernia) and T. turgidum (Capeiti, Cappelli, Mazzancoio, Trinakria, and Timilia). We found that cultivar influences the seed fungal microbiome in both species. We found that in T. aestivum the seed fungal microbiota is more influenced by stochastic processes, while in T. turgidum selection plays a major role. Collectively, our results contribute to fill the knowledge gap on the wheat seed microbiome assembly and, together with other studies, might contribute to understand how we can manipulate this process to improve agriculture sustainability.
A clinical KPC-producing Klebsiella michiganensis strain carrying IncFII/IncFIA (HI1)/IncFIB (K) multiple replicon plasmid
Authors: Zhang Na , Liu Xiong , Qi Lihua , Chen Jiali , Qin Shiyu , Jin Meiling , Yang Xiaojing , Liu Fangni , Guo Jinpeng , Liu Jie , Wang Changjun , Chen Yong
Published: January 2023

Klebsiella michiganensis is an increasingly important bacterial pathogen causing nosocomial infections in clinical patients. In this study, we described the molecular and genomic characteristics of a carbapenem-resistant K. michiganensis strain KM166 cultured from a one-month premature baby’s blood sample. KM166 showed lower biofilm forming ability in optical density (OD) than K. pneumoniae NTUH-K2044 (0.271 ± 0.027 vs. 0.595 ± 0.054, p = 0.001), and the median lethal dose (0.684 lg CFU/mL) was lower than K. pneumoniae strain NTUH-K2044 (6.679 lg CFU/mL). A IncFII/IncFIA(HI1)/IncFIB(K) multiple replicon plasmid in KM166 was identified carrying three replicon types. It has low homology to Escherichia coli pMRY09-581ECO_1 and the highest homology similarity to the INcFIA/INcFII(p14)-type plasmid in K. michiganensis strain fxq plasmid pB_KPC, suggesting that this multiple replicon plasmid was unlikely to have been transmitted from E. coli and probably a transfer of repFIB replicon genes from other K. michiganensis strains into the INcFIA/INcFII(p14)-type plasmid of KM166 had occurred. Mapping of the gene environment revealed that blaKPC-2 in KM166 plasmid 3 had high identity and same Tn3-tnpR-IS481-blaKPC-2-klcA_1 genomic context structure with K. pneumoniae strain JKP55, plasmid pKPC-J5501, and blaKPC-2-carrying plasmid proved to be autonomously transferred under the help of mobile genetic elements into Escherichia coli 600 by plasmid conjugation experiment. In conclusion, we have characterized a K. michiganensis strain carrying multi-replicon IncFII/IncFIA(HI1)/IncFIB(K) plasmid and blaKPC-2-carrying IncFII(p14)/IncFIA plasmid in this study, which provided insights about the evolutionary diversity of plasmids carried by K. michiganensis.
High rates of antibodies against Toscana and Sicilian phleboviruses in common quail Coturnix coturnix birds
Authors: Ayhan Nazli , Rodríguez-Teijeiro José Domingo , López-Roig Marc , Vinyoles Dolors , Ferreres Josep Anton , Monastiri Abir , Charrel Remi , Serra-Cobo Jordi
Published: January 2023

Introduction

Birds are involved natural cycle of a number of vector-borne viruses in both rural and urban areas. Toscana (TOSV) and Sicilian (SFSV) phleboviruses are sandfly-borne viruses in the genus Phlebovirus that can cause diseases in human. However, there is limited information on the role of the birds in sandfly-borne phleboviruses natural cycle and reservoirs ofthese viruses remain unknown.

Methods

In this study, we analyzed Common Quail (Coturnix coturnix) sera from Spain to identify the seroprevalence of these two phleboviruses. We tested respectively, 106 and 110 quail serum against TOSV and SFSV from 2018, 2019, and 2021 from two locations in northern Spain with using virus neutralization test.

Results

We identified high neutralizing antibody rates for SFSV (45.45%) and TOSV (42.45%) with yearly fluctuation.

Discussion

This is the first identification of SFSV and TOSV neutralizing antibodies in wild birds. High seroprevalence rates of TOSV and SFSV in quail birds raises the question whether birds have a role as amplifying hosts in the natural cycle of phleboviruses.
Intense pulsed light for inactivating planktonic and biofilm molds in food
Authors: Li Xuejie , Gu Nixuan , Ye Yanrui , Lan Haifeng , Peng Fang , Peng Gongyong
Published: January 2023

It has been reported that about a quarter of the world’s agriculture products is unable to be consumed each year because of mold contamination, resulting in incalculable economic losses. Despite modern food technology and the various preservation techniques available, the problem of mold contamination of food is still not adequately controlled. In this study, we simulated the biofilm formed by Aspergillus niger and Penicillium glaucum in liquid and solid food in 96 well cell culture plates and polycarbonate membrane models, respectively, and investigated the fungicidal effect of IPL on planktonic and biofilm molds at three different capacitance parameters at room and refrigerator temperatures. The results show that IPL can achieve fungicidal rates of over 99% for planktonic molds and over 90% for biofilm molds, and that the smaller the capacitance, the more frequent the irradiation required to achieve the same fungicidal rate. In addition, temperature, A. niger or Penicillium glaucum have no effect on the fungicidal effect of IPL. We believe that IPL is a promising non-thermal physical sterilization technique for fungal inhibition on food surfaces.
The structural and functional roles of the flavin cofactor FAD in mammalian cryptochromes
Authors: Calloni Giulia , Vabulas R. Martin
Published: January 2023

The importance of circadian rhythms in human health and disease calls for a thorough understanding of the underlying molecular machinery, including its key components, the flavin adenine dinucleotide (FAD)-containing flavoproteins cryptochrome 1 and 2. Contrary to their Drosophila counterparts, mammalian cryptochromes are direct suppressors of circadian transcription and act independently of light. Light-independence poses the question regarding the role of the cofactor FAD in mammalian cryptochromes. The weak binding of the cofactor in vitro argues against its relevance and might be a functionless evolutionary remnant. From the other side, the FAD-binding pocket constitutes the part of mammalian cryptochromes directly related to their ubiquitylation by the ubiquitin ligase Fbxl3 and is the target for protein-stabilizing small molecules. Increased supplies of FAD stabilize cryptochromes in cell culture, and the depletion of the FAD precursor riboflavin with simultaneous knock-down of riboflavin kinase affects the expression of circadian genes in mice. This review presents the classical and more recent studies in the field, which help to comprehend the role of FAD for the stability and function of mammalian cryptochromes.
The role of cell membrane-coated nanoparticles as a novel treatment approach in glioblastoma
Authors: Allami Pantea , Heidari Arash , Rezaei Nima
Published: January 2023

Glioblastoma multiform (GBM) is the most prevalent and deadliest primary brain malignancy in adults, whose median survival rate does not exceed 15 months after diagnosis. The conventional treatment of GBM, including maximal safe surgery followed by chemotherapy and radiotherapy, usually cannot lead to notable improvements in the disease prognosis and the tumor always recurs. Many GBM characteristics make its treatment challenging. The most important ones are the impermeability of the blood-brain barrier (BBB), preventing chemotherapeutic drugs from reaching in adequate amounts to the tumor site, intratumoral heterogeneity, and roles of glioblastoma stem cells (GSCs). To overcome these barriers, the recently-developed drug-carrying approach using nanoparticles (NPs) may play a significant role. NPs are tiny particles, usually less than 100 nm showing various diagnostic and therapeutic medical applications. In this regard, cell membrane (CM)-coated NPs demonstrated several promising effects in GBM in pre-clinical studies. They benefit from fewer adverse effects due to their specific targeting of tumor cells, biocompatibility because of their CM surfaces, prolonged half-life, easy penetrating of the BBB, and escaping from the immune reaction, making them an attractive option for GBM treatment. To date, CM-coated NPs have been applied to enhance the effectiveness of major therapeutic approaches in GBM treatment, including chemotherapy, immunotherapy, gene therapy, and photo-based therapies. Despite the promising results in pre-clinical studies regarding the effectiveness of CM-coated NPs in GBM, significant barriers like high expenses, complex preparation processes, and unknown long-term effects still hinder its mass production for the clinic. In this regard, the current study aims to provide an overview of different characteristics of CM-coated NPs and comprehensively investigate their application as a novel treatment approach in GBM.
Histone H3 core domain in chromatin with different DNA linker lengths studied by 1H-Detected solid-state NMR spectroscopy
Authors: Smrt Sean T. , Gonzalez Salguero Nicole , Thomas Justin K. , Zandian Mohamad , Poirier Michael G. , Jaroniec Christopher P.
Published: January 2023

Chromatin, a dynamic protein-DNA complex that regulates eukaryotic genome accessibility and essential functions, is composed of nucleosomes connected by linker DNA with each nucleosome consisting of DNA wrapped around an octamer of histones H2A, H2B, H3 and H4. Magic angle spinning solid-state nuclear magnetic resonance (NMR) spectroscopy can yield unique insights into histone structure and dynamics in condensed nucleosomes and nucleosome arrays representative of chromatin at physiological concentrations. Recently we used J-coupling-based solid-state NMR methods to investigate with residue-specific resolution the conformational dynamics of histone H3 N-terminal tails in 16-mer nucleosome arrays containing 15, 30 or 60 bp DNA linkers. Here, we probe the H3 core domain in the 16-mer arrays as a function of DNA linker length via dipolar coupling-based 1H-detected solid-state NMR techniques. Specifically, we established nearly complete assignments of backbone chemical shifts for H3 core residues in arrays with 15–60 bp DNA linkers reconstituted with 2H,13C,15N-labeled H3. Overall, these chemical shifts were similar irrespective of the DNA linker length indicating no major changes in H3 core conformation. Notably, however, multiple residues at the H3-nucleosomal DNA interface in arrays with 15 bp DNA linkers exhibited relatively pronounced differences in chemical shifts and line broadening compared to arrays with 30 and 60 bp linkers. These findings are consistent with increased heterogeneity in nucleosome packing and structural strain within arrays containing short DNA linkers that likely leads to side-chains of these interfacial residues experiencing alternate conformations or shifts in their rotamer populations relative to arrays with the longer DNA linkers.
The oral manifestations and related mechanisms of COVID-19 caused by SARS-CoV-2 infection
Authors: Lin Weiming , Gao Feng , Wang Xia , Qin Nianhong , Chen Xianxiong , Tam Kin Yip , Zhang Chengfei , Zhang Mingxia , Sha Ou
Published: January 2023

Coronavirus disease 2019 (COVID-19) was reported to be associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, and patients present mostly with respiratory symptoms. There have been an increasing number of reports on oral manifestations, and some of these signs are informative in terms of identifying SARS-CoV-2 infection. The goal of present study was to review and synthesize the clinical characteristics and underlying mechanisms of COVID-19 oral manifestations, as well as to evaluate the factors influencing SARS-CoV-2 infectivity, in order to conduct further in-depth investigations and help clinicians diagnose COVID-19 patients exhibiting oral symptoms.
Effects of medication intake on the risk of hemorrhage in patients with sporadic cerebral cavernous malformations
Authors: Chen Bixia , Lahl Kirstin , Saban Dino , Lenkeit Annika , Rauschenbach Laurèl , Santos Alejandro N. , Li Yan , Schmidt Boerge , Zhu Yuan , Jabbarli Ramazan , Wrede Karsten H. , Kleinschnitz Christoph , Sure Ulrich , Dammann Philipp
Published: January 2023

Objective

Recurrent intracerebral hemorrhage (ICH) poses a high risk for patients with cerebral cavernous malformations (CCMs). This study aimed to assess the influence of medication intake on hemorrhage risk in sporadic CCMs.

Methods

From a database of 1,409 consecutive patients with CCM (2003–2021), subjects with sporadic CCMs and complete magnetic resonance imaging data were included. We evaluated the presence of ICH as a mode of presentation, the occurrence of ICH during follow-up, and medication intake, including beta blockers, statins, antithrombotic therapy, and thyroid hormones. The impact of medication intake on ICH at presentation was calculated using univariate and multivariate logistic regression with age and sex adjustment. The longitudinal cumulative 5-year risk for (re-)hemorrhage was analyzed using the Kaplan–Meier curves and the Cox regression analysis.

Results

A total of 1116 patients with CCM were included. Logistic regression analysis showed a significant correlation (OR: 0.520, 95% CI: 0.284–0.951, p = 0.034) between antithrombotic therapy and ICH as a mode of presentation. Cox regression analysis revealed no significant correlation between medication intake and occurrence of (re-)hemorrhage (hazard ratios: betablockers 1.270 [95% CI: 0.703–2.293], statins 0.543 [95% CI: 0.194–1.526], antithrombotic therapy 0.507 [95% CI: 0.182–1.410], and thyroid hormones 0.834 [95% CI: 0.378–1.839]).

Conclusion

In this observational study, antithrombotic treatment was associated with the tendency to a lower rate of ICH as a mode of presentation in a large cohort of patients with sporadic CCM. Intake of beta blockers, statins, and thyroid hormones had no effect on hemorrhage as a mode of presentation. During the 5-year follow-up period, none of the drugs affected the further risk of (re-)hemorrhage.
Case Report: Abnormalities of sperm motility and morphology in a patient with Leber hereditary optic neuropathy: Improvement after idebenone therapy
Authors: Orssaud Christophe , Barraud Lange Virginie , Wolf Jean Philippe , LeFoll Nathalie , Soufir Jean Claude
Published: January 2023

Case

We report the sperm characteristics of a male patient who developed, when he was 18 years old, a Leber hereditary optic neuropathy, a hereditary optic neuropathy due to mtDNA mutation as well as variants in the nuclear DNA. At the age of 30 years-old, he complained of infertility lasting for 2 years. Semen analyses showed low motility spermatozoa and a high percentage of morphological or ultrastructural abnormalities. Levels of epididymal markers were strongly atypical. Idebenone was prescribed as treatment of his Leber hereditary optic neuropathy in order to improve his visual acuity. After 5 months of this treatment, motility of spermatozoa increased, and their vitality improved. A natural conception occurred.

Outcome

This case is the first description of an anomaly of spermatozoas and of the epididymis epithelium in a patient with Leber hereditary optic neuropathy. It draws attention to sperm pathologies in patients with mitochondrial disorders. The role of the mtDNA mutations must be suspected since it plays an important role in the development and motility of spermatozoa. In addition, idebenone can by-pass the complex I and transfer electrons to complex III. It has been suspected to have a favorable effect on spermatogenesis.

Conclusion

This case confirms the possibility of sperm dysfunction in Leber hereditary optic neuropathy and the interest of idebenone as a treatment for infertility due to mtDNA mutations in human.
Large mismatch profile predicts rapidly progressing brain edema in acute anterior circulation large vessel occlusion patients undergoing endovascular thrombectomy
Authors: Shao Yanqi , Chen Xinyi , Wang Huiyuan , Shang Yafei , Xu Jie , Zhang Jinshi , Wang Peng , Geng Yu
Published: January 2023

Background

Brain edema is a severe complication in patients with large vessel occlusion (LVO) that can reduce the effectiveness of endovascular therapy (EVT). This study aimed to investigate the association of the perfusion profile at baseline computed tomography (CT) perfusion with rapidly progressing brain edema (RPBE) after EVT in patients with acute anterior LVO.

Methods

We retrospectively reviewed consecutive data collected from 149 patients with anterior LVO who underwent EVT at our center. Brain edema was measured by the swelling score (0–6 score), and RPBE was defined as the swelling score increased by more than 2 scores within 24 h after EVT. We investigated the effect of RPBE on poor outcomes [National Institute of Health Stroke Scale (NIHSS) score and modified Rankin scale (mRS) score at discharge, the occurrence of hemorrhagic transformation, and mortality rate in the hospital] using the Mann–Whitney U-test and chi-square test. A multivariate logistic regression model was used to assess the relationship between perfusion imaging parameters and RPBE occurrence.

Results

Overall, 39 patients (26.2%) experienced RPBE after EVT. At discharge, RPBE was associated with higher NIHSS scores (Z = 3.52, 95% CI 2.0–12.0, P < 0.001) and higher mRS scores (Z = 3.67, 95% CI 0.0–1.0, P < 0.001) including the more frequent occurrence of hemorrhagic transformation (χ2 = 22.17, 95% CI 0.29–0.59, P < 0.001) and higher mortality rates in hospital (χ2 = 9.54, 95% CI 0.06–0.36, P = 0.002). Univariate analysis showed that intravenous thrombolysis, baseline ischemic core volume, and baseline mismatch ratio correlated with RPBE (all P < 0.05). After dividing the mismatch ratio into quartiles and performing a chi-square test between quartiles, we found that the occurrence of RPBE in Q4 (mismatch ratio > 11.3) was significantly lower than that in Q1 (mismatch ratio ≤ 3.0) (P < 0.05). The result of multivariate logistic regression analysis showed that compared with baseline mismatch ratio <5.1, baseline mismatch ratio between 5.1 and 11.3 (OR:3.85, 95% CI 1.06–14.29, P = 0.040), and mismatch ratio >11.3 (OR:5.26, 95% CI 1.28–20.00, P = 0.021) were independent protective factors for RPBE.

Conclusion

In patients with anterior circulation LVO stroke undergoing successful EVT, a large mismatch ratio at baseline is a protective factor for RPBE, which is associated with poor outcomes.
Chronology of auditory processing and related co-activation in the orbitofrontal cortex depends on musical expertise
Authors: Bücher Steffen , Bernhofs Valdis , Thieme Andrea , Christiner Markus , Schneider Peter
Published: January 2023

Introduction

The present study aims to explore the extent to which auditory processing is reflected in the prefrontal cortex.

Methods

Using magnetoencephalography (MEG), we investigated the chronology of primary and secondary auditory responses and associated co-activation in the orbitofrontal cortex in a large cohort of 162 participants of various ages. The sample consisted of 38 primary school children, 39 adolescents, 43 younger, and 42 middle-aged adults and was further divided into musically experienced participants and non-musicians by quantifying musical training and aptitude parameters.

Results

We observed that the co-activation in the orbitofrontal cortex [Brodmann-Area 10 (BA10)] strongly depended on musical expertise but not on age. In the musically experienced groups, a systematic coincidence of peak latencies of the primary auditory P1 response and the co-activated response in the orbitofrontal cortex was observed in childhood at the onset of musical education. In marked contrast, in all non-musicians, the orbitofrontal co-activation occurred 25–40 ms later when compared with the P1 response. Musical practice and musical aptitude contributed equally to the observed activation and co-activation patterns in the auditory and orbitofrontal cortex, confirming the reciprocal, interrelated influence of nature, and nurture in the musical brain.

Discussion

Based on the observed ageindependent differences in the chronology and lateralization of neurological responses, we suggest that orbitofrontal functions may contribute to musical learning at an early age.
New natural compound inhibitors of PDGFRA (platelet-derived growth factor receptor α) based on computational study for high−grade glioma therapy
Authors: Yang Wenzhuo , Wang Shengnan , Zhang Xiangmao , Sun Hu , Zhang Menghan , Chen Hongyu , Cui Junxiang , Li Jinyang , Peng Fei , Zhu Mingqin , Yu Bingcheng , Li Yifan , Yang Liu , Min Wanwan , Xue Mengru , Pan Lin , Zhu Hao , Wu Bo , Gu Yinghao
Published: January 2023

Background

High-grade glioma (HGG) is a malignant brain tumor that is common and aggressive in children and adults. In the current medical paradigm, surgery and radiotherapy are the standard treatments for HGG patients. Despite this, the overall prognosis is still very bleak. Studies have shown that platelet-derived growth factor receptor α (PDGFRA) is an essential target to treat tumors and inhibiting the activity of PDGFRA can improve the prognosis of HGG. Thus, PDGFRA inhibitors are critical to developing drugs and cancer treatment.

Objective

The purpose of this study was to screen lead compounds and candidate drugs with potential inhibitors against platelet-derived growth factor receptor α (PDGFRA) from the drug library (ZINC database) in order to improve the prognosis of patients with high-grade glioma (HGG).

Materials and methods

In our study, we selected Imatinib as the reference drug. A series of computer-aided technologies, such as Discovery Studio 2019 and Schrodinger, were used to screen and assess potential inhibitors of PDGFRA. The first step was to calculate the LibDock scores and then analyze the pharmacological and toxicological properties. Following this, we docked the small molecules selected in the previous steps with PDGFRA to study their docking mechanism and affinity. In addition, molecular dynamics simulation was used to determine whether the ligand-PDGFRA complex was stable in nature.

Results

Two novel natural compounds 1 and 2 (ZINC000008829785 and ZINC000013377891) from the ZINC database were found binding to PDGFRA with more favorable interaction energy. Also, they were predicted with less Ames mutagenicity, rodent carcinogenicity, non-developmental toxic potential, and tolerant with cytochrome P450 2D6 (CYP2D6). The dynamic simulation analysis demonstrated that ZINC000008829785-PDGFRA and ZINC000013377891-PDGFRA dimer complex had more favorable potential energy compared with Imatinib, and they can exist in natural environments stably.

Conclusion

ZINC000008829785 and ZINC000013377891 might provide a solid foundation for drugs that inhibit PDGFRA in HGG. In addition to being safe drug candidates, these compounds had important implications for improving drugs targeting PDGFRA.