bluuebunny/crossref_metadata_2025 huggingface dataset:
The offshore renewables industry may be better served by new bespoke design guidelines than by automatic adoption of recommended practices developed for oil and gas infrastructure: A recommendation illustrated by subsea cable design
Authors: Griffiths Terry , Draper Scott , Cheng Liang , An Hongwei , Schläppy Marie-Lise , Fogliani Antonino , White David , Noble Stuart , Coles Daniel , Johnson Fraser , Thurstan Bryan , Teng Yunfei
Published: May 2023

Introduction

There is an emerging need for the offshore renewable industry to have their own bespoke design guidelines because the associated projects and offshore facilities differ in fundamental ways to oil and gas facilities. Offshore renewable energy (ORE) facilities have already surpassed the numbers of installed facilities in the oil and gas industry by an order of magnitude and demand is forecast to continue growing exponentially. In addition ORE facilities often have different response characteristics and limit states or failure modes as well as profoundly different risk and consequence profiles given they are generally uncrewed and do not contain explosive hydrocarbon fluids which might be released into the environment. Therefore, the purpose of this paper is to advocate for licensing bodies and regulators (such as the various national PEL 114 committees) to challenge the process of automatic adoption of oil and gas design processes, while pushing for offshore renewables to be treated differently, when appropriate, with more relevant and applicable guidance.

Methods

To support this argument we present new bespoke design guidance developed for subsea cables based on specific modes of cable behaviour, which often differ from pipelines. We also show worked examples from recent project experience. The results from on-bottom stability analyses of a set of cables are compared between conventional oil and gas guidance following DNV-RP-F109 versus the stability using cable-optimised approaches.

Results

The outcomes from the ‘conventional’ oil and gas results are not simply biased compared to cable-optimised design methods, with a trend of being either conservative or unconservative. Instead, the results of the two methods are very poorly correlated. This shows that the oil and gas approach isn't simply biased when applied to cables, but is instead unreliable because it doesn't capture the underlying failure conditions. These analytical comparisons are supported by field observation - the ocean doesn't lie, and makes short work of any anthropogenic structures which are designed with inadequate appreciation of the real world conditions.

Discussion

To support the rapid growth of ORE, we should therefore actively pursue opportunities to rewrite the design rules and standards, so that they better support the specific requirements of ORE infrastructure, rather than legacy oil and gas structures. With more appropriate design practices, we can accelerate the roll out of ORE to meet net zero, and mitigate the climate crisis.
Fatty acid profiles of cultured Hippocampus hippocampus trunk muscles and potential nutritional value
Authors: Cabral Ana Elisa , Rey Felisa , Domingues M. Rosário , Cabral Miguel , Planas Miquel , Palma Jorge , Calado Ricardo
Published: May 2023

Syngnathids (seahorses, pipefishes and seadragons) are an attractive resource for Traditional Chinese Medicine (TCM). Despite few scientific studies supporting seahorse nutritional benefits, they are believed to possess medicinal properties that enhance human health. The European short-snout seahorse Hippocampus hippocampus is classified as Data Deficient by the IUCN Red List of Threatened Species. Nevertheless, there are increasing records of this species being illegally captured and traded to supply TCM. This study investigated the fatty acid (FA) profiles of the trunk muscles of cultured female and male H. hippocampus, to assess sex and intraspecific variation, as well as their potential nutritional value. The contents of crude lipid (4.05 ± 2.15% dry weight, DW in females and 2.82 ± 1.48% DW in males) and phospholipid (8.23 ± 3.34 μg mg−1 DW in females and 7.91 ± 2.36 μg mg−1 DW in males) were not significantly different between the two sexes. The absolute FA compositions of H. hippocampus trunk muscles revealed higher mean values for FA 16:0, 18:0, 18:1 n-9 and 22:6 n-3 (DHA), in both female (2.82 ± 1.11, 1.81 ± 0.89, 0.90 ± 0.41 and 0.93 ± 0.35 μg mg−1 DW, respectively) and male specimens (1.99 ± 0.95, 1.52 ± 0.78, 0.74 ± 0.44 and 0.80 ± 0.41 μg mg−1 DW, respectively). In terms of FA classes, saturated fatty acids (SFA) showed the highest absolute value of the total pool of FA, for both sexes (4.73 ± 1.94 μg mg−1 DW in females and 3.58 ± 1.76 μg mg−1 DW in males). Males tended to exhibit a more suitable profile for human nutrition, displaying a lower atherogenic index (AI) and thrombogenic index (TI). The relative composition of H. hippocampus trunk muscles followed the patterns of seahorse species valued in TCM, with DHA ranking amongst the PUFA with higher mean relative abundances (12.0% of total FA). While seahorse FA profiles may be of interest in terms of their nutritional value for humans, only specimens originating from sustainable production practices should be traded and the conservation of their populations in the wild should continue to be a global priority.
Characteristics and hazard risk of microplastics in Sinonovacula constricta: from farming to market
Authors: Chen Bin
Published: May 2023

In this paper, I selected Sinonovacula constricta, a typical representative of commercial bivalve shellfish from Zhangzhou City, and found that microplastics were detected in all the samples with small sizes. The abundance in farm samples (3.65 n/g) was higher than in market samples (0.89 n/g), despite their smaller weight, which was mainly contributed by body fluid. Microplastics transported from the body fluid to the viscera and then metabolized into muscle were substantially reduced (69.3%), with only 0 or 1 microplastic observed in the muscles on the micron scale. The microplastics detected in the market samples were mainly concentrated in the viscera, accounting for 81%, while distributed in all the organs of farm samples, with body fluids accounting for 52%. A total of four shapes were detected, with the highest percentage of fibrous shape, while foam-like microplastics were not detected in the market samples. The abundance was not correlated with sample weight, but market samples showed a positive correlation. A total of seven polymers were detected, with the highest rate of polypropylene (PP) (27%). The polymer risk level reached level III. The percentage of polyvinyl chloride (PVC) in the market samples exceeded that of farms, which resulted in a higher hazard risk index despite their lower abundance. The cleaning process and excretory behavior, from farms to markets, greatly reduced microplastic contamination.
Desorption of bisphenol A from microplastics under simulated gastrointestinal conditions
Authors: Li Wang , Zu Bo , Li Lei , Li Jian , Li Jiawen , Mei Xueyu
Published: May 2023

Microplastics are prevalent in the environment and have a strong affinity to pollutants owing to their large specific surface area and hydrophobicity. Once ingested, microplastics transport pollutants into organisms. This study investigated bisphenol A (BPA) desorption behavior from three microplastic materials, namely, polystyrene (PS), polypropylene (PP), and polyamide (PA), under simulated biological gastrointestinal conditions. The results showed that BPA can rapidly desorb from microplastic carriers under simulated gastrointestinal conditions, with different BPA desorption percentages in the order of PP > PS > PA. This was related to the amorphous structure and functional groups of the polymers. The BPA desorption behavior of microplastics in gastric juices was not significantly affected by pH; however, within the pH range of intestinal juices, the BPA desorption percentage increased significantly as the pH increased. The increase in Na+ concentration in the gastrointestinal tract exhibited a certain inhibitory effect on BPA desorption from microplastics owing to the salting-out effect. The temperature of digestive juices positively affected BPA desorption, suggesting that endothermic organisms are more susceptible to it. Our findings help elucidate the potential health risks of exposure to microplastics and their sorbed pollutants in the environment.
Region-specific deep learning models for accurate segmentation of rectal structures on post-chemoradiation T2w MRI: a multi-institutional, multi-reader study
Authors: DeSilvio Thomas , Antunes Jacob T. , Bera Kaustav , Chirra Prathyush , Le Hoa , Liska David , Stein Sharon L. , Marderstein Eric , Hall William , Paspulati Rajmohan , Gollamudi Jayakrishna , Purysko Andrei S. , Viswanath Satish E.
Published: May 2023

Introduction

For locally advanced rectal cancers, in vivo radiological evaluation of tumor extent and regression after neoadjuvant therapy involves implicit visual identification of rectal structures on magnetic resonance imaging (MRI). Additionally, newer image-based, computational approaches (e.g., radiomics) require more detailed and precise annotations of regions such as the outer rectal wall, lumen, and perirectal fat. Manual annotations of these regions, however, are highly laborious and time-consuming as well as subject to inter-reader variability due to tissue boundaries being obscured by treatment-related changes (e.g., fibrosis, edema).

Methods

This study presents the application of U-Net deep learning models that have been uniquely developed with region-specific context to automatically segment each of the outer rectal wall, lumen, and perirectal fat regions on post-treatment, T2-weighted MRI scans.

Results

In multi-institutional evaluation, region-specific U-Nets (wall Dice = 0.920, lumen Dice = 0.895) were found to perform comparably to multiple readers (wall inter-reader Dice = 0.946, lumen inter-reader Dice = 0.873). Additionally, when compared to a multi-class U-Net, region-specific U-Nets yielded an average 20% improvement in Dice scores for segmenting each of the wall, lumen, and fat; even when tested on T2-weighted MRI scans that exhibited poorer image quality, or from a different plane, or were accrued from an external institution.

Discussion

Developing deep learning segmentation models with region-specific context may thus enable highly accurate, detailed annotations for multiple rectal structures on post-chemoradiation T2-weighted MRI scans, which is critical for improving evaluation of tumor extent in vivo and building accurate image-based analytic tools for rectal cancers.
Real-world experience with secukinumab in the entire axial spondyloarthritis spectrum
Authors: Sivera Francisca , Núñez-Monje Victoria , Campos-Fernández Cristina , Balaguer-Trull Isabel , Robustillo-Villarino Montserrat , Aguilar-Zamora Marta , Garijo-Bufort Marta , López-Gómez Juan Miguel , Peña-González Carolina , de la Morena Isabel , Bedoya-Sanchís Diego , Yankova-Komsalova Liliya , Conesa-Mateos Arantxa , Martínez-Cristóbal Anna , Navarro-Blasco Francisco Javier , Senabre-Gallego José Miguel , Alegre-Sancho Juan José
Published: May 2023

Background

Secukinumab is a biologic disease-modifying antirheumatic drug (bDMARD) that has demonstrated efficacy in the treatment of axial spondyloarthritis (axSpA, i.e., ankylosing spondylitis and non-radiographic axSpA) across various clinical trials. However, data of secukinumab in clinical practice is still limited. Here, we aimed to provide real-world data on secukinumab use, effectiveness, and persistence in axSpA.

Patients and methods

Retrospective, multicenter study of patients with a diagnosis of axSpA treated with secukinumab at 12 centers up to June 2021 in the Valencian Community (Spain). Information was gathered on BASDAI measurement, pain, patient and physician global assessment (ptGA, phGA) using a 100-mm visual analog scale (VAS), persistence and other secondary variables by treatment line (first, second, and ≥ third) for up to 24 months.

Results

221 patients were included (69% men; mean age [standard deviation, SD]: 46.7 [12.1] years old). Secukinumab was used as a first-line bDMARD in 38% of patients, as a second-line in 34% and as a ≥ hird-line in 28%. The percentage of patients achieving low disease activity (BASDAI<4) increased from 9% at baseline to 48% at month 6 and was maintained (49%) up to month 24. Improvements in BASDAI were observed across all treatment lines: in naïve patients (month 6: −2.6; month 24: −2.7), in second-line (month 6: −1.9; month 24: −3.1), and in patients on third lines (month 6: −1.3; month 24: −1.7). Reductions in mean pain VAS (−23.3; −31.9), ptGA (−25.1; −31.9) and phGA (−25.1; −31) were also observed at 6 and 24 months. Secukinumab showed an overall 12-months persistence rate of 70% (95% confidence interval [CI]: 63–77%) and a 24-months persistence rate of 58% (95% CI, 51–66%). Patients receiving first-line secukinumab had the highest 24-months persistence rate (p = 0.05).

Conclusion

Secukinumab improved disease activity in axSpA patients, especially in naive, and second-line patients, which was accompanied by high persistence rates up to 24 months.
mTOR-inhibitors and post-transplant diabetes mellitus: a link still debated in kidney transplantation
Authors: Granata Simona , Mercuri Silvia , Troise Dario , Gesualdo Loreto , Stallone Giovanni , Zaza Gianluigi
Published: May 2023

The mammalian target of rapamycin inhibitors (mTOR-Is, Sirolimus, and Everolimus) are immunosuppressive drugs widely employed in kidney transplantation. Their main mechanism of action includes the inhibition of a serine/threonine kinase with a pivotal role in cellular metabolism and in various eukaryotic biological functions (including proteins and lipids synthesis, autophagy, cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis). Moreover, as well described, the inhibition of the mTOR pathway may also contribute to the development of the post-transplant diabetes mellitus (PTDM), a major clinical complication that may dramatically impact allograft survival (by accelerating the development of the chronic allograft damage) and increase the risk of severe systemic comorbidities. Several factors may contribute to this condition, but the reduction of the beta-cell mass, the impairment of the insulin secretion and resistance, and the induction of glucose intolerance may play a pivotal role. However, although the results of several in vitro and in animal models, the real impact of mTOR-Is on PTDM is still debated and the entire biological machinery is poorly recognized. Therefore, to better elucidate the impact of the mTOR-Is on the risk of PTDM in kidney transplant recipients and to potentially uncover future research topics (particularly for the clinical translational research), we decided to review the available literature evidence regarding this important clinical association. In our opinion, based on the published reports, we cannot draw any conclusion and PTDM remains a challenge. However, also in this case, the administration of the lowest possible dose of mTOR-I should also be recommended.
Content development and validation for a mobile application designed to train family caregivers in the use of music to support care of people living with dementia
Authors: Thompson Zara , Tamplin Jeanette , Vieira Sousa Tanara , Carrasco Romina , Flynn Libby , Lamb Karen E. , Lampit Amit , Lautenschlager Nicola T. , McMahon Kate , Waycott Jenny , Vogel Adam P. , Woodward-Kron Robyn , Stretton-Smith Phoebe A. , Baker Felicity A.
Published: May 2023

Background

Music therapy is increasingly recognized as an effective support for people living with dementia. However, with incidences of dementia increasing, and limited availability of music therapists, there is a need for affordable and accessible ways that caregivers can learn to use music-therapy based strategies to support the people they care for. The MATCH project aims to address this by creating a mobile application that can train family caregivers in the use of music to support people living with dementia.

Methods

This study details the development and validation of training material for the MATCH mobile application. Training modules developed based on existing research were assessed by 10 experienced music therapist clinician-researchers, and seven family caregivers who had previously completed personalized training in music therapy strategies via the HOMESIDE project. Participants reviewed the content and scored each training module based on content (music therapists) and face (caregivers) validity scales. Descriptive statistics were used to calculate scores on the scales, while thematic analysis was used to analyze short-answer feedback.

Results

Participants scored the content as valid and relevant, however, they provided additional suggestions for improvement via short-answer feedback.

Conclusion

The content developed for the MATCH application is valid and will be trailed by family caregivers and people living with dementia in a future study.
Characterization of vB_ValM_PVA8, a broad-host-range bacteriophage infecting Vibrio alginolyticus and Vibrio parahaemolyticus
Authors: Fu Jingyun , Li Ying , Zhao Lihong , Wu Chunguang , He Zengguo
Published: May 2023

Phage therapy was taken as an alternative strategy to antibiotics in shrimp farming for the control of Vibrio species of Vibrio parahaemolyticus and Vibrio alginolyticus, which cause substantial mortality and significant economic losses. In this study, a new Vibrio phage vB_ValM_PVA8 (PVA8), which could efficiently infect pathogenic isolates of V. alginolyticus and V. parahaemolyticus, was isolated from sewage water and characterized by microbiological and in silico genomic analyses. The phage was characterized to be a member of the Straboviridae family with elongated head and contractile tail by transmission electron microscopy. Genome sequencing showed that PVA8 had a 246,348-bp double-stranded DNA genome with a G + C content of 42.6%. It harbored totally 388 putative open reading frames (ORFs), among them 92 (23.71%) assigned to functional genes. Up to 27 transfer RNA (tRNA) genes were found in the genome, and the genes for virulence, antibiotic resistance, and lysogeny were not detected. NCBI genomic blasting results and the phylogenetic analysis based on the sequences of the large terminase subunits and the DNA polymerase indicated that PVA8 shared considerable similarity with Vibrio phage V09 and bacteriophage KVP40. The phage had a latent period of 20 min and a burst size of 309 PFUs/infected cell with the host V. alginolyticus, and it was stable over a broad pH range (4.0–11.0) and a wide temperature span (−80°C to 60°C), respectively, which may benefit its feasibility for phage therapy. In addition, it had the minimum multiplicity of infection (MOI) of 0.0000001, which revealed its strong multiplication capacity. The shrimp cultivation lab trials demonstrated that PVA8 could be applied in treating pathogenic V. parahaemolyticus infection disease of shrimp with a survival rate of 88.89% comparing to that of 34.43% in the infected group, and the pond application trails confirmed that the implementation of PVA8 could rapidly yet effectively reduce the level of the Vibrio. Taken together, PVA8 may be potential to be explored as a promising biological agent for Vibrio control in aquaculture farming industry.
Altered gut microbiome profile in patients with knee osteoarthritis
Authors: Wang Xi , Wu Yifan , Liu Yanli , Chen Feihong , Chen Sijie , Zhang Feiyu , Li Shujin , Wang Chaowei , Gong Yi , Huang Ruitian , Hu Minhan , Ning Yujie , Zhao Hongmou , Guo Xiong
Published: May 2023

Introduction

Osteoarthritis (OA) is a kind of chronic, degenerative disorder with unknown causes. In this study, we aimed to improve our understanding of the gut microbiota profile in patients with knee OA.

Methods

16S rDNA gene sequencing was performed to detect the gut microbiota in fecal samples collected from the patients with OA (n = 32) and normal control (NC, n = 57). Then the metagenomic sequencing was used to identify the genes or functions linked with gut microbial changes at the species level in the fecal samples from patients with OA and NC groups.

Results

The Proteobacteria was identified as dominant bacteria in OA group. We identified 81 genera resulted significantly different in abundance between OA and NC. The abundance of Agathobacter, Ruminococcus, Roseburia, Subdoligranulum, and Lactobacillus showed significant decrease in the OA compared to the NC. The abundance of genera Prevotella_7, Clostridium, Flavonifractor and Klebsiella were increasing in the OA group, and the families Lactobacillaceae, Christensenellaceae, Clostridiaceae_1 and Acidaminococcaceae were increasing in the NC. The metagenomic sequencing showed that the abundance of Bacteroides stercoris, Bacteroides vulgatus and Bacteroides uniformis at the species level were significantly decreasing in the OA, and the abundance of Escherichia coli, Klebsiella pneumoniae, Shigella flexneri and Streptococcus salivarius were significantly increased in OA.

Discussion

The results of our study interpret a comprehensive profile of the gut microbiota in patients with knee OA and offer the evidence that the cartilage-gut-microbiome axis could play a crucial role in underlying the mechanisms and pathogenesis of OA.
Simplicillium sinense sp. nov., a novel potential pathogen of tinea faciei
Authors: Yan Qiu-Hong , Ni Qing-Rong , Gu Wei-Jie , Liu Hong-Wei , Yuan Xiao-Ying , Sun Jing-Zu
Published: May 2023

Simplicillium species are widely distributed with a broad spectrum of hosts and substrates. Generally, these species are entomopathogenic or mycoparasitic. Notably, some isolates of Simplicillium lanosoniveum and Simplicillium obclavatum were obtained from human tissues. In this study, two fungi were isolated from the annular itchy patch of infected skin of a 46-year-old man with diabetes mellitus. Based on a combination of morphological characteristics and phylogenetic analysis, a novel species, Simplicillium sinense, was introduced herein. It morphologically differs from the remaining Simplicillium in the size of phialides and conidia. Additionally, it grows slowly on YPD at 37°C. Antimicrobial susceptibility testing presented that this fungus is resistant to most azole antifungals. Therefore, the diagnosis of tinea faciei was made, and after 2 weeks of being treated with oral terbinafine (250 mg, once a day) and topical terbinafine cream for 1 month, the rash was mainly resolved and no recurrence happened after 6 months of follow-up. Herein, Simplicillium sinense was introduced as a new fungal taxon. Meanwhile, a case of superficial infection caused by S. sinense was reported. So far, it is the third Simplicillium species obtained from human tissue. Meanwhile, terbinafine is recommended as the first-line antifungal treatment against Simplicillium infection.
RpoZ regulates 2,4-DAPG production and quorum sensing system in Pseudomonas fluorescens 2P24
Authors: Wei Yarui , Dong Baozhu , Wu Xiaogang , Zhao Mingmin , Wang Dong , Li Na , Zhang Qian , Zhang Liqun , Zhou Hongyou
Published: May 2023

Introduction

Pseudomonas fluorescens 2P24 was isolated from soil of natural decay associated with wheat take-all and it can effectively control soil-borne diseases caused by a variety of plant pathogens. 2,4-diacetylphloroglucinol (2,4-DAPG), is produced by P. fluorescens 2P24 and plays an important role in the prevention and control of plant diseases. To understand the resistant mechanism, in this study, we conducted experiments to explore the regulation role of rpoZ in the synthesis of the antibiotic 2,4-DAPG and regulation of QS system.

Methods

A random mini-Tn5 mutagenesis procedure was used to screen regulators for phlA transcription in stain PM901, which containing a phlA∷lacZ transcriptional fusion reporter plasmid. We identified 12 insertion mutants could significantly change phlA gene expression. By analyzing the amino acid sequences of the interrupted gene, we obtained a mutant strain Aa4-29 destroyed the rpoZ gene, which encodes the omiga subunit. We constructed the plasmid of rpoZ mutant (pBBR-△rpoZ) transformed into competent cells of P. fluorescens 2P24 by electro-transformation assay. The strains of P. fluorescens 2P24/pBBR, 2P24-△rpoZ/pBBR, 2P24-△rpoZ/pBBR-rpoZ were used to evaluate the regulation role of rpoZ in 2,4-DAPG production and quorum sensing system.

Results

According to β-galactosidase activity, we found that rpoZ positively regulated the expression of phlA (a synthesis gene of 2,4-DAPG) and PcoI (a synthesis gene of PcoI/PcoR QS signal system) at the transcriptional level. The production of 2,4-DAPG antibiotic and signal molecule AHL was influenced by rpoZ. Further, rpoZ was involved in regulating rsmA expression. RpoZ also has a certain regulatory effect on rpoS transcription, but no effect on the transcription of phlF, emhABC and emhR. According to the biocontrol assay, P. fluorescens 2P24 strains with rpoZ showed obvious antagonism ability against the Rhizoctonia solani in cotton, while the mutant strain of rpoZ lost the biocontrol effect. RpoZ had a significant effect on the swimming and biofilm formation in P. fluorescens 2P24.

Conclusion

Our data showed that rpoZ was an important regulator of QS system, 2,4-DAPG in P. fluorescens 2P24. This may imply that P. fluorescens 2P24 has evolved different regulatory features to adapt to different environmental threats.
Crosslink between SARS-CoV-2 replication and cystic fibrosis hallmarks
Authors: Lotti Virginia , Lagni Anna , Diani Erica , Sorio Claudio , Gibellini Davide
Published: May 2023

SARS-CoV-2, the etiological cause of the COVID-19 pandemic, can cause severe illness in certain at-risk populations, including people with cystic fibrosis (pwCF). Nevertheless, several studies indicated that pwCF do not have higher risks of SARS-CoV-2 infection nor do they demonstrate worse clinical outcomes than those of the general population. Recent in vitro studies indicate cellular and molecular processes to be significant drivers in pwCF lower infection rates and milder symptoms than expected in cases of SARS-CoV-2 infection. These range from cytokine releases to biochemical alterations leading to morphological rearrangements inside the cells associated with CFTR impairment. Based on available data, the reported low incidence of SARS-CoV-2 infection among pwCF is likely a result of several variables linked to CFTR dysfunction, such as thick mucus, IL-6 reduction, altered ACE2 and TMPRSS2 processing and/or functioning, defective anions exchange, and autophagosome formation. An extensive analysis of the relation between SARS-CoV-2 infection and pwCF is essential to elucidate the mechanisms involved in this lower-than-expected infection impact and to possibly suggest potential new antiviral strategies.
Porphyromonas gingivalis outer membrane vesicles exacerbate retinal microvascular endothelial cell dysfunction in diabetic retinopathy
Authors: Huang Shengyuan , Cao Guoqin , Dai Dong , Xu Qiuping , Ruiz Sunniva , Shindo Satoru , Nakamura Shin , Kawai Toshihisa , Lin Jiang , Han Xiaozhe
Published: May 2023

Diabetic retinopathy (DR) is one of the leading causes of blindness. Periodontitis is one of the highest oral incidences and has been closely related to various systemic conditions through Porphyromonas gingivalis (P. gingivalis). P. gingivalis OMVs, derived from P. gingivalis, can cause endothelial dysfunction and potentially affect microvascular diseases. Current epidemiological studies provide limited evidence suggesting that periodontitis is associated with DR. However, there is a lack of basic research elucidating how periodontitis affects the severity of DR. This study aimed to explore the potential of P. gingivalis OMVs to contribute to the pathogenesis of DR and explore how it affect the retinal microvascular endothelium. The results demonstrated that P. gingivalis OMVs accelerated the blood-retinal barrier damage in DR mice. In vitro studies showed that the expression of inflammatory factors in human retinal microvascular endothelial cells (HRMECs) was increased after P. gingivalis OMVs stimulation, and the increased reactive oxygen species production, mitochondrial dysfunction, apoptosis, and altered endothelial permeability were observed in HRMECs under P. gingivalis OMVs stimulation. In addition, we found that protease-activated receptor-2 (PAR-2) regulated OMVs-induced TNF-α, MMP-9 mRNA expression, cell death, and endothelial permeability. Overall, we suggested that P. gingivalis OMVs induced mitochondria-related cell death of HRMECs and accelerated endothelial dysfunction, thus aggravating DR, in which PAR-2 plays a potential role. This study is the first research report to delineate the potential molecular mechanism of P. gingivalis OMVs on DR pathogenesis, which uniquely focused on elucidating the possible impact of periodontal pathogen derivatives on DR progression.
L-leucine increases the sensitivity of drug-resistant Salmonella to sarafloxacin by stimulating central carbon metabolism and increasing intracellular reactive oxygen species level
Authors: Yang Heng , Zhou Yanhong , Luo Qiong , Zhu Chunyang , Fang Binghu
Published: May 2023

Introduction

The overuse of antibiotics has made public health and safety face a serious cisis. It is urgent to develop new clinical treatment methods to combat drug resistant bacteria to alleviate the health crisis. The efficiency of antibiotics is closely related to the metabolic state of bacteria. However, studies on fluoroquinolone resistant Salmonella are relatively rare.

Methods

CICC21484 were passaged in medium with and without sarafloxacin and obtain sarafloxacin- susceptible Salmonella Typhimurium (SAR-S) and sarafloxacin resistant Salmonella Typhimurium (SAR-R), respectively. Non-targeted metabolomics was used to analyze the metabolic difference between SAR-S and SAR-R. Then we verified that exogenous L-leucine promoted the killing effect of sarafloxacin in vitro, and measured the intracellular ATP, NADH and reactive oxygen species levels of bacteria. Gene expression was determined using Real Time quantitative PCR.

Results

We confirmed that exogenous L-leucine increased the killing effect of sarafloxacin on SAR-R and other clinically resistant Salmonella serotypes. Exogenous L-leucine stimulated the metabolic state of bacteria, especially the TCA cycle, which increased the working efficiency of the electron transfer chain and increased the intracellular NADH, ATP concentration, and reactive oxygen species level. Our results suggest that when the metabolism of drug-resistant bacteria is reprogrammed, the bactericidal effect of antibiotics improves.

Discussion

This study further enhances research in the anti-drug resistance field at the metabolic level and provides theoretical support for solving the current problem of sarafloxacin drug resistance, a unique fluoroquinolone drug for animals and indicating the potential of L-leucine as a new antibiotic adjuvant.
Docking guided phase display to develop fusion protein with novel scFv and alkaline phosphatase for one-step ELISA salbutamol detection
Authors: Hu Shuai , Yang Guangbo , Chen Zhou , Li Qiuye , Liu Bin , Liu Ming , Zhang Dawei , Chang Shan , Kong Ren
Published: May 2023

Introduction

Salbutamol (SAL) is a β2 adrenergic receptor agonist which has potential hazardous effects for human health. It is very important to establish a sensitive and convenient method to monitor SAL.

Methods

Here we introduce a method to combine the information from docking and site specific phage display, with the aim to obtain scFv with high affinity to SAL. First, single chain variable fragment (scFv) antibodies against SAL were generated through phage display. By using molecular docking approach, the complex structure of SAL with antibody was predicted and indicated that H3 and L3 contribute to the binding. Then new libraries were created by randomization specific residues located on H3 and L3 according to the docking results.

Results and discussion

Anti-SAL scFv antibodies with high efficiency were finally identified. In addition, the selected scFv was fused with alkaline phosphatase and expressed in E coli to develop a rapid and low-cost one step ELISA to detect SAL.
Crystal structures of glycoprotein D of equine alphaherpesviruses reveal potential binding sites to the entry receptor MHC-I
Authors: Kremling Viviane , Loll Bernhard , Pach Szymon , Dahmani Ismail , Weise Christoph , Wolber Gerhard , Chiantia Salvatore , Wahl Markus C. , Osterrieder Nikolaus , Azab Walid
Published: May 2023

Cell entry of most alphaherpesviruses is mediated by the binding of glycoprotein D (gD) to different cell surface receptors. Equine herpesvirus type 1 (EHV-1) and EHV-4 gDs interact with equine major histocompatibility complex I (MHC-I) to initiate entry into equine cells. We have characterized the gD-MHC-I interaction by solving the crystal structures of EHV-1 and EHV-4 gDs (gD1, gD4), performing protein–protein docking simulations, surface plasmon resonance (SPR) analysis, and biological assays. The structures of gD1 and gD4 revealed the existence of a common V-set immunoglobulin-like (IgV-like) core comparable to those of other gD homologs. Molecular modeling yielded plausible binding hypotheses and identified key residues (F213 and D261) that are important for virus binding. Altering the key residues resulted in impaired virus growth in cells, which highlights the important role of these residues in the gD-MHC-I interaction. Taken together, our results add to our understanding of the initial herpesvirus-cell interactions and will contribute to the targeted design of antiviral drugs and vaccine development.
Innovative retargeted oncolytic herpesvirus against nectin4-positive cancers
Authors: Vannini Andrea , Parenti Federico , Forghieri Cristina , Barboni Catia , Zaghini Anna , Campadelli-Fiume Gabriella , Gianni Tatiana
Published: May 2023

Nectin4 is a recently discovered tumor associated antigen expressed in cancers that constitute relevant unmet clinical needs, including the undruggable triple negative breast cancer, pancreatic ductal carcinoma, bladder/urothelial cancer, cervical cancer, lung carcinoma and melanoma. So far, only one nectin4-specific drug—Enfortumab Vedotin—has been approved and the clinical trials that test novel therapeutics are only five. Here we engineered R-421, an innovative retargeted onco-immunotherapeutic herpesvirus highly specific for nectin4 and unable to infect through the natural herpes receptors, nectin1 or herpesvirus entry mediator. In vitro, R-421 infected and killed human nectin4-positive malignant cells and spared normal cells, e.g., human fibroblasts. Importantly from a safety viewpoint, R-421 failed to infect malignant cells that do not harbor nectin4 gene amplification/overexpression, whose expression level was moderate-to-low. In essence, there was a net threshold value below which cells were spared from infection, irrespective of whether they were malignant or normal; the only cells that R-421 targeted were the malignant overexpressing ones. In vivo, R-421 decreased or abolished the growth of murine tumors made transgenic for human nectin4 and conferred sensitivity to immune checkpoint inhibitors in combination therapies. Its efficacy was augmented by the cyclophosphamide immunomodulator and decreased by depletion of CD8-positive lymphocytes, arguing that it was in part T cell-mediated. R-421 elicited in-situ vaccination that protected from distant challenge tumors. This study provides proof-of-principle specificity and efficacy data justifying nectin4-retargeted onco-immunotherapeutic herpesvirus as an innovative approach against a number of difficult-to-drug clinical indications.
Emerging field: O-GlcNAcylation in ferroptosis
Authors: Zhang Hongshuo , Zhang Juan , Dong Haojie , Kong Ying , Guan Youfei
Published: May 2023

In 2012, researchers proposed a non-apoptotic, iron-dependent form of cell death caused by lipid peroxidation called ferroptosis. During the past decade, a comprehensive understanding of ferroptosis has emerged. Ferroptosis is closely associated with the tumor microenvironment, cancer, immunity, aging, and tissue damage. Its mechanism is precisely regulated at the epigenetic, transcriptional, and post-translational levels. O-GlcNAc modification (O-GlcNAcylation) is one of the post-translational modifications of proteins. Cells can modulate cell survival in response to stress stimuli, including apoptosis, necrosis, and autophagy, through adaptive regulation by O-GlcNAcylation. However, the function and mechanism of these modifications in regulating ferroptosis are only beginning to be understood. Here, we review the relevant literature within the last 5 years and present the current understanding of the regulatory function of O-GlcNAcylation in ferroptosis and the potential mechanisms that may be involved, including antioxidant defense system-controlled reactive oxygen species biology, iron metabolism, and membrane lipid peroxidation metabolism. In addition to these three areas of ferroptosis research, we examine how changes in the morphology and function of subcellular organelles (e.g., mitochondria and endoplasmic reticulum) involved in O-GlcNAcylation may trigger and amplify ferroptosis. We have dissected the role of O-GlcNAcylation in regulating ferroptosis and hope that our introduction will provide a general framework for those interested in this field.
Lipoprotein(a) and stroke: a two-sample Mendelian randomization study
Authors: Huang Yi , Zhang Ruijie , Han Liyuan , Wu Yiwen , Deng Xinpeng , Xu Tianqi , Wu Yuefei , Gao Xiang , Zhou Chenhui , Sun Jie
Published: May 2023

Background

To evaluate the causal relationship between lipoprotein(a) Lp(a) and stroke risk.

Method

Adopting two grand scale genome-wide association study (GWAS) databases, the instrumental variables were selected on the basis that the genetic loci met the criteria of being independent of each other and closely related to Lp(a). Summary-level data for outcomes, ischemic stroke and its subtypes were acquired from the UK Biobank and MEGASTROKE consortium databases. Two-sample MR analyses were achieved using inverse variance-weighted (IVW) meta-analysis (primary analysis), weighted median analysis, and the MR Egger regression method. Multivariable-adjusted Cox regression models were also used for observational analysis.

Result

Genetically predicted Lp(a) was marginally related with higher odds of total stroke (odds ratio (OR) [95% confidence intervals (CI)]: 1.003 [1.001–1.006], p = 0.010), ischemic stroke (OR [95% CI]: 1.004[1.001–1.007], p = 0.004), and large-artery atherosclerotic stroke (OR [95% CI]: 1.012 [1.004–1.019], p = 0.002) when the IVW estimator was used on the MEGASTROKE data. The associations of Lp(a) with stroke and ischemic stroke were also remarkable in the primary analysis using the UK Biobank data. Higher Lp(a) levels were also related with increased total stroke and ischemic stroke risk in the observational research data in the UK Biobank database.

Conclusion

Genetically predicted higher Lp(a) perhaps rise the risk of total stroke, ischemic stroke, and large-artery atherosclerotic stroke.
Efficient push-grasping for multiple target objects in clutter environments
Authors: Wu Liangdong , Chen Yurou , Li Zhengwei , Liu Zhiyong
Published: May 2023

Intelligent manipulation of robots in an unstructured environment is an important application field of artificial intelligence, which means that robots must have the ability of autonomous cognition and decision-making. A typical example of this type of environment is a cluttered scene where objects are stacked and close together. In clutter, the target(s) may be one or more, and efficiently completing the target(s) grasping task is challenging. In this study, an efficient push-grasping method based on reinforcement learning is proposed for multiple target objects in clutter. The key point of this method is to consider the states of all the targets so that the pushing action can expand the grasping space of all targets as much as possible to achieve the minimum total number of pushing and grasping actions and then improve the efficiency of the whole system. At this point, we adopted the mask fusion of multiple targets, clearly defined the concept of graspable probability, and provided the reward mechanism of multi-target push-grasping. Experiments were conducted in both the simulation and real systems. The experimental results indicated that, compared with other methods, the proposed method performed better for multiple target objects and a single target in clutter. It is worth noting that our policy was only trained under simulation, which was then transferred to the real system without retraining or fine-tuning.
The impact of heterogeneity of the air-blood barrier on control of lung extravascular water and alveolar gas exchange
Authors: Miserocchi Giuseppe
Published: May 2023

The architecture of the air-blood barrier is effective in optimizing the gas exchange as long as it retains its specific feature of extreme thinness reflecting, in turn, a strict control on the extravascular water to be kept at minimum. Edemagenic conditions may perturb this equilibrium by increasing microvascular filtration; this characteristically occurs when cardiac output increases to balance the oxygen uptake with the oxygen requirement such as in exercise and hypoxia (either due to low ambient pressure or reflecting a pathological condition). In general, the lung is well equipped to counteract an increase in microvascular filtration rate. The loss of control on fluid balance is the consequence of disruption of the integrity of the macromolecular structure of lung tissue. This review, merging data from experimental approaches and evidence in humans, will explore how the heterogeneity in morphology, mechanical features and perfusion of the terminal respiratory units might impact on lung fluid balance and its control. Evidence is also provided that heterogeneities may be inborn and they could actually get worse as a consequence of a developing pathological process. Further, data are presented how in humans inter-individual heterogeneities in morphology of the terminal respiratory hinder the control of fluid balance and, in turn, hamper the efficiency of the oxygen diffusion-transport function.
Genetic and clinical features of pediatric-onset hereditary spastic paraplegia: a single-center study in Japan
Authors: Ikeda Azusa , Kumaki Tatsuro , Tsuyusaki Yu , Tsuji Megumi , Enomoto Yumi , Fujita Atsushi , Saitsu Hirotomo , Matsumoto Naomichi , Kurosawa Kenji , Goto Tomohide
Published: May 2023

Background and purpose

Hereditary spastic paraplegias (HSPs) are a set of heterogeneous neurodegenerative disorders characterized by bilateral lower limb spasticity. They may present from infancy onwards at any time. Although next-generation sequencing has allowed the identification of many causative genes, little is known about which genes are specifically associated with pediatric-onset variants.

Methods

This study retrospectively evaluated the genetic analyses, family history clinical courses, magnetic resonance imaging (MRI) findings, and electrophysiologic findings of patients diagnosed with HSP in childhood at a tertiary pediatric hospital in Japan. Genetic analyses were performed using direct sequencing, disease-associated panels, and whole-exome sequencing.

Results

Of the 37 patients included, 14 had a family history of HSP and 23 had a sporadic form of the disease. In 20 patients, HSP was the pure type, whereas the remaining 17 patients had complex types of HSP. Genetic data were available for 11 of the pure-type patients and 16 of those with complex types. Of these, genetic diagnoses were possible in 5 (45%) of the pure-type and 13 (81%) of the complex-type patients. SPAST variants were found in five children, KIF1A variants in four, ALS2 variants in three, SACS and L1CAM variants in two each, and an ATL1 variant in one. One child had a 10p15.3p13 duplication. Four patients with pure-type HSPs had SPAST variants and one had an ALT1 variant. The KIF1A, ALS2, SACS, and L1CAM variants and the 10p15.3p13 duplication were seen in children with complex-type HSPs, with just one complex-type patient having a SPAST variant. The identification of brain abnormalities on MRI was significantly more common among children with complex-type (11 [69%] of 16) than pure-type HSPs (one [5%] of 19) (p < 0.001). Scores on the modified Rankin Scale for Neurologic Disability were also significantly higher among children with complex-type compared with pure-type HSPs (3.5 ± 1.0 vs. 2.1 ± 0.9, p < 0.001).

Conclusion

Pediatric-onset HSP was found to be sporadic and genetic in a substantial proportion of patients. The causative gene patterns differed between children with pure-type and complex-type HSPs. The causative roles of SPAST and KIF1A variants in pure-type and complex-type HSPs, respectively, should be explored further.
Associations of plaque morphology and location with Intraplaque neovascularization in the carotid artery by contrast-enhanced ultrasound imaging
Authors: Gu Shi-Yao , Zhang Lu-Ni , Chen Jing , Li Fang , Yao Ming-Hua , Jia Cai-Xia , Wu Rong
Published: May 2023

Objective

Intraplaque neovascularization (IPN) is a known indicator of plaque vulnerability, and is thus considered a predictor of stroke. The morphology and location of the carotid plaque may be correlated with plaque vulnerability. Therefore, our study aimed to examine the associations of carotid plaque morphology and location with IPN.

Methods

A total of 141 patients with carotid atherosclerosis (mean age, 64.99 ± 10.96 years) who underwent carotid contrast-enhanced ultrasound (CEUS) between November 2021 and March 2022 were retrospectively analyzed. IPN was graded according to the presence and location of microbubbles within the plaque. The association of IPN grade with carotid plaque morphology and location was evaluated using ordered logistic regression.

Results

Of the 171 plaques, 89 (52%) were IPN Grade 0, 21 (12.2%) were Grade 1, and 61 (35.6%) were Grade 2. IPN grade significantly associated with both plaque morphology and location, with higher grades observed among Type III morphology and common carotid artery plaques. Significant negative association was further shown between IPN grade and serum high-density lipoprotein cholesterol (HDL-C) level. Plaque morphology and location, and HDL-C remained significantly associated with IPN grade after adjusting for confounding factors.

Conclusion

The location and morphology of carotid plaques were significantly associated with the IPN grade on CEUS, and therefore show potential as biomarkers for plaque vulnerability. Serum HDL-C was also identified as a protective factor against IPN, and may play a role in the management of carotid atherosclerosis. Our study provided a potential strategy for identification of vulnerable carotid plaques and elucidated the important imaging predictors of stroke.