bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of risk factors for positive surgical margin after laparoscopic radical prostatectomy with and without neoadjuvant hormonal therapy
Authors: Wang Fangming , Zhang Gang , Tang Yuzhe , Wang Yunpeng , Li Jianxing , Xing Nianzeng
Published: October 2023

Background

Positive surgical margins (PSM) is not only an independent risk factor for recurrence, metastasis, and prognosis, but also an important indicator of adjuvant therapy for prostate cancer (PCa) patients treated with radical prostatectomy (RP). At present, there are few reports analyzing risk factors of PSM in laparoscopic RP (LRP), especially for those PCa cases who accepted neoadjuvant hormonal therapy (NHT). Hence, the aim of the current study was to explore risk factors for PSM after LRP in PCa patients with and without NHT.

Methods

The clinicopathological data of patients who underwent LRP from January 2012 to July 2020 was retrospectively analyzed. Risk factors for PSM after LRP in NHT and non-NHT groups were respectively explored.

Results

The overall PSM rate was 33.3% (90/270), PSM rate was 39.3% (64/163) in patients without NHT and 24.3% (26/107) in those with NHT. The apex was the most common location of PSM in non-NHT group (68.8%, 44/64), while the fundus was the most common location of PSM in NHT group (57.7%, 15/26). Multiple logistic regression revealed that body mass index (BMI), PSA, ISUP grade after LRP, pathological stage T (pT) and pathological lymph node status (pN) were independent factors affecting the PSM for patients without NHT (OR=1.160, 95%CI:1.034-1.301, p=0.011; OR=3.385, 95%CI:1.386-8.268, p=0.007; OR=3.541, 95%CI:1.008-12.444, p=0.049; OR=4.577, 95%CI:2.163-9.686, p<0.001; OR=3.572, 95%CI:1.124-11.347, p=0.031), while pT, pN, and lymphovascular invasion (LVI) were independent risk factors affecting PSM for patients with NHT (OR=18.434, 95%CI:4.976-68.297, p<0.001; OR=7.181, 95%CI:2.089-24.689, p=0.002; OR=3.545, 95%CI:1.109-11.327, p=0.033).

Conclusions

The apex was the most common location in NHT group, and BMI, PSA, ISUP after LRP, pT and pN were independent risk factors affecting PSM for NHT patients; while the fundus was the most common location in non-NHT group, and pT, pN, and LVI were independent risk factors affecting PSM for non-NHT patients.
NEUROD2 function is dispensable for human pancreatic β cell specification
Authors: Cota Perla , Saber Lama , Taskin Damla , Jing Changying , Bastidas-Ponce Aimée , Vanheusden Matthew , Shahryari Alireza , Sterr Michael , Burtscher Ingo , Bakhti Mostafa , Lickert Heiko
Published: October 2023

Introduction

The molecular programs regulating human pancreatic endocrine cell induction and fate allocation are not well deciphered. Here, we investigated the spatiotemporal expression pattern and the function of the neurogenic differentiation factor 2 (NEUROD2) during human endocrinogenesis.

Methods

Using Crispr-Cas9 gene editing, we generated a reporter knock-in transcription factor (TF) knock-out human inducible pluripotent stem cell (iPSC) line in which the open reading frame of both NEUROD2 alleles are replaced by a nuclear histone 2B-Venus reporter (NEUROD2nVenus/nVenus).

Results

We identified a transient expression of NEUROD2 mRNA and its nuclear Venus reporter activity at the stage of human endocrine progenitor formation in an iPSC differentiation model. This expression profile is similar to what was previously reported in mice, uncovering an evolutionarily conserved gene expression pattern of NEUROD2 during endocrinogenesis. In vitro differentiation of the generated homozygous NEUROD2nVenus/nVenus iPSC line towards human endocrine lineages uncovered no significant impact upon the loss of NEUROD2 on endocrine cell induction. Moreover, analysis of endocrine cell specification revealed no striking changes in the generation of insulin-producing b cells and glucagon-secreting a cells upon lack of NEUROD2.

Discussion

Overall, our results suggest that NEUROD2 is expendable for human b cell formation in vitro.
Research on technological innovation and marketing publicity decision of green intelligent home appliance supply chain considering consumer subsidy and cost-sharing contract
Authors: Che Cheng , Li Qing , Yin Qi , Li Suhui , Zheng Huixian , Geng Xin
Published: October 2023

Under the leadership of China’s “dual-carbon” policy, how to reduce energy consumption, reduce carbon emissions, and realize intelligent, low-carbon development has become a key issue faced by the home appliance industry. Studies have shown that green intelligent home appliances can save electricity and reduce carbon emissions. In the context of China’s “dual-carbon” goal, this study examines the technological innovation and marketing publicity decisions of the green intelligent home appliance supply chain considering the consumer subsidy and cost-sharing contract. By constructing a three-level supply chain model that includes home appliance manufacturers, retailers, and consumers, we use the Stackelberg game method to study the decision-making models under four scenarios with and without consumer subsidy and cost-sharing contract and consider the impact of consumers’ green intelligent preference, consumers’ green marketing sensitivity, consumer subsidy and cost-sharing contract on the supply chain optimal decision. Through model solving and further numerical simulation, the results show that 1) the increase of consumers’ green intelligent preference and consumers’ green marketing sensitivity can produce positive spillover effects and promote the improvement of home appliance manufacturers’ technological innovation efforts and retailers’ marketing publicity efforts; 2) consumer subsidy is always beneficial for the green intelligent development of the supply chain, which can effectively increase the total revenue of the supply chain; 3) the reasonable cost-sharing ratio can stimulate the enthusiasm of supply chain enterprises to increase technological innovation and marketing publicity investments and increase the total profit of the supply chain. However, the excessive cost-sharing ratio frustrates the enthusiasm of home appliance retailers to participate in the coordination, which results in a decline in the overall benefit of the supply chain; 4) by considering both consumer subsidy and cost-sharing contract, a reasonable level of consumer subsidy and cost-sharing ratio have a better incentive effect on the supply chain members than in the other three scenarios. This study can provide a broader reference for the green intelligent development of China’s home appliance industry, which plays an important role in the implementation of China’s “dual carbon” goal.
Public willingness to pay for personal carbon trading of green travel: based on survey data from five capital cities in eastern China
Authors: Geng Jichao , Yang Na , Yang Li , Long Ruyin
Published: October 2023

Personal carbon trading is a form of pollution rights trading that is worth exploring as an innovative tool to cut back carbon emissions from travel. This paper proposes a policy scenario in which car users who exceed the average distance traveled quota are required to purchase travel credits from those who do not reach the quota and pay for them on a per hundred kilometer basis. Willingness to pay (WTP) for personal carbon trading is introduced to calculate the travel cost and its influencing factors are analyzed from the perspective of green travel. Using the double-bounded dichotomous choice contingent valuation method (DBDC), 2712 residents’ data from five provincial capital cities in eastern China is obtained. Based on this, this study first uses a binary logistic regression model to analyze the characteristics of people who are not willing to pay for green travel carbon trading, and then leverages an interval regression model to explore the willingness and intrinsic motivation of being willing to pay more or less for green travel. The results suggest that perceived usefulness is a key influencing factor of residents’ willingness to pay or pay more for green travel; Personal habits have a significant positive effect among those willing to pay; Subjective norms and moral norms can well account for the unwillingness to pay; Attitudes, perceived behavioral control, and environmental awareness fail to predict the willingness to pay among those who are unwilling to pay. In addition, WTP is also affected by demographic variables such as income and educational background. The empirical results as well indicate that the final average level of respondents’ WTP is 39.95 yuan per 100 km. The findings of this paper can provide a pricing basis while formulating personal travel carbon trading policies.
Invasion of fall armyworm, (Spodoptera frugiperda, J E Smith) (Lepidoptera, Noctuidae) on onion in the maize–onion crop sequence from Maharashtra, India
Authors: Soumia P. S. , Shirsat Dhananjay V. , Chitra N. , Guru-Pirasanna-Pandi Govindharaj , Karuppaiah Vadivelu , Gadge Ankush S. , Thangasamy Arunachalam , Mahajan Vijay
Published: October 2023

Introduction

Climate change affects geographical distribution of insect pests which poses threats to the environment, as well as agricultural productivity and production worldwide. Spodoptera frugiperda is commonly known as fall armyworm (FAW), a potential insect pest of monocot crops like maize, wheat, rice and sorghum globally. Among these, maize is the most preferred host crop while worldwide there are very few reports on onion being a host of fall armyworm.

Methods

The fall armyworm (FAW) was identified by examining the morphological characteristics of its immature and mature stages, as well as by analyzing the mitochondrial cytochrome oxidase 1 (COX1) gene. Further, the strain identity was confirmed through multiple sequence alignment with previously identified S. frugiperda strains from corn and rice. Also studied the biology and damage symptoms caused by FAW in onion crops.

Results

During our experiments, the incidence of FAW ranged from 5 to 20 percent in different plots. The highest incidence was observed in young crops (30–45 days after transplanting) that were sown in November 2020. The FAW larvae exhibited six instars, with a total larval duration of 22.2 ± 0.37 days. The pest had multiple generations per year. The fully developed larvae formed earthen cocoons in the soil for pupation, with a pupal duration of 8.0 ± 0.45 days. The male adults had a recorded longevity of 6.4± 0.40days, while the female adults lived for approximately 9.2 ± 0.37 days. The COX1 gene sequencing revealed its 100% similarity with Spodoptera frugiperda and the comparison of sequences among FAW infecting rice and maize by using multiple sequence alignment showed differences at 11 positions.

Discussion

The present study is the first report of FAW invasion in onion in India and provides basic ideas about FAW characteristics which will help to control this new invasive pest in onion. In tropical regions with multiple cropping system and seasons, it becomes very important to investigate invasive pests as well as its host range in order to forecast its potential damage and devise suitable control measures.
Characterization of transcriptional enhancers in the chicken genome using CRISPR-mediated activation
Authors: Han Jeong Hoon , Lee Hong Jo , Kim Tae Hyun
Published: October 2023

DNA regulatory elements intricately control when, where, and how genes are activated. Therefore, understanding the function of these elements could unveil the complexity of the genetic regulation network. Genome-wide significant variants are predominantly found in non-coding regions of DNA, so comprehending the predicted functional regulatory elements is crucial for understanding the biological context of these genomic markers, which can be incorporated into breeding programs. The emergence of CRISPR technology has provided a powerful tool for studying non-coding regulatory elements in genomes. In this study, we leveraged epigenetic data from the Functional Annotation of Animal Genomes project to identify promoter and putative enhancer regions associated with three genes (HBBA, IRF7, and PPARG) in the chicken genome. To identify the enhancer regions, we designed guide RNAs targeting the promoter and candidate enhancer regions and utilized CRISPR activation (CRISPRa) with dCas9-p300 and dCas9-VPR as transcriptional activators in chicken DF-1 cells. By comparing the expression levels of target genes between the promoter activation and the co-activation of the promoter and putative enhancers, we were able to identify functional enhancers that exhibited augmented upregulation. In conclusion, our findings demonstrate the remarkable efficiency of CRISPRa in precisely manipulating the expression of endogenous genes by targeting regulatory elements in the chicken genome, highlighting its potential for functional validation of non-coding regions.
Macrophage migration inhibitory factor receptor CD74 expression is associated with expansion and differentiation of effector T cells in COVID-19 patients
Authors: Westmeier Jaana , Brochtrup Annika , Paniskaki Krystallenia , Karakoese Zehra , Werner Tanja , Sutter Kathrin , Dolff Sebastian , Limmer Andreas , Mittermüller Daniela , Liu Jia , Zheng Xin , Koval Tetiana , Kaidashev Igor , Berger Marc Moritz , Herbstreit Frank , Brenner Thorsten , Witzke Oliver , Trilling Mirko , Lu Mengji , Yang Dongliang , Babel Nina , Westhoff Timm , Dittmer Ulf , Zelinskyy Gennadiy
Published: October 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused millions of COVID-19 cases and deaths worldwide. Severity of pulmonary pathologies and poor prognosis were reported to be associated with the activation non-virus-specific bystander T cells. In addition, high concentrations of the macrophage migration inhibitory factor (MIF) were found in serum of COVID-19 patients. We hypothesized that these two pathogenic factors might be related and analyzed the expression of receptors for MIF on T cells in COVID-19. T cells from PBMCs of hospitalized patients with mild and severe COVID-19 were characterized. A significantly higher proportion of CD4+ and CD8+ T cells from COVID-19 patients expressed CD74 on the cell surface compared to healthy controls. To induce intracellular signaling upon MIF binding, CD74 forms complexes with CD44, CXCR2, or CXCR4. The vast majority of CD74+ T cells expressed CD44, whereas expression of CXCR2 and CXCR4 was low in controls but increased upon SARS-CoV-2 infection. Hence, T cells in COVID-19 patients express receptors that render them responsive to MIF. A detailed analysis of CD74+ T cell populations revealed that most of them had a central memory phenotype early in infection, while cells with an effector and effector memory phenotype arose later during infection. Furthermore, CD74+ T cells produced more cytotoxic molecules and proliferation markers. Our data provide new insights into the MIF receptor and co-receptor repertoire of bystander T cells in COVID-19 and uncovers a novel and potentially druggable aspect of the immunological footprint of SARS-CoV-2.
A novel ΔNp63-dependent immune mechanism improves prognosis of HPV-related head and neck cancer
Authors: Mourtada Jana , Lony Christelle , Nicol Anaïs , De Azevedo Justine , Bour Cyril , Macabre Christine , Roncarati Patrick , Ledrappier Sonia , Schultz Philippe , Borel Christian , Burgy Mickaël , Wasylyk Bohdan , Mellitzer Georg , Herfs Michaël , Gaiddon Christian , Jung Alain C.
Published: October 2023

Background

Deconvoluting the heterogenous prognosis of Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) is crucial for enhancing patient care, given its rapidly increasing incidence in western countries and the adverse side effects of OSCC treatments.

Methods

Transcriptomic data from HPV-positive OSCC samples were analyzed using unsupervised hierarchical clustering, and clinical relevance was evaluated using Kaplan-Meier analysis. HPV-positive OSCC cell line models were used in functional analyses and phenotypic assays to assess cell migration and invasion, response to cisplatin, and phagocytosis by macrophages in vitro.

Results

We found, by transcriptomic analysis of HPV-positive OSCC samples, a ΔNp63 dependent molecular signature that is associated with patient prognosis. ΔNp63 was found to act as a tumor suppressor in HPV-positive OSCC at multiple levels. It inhibits cell migration and invasion, and favors response to chemotherapy. RNA-Seq analysis uncovered an unexpected regulation of genes, such as DKK3, which are involved in immune response-signalling pathways. In agreement with these observations, we found that ΔNp63 expression levels correlate with an enhanced anti-tumor immune environment in OSCC, and ΔNp63 promotes cancer cell phagocytosis by macrophages through a DKK3/NF-κB-dependent pathway.

Conclusion

Our findings are the first comprehensive identification of molecular mechanisms involved in the heterogeneous prognosis of HPV-positive OSCC, paving the way for much-needed biomarkers and targeted treatment.
Mechanistic and therapeutic insights into the function of NLRP3 inflammasome in sterile arthritis
Authors: Xiao Yi , Zhang Li
Published: October 2023

The NLRP3 inflammasome, which belongs to the pyrin domain containing 3 family of NOD-like receptors, has a significant impact on both the innate and adaptive immune responses. Regulating host immune function and protecting against microbial invasion and cell damage, the NLRP3 inflammasome plays a crucial role. By triggering caspase-1, it facilitates the development of the inflammatory cytokines IL-1β and IL-18, and triggers cell pyroptosis, resulting in cell lysis and demise. Common sterile arthritis includes osteoarthritis (OA), rheumatoid arthritis (RA) and gouty arthritis (GA), all of which manifest as bone destruction and synovial inflammation in a complex inflammatory state, placing a significant medical burden on the families of patients and government agencies. In the past few years, there has been a growing interest in investigating the impact of cell pyroptosis on arthritis development, particularly the widespread occurrence of pyroptosis mediated by the NLRP3 inflammasome. The NLRP3 inflammasome’s biological properties are briefly described in this review, along with the presentation of the fundamental processes of pyroptosis resulting from its activation. Furthermore, we provide a summary of the advancements made in studying the NLRP3 inflammasome in various forms of arthritis and enumerate the intervention approaches that target the NLRP3-mediated pyroptosis, either directly or indirectly. These discoveries lay the groundwork for future investigations on medications for arthritis, offering fresh approaches for the clinical identification and treatment of this condition.
The role of cGAS-STING signaling in pulmonary fibrosis and its therapeutic potential
Authors: Zhang Jing , Zhang Lanlan , Chen Yutian , Fang Xiaobin , Li Bo , Mo Chunheng
Published: October 2023

Pulmonary fibrosis is a progressive and ultimately fatal lung disease, exhibiting the excessive production of extracellular matrix and aberrant activation of fibroblast. While Pirfenidone and Nintedanib are FDA-approved drugs that can slow down the progression of pulmonary fibrosis, they are unable to reverse the disease. Therefore, there is an urgent demand to develop more efficient therapeutic approaches for pulmonary fibrosis. The intracellular DNA sensor called cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) plays a crucial role in detecting DNA and generating cGAMP, a second messenger. Subsequently, cGAMP triggers the activation of stimulator of interferon genes (STING), initiating a signaling cascade that leads to the stimulation of type I interferons and other signaling molecules involved in immune responses. Recent studies have highlighted the involvement of aberrant activation of cGAS-STING contributes to fibrotic lung diseases. This review aims to provide a comprehensive summary of the current knowledge regarding the role of cGAS-STING pathway in pulmonary fibrosis. Moreover, we discuss the potential therapeutic implications of targeting the cGAS-STING pathway, including the utilization of inhibitors of cGAS and STING.
Associations of genetically predicted circulating levels of cytokines with telomere length: a Mendelian randomization study
Authors: Pan Renbing , Xiao Mingjia , Wu Zhigang , Liu Jingwen , Wan Lijun
Published: October 2023

Background

Telomere length (TL) has been regarded as a biomarker of aging, and TL shortening is associated with numerous chronic illnesses. The mounting evidence has shown that inflammatory cytokines are involved in maintaining or shortening TL, the causality of cytokines with TL remains unknown. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to estimate the underlying correlations of circulating inflammatory cytokines with TL.

Methods

Genetic instrumental variables for inflammatory cytokines were identified through a genome-wide association study (GWAS) involving 8,293 European individuals. Summary statistics of TL were derived from a UK Bio-bank cohort comprising 472,174 samples of individuals with European descent. We employed the inverse-variance weighted (IVW) approach as our main analysis, and to ensure the reliability of our findings, we also conducted additional analyses including the weighted median, MR-Egger, MR pleiotropy residual sum and outlier test, and weighted model. Lastly, the reverse MR analyses were performed to estimate the likelihood of inverse causality between TL and the cytokines identified in the forward MR analysis. Cochran’s Q test were employed to quantify the degree of heterogeneity.

Results

After applying Bonferroni correction, a higher circulating level of Interleukin-7 (IL-7) was suggestively associated with TL maintaining (OR:1.01, 95%CI:1.00-1.02, P=0.032 by IVW method). The study also revealed suggestive evidence indicating the involvement of Interleukin-2 receptor, alpha subunit (IL-2Rα) level was negatively associated with TL maintaining (OR:0.98, 95%CI:0.96-1.00, P=0.045 by IVW method), and the weighted median approach was consistent (OR:0.99, 95%CI:0.97-1.00, P=0.035). According to the findings of reverse MR analysis, no significant causal relationship between TL and cytokines was explored. Our analysis did not reveal any substantial heterogeneity in the Single nucleotide polymorphisms or horizontal pleiotropy.

Conclusions

Our MR analysis yielded suggestive evidence supporting the causality between circulating IL-7 and IL-2Rα and telomere length, necessitating further investigations to elucidate the mechanisms by which these inflammatory cytokines may impact the progression of telomeres.
Establishing the best combination of the kappa free light chain index and oligoclonal bands for an accurate diagnosis of multiple sclerosis
Authors: Monreal Enric , Fernández-Velasco José Ignacio , García-Soidán Ana , Sainz de la Maza Susana , Espiño Mercedes , Villarrubia Noelia , Rodríguez-Jorge Fernando , Chico-García Juan Luís , Sainz-Amo Raquel , Masjuan Jaime , Costa-Frossard Lucienne , Villar Luisa María
Published: October 2023

Introduction

The immunoglobulin kappa free light chain (KFLC) index has been proposed as a potentially suitable alternative to oligoclonal IgG bands (OCGB) for diagnosing multiple sclerosis (MS), offering automation and reduced processing time. However, there is no consensus on the preferred approach or how to combine both techniques.

Methods

This prospective cohort study aimed to determine the best utilization of OCGB and KFLC index in patients with a clinically isolated syndrome (CIS) followed for at least two years. OCGB and KFLC were assessed using isoelectric focusing and immunoblotting and turbidimetry, respectively. Sensitivity, specificity, and accuracy for diagnosing MS were calculated for each method.

Results

The study included 371 patients, with 260 (70.1 %) being women, and a median age of 34.9 (27.8 – 43.9) years. Using a cut-off value of 6.1, the KFLC index demonstrated a sensitivity and specificity of 86.3% and 93.9%, respectively. The sensitivity of OCGB (95.3%) was higher (p < 0.001 vs. KFLC index) and the specificity (100%) was comparable to that of the KFLC index (p = 0.5). The concordance between the methods was not uniform across all patients, with 97.8% agreement in patients with KFLC index ≥ 6.1 and 56.0 % in patients with KFLC index < 6.1. In patients with a KFLC index < 6.1, OCGB still identified 75.0 % of MS patients due to its higher sensitivity. An algorithm using the KFLC index as a screening tool and OCGB as an alternative for patients with a negative KFLC index result achieved an accuracy of 96.3 %.

Discussion

Combining the KFLC index and OCGB can provide an easily reproducible and accurate method for diagnosing MS, with OCGB primarily reserved for patients with a KFLC index < 6.1.
A novel nanobody-based HER2-targeting antibody exhibits potent synergistic antitumor efficacy in trastuzumab-resistant cancer cells
Authors: Liu Xinlin , Luan Linli , Liu Xi , Jiang Dingwen , Deng Junwen , Xu Jiazhen , Yuan Yang , Xing Jiyao , Chen Bingguan , Xing Dongming , Huang Haiming
Published: October 2023

Human epithelial growth factor receptor-2 (HER2) plays an oncogenic role in numerous tumors, including breast, gastric, and various other solid tumors. While anti-HER2 therapies are approved for the treatment of HER2-positive tumors, a necessity persists for creating novel HER2-targeted agents to resolve therapeutic resistance. Utilizing a synthetic nanobody library and affinity maturation, our study identified four anti-HER2 nanobodies that exhibited high affinity and specificity. These nanobodies recognized three distinct epitopes of HER2-ECD. Additionally, we constructed VHH-Fc and discovered that they facilitated superior internalization and showed moderate growth inhibition. Compared to the combination of trastuzumab and pertuzumab, the VHH-Fc combos or their combination with trastuzumab demonstrated greater or comparable antitumor activity in both ligand-independent and ligand-driven tumors. Most remarkably, A9B5-Fc, which targeted domain I of HER2-ECD, displayed significantly enhanced trastuzumab-synergistic antitumor efficacy compared to pertuzumab under trastuzumab-resistant conditions. Our findings offer anti-HER2 nanobodies with high affinity and non-overlapping epitope recognition. The novel nanobody-based HER2-targeted antibody, A9B5-Fc, binding to HER2-ECD I, mediates promising receptor internalization. It possesses the potential to serve as a potent synergistic partner with trastuzumab, contributing to overcoming acquired resistance.
Proposed synergies between oceanography and metrology
Authors: Hartman Susan E. , Gates Andrew R. , Lopez-Garcia Patricia , Bozzano Roberto , Delory Eric , Favali Paolo , Lefevre Dominique , Chirurgien Laure , Pensieri Sara , Petihakis George , Nair Rajesh , Neves Silvana , Dañobeitia Juan José , Salvetat Florence , Le Menn Marc , Seppälä Jukka , Schroeder Katrin , Piera Jaume
Published: October 2023

Accurate and traceable measurements are required to understand ocean processes, to address pressing societal challenges, such as climate change and to sustainably manage marine resources. Although scientific and engineering research has resulted in advanced methods to measure Essential Ocean Variables (EOVs) there is a need for cross comparison of the techniques and traceability to recognized standards. Metrological laboratories are experienced in accredited methods and assessment of methodology. An EU INFRAIA-02-2020: Integrating Activities for Starting Communities project MINKE (Metrology for Integrated marine maNagement and Knowledge-transfer nEtwork https://minke.eu) brings European marine science and metrology Research Infrastructures together to identify synergies and create an innovative approach to Quality Assurance of oceanographic data. Quality depends both on the accuracy (that can be provided through the metrology component) and the completeness of the data sets. The collaboration between different Marine Research Infrastructures (RIs) places a fundamental role on assuring the completeness of the datasets, particularly at global scales. The MINKE project encourages enhancement through collaboration of national metrology laboratories and the oceanographic community. Metrological assessment of the accuracy and uncertainties within multidisciplinary ocean observations will provide data that are key to delivering policy information. Objectives across all the RIs are to facilitate ocean observation and build wider synergies. MINKE will investigate these synergies, then introduce metrology to the core of various EOV measurements. Currently the marine RIs cover laboratory and field operations, from the surface seafloor, coastal waters to deep sea, fixed ocean stations to ship and autonomous vehicle operations to ships of opportunity, and flux stations focusing on carbonate system variables. The nexus of these operations is the focal point for coordinated improvement of ocean observing methods. Measurement intercomparisons, traceability and uncertainty assessments should be at the core of the scientific observations. Specifically, MINKE will work with RIs and Metrology Institutes to improve the quality of dissolved oxygen, carbonate system, chlorophyll-fluorescence, ocean sound and current meter measurements, through access to metrology laboratories, Transnational Access and intercomparison studies across existing marine consortia and RIs. MINKE will also promote the development of absolute salinity observation, and improvements in marine litter measurements.
Ocean mixing induced by three-dimensional structure of equatorial mode tropical instability waves in the Pacific Ocean
Authors: Fang Liyuan , Ma Kai , Liu Chuanyu , Wang Xiaowei , Wang Fan
Published: October 2023

Observations have revealed that tropical instability waves (TIWs) play an important role in the ocean mixing of the equatorial thermocline. However, most studies have not distinguished the individual effects from the TIWs’ two modes, and most of them focused on the effect of the TIW-induced vertical shear on the formation of mixing. In this study, we utilize the high-resolution ocean reanalysis data to isolate the 3D structure of the equatorial mode of TIW (eTIW) and examine the detailed mechanisms of its mixing effects. Horizontally, the temperature associated with the eTIWs shows a centrosymmetric structure in the upper layers, but vertically, the phase begins to transition at ~70 and becomes opposite to that of the upper layer below 90 m. The centrosymmetric temperature structure leads to a similar stratification pattern in the upper layers. We find that the pattern of the eTIW-associated reduced shear squared (RSS), an indicator for potential shear instability, is controlled by its stratification rather than shear, suggesting that the former plays a more important role than the latter in resulting in shear instability and mixing. Specifically, it is in the northern (southern) part of the clockwise (anticlockwise) phase of the eTIWs that the eTIW-associated RSS is positively large, where the total flow is more likely to be modulated by shear instability and mixing. Hence, the present study provides a new mechanism for the TIW-induced mixing in the equatorial thermocline. However, in specific regions where the eTIW-induced shear has the same sign as that of the mean flow, the eTIW-associated shear squared can also significantly enhance the total RSS and lead to shear instability, consistent with previous studies.
Sentinel lymph node mapping: current applications and future perspectives in thyroid carcinoma
Authors: Boschin Isabella Merante , Bertazza Loris , Scaroni Carla , Mian Caterina , Pelizzo Maria Rosa
Published: October 2023

Sentinel lymph node (SLN) mapping is a standard, minimally-invasive diagnostic method in the surgical treatment of many solid tumors, as for example melanoma and breast cancer, for detecting the presence of regional nodal metastases. A negative SLN accurately indicates the absence of metastases in the other regional lymph nodes (LN), thus avoiding unnecessary lymph nodal dissection. Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma (TC) with cervical LN metastases at diagnosis in 20–90%, and nodal involvement correlates with local persistence/recurrence. The SLN in PTC is an intraoperative method for staging preoperative N0 patients and for detecting metastatic LNs “in and outside” the cervical LN central compartment; it represents an alternative method to prophylactic central neck node dissection. In this review we summarize different methods and results of the use of SLN in TC. The SLN identification techniques currently used include the selective vital-dye (VD) method, 99mTc-nanocolloid planar lymphoscintigraphy with intraoperative use of a hand-held gamma probe (LS), the combination LS + VD, and the combination LS and preoperative SPECT–CT (LS + SPECT/CT). The application of the SLN procedure in TC has been described in many studies, however, the techniques are heterogeneous, and the role of SLN in TC, with indications, results, advantages and limits, is still debated.
The impact of light/dark regimes on structure and physiology of Chlorella vulgaris biofilms
Authors: Gao Yan , Bernard Olivier , Fanesi Andrea , Perré Patrick , Lopes Filipa
Published: October 2023

Introduction

Biofilm-based microalgae production technologies offer enormous potential for improving sustainability and productivity. However, the light pattern induced by these technologies is a key concern for optimization.

Methods

In this work, the effects of light/dark cycles on architecture, growth, and physiology of Chlorella vulgaris biofilms were assessed in a millifluidic flow-cell with different time cycles (15 s to 3 min) keeping the average light constant at 100 μmol·m−2·s−1.

Results and discussion

Results showed that photoinhibition can be mitigated by applying a light fraction of 1/3 and a cycle time of 15 s. By contrast, when the cycle time is extended to 90 s and 3 min, photoinhibition is high and photoefficiency dramatically decreases. To cope with light stress, cells acclimate and organize themselves differently in space. A high peak light (500 μmol·m−2·s−1) triggers a stress, reducing cell division and inducing clusters in the biofilm. This work provides guidelines for optimizing rotating microalgae production systems in biofilms and assesses the minimum rotating frequency required to maintain the net growth rate close to that of continuous light of the same average intensity, mitigating photo-inhibition. The overall gain in productivity is then provided by the total surface of the biofilm turning in the illuminated surface area.
Effects of temperature on the interaction between amphibian skin bacteria and Batrachochytrium dendrobatidis
Authors: Robak Matthew J. , Saenz Veronica , de Cortie Esmee , Richards-Zawacki Corinne L.
Published: October 2023

Symbiotic relationships between animals and microbes are important for a range of functions, from digestion to protection from pathogens. However, the impact of temperature variation on these animal-microbe interactions remains poorly understood. Amphibians have experienced population declines and even extinctions on a global scale due to chytridiomycosis, a disease caused by chytrid fungi in the genus Batrachochytrium. Variation in susceptibility to this disease exists within and among host species. While the mechanisms generating differences in host susceptibility remain elusive, differences in immune system components, as well as variation in host and environmental temperatures, have been associated with this variation. The symbiotic cutaneous bacteria of amphibians are another potential cause for variation in susceptibility to chytridiomycosis, with some bacterial species producing antifungal metabolites that prevent the growth of Bd. The growth of both Bd and bacteria are affected by temperature, and thus we hypothesized that amphibian skin bacteria may be more effective at preventing Bd growth at certain temperatures. To test this, we collected bacteria from the skins of frogs, harvested the metabolites they produced when grown at three different temperatures, and then grew Bd in the presence of those metabolites under those same three temperatures in a three-by-three fully crossed design. We found that both the temperature at which cutaneous bacteria were grown (and metabolites produced) as well as the temperature at which Bd is grown can impact the ability of cutaneous bacteria to inhibit the growth of Bd. While some bacterial isolates showed the ability to inhibit Bd growth across multiple temperature treatments, no isolate was found to be inhibitive across all combinations of bacterial incubation or Bd challenge temperatures, suggesting that temperature affects both the metabolites produced and the effectiveness of those metabolites against the Bd pathogen. These findings move us closer to a mechanistic understanding of why chytridiomycosis outbreaks and related amphibian declines are often limited to certain climates and seasons.
Antimicrobial peptide 2K4L disrupts the membrane of multidrug-resistant Acinetobacter baumannii and protects mice against sepsis
Authors: Ji Fangyu , Tian Guoxu , Shang Dejing , Jiang Fengquan
Published: October 2023

Antimicrobial peptides represent a promising therapeutic alternative for the treatment of antibiotic-resistant bacterial infections. 2K4L is a rationally-designed analog of a short peptide temporin-1CEc, a natural peptide isolated and purified from the skin secretions of the Chinese brown frog Rana chensinensis by substituting amino acid residues. 2K4L adopt an α-helical confirm in a membrane-mimetic environment and displayed an improved and broad-spectrum antibacterial activity against sensitive and multidrug-resistant Gram-negative and Gram-positive bacterial strains. Here, the action mechanism of 2K4L on multidrug resistant Acinetobacter baumannii (MRAB) and protection on MRAB-infected mice was investigated. The results demonstrated high bactericidal activity of 2K4L against both a multidrug resistant A. baumannii 0227 strain (MRAB 0227) and a sensitive A. baumannii strain (AB 22934), indicating a potential therapeutic advantage of this peptide. Strong positively-charged residues significantly promoted the electrostatic interaction on 2K4L with lipopolysaccharides (LPS) of the bacterial outer membrane. High hydrophobicity and an α-helical confirm endowed 2K4L remarkably increase the permeability of A. baumannii cytoplasmic membrane by depolarization of membrane potential and disruption of membrane integration, as well as leakage of fluorescein from the liposomes. Additionally, 2K4L at low concentrations inhibited biofilm formation and degraded mature 1-day-old MRAB 0227 biofilms by reducing the expression of biofilm-related genes. In an invasive A. baumannii infection model, 2K4L enhanced the survival of sepsis mice and decreased the production of the proinflammatory cytokines downregulating the phosphorylation level of signaling protein in MAPK and NF-κB signaling pathways, indicating that 2K4L represents a novel therapeutic antibiotic candidate against invasive multidrug-resistant bacterial strain infections.
ReDirection: an R-package to compute the probable dissociation constant for every reaction of a user-defined biochemical network
Authors: Kundu Siddhartha
Published: October 2023

Biochemical networks integrate enzyme-mediated substrate conversions with non-enzymatic complex formation and disassembly to accomplish complex biochemical and physiological functions. The choice of parameters and constraints used in most of these studies is numerically motivated and network-specific. Although sound in theory, the outcomes that result depart significantly from the intracellular milieu and are less likely to retain relevance in a clinical setting. There is a need for a computational tool which is biochemically relevant, mathematically rigorous, and unbiased, and can ascribe functionality to and generate potentially testable hypotheses for a user-defined biochemical network. Here, we present “ReDirection,” an R-package which computes the probable dissociation constant for every reaction of a biochemical network directly from a null space-generated subspace of the stoichiometry number matrix of the modeled network. “ReDirection” delineates this subspace by excluding all trivial and redundant or duplicate occurrences of non-trivial vectors, combinatorially summing the vectors that remain and verifying that the upper or lower bounds of the sequence of terms formed by each row of this subspace belong to the open real-valued intervals −∞,−1 or 1,∞ or whether the number of terms that are differently signed are almost equal. “ReDirection” iterates these steps until these bounds are consistent and unambiguous for all reactions of the modeled biochemical network. Thereafter, “ReDirection” filters the terms from each row of this subspace, bins them to outcome-specific subsets, sums and maps this to an outcome-specific reaction vector, and computes the p1-norm, which is the probable dissociation constant for a reaction. “ReDirection” works on first principles, does not discriminate between enzymatic and non-enzymatic reactions, offers a biochemically relevant and mathematically rigorous environment to explore user-defined biochemical networks under baseline and perturbed conditions, and can be used to address empirically intractable biochemical problems. The utility and relevance of “ReDirection” are highlighted by numerical studies on stoichiometric number models of biochemical networks of galactose metabolism and heme and cholesterol biosynthesis. “ReDirection” is freely available and accessible from the comprehensive R archive network (CRAN) with the URL (https://cran.r-project.org/package=ReDirection).
Emerging theragnostic radionuclide applications for hepatocellular carcinoma
Authors: Nyakale N. E. , Aldous C. , Gutta A. A. , Khuzwayo X. , Harry L. , Sathekge M. M.
Published: October 2023

Hepatocellular carcinoma (HCC) is a major global health problem. Theragnostic is a term that refers to the integration of diagnostic and therapeutic modalities into a single system for personalized medicine. Theragnostic care in HCC involves the use of imaging techniques to diagnose the cancer and assess its characteristics, such as size, location, and extent of spread. Theragnostics involves the use of molecular and genetic tests to identify specific biomarkers that can help guide treatment decisions and, post-treatment, assess the dosimetry and localization of the treatment, thus guiding future treatment. This can be done through either positron emission tomography (PET) scanning or single photon emission tomography (SPECT) using radiolabeled tracers that target specific molecules expressed by HCC cells or radioembolization. This technique can help identify the location and extent of the cancer, as well as provide information on the tumor's metabolic activity and blood supply. In summary, theragnostics is an emerging field that holds promise for improving the diagnosis and treatment of HCC. By combining diagnostic and therapeutic modalities into a single system, theragnostics can help guide personalized treatment decisions and improve patient outcomes.
An artificial intelligence prediction model outperforms conventional guidelines in predicting lymph node metastasis of T1 colorectal cancer
Authors: Piao Zheng Hua , Ge Rong , Lu Lu
Published: October 2023

Background

According to guidelines, a lot of patients with T1 colorectal cancers (CRCs) undergo additional surgery with lymph node dissection after being treated by endoscopic resection (ER) despite the low incidence of lymph node metastasis (LNM).

Aim

The aim of this study was to develop an artificial intelligence (AI) model to more effectively identify T1 CRCs at risk for LNM and reduce the rate of unnecessary additional surgery.

Methods

We retrospectively analyzed 651 patients with T1 CRCs. The patient cohort was randomly divided into a training set (546 patients) and a test set (105 patients) (ratio 5:1), and a classification and regression tree (CART) algorithm was trained on the training set to develop a predictive AI model for LNM. The model used 12 clinicopathological factors to predict positivity or negativity for LNM. To compare the performance of the AI model with the conventional guidelines, the test set was evaluated according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) and National Comprehensive Cancer Network (NCCN) guidelines. Finally, we tested the performance of the AI model using the test set and compared it with the JSCCR and NCCN guidelines.

Results

The AI model had better predictive performance (AUC=0.960) than the JSCCR (AUC=0.588) and NCCN guidelines (AUC=0.850). The specificity (85.8% vs. 17.5%, p<0.001), balanced accuracy (92.9% vs. 58.7%, p=0.001), and the positive predictive value (36.3% vs. 9.0%, p=0.001) of the AI model were significantly better than those of the JSCCR guidelines and reduced the percentage of the high-risk group for LNM from 83.8% (JSCCR) to 20.9%. The specificity of the AI model was higher than that of the NCCN guidelines (85.8% vs. 82.4%, p=0.557), but there was no significant difference between the two. The sensitivity of the NCCN guidelines was lower than that of our AI model (87.5% vs. 100%, p=0.301), and according to the NCCN guidelines, 1.2% of the 105 test set patients had missed diagnoses.

Conclusion

The AI model has better performance than conventional guidelines for predicting LNM in T1 CRCs and therefore could significantly reduce unnecessary additional surgery.
Key changes in the future clinical application of ultra-high dose rate radiotherapy
Authors: Lin Binwei , Fan Mi , Niu Tingting , Liang Yuwen , Xu Haonan , Tang Wenqiang , Du Xiaobo
Published: October 2023

Ultra-high dose rate radiotherapy (FLASH-RT) is an external beam radiotherapy strategy that uses an extremely high dose rate (≥40 Gy/s). Compared with conventional dose rate radiotherapy (≤0.1 Gy/s), the main advantage of FLASH-RT is that it can reduce damage of organs at risk surrounding the cancer and retain the anti-tumor effect. An important feature of FLASH-RT is that an extremely high dose rate leads to an extremely short treatment time; therefore, in clinical applications, the steps of radiotherapy may need to be adjusted. In this review, we discuss the selection of indications, simulations, target delineation, selection of radiotherapy technologies, and treatment plan evaluation for FLASH-RT to provide a theoretical basis for future research.
DNA damage repair mutations in pancreatic cancer– prognostic or predictive?
Authors: Hu Ya-Fei , Hu Hai-Jie , Kung Heng-Chung , Lv Tian-Run , Yu Jun , Li Fu-Yu
Published: October 2023

Objective

The efficacy of platinum-based chemotherapy (PtCh) for pancreatic cancer (PC) patients with DNA damage repair gene mutations (DDRm) compared to those without DDRm remains uncertain.

Methods

After a thorough database searching in PubMed, Embase, and Web of Science, a total of 19 studies that met all the inclusion criteria were identified. The primary outcomes were overall survival (OS) and progression-free survival (PFS) for PC patients with DDRm versus those without DDRm after PtCh.

Results

Patients with advanced-stage PC who have DDRm tend to have longer OS compared to patients without DDRm, regardless of their exposure to PtCh (HR=0.63; I2 = 66%). Further analyses indicated that the effectiveness of PtCh for OS was modified by DDRm (HR=0.48; I2 = 59%). After the first- line PtCh (1L-PtCh), the PFS of advanced-stage PC with DDRm was also significantly improved (HR=0.41; I2 = 0%). For patients with resected PC, regardless of their exposure to PtCh, the OS for patients with DDRm was comparable to those without DDRm (HR=0.82; I2 = 71%). Specifically, for patients with resected PC harboring DDRm who received PtCh (HR=0.85; I2 = 65%) and for those after non-PtCh (HR=0.87; I2 = 0%), the presence of DDRm did not show a significant association with longer OS.

Conclusion

1L-PtCh treatment is correlated with favorable survival for advanced-stage PC patients with DDRm. For resected-stage PC harboring DDRm, adjuvant PtCh had limited effectiveness. The prognostic value of DDRm needs to be further verified by prospective randomized controlled trials.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/, identifier CRD42022302275.