bluuebunny/crossref_metadata_2025 huggingface dataset:
Universal cutoff for tumor mutational burden in predicting the efficacy of anti-PD-(L)1 therapy for advanced cancers
Authors: Mo Shu-Fen , Cai Zeng-Zhi , Kuai Wen-Hao , Li Xuexin , Chen Yu-Tong
Published: May 2023

Background: The US Food and Drug Administration (FDA)’s tumor-agnostic approval of pembrolizumab in high tumor mutational burden (TMB-high, i.e., TMB≥10 mut/Mb) cases, based on the data from KEYNOTE-158, has raised considerable concerns among the immuno-oncology community. This study aims to statistically infer the optimal universal cutoff in defining TMB-high that is predictive of the efficacy of anti-PD-(L) 1 therapy in advanced solid tumors.

Methods: We integrated MSK-IMPACT TMB data from a public cohort and the objective response rate (ORR) for anti-PD-(L) 1 monotherapy across diverse cancer types in published trials. The optimal TMB cutoff was determined by varying the universal cutoff to define TMB-high across cancer types and examining the cancer-level correlation between objective response rate and the proportion of TMB-high cases. The utility of this cutoff in predicting overall survival (OS) benefits from anti-PD-(L) 1 therapy was then evaluated in a validation cohort of advanced cancers with coupled MSK-IMPACT TMB and OS data. In silico analysis of whole-exome sequencing data from The Cancer Genome Atlas was further employed to assess the generalizability of the identified cutoff among panels comprising several hundred genes.

Results: The cancer type-level analysis identified 10 mut/Mb as the optimal cutoff for MSK-IMPACT in defining TMB-high, with the corresponding TMB-high (TMB≥10 mut/Mb) percentage strongly correlated with ORR for PD-(L) 1 blockade across cancer types [correlation coefficient, 0.72 (95% CI, 0.45–0.88)]. This cutoff was also the optimum in defining TMB-high (via MSK-IMPACT) when predicting OS benefits from anti-PD-(L) 1 therapy in the validation cohort. In this cohort, TMB≥10 mut/Mb was associated with significantly improved OS (hazard ratio, 0.58 [95% CI, 0.48–0.71]; p < 0.001). Moreover, in silico analyses revealed excellent agreement of TMB≥10 mut/Mb cases between MSK-IMPACT and the FDA-approved panels and between MSK-IMPACT and various randomly sampled panels.

Conclusion: Our study demonstrates that 10 mut/Mb is the optimal, universal cutoff for TMB-high that guides the clinical application of anti-PD-(L) 1 therapy for advanced solid tumors. It also provides rigorous evidence beyond KEYNOTE-158 for the utility of TMB≥10 mut/Mb in predicting the efficacy of PD-(L) 1 blockade in broader settings, which could help to mitigate the challenges in embracing the tumor-agnostic approval of pembrolizumab in TMB-high cases.
SUMOylation and related post-translational modifications in natural killer cell anti-cancer responses
Authors: Molfetta Rosa , Petillo Sara , Cippitelli Marco , Paolini Rossella
Published: May 2023

SUMOylation is a reversible modification that involves the covalent attachment of small ubiquitin-like modifier (SUMO) to target proteins, leading to changes in their localization, function, stability, and interactor profile. SUMOylation and additional related post-translational modifications have emerged as important modulators of various biological processes, including regulation of genomic stability and immune responses. Natural killer (NK) cells are innate immune cells that play a critical role in host defense against viral infections and tumors. NK cells can recognize and kill infected or transformed cells without prior sensitization, and their activity is tightly regulated by a balance of activating and inhibitory receptors. Expression of NK cell receptors as well as of their specific ligands on target cells is finely regulated during malignant transformation through the integration of different mechanisms including ubiquitin- and ubiquitin-like post-translational modifications. Our review summarizes the role of SUMOylation and other related pathways in the biology of NK cells with a special emphasis on the regulation of their response against cancer. The development of novel selective inhibitors as useful tools to potentiate NK-cell mediated killing of tumor cells is also briefly discussed.
Reducing the matrix effect in mass spectral imaging of biofilms using flow-cell culture
Authors: Zhang Yuchen , Plymale Andrew , Son Jiyoung , Huang Qiaoyun , Chen Wenli , Yu Xiao-Ying
Published: May 2023

The interactions between soil microorganisms and soil minerals play a crucial role in the formation and evolution of minerals and the stability of soil aggregates. Due to the heterogeneity and diversity of the soil environment, the under-standing of the functions of bacterial biofilms in soil minerals at the microscale is limited. A soil mineral-bacterial biofilm system was used as a model in this study, and it was analyzed by time-of-flight secondary ion mass spectrometry (ToF-SIMS) to acquire molecular level information. Static culture in multi-wells and dynamic flow-cell culture in microfluidics of biofilms were investigated. Our results show that more characteristic molecules of biofilms can be observed in SIMS spectra of the flow-cell culture. In contrast, biofilm signature peaks are buried under the mineral components in SIMS spectra in the static culture case. Spectral overlay was used in peak selection prior to performing Principal component analysis (PCA). Comparisons of the PCA results between the static and flow-cell culture show more pronounced molecular features and higher loadings of organic peaks of the dynamic cultured specimens. For example, fatty acids secreted from bacterial biofilm extracellular polymeric substance are likely to be responsible for biofilm dispersal due to mineral treatment up to 48 h. Such findings suggest that the use of microfluidic cells to dynamically culture biofilms be a more suitable method for reducing the matrix effect arisen from the growth medium and minerals as a perturbation fac-tor for improved spectral and multivariate analysis of complex mass spectral data in ToF-SIMS. These results show that the interaction mechanism between biofilms and soil minerals at the molecular level can be better studied using the flow-cell culture and advanced mass spectral imaging techniques like ToF-SIMS.
Causal associations between human gut microbiota and cholelithiasis: a mendelian randomization study
Authors: Li Wei , Ren Ao , Qin Qiong , Zhao Ling , Peng Qiufeng , Ma Ruidong , Luo Shiqiao
Published: May 2023

Background

There was some evidence that gut microbiota was closely related to cholelithiasis, but the causal relationship between them remained unclear. In this study, we try to use Two-sample Mendelian randomization (MR) to clarify the potential causal relationship between gut microbiota and cholelithiasis.

Methods

Summary Genome-Wide Association Studies (GWAS) statistical data for gut microbiota was obtained from MiBioGen, and the data of cholelithiasis was obtained from UK Biobank (UKB). Two-sample MR analyses were performed to assess causalities between gut microbiota and cholelithiasis mainly using the inverse-variance weighted (IVW) method. Sensitivity analyses were used to determine the robustness of the MR results. Reverse MR analyses were performed to examine the reverse causal association.

Results

Our research results, based primarily on the IVW method, support the existence of a causal relationship between nine gut microbial taxa and cholelithiasis. We observed a positive association between Genus Butyrivibrio (p=0.032), Genus Lachnospiraceae_UCG_001 (p=0.015), Genus Ruminococcaceae_NK4A214_group (p=0.003), Genus Ruminococcaceae_UCG_011 (p=0.010) and cholelithiasis, while Order Rhodospirillales (p=0.031), Genus Actinomyces (p=0.010), Genus Phascolarctobacterium (p=0.036), Genus Rikenellaceae_RC9_gutgroup (p=0.023), Genus Ruminococcaceae_UCG_013 (p=0.022) may be associated with a reduced risk of cholelithiasis. We did not find a reverse causal relationship between cholelithiasis and 9 specific gut microbial taxa.

Conclusions

This is the first mendelian randomization study to explore the causalities between specific gut microbiota taxa and cholelithiasis, which may provide new ideas and a theoretical basis for the prevention and treatment of cholelithiasis in the future.
Establishment of a risk prediction model for multidrug-resistant bacteria in deceased organ donors: a retrospective cohort study in China
Authors: Shen Guojie , Zhang Li , Fan Weina , Lv Haifeng , Wang Feifei , Ye Qingqing , Lin Miaozuo , Yu Xia , Cai Hongliu , Wu Xiaoliang
Published: May 2023

Background

Multidrug resistance in bacteria is a serious problem in organ transplantations. This study aimed to identify risk factors and establish a predictive model for screening deceased organ donors for multidrug-resistant (MDR) bacteria.

Methods

A retrospective cohort study was conducted at the First Affiliated Hospital of Zhejiang University School of Medicine from July 1, 2019 to December 31, 2022. The univariate and multivariate logistic regression analysis was used to determine independent risk factors associated with MDR bacteria in organ donors. A nomogram was established based on these risk factors. A calibration plot, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to estimated the model.

Results

In 164 organ donors, the incidence of MDR bacteria in culture was 29.9%. The duration of antibiotic use ≥3 days (odds ratio [OR] 3.78, 95% confidence interval [CI] 1.62–8.81, p=0.002), length of intensive care unit (ICU) stay per day(OR 1.06, 95% CI 1.02–1.11, p=0.005) and neurosurgery (OR 3.31, 95% CI 1.44–7.58, p=0.005) were significant independent predictive factors for MDR bacteria. The nomogram constructed using these three predictors displayed good predictive ability, with an area under the ROC curve value of 0.79. The calibration curve showed a high consistency between the probabilities and observed values. DCA also revealed the potential clinical usefulness of this nomogram.

Conclusions

The duration of antibiotic use ≥3 days, length of ICU stay and neurosurgery are independent risk factors for MDR bacteria in organ donors. The nomogram can be used to monitor MDR bacteria acquisition risk in organ donors.
Management of the arrhythmic manifestations of cardiac sarcoidosis
Authors: Cherrett Callum , Lee William , Bart Nicole , Subbiah Rajesh
Published: May 2023

Cardiac sarcoidosis (CS) is characterised by a high burden of arrhythmic manifestations and cardiac electrophysiologists play an important role in both the diagnosis and management of this challenging condition. CS is characterised by the formation of noncaseating granulomas within the myocardium, which can subsequently lead to fibrosis. Clinical presentations of CS are varied and depend on the location and extent of granulomas. Patients may present with atrioventricular block, ventricular arrhythmias, sudden cardiac death or heart failure. CS is being increasing diagnosed through use of advanced cardiac imaging, however endomyocardial biopsy is often still required to confirm the diagnosis. Due to the low sensitivity of fluoroscopy-guided right ventricular biopsies, three-dimensional electro-anatomical mapping and electrogram-guided biopsies are being investigated as a means to improve diagnostic yield. Cardiac implantable electronic devices are often required in the management of CS, either for pacing or for primary or secondary prevention of ventricular arrhythmias. Catheter ablation for ventricular arrythmias may also be required, although this is often associated with high recurrence rates due to the challenging nature of the arrhythmogenic substrate. This review will explore the underlying mechanisms of the arrhythmic manifestations of CS, provide an overview of current clinical practice guidelines, and examine the important role that cardiac electrophysiologists play in managing patients with CS.
Ginsenoside Rb1 protects human vascular smooth muscle cells against resistin-induced oxidative stress and dysfunction
Authors: Lu Weifeng , Lin Yue , Haider Nezam , Moly Pricila , Wang Lixin , Zhou Wei
Published: May 2023

Resistin has been shown to play a key role in inducing vascular smooth muscle cells (VSMCs) malfunction in the atherosclerosis progression. Ginsenoside Rb1 is the main component of ginseng, which has been used for thousands of years and has been reported to have a powerful vascular protective effect. The aim of this study was to explore the protective effect of Rb1 on VSMCs dysfunction induced by resistin. In the presence or absence of Rb1, human coronary artery smooth muscle cells (HCASMC) were treated at different time points with or without 40 ng/ml resistin and acetylated low-density lipoprotein (acetylated LDL). Cell migration and proliferation were analyzed using wound healing test and CellTiter Aqueous Cell Proliferation Assay (MTS) test, respectively. Intracellular reactive oxygen species (ROS) (H2DCFDA as a dye probe) and superoxide dismutase (SOD) activities were measured by a microplate reader and the differences between groups were compared. Rb1 significantly reduced resistin-induced HCASMC proliferation. Resistin increased HCASMC migration time-dependently. At 20 µM, Rb1 could significantly reduce HCASMC migration. Resistin and Act-LDL increased ROS production to a similar level in HCASMCs, while Rb1 pretreated group reversed the effects of resistin and acetyl-LDL. Besides, the mitochondrial SOD activity was significantly reduced by resistin but was restored when pretreated with Rb1. We confirmed the protection of Rb1 on HCASMC and suggested that the mechanisms involved might be related to the reduction of ROS generation and increased activity of SOD. Our study clarified the potential clinical applications of Rb1 in the control of resistin-related vascular injury and in the treatment of cardiovascular disease.
Study on failure behaviors and control technology of surrounding rock in a weakly cemented soft rock roadway: A case study
Authors: Zhou Kai , Yu Fenghai , Tan Yunliang , Guo Weiyao , Zhao Tongbin
Published: May 2023

During coal mining, the deformation and failure of a weakly cemented soft rock roadway roof could cause difficulties for roadway support. In this paper, a combination of on-site measurement and theoretical analysis is used to solve this issue. Firstly this paper investigates the in situ deformation and failure behaviors of a soft rock roadway in a mine in Western China. Then, the failure mechanism and corresponding support principles are discussed and given. Third, various support schemes (bolt and cable reinforcement optimization, grouting, and single prop + top beam combined reinforcement) are proposed and tested. Results show the support capacity can meet the requirements after optimizing the bolt and cable reinforcement support. Due to the development of roof cracks and low grouting pressure, the grouting slurry did not completely fill the roof cracks, resulting in a poor roof control effect. The passive support of a “single prop + top beam” can effectively control the roof subsidence and achieve good application results.
High-resolution record of stable isotopes in soil carbonates reveals environmental dynamics in an arid region (central Iran) during the last 32 ka
Authors: Bayat Omid , Karimi Alireza , May Jan-Hendrik , Fattahi Morteza , Wiesenberg Guido L. B. , Egli Markus
Published: May 2023

Although central Iran is pivotal for palaeoclimatic correlations, palaeoenvironmental data for this region is very sparse and a reliable chronology for pedogenic features is lacking. We therefore tried to answer the question how the environmental conditions and, in particular, the climate developed over time by using the isotopic signatures of pedogenic carbonates. We present a chronology of pedogenic carbonates in association with stable carbon and oxygen isotopes in both the matrix and coating carbonates of a relict palаeosol (Baharan palaeosol) in central Iran to understand the dynamics of environmental changes in this region during the late Quaternary. The palаeosol experienced several episodes of leaching during pedogenesis as reflected in its morphology (carbonate coatings under the rock fractions) and geochemical characteristics (Ba/Sr ratios). The δ18O values of both the matrix and coating carbonates in the upper 60 cm (especially in the upper 20 cm) of the pedon are enriched (∼4‰) compared to the subsoil and are mainly related to the impact of evaporation. Moreover, the δ13C values of the carbonates are in isotopic disequilibrium with the modern vegetation cover (desert shrubs) of the study area and are enriched in different degrees. The carbonates in the top 60 cm are formed by the input of atmospheric CO2 and calcareous dust while deeper carbonates formed in an environment exhibiting a higher contribution of C4 plants. Based on the radiocarbon chronology of carbonate coatings, it seems that three main stages of palaeoenvironmental changes occurred in the region during the last 32 ka. The first stage lasted ca. 5,000 years (between 31.6 and 26.0 ka) and was accompanied by deep leaching under sub-humid climatic conditions and the expansion of C4 plants. Under the dominance of semi-arid conditions during the second stage until the late Holocene, a gradual increase in the δ18O values and aridity occurred in the region. The last phase in the late Holocene was characterised by the establishment of an arid and evaporative environment with a sparse vegetation cover. A climatic correlation using the oxygen isotopic composition of secondary carbonates from the Baharan palaeosol, Soreq Cave (the Levant) and Hoti Cave (Oman; both having speleothems records) suggested a climatic connection between central Iran and the eastern Mediterranean during the late Pleistocene and between central Iran and northern Oman during the late Holocene.
3D macro- and microfabric analyses of Neoproterozoic diamictites from the Valjean Hills, California (United States)
Authors: Kettler C. , Phillips E. , Pichler K. , Smrzka D. , Vandyk T. M. , Le Heron D. P.
Published: May 2023

The Cryogenian interval (720–635 Ma) is famous for a rich archive of diamictites, many of which were deposited during glaciations. Classic examples are exposed in the Kingston Peak Formation of the Valjean Hills, near Death Valley (United States), with previous work pointing to multiple glacial cycles in other outcrop belts. Within any glacial period, diamictites are widespread, and in addition, their mechanics of deposition are highly variable. Some are massive in appearance at outcrop or in hand specimens and apparently lack any information that allows their mode of emplacement to be elucidated. Yet, the correct interpretation for deep-time successions in this area is especially important, since it is debated whether the diamictites are either associated with a tectonically driven origin, associated with rifting at the south-western Laurentian margin alongside slope-controlled gravitational mass movement, or predominantly deposited as (sub)glacial diamictites. In this paper, we demonstrate how diamictite texture can be objectively quantified based on clast orientations, at both macroscale and microscale (micromorphology), guiding interpretations. Our method is based on a technique used for Quaternary sediments, by mapping the apparent longest axes of skeleton grains (ranging from fine-grained sand to fine-grained pebbles) in oriented thin sections and reconstructing their microfabric in a 3D space coupled with macrofabric data for each diamictite. In this way, we could identify a bimodal signal in the orientation of the longest axes for each sample. Evidence for shearing and soft sediment deformation supports either subaqueous or subglacial deposition with deformation induced by basal sliding with a paleoflow directed toward the southeast. Our combined approach of micro- and macrofabric analyses can also encourage acquiring accurate fabric data for seemingly structureless diamictites from other deep-time rock archives in an objective manner.
Multi-agent interaction of source, load and storage to realize peak shaving and valley filling under the guidance of the market mechanism
Authors: Wang Chunhui , Wu Zhigang , Lin Zihui , Liu Jianing
Published: May 2023

In the construction of new power system, traditional methods and capabilities for regulating the power grid are no longer applicable due to the increasing types and quantities of source, load and storage agents. Currently, research on the participation of these agents in the electricity market has mainly focused on either traditional power systems or the demand side, without exploring the potential interaction between them. To address this issue, this paper proposes a real-time pricing regulation mechanism that incorporates source, load and storage agents into regulation. This mechanism is suitable for new power systems and satisfies the interests of the agents while meeting the needs of grid regulation. Specifically, it is based on time-of-use and real-time pricing regulation mechanisms. In a simulated scenario of load shifting, the proposed pricing regulation mechanism effectively meets the grid regulation requirements and improves the stability of grid operation. Overall, this approach offers a promising solution for the regulation of new power system with diverse and complex agents.
Effects of turning rainforest into oil-palm plantations on silicon pools in soils within the first 20 years after the transformation
Authors: Greenshields Britta , von der Lühe Barbara , Hughes Harold , Tjoa Aiyen , Hennings Nina , Sauer Daniela
Published: May 2023

Potential effects of land-use/land-cover (LULC) transformation from lowland rainforest into oil-palm plantations on silicon (Si) pools in tropical soils remain poorly understood, although appropriate levels of plant-available Si in soils may contribute to maintain high crop yields and increase the vitality and drought resistance of oil palms. Therefore, the aim of our study was to identify possible effects of such LULC change on soil Si pools. For this purpose, we compared soil Si pools under lowland rainforest and ca. 20 year-old oil-palm plantations in Jambi Province, Indonesia. The investigated soils were Acrisols and Stagnosols, in which we quantified six different soil Si pools following a sequential extraction procedure to evaluate, whether 20 years of oil-palm cultivation has led to a depletion of these soil Si pools. The considered pools included mobile Si, adsorbed Si, Si bound in soil organic matter (SOM), Si included in pedogenic oxides and hydroxides, and Si in amorphous silica of biogenic and pedogenic origin. Finally, we also determined total Si. All oil-palm plantations established on sloping terrain and Acrisols only showed decreased Si stocks of mobile Si, adsorbed Si and SOM-bound Si; those established in floodplains and Stagnosols had decreased stocks of SOM-bound Si and biogenic-amorphous silica. Lower Si stocks were mostly attributed to a missing “stable” phytolith pool in the subsoil and less organic matter in topsoils under oil-palm plantations. When comparing well-drained and riparian areas, flooding seemed to increase phytolith dissolution. We conclude that 20 years of oil-palm cultivation has not yet led to a significant depletion of soil Si pools. As topsoils comprise the highest concentrations of SOM-bound Si and Si in amorphous silica of biogenic origin but are susceptible to erosion and surface runoff under managed oil-palm plantations, it would be advisable to instate specific management practices that maintain organic-rich and well-aired topsoils on oil-palm plantations.
The importance of urban green spaces in the development of smart cities
Authors: Addas Abdullah
Published: May 2023

In the era of modernization, urban green spaces (UGSs) are attracting increasing attention in smart city (SC) development. There is currently a paucity of UGSs, and their importance has become crucial in enhancing life expectancy and health. To meet people’s demands, scientists are busy designing smart cities under flagship programs for urban transformation. UGSs are relevant in the analysis and investigation of improved lifestyles. The scarcity of UGSs can have many social and physical impacts. The presence of UGSs in smart cities is proposed to improve residents’ lifestyles. Semi-structured interviews were conducted with residents, officials and government experts to inform the development of UGSs further. The result of the surveys analyzed using the MAXQDA software, which presents the importance of SC and the residents’ satisfaction. The results show an urgent requirement for larger UGSs to enhance the security and economic opportunities within urban environments. The deployment of USGs is particularly relevant to fully enhancing residents’ lifestyles and health. The present research aligned with the World Health Organization (WHO) standards to identify the scope of UGS initiatives in different parts of the city of Graz, Austria, and recommendations for improving the quality of future UGS planning is provided. The proposed research results conclude that UGS is a valid alternative to enhance air quality, with measurable and substantial air pollution changes even in space-constrained sites.
The burden of cardiovascular diseases attributable to metabolic risk factors and its change from 1990 to 2019: a systematic analysis and prediction
Authors: Wang Huaigen , Liu Jing , Feng Yunfei , Ma Aiqun , Wang Tingzhong
Published: May 2023

Background

Metabolic disorders are the most important risk factors for cardiovascular diseases (CVDs). The purpose of this study was to systematically analyze and summarize the most recent data by age, sex, region, and time, and to forecast the future burden of diseases.

Methods

Data on the burden of CVDs associated with metabolic risk factors were obtained from the Global Burden of Disease (GBD) Study 2019; and then the burden of disease was assessed using the numbers and age-standardized rates (ASR) of deaths, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) and analyzed for temporal changes, differences in age, region, sex, and socioeconomic aspects; finally, the burden of disease was predicted using an autoregressive integrated moving average (ARIMA) model.

Results

From 1990 to 2019, the numbers of deaths, DALYs, YLDs, and YLLs attributed to metabolic risk factors increased by 59.3%, 51.0%, 104.6%, and 47.8%, respectively. The ASR decreased significantly. The burden of metabolic risk factor-associated CVDs was closely related to socioeconomic position and there were major geographical variations; additionally, men had a significantly greater disease burden than women, and the peak shifted later based on the age group. We predicted that the numbers of deaths and DALYs would reach 16.5 million and 324.8 million, respectively, by 2029.

Conclusions

The global burden of CVDs associated with metabolic risk factors is considerable and still rising, and more effort is needed to intervene in metabolic disorders.
Targeted modification of CmACO1 by CRISPR/Cas9 extends the shelf-life of Cucumis melo var. reticulatus melon
Authors: Nonaka Satoko , Ito Maki , Ezura Hiroshi
Published: May 2023

The gaseous plant hormone ethylene is a regulator of fruit shelf-life, one of the essential traits in fruits. Extending fruit shelf-life reduces food loss, thereby expected to contribute to food security. The enzyme 1-aminocyclopropane-1-carboxylic acid oxidase (ACO) is the final step of the ethylene production pathway. Its suppression via antisense technology has been demonstrated to extend the shelf-life of melon, apple, and papaya. Genome editing technology is an innovative technique for plant breeding. Because the genome editing technology would not leave the exogenous genes in the final crop products, the crops via genome editing can be considered non-genetically modified yields; compared to conventional breeding, such as mutation breeding, the breeding term would be expected to be relatively short. These points include the advantage of this technique in utilization for commercial applications. We attempted to extend the shelf-life of the Japanese luxury melon (Cucumis melo var. reticulatus, ‘Harukei-3’) via modification of the ethylene synthesis pathway with the genome editing technology, CRISPR/Cas9 system. The Melonet-DB (https://melonet-db.dna.affrc.go.jp/ap/top) showed that the melon genome had the five CmACOs and the gene CmACO1 predominantly expressed in harvested fruits. From this information, CmACO1 was expected to be a key gene for shelf-life in melons. Based on this information, the CmACO1 was selected as the target of the CRISPR/Cas9 system and introduced the mutation. The final product of this melon did not have any exogenous genes. The mutation was inherited for at least two generations. In the T2 generation, the fruit phenotypes 14 days after harvest were as follows: ethylene production was reduced to one-tenth that of the wild type, pericarp colour remained green, and higher fruit firmness. Early fermentation of the fresh fruit was observed in the wild-type fruit but not in the mutant. These results show that CmACO1 knockout via CRISPR/Cas9 extended the melon’s shelf-life. Moreover, our results suggest that genome editing technology would reduce food loss and contribute to food security.
Chromosome-scale assembly and quantitative trait locus mapping for major economic traits of the Culter alburnus genome using Illumina and PacBio sequencing with Hi-C mapping information
Authors: Liu Shili , Zheng Jianbo , Li Fei , Chi Meili , Cheng Shun , Jiang Wenping , Liu Yinuo , Gu Zhimin , Zhao Jinliang
Published: May 2023

Topmouth culter (Culter alburnus) is an economically important freshwater fish with high nutritional value. However, its potential genetic advantages have not been fully exploited. Therefore, we aimed to determine the genome sequence of C. alburnus and examine quantitative trait loci (QTLs) related to major economic traits. The results showed that 24 pseudochromosomes were anchored by 914.74 Mb of the C. alburnus genome sequence. De novo sequencing identified 31,279 protein-coding genes with an average length of 8507 bp and average coding sequ ence of 1115 bp. In addition, a high-density genetic linkage map consisting of 24 linkage groups was constructed based on 353,532 high-quality single nucleotide polymorphisms and 4,710 bin markers. A total of 28 QTLs corresponding to 11 genes, 26 QTLs corresponding to 11 genes, and 12 QTLs corresponding to 5 genes were identified for sex, intermuscular spine number and body weight traits, respectively. In this study, we assembled an accurate and nearly complete genome of C. alburnus by combining Illumina, PacBio, and high-throughput Chromosome conformation capture (Hi-C) technologies. In addition, we identified QTLs that explained variances in intermuscular spine number, body weight, and sex differences in C. alburnus. These genetic markers or candidate genes associated with growth traits provide a basis for marker-assisted selection in C. alburnus.
Prognostic immunogenic characteristics of iron pendant disease modifiers in colon cancer
Authors: Wang Xian , Meng Qingyu , Chen Yawen , Zhang Yanjun , Huang Xiaohui , Xiang Longquan , Kong Haiyang , Wang Chunxi , Wang Xueyang , Zhang Dekang
Published: May 2023

Background

We explored the prognostic and immunogenic characteristics of iron pendant disease regulators in colon cancer to provide a scientific basis for the prediction of tumor prognosis-related markers and potential immunotherapeutic drug targets.

Methods

RNA sequencing and matched complete clinical information of colon cancer (COAD) were retrieved from the UCSC Xena database, and genomic and transcriptomic data of colon cancer from the TCGA database were downloaded. Then univariate and multifactorial Cox regression were used to process these data. The prognostic factors were analyzed by single-factor and multi-factor Cox regression, followed by Kaplan-Meier survival curves with the aid of R software “survival” package. Then we use FireBrowse online analysis tool to analyze the expression variation of all cancer genes, and draw a histogram according to the influencing factors to predict the 1, 3, and 5 year survival rates of patients.

Results

The results show that age, tumor stage and iron death score were significantly correlated with prognosis (p<0.05). Further multivariate cox regression analysis confirmed that age, tumor stage and iron death score were still significantly correlated with prognosis (p<0.05); The calibration curve results show that the deviation between the predicted values of 1 year, 3 years and 5 years and the diagonal of the figure is very small; the ROC curve results show that the AUC values of the 1-year and 5-year ROC curves of the bar graph are high; the DCA curve results show that the net yield of the bar graph is the largest; The scores of T cells and B cells in the high iron death score group were significantly lower than those in the low iron death score group, and the activities of immune related pathways were significantly reduced. There was a significant difference in the iron death score between the iron death molecular subtype and the gene cluster subtype.

Conclusions

The model showed a superior response to immunotherapy in the high-risk group, revealing a potential relationship between iron death and tumor immunotherapy, which will provide new ideas for the treatment and prognostic assessment of colon cancer patients.
Yeast cell wall extracts from Saccharomyces cerevisiae varying in structure and composition differentially shape the innate immunity and mucosal tissue responses of the intestine of zebrafish (Danio rerio)
Authors: Rawling Mark , Schiavone Marion , Apper Emmanuelle , Merrifield Daniel L. , Castex Mathieu , Leclercq Eric , Foey Andrew
Published: May 2023

With the rising awareness of antimicrobial resistance, the development and use of functional feed additives (FFAs) as an alternative prophylactic approach to improve animal health and performance is increasing. Although the FFAs from yeasts are widely used in animal and human pharma applications already, the success of future candidates resides in linking their structural functional properties to their efficacy in vivo. Herein, this study aimed to characterise the biochemical and molecular properties of four proprietary yeast cell wall extracts from S. cerevisiae in relation to their potential effect on the intestinal immune responses when given orally. Dietary supplementation of the YCW fractions identified that the α-mannan content was a potent driver of mucus cell and intraepithelial lymphocyte hyperplasia within the intestinal mucosal tissue. Furthermore, the differences in α-mannan and β-1,3-glucans chain lengths of each YCW fraction affected their capacity to be recognised by different PRRs. As a result, this affected the downstream signalling and shaping of the innate cytokine milieu to elicit the preferential mobilisation of effector T-helper cell subsets namely Th17, Th1, Tr1 and FoxP3+-Tregs. Together these findings demonstrate the importance of characterising the molecular and biochemical properties of YCW fractions when assessing and concluding their immune potential. Additionally, this study offers novel perspectives in the development specific YCW fractions derived from S. cerievisae for use in precision animal feeds.
Tuberculosis infection following immune checkpoint inhibitor treatment for advanced cancer: a case report and literature review
Authors: Lin Chen , Xu Guixiang , Gao Shuyan , Feng Tao , Li Shuang
Published: May 2023

Objective

To investigate the clinical features of active tuberculosis (TB) infection due to immune checkpoint inhibitors (ICIs) treatment in patients with advanced cancer.

Methods

We report the diagnosis and treatment of a case of pulmonary malignancy (squamous cell carcinoma, cT4N3M0 IIIC), secondary to active TB infection following ICIs therapy. Moreover, we summarize and analyze other related cases collected from the China National Knowledge Infrastructure (CNKI), Wanfang Database, PubMed, the Web of Science, and EMBASE (up to October 2021).

Results

A total of 23 patients, including 20 males and 3 females who were aged 49-87 years with a median age of 65 years, were included in the study. Twenty-two patients were diagnosed by Mycobacterium tuberculosis culture or DNA polymerase chain reaction (PCR), while the remaining patient was diagnosed by tuberculin purified protein derivative and pleural biopsy. One case had an interferon-gamma release assay (IGRA) to rule out latent TB infection prior to the application of ICI. Fifteen patients received an anti-tuberculosis regimen. Among the 20 patients with a description of clinical regression, 13 improved and 7 died. Seven of the patients who improved were treated with ICI again and four of them did not experience a recurrence or worsening of TB. The case diagnosed in our hospital also improved after receiving anti-TB treatment after stopping ICI therapy, and continued chemotherapy on the basis of anti-TB treatment, and his condition is relatively stable at present.

Conclusion

Due to the lack of specificity of TB infection following ICIs therapy, patients should be followed for fever and respiratory symptoms for 6.3 months after drug administration. It is recommended that IGRA should be performed before ICIs therapy and the development of TB during immunotherapy in patients who are positive in IGRA should be closely monitored. The symptoms of TB in most patients can be improved with ICIs withdrawal and anti-TB treatment, but there is still a need to be alert to the potentially fatal risk of TB.
Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases
Authors: Wang Shan , Wang Jirui , Li Baizhu , Hu Ning , Jin Yingbin , Han Shiyu , Shang Xiuli
Published: May 2023

Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common kind of autoimmune encephalitis following anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. Anti-LGI1 encephalitis is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders, epileptic seizures, faciobrachial dystonic seizures (FBDS), and refractory hyponatremia. Recently, we found an atypical manifestation of anti-LGI1 encephalitis, in which paroxysmal limb weakness was the initial symptom. In this report, we describe five cases of anti-LGI1 encephalitis with paroxysmal limb weakness. Patients had similar presentations, where a sudden weakness involving a unilateral limb was observed, which lasted several seconds and occurred dozens of times each day, with the anti-LGI1 antibody being positive in both serum and cerebrospinal fluid (CSF). FBDS occurred after a mean of 12 days following paroxysmal limb weakness in three of five patients (Cases 1, 4, and 5). All patients were given high-dose steroid therapy, which had a good effect on their condition. Based on this report, we suggest that paroxysmal unilateral weakness may be a kind of epilepsy and be connected to FBDS. As an unusual neurological presentation, paroxysmal weakness can be included in the clinical manifestations of anti-LGI1 encephalitis, helping to raise awareness of the recognition of anti-LGI1 encephalitis in patients with this symptom and leading to early diagnosis and early treatment, which would contribute to improved clinical outcomes.
Controlled human infection models in COVID-19 and tuberculosis: current progress and future challenges
Authors: Morrison Hazel , Jackson Susan , McShane Helen
Published: May 2023

Controlled Human Infection Models (CHIMs) involve deliberately exposing healthy human volunteers to a known pathogen, to allow the detailed study of disease processes and evaluate methods of treatment and prevention, including next generation vaccines. CHIMs are in development for both tuberculosis (TB) and Covid-19, but challenges remain in their ongoing optimisation and refinement. It would be unethical to deliberately infect humans with virulent Mycobacteria tuberculosis (M.tb), however surrogate models involving other mycobacteria, M.tb Purified Protein Derivative or genetically modified forms of M.tb either exist or are under development. These utilise varying routes of administration, including via aerosol, per bronchoscope or intradermal injection, each with their own advantages and disadvantages. Intranasal CHIMs with SARS-CoV-2 were developed against the backdrop of the evolving Covid-19 pandemic and are currently being utilised to both assess viral kinetics, interrogate the local and systemic immunological responses post exposure, and identify immune correlates of protection. In future it is hoped they can be used to assess new treatments and vaccines. The changing face of the pandemic, including the emergence of new virus variants and increasing levels of vaccination and natural immunity within populations, has provided a unique and complex environment within which to develop a SARS-CoV-2 CHIM. This article will discuss current progress and potential future developments in CHIMs for these two globally significant pathogens.
Reduced survival of Steller sea lions in the Gulf of Alaska following marine heatwave
Authors: Hastings Kelly K. , Gelatt Thomas S. , Maniscalco John M. , Jemison Lauri A. , Towell Rod , Pendleton Grey W. , Johnson Devin S.
Published: May 2023

The North Pacific marine heatwave of 2014–2016 (PMH), one of the most geographically-extensive and severe marine heatwaves on record, resulted in widespread and persistent perturbation of the Gulf of Alaska and California Current ecosystems. Negative effects of the PMH on marine mammals have been observed, but are not yet well understood. The endangered Steller sea lion Eumetopias jubatus is an important top predator in the Gulf of Alaska that is also particularly vulnerable to sudden or severe ecosystem shifts. We examined survival of 4,178 known-aged Steller sea lions marked from 2000 to 2016 from Kodiak Island through Southeast Alaska, using mark-recapture models and 12,811 resightings collected from 2001 to 2021. Survival of adult females aged 3–15 was reduced -0.05 to -0.23 during the PMH in the areas east, but not west, of Cook Inlet. Survival of Kodiak females was unaffected by the PMH, but survival of Sugarloaf females aged 5–8 was reduced -0.13 from summer 2015 to summer 2016. Lowest survival in Southeast Alaska occurred from summer 2016 to summer 2017, but was also reduced from summer 2014 to summer 2016. Reduced survival continued post-PMH in Kenai Peninsula/Prince William Sound, but not in Southeast Alaska. Survival of adult males was insensitive to the PMH, except in Southeast Alaska where male survival was reduced -0.25 from summer 2016 to summer 2017. Prolonged or intermittent high adult female mortality may reduce population growth and initiate regional declines. Survival response of Steller sea lions to the PMH varied regionally despite similar patterns of ocean warming throughout our study area, suggesting areas east versus west of Cook Inlet were affected differently by the PMH, perhaps due to habitat and oceanographic differences.
Predicting the Loop Current dynamics combining altimetry and deep flow measurements through the Yucatan Channel
Authors: Manta Gaston , Durante Giovanni , Candela Julio , Send Uwe , Sheinbaum Julio , Lankhorst Matthias , Laxenaire Rémi
Published: May 2023

The Loop Current is the main mesoscale feature of the Gulf of Mexico oceanic circulation. With peak velocities above 1.5 m s–1, the Loop Current and its mesoscale eddies are of interest to fisheries, hurricane prediction and of special concern for the security of oil rig operations in the Gulf of Mexico, and therefore understanding their predictability is not only of scientific interest but also a major environmental security issue. Combining altimetric data and an eddy detection algorithm with 8 years of deep flow measurements through the Yucatan Channel, we developed a predictive model for the Loop Current extension in the following month that explains 74% of its variability. We also show that 4 clusters of velocity anomalies in the Yucatan Channel represent the Loop Current dynamics. A dipole with positive and negative anomalies towards the western side of the Channel represents the growing and retracted phases respectively, and two tripole shape clusters represent the transition phases, the one with negative anomalies in the center associated with 50% of the eddy separation events. The transition between these clusters is not equally probable, therefore adding predictability. Finally, we show that eddy separation probability begins when the Loop Current extends over 1800 km (~27.2°N), and over 2200 km of extension, eddy detachment and reattachment is more frequent than separation. These results represent a step forward towards having the best possible operational Loop Current forecast in the near future, incorporating near real-time data transmission of deep flow measurements and high resolution altimetric data.
First successful production of adult corals derived from cryopreserved larvae
Authors: Narida Arah , Tsai Sujune , Hsieh Wen-Chung , Wen Zhi-Hong , Wang Li-Hsueh , Huang Cheng-Liang , Lin Chiahsin
Published: May 2023

Coral reefs worldwide are declining due to increasing concentrations of greenhouse gases, which, combined with local anthropogenic pressure, are exacerbating unprecedented mass coral bleaching. For corals to survive, restoring coral reefs through cryopreservation is crucial. The aim of this study was to vitrify and laser-warm Stylophora pistillata planulae to allow for feasible settlement, post-settlement survival, and the production of adult corals. The no-observed-effect concentrations were used to determine the best cryoprotective agents for S. pistillata. The larvae were then subjected to cooling and nanolaser warming (300 V, 10 ms pulse width, 2 mm beam diameter) by using two vitrification solutions (VSs; VS1: 2 M dimethyl sulfoxide and 1 M ethylene glycol and VS2: 2M EG and 1M DMSO and gold nanoparticles. The results revealed that VS1-treated larvae had a higher vitrification rate (65%), swimming rate (23.1%), settlement rate (11.54%), and post settlement survival rate (11.54%) than those treated with VS2. Seasonal variations also affected the cryopreservation of the planulae; VS1 was more favorable for the planulae in spring than in fall. Although laser-warmed larvae developed slower morphologically than their controlled counterparts, the production of adult S. pistillata corals from cryopreserved larvae was achieved. The proposed technique can improve the cryopreservation of corals and advance efforts to protect endangered coral species.