bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of potential models for predicting progestin insensitivity in patients with endometrial atypical hyperplasia and endometrioid endometrial cancer based on ATAC-Seq and RNA-Seq integrated analysis
Authors: Hu Jia-Li , Yierfulati Gulinazi , Wang Lu-Lu , Yang Bing-Yi , Lv Qiao-Ying , Chen Xiao-Jun
Published: August 2022

Objective: The aim of this study was to establish predictive models based on the molecular profiles of endometrial lesions, which might help identify progestin-insensitive endometrial atypical hyperplasia (EAH) or endometrioid endometrial cancer (EEC) patients before progestin-based fertility-preserving treatment initiation.

Methods: Endometrial lesions from progestin-sensitive (PS, n = 7) and progestin-insensitive (PIS, n = 7) patients were prospectively collected before progestin treatment and then analyzed by ATAC-Seq and RNA-Seq. Potential chromatin accessibility and expression profiles were compared between the PS and PIS groups. Candidate genes were identified by bioinformatics analyses and literature review. Then expanded samples (n = 35) were used for validating bioinformatics data and conducting model establishment.

Results: ATAC-Seq and RNA-Seq data were separately analyzed and then integrated for the subsequent research. A total of 230 overlapping differentially expressed genes were acquired from ATAC-Seq and RNA-Seq integrated analysis. Further, based on GO analysis, REACTOME pathways, transcription factor prediction, motif enrichment, Cytoscape analysis and literature review, 25 candidate genes potentially associated with progestin insensitivity were identified. Finally, expanded samples were used for data verification, and based on these data, three predictive models comprising 9 genes (FOXO1, IRS2, PDGFC, DIO2, SOX9, BCL11A, APOE, FYN, and KLF4) were established with an overall predictive accuracy above 90%.

Conclusion: This study provided potential predictive models that might help identify progestin-insensitive EAH and EEC patients before fertility-preserving treatment.
Small RNA sequencing reveals sex-related miRNAs in Collichthys lucidus
Authors: Song Wei , Gan Wu , Xie Zhengli , Chen Jia , Wang Lumin
Published: August 2022

Collichthys lucidus (C. lucidus) is an economically important fish species, exhibiting sexual dimorphism in its growth rate. However, there is a lack of research on its underlying sex-related mechanisms. Therefore, small RNA sequencing was performed to better comprehend these sex-related molecular mechanisms. In total, 171 differentially expressed miRNAs (DE-miRNAs) were identified between the ovaries and testes. Functional enrichment analysis revealed that the target genes of DE-miRNAs were considerably enriched in the p53 signaling, PI3K–Akt signaling, and TGF-beta signaling pathways. In addition, sex-related miRNAs were identified, and the expression of miR-430c-3p and miR-430f-3p was specifically observed in the gonads compared with other organs and their expression was markedly upregulated in the testes relative to the ovaries. Bmp15 was a target of miR-430c-3p and was greatly expressed in the ovaries compared with the testes. Importantly, miR-430c-3p and bmp15 co-expressed in the ovaries and testes. This research provides the first detailed miRNA profiles for C. lucidus concerning sex, likely laying the basis for further studies on sex differentiation in C. lucidus.
Cross-talk between the cytokinin, auxin, and gibberellin regulatory networks in determining parthenocarpy in cucumber
Authors: Mandal Neha Kumari , Kumari Khushboo , Kundu Aditi , Arora Ajay , Bhowmick Prolay K. , Iquebal Mir Asif , Jaiswal Sarika , Behera Tusar Kanti , Munshi A. D. , Dey Shyam S.
Published: August 2022

Cucumber is a model plant for studying parthenocarpy with abundant slicing- and pickling-type germplasm. This study was undertaken to understand the role of the important cytokines (CKs), auxin (AUX) and gibberellin (GA) biosynthesis and degradation genes for the induction of parthenocarpy in slicing and pickling germplasm. Two genotypes of gynoecious parthenocarpic cucumber, PPC-6 and DG-8, along with an MABC-derived gynoecious non-parthenocarpic line, IMPU-1, were evaluated in this study. The slicing and pickling cucumber genotypes PPC-6 and DG-8 were strongly parthenocarpic in nature and set fruit normally without pollination. Endogenous auxin and gibberellin were significantly higher in parthenocarpic than non-parthenocarpic genotypes, whereas the concentration of cytokinins varied among the genotypes at different developmental stages. However, the exogenous application of Zeatin and IAA + Zeatin was effective in inducing parthenocarpic fruit in IMPU-1. Expression analysis with important CK, AUX, and GA biosynthesis-related genes was conducted in IMPU-1, PPC-6, and DG-8. The expression of the CK synthase, IPT, IPT3, PaO, LOG1, LOG2, CYP735A1, and CYP735A2 was up-regulated in the parthenocarpic genotypes. Among the transcription factor response regulators (RRs), positive regulation of CSRR8/9b, CSRR8/9d, CSRR8/9e, and CSRR16/17 and negative feedback of the CK signalling genes, such as CsRR3/4a, CsRR3/4b, CsRR8/9a, and CsRR8/9c, were recorded in the parthenocarpic lines. Homeostasis between cytokinin biosynthesis and degradation genes such as CK oxidases (CKXs) and CK dehydrogenase resulted in a non-significant difference in the endogenous CK concentration in the parthenocarpic and non-parthenocarpic genotypes. In addition, up-regulation of the key auxin-inducing proteins and GA biosynthesis genes indicated their crucial role in the parthenocarpic fruit set of cucumber. This study establishes the critical role of the CKs, AUX, and GA regulatory networks and their cross-talk in determining parthenocarpy in slicing and pickling cucumber genotypes.
Case Report: Novel compound heterozygous variants in CHRNA1 gene leading to lethal multiple pterygium syndrome: A case report
Authors: Zhuang Jianlong , Wang Junyu , Luo Qi , Zeng Shuhong , Chen Yu’e , Jiang Yuying , Chen Xinying , Wang Yuanbai , Xie Yingjun , Wang Gaoxiong , Chen Chunnuan
Published: August 2022

Background: Lethal multiple pterygium syndrome (LMPS) is a rare autosomal recessive inherited disorder typically characterized by intrauterine growth retardation, multiple pterygia, and flexion contractures.

Case presentation: We herein report a Chinese case with a history of three adverse pregnancies demonstrating the same ultrasonic phenotypes, including increased nuchal translucency, edema, fetal neck cystoma, reduced movement, joint contractures, and other congenital features. Whole-exome sequencing (WES) revealed novel compound heterozygous variants in the CHRNA1 gene NM_000079.4: c.[1128delG (p.Pro377LeufsTer10)]; [505T>C (p.Trp169Arg)] in the recruited individual, and subsequent familial segregation showed that both parents transmitted their respective mutation.

Conclusion: For the first time, we identified an association between the CHRNA1 gene and the recurrent lethal multiple pterygium syndrome (LMPS) in a Chinese family. This finding may also enrich the mutation spectrum of the CHRNA1 gene and promote the applications of WES technology in etiologic diagnosis of ultrasound anomalies in prenatal examination.
Expression of T cell-related lncRNAs in multiple sclerosis
Authors: Dadyar Maryam , Hussen Bashdar Mahmud , Eslami Solat , Taheri Mohammad , Emadi Farhad , Ghafouri-Fard Soudeh , Sayad Arezou
Published: August 2022

Long non-coding RNAs (lncRNAs) have been demonstrated to in the pathophysiology of multiple sclerosis (MS). In order to appraise the role of T cell-related lncRNAs in this disorder, we assessed expressions of NEST, RMRP, TH2-LCR, MAFTRR and FLICR in MS patients and healthy individuals. We detected significant difference in the expression of RMRP and FLICR between cases and controls. There were substantial correlations between expressions of NEST, RMRP, TH2-LCR, MAFTRR and FLICR lncRNAs among patients, but not controls. The strongest correlations were found between RMRP and TH2-LCR, and between MAFTRR and RMRP with correlation coefficients of 0.69 and 0.59, respectively. ROC curve analysis revealed appropriate power of FLICR in differentiating between MS patients and healthy controls (AUC value = 0.84). Expression of NEST lncRNA was positively correlated with disease duration in MS patients, but negatively correlated with age at onset. In brief, we reported dysregulation of two T cell-related lncRNAs in MS patients and proposed FLICR as a putative marker for this disorder.
The interplay between serine proteases and caspase-1 regulates the autophagy-mediated secretion of Interleukin-1 beta in human neutrophils
Authors: Keitelman Irene A. , Shiromizu Carolina M. , Zgajnar Nadia R. , Danielián Silvia , Jancic Carolina C. , Martí Marcelo A. , Fuentes Federico , Yancoski Judith , Vera Aguilar Douglas , Rosso David A. , Goris Verónica , Buda Guadalupe , Katsicas María Martha , Galigniana Mario D. , Galletti Jeremías G. , Sabbione Florencia , Trevani Analia S.
Published: August 2022

Neutrophils play major roles against bacteria and fungi infections not only due to their microbicide properties but also because they release mediators like Interleukin-1 beta (IL-1β) that contribute to orchestrate the inflammatory response. This cytokine is a leaderless protein synthesized in the cytoplasm as a precursor (pro-IL-1β) that is proteolytically processed to its active isoform and released from human neutrophils by secretory autophagy. In most myeloid cells, pro-IL-1β is processed by caspase-1 upon inflammasome activation. Here we employed neutrophils from both healthy donors and patients with a gain-of-function (GOF) NLRP3-mutation to dissect IL-1β processing in these cells. We found that although caspase-1 is required for IL-1β secretion, it undergoes rapid inactivation, and instead, neutrophil serine proteases play a key role in pro-IL-1β processing. Our findings bring to light distinctive features of the regulation of caspase-1 activity in human neutrophils and reveal new molecular mechanisms that control human neutrophil IL-1β secretion.
Characterization of the immune related lncRNAs in bladder cancer to aid immunotherapy
Authors: Xiao Ying , Dong Yipeng , Yu Tiannan , Wang Rujie , Gao Yang , Li Song , Nong Shaojun , Li Wenguang
Published: August 2022

Bladder cancer (BLCA) is the 10th most common form of cancer worldwide. Currently, the response rate of BLCA patients to novel immunotherapy and immune checkpoint inhibitor (ICI) treatment is around 30% or less. Therefore, there is an urgent clinical demand to understand the regulation of immune function in BLCA patients. LncRNAs are known to play fundamental roles in the regulation of the immune system in the tumor microenvironment. In this report, we performed a comprehensive analysis to identify immune-related lncRNAs (IRLs) in BLCA patients using The Cancer Genome Atlas (TCGA) databases. BLCA patients were divided into five TME subtypes. Subtype HMIE was strongly related to survival and high anti-tumor activity of patients. Through a four-step analysis, we identified 34 IRLs as subtype HMIE related lncRNAs (HMIE-lncs).The correlation analysis with immune cell infiltration and target gene pathway enrichment showed that 34 HMIE-lncs were correlated with immune cell activation and tumor cell killing. Among them, 24 lncRNAs were related to good prognosis. We constructed a risk model to predict BLCA. Cross tumor validation was performed, and the results showed that the 34 HMIE-lncs identified in the BLCA patients in this study were highly expressed in the immune-favorable TME subtype (IE) in most of the other cancer types.
Case report: Single-cell mapping of peripheral blood mononuclear cells from a patient with both Crohn’s disease and isolated congenital asplenia
Authors: Pu Dan , Liu Lu , Wang Na , Wang Dandan , Zhang Zhe , Feng Baisui
Published: August 2022

Crohn’s disease (CD), as one of the principal form of inflammatory bowel disease (IBD), is characterized by the chronic and recurring inflammatory conditions in the intestine resulting from the over-activation of intestinal immunity. Hyposplenism is strongly associated with CD, while the effect of human spleen on the differentiation and development of immune cell subsets in CD patients remains unclear. Isolated congenital asplenia (ICA) is an extremely rare condition characterized by the absence of a spleen at birth without any other developmental defects. Here, we describe the first case of a patient with both ICA and CD, and follow the progression of CD from remission to active stage. Using cytometry by time of flight (CyTOF) analysis, we draw the first single-cell mapping of peripheral blood mononuclear cells (PBMC) from this unique patient, tracing back to the innate or adaptive immune cell subsets and cell surface markers affected by the spleen. Based on our analysis, it is speculated that the spleen contributes to maintaining immune homeostasis, alleviating intestinal inflammation and improving prognosis by influencing the differentiation and development of peripheral immune cell subsets and the expression of cell surface markers in patients with CD.
Precise somatic genome editing for treatment of inborn errors of immunity
Authors: Meng Qingzhou , Sun Haixiang , Liu Jianghuai
Published: August 2022

Rapid advances in high throughput sequencing have substantially expedited the identification and diagnosis of inborn errors of immunity (IEI). Correction of faulty genes in the hematopoietic stem cells can potentially provide cures for the majority of these monogenic immune disorders. Given the clinical efficacies of vector-based gene therapies already established for certain groups of IEI, the recently emerged genome editing technologies promise to bring safer and more versatile treatment options. Here, we review the latest development in genome editing technologies, focusing on the state-of-the-art tools with improved precision and safety profiles. We subsequently summarize the recent preclinical applications of genome editing tools in IEI models, and discuss the major challenges and future perspectives of such treatment modalities. Continued explorations of precise genome editing for IEI treatment shall move us closer toward curing these unfortunate rare diseases.
Systemic consequences of abnormal cholesterol handling: Interdependent pathways of inflammation and dyslipidemia
Authors: O’Hagan Ross , Berg Alex R. , Hong Christin G. , Parel Philip M. , Mehta Nehal N. , Teague Heather L.
Published: August 2022

Metabolic conditions such as obesity and associated comorbidities are increasing in prevalence worldwide. In chronically inflamed pathologies, metabolic conditions are linked to early onset cardiovascular disease, which remains the leading cause of death despite decades of research. In recent years, studies focused on the interdependent pathways connecting metabolism and the immune response have highlighted that dysregulated cholesterol trafficking instigates an overactive, systemic inflammatory response, thereby perpetuating early development of cardiovascular disease. In this review, we will discuss the overlapping pathways connecting cholesterol trafficking with innate immunity and present evidence that cholesterol accumulation in the bone marrow may drive systemic inflammation in chronically inflamed pathologies. Lastly, we will review the current therapeutic strategies that target both inflammation and cholesterol transport, and how biologic therapy restores lipoprotein function and mitigates the immune response.
Machine learning applied to big data from marine cabled observatories: A case study of sablefish monitoring in the NE Pacific
Authors: Bonofiglio Federico , De Leo Fabio C. , Yee Connor , Chatzievangelou Damianos , Aguzzi Jacopo , Marini Simone
Published: August 2022

Ocean observatories collect large volumes of video data, with some data archives now spanning well over a few decades, and bringing the challenges of analytical capacity beyond conventional processing tools. The analysis of such vast and complex datasets can only be achieved with appropriate machine learning and Artificial Intelligence (AI) tools. The implementation of AI monitoring programs for animal tracking and classification becomes necessary in the particular case of deep-sea cabled observatories, as those operated by Ocean Networks Canada (ONC), where Petabytes of data are now collected each and every year since their installation. Here, we present a machine-learning and computer vision automated pipeline to detect and count sablefish (Anoplopoma fimbria), a key commercially exploited species in the N-NE Pacific. We used 651 hours of video footage obtained from three long-term monitoring sites in the NEPTUNE cabled observatory, in Barkley Canyon, on the nearby slope, and at depths ranging from 420 to 985 m. Our proposed AI sablefish detection and classification pipeline was tested and validated for an initial 4.5 month period (Sep 18 2019-Jan 2 2020), and was a first step towards validation for future processing of the now decade-long video archives from Barkley Canyon. For the validation period, we trained a YOLO neural network on 2917 manually annotated frames containing sablefish images to obtain an automatic detector with a 92% Average Precision (AP) on 730 test images, and a 5-fold cross-validation AP of 93% (± 3.7%). We then ran the detector on all video material (i.e., 651 hours from a 4.5 month period), to automatically detect and annotate sablefish. We finally applied a tracking algorithm on detection results, to approximate counts of individual fishes moving on scene and obtain a time series of proxy sablefish abundance. Those proxy abundance estimates are among the first to be made using such a large volume of video data from deep-sea settings. We discuss our AI results for application on a decade-long video monitoring program, and particularly with potential for complementing fisheries management practices of a commercially important species.
Policy gaps in the East African Blue economy: Perspectives of small-scale fishers on port development in Kenya and Tanzania
Authors: Thoya Pascal , Horigue Vera , Möllmann Christian , Maina Joseph , Schiele Kerstin S.
Published: August 2022

Recently, the rights of small-scale fishers have increasingly been acknowledged in ocean governance because coastal development and various maritime activities have reduced traditional fishing grounds. More specifically, small-scale fisheries (SSF) are increasingly being threatened by ocean grabbing, pollution, and a lack of inclusiveness in decision-making processes. Although there are guidelines to resolve and reduce conflict, formal avenues to include fisher concerns, particularly in the context of ocean development and governance, remain a difficult task. Moreover, there is insufficient information on how fishers are impacted by coastal and marine development and how their concerns are included in the decision-making process. Hence, this study contributes to the SSF discourse by understanding and describing the characteristics and concerns of small-scale fishers from two coastal towns in East Africa with different levels of port development. Using data from perception surveys, focus group discussions, and participatory mapping, we discuss how fishers were involved in the decision-making processes to develop ports in Lamu, Kenya, and Bagamoyo, Tanzania. We found that fishers rely on nearshore ecosystems such as mangroves and coral reefs because of their accessibility since most fishers only use low-powered boats for fishing. Moreover, we found that the fishers’ livelihoods were severely affected by port development and that they were excluded from the decision-making process concerning the port’s construction and fishers’ compensations. While some fishers believe that new ports in the region can increase their livelihoods by creating new markets and jobs, this is unlikely to happen since most fishers are not qualified to work in formal port-related jobs. We propose three steps that will allow fishermen to participate in port development decision-making processes and contribute to the development of a sustainable SSF. These include improving engagement with fishers to allow meaningful participation in decision-making, developing a blue economy policy focused on SSF, and implementing maritime spatial planning.
Coral-inhabiting Trapezia crabs forage on demersal plankton
Authors: Shmuel Yaniv , Ziv Yaron , Rinkevich Baruch
Published: August 2022

The Trapeziidae constitute a widely distributed and common family of obligatory coral-dwelling crabs on Indo-west Pacific coral reefs, feeding on coral tissue and mucus. In situ nocturnal surveys on Stylophora pistillata (a common branching pocilloporid coral species in the Gulf of Eilat, Red Sea), revealed Trapezia cymodoce and Trapezia digitalis crabs foraging on swimming demersal plankton, including amphipods, copepods, isopods, swimming polychaetes, and occasionally fishes, employing three plankton feeding mechanisms. Laboratory experiments demonstrated that crabs actively searched for Artemia when these were present in the aquaria together with either dead or live coral branches, but did not do so when corals were absent. Overall, the results indicate that trapeziid crabs play a role as planktivorous reef organisms. This suggests the need for further study of the feeding habits of members of this family, considering the potential impacts of their foraging on demersal plankton dynamics in coral reefs.
Comparative analysis of four types of mesoscale eddies in the Kuroshio-Oyashio extension region
Authors: Sun Wenjin , An Mengxuan , Liu Jie , Liu Jishan , Yang Jingsong , Tan Wei , Dong Changming , Liu Yu
Published: August 2022

Oceanic mesoscale cyclonic (anticyclonic) eddies usually have cold (warm) cores and counterclockwise (clockwise) flow fields in the Northern Hemisphere. However, “abnormal” cyclonic (anticyclonic) eddies with warm (cold) cores and counterclockwise (clockwise) flow fields have recently been identified in the Kuroshio-Oyashio Extension (KOE) region. Here, traditional cyclonic cold-core eddies (CCEs) and anticyclonic warm-core eddies (AWEs) are termed normal eddies, and cyclonic warm-core eddies (CWEs) and anticyclonic cold-core eddies (ACEs) are called abnormal eddies. Applying a vector geometry-based automatic eddy detection method to the Ocean General Circulation Model for the Earth Simulator reanalysis data (OFES), a three-dimensional eddy dataset is obtained and used to quantify the statistical characteristics of these eddies. Results illustrate that the number of CCEs, AWEs, CWEs, and ACEs accounted for 38.46, 36.15, 13.40, and 11.99%, respectively. In the vertical direction, normal eddies are concentrated in the upper 2,000 m, while abnormal eddies are mainly found in the upper 600 m of the ocean. On seasonal scales, normal eddies are more abundant in winter and spring than in summer and autumn, with the opposite trend found for abnormal eddies. Potential density changes modulated by normal eddies are dominated by eddies-induced temperature anomalies, while salinity anomalies dominate the changes modulated by abnormal eddies. This study expands the types of eddies and enriches their understanding in the KOE region.
Case report: Early detection of mesenteric ischemia by intravital microscopy in a patient with septic shock
Authors: Praxenthaler Janina , Kirchner Carmen , Schwier Elke , Altmann Simon , Wittmer Axel , Henzler Dietrich , Köhler Thomas
Published: August 2022

Gut ischemia is a frequent but underdiagnosed complication, especially in critically ill intensive care patients, and represents a special diagnostic challenge that can only be solved in an interdisciplinary manner. We report a case of a 54-year-old woman with acute mesenteric ischemia (AMI) as a cause of septic shock diagnosed by intravital microscopy (IVM) 2 days before visible necrotic changes in a multimodality approach. We show that intravital microscopy can be a serious alternative for the early diagnosis of mesenteric ischemia in the hands of the skilled. We use this case to discuss the value and clinical perspective of IVM in the intensive care setting.
Hotspots and trends in ophthalmology in recent 5 years: Bibliometric analysis in 2017–2021
Authors: Tan Yuan , Zhu Weining , Zou Yingshi , Zhang Bowen , Yu Yinglin , Li Wei , Jin Guangming , Liu Zhenzhen
Published: August 2022

Purpose

The purpose of this study was to investigate the hotspots and research trends of ophthalmology research.

Method

Ophthalmology research literature published between 2017 and 2021 was obtained in the Web of Science Core Collection database. The bibliometric analysis and network visualization were performed with the VOSviewer and CiteSpace. Publication-related information, including publication volume, citation counts, countries, journals, keywords, subject categories, and publication time, was analyzed.

Results

A total of 10,469 included ophthalmology publications had been cited a total of 7,995 times during the past 5 years. The top countries and journals for the number of publications were the United States and the Ophthalmology. The top 25 global high-impact documents had been identified using the citation ranking. Keyword co-occurrence analysis showed that the hotspots in ophthalmology research were epidemiological characteristics and treatment modalities of ocular diseases, artificial intelligence and fundus imaging technology, COVID-19-related telemedicine, and screening and prevention of ocular diseases. Keyword burst analysis revealed that “neural network,” “pharmacokinetics,” “geographic atrophy,” “implementation,” “variability,” “adverse events,” “automated detection,” and “retinal images” were the research trends of research in the field of ophthalmology through 2021. The analysis of the subject categories demonstrated the close cooperation relationships that existed between different subject categories, and collaborations with non-ophthalmology-related subject categories were increasing over time in the field of ophthalmology research.

Conclusions

The hotspots in ophthalmology research were epidemiology, prevention, screening, and treatment of ocular diseases, as well as artificial intelligence and fundus imaging technology and telemedicine. Research trends in ophthalmology research were artificial intelligence, drug development, and fundus diseases. Knowledge from non-ophthalmology fields is likely to be more involved in ophthalmology research.
Synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology
Authors: Revilla-Guarinos Ainhoa , Popp Philipp F. , Dürr Franziska , Lozano-Cruz Tania , Hartig Johanna , de la Mata Francisco Javier , Gómez Rafael , Mascher Thorsten
Published: August 2022

Over the course of the last decades, the continuous exposure of bacteria to antibiotics—at least in parts due to misprescription, misuse, and misdosing—has led to the widespread development of antimicrobial resistances. This development poses a threat to the available medication in losing their effectiveness in treating bacterial infections. On the drug development side, only minor advances have been made to bring forward novel therapeutics. In addition to increasing the efforts and approaches of tapping the natural sources of new antibiotics, synthetic approaches to developing novel antimicrobials are being pursued. In this study, BDTL049 was rationally designed using knowledge based on the properties of natural antibiotics. BDTL049 is a carbosilane dendritic system with bow-tie type topology, which has antimicrobial activity at concentrations comparable to clinically established natural antibiotics. In this report, we describe its mechanism of action on the Gram-positive model organism Bacillus subtilis. Exposure to BDTL049 resulted in a complex transcriptional response, which pointed toward disturbance of the cell envelope homeostasis accompanied by disruption of other central cellular processes of bacterial metabolism as the primary targets of BDTL049 treatment. By applying a combination of whole-cell biosensors, molecular staining, and voltage sensitive dyes, we demonstrate that the mode of action of BDTL049 comprises membrane depolarization concomitant with pore formation. As a result, this new molecule kills Gram-positive bacteria within minutes. Since BDTL049 attacks bacterial cells at different targets simultaneously, this might decrease the chances for the development of bacterial resistances, thereby making it a promising candidate for a future antimicrobial agent.
Ecological health evaluation of rivers based on phytoplankton biological integrity index and water quality index on the impact of anthropogenic pollution: A case of Ashi River Basin
Authors: Li Zhenxiang , Ma Chao , Sun Yinan , Lu Xinxin , Fan Yawen
Published: August 2022

Based on the phytoplankton community matrices in the Ashi River Basin (ASRB), Harbin city, we developed an evaluation method using the phytoplankton index of biotic integrity (P-IBI) to evaluate ecological health while investigating the response of P-IBI to anthropogenic activities. We compared the effectiveness of P-IBI with that of the water quality index (WQI) in assessing ecological health. Between April and October 2019, phytoplankton and water samples were collected at 17 sampling sites in the ASRB on a seasonal basis. Our results showed that seven phyla were identified, comprising 137 phytoplankton species. From a pool of 35 candidate indices, five critical ecological indices (Shannon–Wiener index, total biomass, percentage of motile diatoms, percentage of stipitate diatom, and diatom quotient) were selected to evaluate the biological integrity of phytoplankton in the ASRB. The ecological status of the ASRB as measured by the P-IBI and WQI exhibited a similar spatial pattern. It showed a spatial decline in ecological status in accordance with the flow of the river. These results highlighted that P-IBI was a reliable tool to indicate the interaction between habitat conditions and environmental factors in the ASRB. Our findings contribute to the ecological monitoring and protection of rivers impacted by anthropogenic pollution.
Overexpression of Bacillus circulans alkaline protease in Bacillus subtilis and its potential application for recovery of protein from soybean dregs
Authors: Chen Hao , Wu Jie , Huang Xiaodan , Feng Xuzhong , Ji Hongwu , Zhao Liangzhong , Wang Jianrong
Published: August 2022

Proteases are important for decomposition of proteins to generate peptides or amino acids and have a broad range of applications in different industries. Herein, a gene encoding an alkaline protease (AprBcp) from Bacillus circulans R1 was cloned and bioinformatics analyzed. In addition, a series of strategies were applied to achieve high-level expression of AprBcp in Bacillus subtilis. The maximum activity of AprBcp reached 165,870 U/ml after 60 h fed-batch cultivation in 50 l bioreactor. The purified recombinant AprBcp exhibited maximum activity at 60°C and pH 10.0, and remained stable in the range from pH 8.0 to 11.0 and 30 to 45°C. Metal ions Ca2+, Mn2+, and Mg2+ could improve the stability of AprBcp. Furthermore, the recombinant AprBcp displayed great potential application on the recovery of protein from soybean dregs. The results of this study will provide an effective method to prepare AprBcp in B. subtilis and its potential application on utilization of soybean dregs.
The molecular, immune features, and risk score construction of intraductal papillary mucinous neoplasm patients
Authors: Huang Xing , Feng Yipeng , Ma Dawei , Ding Hanlin , Dong Gaochao , Chen Yan , Huang Xiaochen , Zhang Jingyuan , Xu Xinyu , Chen Chen
Published: August 2022

Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precancerous lesion, with increasing incidence in recent years. However, the mechanisms of IPMN progression into invasive cancer remain unclear. The mRNA expression data of IPMN/PAAD patients were extracted from the TCGA and GEO databases. First, based on GSE19650, we analyzed the molecular alterations, tumor stemness, immune landscape, and transcriptional regulation of IPMN progression. The results indicated that gene expression changed dramatically, specifically at the intraductal papillary-mucinous adenoma (IPMA) stage. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Kyoto Encyclopedia of Genes and Genomes (GSEA) pathway analyses showed that glycoprotein-related, cell cycle, and P53 pathways displayed the most significant changes during progression. With IPMN progression, tumor stemness increased continuously, and KRAS, ERBB3, RUNX1, and ELF3 are essential driver genes affecting tumor stemness. Motif analysis suggested that KLF4 may be a specific transcription factor that regulates gene expression in the IPMA stage, while MYB and MYBL1 control gene expression in the IPMC and invasive stages, respectively. Then, GSE19650 and GSE71729 transcriptome data were combined to perform the least absolute shrinkage and selection operator (LASSO) method and Cox regression analysis to develop an 11-gene prediction model (KCNK1, FHL2, LAMC2, CDCA7, GPX3, C7, VIP, HBA1, BTG2, MT1E, and LYVE1) to predict the prognosis of pancreatic cancer patients. The reliability of the model was validated in the GSE71729 and TCGA databases. Finally, 11 additional IPMN patients treated in our hospital were included, and the immune microenvironment changes during IPMN progression were analyzed by immunohistochemistry (IHC). IHC results suggest that Myeloid-derived suppressor cells (MDSCs) and macrophages may be key in the formation of immunosuppressive microenvironment of IPMN progression. Our study deepens our understanding of IPMN progression, especially the changes in the immune microenvironment. The findings of this work may contribute to the development of new therapeutic strategies for IPMN.
Impaired autophagy with augmented apoptosis in a Th1/Th2-imbalanced placental micromilieu is associated with spontaneous preterm birth
Authors: Akram Khondoker M. , Frost Lucy I. , Anumba Dilly OC.
Published: August 2022

Background: Despite decades of research, the pathogenesis of spontaneous preterm birth (PTB) remains largely unknown. Limited currently available data on PTB pathogenesis are based on rodent models, which do not accurately reflect the complexity of the human placenta across gestation. While much study has focused on placental infection and inflammation associated with PTB, two key potentially important cellular events in the placenta—apoptosis and autophagy—remained less explored. Understanding the role of these processes in the human placenta may unravel currently ill-understood processes in the pathomechanism of PTB.

Methods: To address this necessity, we conducted qRT-PCR and ELISA assays on placental villous tissue from 20 spontaneous preterm and 20 term deliveries, to assess the inter-relationships between inflammation, apoptosis, and autophagy in villous tissue in order to clarify their roles in the pathogenesis of PTB.

Results: We found disrupted balance between pro-apoptotic BAX and anti-apoptotic BCL2 gene/protein expression in preterm placenta, which was associated with significant reduction of BCL2 and increase of BAX proteins along with upregulation of active CASP3 and CASP8 suggesting augmented apoptosis in PTB. In addition, we detected impaired autophagy in the same samples, evidenced by significant accumulation of autophagosome cargo protein p62/SQSTM1 in the preterm villous placentas, which was associated with simultaneous downregulation of an essential autophagy gene ATG7 and upregulation of Ca2+-activated cysteine protease CAPN1. Placental aggregation of p62 was inversely correlated with newborn birth weight, suggesting a potential link between placental autophagy impairment and fetal development. These two aberrations were detected in a micromilieu where the genes of the Th2 cytokines IL10 and IL13 were downregulated, suggesting an alteration in the Th1/Th2 immune balance in the preterm placenta.

Conclusion: Taken together, our observations suggest that impaired autophagy and augmented apoptosis in a Th1/Th2 imbalanced placental micro-environment may be associated with the pathogenesis of spontaneous PTB.
Characterizing the molecular heterogeneity of clear cell renal cell carcinoma subgroups classified by miRNA expression profile
Authors: Shen Tao , Song Yingdong , Wang Xiangting , Wang Haiyang
Published: August 2022

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous disease that is associated with poor prognosis. Recent works have revealed the significant roles of miRNA in ccRCC initiation and progression. Comprehensive characterization of ccRCC based on the prognostic miRNAs would contribute to clinicians’ early detection and targeted treatment. Here, we performed unsupervised clustering using TCGA-retrieved prognostic miRNAs expression profiles. Two ccRCC subtypes were identified after assessing principal component analysis (PCA), t-distributed stochastic neighbor embedding (t-SNE), and consensus heatmaps. We found that the two subtypes are associated with distinct clinical features, overall survivals, and molecular characteristics. C1 cluster enriched patients in relatively early stage and have better prognosis while patients in C2 cluster have poor prognosis with relatively advanced state. Mechanistically, we found the differentially expressed genes (DEGs) between the indicated subgroups dominantly enriched in biological processes related to transmembrane transport activity. In addition, we also revealed a miRNA-centered DEGs regulatory network, which severed as essential regulators in both transmembrane transport activity control and ccRCC progression. Together, our work described the molecular heterogeneity among ccRCC cancers, provided potential targets served as effective biomarkers for ccRCC diagnosis and prognosis, and paved avenues to better understand miRNA-directed regulatory network in ccRCC progression.
RL-MLZerD: Multimeric protein docking using reinforcement learning
Authors: Aderinwale Tunde , Christoffer Charles , Kihara Daisuke
Published: August 2022

Numerous biological processes in a cell are carried out by protein complexes. To understand the molecular mechanisms of such processes, it is crucial to know the quaternary structures of the complexes. Although the structures of protein complexes have been determined by biophysical experiments at a rapid pace, there are still many important complex structures that are yet to be determined. To supplement experimental structure determination of complexes, many computational protein docking methods have been developed; however, most of these docking methods are designed only for docking with two chains. Here, we introduce a novel method, RL-MLZerD, which builds multiple protein complexes using reinforcement learning (RL). In RL-MLZerD a multi-chain assembly process is considered as a series of episodes of selecting and integrating pre-computed pairwise docking models in a RL framework. RL is effective in correctly selecting plausible pairwise models that fit well with other subunits in a complex. When tested on a benchmark dataset of protein complexes with three to five chains, RL-MLZerD showed better modeling performance than other existing multiple docking methods under different evaluation criteria, except against AlphaFold-Multimer in unbound docking. Also, it emerged that the docking order of multi-chain complexes can be naturally predicted by examining preferred paths of episodes in the RL computation.
Some useful ideas for multistate protein design: Effect of amino acid substitutions on the multistate proteins stability and the rate of protein structure formation
Authors: Majorina M. A. , Melnik T. N. , Glukhov A. S. , Melnik B. S.
Published: August 2022

The design of new protein variants is usually confined to slightly “fixing” an already existing protein, adapting it to certain conditions or to a new substrate. This is relatively easy to do if the fragment of the protein to be affected, such as the active site of the protein, is known. But what if you need to “fix” the stability of a protein or the rate of its native or intermediate state formation? Having studied a large number of protein mutant forms, we have established the effect of various amino acid substitutions on the energy landscape of the protein. As a result, we have revealed a number of patterns to help researchers identify amino acid residues that determine the folding rate and the stability of globular proteins states and design a mutant form of a protein with desired properties.
White matter hyperintensities in dementia with Lewy bodies are associated with poorer cognitive function and higher dementia stages
Authors: Chen Tai-Yi , Chan Po-Chi , Tsai Ching-Fang , Wei Cheng-Yu , Chiu Pai-Yi
Published: August 2022

Purpose

White matter hyperintensities (WMHs) are frequently found in elderly individuals with or without dementia. However, the association between WMHs and clinical presentations of dementia with Lewy bodies (DLB) has rarely been studied.

Methods

We conducted a retrospective analysis of patients with DLB registered in a dementia database. WMHs were rated visually using the Fazekas scale, and its associated factors including dementia severity, cognitive functions, neuropsychiatric symptoms, and core clinical features were compared among different Fazekas scores. Domains in the Clinical Dementia Rating (CDR), Cognitive abilities Screening Instruments (CASI), and Neuropsychiatric Inventory (NPI) were compared among different Fazekas groups after adjusting for age, sex, education, and disease duration.

Results

Among the 449 patients, 76, 207, 110, and 56 had Fazekas score of 0, 1, 2, and 3, respectively. There was a positive association between dementia severity and WMHs severity, and the mean sums of boxes of the Clinical Dementia Rating (CDR-SB) were 5.9, 7.8, 9.5, and 11.2 (f = 16.84, p < 0.001) for the Fazekas scale scores 0, 1, 2, and 3, respectively. There was a negative association between cognitive performance and WMHs severity, and the mean CASI were 57.7, 45.4, 4.06, and 33.4 (f = 14.22, p < 0.001) for the Fazekas scale scores 0, 1, 2, and 3, respectively. However, WMHs were not associated with the core clinical features of DLB. After adjustment, all cognitive domains in CDR increased as the Fazekas score increased. In addition, performance on all cognitive domains in CASI decreased as the Fazekas score increased (all p < 0.001). Among neuropsychiatric symptoms, delusions, euphoria, apathy, aberrant motor behavior, and sleep disorders were significantly worse in the higher Fazekas groups compared to those in the group with Fazekas score of 0 after adjustment.

Conclusion

WMHs in DLB might contribute to deterioration of cognitive function, neuropsychiatric symptoms, and dementia stages. However, core clinical features were not significantly influenced by WMHs in DLB.
A zona incerta-basomedial amygdala circuit modulates aversive expectation in emotional stress-induced aversive learning deficits
Authors: Zhang Lijun , Zhang Pei , Qi Guangjian , Cai Hongwei , Li Tongxia , Li Ming , Cui Chi , Lei Jie , Ren Kun , Yang Jian , Ming Jie , Tian Bo
Published: August 2022

A previously published study showed that stress may interfere with associative aversive learning and facilitate mood-related disorders. However, whether emotional stress alone affects aversive learning is unknown. Using three chamber-vicarious social defeat stress (3C-VSDS) model mice, we investigated the effect of emotional stress on aversive learning. An important origin of dopamine (DA) neurons, the zona incerta (ZI), is expected to be a novel target for the modulation of aversive learning. However, less is known about the circuit mechanism of ZIDA neurons in aversive learning. Here, we subjected mice to a fear-conditioning system (FCS) and observed an increased calcium activity of ZI TH+ neurons in aversive expectation during the conditioning phase, especially during the late stage of the conditional stimulus (CS) when CS and unconditional stimulus (US) pairings were used. Optogenetic inhibition of ZI TH+ neurons at the late stage of CS disrupted conditioned fear learning in mice. We further identified a TH+ projection from the ZI to the basomedial amygdala (BMA) and found that optogenetic inhibition of the ZI-BMA circuit could also block aversive learning. Finally, we used 3C-VSDS mice as a model of emotional stress. We found that the 3C-VSDS model mice demonstrated reduced aversive expectation associated with ZI TH+ neurons in the late stage of CS and impaired aversive learning in FCS. Optogenetic activation of ZI-BMA TH+ projections in the late stage of CS significantly reversed the aversive FCS learning disability of 3C-VSDS model mice. These data suggest that a TH+ circuit from the ZI to the BMA is required for aversive expectation, both at baseline and in 3C-VSDS-induced aversive learning deficits and that this circuit is a potential target for the modulation of aversive learning. Low activity of ZI-BMA TH+ projections is one reason for 3C-VSDS-induced aversive learning deficits.
Profiling hearing aid users through big data explainable artificial intelligence techniques
Authors: Iliadou Eleftheria , Su Qiqi , Kikidis Dimitrios , Bibas Thanos , Kloukinas Christos
Published: August 2022

Debilitating hearing loss (HL) affects ~6% of the human population. Only 20% of the people in need of a hearing assistive device will eventually seek and acquire one. The number of people that are satisfied with their Hearing Aids (HAids) and continue using them in the long term is even lower. Understanding the personal, behavioral, environmental, or other factors that correlate with the optimal HAid fitting and with users' experience of HAids is a significant step in improving patient satisfaction and quality of life, while reducing societal and financial burden. In SMART BEAR we are addressing this need by making use of the capacity of modern HAids to provide dynamic logging of their operation and by combining this information with a big amount of information about the medical, environmental, and social context of each HAid user. We are studying hearing rehabilitation through a 12-month continuous monitoring of HL patients, collecting data, such as participants' demographics, audiometric and medical data, their cognitive and mental status, their habits, and preferences, through a set of medical devices and wearables, as well as through face-to-face and remote clinical assessments and fitting/fine-tuning sessions. Descriptive, AI-based analysis and assessment of the relationships between heterogeneous data and HL-related parameters will help clinical researchers to better understand the overall health profiles of HL patients, and to identify patterns or relations that may be proven essential for future clinical trials. In addition, the future state and behavioral (e.g., HAids Satisfiability and HAids usage) of the patients will be predicted with time-dependent machine learning models to assist the clinical researchers to decide on the nature of the interventions. Explainable Artificial Intelligence (XAI) techniques will be leveraged to better understand the factors that play a significant role in the success of a hearing rehabilitation program, constructing patient profiles. This paper is a conceptual one aiming to describe the upcoming data collection process and proposed framework for providing a comprehensive profile for patients with HL in the context of EU-funded SMART BEAR project. Such patient profiles can be invaluable in HL treatment as they can help to identify the characteristics making patients more prone to drop out and stop using their HAids, using their HAids sufficiently long during the day, and being more satisfied by their HAids experience. They can also help decrease the number of needed remote sessions with their Audiologist for counseling, and/or HAids fine tuning, or the number of manual changes of HAids program (as indication of poor sound quality and bad adaptation of HAids configuration to patients' real needs and daily challenges), leading to reduced healthcare cost.