bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimal improvement in coronary artery disease risk prediction in Chinese population using polygenic risk scores: Evidence from the China Kadoorie Biobank
Authors: Yang Songchun , Sun Dong , Sun Zhijia , Yu Canqing , Guo Yu , Si Jiahui , Sun Dianjianyi , Pang Yuanjie , Pei Pei , Yang Ling , Millwood Iona Y. , G.Walters Robin , Chen Yiping , Du Huaidong , Pang Zengchang , Schmidt Dan , Stevens Rebecca , Clarke Robert , Chen Junshi , Chen Zhengming , Lv Jun , Li Liming
Published: May 2023

Background:

Several studies have reported that polygenic risk scores (PRSs) can enhance risk prediction of coronary artery disease (CAD) in European populations. However, research on this topic is far from sufficient in non-European countries, including China. We aimed to evaluate the potential of PRS for predicting CAD for primary prevention in the Chinese population.

Methods:

Participants with genome-wide genotypic data from the China Kadoorie Biobank were divided into training (n = 28,490) and testing sets (n = 72,150). Ten previously developed PRSs were evaluated, and new ones were developed using clumping and thresholding or LDpred method. The PRS showing the strongest association with CAD in the training set was selected to further evaluate its effects on improving the traditional CAD risk-prediction model in the testing set. Genetic risk was computed by summing the product of the weights and allele dosages across genome-wide single-nucleotide polymorphisms. Prediction of the 10-year first CAD events was assessed using hazard ratios (HRs) and measures of model discrimination, calibration, and net reclassification improvement (NRI). Hard CAD (nonfatal I21–I23 and fatal I20–I25) and soft CAD (all fatal or nonfatal I20–I25) were analyzed separately.

Results:

In the testing set, 1214 hard and 7201 soft CAD cases were documented during a mean follow-up of 11.2 years. The HR per standard deviation of the optimal PRS was 1.26 (95% CI:1.19–1.33) for hard CAD. Based on a traditional CAD risk prediction model containing only non-laboratory-based information, the addition of PRS for hard CAD increased Harrell's C index by 0.001 (–0.001 to 0.003) in women and 0.003 (0.001 to 0.005) in men. Among the different high-risk thresholds ranging from 1% to 10%, the highest categorical NRI was 3.2% (95% CI: 0.4–6.0%) at a high-risk threshold of 10.0% in women. The association of the PRS with soft CAD was much weaker than with hard CAD, leading to minimal or no improvement in the soft CAD model.

Conclusions:

In this Chinese population sample, the current PRSs minimally changed risk discrimination and offered little to no improvement in risk stratification for soft CAD. Therefore, this may not be suitable for promoting genetic screening in the general Chinese population to improve CAD risk prediction.
Interaction between mucus layer and gut microbiota in non-alcoholic fatty liver disease: Soil and seeds
Authors: Zhang Binbin , Li Jie , Fu Jinlong , Shao Li , Yang Luping , Shi Junping
Published: May 2023

The intestinal mucus layer is a barrier that separates intestinal contents and epithelial cells, as well as acts as the "mucus layer-soil" for intestinal flora adhesion and colonization. Its structural and functional integrity is crucial to human health. Intestinal mucus is regulated by factors such as diet, living habits, hormones, neurotransmitters, cytokines, and intestinal flora. The mucus layer's thickness, viscosity, porosity, growth rate, and glycosylation status affect the structure of the gut flora colonized on it. The interaction between "mucus layer-soil" and "gut bacteria-seed" is an important factor leading to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Probiotics, prebiotics, fecal microbiota transplantation (FMT), and wash microbial transplantation are efficient methods for managing NAFLD, but their long-term efficacy is poor. FMT is focused on achieving the goal of treating diseases by enhancing the "gut bacteria-seed". However, a lack of effective repair and management of the "mucus layer-soil" may be a reason why "seeds" cannot be well colonized and grow in the host gut, as the thinning and destruction of the "mucus layer-soil" is an early symptom of NAFLD. This review summarizes the existing correlation between intestinal mucus and gut microbiota, as well as the pathogenesis of NAFLD, and proposes a new perspective that "mucus layer-soil" restoration combined with "gut bacteria-seed" FMT may be one of the most effective future strategies for enhancing the long-term efficacy of NAFLD treatment.
Single Center Experience With Durable Continuous Flow Single Ventricle Assist Device: A Viable Option in Fontan Circulatory Failure
Authors: Fahnhorst Sarah E. , Brandewie Katie , Perry Tanya , Opotowsky Alexander R. , Lubert Adam M. , Lorts Angela , Morales David L. S. , Villa Chet R.
Published: May 2023

Ventricular assist devices are increasingly used for patients with single ventricle physiology. We describe the use of durable, continuous flow, single ventricular assist device (SVAD) therapy in Fontan circulatory failure patients. Retrospective, single-center review of patients with Fontan circulation implanted with a SVAD between 2017 and 2022. Patient characteristics and outcomes were obtained by chart review. Nine patients underwent SVAD implantation (median age 24 years). Most patients had a total cavopulmonary connection; one had an atriopulmonary Fontan. Five patients had a systemic right ventricle. SVAD was most often utilized as bridge to candidacy (67%). Eight patients had at least moderate systemic ventricular systolic dysfunction. SVAD support continued for a median of 65 days (longest duration, 1,105 days) and one patient remains on support at time of submission. Of five patients discharged home, median length of stay after SVAD was 24 days. Six patients were transplanted (median 96 days from SVAD). Two patients died from pretransplant multisystem organ failure before transplant. All transplanted patients remain alive (median time since transplant 593 days). Continuous flow SVAD therapy can be effective for patients with Fontan circulatory failure and systolic dysfunction. Further studies should investigate feasibility and optimal SVAD timing with more advanced Fontan associated end-organ dysfunction.
Human leukocyte antigen-DRB1 gene polymorphism and aplastic anemia: A meta-analysis
Authors: Liang Lijie , Li Ning , Wang Yaomei , Luo Suxia , Song Yongping , Fang Baijun
Published: May 2023

Background:

The human leukocyte antigen-DRB1 (HLA-DRB1) gene plays key roles in mediating immune response and activating autoreactive T-cells during aplastic anemia (AA) etiology. However, inconsistency appeared in the associations between HLA-DRB1 polymorphism and AA. We aimed to comprehensively clarify their associations in the meta-analysis.

Methods:

PubMed, Embase, Web of Science, Science Direct, SinoMed, WanFang Data, China National Knowledge Infrastructure, and Chongqing VIP Chinese Science Database were searched from January 2000 to June 2022. Statistical analysis was performed in STATA 15.0 and Comprehensive Meta-analysis Software 3.0.

Results:

A total of 16 studies with 4428 patients were eventually analyzed. The results of the meta-analysis suggested that HLA-DRB1*0301 could decrease the risk of AA (odd ratio (OR) = 0.600, 95% CI: 0.427, 0.843). Besides, HLA-DRB1*0901 and HLA-DRB1*1501 were risk factors of AA (OR = 1.591, 95% CI: 1.045, 2.424; OR = 2.145, 95% CI: 1.501, 3.063; respectively). Sensitivity analysis showed heterogeneity among included studies.

Conclusion:

HLA-DRB1 polymorphisms could play roles in the occurrence of AA, however more population-based studies with larger sample sizes are required to certify our findings.
A network pharmacology-based investigation of emodin against pancreatic adenocarcinoma
Authors: Shi Xueying , Huang Bingqian , Zhu Jingyi , Yamaguchi Takuji , Hu Ailing , Tabuchi Masahiro , Watanabe Daisuke , Yoshikawa Seiichiro , Mizushima Shinobu , Mizushima Akio , Xia Shilin
Published: May 2023

Pancreatic adenocarcinoma (PAAD) is one of the most common malignancies worldwide with an increasing incidence and poor outcome due to the lack of effective diagnostic and treatment methods. Emerging evidence implicates that emodin displays extensive spectrum anticancer properties. Differential expression genes in PAAD patients were analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) website, and the targets of emodin were obtained via Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Subsequently, enrichment analyses were performed using R software. A protein–protein interaction (PPI) network was constructed by STRING database and Cytoscape software was used to identify the hub genes. Prognostic value and immune infiltration landscapes were explored through Kaplan–Meier plotter (KM plotter) website and the Single-Sample Gene Set Enrichment Analysis package of R. Finally, molecular docking was used to computationally verify the interaction of ligand and receptor proteins. A total of 9191 genes were significantly differentially expressed in PAAD patients and 34 potential targets of emodin were obtained. Intersections of the 2 groups were considered as potential targets of emodin against PAAD. Functional enrichment analyses illustrated that these potential targets were linked to numerous pathological processes. Hub genes identified through PPI networks were correlated with poor prognosis and infiltration level of different immune cells in PAAD patients. Perhaps emodin interacted with the key molecules and regulate the activity of them. We revealed the inherent mechanism of emodin against PAAD with the aid of network pharmacology, which provided reliable evidence and a novel guideline for clinical treatment.
Comparison of prophylactic effects for chemotherapy induced neutropenia between same-day versus next-day administration of pegteograstim (Neurapeg®) in patients treated with chemotherapy regimen composed of day 1 intensive myleosuppressive agent: A randomized phase III clinical trial
Authors: Park Kwonoh , Jeon Young-Kyung , Kim Jung Hoon , Choi Younak , Kim Jae-Joon , Oh Sang-Bo , Oh So Yeon , Hong Yun Jeong , Huh Seok Jae , Kim Ilhwan , Shin Seong Hoon
Published: May 2023

Background and purpose:

Administration of pegylated granulocyte-colony-stimulating factor (peg-GCSF) 24 to 72 hours after chemotherapy is usually recommended. Next-day administration (after 24 hours) resulted in fewer duration of grade (Gr) 4 chemotherapy-induced neutropenia (CIN) and decreased severity of CIN than same-day (within 4 hours). However, patients sometimes receive same-day Peg-GCSF for the sake of convenience. In addition, a few prior studies showed that the same-day method is comparable or superior to the next-day method in preventing CIN, especially in chemotherapy regimens that include day 1 myelosuppressive agents. Thus, we aim to verify the hypothesis that same-day administration of pegteograstim, a new formulation of peg-GCSF, is non-inferior to next-day administration in terms of Gr4 CIN duration.

Methods:

This study is a randomized, multicenter, open-label, investigator-initiated phase 3 study. Patients with adjuvant/neoadjuvant or first-line palliative chemotherapy comprising intensively myelosuppressive agents on day 1 (mFOLFIRINOX, ECb, EP, FOLFIRI, and FOLFOX) are enrolled. The patients are assigned to the same-day arm or the next-day arm in a 1:1 ratio. The randomizations are stratified according to number of patient CIN risk factors (1 vs ≥2), chemotherapy setting (perioperative vs palliative), and interval (2-week vs 3-week). In the same-day arm, pegteograstim 6 mg is subcutaneously injected within 4 hours after completion of chemotherapy. In the next-day arm, pegetograstim is injected at 24 to 36 hours post-chemotherapy. A complete blood count test is performed daily from day 5 to 9 during the cycle 1. The primary endpoint is duration of Gr4 CIN (cycle 1), and secondary endpoints include incidence of Gr 3 to 4 CIN (cycle 1), severity of CIN (cycle 1), time to recovery absolute neutrophil count 1000/μL (cycle 1), incidence of febrile neutropenia, incidence of CIN-related dose delay, and dose intensity. In order to verify non-inferiority of 0.6 days, we estimated a significance level of 5%, power of 80%, and drop-out rate of 15%. This results in the need for a total of 160 patients, 80 in each group.
Value of applying interactive micro-courses on occupational protection in operating room for nursing trainees
Authors: Wang Cai-Xing , Wu Chao
Published: May 2023

This study aimed to investigate the application value of an interactive micro class on occupational protection in the operating room for nursing interns. Using a cluster sampling approach, 200 junior college nursing interns were selected as participants at our hospital, who were practicing from June 2020 to April 2021. They were randomly assigned to either the observation group or the control group, with 100 participants in each. Data on teaching-related evaluation indicators, including clarity of teaching objectives, learning atmosphere, rational use of learning resources, effectiveness of teaching process regulation, and degree of students’ participation in activities, were collected for both groups. Additionally, the scores of occupational protection assessment in the operating room, which encompassed physical, chemical, biological, environmental, and physiological and psychological factors, were also recorded. The comparative analysis of teaching-related evaluation indicators between the 2 groups revealed statistically significant differences. Specifically, significant differences were found between the 2 groups in the clarity of teaching objectives (P = .007), learning atmosphere (P < .001), rational use of learning resources (P < .001), effectiveness of teaching process regulation (P = .01), and degree of students’ participation in activities (P < .001). Furthermore, the scores of all items in the observation group were higher than those in the control group. Additionally, the comparison results of the scores of the occupational protection assessment in the operating room between the 2 groups showed that while there was no statistically significant difference between the 2 groups before the intervention (P > .05). However, after the intervention, statistically significant differences were found between the 2 groups in physical (P < .001), chemical (P = .001), biological (P < .001), environmental (P < .001), and physiological and psychological factors (P < .001). Additionally, the scores of all items in the observation group were higher than those in the control group. The implementation of the interactive micro class enhanced the quality of teaching related to occupational protection in the operating room for interning nurses, thus verifying its benefits in clinical teaching practices.
Changes of intestinal flora in children with febrile seizure
Authors: Yang Lin , Tian Jianmei
Published: May 2023

Febrile seizure (FS) is a highly recurrent neuro-system disorder in children that affects their nervous system development and quality of life. However, the pathogenesis of febrile seizures remains unclear. Our study aims to investigate the potential differences in the intestinal flora and metabolomics between healthy children and those with FS. By examining the relationship between specific flora and different metabolites, we hope to shed light on the pathogenesis of FS. Fecal specimens were collected from healthy children (n = 15) and children with febrile seizures (n = 15), and 16S rDNA sequencing was conducted to characterize intestinal flora. Subsequently, fecal samples from healthy (n = 6) and febrile seizure children (n = 6) were used to characterize metabolomics using linear discriminant analysis of effect size, orthogonal partial least squares discriminant analysis, Kyoto Encyclopedia of Genes and Genomes (pathway enrichment analysis), and Kyoto encyclopedia of genes and genomes topology analysis. Liquid chromatography-mass spectrometry was used to identify metabolites in the fecal samples. The intestinal microbiome in the febrile seizure children significantly differed from that in the healthy children at the phylum level. Ten differentially accumulated metabolites (xanthosine, (S)-abscisic acid, N-palmitoylglycine, (+/−)-2-(5-methyl-5-vinyl-tetrahydrofuran-2-yl) propionaldehyde, (R)-3-hydroxybutyrylcarnitine, lauroylcarnitine, oleoylethanolamide, tetradecyl carnitine, taurine, and lysoPC [18:1 (9z)/0:0] were considered the potential febrile seizure markers. Three metabolic pathways (taurine metabolism; glycine, serine, and threonine metabolism; and arginine biosynthesis) were found essential in febrile seizure. Bacteroides were significantly correlated with the 4 differential metabolites. Adjusting the balance of intestinal flora may be an effective method for preventing and treating febrile seizures.
Decreasing expression of HIF-1α, VEGF-A, and Ki67 with efficacy of neoadjuvant therapy in locally advanced cervical cancer
Authors: Zhao Ke , Hu Min , Yang Runfeng , Liu Jing , Zeng Pingfan , Zhao Tingkuan
Published: May 2023

Background:

Neoadjuvant chemotherapy (NACT) before radical hysterectomy has been widely used for locally advanced cervical cancer (LACC); However, its efficacy is yet to be determined.

Methods:

Effective and predictive biomarkers, which may aid in predicting the chemotherapy responses, were explored in this study. Initially, the expression of HIF-1α, VEGF-A, and Ki67 was detected in 42 paired (pre-NACT and post-NACT) LACC tissues, as well as 40 nonneoplastic cervical epithelial tissues by immunohistochemistry. Then, the correlation of the expression of HIF-1α, VEGF-A, Ki67 with the efficacy of NACT, as well as factors that affect the efficacy of NACT was analyzed.

Results:

A clinical response occurred in 66.7% (28/42) of the patients, including 57.1% (16/28) with a complete response and 42.9% (12/28) with a partial response; While 33.33% (14/42) were non-responders, including 42.9% (6/14) with stable disease and 57.1% (8/14) with progressive disease. HIF-1α, VEGF-A, and Ki67 were overexpressed in LACC tissues compared to nonneoplastic tissues (P < .01, respectively); While the expression of HIF-1α, VEGF-A, and Ki67 was significantly decreased after NACT (P < .01, respectively). What’s more, in the response group, HIF-1α, VEGF-A, and Ki67 expression were significantly decreased after chemotherapy in the post-chemotherapy cervical cancer tissues compared with the pre-chemotherapy cervical cancer tissues (all P < .05). Additionally, patients with lower histological grade and lower expression of HIF-1α, VEGF-A, and Ki67 were more responsive to NACT (P < .05, respectively); Moreover, the histological grade [P = .025, HR (95% CI): 0.133 (0.023–0.777)], HIF-1α [P = .019, HR (95% CI): 0.599 (0.390–0.918)], and Ki67 [P = .036, HR (95% CI): 0.946 (0898–0.996)] were independent risk factors affecting the efficacy of NACT in LACC.

Conclusion:

Expression of HIF-1α, VEGF-A, and Ki67 were significantly decreased after NACT, and decreasing expression of HIF-1α, VEGF-A, and Ki67 were related to good response to NACT, suggesting HIF-1α, VEGF-A, and Ki67 may be implicated in evaluating the efficacy of NACT in LACC.
Comparisons of gene expression between peripheral blood mononuclear cells and bone tissue in osteoporosis
Authors: Xie Lihua , Feng Eryou , Li Shengqiang , Chai Hao , Chen Juan , Li Li , Ge Jirong
Published: May 2023

Osteoporosis (OP) is one of the major public health problems in the world. However, the biomarkers between the peripheral blood mononuclear cells (PBMs) and bone tissue for prognosis of OP have not been well characterized. This study aimed to explore the similarities and differences of the gene expression profiles between the PBMs and bone tissue and identify potential genes, transcription factors (TFs) and hub proteins involved in OP. The patients were enrolled as an experimental group, and healthy subjects served as normal controls. Human whole-genome expression chips were used to analyze gene expression profiles from PBMs and bone tissue. And the differentially expressed genes (DEGs) were subsequently studied using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. The above DEGs were constructed into protein-protein interaction network. Finally, TF-DEGs regulation networks were constructed. Microarray analysis revealed that 226 DEGs were identified between OP and normal controls in the PBMs, while 2295 DEGs were identified in the bone tissue. And 13 common DEGs were obtained by comparing the 2 tissues. The Gene Ontology analysis indicated that DEGs in the PBMs were more involved in immune response, while DEGs in bone were more involved in renal response and urea transmembrane transport. And the Kyoto Encyclopedia of Genes and Genomes analysis indicated almost all of the pathways in the PBMs were overlapped with those in the bone tissue. Furthermore, protein-protein interaction network presented 6 hub proteins: PI3K1, APP, GNB5, FPR2, GNG13, and PLCG1. APP has been found to be associated with OP. Finally, 5 key TFs were identified by TF-DEGs regulation networks analysis (CREB1, RUNX1, STAT3, CREBBP, and GLI1) and were supposed to be associated with OP. This study enhanced our understanding of the pathogenesis of OP. PI3K1, GNB5, FPR2, GNG13, and PLCG1 might be the potential targets of OP.
Erectile dysfunction after acetabular fracture
Authors: Elliott Iain S. , Kleweno Conor , Agel Julie , Coale Max , Patterson Joseph T. , Firoozabadi Reza , Githens Michael , Johnsen Niels V.
Published: May 2023

Objectives:

To determine the rate of erectile dysfunction in male patients who have sustained an acetabular fracture with no previously identified urogenital injury.

Design:

Cross-sectional survey.

Setting:

Level 1 Trauma Center.

Patients/Participants:

All male patients treated for acetabular fracture without urogenital injury.

Intervention:

The International Index of Erectile Function (IIEF), a validated patient-reported outcome measure for male sexual function, was administered to all patients.

Main Outcome Measurements:

Patients were asked to complete the International Index of Erectile Function score for both preinjury and current sexual function, and the erectile function (EF) domain was used to quantify the degree of erectile dysfunction. Fractures were classified according the OTA/AO classification schema, fracture classification, injury severity score, race, and treatment details, including surgical approach were collected from the database.

Results:

Ninety-two men with acetabular fractures without previously diagnosed urogenital injury responded to the survey at a minimum of 12 months and an average of 43 ± 21 months postinjury. The mean age was 53 ± 15 years. 39.8% of patients developed moderate-to-severe erectile dysfunction after injury. The mean EF domain score decreased 5.02 ± 1.73 points, which is greater than the minimum clinically important difference of 4. Increased injury severity score and associated fracture pattern were predictive of decreased EF score.

Conclusion:

Patients with acetabular fractures have an increased rate of erectile dysfunction at intermediate-term follow-up. The orthopaedic trauma surgeon treating these injuries should be aware of this as a potential associated injury, ask their patients about their function, and make appropriate referrals.

Level of Evidence:

III.
Pharmacogenomic panel testing provides insight and enhances medication management in persons living with HIV
Authors: Zeuli John D. , Rivera Christina G. , Wright Jessica A. , Kasten Mary J. , Mahmood Maryam , Ragan Ashley K. , Rizza Stacey A. , Temesgen Zelalem M. , Vergidis Paschalis , Wilson John W. , Cummins Nathan W.
Published: May 2023

Objective:

Our study aimed to assess the impact of pharmacogenomic panel testing in persons living with HIV (PWH).

Design:

Prospective, observational intervention assessment

Methods:

One hundred PWH were provided a comprehensive pharmacogenomic panel during routine care visits within the HIV specialty clinic of a large academic medical center. The panel determined the presence of specific genetic variants that could predict response or toxicity to commonly prescribed antiretroviral therapy (ART) and non-ART medications. An HIV specialty pharmacist reviewed the results with participants and the care team. The pharmacist (1) recommended clinically actionable interventions based on the participants current drug therapy, (2) assessed for genetic explanations for prior medication failures, adverse effects, or intolerances, and (3) advised on potential future clinically actionable care interventions based on individual genetic phenotypes.

Results:

Ninety-six participants (median age 53y, 74% white, 84% male, 89% viral load <50 copies/ml) completed panel testing yielding 682 clinically relevant pharmacogenomic results (133 major, 549 mild-moderate). Ninety participants (89 on ART) completed follow-up visits with 65 (72%) receiving clinical recommendations based on current medication profiles. Of the 105 clinical recommendations, 70% advised additional monitoring for efficacy or toxicity, and 10% advised alteration of drug therapy. Panel results offered explanation for prior ART inefficacy in 1 participant and ART intolerance in 29%. Genetic explanation for non-ART toxicity was seen in 21% of participants, with genetic contributors to inefficacy of non-ART therapy identified in 39% of participants.

Conclusions:

Preliminary data in a small cohort of PWH demonstrates benefit of routine pharmacogenomic panel testing.
Physicochemical characteristics of new breed white Hypsizygus marmoreus for cold storage after harvest
Authors: Park Jae-Seok , Park Hye-Jin , Kim Jong-Seok , Jeong Da-Eun , Han Chae-Won , Lee Seung-Yeol , Jung Hee-Young , Cho Young-Je
Published: May 2023

Fresh mushrooms are vulnerable to browning and tissue changes after harvest. This study monitored the external appearance, physicochemical quality indicators, and nutritional and functional components of a white beech mushroom (Hypsizygus marmoreus) variety (EG2020) newly developed in Korea during cold storage for up to 42 days. Two existing varieties of white H. marmoreus, namely H6 from Korea and HKT from Japan, were used for comparison. The mechanical texture of EG2020 was superior to H6 and HKT due to the increasing hardness of the pileus with time. Browning, in terms of the total color difference during storage, was found to be the most severe in HKT. In terms of composition, EG2020 had the highest total free sugar content, a large amount of organic acids, and higher sugar content than H6 and HKT. EG2020 also contained the largest amount of β-glucan, and its amount increased during storage. In sensory evaluation, EG2020 received higher scores than HKT in flavor, taste, appearance, and texture. Therefore, the EG2020 variety is more stable than HKT during storage and distribution.
Striking allelic diversity despite structural homogeneity oface-1duplications inAnophelesmosquitoes
Authors: Claret Jean-Loup , Di-Liegro Marion , Namias Alice , Assogba Benoit , Makoundou Patrick , Koffi Alphonsine , Pennetier Cédric , Weill Mylène , Milesi Pascal , Labbé Pierrick
Published: May 2023

A. gambiae s.l.has been the target of intense insecticide treatment since the mid-XXth century to try and control malaria, and a substitution in theace-1locus allowing resistance to organophosphate and carbamates insecticides has been rapidly selected for. Since then, several duplications of the ace-1 locus have been found in A. gambiae s.l. populations. They associate either several resistance copies (homogeneous duplications) or both resistance and susceptible copies (heterogeneous duplications). Heterogeneous duplications confer an intermediate trade-off between resistance in presence of insecticide and disadvantage in their absence. So far, and in striking contrast withC. pipiensmosquitoes, a single heterogeneous duplication had been describe in A. gambiae populations. We use an innovative approach, combining information from long and short read sequencing with Sanger sequencing to precisely identify and describe at least nine different heterogeneous duplications in A. gambiae. We further show that these alleles share the exact same structure than the previously identified heterogeneous and homogeneous duplications, namely 203-kb tandem amplifications with conserved breakpoints. Our study sheds a new light on the origin and maintenance of these alleles in A. gambiae populations, and pushes one step further the striking evolutionary convergence withC. pipiensmosquitoes.
Lipids of different phytoplankton groups differ in sensitivity to degradation: implications for carbon export
Authors: Godrijan Jelena , Pfannkuchen Daniela Marić , Djakovac Tamara , Frka Sanja , Gašparović Blaženka
Published: May 2023

The future of life on Earth depends on how the ocean might change, as it plays an important role in mitigating the effects of global warming. The main role is played by phytoplankton. Not only are phytoplankton the base of the oceans’ food web, but they also play an important role in the biological carbon pump (BCP), the process of forming organic matter (OM) and transporting it to the deep sea, representing a sink of atmospheric CO2. Lipids are considered important vectors for carbon sequestration. A change in the phytoplankton community composition as a result of ocean warming is expected to affect the BCP. Many predictions indicate a dominance of small at the expense of large phytoplankton. To gain insight into interplay between the phytoplankton community structure, lipid production and degradation and adverse environmental conditions, we analyzed phytoplankton composition, POC and its lipid fraction in the northern Adriatic over a period from winter to summer at seven stations with a gradient of trophic conditions. We found that at high salinity and low nutrient content, where nanophytoplankton prevailed over diatoms, the newly fixed carbon is substantially directed toward the synthesis of lipids. Lipids produced by nanophytoplankton, coccolithophores and phytoflagellates, are more resistant to degradation than those produced by diatoms. This suggests a more successful lipid carbon sink of nanophytoplankton and thus a negative feedback on global warming. The difference in lipid degradability is discussed as a difference in the size of the cell phycosphere. We hypothesize that the lipids of nanophytoplankton are less degradable due to the small phycosphere with a poorer bacterial community and consequently a lower lipid degradation rate compared to diatoms. The chemical composition of the lipids of the different phytoplankton groups could have a different susceptibility to degradation, which could also contribute to the differences in lipid degradability.
High Resolution Acoustic Mapping of Gelatin-Based Soft Tissue Phantoms
Authors: Badawe Heba M. , Raad Petra , Khraiche Massoud L.
Published: May 2023

Background

Utilizing spatially and temporally uniform tissue-mimicking phantoms for ultrasonic applications can facilitate the characterization of beam distortion and attenuation. The implementation of acoustic phantoms can enhance the efficacy of ultrasound therapy or imaging by providing guidance on optimal ultrasonic parameters, such as frequency and power. The efficacy of phantoms is heavily dependent on the accuracy and reliability of measurement techniques employed for assessing their acoustic properties.

Purpose

The work aims to develop, build, and characterize, via high resolution acoustic mapping, Gelatin-Based ultrasound (US) soft tissue phantoms. To that effect, we built acoustic maps of the intensity distribution of US waves passing through the phantoms and studied the effect of gelatin concentrations and US frequency, duty cycle, and applied voltage on the acoustic intensity and focal region of the US waves. The methodology developed here offers well characterized and reproducible Gelatin-Based US phantoms for soft tissue (both acoustically and mechanically).

Methods

We developed gelatin-based phantoms, with conveniently adjustable parameters and measured, with high resolution, the acoustic attenuation of ultrasound waves when encountering the gelatin phantoms. This was done via a motorized acoustic system built for 3D-acoustic mapping of ultrasound waves. Mechanical assessment of the phantoms’ elasticity was carried out through unconfined compression tests. We characterized tissue mimicking phantoms with realistic acoustic properties and mechanical elasticity, emphasizing the effect of varying gelatin concentration on the ultrasound maximal intensity, thus causing acoustic attenuation throughout the acoustic profile. For validation, we used computational simulations to compare our data to predicted acoustical outcomes.

Results

Our results show high-resolution mapping of US waves in fluid with and without Gelatin-Based phantoms. We also confirm the impact of recipe and gelatin concentration on mechanical and acoustic characterization of phantoms. The density of the gelatin-based phantoms scales with the Young’s modulus. When characterizing the acoustic profiles of the different ultrasound transducers, the focal areas increased systematically as a function of increasing applied voltage and duty cycle yet decreased as a function of increased ultrasonic frequency.

Conclusions

We developed a Gelatin-Based US phantoms are a reliable and reproduce tool for examining the acoustic attenuations taking place as a function of increased tissue elasticity and stiffness. High resolution acoustic maps of the intensity distribution of US can provide essential information on the spatial changes in US wave intensity and focal point enabling a more in-depth examination of the effect of tissue on US waves.
Comparison of spontaneous recurrent seizures in rats following status epilepticus induced by organophosphate paraoxon, DFP, and sarin
Authors: Blair Robert E. , Hawkins Elisa , Lauren R. Pinchbeck , DeLorenzo Robert J. , Deshpande Laxmikant S.
Published: May 2023

Organophosphate (OP) compounds are highly toxic and include household, industrial, agricultural, and chemical warfare nerve agents (CWNA). OP exposure inhibits acetylcholinesterase enzyme, causing cholinergic overstimulation that can evolve into status epilepticus (SE) and produce lethality. Furthermore, OP-SE survival is associated with mood and memory dysfunction and spontaneous recurrent seizures (SRS). Here we assessed hippocampal pathology and chronic SRS following SE induced by OP agents in rats. Male Sprague-Dawley rats were injected with 1.5x LD50of various OP agents, followed by atropine and 2-PAM. At 1-h post-OP-SE onset, midazolam was administered to control SE. Approximately 6 months following OP-SE, SRS were evaluated using continuous video-EEG monitoring. Histopathology was conducted using Hematoxylin and Eosin (H&E), while silver sulfide (Timm) staining was utilized to assess Mossy Fiber Sprouting (MFS). Over 60% of OP-SE surviving rats developed SRS with varying seizure frequencies, durations, and Racine severity scores. H&E staining revealed a significant hippocampal neuronal loss, while Timm staining revealed extensive MFS within the inner molecular region of the dentate gyrus of SRS-expressing OP-SE rats. This study demonstrates that OP-SE is associated with hippocampal neuronal loss, extensive MFS, and SRS, all hallmarks of chronic epilepsy.
Advancing multi-day ex vivo kidney perfusion using spatially resolved metabolomics
Authors: de Haan Marlon J.A. , Witjas Franca M.R. , de Graaf Annemarie M.A. , Jacobs Marleen E. , Sánchez-López Elena , Kostidis Sarantos , Giera Martin , Maanaoui Mehdi , Hubert Thomas , Kerr-Conte Julie , Pattou François , de Vries Dorottya K. , Kers Jesper , Alwayn Ian P.J. , van Kooten Cees , Heijs Bram P.A.M. , Wang Gangqi , Engelse Marten A. , Rabelink Ton J.
Published: May 2023

The ability to preserve metabolically active kidneys ex vivo for multiple days may permit reconditioning, repair and regeneration of deceased donor kidneys. However, the kidneys high metabolic demand limits its functional preservation. Current approaches focus on normothermic machine perfusion (NMP) at 37°C or hypothermic machine perfusion (HMP) at 4-8°C. At normothermia, kidneys are metabolically active butex vivopreservation is limited to hours. During hypothermia kidneys can be preserved up to 24 hours but are metabolically inactive and suffer cold-induced injury. Therefore, we revisited sub normothermic perfusion (at 25°C) as an alternative approach to preserve human kidneys in a metabolically active state for extended periods of time.

In a custom-made platform that includes a cell-free perfusate enriched with TCA cycle fuels, urine recirculation, and continuous hemofiltration we perfused discarded human kidneys up to 8 days. Using spatially resolved single cell resolution isotope tracing we demonstrate active metabolism in all the different renal cell types over this period. However, beyond 4 days cell composition of nephron segments assessed with spatial lipidomics changed substantially and injury markers such as NGAL and LDH increased in the perfusate. Up to 4 days, perfused human discarded donor kidneys maintained metabolic fluxes, functional parameters and allow for reperfusion using a porcine auto transplantation model. These data underpin that extended multi-day metabolic preservation of human kidneys is achievable using a sub normothermic perfusion platform.
Chromatin and Gene Regulatory Dynamics of Optic Nerve Invasion in Retinoblastoma at Single-Cell Resolution
Authors: Zhao Yihan , Liu Peng , Hu Lei , Ke Mingxi , Min Nan , Zeng Zehua , Du Hongwu
Published: May 2023

Retinoblastoma is a rare and aggressive form of eye cancer that arises from the retina’s photoreceptor precursor cells. Yet, the mechanism of cancer evolution in optic invasion and the identification of molecularly defined tumor-propagating cells has not been reported. Using single-cell RNA and ATAC sequencing, we uncovered a propagating cell named STER after invasion of the optic nerve. We also report on the dynamic processes of photoreceptor degeneration and optic nerve injury in the retina and identify potential regulatory elements and transcription factors involved. STER cells mediate optic nerve destruction and retinal degeneration during the proliferation and migration of retinoblastoma. Finally, we develop drug sensitivity testing algorithms for malignant clusters, providing potential therapeutic targets and drug predictions for retinoblastoma invasion.
Development of genomic markers associated to production traits in lumpfish (Cyclopterus lumpus)
Authors: Gutierrez Alejandro P. , Selly Sarah-Louise Counter , Taggart John B. , Kokkinias Panagiotis , Cavrois-Rogacki Thomas , Fernandez Eduardo Jimenez , Migaud Herve , Lein Ingrid , Davie Andrew , Bekaert Michaël
Published: May 2023

Cleaner fish species have gained great importance in the control of sea lice, among them, lumpfish (Cyclopterus lumpus) has become one of the most popular. Lumpfish life cycle has been closed, and hatchery reproduction is now possible, however, current production is reliant on wild caught broodstock to meet the increasing demand. Selective breeding practices are called to play an important role in the successful breeding of most aquaculture species, including lumpfish.

In this study we analysed a lumpfish population for the identification of genomic markers linked to production traits. Sequencing of RAD libraries allowed us to identify, 7,193 informative markers within the sampled individuals. Genome wide association analysis for sex, weight, condition factor and standard length was performed. One single major QTL region was identified for sex determination, while nine QTL regions were detected for weight, and three QTL regions for standard length.

A total of 177 SNP markers of interest (from QTL regions) and 399 top FstSNP markers were combined in a low-density panel, useful to obtain relevant genetic information from lumpfish populations. Moreover, a robust combined subset of 29 SNP markers (10 associated to sex, 14 to weight and 18 to standard length) provided over 90% accuracy in predicting the animal’s phenotype. Overall, our findings provide significant insights into the genetic control of important traits in lumpfish and deliver important genomic resources that will facilitate the establishment of selective breeding programs in lumpfish.
Biomechanics of cutting: sharpness, wear sensitivity, and the scaling of cutting forces in leaf-cutter ant mandibles
Authors: Püffel Frederik , Walthaus O. K. , Kang Victor , Labonte David
Published: May 2023

Herbivores large and small need to mechanically process plant tissue. Their ability to do so is determined by two forces: the maximum force they can generate, and the minimum force required to fracture the plant tissue. The ratio of these forces determines the required relative mechanical effort; how this ratio varies with animal size is challenging to predict. We measured the forces required to cut thin polymer sheets with mandibles from leaf-cutter ant workers which vary by more than one order of magnitude in body mass. Cutting forces were independent of mandible size, but differed by a factor of two between pristine and worn mandibles. Mandibular wear is thus likely a more important determinant of cutting force than mandible size. We rationalise this finding with a biomechanical analysis which suggests that pristine mandibles are ideally ‘sharp’ – cutting forces are close to a theoretical minimum, which is independent of tool size and shape, and instead solely depends on the geometric and mechanical properties of the cut tissue. The increase of cutting force due to mandibular wear may be particularly problematic for small ants, which generate lower absolute bite forces, and thus require a larger fraction of their maximum bite force to cut the same plant.
Analysis of the heterogeneity and complexity of murine extraorbital lacrimal gland via single-cell RNA sequencing
Authors: Zou Sen , Jiao Xinwei , Huang Shenzhen , Liu Jiangman , Si Hongli , Qi Di , Pei Xiaoting , Lu Dingli , Wang Yimian , Li Zhijie
Published: May 2023

Purpose

The lacrimal gland is essential for maintaining ocular surface health and avoiding external damage by secreting the aqueous layer of the tear film. However, a healthy lacrimal gland’s inventory of cell types and heterogeneity remains understudied.

Methods

Here, 10X genome-based single-cell RNA sequencing was used to generate an unbiased classification of cellular diversity in the extraorbital lacrimal gland (ELG) of C57BL/6J mice. From 48,077 high-quality cells, an atlas of cell heterogeneity was produced, and cell types were defined by classic marker genes. The possible functions of these cells and the pseudotime trajectories for certain cell populations were analyzed through bioinformatics. In addition, a preliminary analysis of the cell-cell communication network in ELG was performed.

Results

Over 41 subclasses of cells were identified, including 9 kinds of glandular epithelial cells, 7 kinds of fibroblasts, 10 kinds of myeloid-derived immune cells, at least 10 kinds of lymphoid-derived immune cells, 3 kinds of vascular-associated cell subsets, and 2 kinds of Schwann cells. Analysis of cell–cell communication networks revealed that innate lymphoid cells were closely associated with other cells.

Conclusions

This study provides the first comprehensive transcriptome atlas and related database of mouse ELG. This resource can aid in a deeper understanding of lacrimal gland biology and pathophysiology of its related diseases.
EASTR: Correcting systematic alignment errors in multi-exon genes
Authors: Shinder Ida , Hu Richard , Ji Hyun Joo , Chao Kuan-Hao , Pertea Mihaela
Published: May 2023

Accurate alignment of transcribed RNA to reference genomes is a critical step in the analysis of gene expression, which in turn has broad applications in biomedical research and in the basic sciences. We have discovered that widely used splice-aware aligners, such as STAR and HISAT2, can introduce erroneous spliced alignments between repeated sequences, leading to the inclusion of falsely spliced transcripts in RNA-seq experiments. In some cases, the “phantom” introns resulting from these errors have made their way into widely-used genome annotation databases. To address this issue, we have developed EASTR (Emending Alignments of Spliced Transcript Reads), a novel software tool that can detect and remove falsely spliced alignments or transcripts from alignment and annotation files. EASTR improves the accuracy of spliced alignments across diverse species, including human, maize, andArabidopsis thaliana, by detecting sequence similarity between intron-flanking regions. We demonstrate that applying EASTR before transcript assembly substantially reduces false positive introns, exons, and transcripts, improving the overall accuracy of assembled transcripts. Additionally, we show that EASTR’s application to reference annotation databases can detect and correct likely cases of mis-annotated transcripts.
Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis
Authors: Kohlmayr Johanna M. , Grabner Gernot F. , Nusser Anna , Höll Anna , Halwachs Bettina , Jany-Luig Evelyne , Engelke Hanna , Zimmermann Robert , Stelzl Ulrich
Published: May 2023

ATGL is the key enzyme in intracellular lipolysis playing a critical role in metabolic and cardiovascular diseases. ATGL is tightly regulated through a known set of protein-protein interaction partners with activating or inhibiting functions in control of lipolysis. However, the binding mode and protein interaction sites of ATGL and its partners are unknown. Using deep mutational protein interaction perturbation scanning we generated comprehensive profiles of single amino acid variants effecting the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL variants gave a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identified and characterized eleven, highly selective ATGL “switch” mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provided distinct interaction determinants for ATGL’s key regulatory proteins at an amino acid resolution. When tested for triglyceride hydrolase activityin vitroand lipolysis in cells, the activity patterns of the ATGL switch variants traced to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provided important insights into lipolysis regulation and the impact of mutations in human disease.