bluuebunny/crossref_metadata_2025 huggingface dataset:
PDR Transporter ABC1 Is Involved in the Innate Azole Resistance of the Human Fungal Pathogen Fusarium keratoplasticum
Authors: James Jasper Elvin , Lamping Erwin , Santhanam Jacinta , Cannon Richard David
Published: June 2021

Fusarium keratoplasticum is arguably the most common Fusarium solani species complex (FSSC) species associated with human infections. Invasive fusariosis is a life-threatening fungal infection that is difficult to treat with conventional azole antifungals. Azole drug resistance is often caused by the increased expression of pleiotropic drug resistance (PDR) ATP-binding cassette (ABC) transporters of the ABCG sub-family. Most investigations of Fusarium ABC transporters associated with azole antifungal drug resistance are limited to plant pathogens. Through the manual curation of the entire ABCG protein family of four FSSC species including the fully annotated genome of the plant pathogen Nectria haematococca we identified PDR transporters ABC1 and ABC2 as the efflux pump candidates most likely to be associated with the innate azole resistance phenotype of Fusarium keratoplasticum. An initial investigation of the transcriptional response of logarithmic phase F. keratoplasticum cells to 16 mg/L voriconazole confirmed strong upregulation (372-fold) of ABC1 while ABC2 mRNA levels were unaffected by voriconazole exposure over a 4 h time-period. Overexpression of F. keratoplasticum ABC1 and ABC2 in the genetically modified Saccharomyces cerevisiae host ADΔΔ caused up to ∼1,024-fold increased resistance to a number of xenobiotics, including azole antifungals. Although ABC1 and ABC2 were only moderately (20% and 10%, respectively) expressed compared to the Candida albicans multidrug efflux pump CDR1, overexpression of F. keratoplasticum ABC1 caused even higher resistance levels to certain xenobiotics (e.g., rhodamine 6G and nigericin) than CDR1. Our investigations suggest an important role for ABC1 orthologues in the innate azole resistance phenotype of FSSC species.
Molecular Mechanisms Influencing Bacterial Conjugation in the Intestinal Microbiota
Authors: Neil Kevin , Allard Nancy , Rodrigue Sébastien
Published: June 2021

Bacterial conjugation is a widespread and particularly efficient strategy to horizontally disseminate genes in microbial populations. With a rich and dense population of microorganisms, the intestinal microbiota is often considered a fertile environment for conjugative transfer and a major reservoir of antibiotic resistance genes. In this mini-review, we summarize recent findings suggesting that few conjugative plasmid families present inEnterobacteriaceaetransfer at high rates in the gut microbiota. We discuss the importance of mating pair stabilization as well as additional factors influencing DNA transfer efficiency and conjugative host range in this environment. Finally, we examine the potential repurposing of bacterial conjugation for microbiome editing.
Visualization of Respiratory Commensal Bacteria in Context of Their Natural Host Environment
Authors: Bonifacio Joao P. P. , Schmolke Mirco
Published: June 2021

Commensal microbes are an integral component of mammalian physiology. 16S rRNA gene-specific next generation sequencing from DNA of total organs, swabs or lavages has revolutionized the characterization of bacterial communities in virtually every ecological niche of the body. Culturomics, next allowed the isolation and characterization of commensal bacteria in the lab and the establishment of artificial communities of bacteria, which were eventually reintroduced in model organisms. Spatial organization of microbiota within a given host environment is critical to the physiological or pathological phenotypes provoked by commensal microbiota. In situ hybridization (ISH) is a complementary technique to sequencing and culturing to visualize the presence of individual bacterial operational taxonomic unit (OTUs) in context of the colonized organ. We recently applied highly sensitive in situ RNA hybridization to detection of commensal bacteria in low abundance respiratory tract samples of mice housed under specific pathogen free conditions. This technique allows species-specific detection of living bacteria using RNAScopeTM technology, while preserving the natural environment of the organ. We here provide a detailed step-by-step protocol describing the detection of commensal lung bacteria in respiratory tissue.
Stress Granule-Mediated Oxidized RNA Decay in P-Body: Hypothetical Role of ADAR1, Tudor-SN, and STAU1
Authors: Alluri Ravi Kumar , Li Zhongwei , McCrae Keith R.
Published: June 2021

Reactive oxygen species (ROS) generated under oxidative stress (OS) cause oxidative damage to RNA. Recent studies have suggested a role for oxidized RNA in several human disorders. Under the conditions of oxidative stress, mRNAs released from polysome dissociation accumulate and initiate stress granule (SG) assembly. SGs are highly enriched in mRNAs, containing inverted repeat (IR) Alus in 3′ UTRs, AU-rich elements, and RNA-binding proteins. SGs and processing bodies (P-bodies) transiently interact through a docking mechanism to allow the exchange of RNA species. However, the types of RNA species exchanged, and the mechanisms and outcomes of exchange are still unknown. Specialized RNA-binding proteins, including adenosine deaminase acting on RNA (ADAR1-p150), with an affinity toward inverted repeat Alus, and Tudor staphylococcal nuclease (Tudor-SN) are specifically recruited to SGs under OS along with an RNA transport protein, Staufen1 (STAU1), but their precise biochemical roles in SGs and SG/P-body docking are uncertain. Here, we critically review relevant literature and propose a hypothetical mechanism for the processing and decay of oxidized-RNA in SGs/P-bodies, as well as the role of ADAR1-p150, Tudor-SN, and STAU1.
Changes in Metabolic Activity and Gait Function by Dual-Task Cognitive Game-Based Treadmill System in Parkinson’s Disease: Protocol of a Randomized Controlled Trial
Authors: Szturm Tony , Kolesar Tiffany A. , Mahana Bhuvan , Goertzen Andrew L. , Hobson Douglas E. , Marotta Jonathan J. , Strafella Antonio P. , Ko Ji Hyun
Published: June 2021

Balance and gait impairments, and consequently, mobility restrictions and falls are common in Parkinson’s disease (PD). Various cognitive deficits are also common in PD and are associated with increased fall risk. These mobility and cognitive deficits are limiting factors in a person’s health, ability to perform activities of daily living, and overall quality of life. Community ambulation involves many dual-task (DT) conditions that require processing of several cognitive tasks while managing or reacting to sudden or unexpected balance challenges. DT training programs that can simultaneously target balance, gait, visuomotor, and cognitive functions are important to consider in rehabilitation and promotion of healthy active lives. In the proposed multi-center, randomized controlled trial (RCT), novel behavioral positron emission tomography (PET) brain imaging methods are used to evaluate the molecular basis and neural underpinnings of: (a) the decline of mobility function in PD, specifically, balance, gait, visuomotor, and cognitive function, and (b) the effects of an engaging, game-based DT treadmill walking program on mobility and cognitive functions. Both the interactive cognitive game tasks and treadmill walking require continuous visual attention, and share spatial processing functions, notably to minimize any balance disturbance or gait deviation/stumble. The ability to “walk and talk” normally includes activation of specific regions of the prefrontal cortex (PFC) and the basal ganglia (site of degeneration in PD). The PET imaging analysis and comparison with healthy age-matched controls will allow us to identify areas of abnormal, reduced activity levels, as well as areas of excessive activity (increased attentional resources) during DT-walking. We will then be able to identify areas of brain plasticity associated with improvements in mobility functions (balance, gait, and cognition) after intervention. We expect the gait-cognitive training effect to involve re-organization of PFC activity among other, yet to be identified brain regions. The DT mobility-training platform and behavioral PET brain imaging methods are directly applicable to other diseases that affect gait and cognition, e.g., cognitive vascular impairment, Alzheimer’s disease, as well as in aging.
Heterogeneity and Development of Fine Astrocyte Morphology Captured by Diffraction-Limited Microscopy
Authors: Minge Daniel , Domingos Cátia , Unichenko Petr , Behringer Charlotte , Pauletti Alberto , Anders Stefanie , Herde Michel K. , Delekate Andrea , Gulakova Polina , Schoch Susanne , Petzold Gabor C. , Henneberger Christian
Published: June 2021

The fine processes of single astrocytes can contact many thousands of synapses whose function they can modulate through bi-directional signaling. The spatial arrangement of astrocytic processes and neuronal structures is relevant for such interactions and for the support of neuronal signaling by astrocytes. At the same time, the geometry of perisynaptic astrocyte processes is variable and dynamically regulated. Studying these fine astrocyte processes represents a technical challenge, because many of them cannot be fully resolved by diffraction-limited microscopy. Therefore, we have established two indirect parameters of astrocyte morphology, which, while not fully resolving local geometry by design, provide statistical measures of astrocyte morphology: the fraction of tissue volume that astrocytes occupy and the density of resolvable astrocytic processes. Both are straightforward to obtain using widely available microscopy techniques. We here present the approach and demonstrate its robustness across various experimental conditions using mainly two-photon excitation fluorescence microscopy in acute slices and in vivo as well as modeling. Using these indirect measures allowed us to analyze the morphology of relatively large populations of astrocytes. Doing so we captured the heterogeneity of astrocytes within and between the layers of the hippocampal CA1 region and the developmental profile of astrocyte morphology. This demonstrates that volume fraction (VF) and segment density are useful parameters for describing the structure of astrocytes. They are also suitable for online monitoring of astrocyte morphology with widely available microscopy techniques.
Safety of Low Dose Intravenous Cangrelor in Acute Ischemic Stroke: A Case Series
Authors: Salahuddin Hisham , Dawod Giana , Zaidi Syed F. , Shawver Julie , Burgess Richard , Jumaa Mouhammad A.
Published: June 2021

Background: Neurointerventional procedures in acute ischemic stroke often require immediate antiplatelet therapy in the cases of acute stenting and occasionally re-occluding vessels. Intravenous cangrelor is a P2Y12 receptor antagonist with short onset and quick offset. The study objective was to evaluate the safety and efficacy of intravenous cangrelor in patients with acute ischemic stroke requiring urgent antiplatelet effect.

Methods: Patients who received intravenous cangrelor intra-procedurally during acute ischemic stroke treatment were identified from a prospectively collected database. Cangrelor was administered as a bolus of 15 mcg/kg, followed by an infusion rate of 2 mcg/kg/min. A historical control group consisting of anterior circulation tandem occlusions was used to compare to patients with similar lesions who received intravenous cangrelor. Outcomes of interest included in-stent thrombosis, thromboembolic complications, intracranial hemorrhage, and functional outcomes at 90 days.

Results: Twelve patients received intravenous cangrelor for acute ischemic stroke between October 2018 and April 2020 at a comprehensive stroke center. Eleven patients had intra or extracranial stenting performed, which included two posterior circulation lesions. No cases of symptomatic intracranial hemorrhage were reported. At 90 day follow-up, two patients had died and 10 had a good functional outcome. Patients with anterior circulation tandem occlusions who received cangrelor and those who received dual antiplatelets orally had similar radiographic and clinical outcomes.

Conclusion: Low dose intravenous cangrelor is similar in safety and efficacy to oral antiplatelets in acute ischemic stroke in a small case series. Larger prospective studies on the efficacy, safety, and effect on procedure times of intravenous cangrelor in neurointervention are warranted.
Combined Anticancer Effect of Plasma-Activated Infusion and Salinomycin by Targeting Autophagy and Mitochondrial Morphology
Authors: Ando Takashi , Suzuki-Karasaki Manami , Suzuki-Karasaki Miki , Ichikawa Jiro , Ochiai Toyoko , Yoshida Yukihiro , Haro Hirotaka , Suzuki-Karasaki Yoshihiro
Published: June 2021

Non-thermal atmospheric pressure plasma (NTAPP)-activated liquids have emerged as new promising anticancer agents because they preferentially injure malignant cells. Here, we report plasma-activated infusion (PAI) as a novel NTAPP-based anti-neoplastic agent. PAI was prepared by irradiating helium NTAP to form a clinically approved infusion fluid. PAI dose-dependently killed malignant melanoma and osteosarcoma cell lines while showing much lower cytotoxic effects on dermal and lung fibroblasts. We found that PAI and salinomycin (Sal), an emerging anticancer stem cell agent, mutually operated as adjuvants. The combined administration of PAI and Sal was much more effective than single-agent application in reducing the growth and lung metastasis of osteosarcoma allografts with minimal adverse effects. Mechanistically, PAI explicitly induced necroptosis and increased the phosphorylation of receptor-interacting protein 1/3 rapidly and transiently. PAI also suppressed the ambient autophagic flux by activating the mammalian target of the rapamycin pathway. PAI increased the phosphorylation of Raptor, Rictor, and p70-S6 kinase, along with decreased LC3-I/II expression. In contrast, Sal promoted autophagy. Moreover, Sal exacerbated the mitochondrial network collapse caused by PAI, resulting in aberrant clustering of fragmented mitochondrial in a tumor-specific manner. Our findings suggest that combined administration of PAI and Sal is a promising approach for treating these apoptosis-resistant cancers.
Integrated Analysis of Cell Cycle–Related and Immunity-Related Biomarker Signatures to Improve the Prognosis Prediction of Lung Adenocarcinoma
Authors: Chen Fangyu , Song Jiahang , Ye Ziqi , Xu Bing , Cheng Hongyan , Zhang Shu , Sun Xinchen
Published: June 2021

Background

Lung adenocarcinoma (LUAD) is a leading malignancy and has a poor prognosis over the decades. LUAD is characterized by dysregulation of cell cycle. Immunotherapy has emerged as an ideal option for treating LUAD. Nevertheless, optimal biomarkers to predict outcomes of immunotherapy is still ill-defined and little is known about the interaction of cell cycle-related genes (CCRGs) and immunity-related genes (IRGs).

Methods

We downloaded gene expression and clinical data from TCGA and GEO database. LASSO regression and Cox regression were used to construct a differentially expressed CCRGs and IRGs signature. We used Kaplan-Meier analysis to compare survival of LUAD patients. We constructed a nomogram to predict the survival and calibration curves were used to evaluate the accuracy.

Results

A total of 61 differentially expressed CCRGs and IRGs were screened out. We constructed a new risk model based on 8 genes, including ACVR1B, BIRC5, NR2E1, INSR, TGFA, BMP7, CD28, NUDT6. Subgroup analysis revealed the risk model accurately predicted the overall survival in LUAD patients with different clinical features and was correlated with immune cells infiltration. A nomogram based on the risk model exhibited excellent performance in survival prediction of LUAD.

Conclusions

The 8 gene survival signature and nomogram in our study are effective and have potential clinical application to predict prognosis of LUAD.
18F-RGD PET/CT and Systemic Inflammatory Biomarkers Predict Outcomes of Patients With Advanced NSCLC Receiving Combined Antiangiogenic Treatment
Authors: Liu Jie , Wu Leilei , Liu Zhiguo , Seery Samuel , Li Jianing , Gao Zhenhua , Yu Jinming , Meng Xue
Published: June 2021

Background

The aim of this study was to evaluate 18F-AlF-NOTA-PRGD2 positron emission tomography/computed tomography (18F-RGD PET/CT) and serum inflammation biomarkers for predicting outcomes of patients receiving combined antiangiogenic treatment for advanced non-small cell lung cancer (NSCLC).

Methods

Patients with advanced NSCLC underwent 18F-RGD PET/CT examination and provided blood samples before treatments commenced. PET/CT parameters included maximum standard uptake value (SUVmax) and mean standard uptake value (SUVmean), peak standard uptake value (SUVpeak) and metabolic tumor volume (MTV) for all contoured lesions. Biomarkers for inflammation included pretreatment neutrophil-to-lymphocyte ratio (PreNLR), pretreatment platelet-to-lymphocyte ratio (PrePLR), and pretreatment lymphocyte-to-monocyte ratio (PreLMR). Receiver operating characteristic (ROC) curve analysis was used to describe response prediction accuracy. Logistic regression and Cox’s regression analysis was implemented to identify independent factors for short-term responses and progression-free survival (PFS).

Results

This study included 23 patients. According to ROC curve analysis, there were significant correlations between the SUVmax, SUVmean, and 18F-RGD PET/CT MTV and short-term responses (p<0.05). SUVmax was identified using logistic regression analysis as a significant predictor of treatment sensitivity (p=0.008). Cox’s multivariate regression analysis suggested that high SUVpeak (p=0.021) and high PreLMR (p=0.03) were independent PFS predictors. Combining SUVpeak and PreLMR may also increase the prognostic value for PFS, enabling us to identify a subgroup of patients with intermediate PFS.

Conclusion

18F-RGD uptake on PET/CT and serum inflammation biomarker pretreatment may predict outcomes for combined antiangiogenic treatments for advanced NSCLC patients. Higher 18F-RGD uptake and higher PreLMR also appear to predict improved short-term responses and PFS. Combining biomarkers may therefore provide a basis for risk stratification, although further research is required.
Identification of a Glypican-3 Binding Peptide From a Phage-Displayed Peptide Library for PET Imaging of Hepatocellular Carcinoma
Authors: Yan Jiayao , Yu Xiaoxiao , Chen Xiaotong , Liu Fangcen , Chen Fangjun , Ding Naiqing , Yu Lixia , Meng Fanyan , Shen Jie , Wei Jia , Liu Baorui
Published: June 2021

Tumor-targeting peptides functioned as molecular probes are essential for multi-modality imaging and molecular-targeting therapy in caner theronostics. Here, we performed a phage-displayed bio-panning to identify a specific binding peptide targeting Glypican-3 (GPC-3), a promising biomarker in hepatocellular carcinoma (HCC). After screening in the cyclic peptide library, a candidate peptide named F3, was isolated and showed specific binding to HCC cell lines. In a bio-distribution study, higher accumulation of F3 peptide was observed in HepG-2 tumors compared to PC-3 tumors in xenograft models. After labeling with radioactive 68Ga, the F3 peptide tracer enabled the specific detection of tumors in HCC tumor models with PET imaging. More importantly, the expression of GPC-3 in human tissue samples may be distinguished by an F3 fluorescent peptide probe indicating its potential for clinical application. This cyclic peptide targeting GPC-3 has been validated, and may be an alternative to serve as an imaging probe or a targeting domain in the drug conjugate.
Inflammatory Markers and Duration of Symptoms Have a Close Connection With Diagnosis and Staging of Acute Appendicitis in Children
Authors: Lan Jiaming , Zhu Hai , Liu Qingshuang , Guo Chunbao
Published: June 2021

Background: For children with acute appendicitis (AA), a clear diagnosis is a challenge. The purpose of this study is to explore whether inflammatory markers in the blood combined with symptom duration are helpful in the diagnosis of acute appendicitis and in predicting the severity of acute appendicitis.

Methods: All the selected patients underwent appendectomy between November 10, 2011 and November 15, 2019, in whom preoperative WBCC, CRP, and NE% had been measured in a short time. All patients were divided into two groups: uncomplicated AA and complicated AA, postoperatively.

Results: For our standards, 813 patients were selected, 442 of them had complicated AA. The mean [standard deviation (SD)] age for the uncomplicated AA group was 9.78 ± 2.02 years and for the complicated AA group was 9.69 ± 2.16 years (P = 0.55). Elevated WBCC, CRP, and NE% had a higher relatively sensitivity in complicated AA than uncomplicated AA especially when WBCC, CRP, and NE% were at normal levels, which had a sensitivity of 100% in uncomplicated AA, but this only applied to nine patients. CRP values were significantly different in three time groups, whether uncomplicated or complicated AA.

Conclusion: The combination of WBCC, CRP, and NE% values is very sensitive for the diagnosis of acute appendicitis, and when we predict complicated AA using the CRP value, we also need to consider the time of symptom onset.
Association Between Vitamin D Status and Undernutrition Indices in Children: A Systematic Review and Meta-Analysis of Observational Studies
Authors: Song Chunhua , Sun Hongzhi , Wang Ben , Song Chunli , Lu Hongying
Published: June 2021

Introduction: Undernutrition, defined as stunting, wasting, and underweight, still implicates millions of infants and children worldwide. Micronutrients have pivotal effects on growth rate. The outcomes of vitamin D deficiency on undernutrition indices have stayed controversial. The object of current study is to answer this question: is there any association between vitamin D status and undernutrition indices?

Methods: The international databases were used for a systematic search to identify relevant observational studies in English up to January 2021. A random-effect model was applied to combine the results of included essays.

Results: Among 3,400 citations, 7 observational studies (4 cohorts and 3 cross-sectional) were eligible to enter in meta-analysis. Analysis of the lowest 8,295 children indicated that low vs. high serum level of vitamin D is directly associated with a higher risk of wasting (Summary Risk Estimate: 1.30; 95% CI: 1.04, 1.62; I2 = 0%). However, there is no significant association between vitamin status and risk of stunting (Summary Risk Estimate: 1.10; 95% CI: 0.72, 1.70; I2 = 81.6%) and underweight (Summary Risk Estimate: 1.12; 95% CI: 0.81, 1.56; I2 = 49.2%).

Conclusion: When comparing low and high serum vitamin D concentration categories, there is an inverse link between vitamin D status and wasting, but no relationship with stunting as well as underweight. However, further prospective and trial studies are required to deepen our understanding of these associations.
Changes in Physicians' Perceptions and Practices on Neonatal Pain Management Over the Past 20 Years. A Survey Conducted at Two Time-Points
Authors: Agakidou Eleni , Tsoni Konstantia , Stathopoulou Theodora , Thomaidou Agathi , Farini Maria , Kontou Angeliki , Karagianni Paraskevi , Sarafidis Kosmas
Published: June 2021

Intense research for more than three decades expelled the view that neonates do not experience pain. The aim of this survey was to investigate whether the Greek physicians involved in neonatal intensive care have changed their perceptions regarding neonatal pain, adapting their management practices to the knowledge that have emerged in the past 20-years. This study is a survey conducted at two time-points, 20 years apart. Anonymous questionnaires were distributed to 117 and 145 physicians working in neonatal intensive care units (NICUs) all over Greece in years 2000 and 2019, respectively. The response rate was 90.6 and 80.7% in 2000 and 2019, respectively. All respondents, at both time-points, believed that neonates experience pain, which has serious acute and long-term consequences, while the vast majority considered analgesia-sedation (A-S) during painful interventions as obligatory. Utilization of NICU protocols and pain assessment tools remained low although increased significantly between 2000 and 2019. The use of systemic A-S postoperatively was high at both time-points, while its implementation in infants subjected to prolonged pain, specifically mechanical ventilation, increased significantly by 2019. Systemic or local analgesia for acute procedural pain was used by lower proportions of physicians in 2019, except for the tracheal intubation. In contrast, the use of sweet solutions and non-pharmacological measures prior to or during bedside procedures significantly increased over time. Opioid administration significantly increased, while a shift from morphine to fentanyl was observed. International literature and perinatal–neonatal congresses were stated as the main sources of updating physicians' knowledge and improving management practice on neonatal pain prevention and treatment. In conclusion, Greek NICU-physicians' perceptions that neonates can experience pain with potentially serious acute and long-term consequences remained strong over the past 20 years. Although physicians' practices on neonatal pain management improved, they are still suboptimal, while significant differences exist among centers. Continuing education, globally accepted management protocols, and readily applied pain assessment tools would further improve the management of procedural pain and stress in neonates.
Multisystem Inflammatory Syndrome in Children: Unique Disease or Part of the Kawasaki Disease Spectrum?
Authors: Matucci-Cerinic Caterina , Caorsi Roberta , Consolaro Alessandro , Rosina Silvia , Civino Adele , Ravelli Angelo
Published: June 2021

One of the most intriguing and mysterious phenomena observed during the COVID-19 pandemic has been represented by the occurrence of the multisystem inflammatory syndrome in children and adolescents (MIS-C). Patients with this condition have some overlapping signs and symptoms with those of Kawasaki disease (KD), but also display clinical features that are uncommon or less frequent in this illness, such as diarrhea, abdominal pain and myocardial involvement. The sickest patients may develop multiorgan failure and shock, usually due to myocarditis. Management is based on the administration of intravenous immunoglobulin, glucocorticoids and, in the most severe instances, anakinra. It is still debated whether MIS-C and KD represent different illnesses or are part of the same disease spectrum. The aim of the present review is to analyze critically the evidence in favor of the latter hypothesis and to provide the authors' personal interpretation of the relationship between the two conditions.
Implementation of a Follow-Up System for Pediatric Sepsis Survivors in a Large Academic Pediatric Intensive Care Unit
Authors: Fitzgerald Julie C. , Kelly Nancy-Ann , Hickey Christopher , Balamuth Fran , Thomas Nina H. , Hogan Annique , Stack Noelle J. , Trimarchi Tara , Weiss Scott L.
Published: June 2021

Background: Survivors of pediatric sepsis often develop new morbidities and deterioration in quality of life after sepsis, leading to a need for improved follow-up for children who survive sepsis.

Objective: To implement a follow-up system for pediatric sepsis survivors in a pediatric health system.

Methods: We performed a retrospective case series of patients treated for sepsis from October 2018 through October 2019 in a pediatric intensive care unit in a quaternary children's hospital, and describe implementation of a follow-up system for sepsis survivors. Program planning started in 2017 with multidisciplinary meetings including physical, occupational, and speech therapists, teachers, neuropsychologists, and coordinators from other survivorship programs (neonatology, stroke, and oncology). In 2018, a workshop was held to consult with local and national experts. The Pediatric Sepsis Survivorship Program launched in October 2018 led by a nurse coordinator who met with families to educate about sepsis and offer post-discharge follow-up. Patients with high pre-existing medical complexity or established subspecialty care were referred for follow-up through existing care coordination or subspecialty services plus guidance to monitor for post-sepsis morbidity. For patients with low-moderate medical complexity, the nurse coordinator administered a telephone-based health-assessment 2–3 months after discharge to screen for new physical or psychosocial morbidity. Patients flagged with concerns were referred to their primary physician and/or to expedited neuropsychological evaluation to utilize existing medical services.

Results: Of 80 sepsis patients, 10 died, 20 were referred to care coordination by the program, and 13 had subspecialty follow-up. Five patients were followed in different health systems, four were adults not appropriate for existing follow-up programs, four remained hospitalized, and four were missed due to short stay or unavailable caregivers. The remaining 20 patients were scheduled for follow-up with the Pediatric Sepsis Program. Nine patients completed the telephone assessment. Four patients were receiving new physical or occupational therapy, and one patient was referred for neuropsychology evaluation due to new difficulties with attention, behavior, and completion of school tasks.

Conclusions: Implementation of an efficient, low-cost pediatric sepsis survivorship program was successful by utilizing existing systems of care, when available, and filling a follow-up gap in screening for select patients.
Identification of the Main Active Components and Mechanism of Wang Bi Tablet in Treating Rheumatoid Arthritis Based on Integrative Pharmacology
Authors: Jiao Yuanyuan , Xu Jia , Chen Hong , Guo Qiuyan , Deng Xiaofang , Zhang Tong , Zhang Jingbo , Shi Chenjing , Wang Ping
Published: June 2021

Wang Bi tablet (WBT) is used to treat rheumatoid arthritis (RA) in China. We employed integrative pharmacology, including rapid analysis of chemical composition, pharmacological experiment, and network pharmacology analysis, to elucidate the active components and mechanism underlying the effect of WBT against RA. The chemical fingerprint of WBT was revealed by UPLC-QTOF-MS/MS, and the chemical composition was identified. The anti-inflammatory effect of WBT was evaluated in TNF-α-stimulated RAW264.7 cells by ELISA and transcriptome sequencing. Network pharmacology analysis, functional enrichment analysis, and network visualization were performed. A total of 293 chemical constituents were preliminarily identified or tentatively characterized in WBT extract, and they effectively inhibited inflammatory response in TNF-α-stimulated RAW264.7 cells. Forty-eight key active constituents were identified based on high-frequency binding to hub targets and their corresponding targets number. Next, 135 corresponding hub genes, which may be the putative targets of WBT in treating RA, were selected. Functionally, the putative targets were significantly associated with the inflammatory immune response regulation module, energy metabolism regulation module, and cell function regulation module, corresponding to the traditional efficacy of WBT. In summary, this study revealed, for the first time using integrative pharmacology, that WBT may attenuate RA through the inflammation-immune regulation system.
Coarse-Grained Modeling of Coronavirus Spike Proteins and ACE2 Receptors
Authors: Leong Timothy , Voleti Chandhana , Peng Zhangli
Published: June 2021

We developed coarse-grained models of spike proteins in SARS-CoV-2 coronavirus and angiotensin-converting enzyme 2 (ACE2) receptor proteins to study the endocytosis of a whole coronavirus under physiologically relevant spatial and temporal scales. We first conducted all-atom explicit-solvent molecular dynamics simulations of the recently characterized structures of spike and ACE2 proteins. We then established coarse-grained models using the shape-based coarse-graining approach based on the protein crystal structures and extracted the force field parameters from the all-atom simulation trajectories. To further analyze the coarse-grained models, we carried out normal mode analysis of the coarse-grained models to refine the force field parameters by matching the fluctuations of the internal coordinates with the original all-atom simulations. Finally, we demonstrated the capability of these coarse-grained models by simulating the endocytosis of a whole coronavirus through the host cell membrane. We embedded the coarse-grained models of spikes on the surface of the virus envelope and anchored ACE2 receptors on the host cell membrane, which is modeled using a one-particle-thick lipid bilayer model. The coarse-grained simulations show the spike proteins adopt bent configurations due to their unique flexibility during their interaction with the ACE2 receptors, which makes it easier for them to attach to the host cell membrane than rigid spikes.
Myofibre Hypertrophy in the Absence of Changes to Satellite Cell Content Following Concurrent Exercise Training in Young Healthy Men
Authors: Shamim Baubak , Camera Donny M. , Whitfield Jamie
Published: June 2021

Concurrent exercise training has been suggested to create an ‘interference effect,’ attenuating resistance training-based skeletal muscle adaptations, including myofibre hypertrophy. Satellite cells support myofibre hypertrophy and are influenced by exercise mode. To determine whether satellite cells contribute to the ‘interference effect’ changes in satellite cell and myonuclear content were assessed following a period of training in 32 recreationally active males (age: 25 ± 5 year; body mass index: 24 ± 3 kg⋅m–2; mean ± SD) who undertook 12-week of either isolated (3 d⋅w–1) resistance (RES; n = 10), endurance (END; n = 10), or alternate day (6 d⋅w–1) concurrent (CET, n = 12) training. Skeletal muscle biopsies were obtained pre-intervention and after 2, 8, and 12 weeks of training to determine fibre type-specific cross-sectional area (CSA), satellite cell content (Pax7+DAPI+), and myonuclei (DAPI+) using immunofluorescence microscopy. After 12 weeks, myofibre CSA increased in all training conditions in type II (P = 0.0149) and mixed fibres (P = 0.0102), with no difference between conditions. Satellite cell content remained unchanged after training in both type I and type II fibres. Significant correlations were observed between increases in fibre type-specific myonuclear content and CSA of Type I (r = 0.63, P < 0.0001), Type II (r = 0.69, P < 0.0001), and mixed fibres (r = 0.72, P < 0.0001). Resistance, endurance, and concurrent training induce similar myofibre hypertrophy in the absence of satellite cell and myonuclear pool expansion. These findings suggest that myonuclear accretion via satellite cell fusion is positively correlated with hypertrophy after 12 weeks of concurrent training, and that individuals with more myonuclear content displayed greater myofibre hypertrophy.
Long-Term Effect of Elevated CO2 on the Development and Nutrition Contents of the Pea Aphid (Acyrthosiphon pisum)
Authors: Li Chunchun , Sun Qian , Gou Yuping , Zhang Kexin , Zhang Qiangyan , Zhou Jing-Jiang , Liu Changzhong
Published: June 2021

It is predicted that the current atmospheric CO2 level will be doubled by the end of this century. Here, we investigate the impacts of elevated CO2 (550 and 750 μL/L) on the development and nutrition status of the green pea aphid for six generations, which is longer than previous studies. All seven examined physiological parameters were not affected over six generations under the ambient CO2 level (380 μL/L). However, the elevated CO2 levels (550 and 750 μL/L) prolonged nymph duration, decreased adult longevity, female fecundity and protein content, and increased the contents of total lipid, soluble sugar and glycogen. There was a significant interaction between the effect of CO2 levels and the effect of generations on nymph duration, female fecundity and adult longevity. The elevated CO2 had immediate effects on the female fecundity and the contents of total protein, total lipid and soluble sugar, starting within F0 generation. The adult longevity decreased, and the glycogen content increased from the F1 generation. However, the significant effect on the nymph development was only observed after three generations. Our study indicates that the elevated CO2 levels first influence the reproduction, the nutrition and the energy supply, then initiate aphid emergency responses by shortening lifespan and increasing glucose metabolism, and finally result in the slow development under further persistent elevated CO2 conditions after three generations, possibly leading to population decline under elevated CO2 conditions. Our results will guide further field experiments under climate change conditions to evaluate the effects of elevated CO2 on the development of the pea aphids and other insects, and to predict the population dynamics of the green pea aphid.
Irisin, Fibroplast Growth Factor-21, and Follistatin Responses to Endurance Rowing Training Session in Female Rowers
Authors: Jürimäe Jaak , Vaiksaar Sille , Purge Priit , Tillmann Vallo
Published: June 2021

Purpose:This study examined selected myokine responses to an endurance rowing training session, and whether metabolic demands of the acute aerobic rowing exercise together with training volume, aerobic capacity, and body composition variables affect potential exercise-induced changes in the myokine levels in female rowers.

Methods:Fifteen national level female rowers [18.3 ± 1.6 years; 172.0 ± 5.0 cm, 67.5 ± 8.8 kg; maximal oxygen consumption (VO2max): 47.2 ± 7.9 ml.min.−1kg−1] performed a 1-h rowing ergometer exercise at the intensity of 70% of VO2max [distance: 12.1 ± 1.1 km; energy expenditure (EE): 639 ± 69 kcal; heart rate (HR): 151 ± 7 beats.min−1] followed by a 30-min recovery period. Venous blood samples were collected before and after exercise, and analyzed for irisin, fibroplast growth factor-21 (FGF-21), and follistatin conentrations.

Results:Plasma irisin and FGF-21 concentrations were increased (by 8%;p= 0.013 and by 13%;p< 0.0001, respectively) immediately after the aerobic rowing exercise. Follistatin was significantly increased (by 11%;p= 0.001) only after the first 30 min of recovery. Exercise metabolic demand variables such as distance covered and total EE were correlated with the pre-to-post-exercise increases in FGF-21 concentrations (r= 0.52;p= 0.047 andr= 0.68;p= 0.005, respectively). Exercise-induced increases in irisin levels were related to aerobic capacity as measured by VO2max (r= 0.53;p= 0.041) and training stress as measured by weekly training volume (r= 0.54;p= 0.039) in female rowers.

Conclusion:Acute negative energy balance induced by a single endurance rowing training session elicited significant increases in irisin, FGF-21, and follistatin levels in national level female rowers. While exercise-induced increases in FGF-21 levels were associated with exercise metabolic demand measures, exercise-induced increases in irisin concentrations were related to aerobic capacity and training stress measures in female rowers.
Natural Genetic Diversity in Tomato Flavor Genes
Authors: Pereira Lara , Sapkota Manoj , Alonge Michael , Zheng Yi , Zhang Youjun , Razifard Hamid , Taitano Nathan K. , Schatz Michael C. , Fernie Alisdair R. , Wang Ying , Fei Zhangjun , Caicedo Ana L. , Tieman Denise M. , van der Knaap Esther
Published: June 2021

Fruit flavor is defined as the perception of the food by the olfactory and gustatory systems, and is one of the main determinants of fruit quality. Tomato flavor is largely determined by the balance of sugars, acids and volatile compounds. Several genes controlling the levels of these metabolites in tomato fruit have been cloned, includingLIN5,ALMT9,AAT1,CXE1, andLoxC. The aim of this study was to identify any association of these genes with trait variation and to describe the genetic diversity at these loci in the red-fruited tomato clade comprised of the wild ancestorSolanum pimpinellifolium, the semi-domesticated speciesSolanum lycopersicum cerasiformeand early domesticatedSolanum lycopersicum. High genetic diversity was observed at these five loci, including novel haplotypes that could be incorporated into breeding programs to improve fruit quality of modern tomatoes. Using newly available high-quality genome assemblies, we assayed each gene for potential functional causative polymorphisms and resolved a duplication at theLoxClocus found in several wild and semi-domesticated accessions which caused lower accumulation of lipid derived volatiles. In addition, we explored gene expression of the five genes in nine phylogenetically diverse tomato accessions. In general, the expression patterns of these genes increased during fruit ripening but diverged between accessions without clear relationship between expression and metabolite levels.
Night Temperature Determines the Interannual Yield Variation in Hybrid and Inbred Rice Widely Used in Central China Through Different Effects on Reproductive Growth
Authors: Huang Liying , Wang Fei , Liu Yi , Zhang Yunbo
Published: June 2021

Interannual variation in grain yield of rice has been observed at both farm and regional scales, which is related to the climate variability. Previous studies focus on predicting the trend of climate change in the future and its potential effects on rice production using climate models; however, field studies are lacking to examine the climatic causes underlying the interannual yield variability for different rice cultivars. Here a 6-year field experiment from 2012 to 2017 was conducted using one hybrid (Yangliangyou6, YLY6) cultivar and one inbred (Huanghuazhan, HHZ) cultivar to determine the climate factors responsible for the interannual yield variation. A significant variation in grain yield was observed for both the inbred and hybrid cultivars across six planting years, and the coefficient of variation for grain yield was 7.3–10.5%. The night temperature (average daily minimum temperature, Tmin) contributed to the yield variability in both cultivars. However, the two cultivars showed different responses to the change in Tmin. The yield variation in HHZ was mainly explained by the effects of Tmin on grain filling percentage and grain weight, while the change in spikelets m−2 in response to Tmin accounted for the yield variability in YLY6. Further analysis found that spikelets m−2 of YLY6 significantly and negatively correlated with Tmin from transplanting to heading. For HHZ, the grain filling percentage and grain weight were significantly affected by Tmin of the week prior to heading and from heading to maturity, respectively. Overall, there were differences in the response mechanism between hybrid and inbred cultivars to high night temperature. These will facilitate the development of climate-resilient cultivars and appropriate management practices to achieve a stable grain yield.
Development of GBTS and KASP Panels for Genetic Diversity, Population Structure, and Fingerprinting of a Large Collection of Broccoli (Brassica oleracea L. var. italica) in China
Authors: Shen Yusen , Wang Jiansheng , Shaw Ranjan K. , Yu Huifang , Sheng Xiaoguang , Zhao Zhenqing , Li Sujuan , Gu Honghui
Published: June 2021

Broccoli (Brassica oleracea var. italica) is one of the most important and nutritious vegetables widely cultivated in China. In the recent four decades, several improved varieties were bred and developed by Chinese breeders. However, the efforts for improvement of broccoli are hindered by limited information of genetic diversity and genetic relatedness contained within the available germplasms. This study evaluated the genetic diversity, genetic relationship, population structure, and fingerprinting of 372 accessions of broccoli representing most of the variability of broccoli in China. Millions of SNPs were identified by whole-genome sequencing of 23 representative broccoli genotypes. Through several stringent selection criteria, a total of 1,167 SNPs were selected to characterize genetic diversity and population structure. Of these markers, 1,067 SNPs were genotyped by target sequencing (GBTS), and 100 SNPs were genotyped by kompetitive allele specific PCR (KASP) assay. The average polymorphism information content (PIC) and expected heterozygosity (gene diversity) values were 0.33 and 0.42, respectively. Diversity analysis revealed the prevalence of low to moderate genetic diversity in the broccoli accessions indicating a narrow genetic base. Phylogenetic and principal component analyses revealed that the 372 accessions could be clustered into two main groups but with weak groupings. STRUCTURE analysis also suggested the presence of two subpopulations with weak genetic structure. Analysis of molecular variance (AMOVA) identified 13% variance among populations and 87% within populations revealing very low population differentiation, which could be attributed to massive gene flow and the reproductive biology of the crop. Based on high resolving power, a set of 28 KASP markers was chosen for DNA fingerprinting of the broccoli accessions for seed authentication and varietal identification. To the best of our knowledge, this is the first comprehensive study to measure diversity and population structure of a large collection of broccoli in China and also the first application of GBTS and KASP techniques in genetic characterization of broccoli. This work broadens the understanding of diversity, phylogeny, and population structure of a large collection of broccoli, which may enhance future breeding efforts to achieve higher productivity.
Acetic Acid-Producing Endophyte Lysinibacillus fusiformis Orchestrates Jasmonic Acid Signaling and Contributes to Repression of Cadmium Uptake in Tomato Plants
Authors: Zhu Lin , Guo Jiansheng , Sun Yujun , Wang Songhua , Zhou Cheng
Published: June 2021

Diverse signaling pathways regulated by phytohormones are essential for the adaptation of plants to adverse environments. Root endophytic bacteria can manipulate hormone-related pathways to benefit their host plants under stress conditions, but the mechanisms underlying endophyte-mediated plant stress adaptation remain poorly discerned. Herein, the acetic acid-producing endophytic bacteria Lysinibacillus fusiformis Cr33 greatly reduced cadmium (Cd) accumulation in tomato plants. L. fusiformis led to a marked increase in jasmonic acid (JA) content and down-regulation of iron (Fe) uptake-related genes in Cd-exposed roots. Accordantly, acetic acid treatment considerably increased the JA content and inhibited root uptake of Cd uptake. In addition, the Cr33-inoculated roots displayed the increased availability of cell wall and rhizospheric Fe. Inoculation with Cr33 notably reduced the production of nitric oxide (NO) and suppressed Fe uptake systems in the Cd-treated roots, thereby contributing to hampering Cd absorption. Similar results were also observed for Cd-treated tomato plants in the presence of exogenous JA or acetic acid. However, chemical inhibition of JA biosynthesis greatly weakened the endophyte-alleviated Cd toxicity in the plants. Collectively, our findings indicated that the endophytic bacteria L. fusiformis effectively prevented Cd uptake in plants via the activation of acetic acid-mediated JA signaling pathways.