bluuebunny/crossref_metadata_2025 huggingface dataset:
Determinants of Persistent Patterns of Pepino Mosaic Virus Mixed Infections
Authors: Alcaide Cristina , Aranda Miguel A.
Published: July 2021

Pepino mosaic virus (PepMV) has become a pandemic virus in tomato crops, causing important economic losses worldwide. In Spain, isolates of the EU and CH2 strains co-circulate, with PepMV-EU predominantly found in mixed infections. Simultaneous in planta mixed infections result in an asymmetric antagonism against PepMV-CH2, but the outcome of over-infections has never been tested. PepMV-EU and PepMV-CH2 time-lagged inoculations were performed, and viral accumulation was measured 10 days after challenge inoculation. PepMV-EU had a protective effect over PepMV-CH2; in contrast, the accumulation of PepMV-EU increased in plants pre-inoculated with PepMV-CH2 as compared to single infections. We also studied the effect of the type of infection on viral transmission. Independently of the nature of the infection (single or mixed), we observed a strong positive correlation between virus accumulation in the source plant and transmission, excluding mixed infection effects different than modulating viral accumulation. Finally, in order to determine the genetic variability of PepMV strains in single and mixed infections, a 430 nucleotide region was RT-PCR amplified from samples from a serial passages experiment and deep-sequenced. No significant differences were found in the number of nucleotide substitutions between single and mixed infections for PepMV-EU; in contrast, significant differences were found for PepMV-CH2, which was more variable in single than in mixed infections. Comparing PepMV-EU with PepMV-CH2, a higher nucleotide diversity was found for PepMV-CH2. Collectively, our data strongly suggest that PepMV mixed infections can impact the virus epidemiology by modulating in planta virus strain accumulation and diversification.
Novel Scalable and Simplified System to Generate Microglia-Containing Cerebral Organoids From Human Induced Pluripotent Stem Cells
Authors: Bodnar Brittany , Zhang Yongang , Liu Jinbiao , Lin Yuan , Wang Peng , Wei Zhengyu , Saribas Sami , Zhu Yuanjun , Li Fang , Wang Xu , Yang Wenli , Li Qingsheng , Ho Wen-Zhe , Hu Wenhui
Published: July 2021

Human cerebral organoid (CO) is a three-dimensional (3D) cell culture system that recapitulates the developing human brain. While CO has proved an invaluable tool for studying neurological disorders in a more clinically relevant matter, there have still been several shortcomings including CO variability and reproducibility as well as lack of or underrepresentation of certain cell types typically found in the brain. As the technology to generate COs has continued to improve, more efficient and streamlined protocols have addressed some of these issues. Here we present a novel scalable and simplified system to generate microglia-containing CO (MCO). We characterize the cell types and dynamic development of MCOs and validate that these MCOs harbor microglia, astrocytes, neurons, and neural stem/progenitor cells, maturing in a manner that reflects human brain development. We introduce a novel technique for the generation of embryoid bodies (EBs) directly from induced pluripotent stem cells (iPSCs) that involves simplified steps of transitioning directly from 3D cultures as well as orbital shaking culture in a standard 6-well culture plate. This allows for the generation of MCOs with an easy-to-use system that is affordable and accessible by any general lab.
Contextual Fear Memory Maintenance Changes Expression of pMAPK, BDNF and IBA-1 in the Pre-limbic Cortex in a Layer-Specific Manner
Authors: Chaaya Nicholas , Wang Joshua , Jacques Angela , Beecher Kate , Chaaya Michael , Battle Andrew Raymond , Johnson Luke R. , Chehrehasa Fatemeh , Belmer Arnauld , Bartlett Selena E.
Published: July 2021

Post-traumatic stress disorder (PTSD) is a debilitating and chronic fear-based disorder. Pavlovian fear conditioning protocols have long been utilised to manipulate and study these fear-based disorders. Contextual fear conditioning (CFC) is a particular Pavlovian conditioning procedure that pairs fear with a particular context. Studies on the neural mechanisms underlying the development of contextual fear memories have identified the medial prefrontal cortex (mPFC), or more specifically, the pre-limbic cortex (PL) of the mPFC as essential for the expression of contextual fear. Despite this, little research has explored the role of the PL in contextual fear memory maintenance or examined the role of neuronal mitogen-activated protein kinase (pMAPK; ERK 1/2), brain-derived neurotrophic factor (BDNF), and IBA-1 in microglia in the PL as a function of Pavlovian fear conditioning. The current study was designed to evaluate how the maintenance of two different long-term contextual fear memories leads to changes in the number of immune-positive cells for two well-known markers of neural activity (phosphorylation of MAPK and BDNF) and microglia (IBA-1). Therefore, the current experiment is designed to assess the number of immune-positive pMAPK and BDNF cells, microglial number, and morphology in the PL following CFC. Specifically, 2 weeks following conditioning, pMAPK, BDNF, and microglia number and morphology were evaluated using well-validated antibodies and immunohistochemistry (n= 12 rats per group). A standard CFC protocol applied to rats led to increases in pMAPK, BDNF expression and microglia number as compared to control conditions. Rats in the unpaired fear conditioning (UFC) procedure, despite having equivalent levels of fear to context, did not have any change in pMAPK, BDNF expression and microglia number in the PL compared to the control conditions. These data suggest that alterations in the expression of pMAPK, BDNF, and microglia in the PL can occur for up to 2 weeks following CFC. Together the data suggest that MAPK, BDNF, and microglia within the PL of the mPFC may play a role in contextual fear memory maintenance.
A Kinetic Model for Blood Biomarker Levels After Mild Traumatic Brain Injury
Authors: Azizi Sima , Hier Daniel B. , Allen Blaine , Obafemi-Ajayi Tayo , Olbricht Gayla R. , Thimgan Matthew S. , Wunsch Donald C.
Published: July 2021

Traumatic brain injury (TBI) imposes a significant economic and social burden. The diagnosis and prognosis of mild TBI, also called concussion, is challenging. Concussions are common among contact sport athletes. After a blow to the head, it is often difficult to determine who has had a concussion, who should be withheld from play, if a concussed athlete is ready to return to the field, and which concussed athlete will develop a post-concussion syndrome. Biomarkers can be detected in the cerebrospinal fluid and blood after traumatic brain injury and their levels may have prognostic value. Despite significant investigation, questions remain as to the trajectories of blood biomarker levels over time after mild TBI. Modeling the kinetic behavior of these biomarkers could be informative. We propose a one-compartment kinetic model for S100B, UCH-L1, NF-L, GFAP, and tau biomarker levels after mild TBI based on accepted pharmacokinetic models for oral drug absorption. We approximated model parameters using previously published studies. Since parameter estimates were approximate, we did uncertainty and sensitivity analyses. Using estimated kinetic parameters for each biomarker, we applied the model to an available post-concussion biomarker dataset of UCH-L1, GFAP, tau, and NF-L biomarkers levels. We have demonstrated the feasibility of modeling blood biomarker levels after mild TBI with a one compartment kinetic model. More work is needed to better establish model parameters and to understand the implications of the model for diagnostic use of these blood biomarkers for mild TBI.
Electroacupuncture Ameliorates Chronic Inflammatory Pain-Related Anxiety by Activating PV Interneurons in the Anterior Cingulate Cortex
Authors: Shao Fangbing , Fang Junfan , Qiu Mengting , Wang Sisi , Xi Danning , Shao Xiaomei , He Xiaofen , Fang Jianqiao , Du Junying
Published: July 2021

Chronic inflammatory pain is a common clinical disease that tends to be associated with negative emotions such as anxiety and depression. The anterior cingulate cortex (ACC) is involved in pain and pain-related anxiety, and γ-aminobutyric acid (GABA)-ergic interneurons play an important role in chronic pain and anxiety. Electroacupuncture (EA) has good analgesic and antianxiety effect, but the underlying mechanisms have not yet been fully elucidated. In this study, we established a chronic inflammatory pain model and observed that this model induced anxiety-like behaviors and decreased the numbers of parvalbumin (PV) and somatostatin (SOM) positive cells. Activation of PV but not SOM interneurons by chemogenetic techniques alleviated anxiety-like behaviors and pain sensation. EA treatment improved pain sensation, anxiety-like behaviors and increased the number of PV- positive cells in the ACC, but did not affect on the number of SOM-positive cells in the ACC. Moreover, specific inhibition of PV interneurons by chemogenetic methods reversed the analgesic and antianxiety effects of EA. These results suggest that EA ameliorates chronic inflammatory pain and pain-related anxiety by upregulating PV but not SOM interneurons in the ACC.
Dietary Intake of Tomato and Lycopene and Risk of All-Cause and Cause-Specific Mortality: Results From a Prospective Study
Authors: Xu Xin , Li Shiqi , Zhu Yi
Published: July 2021

Evidence on the relationship between consumption of tomato or lycopene and mortality is limited. We investigated the associations of raw tomato, tomato catsup or lycopene intake with all-cause and cause-specific mortality using data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial. A multivariate Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a total of 1,672,715 follow-up years, 24,141 all-cause deaths, 7,534 cardiovascular disease (CVD) deaths and 7,161 cancer deaths occurred. Total mortality was statistically significantly inversely associated with intake of raw tomato (Q5 vs. Q1; HR, 0.95 [95% CI, 0.91–0.99]), tomato catsup (Q5 vs. Q1; HR, 0.93 [95% CI, 0.89–0.97]), and moderate lycopene (Q4 vs. Q1; HR, 0.88 [95% CI, 0.85–0.93]). CVD mortality was significantly inversely related with intake of moderate raw tomato (Q4 vs. Q1; HR, 0.90 [95% CI, 0.83–0.97]), tomato catsup (Q5 vs. Q1; HR, 0.92 [95% CI, 0.85–0.99]), and moderate lycopene (Q4 vs. Q1; HR, 0.90 [95% CI, 0.83–0.98]). Dietary intake of raw tomato (Q5 vs. Q1; HR, 1.04 [95% CI, 0.96–1.14]) and tomato catsup (Q5 vs. Q1; HR, 1.00 [95% CI, 0.93–1.08]) were not related with cancer mortality. Moderate dietary intake of lycopene was significantly associated with a lower cancer mortality (Q4 vs. Q1; HR, 0.89 [95% CI, 0.82–0.96]). There was a non-linear J-shaped association between consumption of raw tomato, tomato catsup or lycopene and total mortality (Pfor non-linearity <0.001). In conclusion, in this large nationally representative sample of US adult population, tomato products, and lycopene intake were associated with lower risks of total and CVD mortality. Moderate consumption of lycopene was also related with a reduced cancer mortality. Further clinical studies and dietary intervention studies are warranted to confirm our premilitary findings.
Adherence to a Healthy Lifestyle and the Risk of All-Cause Mortality and Cardiovascular Events in Individuals With Diabetes: The ARIC Study
Authors: Li Dongze , Jia Yu , Yu Jing , Liu Yi , Li Fanghui , Liu Yanmei , Wu Qinqin , Liao Xiaoyang , Zeng Zhi , Wan Zhi , Zeng Rui
Published: July 2021

Objective:The relationship between combined healthy lifestyle and cardiovascular (CV) events in diabetes is unclear. We aim to investigate the association between a healthy lifestyle score (HLS) and the risk of mortality and CV events in diabetes.

Methods:We examined the associations of six lifestyle factors scores (including healthy diet, moderate alcohol and regular coffee intakes, never smoking, physical activity, and normal weight) with diabetes in the Atherosclerosis Risk in Communities (ARIC) study of 3,804 participants with diabetes from the United States at baseline. Primary outcomes included all-cause mortality, CV mortality, and composite CV events (heart failure hospitalizations, myocardial infarction, fatal coronary heart disease, and stroke).

Results:Among these diabetic participants, 1,881 (49.4%), 683 (18.0%), and 1,600 (42.0%) cases of all-cause mortality, CV mortality, and CV events were documented, respectively, during the 26 years of follow-up. Further, the prevalence of these adverse events became lower with the increase of HLS (allP< 0.001). In the risk-factors adjusted Cox regression model, compared to participants with HLS of 0, participants with HLS of 2 had significant lower risk of all-cause mortality (HR = 0.811, 95% CI: 0.687–0.957,P= 0.013), CV mortality (HR = 0.744, 95% CI: 0.576–0.962,P= 0.024), and CV events (HR = 0.789, 95% CI: 0.661–0.943,P= 0.009). The association of HLS with CV events was stronger for women than men (Pfor interaction <0.05).

Conclusion:Adherence to a healthy lifestyle was associated with a lower risk of CV events and mortality in diabetics. Our findings suggest that the promotion of a healthy lifestyle would help reduce the increasing healthcare burden of diabetes.

Clinical Trial Registration:https://clinicaltrials.gov, Identifier: NCT00005131.
Ixabepilone: Overview of Effectiveness, Safety, and Tolerability in Metastatic Breast Cancer
Authors: Ibrahim Nuhad K.
Published: July 2021

Treatment algorithms for metastatic breast cancer describe sequential treatment with chemotherapy and, if appropriate, targeted therapy for as long as the patient receives benefit. The epothilone ixabepilone is a microtubule stabilizer approved as a monotherapy and in combination with capecitabine for the treatment of metastatic breast cancer in patients with demonstrated resistance to anthracyclines and taxanes. While chemotherapy and endocrine therapy form the backbone of treatment for metastatic breast cancer, the epothilone drug class has distinguished itself for efficacy and safety among patients with disease progression during treatment with chemotherapy. In phase III trials, ixabepilone has extended progression-free survival and increased overall response rates, with a manageable toxicity profile. Recent analyses of subpopulations within large pooled datasets have characterized the clinical benefit for progression-free survival and overall survival for ixabepilone in special populations, such as patients with triple-negative breast cancer or those who relapsed within 12 months of prior treatment. Additional investigation settings for ixabepilone therapy discussed here include adjuvant therapy, weekly dosing schedules, and ixabepilone in new combinations of treatment. As with other microtubule stabilizers, ixabepilone treatment can lead to peripheral neuropathy, but evidence-based management strategies may reverse these symptoms. Dose reductions did not appear to have an impact on the efficacy of ixabepilone plus capecitabine. Incorporation of ixabepilone into individualized treatment plans can extend progression-free survival in a patient population that continues to represent an unmet need.
Circular RNAs in Lung Cancer: Recent Advances and Future Perspectives
Authors: Chen Huan-Huan , Zhang Tie-Ning , Wu Qi-Jun , Huang Xin-Mei , Zhao Yu-Hong
Published: July 2021

Globally, lung cancer is the most commonly diagnosed cancer and carries with it the greatest mortality rate, with 5-year survival rates varying from 4–17% depending on stage and geographical differences. For decades, researchers have studied disease mechanisms, occurrence rates and disease development, however, the mechanisms underlying disease progression are not yet fully elucidated, thus an increased understanding of disease pathogenesis is key to developing new strategies towards specific disease diagnoses and targeted treatments. Circular RNAs (circRNAs) are a class of non-coding RNA widely expressed in eukaryotic cells, and participate in various biological processes implicated in human disease. Recent studies have indicated that circRNAs both positively and negatively regulate lung cancer cell proliferation, migration, invasion and apoptosis. Additionally, circRNAs could be promising biomarkers and targets for lung cancer therapies. This review systematically highlights recent advances in circRNA regulatory roles in lung cancer, and sheds light on their use as potential biomarkers and treatment targets for this disease.
HOTTIP Enhances Gemcitabine and Cisplatin Resistance Through Sponging miR-637 in Cholangiocarcinoma
Authors: Gao Kun , Chen Shuhua , Yang Xiangyu
Published: July 2021

Chemo-resistance prominently hampers the effects of systemic chemotherapy to cholangiocarcinoma (CCA). Long non-coding RNAs (lncRNAs) have been shown to have great importance not only in tumorigenesis but also in therapeutic prognosis. The aim of this study is to investigate the role of lncRNA HOTTIP in the chemo-resistance to cisplatin and gemcitabine (CG) in CCA. The upregulated expression of HOTTIP was observed in CCA patients and the upregulation was associated with therapeutic responsiveness and prognosis. HOTTIP silencing powerfully increased the chemotherapy sensitivity through weakening proliferation and colony formation and increasing apoptosis. Subsequently, miR-637 was identified as the functional target of HOTTIP, since mechanically it could be targeted by HOTTIP and functionally its overexpression dismissed the changes by HOTTIP silencing in vitro and in vivo. Moreover, LIM and SH3 domain protein 1 (LASP1) could be targeted and regulated by miR-637. In all, HOTTIP modulates the sensitivity to CG in CCA through the HOTTIP/miR-637/LASP1 regulatory axis, providing a new opportunities for CCA treatment.
Therapeutic Potential of Targeting Stromal Crosstalk-Mediated Immune Suppression in Pancreatic Cancer
Authors: Du Wenting , Pasca di Magliano Marina , Zhang Yaqing
Published: July 2021

The stroma-rich, immunosuppressive microenvironment is a hallmark of pancreatic ductal adenocarcinoma (PDA). Tumor cells and other cellular components of the tumor microenvironment, such as cancer associated fibroblasts, CD4+ T cells and myeloid cells, are linked by a web of interactions. Their crosstalk not only results in immune evasion of PDA, but also contributes to pancreatic cancer cell plasticity, invasiveness, metastasis, chemo-resistance, immunotherapy-resistance and radiotherapy-resistance. In this review, we characterize several prevalent populations of stromal cells in the PDA microenvironment and describe how the crosstalk among them drives and maintains immune suppression. We also summarize therapeutic approaches to target the stroma. With a better understanding of the complex cellular and molecular networks in PDA, strategies aimed at sensitizing PDA to chemotherapy or immunotherapy through re-programing the tumor microenvironment can be designed, and in turn lead to improved clinical treatment for pancreatic cancer patients.
Zusanli (ST36) Acupoint Injection With Dexamethasone for Chemotherapy-Induced Myelosuppression: A Systematic Review and Meta-Analysis
Authors: Chen Jiangfeng , Lin Zhixian , Ding Jiyuan
Published: July 2021

Objective

Myelosuppression is the most common adverse reaction of chemotherapy, which seriously affects the course of treatment. Zusanli (ST36) acupoint injection with dexamethasone has achieved good clinical efficacy in China. This study aimed to systematically evaluate the efficacy of ST36 acupoint injection with dexamethasone in the treatment of chemotherapy-induced myelosuppression (CIM).

Methods

Randomized controlled trials of CIM treated with ST36 acupoint injection with dexamethasone were retrieved from eight electronic databases. We used the Cochrane Collaboration tool to assess the risk of bias. Excel 2010 was used to establish a database for information extraction, and RevMan 5.3.0 software was used to analyze the included test data. GRADE profiler 3.6 software was used to grade the quality of evidence for the outcome indicators of the study.

Results

A total of 17 studies involving 1177 patients were included in this meta-analysis. The results showed that, compared with conventional western medicine (CWM), ST36 acupoint injection with dexamethasone could significantly improve the clinical total effective rate [RR=1.95, 95% CI (1.53, 2.49), P <0.00001] and increase white blood cell (WBC) (MD=1.38, 95% CI (0.74, 2.01), P<0.0001) and hemoglobin (Hb) levels [MD=3.89, 95% CI (1.57, 6.20), P=0.001]. In addition, ST36 acupoint injection with dexamethasone can shorten recovery time of myelosuppression [MD=-3.94, 95% CI (-4.97 to -2.91), P<0.00001] and improve Karnofsky performance status [MD=10.7, 95% CI (1.36, 20.05), P=0.02<0.05]. However, there was no significant difference among ST36 acupoint injection with dexamethasone and CWM in platelet (PLT) elevation [MD=4.61, 95% CI (-10.14, 19.35), P=0.54].

Conclusion

This study found that ST36 acupoint injection with dexamethasone had a positive effect on CIM. However, more studies with well-designed, large sample size, strict randomization, and clear descriptions about detection and reporting processes are needed in the future to further confirm the efficacy of ST36 acupoint injection with dexamethasone in the treatment of CIM.

Systematic Review Registration

https://www.crd.york.ac.uk/, identifier CRD42021223979.
Additional Value of 18F-FDOPA Amino Acid Analog Radiotracer to Irradiation Planning Process of Patients With Glioblastoma Multiforme
Authors: Sipos David , László Zoltan , Tóth Zoltan , Kovács Peter , Tollár Jozsef , Gulybán Akos , Lakosi Ferenc , Repa Imre , Kovács Arpad
Published: July 2021

Purpose

To investigate the added value of 6-(18F]-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) PET to radiotherapy planning in glioblastoma multiforme (GBM).

Methods

From September 2017 to December 2020, 17 patients with GBM received external beam radiotherapy up to 60 Gy with concurrent and adjuvant temozolamide. Target volume delineations followed the European guideline with a 2-cm safety margin clinical target volume (CTV) around the contrast-enhanced lesion+resection cavity on MRI gross tumor volume (GTV). All patients had FDOPA hybrid PET/MRI followed by PET/CT before radiotherapy planning. PET segmentation followed international recommendation: T/N 1.7 (BTV1.7) and T/N 2 (BTV2.0) SUV thresholds were used for biological target volume (BTV) delineation. For GTV-BTVs agreements, 95% of the Hausdorff distance (HD95%) from GTV to the BTVs were calculated, additionally, BTV portions outside of the GTV and coverage by the 95% isodose contours were also determined. In case of recurrence, the latest MR images were co-registered to planning CT to evaluate its location relative to BTVs and 95% isodose contours.

Results

Average (range) GTV, BTV1.7, and BTV2.0 were 46.58 (6–182.5), 68.68 (9.6–204.1), 42.89 (3.8–147.6) cm3, respectively. HD95% from GTV were 15.5 mm (7.9–30.7 mm) and 10.5 mm (4.3–21.4 mm) for BTV1.7 and BTV2.0, respectively. Based on volumetric assessment, 58.8% (28–100%) of BTV1.7 and 45.7% of BTV2.0 (14-100%) were outside of the standard GTV, still all BTVs were encompassed by the 95% dose. All recurrences were confirmed by follow-up imaging, all occurred within PTV, with an additional outfield recurrence in a single case, which was not DOPA-positive at the beginning of treatment. Good correlation was found between the mean and median values of PET/CT and PET/MRI segmented volumes relative to corresponding brain-accumulated enhancement (r = 0.75; r = 0.72).

Conclusion

18FFDOPA PET resulted in substantial larger tumor volumes compared to MRI; however, its added value is unclear as vast majority of recurrences occurred within the prescribed dose level. Use of PET/CT signals proved to be feasible in the absence of direct segmentation possibilities of PET/MR in TPS. The added value of 18FFDOPA may be better exploited in the context of integrated dose escalation.
Case Report: Analysis of Inflammatory Cytokines IL-6, CCL2/MCP1, CCL5/RANTES, CXCL9/MIG, and CXCL10/IP10 in a Cystic Fibrosis Patient Cohort During the First Wave of the COVID-19 Pandemic
Authors: Baresi Giulia , Giacomelli Mauro , Moratto Daniele , Chiarini Marco , Conforti Immacolata Claudia , Padoan Rita , Poli Piercarlo , Timpano Silviana , Caldarale Francesca , Badolato Raffaele
Published: July 2021

Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, data registered in the European countries revealed increasing cases of infection in cystic fibrosis (CF) patients. In the course of this pandemic, we enrolled 17 CF patients for a study evaluating inflammatory markers. One of them developed COVID-19, giving us the possibility to analyze inflammatory markers in the acute phase as compared to levels detected before and after the infectious episode and to levels measured in the other CF patients enrolled to the study who did not experience COVID-19 and 23 patients referred to our center for SARS-CoV-2 infection.
Sleep Duration and Quality and Sensory Reactivity in School-Aged Children: The Spanish Cross-Sectional InProS Study
Authors: Fernández-Pires Paula , Valera-Gran Desirée , Hurtado-Pomares Miriam , Espinosa-Sempere Cristina , Sánchez-Pérez Alicia , Juárez-Leal Iris , Ruiz-Carbonell María-Pilar , Peral-Gómez Paula , Campos-Sánchez Irene , Pérez-Vázquez María-Teresa , Navarrete-Muñoz Eva-María
Published: July 2021

Background: The relationship between children's sleep and health has been widely examined; however, research focused on the link between sleep and sensory reactivity in children without medical conditions is relatively new and based on studies with small samples. Hence, we aimed at exploring the association between sleep duration and quality and prevalence of sensory reactivity in a population-based sample of children aged 3–7.

Methods: We examined data on 579 school-age children from the InProS project, a cross-sectional population-based study. Children's sleep duration was classified as <10 vs. ≥10 h/day, and sleep quality was measured using the Pediatric Sleep Questionnaire, defining poor quality sleep as a score of ≥0.33. The Short Sensory Profile (SSP) was used to classify children with or without sensory reactivity using the cut-off points proposed by W. Dunn for SSP total score and each SSP subscale. Prevalence ratios (PR) using Poisson multiple regression models with robust variance were estimated to examine main associations.

Results: Around a third (32.6%; n = 189) slept <10 h/day and 10.4% presented poor sleep quality. The prevalence of sensory reactivity was 29.5% for total SSP (<155), 11.4% for tactile sensitivity (<30), 15% for taste/smell sensitivity (<15), 22.5% for movement sensitivity (<13), 49.1% for under-responsive/seeks sensation (<27), 44.4% for auditory filtering (<23), 12.4% for low energy/weak (<26), and 25.4% for visual/auditory sensitivity (<19). Main findings indicated that poor sleep quality was significantly associated with a greater prevalence of sensory reactivity for SSP total score (PR = 1.27; IC 95%: 1.18; 1.38), tactile sensitivity (PR = 1.09, IC95%: 1.00–1.19), taste/smell sensitivity (PR = 1.18, IC95%: 1.08–1.30), under-responsive/seeks sensation (PR = 1.28, IC95%: 1.20–1.37), auditory filtering (PR = 1.31, IC95%: 1.23–1.39), low energy/weak (PR = 1.14, IC95%: 1.04–1.25) and audiovisual sensitivity (PR = 1.15, IC95%: 1.05–1.26) scores after adjusting for potential confounders.

Conclusions: In this study, we observed that poor sleep quality was statistically significantly associated with a higher prevalence of sensory reactivity as measured by the total SSP and almost all SSP subscales. To our knowledge, this is the first time that this association has been explored and reported. Further research from prospective studies is required to confirm these findings.
Fetal Superior Vena Cava Blood Flow and Its Fraction of Cardiac Output: A Longitudinal Ultrasound Study in the Second Half of Pregnancy
Authors: Stefopoulou Maria , Johnson Jonas , Herling Lotta , Lindgren Peter , Kiserud Torvid , Acharya Ganesh
Published: July 2021

Introduction: In the fetus, a large proportion of the superior vena cava blood flow (QSVC) comes from the brain. To provide the possibility of using this blood flow as a representation of fetal brain circulation, we aimed to determine the fetal QSVC and its fraction of cardiac output during the second half of physiological pregnancies.

Materials and Methods: This was a prospective longitudinal study specifically designed for studying fetal hemodynamic development. Healthy women with singleton low-risk pregnancies were included. Ultrasonography was performed at 4-weekly intervals from 20+0 gestational weeks to term. Doppler velocity recordings of the superior vena cava (SVC) and cardiac ventricular outflow tracts were used to obtain the time-averaged maximum velocities (TAMxV). Vessel diameters were measured to calculate their cross-sectional areas (CSA): π(diameter/2)2. Blood flow (Q) was computed as: h*TAMxV*CSA, h being the spatial blood velocity profile, to obtain QSVC and cardiac outputs. The sum of left and right ventricular cardiac outputs constituted the combined cardiac output (CCO). Ultrasound biometry based estimated fetal weight and brain weight were used to normalize the flow. QSVC was also expressed as the fraction (%) of CCO. Gestational age specific percentiles were established for each blood flow parameter using multilevel modeling.

Results: Totally, 134 of the 142 included women were eligible for the study with 575 sets of observations. The SVC mean diameter (19–52 mm), mean TAMxV (8.83–16.14 cm/s), and QSVC (15.4–192.0 ml/min) increased significantly during the second half of pregnancy (p < 0.001) while the mean QSVC normalized by estimated fetal weight (49 ml/min/kg) and by estimated brain weight (50 ml/min/100 g) were relatively stable. Similarly, the mean CCO increased (156–1,776 ml/min; p < 0.001) while the normalized CCO (509 ± 13 ml/min/kg) and QSVC as a fraction of CCO (10 ± 0.92%) did not change significantly with gestational age.

Conclusion: We provide reference values for fetal QSVC which increases significantly with gestation, and constitutes roughly 10% of the fetal CCO at any time during the second half of pregnancy.
Streptococcus pneumoniae Serotypes Carried by Young Children and Their Association With Acute Otitis Media During the Period 2016–2019
Authors: Ekinci Esra , Desmet Stefanie , Van Heirstraeten Liesbet , Mertens Colette , Wouters Ine , Beutels Philippe , Verhaegen Jan , Malhotra-Kumar Surbhi , Theeten Heidi ,   NPcarriage Group
Published: July 2021

Background:Streptococcus pneumoniae(Sp) is a major cause of acute otitis media (AOM). Pneumococcal conjugate vaccine (PCV) programs have altered pneumococcal serotype epidemiology in disease and carriage. In this study, we used samples collected during a cross-sectional study to examine if the clinical picture of acute otitis media (AOM) in young children exposed to the PCV program in Belgium was related to the carried pneumococcal strains, and if their carriage profile differed from healthy children attending daycare centers.

Material/Methods:In three collection periods from February 2016 to May 2018, nasopharyngeal swabs and background characteristics were collected from children aged 6–30 months either presenting at their physician with AOM (AOM-group) or healthy and attending day care (DCC-group). Clinical signs of AOM episodes and treatment schedule were registered by the physicians. Sp was detected, quantified, and characterized using both conventional culture analysis and real-time PCR analysis.

Results:Among 3,264 collected samples, overall pneumococcal carriage and density were found at similar rates in both AOM and DCC. As expected non-vaccine serotypes were most frequent: 23B (AOM: 12.3%; DCC: 17.4%), 11A (AOM: 7.5%; DCC: 7.4%) and 15B (AOM: 7.5%; DCC: 7.1%). Serotypes 3, 6C, 7B, 9N, 12F, 17F, and 29 were more often found in AOM than in DCC (p-value < 0.05), whereas 23A and 23B were less often present in AOM (p-value < 0.05). Antibiotic non-susceptibility of Sp strains was similar in both groups. No predictors of AOM severity were identified.

Conclusion:In the present study, overall carriage prevalence and density ofS. pneumoniaewere found similar in young children with AOM and in healthy children attending day-care centers in Belgium. Certain serotypes not currently included in the PCV vaccines were found to be carried more often in children with AOM than in DCC, a finding that might suggest a relationship between these serotypes and AOM.
A Promising Anticancer Agent Dimethoxycurcumin: Aspects of Pharmacokinetics, Efficacy, Mechanism, and Nanoformulation for Drug Delivery
Authors: Sohail Muhammad , Guo Wenna , Yang Xin , Li Zhiyong , Li Yanli , Xu Hui , Zhao Feng
Published: July 2021

Curcumin is a well-known anticancer natural product with various significant bioactivities that has been well documented, but its widespread use is mainly hindered by insufficient ADME properties such as poor solubility and low metabolic stability. Dimethoxycurcumin (DiMC) is a kind of lipophilic compound derived from curcumin that maintains its anticancer potency and has greatly improved systematic bioavailability. Therefore, DiMC is regarded as a promising plant-derived anticancer agent that deserves to be well developed. Herein, we concentrate on the published work by those from original research groups concerned with the pharmacokinetics, efficacy, and mechanism of DiMC involved in the treatment of various tumors, as well as the nanoformulations for effective drug delivery.
CYP3A5 Genotype-Dependent Drug-Drug Interaction Between Tacrolimus and Nifedipine in Chinese Renal Transplant Patients
Authors: Yang Yilei , Huang Xin , Shi Yinping , Yang Rui , Shi Haiyan , Yang Xinmei , Hao Guoxiang , Zheng Yi , Wang Jianning , Su Lequn , Li Yan , Zhao Wei
Published: July 2021

Purpose: The drug-drug interactions (DDIs) of tacrolimus greatly contributed to pharmacokinetic variability. Nifedipine, frequently prescribed for hypertension, is a competitive CYP3A5 inhibitor which can inhibit tacrolimus metabolism. The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-nifedipine DDI in Chinese renal transplant patients.

Method: All renal transplant patients were divided into CYP3A5*3/*3 homozygotes (group I) and CYP3A5*1 allele carriers (CYP3A5*1/*1 + CYP3A5*1/*3) (group II). Each group was subdivided into patients taking tacrolimus co-administered with nifedipine (CONF) and that administrated with tacrolimus alone (Controls). Tacrolimus trough concentrations (C0) were measured using high performance liquid chromatography. A retrospective analysis compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between CONF and Controls in group I and II, respectively. At the same time, a multivariate line regression analysis was made to evaluate the effect of variates on C0/D.

Results: In this study, a significant DDI between tacrolimus and nifedipine with respect to the CYP3A5*3 polymorphism was confirmed. In group I (n = 43), the C0/D of CONF was significantly higher than in Controls [225.2 ± 66.3 vs. 155.1 ± 34.6 ng/ml/(mg/kg); p = 0.002]. However, this difference was not detected in group II (n = 27) (p = 0.216). The co-administrated nifedipine and CYP3A5*3/*3 homozygotes significantly increased tacrolimus concentrations in multivariate line regression analysis.

Discussion: A CYP3A5 genotype-dependent DDI was found between tacrolimus and nifedipine. Therefore, personalized therapy accounting for CYP3A5 genotype detection as well as therapeutic drug monitoring are necessary for renal transplant patients when treating with tacrolimus and nifedipine.
Intraindividual Doppler Flow Response to Exercise Differs Between Symptomatic and Asymptomatic Achilles Tendons
Authors: Risch Lucie , Stoll Josefine , Schomöller Anne , Engel Tilman , Mayer Frank , Cassel Michael
Published: July 2021

Objective

This study investigated intraindividual differences of intratendinous blood flow (IBF) in response to running exercise in participants with Achilles tendinopathy.

Design

This is a cross-sectional study.

Setting

The study was conducted at the University Outpatient Clinic.

Participants

Sonographic detectable intratendinous blood flow was examined in symptomatic and contralateral asymptomatic Achilles tendons of 19 participants (42 ± 13 years, 178 ± 10 cm, 76 ± 12 kg, VISA-A 75 ± 16) with clinically diagnosed unilateral Achilles tendinopathy and sonographic evident tendinosis.

Intervention

IBF was assessed using Doppler ultrasound “Advanced Dynamic Flow” before (Upre) and 5, 30, 60, and 120 min (U5–U120) after a standardized submaximal constant load run.

Main Outcome Measure

IBF was quantified by counting the number (n) of vessels in each tendon.

Results

At Upre, IBF was higher in symptomatic compared with asymptomatic tendons [mean 6.3 (95% CI: 2.8–9.9) and 1.7 (0.4–2.9), p < 0.01]. Overall, 63% of symptomatic and 47% of asymptomatic Achilles tendons responded to exercise, whereas 16 and 11% showed persisting IBF and 21 and 42% remained avascular throughout the investigation. At U5, IBF increased in both symptomatic and asymptomatic tendons [difference to baseline: 2.4 (0.3–4.5) and 0.9 (0.5–1.4), p = 0.05]. At U30 to U120, IBF was still increased in symptomatic but not in asymptomatic tendons [mean difference to baseline: 1.9 (0.8–2.9) and 0.1 (-0.9 to 1.2), p < 0.01].

Conclusion

Irrespective of pathology, 47–63% of Achilles tendons responded to exercise with an immediate acute physiological IBF increase by an average of one to two vessels (“responders”). A higher amount of baseline IBF (approximately five vessels) and a prolonged exercise-induced IBF response found in symptomatic ATs indicate a pain-associated altered intratendinous “neovascularization.”
Effects of Oral Exposure to Mn-Doped ZnS Quantum Dots on Intestinal Tract and Gut Microbiota in Mice
Authors: Yang Yanjie , Xia Ruixue , Zhang Xiaomei , Wang Xu , Zhou Yuchen , Wang Honggang , Feng Yu , Lv Shuangyu , Ji Shaoping
Published: July 2021

Mn-doped ZnS quantum dots (QDs) with excellent optical properties have been explored in a wide range of fields. Their potential adverse effects on biological systems and human health should be evaluated before biological application. In the present study, we investigated the effect of Mn-doped ZnS QDs on the intestinal tract and gut microbiota structures at 2 h and 14 days (d) after 14 d repeated oral exposure in mice. Flame atomic absorption spectrophotometry (FAAS), histopathological examination, and transmission electron microscopy (TEM) were used to assess the absorption and toxicity of Mn-doped ZnS QDs on the intestinal tract. The 16S rRNA gene sequencing was used to evaluate the gut microbial communities. Mn-doped ZnS QDs did not accumulate in the duodenum, jejunum, ileum, or colon. The Zn content of feces was not significantly higher than in the control group. No major histological changes were found in these tissues. The intestinal microvilli remained regular, but swelling of mitochondria and endoplasmic reticulum was detected by TEM at 14 d after the last gavage. A total of 2,712 operational taxonomic units (OTUs) were generated. Mn-doped ZnS QDs treatment did not significantly change the α-diversity of Richness, Chao1, Shannon, and Simpson indexes. According to principal component analysis (PCA), Mn-doped ZnS QDs had no effect on the overall structure of the gut microbiota. No significant change occurred at the phylum level, while three genera were downregulated at 2 h and seven changed at 14 d after the last gavage. Our findings revealed that Mn-doped ZnS QDs had a little stimulation of the intestinal tract and gut microbiota, and oral administration may be a safe route for biological application (such as bioimaging and drug delivery).
Assessment of Epigenetic and Phenotypic Variation in Populus nigra Regenerated via Sequential Regeneration
Authors: Zhang Weixi , Wang Yanbo , Diao Shu , Zhong Shanchen , Wu Shu , Wang Li , Su Xiaohua , Zhang Bingyu
Published: July 2021

Somatic variation has been demonstrated in tissue culture regenerated plants of many species. In the genus Populus, phenotypic variation caused by changes in 5-methylcytosine within the plant genome have been reported. To date, the phenotypic and epigenetic stability of plants regenerated from sequential regeneration has not been tested in trees. In this study, we detected DNA methylation of CCGG sites in regenerated plants of five generations in Populus nigra using methylation-sensitive amplified polymorphisms, and evaluated their growth performance and physiological traits. About 10.86–26.80% of CCGG sites in the regenerated plant genome were demethylated and 5.50–8.45% were methylated, resulting in significantly lower DNA methylation levels among all regenerated plants than among donor plants. We detected a significant difference in methylation levels between first regeneration regenerated plants (G1) and those of the other four generations (G2–G5); there were no significant differences among the four later generations. Therefore, the dramatic decrease in DNA methylation levels occurred only in the first and second poplar regenerations; levels then stabilized later in the regeneration process, indicating that two regeneration events were sufficient to change the methylation statuses of almost all CCGG sites sensitive to regeneration. Differences in growth and physiological traits were observed between regenerated plants and donor plants, but were significant only among plants of certain generations. Significant correlations were detected between methylation level and transpiration rate, net photosynthetic rate, peroxidase activity, and instant water utilization efficiency, indicating the involvement of epigenetic regulation in this unpredictable phenotypic variation.
Introduction of the Carotenoid Biosynthesis α-Branch Into Synechocystis sp. PCC 6803 for Lutein Production
Authors: Lehmann Martin , Vamvaka Evgenia , Torrado Alejandro , Jahns Peter , Dann Marcel , Rosenhammer Lea , Aziba Amel , Leister Dario , Rühle Thilo
Published: July 2021

Lutein, made by the α-branch of the methyl-erythritol phosphate (MEP) pathway, is one of the most abundant xanthophylls in plants. It is involved in the structural stabilization of light-harvesting complexes, transfer of excitation energy to chlorophylls and photoprotection. In contrast, lutein and the α-branch of the MEP pathway are not present in cyanobacteria. In this study, we genetically engineered the cyanobacterium Synechocystis for the missing MEP α-branch resulting in lutein accumulation. A cassette comprising four Arabidopsis thaliana genes coding for two lycopene cyclases (AtLCYe and AtLCYb) and two hydroxylases (AtCYP97A and AtCYP97C) was introduced into a Synechocystis strain that lacks the endogenous, cyanobacterial lycopene cyclase cruA. The resulting synlut strain showed wild-type growth and only moderate changes in total pigment composition under mixotrophic conditions, indicating that the cruA deficiency can be complemented by Arabidopsis lycopene cyclases leaving the endogenous β-branch intact. A combination of liquid chromatography, UV-Vis detection and mass spectrometry confirmed a low but distinct synthesis of lutein at rates of 4.8 ± 1.5 nmol per liter culture at OD730 (1.03 ± 0.47 mmol mol–1 chlorophyll). In conclusion, synlut provides a suitable platform to study the α-branch of the plastidic MEP pathway and other functions related to lutein in a cyanobacterial host system.
Self-Fertilization, Inbreeding, and Yield in Alfalfa Seed Production
Authors: Dieterich Mabin Molly E. , Brunet Johanne , Riday Heathcliffe , Lehmann Lauren
Published: July 2021

Selfing (self-pollination) is the ultimate form of inbreeding, or mating among close relatives. Selfing can create yield loss when inbreeding depression, defined as a lower survival and reproduction of inbred relative to outbred progeny, is present. To determine the impact of selfing in alfalfa (Medicago sativaL.), we quantified the selfing rate of 32 alfalfa seed production fields located in three regions, namely, the Pacific Northwest (PNW), the Central Valley of California (CEV), and the Imperial Valley of California (IMP). Selfing rates (the proportion of selfed seeds) varied between 5.3 and 30% with an average of 12.2% over the 32 seed production fields. In both the parents and their progeny, we observed an excess of heterozygotes relative to Hardy–Weinberg expectations. We detected notable levels of inbreeding in parents (0.231 ± 0.007 parental inbreeding coefficient) and progeny (0.229 ± 0.005). There were a 15% decrease in the number of seeds per stem (seed set) and a 13% decline in the number of seeds per pod in selfed relative to outcrossed stems, but negligible inbreeding depression for pods per raceme and seed weight. The number of racemes on selfed stems increased significantly in fields with greater selfing rates, supporting the presence of geitonogamous or among flower selfing. Despite the significant level of inbreeding depression, seed set did not decrease in fields with higher selfing rates, where the greater number of racemes on the selfed stems increased the seed set. The effects of the field selfing rate on the seed yield metrics were mostly indirect with direct effects of the number of racemes per stem. Available data indicate that the majority of selfing in alfalfa is pollinator-mediated, and thus, eliminating selfing in alfalfa seed production would require the selection of self-incompatible varieties, which, by eliminating inbreeding depression, would provide a 15% potential increase in seed yield and an increase in future hay yield.
Mapping of Functional Subdomains in the atALKBH9B m6A-Demethylase Required for Its Binding to the Viral RNA and to the Coat Protein of Alfalfa Mosaic Virus
Authors: Alvarado-Marchena Luis , Marquez-Molins Joan , Martinez-Perez Mireya , Aparicio Frederic , Pallás Vicente
Published: July 2021

N6-methyladenosine (m6A) modification is a dynamically regulated RNA modification that impacts many cellular processes and pathways. This epitranscriptomic methylation relies on the participation of RNA methyltransferases (referred to as “writers”) and demethylases (referred to as “erasers”), respectively. We previously demonstrated that the Arabidopsis thaliana proteinatALKBH9B showed m6A-demethylase activity and interacted with the coat protein (CP) of alfalfa mosaic virus (AMV), causing a profound impact on the viral infection cycle. To dissect the functional activity ofatALKBH9B in AMV infection, we performed a protein-mapping analysis to identify the putative domains required for regulating this process. In this context, the mutational analysis of the protein revealed that the residues between 427 and 467 positions are critical forin vitrobinding to the AMV RNA. TheatALKBH9B amino acid sequence showed intrinsically disordered regions (IDRs) located at the N-terminal part delimiting the internal AlkB-like domain and at the C-terminal part. We identified an RNA binding domain containing an RGxxxRGG motif that overlaps with the C-terminal IDR. Moreover, bimolecular fluorescent experiments allowed us to determine that residues located between 387 and 427 are critical for the interaction with the AMV CP, which should be critical for modulating the viral infection process. Finally, we observed thatatALKBH9B deletions of either N-terminal 20 residues or the C-terminal’s last 40 amino acids impede their accumulation in siRNA bodies. The involvement of the regions responsible for RNA and viral CP binding and those required for its localization in stress granules in the viral cycle is discussed.