bluuebunny/crossref_metadata_2025 huggingface dataset:
Behavioral Symptoms May Correlate With the Load and Spatial Location of Tubers and With Radial Migration Lines in Tuberous Sclerosis Complex
Authors: Cohen Rony , Genizi Jacob , Korenrich Liora
Published: October 2021

Objective: Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous genetic disorder. The clinical manifestations are extensive and include neurological, dermatological, cardiac, ophthalmic, nephrological, and neuropsychiatric manifestations. The prediction and pathophysiology of neuropsychiatric disorders such as emotional symptoms, conduct problems, hyperactivity, and poor social behavior are poorly understood. The aim of the study was to diagnose neuropsychiatric symptoms in individuals with TSC, and to examine their possible correlations with quantity, magnitude, and spatial location of tubers and radial migration (RM) lines.

Methods: The cohort comprised 16 individuals with TSC, aged 5–29 years, with normal or low normal intelligence. The participants or their parents were requested to fill Strengths and Difficulties Questionnaire (SDQ) and the TAND (TSC-associated neuropsychiatric disorders) Checklist for assessment of their neuropsychiatric symptoms. Correlations were examined between these symptoms and the magnitude, quantities, and locations of tubers and white matter RM lines, as identified in T2/FLAIR brain MRI scans.

Results: The SDQ score for peer relationship problems showed correlation with the tuber load (r = 0.52, p < 0.05). Tuber load and learning difficulties correlated significantly in the temporal and parietal area. Mood swings correlated with tubers in the parietal area (r = 0.529, p < 0.05). RM lines in the temporal area correlated with abnormal total SDQ (r = 0.51, p < 0.05). Anxiety and extreme shyness were correlated with RM lines in the parietal area, r = 0.513, p < 0.05 and r = 0.593, p < 0.05, respectively. Hyperactive/inattention correlated negatively with RM lines in the parietal area (r = −707, p < 0.01).

Conclusions: These observations may lead to future studies for precise localization of neuropsychiatric symptoms, thereby facilitating directed therapy.
Long-Term Trends in Stroke Management and Burden Among Low-Income Women in a Rural Area From China (1992–2019): A Prospective Population-Based Study
Authors: Tian Xiaobing , Liu Jie , Yu Changshen , Hou Yabing , Zhan Changqing , Lin Qiuxing , Zhang Xinyu , Zhang Xin , Guo Dandan , Yang Qiaoxia , Tu Jun , Wang Yaogang , Ning Xianjia , Wang Jinghua
Published: October 2021

Although an increasing number of studies are considering sex-related differences in stroke burden, the trends in stroke burden and management among women in China, especially among low-income women, remain unclear. This study evaluated the long-term trends in stroke management and burden among low-income Chinese women during the period between 1992 and 2019. Stroke burden was assessed using the age-adjusted incidence of first-ever stroke, whereas stroke management was assessed using the rates of neuroimaging diagnoses, hospitalizations, case fatalities, and stroke recurrence. Stroke burden and management were analyzed during four study periods: 1992–1998, 1999–2004, 2005–2012, and 2013–2019. During the 193,385 person-years of surveillance in this study, 597 female stroke patients were identified. The stroke incidences per 100,000 person-years were 88.1 cases during 1992–1998, 145.4 cases during 1999–2004, 264.3 cases during 2005–2012, and 309.8 cases during 2013–2019 (P < 0.001). Between 1992 and 2019, the incidence of stroke significantly increased (6.4% annually) as did the incidence of ischemic stroke (7.8% annually; both, P < 0.001). The rates of neuroimaging diagnoses and hospitalizations significantly increased during the four periods, while the case fatality rates and 1-year recurrence rates decreased significantly for both overall strokes and ischemic strokes, especially among patients ≥45 years old (all, P < 0.001). Among low-income women in China, stroke management is gradually improving, despite the increasing stroke burden. Thus, improved healthcare coverage is needed to further reduce the stroke burden among low-income Chinese women.
A Long Time Constant May Endorse Sharp Waves and Spikes Over Sharp Transients in Scalp Electroencephalography: A Comparison of After-Slow Among Different Time Constants Concordant With High-Frequency Activity Analysis
Authors: Sultana Shamima , Hitomi Takefumi , Daifu Kobayashi Masako , Shimotake Akihiro , Matsuhashi Masao , Takahashi Ryosuke , Ikeda Akio
Published: October 2021

Objective: To clarify whether long time constant (TC) is useful for detecting the after-slow activity of epileptiform discharges (EDs): sharp waves and spikes and for differentiating EDs from sharp transients (Sts).

Methods: We employed 68 after-slow activities preceded by 32 EDs (26 sharp waves and six spikes) and 36 Sts from 52 patients with partial and generalized epilepsy (22 men, 30 women; mean age 39.08 ± 13.13 years) defined by visual inspection. High-frequency activity (HFA) associated with the apical component of EDs and Sts was also investigated to endorse two groups. After separating nine Sts that were labeled by visual inspection but did not fulfill the amplitude criteria for after-slow of Sts, 59 activities (32 EDs and 27 Sts) were analyzed about the total area of after-slow under three TCs (long: 2 s; conventional: 0.3 s; and short: 0.1 s).

Results: Compared to Sts, HFA was found significantly more with the apical component of EDs (p < 0.05). The total area of after-slow in all 32 EDs under TC 2 s was significantly larger than those under TC 0.3 s and 0.1 s (p < 0.001). Conversely, no significant differences were observed in the same parameter of 27 Sts among the three different TCs. Regarding separated nine Sts, the total area of after-slow showed a similar tendency to that of 27 Sts under three different TCs.

Significance: These results suggest that long TC could be useful for selectively endorsing after-slow of EDs and differentiating EDs from Sts. These findings are concordant with the results of the HFA analysis. Visual inspection is also equally good as the total area of after-slow analysis.
Contralateral Acupuncture for the Treatment of Phantom Limb Pain and Phantom Limb Sensation in Oncologic Lower Limb Amputee: A Case Report
Authors: Guo Qin , Di Zhong , Tian Hong-fang , Zhang Quan-ai
Published: October 2021

Phantom limb pain (PLP) and phantom limb sensation (PLS) are common and distressing sequelae of amputation. Current pain management following amputation is challenging and unsatisfying. In this case study, a 74-year-old woman underwent above-knee amputation because of the rhabdomyosarcoma in the right leg. Despite several analgesics, pain was poorly controlled. The phantom limb pain and sensation were immediately reduced by the contralateral acupuncture, and abolished after the third session with no side-effects, no relapse during the next 9 months. Contralateral acupuncture showed positive effect on PLP and PLS in this case, but more robust evidence would be needed to support the efficacy of this treatment technique for indication.
Revealing the Relevant Spatiotemporal Scale Underlying Whole-Brain Dynamics
Authors: Kobeleva Xenia , López-González Ane , Kringelbach Morten L. , Deco Gustavo
Published: October 2021

The brain rapidly processes and adapts to new information by dynamically transitioning between whole-brain functional networks. In this whole-brain modeling study we investigate the relevance of spatiotemporal scale in whole-brain functional networks. This is achieved through estimating brain parcellations at different spatial scales (100–900 regions) and time series at different temporal scales (from milliseconds to seconds) generated by a whole-brain model fitted to fMRI data. We quantify the richness of the dynamic repertoire at each spatiotemporal scale by computing the entropy of transitions between whole-brain functional networks. The results show that the optimal relevant spatial scale is around 300 regions and a temporal scale of around 150 ms. Overall, this study provides much needed evidence for the relevant spatiotemporal scales and recommendations for analyses of brain dynamics.
Automated Home-Cage Monitoring During Acute Experimental Colitis in Mice
Authors: Zentrich Eva , Talbot Steven R. , Bleich André , Häger Christine
Published: October 2021

For ethical and legal reasons it is necessary to assess the severity of procedures in animal experimentation. To estimate the degree of pain, suffering, distress or lasting harm, objective methods that provide gradebale parameters need to be tested and validated for various models. In this context, automated home-cage monitoring becomes more important as a contactless, objective, continuous and non-invasive method. The aim of this study was to examine a recently developed large scale automated home-cage monitoring system (Digital Ventilated Cage, DVC®) with regard to the applicability and added value for severity assessment in a frequently used acute colitis mouse model. Acute colitis was induced in female C57BL/6J mice by varying doses of DSS (1.5 and 2.5%), matched controls received water only (0%). Besides DVC® activity monitoring and nest scoring, model specific parameters like body weight, clinical colitis score, and intestinal histo-pathology were used. In a second approach, we questioned whether DVC® can be used to detect an influence of different handling methods on the behavior of mice. Therefore, we compared activity patterns of mice that underwent tunnel vs. tail handling for routine animal care procedures. In DSS treated mice, disease specific parameters confirmed induction of a graded colitis. In line with this, DVC® revealed reduced activity in these animals. Furthermore, the system displayed stress-related activity changes due to the restraining procedures necessary in DSS-treatment groups. However, no significant differences between tunnel vs. tail handling procedures were detected. For further analysis of the data, a binary classifier was applied to categorize two severity levels (burdened vs. not burdened) based on activity and body weight. In all DSS-treatment groups data points were allocated to the burdened level, in contrast to a handling group. The fraction of “burdened” animals reflected well the course of colitis development. In conclusion, automated home-cage monitoring by DVC® enabled severity assessment in a DSS-induced colitis model equally well as gold standard clinical parameters. In addition, it revealed changes in activity patterns due to routine handling procedures applied in experimental model work. This indicates that large scale home-cage monitoring can be integrated into routine severity assessment in biomedical research.
A Generalizable and Discriminative Learning Method for Deep EEG-Based Motor Imagery Classification
Authors: Huang Xiuyu , Zhou Nan , Choi Kup-Sze
Published: October 2021

Convolutional neural networks (CNNs) have been widely applied to the motor imagery (MI) classification field, significantly improving the state-of-the-art (SoA) performance in terms of classification accuracy. Although innovative model structures are thoroughly explored, little attention was drawn toward the objective function. In most of the available CNNs in the MI area, the standard cross-entropy loss is usually performed as the objective function, which only ensures deep feature separability. Corresponding to the limitation of current objective functions, a new loss function with a combination of smoothed cross-entropy (with label smoothing) and center loss is proposed as the supervision signal for the model in the MI recognition task. Specifically, the smoothed cross-entropy is calculated by the entropy between the predicted labels and the one-hot hard labels regularized by a noise of uniform distribution. The center loss learns a deep feature center for each class and minimizes the distance between deep features and their corresponding centers. The proposed loss tries to optimize the model in two learning objectives, preventing overconfident predictions and increasing deep feature discriminative capacity (interclass separability and intraclass invariant), which guarantee the effectiveness of MI recognition models. We conduct extensive experiments on two well-known benchmarks (BCI competition IV-2a and IV-2b) to evaluate our method. The result indicates that the proposed approach achieves better performance than other SoA models on both datasets. The proposed learning scheme offers a more robust optimization for the CNN model in the MI classification task, simultaneously decreasing the risk of overfitting and increasing the discriminative power of deeply learned features.
Well-being Messaging for Mammalian Milks: A Scoping Review
Authors: Moradi Saleh , Hort Joanne
Published: October 2021

Having a holistic understanding of research on well-being messaging for milk is vital to allow the optimal communication of the association between milk consumption and various nutritional, physical, and psychological benefits to the consumer. This work is a unique interdisciplinary, scoping review of existing research on well-being messaging for milk. Well-being messages are ways to communicate the broad well-being benefits of specific products to the consumer through information on food content or statements that link a product with favourable components, functions, or well-being outcomes. Leveraging this broad definition, and by proposing a guiding theoretical model that considers well-being messaging as a form of communication, milk well-being messaging literature has been mapped across time, geographical locations, disciplines, and product types. Two hundred forty-six were records included in this review, of which 177 were empirical studies. Studies were disseminated between 1954 and 2019, with 54.9% published after 2011. Food, Agriculture, and Biological Sciences (N= 109), Nutrition and Dietetics (N= 78), and Medicine, Public Health, and Health Professions (N= 69) disciplines have attracted the most publications, with numbers generally increasing in most recent years. The majority of included non-empirical records (69.6%) provide lists of commercially available products carrying well-being messaging and/or regulations on the use of particular well-being messages for milk according to various legislative authorities. Most of the empirical studies were conducted in North America (N= 71), West Europe (N= 52), and Oceania (N= 22), and on plain (i.e., unflavoured) milk (N= 152). Whereas, most studied elements of well-being messaging for milk across time, i.e.,message(N= 169),product(N= 141),receiver(N= 101), andcontext(N= 72) have seen an increasing number of studies in recent years;sender(N= 51) andmedium(N= 27) have been even less studied in the past four years. A more detailed analysis of research trends in each element of well-being messaging is reported. The research highlights immediate and strategic knowledge gaps that need further attention from researchers and/or policymakers in order to improve the “messaging” of well-being benefits of milk consumption to the consumer.
Implementation of a Physical Activity Program Protocol in Schoolchildren: Effects on the Endocrine Adipose Tissue and Cognitive Functions
Authors: Diaz-Castro Javier , Garcia-Vega Jose Eulogio , Ochoa Julio J. , Puche-Juarez María , Toledano Juan M. , Moreno-Fernandez Jorge
Published: October 2021

Practicing exercise is one of the best strategies to promote well-being and quality of life, however physical activity in schoolchildren and adolescents is developed in an unpredictable, intermittent way and in short periods. There are relatively few intervention studies investigating the role of physical activity in schoolchildren endocrine function of adipose tissue and cognitive function. One hundred and three boys, divided into two groups: control (n = 51, did not perform additional physical activity) and exercise (n = 52, performed vigorous physical activity after the regular school classes). The exercise group, developed a 6 months physical activity protocol delivered by the physical education teacher during the second semester of the academic course (6 months). Body composition measurements, adherence to the Mediterranean diet, nutritional intake, hematological and biochemical parameters, endocrine function of the adipose tissue and biomarkers of brain molecular function were assessed at enrolment and after 6 months of intervention. No statistically significant differences between both groups were found for age, height and bone mass. Weight and BMI was lower in the exercise group compared to the control group, increasing lean mass and reducing fat mass. 58.68% of children in the exercise group showed high adherence to the Mediterranean Diet compared to 46.32% of the control group. The exercise group was more concerned about their diet consumed more fiber, vitamin B1, B2, B6, B12, D, Niacin, Folic acid, Fe, Zn, Se and Cu. Triglycerides levels and HDL-cholesterol were higher in the exercise group at the end of the study. Leptin, MCP-1, lipocalin-2, adipsin and PAI-1 levels were lower in the exercise group at the end of the exercise protocol. In contrast, adiponectin and osteocrin markedly increased in the exercise group. Moreover, marked increases were recorded in healthy brain state biomarkers (NGF, BDNF, and irisin) in the exercise group, which could have a positive impact on academic performance. Taken together, all the findings reported are consistent with many benefits of the exercise protocol on adipose tissue and brain molecular function, demonstrating the usefulness of early interventions based on physical activity in children to reduce risk factors related to sedentary lifestyle.
Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Progresses and Challenges
Authors: Liu Hao-Tian , Jiang Meng-Jie , Deng Zhu-Jian , Li Le , Huang Jian-Li , Liu Zhen-Xiu , Li Le-Qun , Zhong Jian-Hong
Published: October 2021

Hepatocellular carcinoma (HCC) is one of the most common malignant tumor in the world and its incidence is increasing in many countries. In recent years, with the deepening understanding of the immune and pathological mechanisms of HCC, immunotherapy based on the regulation of tumor immune microenvironment has become a new treatment choice for patients with HCC. Immune checkpoint inhibitors (ICIs) targeting programmed death protein-1, programmed death protein-ligand-1, or cytotoxic T-lymphocyte-associated antigen 4 are the most widely used. Instead of general immune-enhancing therapies, ICIs can reactivate anti-tumor immune responses by disrupting co-inhibitory T cell signaling. In this review, the research progress and existing problems of ICIs in the treatment of HCC in recent years are reviewed.
Identification of Gene-Set Signature in Early-Stage Hepatocellular Carcinoma and Relevant Immune Characteristics
Authors: Zhao Qijie , Wongpoomchai Rawiwan , Chariyakornkul Arpamas , Xiao Zhangang , Pilapong Chalermchai
Published: October 2021

Background

The incidence of hepatocellular carcinoma (HCC) is rising worldwide, and there is limited therapeutic efficacy due to tumor microenvironment heterogeneity and difficulty in early-stage screening. This study aimed to develop and validate a gene set-based signature for early-stage HCC (eHCC) patients and further explored specific marker dysregulation mechanisms as well as immune characteristics.

Methods

We performed an integrated bioinformatics analysis of genomic, transcriptomic, and clinical data with three independent cohorts. We systematically reviewed the crosstalk between specific genes, tumor prognosis, immune characteristics, and biological function in the different pathological stage samples. Univariate and multivariate survival analyses were performed in The Cancer Genome Atlas (TCGA) patients with survival data. Diethylnitrosamine (DEN)-induced HCC in Wistar rats was employed to verify the reliability of the predictions.

Results

We identified a Cluster gene that potentially segregates patients with eHCC from non-tumor, through integrated analysis of expression, overall survival, immune cell characteristics, and biology function landscapes. Immune infiltration analysis showed that lower infiltration of specific immune cells may be responsible for significantly worse prognosis in HCC (hazard ratio, 1.691; 95% CI: 1.171–2.441; p = 0.012), such as CD8 Tem and cytotoxic T cells (CTLs) in eHCC. Our results identified that Cluster C1 signature presented a high accuracy in predicting CD8 Tem and CTL immune cells (receiver operating characteristic (ROC) = 0.647) and cancerization (ROC = 0.946) in liver. As a central member of Cluster C1, overexpressed PRKDC was associated with the higher genetic alteration in eHCC than advanced-stage HCC (aHCC), which was also connected to immune cell-related poor prognosis. Finally, the predictive outcome of Cluster C1 and PRKDC alteration in DEN-induced eHCC rats was also confirmed.

Conclusions

As a tumor prognosis-relevant gene set-based signature, Cluster C1 showed an effective approach to predict cancerization of eHCC and its related immune characteristics with considerable clinical value.
Development and Validation of an E2F-Related Gene Signature to Predict Prognosis of Patients With Lung Squamous Cell Carcinoma
Authors: Wang Cailian , Gu Xuyu , Zhang Xiuxiu , Zhou Min , Chen Yan
Published: October 2021

Background

Lung squamous cell carcinoma (LUSC) generally correlates with poor clinical prognoses due to the lack of available prognostic biomarkers. This study is designed to identify a potential biomarker significant for the prognosis and treatment of LUSC, so as to provide a scientific basis for clinical treatment decisions.

Methods

Genomic changes in LUSC samples before and after radiation were firstly discussed to identify E2 factor (E2F) pathway of prognostic significance. A series of bioinformatics analyses and statistical methods were combined to construct a robust E2F-related prognostic gene signature. Furthermore, a decision tree and a nomogram were established according to the gene signature and multiple clinicopathological characteristics to improve risk stratification and quantify risk assessment for individual patients.

Results

In our investigated cohorts, the E2F-related gene signature we identified was capable of predicting clinical outcomes and therapeutic responses in LUSC patients, besides, discriminative to identify high-risk patients. Survival analysis suggested that the gene signature was independently prognostic for adverse overall survival of LUSC patients. The decision tree identified the strong discriminative performance of the gene signature in risk stractification for overall survival while the nomogram demonstrated a high accuracy.

Conclusion

The E2F-related gene signature may help distinguish high-risk patients so as to formulate personalized treatment strategy in LUSC patients.
The Molecular Basis and Therapeutic Aspects of Cisplatin Resistance in Oral Squamous Cell Carcinoma
Authors: Cheng Yali , Li Shaoming , Gao Ling , Zhi Keqian , Ren Wenhao
Published: October 2021

Oral squamous cell carcinoma (OSCC) is a kind of malignant tumors with low survival rate and prone to have early metastasis and recurrence. Cisplatin is an alkylating agent which induces DNA damage through the formation of cisplatin-DNA adducts, leading to cell cycle arrest and apoptosis. In the management of advanced OSCC, cisplatin-based chemotherapy or chemoradiotherapy has been considered as the first-line treatment. Unfortunately, only a portion of OSCC patients can benefit from cisplatin treatment, both inherent resistance and acquired resistance greatly limit the efficacy of cisplatin and even cause treatment failure. Herein, this review outline the underlying mechanisms of cisplatin resistance in OSCC from the aspects of DNA damage and repair, epigenetic regulation, transport processes, programmed cell death and tumor microenvironment. In addition, this review summarizes the strategies applicable to overcome cisplatin resistance, which can provide new ideas to improve the clinical therapeutic outcome of OSCC.
Ultrasound-Targeted Microbubble Destruction Alleviates Immunosuppression Induced by CD71+ Erythroid Progenitor Cells and Promotes PDL-1 Blockade Immunotherapy in the Lewis Lung Cancer Model
Authors: Tan Xi , Yi Cuo , Zhang Yi , Tang Najiao , Xu Yali , Liu Zheng
Published: October 2021

The CD71+ erythroid progenitor cells (CECs) exhibit distinctive immunosuppressive properties and regulate antitumor immunity to enable tumor growth. We presented a novel and non-invasive approach to improving immunity by targeting the splenic CECs via sonoporation generated by ultrasound-targeted microbubble destruction (UTMD). The systematic immunity enhanced by the reduction of PDL-1-expressing CECs also benefits the PDL-1 blockade therapy. In the Lewis lung cancer (LLC) model, the study group was treated by UTMD for 10 min at the splenic area with or without anti-mouse PDL-1 intraperitoneal injection. The frequency of splenic CEC, lymphocyte, and cytokine production was analyzed by flow cytometry. Serum interleukin-2 (IL-2) was tested by ELISA. Tumor volume was evaluated by two-dimensional ultrasound. The UTMD treatment consisted of ultrasound sonication and Sonazoid™ microbubble injection through the caudal vein. The mechanic index (MI) of ultrasound was set between 0.98 and 1.03. The results showed a significant reduction of splenic CECs and increased frequency of CD8+ T cells treated by UTMD treatment in the late-stage tumor. Tumor growth could be inhibited by UTMD combined with PDL-1 blockade therapy. The frequencies of interferon-γ (IFN-γ) producing CD8+ and CD4+ T cells were significantly increased after being treated by the combination of UTMD and PDL-1 blockade, while the reactive oxygen species (ROS) production and the fraction of the TGF-β-producing CD11b+ cells were significantly decreased. These preliminary findings suggest that UTMD enhances immune response and facilitates PDL-1 blockade therapy by targeting immunosuppressive CECs in the spleen. Our study provides new aspects and possibilities for treating cancer-related infection and tumor control in oncology.
Cross-Sectional Risk Factors of Anterior Knee Pain in Adolescents
Authors: Borschneck Gregory , St. John Laura , Brundage Kristy , Borschneck Daniel Patrick
Published: October 2021

Background: Anterior knee pain is a common complaint amongst adolescents, which can both be persistent, and in some cases, disabling. This study investigated a series of potential risk factors potentially linked to the onset of anterior knee pain.

Methods: Questionnaires were distributed amongst 367 10–15 years-olds enrolled in the local school board. These surveys included questions on sex, age, sport participation, and history of anterior knee pain verified by a physician. Bivariate correlations and a binomial logistic regression were conducted. Overall rate of AKP in the population studied was 7.4%. The results indicated that past history of knee pain, age, and increased sports participation significantly correlated with increased risk of AKP. AKP was significantly more common in females than males. While sex, height, age, overall sport participation, participation in specific sports, and history of knee injury all contributed to the binomial model.
Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes
Authors: Shillo Pallai , Yiangou Yiangos , Donatien Philippe , Greig Marni , Selvarajah Dinesh , Wilkinson Iain D. , Anand Praveen , Tesfaye Solomon
Published: October 2021

Painful diabetic peripheral neuropathy can be intractable with a major impact, yet the underlying pain mechanisms remain uncertain. A range of neuronal and vascular biomarkers was investigated in painful diabetic peripheral neuropathy (painful-DPN) and painless-DPN and used to differentiate painful-DPN from painless-DPN. Skin biopsies were collected from 61 patients with type 2 diabetes (T2D), and 19 healthy volunteers (HV). All subjects underwent detailed clinical and neurophysiological assessments. Based on the neuropathy composite score of the lower limbs [NIS(LL)] plus seven tests, the T2D subjects were subsequently divided into three groups: painful-DPN (n = 23), painless-DPN (n = 19), and No-DPN (n = 19). All subjects underwent punch skin biopsy, and immunohistochemistry used to quantify total intraepidermal nerve fibers (IENF) with protein gene product 9.5 (PGP9.5), regenerating nerve fibers with growth-associated protein 43 (GAP43), peptidergic nerve fibers with calcitonin gene-related peptide (CGRP), and blood vessels with von Willebrand Factor (vWF). The results showed that IENF density was severely decreased (p < 0.001) in both DPN groups, with no differences for PGP9.5, GAP43, CGRP, or GAP43/PGP9.5 ratios. There was a significant increase in blood vessel (vWF) density in painless-DPN and No-DPN groups compared to the HV group, but this was markedly greater in the painful-DPN group, and significantly higher than in the painless-DPN group (p < 0.0001). The ratio of sub-epidermal nerve fiber (SENF) density of CGRP:vWF showed a significant decrease in painful-DPN vs. painless-DPN (p = 0.014). In patients with T2D with advanced DPN, increased dermal vasculature and its ratio to nociceptors may differentiate painful-DPN from painless-DPN. We hypothesized that hypoxia-induced increase of blood vessels, which secrete algogenic substances including nerve growth factor (NGF), may expose their associated nociceptor fibers to a relative excess of algogens, thus leading to painful-DPN.
Improvement in Asthma Symptoms and Pulmonary Function in Children After SARS-CoV-2 Outbreak
Authors: Taytard Jessica , Coquelin Florence , Beydon Nicole
Published: October 2021

Introduction: Little is known on the effect of SARS-CoV-2 circulation on asthma daily symptoms in children. We compared asthma exacerbations, asthma symptom control and lung function before and after SARS-CoV-2 outbreak in children.

Methods: Retrospective study of children with persistent asthma referred for lung function testing. The second quarter of 2020 being a period with nearly no activity, we compared the activity between the first, third and fourth quarters of 2019 and 2020 (Q1-2019 vs. Q1-2020, Q3-2019 vs. Q3-2020 and Q4-2019 vs. Q4-2020).

Results: We retrieved 1,871 files in 2019 and 1,548 in 2020. The whole population [2,165 (63.3%) boys] had a median [IQR] age of 9.7 [6.8;13.1] years. There was no difference in age, sex, and ethnicity between 2019 and 2020 populations. Asthma was better controlled during Q4-2020 compared to Q4-2019 (P = 0.042), and there was a lower proportion of children with at least one exacerbation in the previous 3 months after the reopening, compared to the same period in 2019 (P < 0.0001). Baseline FEV1 (Z-score) recorded after the reopening was significantly higher (with less reversibility) compared to the same period before the epidemic (P < 0.0001). Baseline FEV1/FVC (Z-score) was significantly higher during Q3-2020 compared to Q3-2019 (P = 0.026), with fewer children having a significant reversibility (P = 0.035).

Discussion: We demonstrated a trend toward increased exacerbations just before the recognition of the epidemic, and fewer exacerbations, better asthma symptom control and improvement in the lung function of asthmatic children after the reopening.
Effect of Earthworm on Wound Healing: A Systematic Review and Meta-Analysis
Authors: Wang Dong , Ruan Zhen , Zhang Rongchao , Wang Xuejing , Wang Ruihui , Tang Zhishu
Published: October 2021

Background: Earthworm, also called dilong (Chinese language), has been used as a traditional Chinese medicine for thousands of years. Recently, some scientists believe that earthworm extracts (EE) can promote wound healing. However, its effectiveness remains controversial. We conducted a meta-analysis to evaluate the effect of EE on wound healing based on the healing rate.

Methods: We comprehensively reviewed literature that mentioned EE for wound healing in the PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), VIP database for Chinese Technical Periodicals, and WanFang database that have been published until January 2021. We computed weighted mean difference (WMD) for analysis with RevMan 5.3 software in animal and human models groups. Two researchers independently selected studies and evaluated the risk of bias with the Cochrane Collaboration tool. The quality of the evidence was assessed with the Cochrane risk of bias tool. This study is registered on PROSPERO (CRD42020168400).

Results: From 2,486 articles, we selected 16 studies for analysis. EE treatment was associated with improvements in wound healing performance based on wound healing rate (mouse model: weighted mean difference (WMD) = 3.55, 95% confidence interval (CI): 2.34–4.77, p < 0.00001; rat model: WMD = 17.29, 95% CI: 5.75–28.82, p = 0.003; rabbit model: WMD = 19.29, 95% CI: 9.95–28.64, p < 0.0001). Clinical studies also confirmed that EE could reduce healing time in hospital (WMD = −8.94, 95% CI: −17.75 to −0.14, p = 0.05).

Conclusion: The results of this meta-analysis demonstrated the efficacy of EE on wound healing process. As a corollary, EE can be a useful natural product for wound healing drug development.

Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=168400, identifier CRD42020168400.
A 3-Biomarker 2-Point-Based Risk Stratification Strategy in Acute Heart Failure
Authors: Álvarez-García Jesús , García-Osuna Álvaro , Vives-Borrás Miquel , Ferrero-Gregori Andreu , Martínez-Sellés Manuel , Vázquez Rafael , González-Juanatey José R. , Rivera Miguel , Segovia Javier , Pascual-Figal Domingo , Bover Ramón , Bascompte Ramón , Delgado Juan , Grau Sepúlveda Andrés , Bardají Alfredo , Pérez-Villa Félix , Zamorano José Luis , Crespo-Leiro Marisa , Sánchez Pedro Luis , Ordoñez-Llanos Jordi , Cinca Juan
Published: October 2021

Introduction and Objectives: Most multi-biomarker strategies in acute heart failure (HF) have only measured biomarkers in a single-point time. This study aimed to evaluate the prognostic yielding of NT-proBNP, hsTnT, Cys-C, hs-CRP, GDF15, and GAL-3 in HF patients both at admission and discharge.

Methods: We included 830 patients enrolled consecutively in a prospective multicenter registry. Primary outcome was 12-month mortality. The gain in the C-index, calibration, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) was calculated after adding each individual biomarker value or their combination on top of the best clinical model developed in this study (C-index 0.752, 0.715–0.789) and also on top of 4 currently used scores (MAGGIC, GWTG-HF, Redin-SCORE, BCN-bioHF).

Results: After 12-month, death occurred in 154 (18.5%) cases. On top of the best clinical model, the addition of NT-proBNP, hs-CRP, and GDF-15 above the respective cutoff point at admission and discharge and their delta during compensation improved the C-index to 0.782 (0.747–0.817), IDI by 5% (p < 0.001), and NRI by 57% (p < 0.001) for 12-month mortality. A 4-risk grading categories for 12-month mortality (11.7, 19.2, 26.7, and 39.4%, respectively; p < 0.001) were obtained using combination of these biomarkers.

Conclusion: A model including NT-proBNP, hs-CRP, and GDF-15 measured at admission and discharge afforded a mortality risk prediction greater than our clinical model and also better than the most currently used scores. In addition, this 3-biomarker panel defined 4-risk categories for 12-month mortality.
Biochemical and Structural Characteristics, Gene Regulation, Physiological, Pathological and Clinical Features of Lipocalin-Type Prostaglandin D2 Synthase as a Multifunctional Lipocalin
Authors: Urade Yoshihiro
Published: October 2021

Lipocalin-type prostaglandin (PG) D2synthase (L-PGDS) catalyzes the isomerization of PGH2, a common precursor of the two series of PGs, to produce PGD2. PGD2stimulates three distinct types of G protein-coupled receptors: (1) D type of prostanoid (DP) receptors involved in the regulation of sleep, pain, food intake, and others; (2) chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) receptors, in myelination of peripheral nervous system, adipocyte differentiation, inhibition of hair follicle neogenesis, and others; and (3) F type of prostanoid (FP) receptors, in dexamethasone-induced cardioprotection. L-PGDS is the same protein as β-trace, a major protein in human cerebrospinal fluid (CSF). L-PGDS exists in the central nervous system and male genital organs of various mammals, and human heart; and is secreted into the CSF, seminal plasma, and plasma, respectively. L-PGDS binds retinoic acids and retinal with high affinities (Kd < 100 nM) and diverse small lipophilic substances, such as thyroids, gangliosides, bilirubin and biliverdin, heme, NAD(P)H, and PGD2, acting as an extracellular carrier of these substances. L-PGDS also binds amyloid β peptides, prevents their fibril formation, and disaggregates amyloid β fibrils, acting as a major amyloid β chaperone in human CSF. Here, I summarize the recent progress of the research on PGD2and L-PGDS, in terms of its “molecular properties,” “cell culture studies,” “animal experiments,” and “clinical studies,” all of which should help to understand the pathophysiological role of L-PGDS and inspire the future research of this multifunctional lipocalin.
Nitric Oxide Pathways in Neurovascular Coupling Under Normal and Stress Conditions in the Brain: Strategies to Rescue Aberrant Coupling and Improve Cerebral Blood Flow
Authors: Lourenço Cátia F. , Laranjinha João
Published: October 2021

The brain has impressive energy requirements and paradoxically, very limited energy reserves, implying its huge dependency on continuous blood supply. Aditionally, cerebral blood flow must be dynamically regulated to the areas of increased neuronal activity and thus, of increased metabolic demands. The coupling between neuronal activity and cerebral blood flow (CBF) is supported by a mechanism called neurovascular coupling (NVC). Among the several vasoactive molecules released by glutamatergic activation, nitric oxide (•NO) is recognized to be a key player in the process and essential for the development of the neurovascular response. Classically, •NO is produced in neurons upon the activation of the glutamatergic N-methyl-D-aspartate (NMDA) receptor by the neuronal isoform of nitric oxide synthase and promotes vasodilation by activating soluble guanylate cyclase in the smooth muscle cells of the adjacent arterioles. This pathway is part of a more complex network in which other molecular and cellular intervenients, as well as other sources of •NO, are involved. The elucidation of these interacting mechanisms is fundamental in understanding how the brain manages its energy requirements and how the failure of this process translates into neuronal dysfunction. Here, we aimed to provide an integrated and updated perspective of the role of •NO in the NVC, incorporating the most recent evidence that reinforces its central role in the process from both viewpoints, as a physiological mediator and a pathological stressor. First, we described the glutamate-NMDA receptor-nNOS axis as a central pathway in NVC, then we reviewed the link between the derailment of the NVC and neuronal dysfunction associated with neurodegeneration (with a focus on Alzheimer’s disease). We further discussed the role of oxidative stress in the NVC dysfunction, specifically by decreasing the •NO bioavailability and diverting its bioactivity toward cytotoxicity. Finally, we highlighted some strategies targeting the rescue or maintenance of •NO bioavailability that could be explored to mitigate the NVC dysfunction associated with neurodegenerative conditions. In line with this, the potential modulatory effects of dietary nitrate and polyphenols on •NO-dependent NVC, in association with physical exercise, may be used as effective non-pharmacological strategies to promote the •NO bioavailability and to manage NVC dysfunction in neuropathological conditions.
Soil Water Availability Changes in Amount and Timing Favor the Growth and Competitiveness of Grass Than a Co-dominant Legume in Their Mixtures
Authors: Xu Weizhou , Deng Xiping , Xu Bingcheng , Palta Jairo A. , Chen Yinglong
Published: October 2021

The grasslands on the semi-arid Loess Plateau of China are expected to be particularly responsive to the size and frequency changes of extreme precipitation events because their ecological processes are largely driven by distinct soil moisture pulses. However, the plant growth and competitiveness of co-dominant species in response to the changes in the amount and timing of soil water are still unclear. Thus, two co-dominant species, Bothriochloa ischaemum and Lespedeza davurica, were grown in seven mixture ratios under three watering regimes [80 ± 5% pot soil capacity (FC) (high watering), 60 ± 5% FC (moderate watering), and 40 ± 5% FC (low watering)] in a pot experiment. The soil water contents were rapidly improved from low to moderate water and from moderate to high water, respectively, at the heading, flowering, and maturity stages of B. ischaemum, and were maintained until the end of the growing season of each species. The biomass production of both species increased significantly with the increased soil water contents, particularly at the heading and flowering periods, with a more pronounced increase in B. ischaemum in the mixtures. The root/shoot ratio of both species was decreased when the soil water availability increased at the heading or flowering periods. The total biomass production, water use efficiency (WUE), and relative yield total (RYT) increased gradually with the increase of B. ischaemum in the mixtures. The relative competition intensity was below zero in B. ischaemum, and above zero in L. davurica. The competitive balance index calculated for B. ischaemum was increased with the increase of the soil water contents. Bothriochloa ischaemum responded more positively to the periodical increase in soil water availability than L. davurica, indicating that the abundance of B. ischaemum could increase in relatively wet seasons or plenty-rainfall periods. In addition, the mixture ratio of 10:2 (B. ischaemum to L. davurica) was the most compatible combination for the improved biomass production, WUE, and RYTs across all soil water treatments.
Coffea arabica L. Resistant to Coffee Berry Borer (Hypothenemus hampei) Mediated by Expression of the Bacillus thuringiensis Cry10Aa Protein
Authors: Valencia-Lozano Eliana , Cabrera-Ponce Jose Luis , Noa-Carrazana Juan C. , Ibarra Jorge E.
Published: October 2021

Coffeaspp. are tropical plants used for brewing beverages from roasted and grounded seeds, the favorite drink in the world. It is the most important commercial crop plant and the second most valuable international commodity after oil. Global coffee trade relies on twoCoffeaspecies:C. arabicaL. (arabica coffee) comprising 60% andC. canephora(robusta) comprising the remaining 40%. Arabica coffee has lower productivity and better market price than robusta. Arabica coffee is threatened by disease (i.e., coffee leaf rust), pests [i.e.,Hypothenemus hampeior coffee berry borer (CBB) and nematodes], and susceptibility to climate change (i.e., drought and aluminum toxicity). Plant biotechnology by means of tissue culture inducing somatic embryogenesis (SE) process, genetic transformation, and genome editing are tools that can help to solve, at least partially, these problems. This work is the continuation of a protocol developed for stable genetic transformation and successful plant regeneration of arabica coffee trees expressing theBacillus thuringiensis(Bt) toxin Cry10Aa to induce CBB resistance. A highly SE line with a high rate of cell division and conversion to plants with 8-month plant regeneration period was produced. To validate this capability, gene expression analysis of master regulators of SE, such as BABY BOOM (BBM), FUS3, and LEC1, embryo development, such as EMB2757, and cell cycle progression, such as ETG1 and MCM4, were analyzed during induction and propagation of non-competent and highly competent embryogenic lines. The particle bombardment technique was used to generate stable transgenic lines after 3 months under selection using hygromycin as selectable marker, and 1 month in plant regeneration. Transgenic trees developed fruits after 2 years and demonstrated expression of the Bt toxin ranging from 3.25 to 13.88 μg/g fresh tissue. Bioassays with transgenic fruits on CBB first instar larvae and adults induced mortalities between 85 and 100% after 10 days. In addition, transgenic fruits showed a seed damage lower than 9% compared to 100% of control fruits and adult mortality. This is the first report on stable transformation and expression of the Cry10Aa protein in coffee plants with the potential to control CBB.
Multimodal Practice for Mobilizing Response: The Case of Turn-Final Tu Vois ‘You See’ in French Talk-in-Interaction
Authors: Stoenica Ioana-Maria , Fiedler Sophia
Published: October 2021

One of the most frequent verbal expressions that people use when interacting with each other in French istu vois‘you see’ (Cappeau, 2004). Drawing on interactional linguistics and multimodal analysis, we examine the interactional functioning of this verbal expression when occurring in turn-final position. Previous studies ontu vois‘you see’ in this position document only its use for marking the end of an utterance or for turn-yielding. The following aspects have thus far remained unexplored: The interactional environment in which the construction occurs, how it is connected to the speaker’s embodied conduct, the way in which it contributes to mobilizing a response from the recipient, as well as the nature of this response. Our paper addresses these issues and shows that turn-finaltu vois‘you see’ is systematically produced with a final rising intonation and coupled with the speaker’s gaze directed to the recipient. This multimodal practice is recurrently deployed in turns conveying the speaker’s emotional stance, in turns performing a dispreferred action, like disagreeing, and in turns claiming insufficient knowledge. The response that is invited using this multimodal practice is distinctly tailored to each of these actions: an affiliative response, an aligning response, and a response addressing the prior speaker’s claim of insufficient knowledge from the recipient’s own point of view. By presenting an in-depth study of the action sequences in whichtu vois‘you see’ is employed, as well as of its multimodal packaging, this contribution highlights the prospective, i.e., response-mobilizing potential of this interactional resource and shows that its use entails sequential implications even when it accompanies actions that project only weakly a response from the recipient.