bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: Noninvasive Clinical Intervention of REBACIN® on Histologic Regression of High Grade Cervical Intraepithelial Neoplasia
Authors: Wang Fan , Liu Rong , Ma Yan , Wu Dai-Fei , Deng Liu-Hong , Wang Sheng , Wang Gui-Yu , Zhang Chun-Fa , Qu Quan-Xin
Published: July 2021

High-risk human papillomavirus (hrHPV) persistent infection is the major cause of cervical cancer. Clinical intervention of hrHPV-associated high-grade squamous intraepithelial lesion (HSIL) is critical to prevent cervical cancer, and current treatment is surgery (an invasive therapy). However, some patients refuse to do so for an afraid of potential adverse effects on future fertility or other concerns which creates a critical need for development of non-invasive therapeutic strategies. Here, we report for the first time the cases of non-invasive intervention with REBACIN®, a proprietary antiviral biologics, in clinical treatment of HSIL. From 12,958 visiting patients assessed for eligibility, 18 HSIL-patients with cervical intraepithelial neoplasia-grade 2, positive of both diffused overexpression of p16 and high-risk HPV were enrolled in this non-invasive clinical intervention mainly due to concerns of future fertility. REBACIN® was administered intravaginally every other day for 3 months (one-course) except during menstrual period, and were followed up for 6-36 months for the examination of high-risk HPV DNA, cervical cytology, and histopathology. After one to three course treatments, most cases (16/18) displayed both the regression from HSIL (CIN2) to normal cervical cytology and clearance of high-risk HPV infection. Further studies demonstrated REBACIN® significantly suppressed HPV16 E7 oncoprotein expression in a human cervical cancer cell line, which is consistent with previous finding that REBACIN® inhibits the growth of tumors induced by expression of E6/E7 oncogenes of either HPV16 or HPV18. This report indicates REBACIN® as a novel effective non-invasive clinical intervention for HSIL-patients as well for high-risk HPV persistent infection, providing a new clinical option for the non-invasive treatment of hrHPV-associated high-grade squamous intraepithelial lesion, which is worthy of further research on clinical validation and application.
Molecular Mechanisms Underlying the Regulation of Biofilm Formation and Swimming Motility by FleS/FleR in Pseudomonas aeruginosa
Authors: Zhou Tian , Huang Jiahui , Liu Zhiqing , Xu Zeling , Zhang Lian-hui
Published: July 2021

Pseudomonas aeruginosa, a major cause of nosocomial infection, can survive under diverse environmental conditions. Its great adaptive ability is dependent on its multiple signaling systems such as the two-component system (TCS). A TCS FleS/FleR has been previously identified to positively regulate a variety of virulence-related traits in P. aeruginosa PAO1 including motility and biofilm formation which are involved in the acute and chronic infections, respectively. However, the molecular mechanisms underlying these regulations are still unclear. In this study, we first analyzed the regulatory roles of each domains in FleS/FleR and characterized key residues in the FleS-HisKA, FleR-REC and FleR-AAA domains that are essential for the signaling. Next, we revealed that FleS/FleR regulates biofilm formation in a c-di-GMP and FleQ dependent manner. Lastly, we demonstrated that FleR can regulate flagellum biosynthesis independently without FleS, which explains the discrepant regulation of swimming motility by FleS and FleR.
The Potential Role of Extracellular Vesicles in COVID-19 Treatment: Opportunity and Challenge
Authors: Yan Yan-yan , Zhou Wen-min , Wang Yu-qing , Guo Qiao-ru , Zhao Fu-xi , Zhu Zhuang-yan , Xing Yan-xia , Zhang Hai-yan , Aljofan Mohamad , Jarrahi Alireza Mosavi , Makabel Bolat , Zhang Jian-ye
Published: July 2021

SARS-CoV-2 infection has become an urgent public health concern worldwide, severely affecting our society and economy due to the long incubation time and high prevalence. People spare no effort on the rapid development of vaccine and treatment all over the world. Amongst the numerous ways of tackling this pandemic, some approaches using extracellular vesicles (EVs) are emerging. In this review, we summarize current prevalence and pathogenesis of COVID-19, involving the combination of SARS-CoV-2 and virus receptor ACE2, endothelial dysfunction and micro thrombosis, together with cytokine storm. We also discuss the ongoing EVs-based strategies for the treatment of COVID-19, including mesenchymal stem cell (MSC)-EVs, drug-EVs, vaccine-EVs, platelet-EVs, and others. This manuscript provides the foundation for the development of targeted drugs and vaccines for SARS-CoV-2 infections.
A Novel Probable Pathogenic PSEN2 Mutation p.Phe369Ser Associated With Early-Onset Alzheimer's Disease in a Chinese Han Family: A Case Report
Authors: Wan Ke , Ma Zhen-Juan , Zhou Xia , Zhang Yi-Mei , Yu Xian-Feng , You Meng-Zhe , Huang Chao-Juan , Zhang Wei , Sun Zhong-Wu
Published: July 2021

The pathogenesis of Alzheimer's disease is complex, and early-onset Alzheimer's disease (EOAD) is mostly influenced by genetic factors. Presenilin-1, presenilin-2 (PSEN2), and amyloid precursor protein are currently known as the three main causative genes for autosomal dominant EOAD, with the PSEN2 mutation being the rarest. In this study, we reported a 56-year-old Chinese Han proband who presented with prominent progressive amnesia, aphasia, executive function impairment, and depression 5 years ago. The 3-year follow-up showed that the patient experienced progressive brain atrophy displayed on magnetic resonance imaging (MRI) and dramatic cognitive decline assessed by neuropsychological evaluation. This patient was clinically diagnosed as EOAD based on established criteria. A heterozygous variant (NM_000447.2: c.1106T>C) of PSEN2 was identified for the first time in this patient and her two daughters. This mutation causing a novel missense mutation (p.Phe369Ser) in transmembrane domain 7 encoded by exon 11 had not been reported previously in 1000Genomes, ExAC, or ClinVar databases. This mutation was predicted by four in silico prediction programs, which all strongly suggested that it was damaging. Our results suggest that this novel PSEN2 Phe369Ser mutation may alter PSEN2 protein function and associate with EOAD.
Robot-Assisted Therapy and Constraint-Induced Movement Therapy for Motor Recovery in Stroke: Results From a Randomized Clinical Trial
Authors: Terranova Thais Tavares , Simis Marcel , Santos Artur César Aquino , Alfieri Fábio Marcon , Imamura Marta , Fregni Felipe , Battistella Linamara Rizzo
Published: July 2021

Background:Stroke is one of the leading causes of adult disability, and up to 80% of stroke survivors undergo upper extremity motor dysfunction. Constraint-Induced Movement Therapy (CIMT) and Robot-Assisted Therapy (RT) are used for upper limb stroke rehabilitation. Although CIMT and RT are different techniques, both are beneficial; however, their results must be compared. The objective is to establish the difference between RT and CIMT after a rehabilitation program for chronic stroke patients.

Method:This is a randomized clinical trial, registered atClinicalTrials.gov(ID number NCT02700061), in which patients with stroke received sessions of RT or CIMT protocol, combined with a conventional rehabilitation program for 12 weeks. The primary outcome was measured by Wolf Motor Function Test (WMFT) and Fugl-Meyer Assessment—Upper Limb (FMA-UL). Activities of daily living were also assessed.

Results:Fifty one patients with mild to moderate upper limb impairment were enrolled in this trial, 25 women and 26 men, mean age of 60,02 years old (SD 14,48), with 6 to 36 months after stroke onset. Function significantly improved regardless of the treatment group. However, no statistical difference was found between both groups asp-values of the median change of function measured by WMFT and FMA were 0.293 and 0.187, respectively.

Conclusion:This study showed that Robotic Therapy (RT) was not different from Constraint-Induced Movement Therapy (CIMT) regardless of the analyzed variables. There was an overall upper limb function, motor recovery, functionality, and activities of daily living improvement regardless of the interventions. At last, the combination of both techniques should be considered in future studies.
Plasma Levels of Brain-Derived Neurotrophic Factor and S100B in Relation to Antidepressant Response to Ketamine
Authors: Jiang Haitang , Veldman Emma R. , Tiger Mikael , Ekman Carl-Johan , Lundberg Johan , Svenningsson Per
Published: July 2021

Background

Evidence demonstrates that brain-derived neurotrophic factor (BDNF) and S100 calcium-binding protein B (S100B) have a pivotal role in the pathogenesis of major depressive disorder (MDD) and they are proposed as predictors of antidepressant response. Ketamine produces rapid antidepressant effects in MDD and pre-clinical studies suggest the necessity of increased BDNF levels for the antidepressant action of ketamine. However, studies observing the change of blood BDNF levels after ketamine intervention are inconsistent and studies about the role of plasma S100B in ketamine administration in MDD patients are lacking.

Method

We evaluated mature BDNF (mBDNF), S100B levels in plasma and their associations with depression severity in 30 Selective Serotonin Reuptake Inhibitor (SSRI)-resistant MDD patients enrolled in a randomized controlled trial of ketamine compared (n= 20) to a placebo (n= 10) control (saline). Severity of depression was assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS).

Results

Plasma mBDNF and S100B were not significantly changed after 1–2 days of single ketamine compared to placebo. Plasma mBDNF and S100B levels did not significantly differ in responders compared to non-responders of ketamine treatment. The change of plasma mBDNF levels was positively correlated with the improvement of MADRS score after 1–2 weeks of open-label ketamine treatment (rho = 0.495,p= 0.031), though this change did not survive correction for multiple comparisons.

Conclusion

These findings do not support the hypothesis that ketamine treatment increases BDNF plasma levels in MDD patients. No effect of ketamine treatment on S100B plasma levels was seen.
Climate Trends and Consumption of Foods and Beverages by Processing Level in Mexican Cities
Authors: López-Olmedo Nancy , Diez-Roux Ana V. , Pérez-Ferrer Carolina , Prado-Galbarro Francisco-Javier , Riojas-Rodríguez Horacio , Rivera-Dommarco Juan , Barrientos-Gutierrez Tonatiuh
Published: July 2021

Background: Little is known about the potential impact of climate change on food systems and diet. We aimed to estimate the association of changes in rainfall and temperatures with consumption of unprocessed and processed foods among residents of Mexican cities by climate region.

Methods: We analyzed 3,312 participants of the 2012 Mexican National Health and Nutrition Survey with dietary intake and sociodemographic information linked to historical rainfall and temperature data collected by the Mexican National Weather Service. We classified foods as unprocessed, processed, or ultra-processed. We performed multilevel linear regression to estimate the association of annual change in rainfalls (for each 0.5 mm decrease) and temperatures (for each 0.1°C increase) at municipality level over the past 5 years with consumption of processed and unprocessed foods measured as the contribution to total energy intake. We investigated whether associations differed by climate region (tropical, temperate, and arid).

Results: Each 0.5 mm annual decrease in precipitation was associated with lower consumption of unprocessed foods and higher consumption of ultra-processed foods [mean differences in percent contribution to total energy intake −0.009% (95% CI: −0.019, < −0.001) and 0.011% (95% CI: 0.001, 0.021), respectively]. Each 0.1 degree Celsius annual increase in temperature was also associated with lower consumption of unprocessed and higher consumption of ultra-processed foods [mean differences in percent contribution to total energy intake was −0.03 (95% CI: −0.05, −0.01) and 0.03% (95% CI: <0.01, 0.05)]. When stratified by climate region these associations were only observed in tropical regions.

Conclusions: Decreases in rainfalls and increases in temperature were associated with lower consumption of unprocessed foods but higher consumption of ultra-processed foods, especially in tropical regions. Previous studies have established how food production affects the climate, our study suggests that climate change could, in turn, reinforce modern food production, closing a vicious circle with clear negative implications for planetary health.
The Provocative Roles of Platelets in Liver Disease and Cancer
Authors: Kanikarla Marie Preeti , Fowlkes Natalie W. , Afshar-Kharghan Vahid , Martch Stephanie L. , Sorokin Alexey , Shen John Paul , Morris Van K. , Dasari Arvind , You Nancy , Sood Anil K. , Overman Michael J. , Kopetz Scott , Menter David George
Published: July 2021

Both platelets and the liver play important roles in the processes of coagulation and innate immunity. Platelet responses at the site of an injury are rapid; their immediate activation and structural changes minimize the loss of blood. The majority of coagulation proteins are produced by the liver—a multifunctional organ that also plays a critical role in many processes: removal of toxins and metabolism of fats, proteins, carbohydrates, and drugs. Chronic inflammation, trauma, or other causes of irreversible damage to the liver can dysregulate these pathways leading to organ and systemic abnormalities. In some cases, platelet-to-lymphocyte ratios can also be a predictor of disease outcome. An example is cirrhosis, which increases the risk of bleeding and prothrombotic events followed by activation of platelets. Along with a triggered coagulation cascade, the platelets increase the risk of pro-thrombotic events and contribute to cancer progression and metastasis. This progression and the resulting tissue destruction is physiologically comparable to a persistent, chronic wound. Various cancers, including colorectal cancer, have been associated with increased thrombocytosis, platelet activation, platelet-storage granule release, and thrombosis; anti-platelet agents can reduce cancer risk and progression. However, in cancer patients with pre-existing liver disease who are undergoing chemotherapy, the risk of thrombotic events becomes challenging to manage due to their inherent risk for bleeding. Chemotherapy, also known to induce damage to the liver, further increases the frequency of thrombotic events. Depending on individual patient risks, these factors acting together can disrupt the fragile balance between pro- and anti-coagulant processes, heightening liver thrombogenesis, and possibly providing a niche for circulating tumor cells to adhere to—thus promoting both liver metastasis and cancer-cell survival following treatment (that is, with minimal residual disease in the liver).
Combination Treatment of CI-994 With Etoposide Potentiates Anticancer Effects Through a Topoisomerase II-Dependent Mechanism in Atypical Teratoid/Rhabdoid Tumor (AT/RT)
Authors: Kim Hee Yeon , Choi Seung Ah , Koh Eun Jung , Kim Kyung Hyun , Phi Ji Hoon , Lee Ji Yeoun , Kim Seung-Ki
Published: July 2021

Purpose

Atypical teratoid/rhabdoid tumor (AT/RT) is arising typically in young children and is associated with a dismal prognosis which there is currently no curative chemotherapeutic regimen. Based on previous studies showing high histone deacetylase 1 (HDAC1) expression in AT/RT, the HDAC1 inhibitor CI-994 was used as a novel treatment strategy in this study. We assessed the anticancer effects of CI-994 and conventional drugs (etoposide, cisplatin or 4-HC) in AT/RT cells.

Methods

AT/RT patient-derived primary cultured cells and cell lines were prepared. HDAC1 was estimated by real-time quantitative polymerase chain reaction (RT-qPCR). The interaction of the drugs was analyzed using isobologram analysis. Cell viability, apoptosis, HDAC enzyme activity and western blot assays were carried out.

Results

HDAC1 was overexpressed in AT/RT compared to medulloblastoma. The combination index (CI) of CI-994 with etoposide revealed a synergistic effect in all AT/RT cells, but no synergistic effect was observed between CI-994 and cisplatin or 4-HC. CI-994 effectively reduced not only Class I HDAC gene expression but also HDAC enzyme activity. The combination treatment of CI-994 with etoposide significantly increased apoptosis compared to the single treatment. The enhanced effect of apoptosis by this combination treatment is related to a signaling pathway which decreases topoisomerase (Topo) II and increases histone H3 acetylation (Ac-H3).

Conclusion

We demonstrate that the combination treatment of CI-994 with etoposide exerts a synergistic anticancer effect against AT/RT by significantly inducing apoptosis through Topo II and Ac-H3 regulation.

Clinical Relevance

This combination treatment might be considered a viable therapeutic strategy for AT/RT patients.
The Genetic Changes of Hepatoblastoma
Authors: Chen Huitong , Guan Qian , Guo Huiqin , Miao Lei , Zhuo Zhenjian
Published: July 2021

Hepatoblastoma is the most common malignant liver cancer in childhood. The etiology of hepatoblastoma remains obscure. Hepatoblastoma is closely related to genetic syndromes, hinting that hepatoblastoma is a genetic predisposition disease. However, no precise exposures or genetic events are reported to hepatoblastoma occurrence. During the past decade, significant advances have been made in the understanding of etiology leading to hepatoblastoma, and several important genetic events that appear to be important for the development and progression of this tumor have been identified. Advances in our understanding of the genetic changes that underlie hepatoblastoma may translate into better patient outcomes. Single nucleotide polymorphisms (SNPs) have been generally applied in the research of etiology’s exploration, disease treatment, and prognosis assessment. Here, we reviewed and discussed the molecular epidemiology, especially SNPs progresses in hepatoblastoma, to provide references for future studies and promote the study of hepatoblastoma’s etiology.
Application of Data Science in Circulating Tumor DNA Detection: A Promising Avenue Towards Liquid Biopsy
Authors: Li Ming , Xie Sisi , Lu Chenyu , Zhu Lingyun , Zhu Lvyun
Published: July 2021

The circulating tumor DNA (ctDNA), as a promising biomarker of liquid biopsy, has potential clinical relevance on the molecular diagnosis and monitoring of cancer. However, the trace concentration level of ctDNA in the peripheral blood restricts its extensive clinical application. Recently, high-throughput-based methodologies have been leveraged to improve the sensitivity and specificity of ctDNA detection, showing a promising avenue towards liquid biopsy. This review briefly summarizes the high-throughput data features concerned by current ctDNA detection strategies and the technical obstacles, potential solutions, and clinical relevance of current ctDNA profiling technologies. We also highlight future directions improving the limit of detection of ctDNA for better clinical application. This review may serve as a reference for the crosslinks between data science and ctDNA-based liquid biopsy, benefiting clinical translation in advanced cancer diagnosis.
Choosing the Right Treatment Option for the Right R/M HNSCC Patient: Should We Adhere to PFE for First-Line Therapy?
Authors: Lübbers Katharina , Pavlychenko Mykola , Wald Theresa , Wiegand Susanne , Dietz Andreas , Zebralla Veit , Wichmann Gunnar
Published: July 2021

Background

The landmark EXTREME trial established cisplatin, 5-fluorouracil and cetuximab (PFE) as first-line chemotherapy (1L-ChT) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). We were interested in outcome differences of R/M HNSCC in 1L-ChT and factors influencing outcome in certain subgroups, especially patients receiving PFE, and the value of PFE compared to other 1L-ChT regimens to provide real world evidence (RWE).

Methods

For this retrospective monocentric study, 124 R/M HNSCC patients without curative surgical or radiotherapy options receiving at least one cycle of 1L-ChT were eligible. We analyzed their outcome using Kaplan-Meier plot and Cox regression to identify predictors for prolonged survival.

Results

Subgroups benefiting significantly from PFE were patients suffering from an index HNSCC outside the oropharynx. The PFE regimen proved to be superior to all other 1L-ChT regimens in clinical routine. Significant outcome differences between PFE treatment within or outside controlled trials were not seen.

Conclusion

This retrospective analysis provides RWE for factors linked to improved outcome. Subgroup analyses highlight the lasting value of PFE among the growing spectrum of 1L-ChT. Importantly, fit smokers with high level alcohol consumption benefit from PFE; considering the patient’s lifestyle factors, PFE should not be ignored in decision-making.
Melphalan as a Promising Treatment for BRCA-Related Ovarian Carcinoma
Authors: Conteduca Vincenza , Scarpi Emanuela , Farolfi Alberto , Brighi Nicole , Rossi Lorena , Gurioli Giorgia , Lolli Cristian , Schepisi Giuseppe , Bleve Sara , Gianni Caterina , Virga Alessandra , Altavilla Amelia , Burgio Salvatore Luca , Menna Cecilia , De Giorgi Ugo
Published: July 2021

Introduction

Melphalan, as a bifunctional alkylating agent has been shown to be selectively efficient in BRCA-deficient case reports of epithelial ovarian cancer (EOC). The clinical benefit of melphalan on unselected platinum-resistant EOC population and stratified by BRCA status has not been clearly elucidated. We aimed to determine the response to melphalan in patients with recurrent EOC after platinum-based therapy.

Material and Methods

This retrospective observational study included patients with recurrent EOC treated with melphalan between February 2007 to July 2020. Eligibility criteria included having a histological confirmation of EOC, previous treatment with carboplatin plus paclitaxel regimens, and disease recurrence during treatment with or within 6 months of the end of the platinum-based chemotherapy.

Results

A total of 75 platinum-resistant EOC patients were enrolled. Median age was 69 years (range 41-82). Median of previous therapies before melphalan was 4 (range 1-7). We observed a median follow-up of 32 months (range 1-62), progression-free survival (PFS) and overall survival (OS) of 3.6 months (range 2.9-4.7) and 9.5 months (range 8.0-14.1), respectively. In the whole population, 1 complete response, 6 partial responses and 37 stable diseases were registered with an overall clinical benefit rate of 58.7%. In BRCA1/2 mutant patients, we showed a significant longer PFS compared to BRCA1/2 wild type patients (6.2 versus 2.6 months; hazard ratio (HR) 0.25, 95% confidence interval (CI) 0.10-0.61; p=0.002). Moreover, a trend was seen for BRCA1/2 mutants to have a better OS (25.9 versus 8.0 months; HR 0.38; 95% CI 0.12-1.19; p=0.097).

Conclusions

Our study represents the largest cohort of heavily-pretreated EOC patients receiving melphalan treatment. Here, we report a considerable clinical activity of melphalan chemotherapy, more evident in a subset of BRCA1/2 mutated patients. Prospective studies to validate these findings are warranted.
Case Report: Ultrasound-Guided Percutaneous Microwave Ablation of Focal Nodular Hyperplasia in a 9-Year-Old Girl
Authors: Yao Zhiguang , Zeng Qingjing , Yu Xuan , Lin Shulian , Jiang Shuanglan , Ma Da , Li Kai
Published: July 2021

Focal nodular hyperplasia (FNH) is a rare benign tumor-like space-occupying lesion of the liver that is especially rare in children. Since there have been no reports of malignant progression of this disease and these lesions remain unchanged for a long period of time or even disappear in some cases, it remains controversial whether clinical treatment is needed. However, if the diagnosis is unclear, the patient has symptoms or the lesion becomes enlarged during follow-up, clinical treatment should be considered. Here, we report the first case of FNH near the gallbladder treated by ultrasound-guided percutaneous microwave ablation (MWA) in a 9-year-old girl.
Monoclonal Antibody Therapy in Neuromyelitis Optica Spectrum Disorders: a Meta-analysis of Randomized Control Trials
Authors: Kong Fanxin , Wang Jianjun , Zheng Haotao , Cai Haobin , Hua Jun , Li Liling
Published: July 2021

Background: To update the efficacy and safety data of monoclonal antibodies for the treatment of neuromyelitis optica spectrum disorders (NMOSD) and explore the differences in the effect of treatment between patients seropositive and seronegative for AQP4-IgG. Methods: PubMed, Embase, and the Cochrane Library published up to July 2020 were searched for randomized controlled trials (RCTs) of monoclonal antibodies treatment (mAb) in patients with NMOSD. The primary outcome was the hazard ratio (HR) for relapse. The secondary outcomes included Expanded Disability Status Scale (EDSS) changes from baseline, adverse events (AEs), and serious adverse events (SAEs). A random-effects model was applied for the effect of heterogeneity among trials. Results: We included 603 patients (monoclonal antibody group, n=382, and control group, n=221) from seven RCTs. There were fewer relapses in the mAb group (HR=0.32, 95% CI: 0.23-0.46, p<0.001), as well as in the AQP4-IgG-seropositive patients (HR=0.18, 95% CI: 0.10–0.32, p<0.001), but not in AQP4-IgG-seronegative NMOSD. Similar results were observed when considering satralizumab only. The mAb had no impact on the changes in EDSS scores from baseline (WMD=−0.21, 95% CI: −0.50-0.09, p=0.176). The mAb did not lead to a higher frequency of AEs (OR=1.18, 95% CI: 0.70–1.98, p=0.529) or SAEs (OR=0.99, 95% CI: 0.63–1.56, p=0.975) compared with the control group. Conclusions: Compared to the control arm, monoclonal antibody therapy showed a significantly better outcome in restraining the HR for relapse among patients with NMOSD but insignificant effects in NMOSD patients with seronegative APQ4-IgG. The safety profile in each arm had no significant difference.
Biomarkers for the Clinical Diagnosis of Alzheimer’s Disease: Metabolomics Analysis of Brain Tissue and Blood
Authors: Wang Yang-Yang , Sun Yan-Ping , Luo Yu-Meng , Peng Dong-Hui , Li Xiao , Yang Bing-You , Wang Qiu-Hong , Kuang Hai-Xue
Published: July 2021

With an increase in aging populations worldwide, age-related diseases such as Alzheimer’s disease (AD) have become a global concern. At present, a cure for neurodegenerative disease is lacking. There is an urgent need for a biomarker that can facilitate the diagnosis, classification, prognosis, and treatment response of AD. The recent emergence of highly sensitive mass-spectrometry platforms and high-throughput technology can be employed to discover and catalog vast datasets of small metabolites, which respond to changed status in the body. Metabolomics analysis provides hope for a better understanding of AD as well as the subsequent identification and analysis of metabolites. Here, we review the state-of-the-art emerging candidate biomarkers for AD.
Modulation of HMGB1 Release in APAP-Induced Liver Injury: A Possible Strategy of Chikusetsusaponin V Targeting NETs Formation
Authors: Liu Jian , Jiang Min , Jin Quan , Wu Yan-Ling , Cui Zhen-Yu , Cui Ben-Wen , Shang Yue , Zhan Zi-Ying , Lin Yong-Ce , Jiao Jing-Ya , Piao Mei-Hua , Zhang Zhi-Hong , Sun Rong-Hui , Nan Ji-Xing , Lian Li-Hua
Published: July 2021

Acetaminophen (APAP), one of the most common antipyretic analgesics, which is safe at therapeutic dose, cause acute liver injury and even death at overdose. However, the mechanism of APAP-induced inflammation in liver injury is still controversial. Therefore, effective drug intervention is urgently needed. The aim of this study was to explore the inflammatory exact mechanism of APAP, especially on neutrophils, and to study the intervention effect of Chikusetsusaponin V (CKV) derived from Panax japonicus. Establishment of hepatotoxicity model of APAP in vitro and in vivo. In vitro, HepG2 cells, AML12 cells, primary mouse hepatocytes and neutrophils were used to mimic APAP-affected hepatocytes and neutrophil. In vivo, C57BL/6 mice were administrated overdose of APAP with or without neutrophil depletion or abolishing neutrophil extracellular traps (NETs) formation. In this study, APAP stimulation increased the level of HMGB1, IL-1β and Caspase-1 in mouse liver, especially hepatocytes, which had a synergistic effect with LPS/ATP combination. NETs were formatted at early stage of APAP or HMGB1-stimulated neutrophils’ damage. Conditioned mediums from APAP-treated hepatocytes induced more significant NETs than direct APAP stimulation. Neutrophil depletion or abolishing NETs formation decreased HMGB1 level, eventually blocked hepatocytes necrosis. CKV pretreatment interfered Caspase-1 activation and HMGB1 release in APAP-damaged hepatocytes. CKV also prevented NETs formation. These results indicate that the production of HMGB1 may depend on the activation of Caspase-1 and play a key role in liver inflammation caused by APAP. The cross-dialogue between hepatocytes and neutrophils can be mediated by HMGB1. Therefore, CKV has a positive intervention effect on NETs-related inflammation in APAP-damaged liver, targeting Caspase-1-HMGB1.
Numerical Simulation Study on the Mechanism of Formation of Apical Aneurysm in Hypertrophic Cardiomyopathy With Midventricular Obstruction
Authors: Deng Long , Zuo Heng , Li An , Yang Chun , Huang Xueying
Published: July 2021

Apical aneurysm was observed to be associated with midventricular obstruction (MVO) in hypertrophic cardiomyopathy (HCM). To investigate the genesis of the apical aneurysm, the idealized numerical left ventricular models (finite-element left ventricle models) of the healthy left ventricle, subaortic obstruction, and midventricular obstruction in HCM of left ventricle were created. The mechanical effects in the formation of apical aneurysm were determined by comparing the myofiber stress on the apical wall between these three models (healthy, subaortic obstruction, and midventricular obstruction models). In comparing the subaortic obstruction model and MVO model with HCM, it was found that, at the time of maximum pressure, the maximum value of myofiber stress in MVO model was 75.0% higher than that in the subaortic obstruction model (654.5 kPa vs. 373.9 kPa). The maximum stress on the apex of LV increased 79.9, 69.3, 117.8% than that on the myocardium around the apex in healthy model, subaortic obstruction model, and MVO model, respectively. Our results indicated that high myofiber stress on the apical wall might initiate the formation process of the apical aneurysm.
Differing Trade-Off Patterns of Tree Vegetative Organs in a Tropical Cloud Forest
Authors: Yang Yuanyuan , Xiao Chuchu , Wu Xianming , Long Wenxing , Feng Guang , Liu Guoying
Published: July 2021

Functional trait ecology demonstrates the significance of the leaf economics spectrum in understanding plants’ trade-off between acquisitive and conservative resource utilization. However, whether trait variations of different vegetative organs are coordinated and whether the plant economics spectrum is characterized by more than one vegetative organ remain controversial. To gain insights into these questions, within a tropical cloud forest in Hainan Island, a total of 13 functional traits of 84 tree species were analyzed here, including leaf, stem and root traits. By using standardized major axis (SMA) regression and principal components analysis, we examined the trait variations and correlations for deciphering plants’ trade-off pattern. We found decreases of leaf phosphorus content, leaf nitrogen content and specific leaf area and increases of leaf mass per unit area (LMA), wood density and leaf thickness along the first principal component, while there were decreases of specific root length and specific root area and increases of root tissue density along the second principal component. Root phosphorus and nitrogen contents were significantly positively associated with the phosphorus and nitrogen contents of both stem and leaf. Wood density was significantly positively associated with LMA and leaf thickness, but negatively associated with leaf thickness and specific leaf area. Our results indicate that, in the tropical cloud forest, there is a “fast–slow” economic spectrum characterized by leaf and stem. Changes of nutrient trait are coordinated, whereas the relationships of morphological traits varied independently between plant above- and below-ground parts, while root nutrient traits are decoupled from root morphological traits. Our findings can provide an insight into the species coexistence and community assembly in high-altitude tropical forests.
Combinations of Blue and Red LEDs Increase the Morphophysiological Performance and Furanocoumarin Production of Brosimum gaudichaudii Trécul in vitro
Authors: Costa Érica Letícia Gomes , Farnese Fernanda dos Santos , de Oliveira Thales Caetano , Rosa Márcio , Rodrigues Arthur Almeida , Resende Erika Crispim , Januario Ana Helena , Silva Fabiano Guimarães
Published: July 2021

Brosimum gaudichaudii is a plant species with medicinal relevance due to its furanocoumarin accumulation. The accumulation of these compounds in the root promotes predatory extractivism, which threatens the conservation of the species. In addition, little is known about the conditions for culturing of this species in vitro. The present study aimed to investigate how the application of different spectra of LEDs (white, blue, red, and combinations of blue and red at 1:1 and 3:1 ratios) can impact the morphophysiological and biochemical characteristics of B. gaudichaudii under different in vitro conditions. To evaluate the production of furanocoumarins in its leaves, which are easy-to-collect perennial organs, we cultured nodal segments in 50-mL tubes with MS medium under 100 μmol m−2 s−1 light and a photoperiod of 16 h for 50 days. We then submitted the seedlings biometric, anatomical, biochemical, and physiological evaluations. The different spectral qualities influenced several characteristics of the seedlings. Plants grown under red light showed greater stem elongation and larger and thinner leaves, strategies aimed at capturing a higher ratio of radiant energy. Exposure to the blue/red ratio of 1:1 induced increases in the concentration of the furanocoumarin psoralen, probably due to the diversion of carbon from primary metabolism, which resulted in lower growth. Cultivation under blue light or blue:red light at 3:1 triggered anatomical and physiological changes that led to higher production of secondary metabolites in the leaves, and at the 3:1 ratio, the seedlings also had a high growth rate. These results highlight the fundamental role of light in stimulating the production of secondary metabolites, which has important implications for the production of compounds of interest and indirect consequences for the conservation of B. gaudichaudii.
Expression of KNUCKLES in the Stem Cell Domain Is Required for Its Function in the Control of Floral Meristem Activity in Arabidopsis
Authors: Kwaśniewska Kamila , Breathnach Caoilfhionn , Fitzsimons Christina , Goslin Kevin , Thomson Bennett , Beegan Joseph , Finocchio Andrea , Prunet Nathanaël , Ó’Maoiléidigh Diarmuid S. , Wellmer Frank
Published: July 2021

In the model plant Arabidopsis thaliana, the zinc-finger transcription factor KNUCKLES (KNU) plays an important role in the termination of floral meristem activity, a process that is crucial for preventing the overgrowth of flowers. The KNU gene is activated in floral meristems by the floral organ identity factor AGAMOUS (AG), and it has been shown that both AG and KNU act in floral meristem control by directly repressing the stem cell regulator WUSCHEL (WUS), which leads to a loss of stem cell activity. When we re-examined the expression pattern of KNU in floral meristems, we found that KNU is expressed throughout the center of floral meristems, which includes, but is considerably broader than the WUS expression domain. We therefore hypothesized that KNU may have additional functions in the control of floral meristem activity. To test this, we employed a gene perturbation approach and knocked down KNU activity at different times and in different domains of the floral meristem. In these experiments we found that early expression in the stem cell domain, which is characterized by the expression of the key meristem regulatory gene CLAVATA3 (CLV3), is crucial for the establishment of KNU expression. The results of additional genetic and molecular analyses suggest that KNU represses floral meristem activity to a large extent by acting on CLV3. Thus, KNU might need to suppress the expression of several meristem regulators to terminate floral meristem activity efficiently.
The Importance of Positive Psychological Strengths in Well-Being and Adjustment of Romanian Emerging Adults: A Pattern and Variable-Oriented Approach
Authors: Ferrer-Wreder Laura , Eichas Kyle , Stefenel Delia , Buzea Carmen , Wiium Nora
Published: July 2021

Transition to adulthood in countries that have seen recent historical structural changes in society as well as changes in what it means to be an adult represents important contexts for investigations of ways in which positive development and transition to adulthood are experienced. Situated in such context, this cross-sectional study aimed to (1) describe profiles of positive psychological strengths, as measured by the Five Cs of positive youth development (PYD) and (2) document how identified profiles might differ in relation to other aspects of positive and problematic development. Participants were 272 Romanian emerging adults attending university (76% female; aged 19–29 years old, Mage = 21 years old). Latent class analysis was performed to identify patterns of psychological strengths using the Five Cs theory of positive youth development. Pairwise Wald chi square difference tests were then conducted to determine if the identified Five Cs profiles were associated with significant differences in other key outcomes. Findings indicated that, a two-class model emerged as the best fitting model, and in this model, Class 1 was similar to Class 2 on strengths of competence, confidence, and connection. However, the two classes were distinguishable by caring and character, with Class 2, the numerically more common profile (89%), being elevated on character and caring relative to Class 1 (which was a less frequently occurring profile, 11%). This finding highlights the importance of examining the diversity of positive development, even within the same theoretical framework. Further results indicated that the two identified classes showed similarities in problematic behaviors as well as in purpose in life and psychological complaints. Other group difference tests by profile/class indicated that Class 2 was higher in general and social well-being relative to Class 1, with a trend in the same direction for hope. However, an unexpected finding was that Class 2 was also elevated in somatic complaints relative to Class 1. These are important findings not only because of the contribution to the generalizability of the Five Cs theory and measure but also because of the implications of the findings to research, policy, and practice in the Romanian context and beyond.
Emotional Expression in Children With ASD: A Pre-Study on a Two-Group Pre-Post-Test Design Comparing Robot-Based and Computer-Based Training
Authors: Lecciso Flavia , Levante Annalisa , Fabio Rosa Angela , Caprì Tindara , Leo Marco , Carcagnì Pierluigi , Distante Cosimo , Mazzeo Pier Luigi , Spagnolo Paolo , Petrocchi Serena
Published: July 2021

Several studies have found a delay in the development of facial emotion recognition and expression in children with an autism spectrum condition (ASC). Several interventions have been designed to help children to fill this gap. Most of them adopt technological devices (i.e., robots, computers, and avatars) as social mediators and reported evidence of improvement. Few interventions have aimed at promoting emotion recognition and expression abilities and, among these, most have focused on emotion recognition. Moreover, a crucial point is the generalization of the ability acquired during treatment to naturalistic interactions. This study aimed to evaluate the effectiveness of two technological-based interventions focused on the expression of basic emotions comparing a robot-based type of training with a “hybrid” computer-based one. Furthermore, we explored the engagement of the hybrid technological device introduced in the study as an intermediate step to facilitate the generalization of the acquired competencies in naturalistic settings. A two-group pre-post-test design was applied to a sample of 12 children (M = 9.33; ds = 2.19) with autism. The children were included in one of the two groups: group 1 received a robot-based type of training (n= 6); and group 2 received a computer-based type of training (n= 6). Pre- and post-intervention evaluations (i.e., time) of facial expression and production of four basic emotions (happiness, sadness, fear, and anger) were performed. Non-parametric ANOVAs found significant time effects between pre- and post-interventions on the ability to recognize sadness [t(1)= 7.35,p= 0.006; pre: M (ds) = 4.58 (0.51); post: M (ds) = 5], and to express happiness [t(1)= 5.72,p= 0.016; pre: M (ds) = 3.25 (1.81); post: M (ds) = 4.25 (1.76)], and sadness [t(1)= 10.89,p< 0; pre: M (ds) = 1.5 (1.32); post: M (ds) = 3.42 (1.78)]. The group*time interactions were significant for fear [t(1)= 1.019,p= 0.03] and anger expression [t(1)= 1.039,p= 0.03]. However, Mann–Whitney comparisons did not show significant differences between robot-based and computer-based training. Finally, no difference was found in the levels of engagement comparing the two groups in terms of the number of voice prompts given during interventions. Albeit the results are preliminary and should be interpreted with caution, this study suggests that two types of technology-based training, one mediatedviaa humanoid robot and the otherviaa pre-settled video of a peer, perform similarly in promoting facial recognition and expression of basic emotions in children with an ASC. The findings represent the first step to generalize the abilities acquired in a laboratory-trained situation to naturalistic interactions.
Maternal PM10 Exposure Increases Risk for Spina Bifida: A Population-Based Case-Control Study
Authors: Li Huan , Huang Yan-Hong , Li Jing , Liu Shu , Chen Yan-Ling , Li Li-Li , Jiang Cheng-Zhi , Chen Zong-Jiao , Li Na
Published: July 2021

Limited studies have focused on the impact of ambient air pollution on spina bifida. A population-based case-control study was conducted in Liaoning Province, China to assess the associations between maternal PM10 exposures in various exposure windows and spina bifida risk. Data on spina bifida cases born between 2010 and 2015 were available from the Maternal and Child Health Certificate Registry of Liaoning Province. Controls were a random sample of healthy livebirths without any birth defects delivered in the selected five cities during 2010–2015. Ambient air monitoring data for PM10 were obtained from 75 monitoring stations in Liaoning Province. The multivariable logistic regression models were established to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI). We further performed sensitivity analyses by using three propensity score methods. A total of 749 spina bifida cases and 7,950 controls were included. After adjusting for potential confounders, spina bifida was associated with a 10 μg/m3 increment in PM10 during the first trimester of pregnancy (adjusted OR = 1.06, 95% CI: 1.00–1.12) and the 3 months before pregnancy (adjusted OR = 1.12, 95% CI: 1.06–1.19). The adjusted ORs in the final model for the highest vs. the lowest quartile were 1.51 (95% CI: 1.04–2.19) for PM10 during the first trimester of pregnancy and 2.01 (95% CI: 1.43–2.81) for PM10 during the 3 months before pregnancy. Positive associations were found between PM10 exposures during the single month exposure windows and spina bifida. Sensitivity analyses based on two propensity score methods largely reported similar positive associations. Our findings support the evidence that maternal PM10 exposure increases the risk of spina bifida in offspring. Further, validation with a prospective design and a more accurate exposure assessment is warranted.
Sociocultural Challenges in the Implementation of COVID-19 Public Health Measures: Results From a Qualitative Study in Punjab, Pakistan
Authors: Zakar Rubeena , Yousaf Farhan , Zakar Muhammad Zakria , Fischer Florian
Published: July 2021

Informed public health measures are crucial to curb the COVID-19 pandemic. The sociocultural context is important to understand the success or failure of implementing public health measures. This study explores the social and behavioral response to COVID-19 and unveils challenges in the implementation of related public health measures in Pakistan. Within this qualitative study, we conducted 34 telephonic/online in-depth interviews with youths, adults, elderly people, and healthcare professionals in the Punjab province of Pakistan. Framework analysis was used for data analysis. People's poor understanding about COVID-19 and the need for preventive measures were the major challenge in implementing public health preventive strategies. Study participants reported that the lockdown strategy increased poverty and unemployment. People's poor living conditions and living environment compelled them not to follow social distancing and restricting themselves to home. Additionally, an underdeveloped healthcare system was one of the major challenges for Pakistan. The culture of denial in Pakistan related to the epidemiology of COVID-19 was an important challenge within the implementation of public health preventive measures. It is extremely important that public health experts and social scientists work together to understand the contextual sociocultural factors which shape behaviors associated with the spread of a pandemic.
Do Human Capital Investment and Technological Innovation Have a Permanent Effect on Population Health? An Asymmetric Analysis of BRICS Economies
Authors: Hu Gang-Gao , Yao Li-Peng
Published: July 2021

This study examines the asymmetric impact of human capital investment, and technological innovation on population health from the years spanning from 1991 to 2019, by using a panel of the BRICS countries. For this purpose, we have employed the PMG panel NARDL approach, which captures the long-run and short-run dynamics of the concerned variables. The empirical results show that human capital investment and technological innovation indeed happen to exert asymmetric effects on the dynamics of health in BRICS countries. Findings also reveal that increased human capital investment and technological innovation have positive effects on health, while the deceased human capital investment and technological innovation tend to have negative effects on population health in the long run. Based on these revelations, some policy recommendations have been proposed for BRICS economies.