bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous Detection of Ebola Virus and Pathogens Associated With Hemorrhagic Fever by an Oligonucleotide Microarray
Authors: Yao Wenwu , Yang Zhangnv , Lou Xiuyu , Mao Haiyan , Yan Hao , Zhang Yanjun
Published: July 2021

Ebola virus infection causes severe hemorrhagic fever, and its mortality rates varied from 25 to 90% in the previous outbreaks. The highly infectious and lethal nature of this virus highlights the need for reliable and sensitive diagnostic methods to distinguish it from other diseases present with similar clinical symptoms. Based on multiplex polymerase chain reaction (PCR) and oligonucleotide microarray technology, a cost-effective, multipathogen and high-throughput method was developed for simultaneous detection of Ebola virus and other pathogens associated with hemorrhagic fever, including Marburg virus, Lassa fever virus, Junin virus, Machupo virus, Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus, malaria parasite, hantavirus, severe fever with thrombocytopenia syndrome virus, dengue virus, yellow fever virus, Chikungunya virus, influenza A virus, and influenza B virus. This assay had an excellent specificity for target pathogens, without overlap signal between the probes. The limit of detection was approximately 103 pathogen copies/μl. A total of 60 positive nucleic acid samples for different pathogens were detected, a concordance of 100% was observed between microarray assay and real-time PCR analysis. Consequently, the described oligonucleotide microarray may be specific and sensitive assay for diagnosis and surveillance of infections caused by Ebola virus and other species of hemorrhagic fever pathogens.
Single-Cell RNA Sequencing of Retina:New Looks for Gene Marker and Old Diseases
Authors: Ying Peixi , Huang Chang , Wang Yan , Guo Xi , Cao Yuchen , Zhang Yuxi , Fu Sheng , Chen Lin , Yi Guoguo , Fu Min
Published: July 2021

The retina is composed of 11 types of cells, including neurons, glial cells and vascular bed cells. It contains five types of neurons, each with specific physiological, morphological, and molecular definitions. Currently, single-cell RNA sequencing (sRNA-seq) is emerging as one of the most powerful tools to reveal the complexity of the retina. The continuous discovery of retina-related gene targets plays an important role in helping us understand the nature of diseases. The revelation of new cell subpopulations can focus the occurrence and development of diseases on specific biological activities of specific cells. In addition, sRNA-seq performs high-throughput sequencing analysis of epigenetics, transcriptome and genome at the single-cell level, with the advantages of high-throughput and high-resolution. In this paper, we systematically review the development history of sRNA-seq technology, and summarize the new subtypes of retinal cells and some specific gene markers discovered by this technology. The progress in the diagnosis of retinal related diseases is also discussed.
Evaluation of the Brain Function State During Mild Cognitive Impairment Based on Weighted Multiple Multiscale Entropy
Authors: Su Rui , Li Xin , Liu Yi , Cui Wei , Xie Ping , Han Ying
Published: July 2021

The mild cognitive impairment (MCI) stage plays an essential role in preventing the progression of older adults to Alzheimer's disease. In this study, neurofeedback training (NFT) is applied to improve MCI brain cognitive function. To assess the improvement effect, a novel algorithm called Weighted Multiple Multiscale Entropy (WMMSE) is proposed to extract and analyze the electroencephalogram (EEG) features of patients with MCI. To overcome the information loss problem of traditional multiscale entropy (MSE), WMMSE fully considered the correlation of the sequence and the contribution of each sequence to the total entropy. The experimental group composed of 39 patients with MCI was subjected to NFT for 10 days during two sessions. The control group included 21 patients with MCI without any intervention. The Lempel-Ziv complexity (LZC) was used for primary assessment, and WMMSE was used to accurately analyze the effect of NFT. The results show that the WMMSE values of F4, C3, C4, O1, and T5 channels post-NFT are higher compared with pre-NFT and significant differences (P < 0.05). Moreover, the cognitive subscale of the Montreal Cognitive Assessment (MoCA) results shows that the post-NFT score is higher than the pre-NFT in the vast majority of the patients with MCI and significant differences (P < 0.05). When compared with the control group, the WMMSE values of the experimental group increased in each channel. Therefore, the NFT intervention method contributes to brain cognitive functional recovery, and WMMSE can be used as a biomarker to evaluate the state of MCI brain cognitive function.
Predicting MCI to AD Conversation Using Integrated sMRI and rs-fMRI: Machine Learning and Graph Theory Approach
Authors: Zhang Tingting , Liao Qian , Zhang Danmei , Zhang Chao , Yan Jing , Ngetich Ronald , Zhang Junjun , Jin Zhenlan , Li Ling
Published: July 2021

Background

Graph theory and machine learning have been shown to be effective ways of classifying different stages of Alzheimer’s disease (AD). Most previous studies have only focused on inter-subject classification with single-mode neuroimaging data. However, whether this classification can truly reflect the changes in the structure and function of the brain region in disease progression remains unverified. In the current study, we aimed to evaluate the classification framework, which combines structural Magnetic Resonance Imaging (sMRI) and resting-state functional Magnetic Resonance Imaging (rs-fMRI) metrics, to distinguish mild cognitive impairment non-converters (MCInc)/AD from MCI converters (MCIc) by using graph theory and machine learning.

Methods

With the intra-subject (MCInc vs. MCIc) and inter-subject (MCIc vs. AD) design, we employed cortical thickness features, structural brain network features, and sub-frequency (full-band, slow-4, slow-5) functional brain network features for classification. Three feature selection methods [random subset feature selection algorithm (RSFS), minimal redundancy maximal relevance (mRMR), and sparse linear regression feature selection algorithm based on stationary selection (SS-LR)] were used respectively to select discriminative features in the iterative combinations of MRI and network measures. Then support vector machine (SVM) classifier with nested cross-validation was employed for classification. We also compared the performance of multiple classifiers (Random Forest, K-nearest neighbor, Adaboost, SVM) and verified the reliability of our results by upsampling.

Results

We found that in the classifications of MCIc vs. MCInc, and MCIc vs. AD, the proposed RSFS algorithm achieved the best accuracies (84.71, 89.80%) than the other algorithms. And the high-sensitivity brain regions found with the two classification groups were inconsistent. Specifically, in MCIc vs. MCInc, the high-sensitivity brain regions associated with both structural and functional features included frontal, temporal, caudate, entorhinal, parahippocampal, and calcarine fissure and surrounding cortex. While in MCIc vs. AD, the high-sensitivity brain regions associated only with functional features included frontal, temporal, thalamus, olfactory, and angular.

Conclusions

These results suggest that our proposed method could effectively predict the conversion of MCI to AD, and the inconsistency of specific brain regions provides a novel insight for clinical AD diagnosis.
Semantic Memory and Lexical Availability in Parkinson’s Disease: A Statistical Learning Study
Authors: Cardona Juan F. , Grisales-Cardenas Johan S. , Trujillo-Llano Catalina , Diazgranados Jesús A. , Urquina Hugo F. , Cardona Sebastián , Torres Alejandra , Torres Liliana A. , Gonzalez Lina M. , Jaramillo Tania , Cediel Judith , Oñate-Cadena Nelcy , Mateus-Ferro Geral , Marmolejo-Ramos Fernando
Published: July 2021

Parkinson’s disease (PD) is a neurodegenerative disorder that causes a progressive impairment in motor and cognitive functions. Although semantic fluency deficits have been described in PD, more specific semantic memory (SM) and lexical availability (LA) domains have not been previously addressed. Here, we aimed to characterize the cognitive performance of PD patients in a set of SM and LA measures and determine the smallest set of neuropsychological (lexical, semantic, or executive) variables that most accurately classify groups. Thirty early-stage non-demented PD patients (age 35–75, 10 females) and thirty healthy controls (age 36–76, 12 females) were assessed via general cognitive, SM [three subtests of the CaGi battery including living (i.e., elephant) and non-living things (i.e., fork)], and LA (eliciting words from 10 semantic categories related to everyday life) measures. Results showed that PD patients performed lower than controls in two SM global scores (picture naming and naming in response to an oral description). This impairment was particularly pronounced in the non-living things subscale. Also, the number of words in the LA measure was inferior in PD patients than controls, in both larger and smaller semantic fields, showing a more inadequate recall strategy. Notably, the classification algorithms indicated that the SM task had high classification accuracy. In particular, the denomination of non-living things had a classification accuracy of ∼80%. These results suggest that frontostriatal deterioration in PD leads to search strategy deficits in SF and the potential disruption in semantic categorization. These findings are consistent with the embodied view of cognition.
The Psychiatric Symptomology of Visual Snow Syndrome
Authors: Solly Emma J. , Clough Meaghan , Foletta Paige , White Owen B. , Fielding Joanne
Published: July 2021

Objective: To characterise the psychiatric symptoms of visual snow syndrome (VSS), and determine their relationship to quality of life and severity of visual symptoms.

Methods: One hundred twenty-five patients with VSS completed a battery of questionnaires assessing depression/anxiety, dissociative experiences (depersonalisation), sleep quality, fatigue, and quality of life, as well as a structured clinical interview about their visual and sensory symptoms.

Results: VSS patients showed high rates of anxiety and depression, depersonalisation, fatigue, and poor sleep, which significantly impacted quality of life. Further, psychiatric symptoms, particularly depersonalisation, were related to increased severity of visual symptoms. The severity/frequency of psychiatric symptoms did not differ significantly due to the presence of migraine, patient sex, or timing of VSS onset (lifelong vs. later onset).

Conclusion: Psychiatric symptoms are highly prevalent in patients with VSS and are associated with increased visual symptom severity and reduced quality of life. Importantly, patients with lifelong VSS reported lower levels of distress and milder self-ratings of visual symptoms compared to patients with a later onset, while being equally likely to experience psychiatric symptoms. This suggests that the psychiatric symptoms of VSS are not solely due to distress caused by visual symptoms. While no consistently effective treatments are available for the visual symptomology of VSS, psychiatric symptoms offer an avenue of treatment that is likely to significantly improve patient quality of life and ability to cope with visual symptoms.
Vaccine Induced Immune Thrombotic Thrombocytopenia Causing a Severe Form of Cerebral Venous Thrombosis With High Fatality Rate: A Case Series
Authors: Wiedmann Markus , Skattør Thor , Stray-Pedersen Arne , Romundstad Luis , Antal Ellen-Ann , Marthinsen Pål Bache , Sørvoll Ingvild Hausberg , Leiknes Ernstsen Siw , Lund Christian G. , Holme Pål Andre , Johansen Tonje Okkenhaug , Brunborg Cathrine , Aamodt Anne Hege , Schultz Nina Haagenrud , Skagen Karolina , Skjelland Mona
Published: July 2021

During a 2-week period, we have encountered five cases presenting with the combination of cerebral venous thrombosis (CVT), intracerebral hemorrhage and thrombocytopenia. A clinical hallmark was the rapid and severe progression of disease in spite of maximum treatment efforts, resulting in fatal outcome in for 4 out of 5 patients. All cases had received ChAdOx1 nCov-19 vaccine 1–2 weeks earlier and developed a characteristic syndrome thereafter. The rapid progressive clinical course and high fatality rate of CVT in combination with thrombocytopenia in such a cluster and in otherwise healthy adults is a recent phenomenon. Cerebral autopsy findings were those of venous hemorrhagic infarctions and thrombi in dural venous sinuses, including thrombus material apparently rich in thrombocytes, leukocytes and fibrin. Vessel walls were free of inflammation. Extra-cerebral manifestations included leech-like thrombi in large veins, fibrin clots in small venules and scattered hemorrhages on skin and membranes. CVT with thrombocytopenia after adenovirus vectored COVID-19 vaccination is a new clinical syndrome that needs to be recognized by clinicians, is challenging to treat and seems associated with a high mortality rate.
Spatial Memory and Microglia Activation in a Mouse Model of Chronic Neuroinflammation and the Anti-inflammatory Effects of Apigenin
Authors: Chesworth Rose , Gamage Rashmi , Ullah Faheem , Sonego Sandra , Millington Christopher , Fernandez Amanda , Liang Huazheng , Karl Tim , Münch Gerald , Niedermayer Garry , Gyengesi Erika
Published: July 2021

Chronic neuroinflammation characterized by microglia reactivity is one of the main underlying processes in the initiation and progression of neurodegenerative diseases such as Alzheimer’s disease. This project characterized spatial memory during healthy aging and prolonged neuroinflammation in the chronic neuroinflammatory model, glial fibrillary acidic protein-interleukin 6 (GFAP-IL6). We investigated whether chronic treatment with the natural flavonoid, apigenin, could reduce microglia activation in the hippocampus and improve spatial memory. GFAP-IL6 transgenic and wild-type-like mice were fed with apigenin-enriched or control chow from 4 months of age and tested for spatial memory function at 6 and 22 months using the Barnes maze. Brain tissue was collected at 22 months to assess microgliosis and morphology using immunohistochemistry, stereology, and 3D single cell reconstruction. GFAP-IL6 mice showed age-dependent loss of spatial memory recall compared with wild-type-like mice. Chronic apigenin treatment decreased the number of Iba-1+ microglia in the hippocampus of GFAP-IL6 mice and changed microglial morphology. Apigenin did not reverse spatial memory recall impairment in GFAP-IL6 mice at 22 months of age. GFAP-IL6 mice may represent a suitable model for age-related neurodegenerative disease. Chronic apigenin supplementation significantly reduced microglia activation, but this did not correspond with spatial memory improvement in the Barnes Maze.
Molecular Alterations and Their Correlation With the Survival of Glioblastoma Patients With Corpus Callosum Involvement
Authors: Cui Meng , Gao Xin , Chi Yihong , Zhang Meng , Lin Hepu , Chen Hewen , Sun Caihong , Ma Xiaodong
Published: July 2021

Purpose: To explore molecular alterations and their correlation with the survival of patients with glioblastoma (GBM) with corpus callosum (CC) involvement (ccGBM).

Methods: Electronic medical records were reviewed for glioma patients tested for molecular alterations and treated at our hospital between January 2016 and July 2020. ccGBM was compared to GBM without CC involvement (non-ccGBM) to identify differences in molecular alterations. Clinical outcomes and survival were compared between ccGBM and non-ccGBM patients, as well as among patients with ccGBM with different molecular alteration statuses. ccGBM was also compared to diffuse midline glioma (DMG) to clarify their correlation in molecular alterations, the progression-free survival (PFS), and overall survival (OS).

Results: Thirty ccGBM and 88 non-ccGBM patients were included. PDGFRA amplification (PDGFRAamp, 33.3 vs. 9.1%, P = 0.004) and missense mutation (PDGFRAmut, 20.0 vs. 3.4%, P = 0.011) both had higher incidences in ccGBM than in non-ccGBM. PDGFRA alteration was associated with the occurrence of ccGBM (OR = 4.91 [95% CI: 1.55–15.52], P = 0.007). ccGBM with PDGFRAamp resulted in a shorter median PFS (8.6 vs. 13.5 months, P = 0.025) and OS (12.4 vs. 17.9 months, P = 0.022) than non-ccGBM with PDGFRAnon-amp. ccGBM with PDGFRAamp combined with PDGFRAmut (PDGFRAamp-mut) had a shorter median PFS (7.6 vs. 8.9 months, P = 0.022) and OS (9.6 vs. 17.8 months, P = 0.006) than non-ccGBM with wild-type PDGFRA and no amplification (PDGFRA-w, non-amp). Compared to ccGBM with PDGFRA-w, non-amp, ccGBM with PDGFRAamp and PDGFRAamp-mut both had a shorter median PFS and OS (P < 0.05). The hazard ratios (HRs) of PDGFRAamp for PFS and OS in ccGBM were 3.08 (95% CI: 1.02–9.35, P = 0.047) and 5.07 (1.52–16.89, P = 0.008), respectively, and the HRs of PDGFRAamp-mut for PFS and OS were 13.16 (95% CI: 3.19–54.40, P < 0.001) and 16.36 (2.66–100.70, P = 0.003). ccGBM may have similar incidences of PDGFRAamp or mut (PDGFRAamp/mut) as DMG, and they also had similar median PFS (10.9 vs. 9.0 months, P = 0.558) and OS (16.8 vs. 11.5 months, P = 0.510).

Conclusion:PDGFRA alterations are significantly associated with the occurrence and poor prognosis of ccGBM. ccGBM with PDGFRAamp/mut may be classified as a single subtype of GBM that has a similar survival rate to DMG. PDGFR inhibitors may be a promising treatment method for ccGBM.
A Developmental Framework for Embodiment Research: The Next Step Toward Integrating Concepts and Methods
Authors: Lux Vanessa , Non Amy L. , Pexman Penny M. , Stadler Waltraud , Weber Lilian A. E. , Krüger Melanie
Published: July 2021

Embodiment research is at a turning point. There is an increasing amount of data and studies investigating embodiment phenomena and their role in mental processing and functions from across a wide range of disciplines and theoretical schools within the life sciences. However, the integration of behavioral data with data from different biological levels is challenging for the involved research fields such as movement psychology, social and developmental neuroscience, computational psychosomatics, social and behavioral epigenetics, human-centered robotics, and many more. This highlights the need for an interdisciplinary framework of embodiment research. In addition, there is a growing need for a cross-disciplinary consensus on level-specific criteria of embodiment. We propose that a developmental perspective on embodiment is able to provide a framework for overcoming such pressing issues, providing analytical tools to link timescales and levels of embodiment specific to the function under study, uncovering the underlying developmental processes, clarifying level-specific embodiment criteria, and providing a matrix and platform to bridge disciplinary boundaries among the involved research fields.
Tumor Growth in the High Frequency Medulloblastoma Mouse Model Ptch1+/−/Tis21KO Has a Specific Activation Signature of the PI3K/AKT/mTOR Pathway and Is Counteracted by the PI3K Inhibitor MEN1611
Authors: Ceccarelli Manuela , D’Andrea Giorgio , Micheli Laura , Gentile Giulia , Cavallaro Sebastiano , Merlino Giuseppe , Papoff Giuliana , Tirone Felice
Published: July 2021

We have previously generated a mouse model (Ptch1+/−/Tis21KO), which displays high frequency spontaneous medulloblastoma, a pediatric tumor of the cerebellum. Early postnatal cerebellar granule cell precursors (GCPs) of this model show, in consequence of the deletion of Tis21, a defect of the Cxcl3-dependent migration. We asked whether this migration defect, which forces GCPs to remain in the proliferative area at the cerebellar surface, would be the only inducer of their high frequency transformation. In this report we show, by further bioinformatic analysis of our microarray data of Ptch1+/−/Tis21KO GCPs, that, in addition to the migration defect, they show activation of the PI3K/AKT/mTOR pathway, as the mRNA levels of several activators of this pathway (e.g., Lars, Rraga, Dgkq, Pdgfd) are up-regulated, while some inhibitors (e.g. Smg1) are down-regulated. No such change is observed in the Ptch1+/− or Tis21KO background alone, indicating a peculiar synergy between these two genotypes. Thus we investigated, by mRNA and protein analysis, the role of PI3K/AKT/mTOR signaling in MBs and in nodules from primary Ptch1+/−/Tis21KO MB allografted in the flanks of immunosuppressed mice. Activation of the PI3K/AKT/mTOR pathway is seen in full-blown Ptch1+/−/Tis21KO MBs, relative to Ptch1+/−/Tis21WT MBs. In Ptch1+/−/Tis21KO MBs we observe that the proliferation of neoplastic GCPs increases while apoptosis decreases, in parallel with hyper-phosphorylation of the mTOR target S6, and, to a lower extent, of AKT. In nodules derived from primary Ptch1+/−/Tis21KO MBs, treatment with MEN1611, a novel PI3K inhibitor, causes a dramatic reduction of tumor growth, inhibiting proliferation and, conversely, increasing apoptosis, also of tumor CD15+ stem cells, responsible for long-term relapses. Additionally, the phosphorylation of AKT, S6 and 4EBP1 was significantly inhibited, indicating inactivation of the PI3K/AKT/mTOR pathway. Thus, PI3K/AKT/mTOR pathway activation contributes to Ptch1+/−/Tis21KO MB development and to high frequency tumorigenesis, observed when the Tis21 gene is down-regulated. MEN1611 could provide a promising therapy for MB, especially for patient with down-regulation of Btg2 (human ortholog of the murine Tis21 gene), which is frequently deregulated in Shh-type MBs.
Dexamethasone Treatment Limits Efficacy of Radiation, but Does Not Interfere With Glioma Cell Death Induced by Tumor Treating Fields
Authors: Linder Benedikt , Schiesl Abigail , Voss Martin , Rödel Franz , Hehlgans Stephanie , Güllülü Ömer , Seifert Volker , Kögel Donat , Senft Christian , Dubinski Daniel
Published: July 2021

Purpose

Dexamethasone (Dex) is the most common corticosteroid to treat edema in glioblastoma (GBM) patients. Recent studies identified the addition of Dex to radiation therapy (RT) to be associated with poor survival. Independently, Tumor Treating Fields (TTFields) provides a novel anti-cancer modality for patients with primary and recurrent GBM. Whether Dex influences the efficacy of TTFields, however, remains elusive.

Methods

Human GBM cell lines MZ54 and U251 were treated with RT or TTFields in combination with Dex and the effects on cell counts and cell death were determined via flow cytometry. We further performed a retrospective analysis of GBM patients with TTFields treatment +/- concomitant Dex and analysed its impact on progression-free (PFS) and overall survival (OS).

Results

The addition of Dex significantly reduced the efficacy of RT in U251, but not in MZ54 cells. TTFields (200 kHz/250 kHz) induced massive cell death in both cell lines. Concomitant treatment of TTFields and Dex did not reduce the overall efficacy of TTFields. Further, in our retrospective clinical analysis, we found that the addition of Dex to TTFields therapy did not influence PFS nor OS.

Conclusion

Our translational investigation indicates that the efficacy of TTFields therapy in patients with GBM and GBM cell lines is not affected by the addition of Dex.
Prescription of Potentially Inappropriate Medication in Older Inpatients of an Internal Medicine Ward: Concordance and Overlap Among the EU(7)-PIM List and Beers and STOPP Criteria
Authors: Perpétuo Carla , Plácido Ana I. , Rodrigues Daniela , Aperta Jorge , Piñeiro-Lamas Maria , Figueiras Adolfo , Herdeiro Maria Teresa , Roque Fátima
Published: July 2021

Background: Age-related comorbidities prone older adults to polypharmacy and to an increased risk of potentially inappropriate medication (PIM) use. This work aims to analyze the concordance and overlap among the EU(7)-PIM list, 2019 Beers criteria, and Screening Tool of Older Person’s Prescriptions (STOPP) version 2 criteria and also to analyze the prevalence of PIM.

Methods: A retrospective cohort study was conducted on older inpatients of an internal medicine ward. Demographic, clinical, and pharmacological data were collected, during March 2020. After PIM identification by the EU(7)-PIM list, Beers criteria, and STOPP v2 criteria, the concordance and overlap between criteria were analyzed. A descriptive analysis was performed, and all the results with a p-value lower than 0.05 were considered statistically significant.

Results: A total of 616 older patients were included in the study whose median age was 85 (Q1–Q3) (78–89) years. Most of the older patients were male (51.6%), and the median (Q1–Q3) number of days of hospitalization was 17 (13–22) days. According to the EU(7)-PIM list, Beers criteria, and STOPP criteria, 79.7, 92.0, and 76.5% of older adults, respectively, used at least one PIM. A poor concordance (<63.4%) among criteria was observed. An association between PIM and the number of prescribed medicines was found in all applied criteria. Moreover, an association between the number of PIMs and diagnoses of endocrine, nutritional, and metabolic diseases, mental, behavioral, and neurodevelopmental disorders, and circulatory system diseases and days of hospitalization was observed according to Beers criteria, and that with diseases of the circulatory system and musculoskeletal system and connective tissue was observed according to STOPP criteria.

Conclusion: Despite the poor concordance between the EU(7)-PIM list, 2019 Beers, and STOPP v2 criteria, this work highlights the need for more studies in inpatients to develop strategies to facilitate the identification of PIM to decrease the high prevalence of PIM in hospitalized patients. The poor concordance among criteria also highlights the need to develop new tools adapting the existing criteria to medical ward inpatients.
Oleanolic Acid Improves Obesity-Related Inflammation and Insulin Resistance by Regulating Macrophages Activation
Authors: Li Wanqing , Zeng Hongxiang , Xu Min , Huang Chenglong , Tao Linfen , Li Jun , Zhang Ting , Chen Hong , Xia Jing , Li Chunli , Li Xi
Published: July 2021

The chronic low-grade inflammation of adipose tissues, primarily mediated by adipose tissue macrophages (ATMs), is the key pathogenic link between obesity and metabolic disorders. Oleanolic acid (OA) is a natural triterpenoid possessing anti-diabetic and anti-inflammation effects, but the machinery is poorly understood. This study investigated the detailed mechanisms of OA on adipose tissue inflammation in obese mice. C57BL/6J mice were fed with high-fat diet (HFD) for 12 weeks, then daily intragastric administrated with vehicle, 25 and 50 mg/kg OA for 4 weeks. Comparing with vehicle, OA administration in obese mice greatly improved insulin resistance, and reduced adipose tissue hypertrophy, ATM infiltration as well as the M1/M2 ratio. The pro-inflammatory markers were significantly down-regulated by OA in both adipose tissue of obese mice and RAW264.7 macrophages treated with interferon gamma/lipopolysaccharide (IFN-γ/LPS). Furthermore, it was found that OA suppressed activation of mitogen-activated protein kinase (MAPK) signaling and NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome through decreasing voltage dependent anion channels (VDAC) expression and reactive oxygen species (ROS) production. This is the first report that oleanolic acid exerts its benefits by affecting mitochondrial function and macrophage activation.
EGFR-IL-6 Signaling Axis Mediated the Inhibitory Effect of Methylseleninic Acid on Esophageal Squamous Cell Carcinoma
Authors: Wang Yu , Liu Xianghe , Hu Guanghui , Hu Chenfei , Gao Yang , Huo Miaomiao , Zhu Hongxia , Liu Mei , Xu Ningzhi
Published: July 2021

Epidemiological and experimental evidence indicate that selenium is associated with a reduced risk of some cancers, including esophageal cancer. However, the exact mechanism is still unclear. In the present study, we used esophageal squamous cell carcinoma (ESCC) cell lines and animal models to explore the anti-cancer mechanism of methylseleninic acid (MSA). Firstly, MSA treatment dramatically attenuated Epidermal Growth Factor Receptor (EGFR) protein expression but did not alter mRNA levels in ESCC cells. On the contrary, EGFR overexpression partly abolished the inhibitory effect of MSA. With a microRNA-array, we found MSA up-regulated miR-146a which directly targeted EGFR, whereas miR-146a inhibitor antagonized MSA-induced decrease of EGFR protein. We further used 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumor mice model to evaluate the inhibitory effect of MSA in vivo. MSA treatment significantly decreased the tumor burden and EGFR protein expression in tumor specimens. Furthermore, MSA treatment inhibited EGFR pathway and subsequntly reduced Interleukin-6 (IL-6) secretion in the supernatant of cancer cell lines. MSA-induced IL-6 suppression was EGFR-dependent. To further evaluate the association of IL-6 and the anti-tumor effect of MSA on esophageal cancer, we established the 4NQO-induced esophageal tumor model in IL-6 knock-out (IL-6 KO) mice. The results showed that IL-6 deficiency did not affect esophageal tumorigenesis in mice, but the inhibitory effect of MSA was abolished in IL-6 KO mice. In conclusion, our study demonstrated that MSA upregulated miR-146a which directly targeted EGFR, and inhibited EGFR protein expression and pathway activity, subsequently decreased IL-6 secretion. The inhibitory effect of MSA on esophageal cancer was IL-6 dependent. These results suggested that MSA may serve as a potential drug treating esophageal cancer.
Similarities and Differences: A Comparative Review of the Molecular Mechanisms and Effectors of NAFLD and AFLD
Authors: Zhang Pengyi , Wang Weiya , Mao Min , Gao Ruolin , Shi Wenting , Li Dongmei , Calderone Richard , Sui Bo , Tian Xuewen , Meng Xiangjing
Published: July 2021

Non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are the most prevalent metabolic liver diseases globally. Due to the complex pathogenic mechanisms of NAFLD and AFLD, no specific drugs were approved at present. Lipid accumulation, oxidative stress, insulin resistance, inflammation, and dietary habits are all closely related to the pathogenesis of NAFLD and AFLD. However, the mechanism that promotes disease progression has not been fully elucidated. Meanwhile, the gut microbiota and their metabolites also play an important role in the pathogenesis and development of NAFLD and AFLD. This article comparatively reviewed the shared and specific signaling pathways, clinical trials, and potential intervention effectors of NAFLD and AFLD, revealing their similarities and differences. By comparing the shared and specific molecular regulatory mechanisms, this paper provides mutual reference strategies for preventing and treating NAFLD, AFLD, and related metabolic diseases. Furthermore, it provides enlightenment for discovering novel therapies of safe and effective drugs targeting the metabolic liver disease.
Response of Leaf Traits of Eastern Qinghai-Tibetan Broad-Leaved Woody Plants to Climatic Factors
Authors: Kang Xiaomei , Li Yanan , Zhou Jieyang , Zhang Shiting , Li Chenxi , Wang Juhong , Liu Wei , Qi Wei
Published: July 2021

Plant ecologists have long been interested in quantifying how leaf traits vary with climate factors, but there is a paucity of knowledge on these relationships given a large number of the relevant leaf traits and climate factors to be considered. We examined the responses of 11 leaf traits (including leaf morphology, stomatal structure and chemical properties) to eight common climate factors for 340 eastern Qinghai-Tibetan woody species. We showed temperature as the strongest predictor of leaf size and shape, stomatal size and form, and leaf nitrogen and phosphorus concentrations, implying the important role of local heat quantity in determining the variation in the cell- or organ-level leaf morphology and leaf biochemical properties. The effects of moisture-related climate factors (including precipitation and humidity) on leaf growth were mainly through variability in leaf traits (e.g., specific leaf area and stomatal density) related to plant water-use physiological processes. In contrast, sunshine hours affected mainly cell- and organ-level leaf size and shape, with plants developing small/narrow leaves and stomata to decrease leaf damage and water loss under prolonged solar radiation. Moreover, two sets of significant leaf trait-climate relationships, i.e., the leaf/stomata size traits co-varying with temperature, and the water use-related leaf traits co-varying with precipitation, were obtained when analyzing multi-trait relationships, suggesting these traits as good indicators of climate gradients. Our findings contributed evidence to enhance understanding of the regional patterns in leaf trait variation and its environmental determinants.
A Framework for Identification of Healthy Potted Seedlings in Automatic Transplanting System Using Computer Vision
Authors: Jin Xin , Wang Chenglin , Chen Kaikang , Ji Jiangtao , Liu Suchwen , Wang Yawei
Published: July 2021

Automatic transplanting of seedlings is of great significance to vegetable cultivation factories. Accurate and efficient identification of healthy seedlings is the fundamental process of automatic transplanting. This study proposed a computer vision-based identification framework of healthy seedlings. Vegetable seedlings were planted in trays in the form of potted seedlings. Two-color index operators were proposed for image preprocessing of potted seedlings. An optimal thresholding method based on the genetic algorithm and the three-dimensional block-matching algorithm (BM3D) was developed to denoise and segment the image of potted seedlings. The leaf area of the potted seedling was measured by machine vision technology to detect the growing status and position information of the potted seedling. Therefore, a smart identification framework of healthy vegetable seedlings (SIHVS) was constructed to identify healthy potted seedlings. By comparing the identification accuracy of 273 potted seedlings images, the identification accuracy of the proposed method is 94.33%, which is higher than 89.37% obtained by the comparison method.
What Do Therapist Defense Mechanisms Have to Do With Their Experience of Professional Self-Doubt and Vicarious Trauma During the COVID-19 Pandemic?
Authors: Aafjes-Van Doorn Katie , Békés Vera , Luo Xiaochen , Prout Tracy A. , Hoffman Leon
Published: July 2021

This is the first study to examine psychotherapists' levels of defense mechanisms, their concurrent relationship with professional work-related stress (professional self-doubt and vicarious trauma), and how their levels of defense mechanisms predict the changes in these professional stresses over the course of 3 months since the start of the COVID-19 pandemic. Data from two online studies (Study 1; N = 105 and Study 2; N = 336), using two self-report measures of therapists' defense mechanisms (Defense Style Questionnaire-40 in Study 1 and Defense Mechanism Rating Scales Self-Report-30 in Study 2), are presented. Therapists reported higher levels of mature defense mechanisms, and lower levels of immature defense mechanisms, compared to published community and clinical populations assessed before and during the pandemic. Therapists' lower level of mature defense mechanisms and higher levels of neurotic and immature defense mechanisms were related to higher concurrent levels of vicarious trauma and professional doubt. Therapists who reported higher levels of mature defense mechanisms at 3-month follow-up showed less vicarious trauma and professional self-doubt at follow-up, after controlling for these professional stressors at baseline. Implications for clinical supervision and training are discussed. The context and professional challenges during the pandemic are unique and future replications of the results outside the pandemic context are warranted.
Animal and Human Brucellosis in Pakistan
Authors: Jamil Tariq , Khan Aman Ullah , Saqib Muhammad , Hussain Muhammad Hammad , Melzer Falk , Rehman Abdul , Shabbir Muhammad Zubair , Khan Mumtaz Ali , Ali Shahzad , Shahzad Asim , Khan Iahtasham , Iqbal Mudassar , Ullah Qudrat , Ahmad Waqas , Mansoor Muhammad Khalid , Neubauer Heinrich , Schwarz Stefan
Published: July 2021

Brucellosis is a bacterial zoonotic disease that affects many animal species and can be transmitted to humansviadirect contact orviacontaminated food. Although brucellosis is a serious health hazard, its public health concern has been neglected in many countries. In some developing countries, such as Pakistan, where brucellosis is endemic, this disease continues to be of importance. A literature search for the past 11 years (2011–2021) provided a comprehensive insight into brucellosis in Pakistan. In this review, particular emphasis was placed on occurrence, diagnostic tests used, and prevention, treatment, and control in the context of the “One Health” approach.
What Teeth Can Tell Us
Authors: Janjić Klara , Kanz Fabian , Agis Hermann
Published: July 2021

Teeth are the hardest substance of the body and the gatekeeper of the digestive tract. They can survive extreme environmental conditions and they are the last part of the body that is decomposed after death. With these unique features, teeth are often the only remaining body part of a deceased person in a criminal case. Teeth can help investigators to find out who a dead person is, how old the person was, if the person was male or female, what kind of daily habits and lifestyle a person had and how the person died. Thus, the examination of teeth plays a key role in crime scene investigations and can help solve crimes.
African Swine Fever in Smallholder Sardinian Farms: Last 10 Years of Network Transmission Reconstruction and Analysis
Authors: Rolesu Sandro , Mandas Daniela , Loi Federica , Oggiano Annalisa , Dei Giudici Silvia , Franzoni Giulia , Guberti Vittorio , Cappai Stefano
Published: July 2021

African swine fever (ASF) is a viral disease of suids that frequently leads to death. There are neither licensed vaccines nor treatments available, and even though humans are not susceptible to the disease, the serious socio-economic consequences associated with ASF have made it one of the most serious animal diseases of the last century. In this context, prevention and early detection play a key role in controlling the disease and avoiding losses in the pig value chain. Target biosecurity measures are a strong strategy against ASF virus (ASFV) incursions in farms nowadays, but to be efficient, these measures must be well-defined and easy to implement, both in commercial holdings and in the backyard sector. Furthermore, the backyard sector is of great importance in low-income settings, mainly for social and cultural practices that are highly specific to certain areas and communities. These contexts need to be addressed when authorities decide upon the provisions that should be applied in the case of infection or decide to combine them with strict preventive measures to mitigate the risk of virus spread. The need for a deeper understanding of the smallholder context is essential to prevent ASFV incursion and spread. Precise indications for pig breeding and risk estimation for ASFV introduction, spread and maintenance, taking into account the fact that these recommendations would be inapplicable in some contexts, are the keys for efficient target control measures. The aim of this work is to describe the 305 outbreaks that occurred in domestic pigs in Sardinia during the last epidemic season (2010–2018) in depth, providing essential features associated with intensive and backyard farms where the outbreaks occurred. In addition, the study estimates the average of secondary cases by kernel transmission network. Considering the current absence of ASF outbreaks in domestic pig farms in Sardinia since 2018, this work is a valid tool to specifically estimate the risk associated with different farm types and update our knowledge in this area.
Neonatal Nav1.5 Protein Expression in Human Colorectal Cancer: Immunohistochemical Characterization and Clinical Evaluation
Authors: Lastraioli Elena , Fraser Scott P. , Guzel R. Mine , Iorio Jessica , Bencini Lapo , Scarpi Emanuela , Messerini Luca , Villanacci Vincenzo , Cerino Giulia , Ghezzi Niccolo’ , Perrone Giuseppe , Djamgoz Mustafa B. A. , Arcangeli Annarosa
Published: July 2021

Voltage-gated Na+ channels (VGSCs) are expressed widely in human carcinomas and play a significant role in promoting cellular invasiveness and metastasis. However, human tissue-based studies and clinical characterization are lacking. In several carcinomas, including colorectal cancer (CRCa), the predominant VGSC is the neonatal splice variant of Nav1.5 (nNav1.5). The present study was designed to determine the expression patterns and clinical relevance of nNav1.5 protein in human CRCa tissues from patients with available clinicopathological history. The immunohistochemistry was made possible by the use of a polyclonal antibody (NESOpAb) specific for nNav1.5. The analysis showed that, compared with normal mucosa, nNav1.5 expression occurred in CRCa samples (i) at levels that were significantly higher and (ii) with a pattern that was more delineated (i.e., apical/basal or mixed). A surprisingly high level of nNav1.5 protein expression also occurred in adenomas, but this was mainly intracellular and diffuse. nNav1.5 showed a statistically significant association with TNM stage, highest expression being associated with TNM IV and metastatic status. Interestingly, nNav1.5 expression co-occurred with other biomarkers associated with metastasis, including hERG1, KCa3.1, VEGF-A, Glut1, and EGFR. Finally, univariate analysis showed that nNav1.5 expression had an impact on progression-free survival. We conclude (i) that nNav1.5 could represent a novel clinical biomarker (‘companion diagnostic’) useful to better stratify CRCa patients and (ii) that since nNav1.5 expression is functional, it could form the basis of anti-metastatic therapies including in combination with standard treatments.
PRKAR1A and Thyroid Tumors
Authors: Pitsava Georgia , Stratakis Constantine A. , Faucz Fabio R.
Published: July 2021

Thyroid cancer is the most common type of endocrine malignancy and the incidence is rapidly increasing. Follicular (FTC) and papillary thyroid (PTC) carcinomas comprise the well-differentiated subtype and they are the two most common thyroid carcinomas. Multiple molecular genetic and epigenetic alterations have been identified in various types of thyroid tumors over the years. Point mutations in BRAF, RAS as well as RET/PTC and PAX8/PPARγ chromosomal rearrangements are common. Thyroid cancer, including both FTC and PTC, has been observed in patients with Carney Complex (CNC), a syndrome that is inherited in an autosomal dominant manner and predisposes to various tumors. CNC is caused by inactivating mutations in the tumor-suppressor gene encoding the cyclic AMP (cAMP)-dependent protein kinase A (PKA) type 1α regulatory subunit (PRKAR1A) mapped in chromosome 17 (17q22–24). Growth of the thyroid is driven by the TSH/cAMP/PKA signaling pathway and it has been shown in mouse models that PKA activation through genetic ablation of the regulatory subunit Prkar1a can cause FTC. In this review, we provide an overview of the molecular mechanisms contributing to thyroid tumorigenesis associated with inactivation of the RRKAR1A gene.
A Multicentre Evaluation of Dosiomics Features Reproducibility, Stability and Sensitivity
Authors: Placidi Lorenzo , Gioscio Eliana , Garibaldi Cristina , Rancati Tiziana , Fanizzi Annarita , Maestri Davide , Massafra Raffaella , Menghi Enrico , Mirandola Alfredo , Reggiori Giacomo , Sghedoni Roberto , Tamborra Pasquale , Comi Stefania , Lenkowicz Jacopo , Boldrini Luca , Avanzo Michele
Published: July 2021

Dosiomics is a texture analysis method to produce dose features that encode the spatial 3D distribution of radiotherapy dose. Dosiomic studies, in a multicentre setting, require assessing the features’ stability to dose calculation settings and the features’ capability in distinguishing different dose distributions. Dose distributions were generated by eight Italian centres on a shared image dataset acquired on a dedicated phantom. Treatment planning protocols, in terms of planning target volume coverage and dose–volume constraints to the organs at risk, were shared among the centres to produce comparable dose distributions for measuring reproducibility/stability and sensitivity of dosiomic features. In addition, coefficient of variation (CV) was employed to evaluate the dosiomic features’ variation. We extracted 38,160 features from 30 different dose distributions from six regions of interest, grouped by four features’ families. A selected group of features (CV < 3 for the reproducibility/stability studies, CV > 1 for the sensitivity studies) were identified to support future multicentre studies, assuring both stable features when dose distributions variation is minimal and sensitive features when dose distribution variations need to be clearly identified. Dosiomic is a promising tool that could support multicentre studies, especially for predictive models, and encode the spatial and statistical characteristics of the 3D dose distribution.
Identification and Functional Characterization of Novel MYC-Regulated Long Noncoding RNAs in Group 3 Medulloblastoma
Authors: Rea Jessica , Carissimo Annamaria , Trisciuoglio Daniela , Illi Barbara , Picard Daniel , Remke Marc , Laneve Pietro , Caffarelli Elisa
Published: July 2021

The impact of protein-coding genes on cancer onset and progression is a well-established paradigm in molecular oncology. Nevertheless, unveiling the contribution of the noncoding genes—including long noncoding RNAs (lncRNAs)—to tumorigenesis represents a great challenge for personalized medicine, since they (i) constitute the majority of the human genome, (ii) are essential and flexible regulators of gene expression and (iii) present all types of genomic alterations described for protein-coding genes. LncRNAs have been increasingly associated with cancer, their highly tissue- and cancer type-specific expression making them attractive candidates as both biomarkers and therapeutic targets. Medulloblastoma is one of the most common malignant pediatric brain tumors. Group 3 is the most aggressive subgroup, showing the highest rate of metastasis at diagnosis. Transcriptomics and reverse genetics approaches were combined to identify lncRNAs implicated in Group 3 Medulloblastoma biology. Here we present the first collection of lncRNAs dependent on the activity of the MYC oncogene, the major driver gene of Group 3 Medulloblastoma. We assessed the expression profile of selected lncRNAs in Group 3 primary tumors and functionally characterized these species. Overall, our data demonstrate the direct involvement of three lncRNAs in Medulloblastoma cancer cell phenotypes.