bluuebunny/crossref_metadata_2025 huggingface dataset:
Stem Cell Factor in Combination With Granulocyte Colony-Stimulating Factor Protects the Brain From Capillary Thrombosis-Induced Ischemic Neuron Loss in a Mouse Model of CADASIL
Authors: Ping Suning , Qiu Xuecheng , Gonzalez-Toledo Maria E. , Liu Xiaoyun , Zhao Li-Ru
Published: January 2021

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a Notch3 mutation-induced cerebral small vessel disease, leading to recurrent ischemic stroke and vascular dementia. There is currently no treatment that can stop or delay CADASIL progression. We have demonstrated the efficacy of treatment with combined stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in reducing cerebral small vessel thrombosis in a TgNotch3R90C mouse model of CADASIL. However, it remains unknown whether SCF+G-CSF treatment protects neurons from microvascular thrombosis-induced ischemic damage. Using bone marrow transplantation to track thrombosis, we observed that capillary thrombosis was widely distributed in the cortex, striatum and hippocampus of 22-month-old TgNotch3R90C mice. However, the capillary thrombosis mainly occurred in the cortex. Neuron loss was seen in the area next to the thrombotic capillaries, and severe neuron loss was found in the areas adjacent to the thrombotic capillaries with bifurcations. SCF+G-CSF repeated treatment significantly attenuated neuron loss in the areas next to the thrombotic capillaries in the cortex of the 22-month-old TgNotch3R90C mice. Neuron loss caused by capillary thrombosis in the cerebral cortex may play a crucial role in the pathogenesis of CADASIL. SCF+G-CSF treatment ameliorates the capillary thrombosis-induced ischemic neuron loss in TgNotch3R90C mice. This study provides new insight into the understanding of CADASIL progression and therapeutic potential of SCF+G-CSF in neuroprotection under microvascular ischemia in CADASIL.
Transmembrane Fluoride Transport by a Cyclic Azapeptide With Two β-Turns
Authors: Zhao Zhixing , Zhang Miaomiao , Tang Bailing , Weng Peimin , Zhang Yueyang , Yan Xiaosheng , Li Zhao , Jiang Yun-Bao
Published: January 2021

Diverse classes of anion transporters have been developed, most of which focus on the transmembrane chloride transport due to its significance in living systems. Fluoride transport has, to some extent, been overlooked despite the importance of fluoride channels in bacterial survival. Here, we report the design and synthesis of a cyclic azapeptide (a peptide-based N-amidothiourea, 1), as a transporter for fluoride transportation through a confined cavity that encapsulates fluoride, together with acyclic control compounds, the analogs 2 and 3. Cyclic receptor 1 exhibits more stable β-turn structures than the control compounds 2 and 3 and affords a confined cavity containing multiple inner –NH protons that serve as hydrogen bond donors to bind anions. It is noteworthy that the cyclic receptor 1 shows the capacity to selectively transport fluoride across a lipid bilayer on the basis of the osmotic and fluoride ion-selective electrode (ISE) assays, during which an electrogenic anion transport mechanism is found operative, whereas no transmembrane transport activity was found with 2 and 3, despite the fact that 2 and 3 are also able to bind fluoride via the thiourea moieties. These results demonstrate that the encapsulation of an anionic guest within a cyclic host compound is key to enhancing the anion transport activity and selectivity.
Structural Insight Into the SARS-CoV-2 Nucleocapsid Protein C-Terminal Domain Reveals a Novel Recognition Mechanism for Viral Transcriptional Regulatory Sequences
Authors: Yang Mei , He Suhua , Chen Xiaoxue , Huang Zhaoxia , Zhou Ziliang , Zhou Zhechong , Chen Qiuyue , Chen Shoudeng , Kang Sisi
Published: January 2021

Coronavirus disease 2019 (COVID-19) has caused massive disruptions to society and the economy, and the transcriptional regulatory mechanisms behind the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are poorly understood. Herein, we determined the crystal structure of the SARS-CoV-2 nucleocapsid protein C-terminal domain (CTD) at a resolution of 2.0 Å, and demonstrated that the CTD has a comparable distinct electrostatic potential surface to equivalent domains of other reported CoVs, suggesting that the CTD has novel roles in viral RNA binding and transcriptional regulation. Further in vitro biochemical assays demonstrated that the viral genomic intergenic transcriptional regulatory sequences (TRSs) interact with the SARS-CoV-2 nucleocapsid protein CTD with a flanking region. The unpaired adeno dinucleotide in the TRS stem-loop structure is a major determining factor for their interactions. Taken together, these results suggested that the nucleocapsid protein CTD is responsible for the discontinuous viral transcription mechanism by recognizing the different patterns of viral TRS during transcription.
Testing Various Pre-treatments on Artificially Waterlogged and Pitch-Contaminated Wood for Strontium Isotope Analyses
Authors: Snoeck Christophe , Schulting Rick J. , Brock Fiona , Rodler Alexandra S. , Van Ham-Meert Alicia , Mattielli Nadine , Ostapkowicz Joanna
Published: January 2021

Strontium isotope ratios (87Sr/86Sr) are commonly used in archeological and forensic studies to assess if humans and fauna are local to the place they were found or not. This approach is largely unexplored for wooden artifacts recovered in archeological contexts, as wood – in the rare instances it does survive – is often poorly preserved. One of the most common ways wood is preserved is through the anoxic conditions found in waterlogged contexts. A more unusual form of preservation is through submergence in natural pitch. These depositional media contribute their own strontium values to the in vivo87Sr/86Sr wood values, which needs to be removed prior to analysis. Here we test several pre-treatment methods to remove potential strontium contamination from wood samples that were artificially immersed in seawater and pitch from Trinidad’s Pitch Lake. Water rinses and acid-leaching tests were carried out with hydrochloric acid and acetic acid to remove exogenous strontium from experimentally waterlogged wood. These tests removed large amounts of strontium from the samples and did not enable the recovery of the endogenous 87Sr/86Sr signal. For samples artificially immersed in pitch, the pre-treatments tested were based on radiocarbon dating procedures and carried out with and without the aqueous-based acid-base-acid (ABA) step. The use of organic solvents alone (methanol and toluene) removed exogenous strontium originating from the pitch. However, the ABA step eliminates large amounts of in vivo strontium from the samples. These tests show that 87Sr/86Sr values of wood are altered by the presence of pitch and water. With adequate pre-treatment using exclusively organic solvents, it may be possible to remove this contamination for samples immersed in pitch. However, the aqueous-based ABA pre-treatment should be avoided. The removal of contamination from waterlogged samples was unsuccessful with the current pre-treatment protocols and more research is needed. More importantly, and unexpectedly, 87Sr/86Sr values may extend outside of the mixing line between the wood’s endogenous strontium and the water. These results indicate the need for extreme caution when attempting to determine the provenance of waterlogged wood.
Pilot Study on Genetic Associations With Age-Related Sarcopenia
Authors: Urzi Felicita , Pokorny Boštjan , Buzan Elena
Published: January 2021

Despite strong evidence of an inheritable component of muscle phenotypes, little progress has been made in identifying the specific genetic factors involved in the development of sarcopenia. Even rarer are studies that focus on predicting the risk of sarcopenia based on a genetic risk score. In the present study, we tested the single and combined effect of seven candidate gene variants on the risk of sarcopenia. Single nucleotide polymorphisms in candidate genes were genotyped using the KASP assay. We examined 190 older adults that were classified as non-sarcopenic or sarcopenic according to the diagnostic criteria of the European Working Group on Sarcopenia in Older People. Sarcopenia was associated with Methylenetetrahydrofolate reductase, Alpha-actinin-3, and Nuclear respiratory factor 2 genotypes. The combined effect of all three polymorphisms explained 39% of the interindividual variation in sarcopenia risk. Our results suggest that the single and combined effect of Methylenetetrahydrofolate reductase, Alpha-actinin-3, and Nuclear respiratory factor 2 polymorphism is associated with sarcopenia risk in older adults. Nowadays, as the population is getting older and older, great efforts are being made to research the etiology, diagnosis and treatment of sarcopenia. At the same time, small progress has been made in understanding the genetic etiology of sarcopenia. Given the importance of research on this disease, further genetic studies are needed to better understand the genetic risk underlying sarcopenia. We believe that this small-scale study will help to demonstrate that there is still much to be discovered in this field.
Detection of Mitochondrial Mutations Through Isothermal Nucleic Acid Amplification Coupled With Clustered Regularly Interspaced Short Palindromic Repeat-Associated Endonuclease Cas13a
Authors: Jiang Hua , Duan Kun , Han Xu , Wang Jun , Liu Xiao , Yan Maoxiao , Wang Yunxiu , Liu Hongyan , Shi Huiling , Gao Xiaoqing , Ouyang Chuan , Fu Xue , Zhang Xinxin , Liu Chao
Published: January 2021

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated endonuclease Cas13a can specifically bind and cleave RNA. After nucleic acid pre-amplification, bacterial Cas13a has been used to detect genetic mutations. In our study, using a transcription-mediated amplification together with Cas13a, we can isothermally amplify and detect mitochondrial point mutations under non-denaturing conditions from human genomic DNA. Unlike previous reports, we prepared CRISPR DNA with T7 promoter sequences and generated CRISPR RNA via transcription-mediated amplification instead of synthesizing and adding CRISPR RNA in a separate step. As a proof-of-concept, we showed that both m.1494C > T and m.1555A > G mutations were detected within 90 min. In addition, we explored various designs of CRISPR DNA to improve assay specificity, including the location and number of nucleotide mismatches, length of protospacer sequence, and different buffering conditions. We also confirmed the possibility of a “one-step single-tube” reaction for mutation detection. This assay can robustly distinguish circular DNA templates that differ by a single nucleotide. It has the potential to be adapted for automated applications, such as the screening of mitochondrial diseases.
Assessing Mental Health of Women Living in Karachi During the Covid-19 Pandemic
Authors: Asim Shabnam Shamim , Ghani Samrah , Ahmed Maheen , Asim Anushae , Qureshi Afzal Fatima Karim
Published: January 2021

Introduction: Women are more susceptible to mental health disorders and have been reported to experience higher levels of depression and anxiety during previous large-scale disease outbreaks. Stressful events like the COVID-19 pandemic can add extra burdens to women's already multifaceted lives. Keeping the gender implications of COVID-19 in mind can assist health care workers to offer more effective management. In our study, we aimed to assess the impact of COVID-19 on the mental health of women in Karachi, Pakistan and investigate the possible risk factors.

Methods: An online questionnaire was distributed to women on social media platforms in the month of June 2020. The questionnaire had two self-assessment scales, Patient Health Questionnaire (PHQ-9) scale which measures the symptoms of depression and General Anxiety Disorder (GAD-7) scale which measures anxiety.

Results: Three hundred and ninety three individuals completed the questionnaire with the mean age calculated to be 27.6 ± 11.7 years. Age, education, marital status, number of children, financial issues, employment status, smoking, comorbidities and mental illnesses were significantly associated with participants' mean anxiety and depression scores. The depression scores were generally higher compared to anxiety scores in each category. As the age increased, their scores decreased, with women aged 18–30 having a significantly higher mean depression and anxiety scores compared to women who were above 50. Severe anxiety was identified in 21.9% women and severe depression was noted in 17.8% women. A frightening number of 148 (37.7%) was found of women who had self-destructive thoughts at one time or another. Out of these women, surprisingly 97 (65.5%) individuals were not previously diagnosed with any mental illnesses.

Discussion: This study supports the existing literature regarding the disturbed psychological state of women close to the peak of the covid-19 pandemic. We noted increased percentage of depressive women as compared to studies conducted before the covid-19 era. This raises concern especially with our thought provoking finding of self-harm or suicidal thoughts among women. Most of our female population is also seen to be anxious. This study highlights the importance for help and support groups of mental health to effectively reach women during this period of social isolation.
Immunostimulatory Endogenous Nucleic Acids Perpetuate Interface Dermatitis—Translation of Pathogenic Fundamentals Into an In Vitro Model
Authors: Braegelmann Christine , Fetter Tanja , Niebel Dennis , Dietz Lara , Bieber Thomas , Wenzel Joerg
Published: January 2021

Interface dermatitis is a histopathological pattern mirroring a distinct cytotoxic immune response shared by a number of clinically diverse inflammatory skin diseases amongst which lichen planus and cutaneous lupus erythematosus are considered prototypic. Interface dermatitis is characterized by pronounced cytotoxic immune cell infiltration and necroptotic keratinocytes at the dermoepidermal junction. The initial inflammatory reaction is established by cytotoxic immune cells that express CXC chemokine receptor 3 and lesional keratinocytes that produce corresponding ligands, CXC motif ligands 9/10/11, recruiting the effector cells to the site of inflammation. During the resulting anti-epithelial attack, endogenous immune complexes and nucleic acids are released from perishing keratinocytes, which are then perceived by the innate immune system as danger signals. Keratinocytes express a distinct signature of pattern recognition receptors and binding of endogenous nucleic acid motifs to these receptors results in interferon-mediated immune responses and further enhancement of CXC chemokine receptor 3 ligand production. In this perspective article, we will discuss the role of innate nucleic acid sensing as a common mechanism in the perpetuation of clinically heterogeneous diseases featuring interface dermatitis based on own data and a review of the literature. Furthermore, we will introduce a keratinocyte-specificin vitromodel of interface dermatitis as follows: Stimulation of human keratinocytes with endogenous nucleic acids alone and in combination with interferon gamma leads to pronounced production of distinct cytokines, which are essential in the pathogenesis of interface dermatitis. This experimental approach bears the capability to investigate potential therapeutics in this group of diseases with unmet medical need.
Down-Regulation of Colonic ACE2 Expression in Patients With Inflammatory Bowel Disease Responding to Anti-TNF Therapy: Implications for COVID-19
Authors: Li Xiao-Zhi , Qiu Yun , Jeffery Louisa , Liu Fen , Feng Rui , He Jin-Shen , Tan Jin-Yu , Ye Zi-Yin , Lin Si-Nan , Ghosh Subrata , Iacucci Marietta , Chen Min-Hu , Mao Ren
Published: January 2021

Background and Aims: Angiotensin-converting enzyme II (ACE2) is the key molecule for understanding the pathophysiology of COVID-19. The risk of COVID-19 and impact of immunosuppressive treatment on disease course in patients with inflammatory bowel disease (IBD) remain controversial. We aimed to determine the change of intestinal ACE2 expression before and after biologics treatment including anti-tumor necrosis factor α (anti-TNFα), anti-integrin, and anti-interleukin (IL)12/23 in IBD patients.

Methods: We analyzed the ACE2 expression through the public database of paired intestinal biopsies from IBD patients before and after biologic therapy. Change of ACE2 RNA and protein expression were validated in two independent cohorts (Birmingham cohort and Guangzhou cohort). The correlation between ACE2 expression and disease activity was also analyzed.

Results: Mining information from the GEO database showed that compared with healthy control, intestinal ACE2 expression was downregulated in ileum of CD patients, while upregulated in colon of both CD and UC patients. Colonic ACE2 RNA expression was decreased significantly in patients responding to anti-TNFα but not anti-integrin and anti-IL12/23, which was validated in the Birmingham cohort. Using the Guangzhou cohort including 53 patients matched by pre- and post-anti-TNFα therapy, colonic ACE2 protein expression was significantly downregulated after anti-TNFα treatment in responders (P < 0.001) rather than non-responders. Colonic ACE2 expression was significantly higher in patients with severe histologically active disease compared with those with moderate (P < 0.0001) and mild (P = 0.0002) histologically active disease.

Conclusion: Intestinal inflammation influences the expression of intestinal ACE2 in IBD patients, with different alterations in the ileum and colon. Colonic ACE2 expression was downregulated after anti-TNFα therapy in IBD patients responding to treatment. This might provide new clues regarding the risk of SARS-CoV-2 infection and the potential benefit of sustaining anti-TNFα treatment in patients with IBD.
Maipomycin A, a Novel Natural Compound With Promising Anti-biofilm Activity Against Gram-Negative Pathogenic Bacteria
Authors: Zhang Junliang , Liang Xiaoyan , Zhang Shiling , Song Zhiman , Wang Changyun , Xu Ying
Published: January 2021

Pathogenic bacterial biofilms play an important role in recurrent nosocomial and medical device-related infections. Once occurred, the complex structure of the biofilm promotes the development of antibiotic resistance and becomes extremely difficult to eradicate. Here we describe a novel and effective anti-biofilm compound maipomycin A (MaiA), which was isolated from the metabolites of a rare actinomycete strain Kibdelosporangium phytohabitans XY-R10. Its structure was deduced from analyses of spectral data and confirmed by single-crystal X-ray crystallography. This natural product demonstrated a broad spectrum of anti-biofilm activities against Gram-negative bacteria. Interestingly, the addition of Fe(II) or Fe(III) ions could block the biofilm inhibition activity of MaiA because it is an iron chelator. However, not all iron chelators showed biofilm inhibition activity, suggesting that MaiA prevents biofilm formation through a specific yet currently undefined pathway. Furthermore, MaiA acts as a synergist to enhance colistin efficacy against Acinetobacter baumannii. Our results indicate that MaiA may potentially serve as an effective antibiofilm agent to prevent Gram-negative biofilm formation in future clinical applications.
Whole Genome Sequencing and Root Colonization Studies Reveal Novel Insights in the Biocontrol Potential and Growth Promotion by Bacillus subtilis MBI 600 on Cucumber
Authors: Samaras Anastasios , Nikolaidis Marios , Antequera-Gómez Maria Luisa , Cámara-Almirón Jesus , Romero Diego , Moschakis Thomas , Amoutzias Grigoris D. , Karaoglanidis Georgios S.
Published: January 2021

Bacillusspp. MBI 600 is a gram-positive bacterium and is characterized as a PGPR strain involved in plant growth promotion and control of various plant pathogens which has recently been introduced into the agricultural practice. In this study we performed a Next Generation Sequencing analysis, to analyze the full genome of this microorganism and to characterize it taxonomically. Results showed that MBI 600 strain was phylogenetically close to otherBacillusspp. strains used as biocontrol agents and identified asB. subtilis. GOG analysis showed clusters contributed to secondary metabolites production such as fengycin and surfactin. In addition, various genes which annotated according to other plant-associated strains, showed that play a main role in nutrient availability from soil. The root colonization ability of MBI 600 strain was analyzedin vivowith a yellow fluorescence protein (yfp) tag. Confocal laser scanning microscopy of cucumber roots treated withyfp-tagged MBI 600 cells, revealed that the strain exhibits a strong colonization ability of cucumber roots, although it is affected significantly by the growth substrate of the roots.In vitroandin plantaexperiments with MBI 600 strain andF. oxysporumf.sp.radicis cucumerinumandP. aphanidernatum, showed a high control ability against these soilborne pathogens. Overall, our study demonstrates the effectiveness of MBI 600 in plant growth promotion and antagonism against different pathogens, highlighting the use of this microorganism as a biocontrol agent.
The Role of Serum Metabolomics in Distinguishing Chronic Rhinosinusitis With Nasal Polyp Phenotypes
Authors: Xie Shaobing , Zhang Hua , Liu Yongzhen , Gao Kelei , Zhang Junyi , Fan Ruohao , Xie Shumin , Xie Zhihai , Wang Fengjun , Jiang Weihong
Published: January 2021

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease characterized by different clinical features and treatment responsiveness. This study aimed to compare the serum metabolomics profiles between eosinophilic CRSwNP (eCRSwNP) and non-eosinophilic CRSwNP (neCRSwNP) and healthy controls (HC) and explore objective biomarkers for distinguishing eCRSwNP before surgery.

Methods: Serum samples were collected from 33 neCRSwNP patients, 37 eCRSwNP patients, and 29 HC. Serum metabolomics profiles were investigated by ultra-high-performance liquid chromatography–mass spectrometry.

Results: The analysis results revealed that neCRSwNP, eCRSwNP, and HC exhibited distinctive metabolite signatures. In addition, eCRSwNP could be distinguished from neCRSwNP referring to their serum metabolic profiles, and the top ten different metabolites were citrulline, choline, linoleic acid, adenosine, glycocholic acid, L-serine, triethanolamine, 4-guanidinobutyric acid, methylmalonic acid, and L-methionine, which were related to several most important pathways including arginine and proline metabolism; glycine, serine, and threonine metabolism; linoleic acid metabolism; and purine metabolism. Among these distinctive metabolites, citrulline, linoleic acid, adenosine, and 4-guanidinobutyric acid showed good predictabilities, and the serum levels of citrulline, linoleic acid, and adenosine were significantly correlated with tissue eosinophil (T-EOS) percentage and T-EOS count.

Conclusion: eCRSwNP patients exhibited discriminative serum metabolic signatures in comparison with neCRSwNP patients and HC. These results suggested that metabolomics profiles contributed to understanding the pathophysiological mechanisms of CRSwNP and distinguishing its phenotypes
RETRACTED: Identification of an Immunologic Signature of Lung Adenocarcinomas Based on Genome-Wide Immune Expression Profiles
Authors: Ling Bo , Ye Guangbin , Zhao Qiuhua , Jiang Yan , Liang Lingling , Tang Qianli
Published: January 2021

Background: Lung cancer is one of the most common types of cancer, and it has a poor prognosis. It is urgent to identify prognostic biomarkers to guide therapy.

Methods: The immune gene expression profiles for patients with lung adenocarcinomas (LUADs) were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). The relationships between the expression of 45 immune checkpoint genes (ICGs) and prognosis were analyzed. Additionally, the correlations between the expression of 45 biomarkers and immunotherapy biomarkers, including tumor mutation burden (TMB), mismatch repair defects, neoantigens, and others, were identified. Ultimately, prognostic ICGs were combined to determine immune subgroups, and the prognostic differences between these subgroups were identified in LUAD.

Results: A total of 11 and nine ICGs closely related to prognosis were obtained from the GEO and TCGA databases, respectively. CD200R1 expression had a significant negative correlation with TMB and neoantigens. CD200R1 showed a significant positive correlation with CD8A, CD68, and GZMB, indicating that it may cause the disordered expression of adaptive immune resistance pathway genes. Multivariable Cox regression was used to construct a signature composed of four prognostic ICGs (IDO1, CD274, CTLA4, and CD200R1): Risk Score = −0.002*IDO1+0.031*CD274−0.069*CTLA4−0.517*CD200R1. The median Risk Score was used to classify the samples for the high- and low-risk groups. We observed significant differences between groups in the training, testing, and external validation cohorts.

Conclusion: Our research provides a method of integrating ICG expression profiles and clinical prognosis information to predict lung cancer prognosis, which will provide a unique reference for gene immunotherapy for LUAD.
Impact of COVID-19 on Mitochondrial-Based Immunity in Aging and Age-Related Diseases
Authors: Ganji Riya , Reddy P. Hemachandra
Published: January 2021

The coronavirus disease 2019 (COVID-19) has become a deadly pandemic with surging mortality rates and no cure. COVID-19 is caused by the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) with a range of clinical symptoms, including cough, fever, chills, headache, shortness of breath, difficulty breathing, muscle pain, and a loss of smell or taste. Aged individuals with compromised immunity are highly susceptible to COVID-19 and the likelihood of mortality increases with age and the presence of comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, or chronic obstructive pulmonary disease. Emerging evidence suggests that COVID-19 highjacks mitochondria of immune cells, replicates within mitochondrial structures, and impairs mitochondrial dynamics leading to cell death. Mitochondria are the powerhouses of the cell and are largely involved in maintaining cell immunity, homeostasis, and cell survival/death. Increasing evidence suggests that mitochondria from COVID-19 infected cells are highly vulnerable, and vulnerability increases with age. The purpose of our article is to summarize the role of various age-related comorbidities such as diabetes, obesity, and neurological diseases in increasing mortality rates amongst the elderly with COVID-19. Our article also highlights the interaction between coronavirus and mitochondrial dynamics in immune cells. We also highlight the current treatments, lifestyles, and safety measures that can help protect against COVID-19. Further research is urgently needed to understand the molecular mechanisms between the mitochondrial virus and disease progression in COVID-19 patients.
Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation
Authors: Liang Yubin , Song Pingping , Chen Wei , Xie Xuemin , Luo Rixin , Su Jiehua , Zhu Yunhui , Xu Jiamin , Liu Rongrong , Zhu Peizhi , Zhang Yusheng , Huang Min
Published: January 2021

Ischemic cerebral infarction represents a significant cause of disability and death worldwide. Caspase-1 is activated by the NLRP3/ASC pathway and inflammasomes, thus triggering pyroptosis, a programmed cell death. In particular, this death is mediated by gasdermin D (GSDMD), which induces secretion of interleukin (IL)-1β and IL-18. Accordingly, inhibition of caspase-1 prevents the development and worsening of multiple neurodegenerative diseases. However, it is not clear whether inhibition of caspase-1 can preserve blood-brain barrier (BBB) integrity following cerebral infarction. This study therefore aimed at understanding the effect of caspase-1 on BBB dysfunction and its underlying mechanisms in permanent middle cerebral artery occlusion (MCAO). Our findings in rat models revealed that expression of caspase-1 was upregulated following MCAO-induced injury in rats. Consequently, pharmacologic inhibition of caspase-1 using vx-765 ameliorated ischemia-induced infarction, neurological deficits, and neuronal injury. Furthermore, inhibition of caspase-1 enhanced the encapsulation rate of pericytes at the ischemic edge, decreased leakage of both Evans Blue (EB) and matrix metalloproteinase (MMP) proteins, and upregulated the levels of tight junctions (TJs) and tissue inhibitors of metalloproteinases (TIMPs) in MCAO-injured rats. This in turn improved the permeability of the BBB. Meanwhile, vx-765 blocked the activation of ischemia-induced pyroptosis and reduced the expression level of inflammatory factors such as caspase-1, NLRP3, ASC, GSDMD, IL-1β, and IL-18. Similarly, vx-765 treatment significantly reduced the expression levels of inflammation-related receptor for advanced glycation end products (RAGE), high-mobility family box 1 (HMGB1), mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB). Evidently, inhibition of caspase-1 significantly improves ischemia-associated BBB permeability and integrity by suppressing pyroptosis activation and the RAGE/MAPK pathway.
Leveraging Prior Concept Learning Improves Generalization From Few Examples in Computational Models of Human Object Recognition
Authors: Rule Joshua S. , Riesenhuber Maximilian
Published: January 2021

Humans quickly and accurately learn new visual concepts from sparse data, sometimes just a single example. The impressive performance of artificial neural networks which hierarchically pool afferents across scales and positions suggests that the hierarchical organization of the human visual system is critical to its accuracy. These approaches, however, require magnitudes of order more examples than human learners. We used a benchmark deep learning model to show that the hierarchy can also be leveraged to vastly improve the speed of learning. We specifically show how previously learned but broadly tuned conceptual representations can be used to learn visual concepts from as few as two positive examples; reusing visual representations from earlier in the visual hierarchy, as in prior approaches, requires significantly more examples to perform comparably. These results suggest techniques for learning even more efficiently and provide a biologically plausible way to learn new visual concepts from few examples.
Specific Gray Matter Volume Changes of the Brain in Unipolar and Bipolar Depression
Authors: Wang Junyan , Liu Penghong , Zhang Aixia , Yang Chunxia , Liu Sha , Wang Jizhi , Xu Yong , Sun Ning
Published: January 2021

To identify the common and specific structural basis of bipolar depression (BD) and unipolar depression (UD) is crucial for clinical diagnosis. In this study, a total of 85 participants, including 22 BD patients, 36 UD patients, and 27 healthy controls, were enrolled. A voxel-based morphology method was used to identify the common and specific changes of the gray matter volume (GMV) to determine the structural basis. Significant differences in GMV were found among the three groups. Compared with healthy controls, UD patients showed decreased GMV in the orbital part of the left inferior frontal gyrus, whereas BD patients showed decreased GMV in the orbital part of the left middle frontal gyrus. Compared with BD, UD patients have increased GMV in the left supramarginal gyrus and middle temporal gyrus. Our results revealed different structural changes in UD and BD patients suggesting BD and UD have different neurophysiological underpinnings. Our study contributes toward the biological determination of morphometric changes, which could help to discriminate between UD and BD.
Comparison of Facial Muscle Activation Patterns Between Healthy and Bell’s Palsy Subjects Using High-Density Surface Electromyography
Authors: Cui Han , Zhong Weizheng , Yang Zhuoxin , Cao Xuemei , Dai Shuangyan , Huang Xingxian , Hu Liyu , Lan Kai , Li Guanglin , Yu Haibo
Published: January 2021

Facial muscle activities are essential for the appearance and communication of human beings. Therefore, exploring the activation patterns of facial muscles can help understand facial neuromuscular disorders such as Bell’s palsy. Given the irregular shape of the facial muscles as well as their different locations, it should be difficult to detect the activities of whole facial muscles with a few electrodes. In this study, a high-density surface electromyogram (HD sEMG) system with 90 electrodes was used to record EMG signals of facial muscles in both healthy and Bell’s palsy subjects when they did different facial movements. The electrodes were arranged in rectangular arrays covering the forehead and cheek regions of the face. The muscle activation patterns were shown on maps, which were constructed from the Root Mean Square (RMS) values of all the 90-channel EMG recordings. The experimental results showed that the activation patterns of facial muscles were distinct during doing different facial movements and the activated muscle regions could be clearly observed. Moreover, two features of the activation patterns, 2D correlation coefficient (corr2) and Centre of Gravity (CG) were extracted to quantify the spatial symmetry and the location of activated muscle regions respectively. Furthermore, the deviation of activated muscle regions on the paralyzed side of a face compared to the healthy side was quantified by calculating the distance between two sides of CGs. The results revealed that corr2 of the activated facial muscle region (classified into forehead region and cheek region) in Bell’s palsy subjects was significantly (p < 0.05) lower than that in healthy subjects, while CG distance of activated facial region in Bell’s palsy subjects was significantly (p < 0.05) higher than that in healthy subjects. The correlation between corr2 of these regions and Bell’s palsy [assessed by the Facial Nerve Grading Scale (FNGS) 2.0] was also significant (p < 0.05) in Bell’s palsy subjects. The spatial information on activated muscle regions may be useful in the diagnosis and treatment of Bell’s palsy in the future.
The Relationship of Functional Connectivity of the Sensorimotor and Visual Cortical Networks Between Resting and Task States
Authors: Xiong Zhenliang , Tian Chong , Zeng Xianchun , Huang Jie , Wang Rongpin
Published: January 2021

The intrinsic activity of the human brain maintains its general operation at rest, and this ongoing spontaneous activity exhibits a high level of spatiotemporally correlated activity among different cortical areas, showing intrinsically organized brain functional connectivity (FC) networks. Many functional network properties of the human brain have been investigated extensively for both rest and task states, but the relationship between these two states has been rarely investigated yet and remains unclear. Comparing well-defined task-specific networks with corresponding intrinsic FC networks may reveal their relationship and improve our understanding of the brain’s operations at both rest and task states. This study investigated the relationship of the sensorimotor and visual cortical FC networks between the resting and task states. The sensorimotor task was to rub right-hand fingers, and the visual task was to open and close eyes, respectively. Our study demonstrated a general relationship of the task-evoked FC network with its corresponding intrinsic FC network, regardless of the tasks. For each task type, the study showed that (1) the intrinsic and task-evoked FC networks shared a common network and the task enhanced the coactivity within that common network compared to the intrinsic activity; (2) some areas within the intrinsic FC network were not activated by the task, and therefore, the task activated only partial but not whole of the intrinsic FC network; and (3) the task activated substantial additional areas outside the intrinsic FC network and therefore recruited more intrinsic FC networks to perform the task.
Machine Learning-Based Identification of Suicidal Risk in Patients With Schizophrenia Using Multi-Level Resting-State fMRI Features
Authors: Bohaterewicz Bartosz , Sobczak Anna M. , Podolak Igor , Wójcik Bartosz , Mȩtel Dagmara , Chrobak Adrian A. , Fa̧frowicz Magdalena , Siwek Marcin , Dudek Dominika , Marek Tadeusz
Published: January 2021

Background

Some studies suggest that as much as 40% of all causes of death in a group of patients with schizophrenia can be attributed to suicides and compared with the general population, patients with schizophrenia have an 8.5-fold greater suicide risk (SR). There is a vital need for accurate and reliable methods to predict the SR among patients with schizophrenia based on biological measures. However, it is unknown whether the suicidal risk in schizophrenia can be related to alterations in spontaneous brain activity, or if the resting-state functional magnetic resonance imaging (rsfMRI) measures can be used alongside machine learning (ML) algorithms in order to identify patients with SR.

Methods

Fifty-nine participants including patients with schizophrenia with and without SR as well as age and gender-matched healthy underwent 13 min resting-state functional magnetic resonance imaging. Both static and dynamic indexes of the amplitude of low-frequency fluctuation (ALFF), the fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity as well as functional connectivity (FC) were calculated and used as an input for five machine learning algorithms: Gradient boosting (GB), LASSO, Logistic Regression (LR), Random Forest and Support Vector Machine.

Results

All groups revealed different intra-network functional connectivity in ventral DMN and anterior SN. The best performance was reached for the LASSO applied to FC with an accuracy of 70% and AUROC of 0.76 (p< 0.05). Significant classification ability was also reached for GB and LR using fALFF and ALFF measures.

Conclusion

Our findings suggest that SR in schizophrenia can be seen on the level of DMN and SN functional connectivity alterations. ML algorithms were able to significantly differentiate SR patients. Our results could be useful in developing neuromarkers of SR in schizophrenia based on non-invasive rsfMRI.
The Neomycin Resistance Cassette in the Targeted Allele of Shank3B Knock-Out Mice Has Potential Off-Target Effects to Produce an Unusual Shank3 Isoform
Authors: Jin Chunmei , Kang Hyojin , Yoo Taesun , Ryu Jae Ryun , Yoo Ye-Eun , Ma Ruiying , Zhang Yinhua , Kang Hyae Rim , Kim Yoonhee , Seong Hyunyoung , Bang Geul , Park Sangwoo , Kwon Seok-Kyu , Sun Woong , Kim Hyunkyung , Kim Jin Young , Kim Eunjoon , Han Kihoon
Published: January 2021

Variants of the SH3 and multiple ankyrin repeat domains 3 (SHANK3), which encodes postsynaptic scaffolds, are associated with brain disorders. The targeted alleles in a fewShank3knock-out (KO) lines contain a neomycin resistance (Neo) cassette, which may perturb the normal expression of neighboring genes; however, this has not been investigated in detail. We previously reported an unexpected increase in the mRNA expression ofShank3exons 1–12 in the brains ofShank3BKO mice generated by replacingShank3exons 13–16 with the Neo cassette. In this study, we confirmed that the increasedShank3mRNA inShank3BKO brains produced an unusual ∼60 kDa Shank3 isoform (Shank3-N), which did not properly localize to the synaptic compartment. Functionally, Shank3-N overexpression altered the dendritic spine morphology in cultured neurons. Importantly, Shank3-N expression inShank3BKO mice was not a compensatory response to a reduction of full-length Shank3 because expression was still detected in the brain after normalizing the level of full-length Shank3. Moreover, in anotherShank3KO line (Shank3gKO) with a similarShank3exonal deletion as that inShank3BKO mice but without a Neo cassette, the mRNA expression levels ofShank3exons 1–12 were lower than those of wild-type mice and Shank3-N was not detected in the brain. In addition, the expression levels of genes neighboringShank3on chromosome 15 were altered in the striatum ofShank3BKO but notShank3gKO mice. These results suggest that the Neo cassette has potential off-target effects inShank3BKO mice.
Polyvinyl Alcohol Carbazate as a Polymer-Based Antitumoral Agent
Authors: Sellberg Felix , Fröbom Robin , Binder Christian , Berglund Erik , Berglund David
Published: January 2021

Development of treatment resistance is a major concern during treatment of cancer, and there is an unmet need for therapeutic strategies with novel modes of action. Polyvinyl alcohol carbazate (PVAC) is a polymer compound with unique biological properties. Herein, we describe the antitumoral effects of PVAC. Three well-established cell lines GIST-T1, B16.F10, and A375 were used to determine the in vitro antitumoral effects of PVAC. Assessments included light microscopy, cell viability, cell cycle, and apoptosis assays. In vivo treatment safety and efficacy were characterized in one immunocompetent (B16.F10) mouse model and one athymic nude (MDA-MB-231) mouse model. Excised tumors were measured, weighed, stained for Ki-67, CD3, and histopathologically evaluated. Intact PVAC expressed a non-linear dose-response antitumoral effect in vitro, whereas its separate components, PVA and carbazate, did not display antitumoral effects alone. In vivo, PVAC induced a significant intratumoral CD3+ T-cell recruitment in immunocompetent mice (B16.F10), which was associated with tumor growth inhibition. Although growth inhibition was not significant in athymic mice (MDA-MB-231), histopathological evaluation detected an increase in stromal tissue and leukocyte infiltration. In conclusion, we present evidence for PVAC antitumoral effects both in vitro and in vivo. The mode of action was not elucidated in vitro, but a potential mechanism of in vivo activity was observed, characterized by an increase of immune cells into both immunocompetent and athymic mice. This finding warrants further study to validate its possible role as an immunomodulatory polymeric agent.
Improving Informed Consent for Novel Vaccine Research in a Pediatric Hospital Setting Using a Blended Research-Design Approach
Authors: Jackson Sally M. , Daverio Margherita , Perez Silvia Lorenzo , Gesualdo Francesco , Tozzi Alberto E.
Published: January 2021

It is necessary to conduct Clinical Trials in children, including for novel vaccines. Children cannot legally provide valid consent, but can assent to research participation. Informed consent and assent communications are frequently criticized for their lack of comprehensibility and often, researchers do not involve patients in informed consent design. We tested a blended research-design approach to co-design multimedia informed consent prototypes for experimental vaccine studies targeted at the pediatric population. We report details on the methodology utilized, and the insights, ideas, and prototype solutions we generated using social media data analysis, a survey, and workshops. A survey of clinical trial researchers indicated that while the most did not use technology for informed consent, they considered its utilization favorable. Social media analysis enabled researchers to quickly understand where community perspectives were concordant and discordant and build their understanding of the types of topics that they may want to focus on during the design workshops. Participatory design workshops for children and their families reaped insights, ideas, and prototypes for a range of tools including apps and websites. Participants felt that the prototypes were better able to communicate necessary content than the original text document format. We propose using a participatory, mixed-methods approach to design informed consent so that it is better adapted to patients' needs. Such an approach would be helpful in better addressing the needs of different segments of the populations involved in clinical trials. Further evidence should be gained about the impact of this strategy in improving recruitment, decreasing withdrawals and litigations, and improving patient satisfaction during clinical trials.
Nutritional Factors in the Prevention of Atopic Dermatitis in Children
Authors: Trikamjee Thulja , Comberiati Pasquale , D'Auria Enza , Peroni Diego , Zuccotti Gian Vincenzo
Published: January 2021

Atopic dermatitis is one of the most frequent chronic skin diseases worldwide and often develops within the first few years of life. Recent advancements in our knowledge of its pathophysiology have brought to light the role of genetic predisposition and environmental triggers. With the increasing prevalence of allergic diseases, there is a strong need for a better understanding of the various modifiable eliciting factors of such conditions. The concomitant rise in food allergy and insights into the skin barrier function has highlighted the role of nutrition and diet in the prevention and modification of allergic disorders. Furthermore, the identification of the skin as an important route of sensitization, and the risk of progression to asthma later in life, stress the significance of optimizing our management of skin inflammation in the prevention of allergies. Many nutritional factors, including the type of maternal diet during pregnancy, the duration of breastfeeding, the epicutaneous exposure of allergenic food proteins in the first few years of life, the timing of the introduction of complementary foods, the supplementation of vitamins and probiotics/prebiotics during prenatal and early life, have been assessed as potential targets for the prevention of atopy and eczema. Here, we review the latest data addressing prenatal and perinatal nutritional and dietary interventions in the primary prevention of atopic dermatitis. Also, we define knowledge gaps and targets for future research in the prevention of atopic dermatitis.
Healthcare Professionals’ Knowledge of Pharmacogenetics and Attitudes Towards Antimicrobial Utilization in Zambia: Implications for a Precision Medicine Approach to Reducing Antimicrobial Resistance
Authors: Mufwambi Webrod , Stingl Julia , Masimirembwa Collen , Manasa Justen , Nhachi Charles , Stadler Nadina , Mwila Chiluba , Kalungia Aubrey Chichonyi , Mukosha Moses , Mutiti Chenai S. , Kamoto Alfred , Kaonga Patrick , Godman Brian , Munkombwe Derick
Published: January 2021

Introduction: Sub-Saharan Africa and other low- and middle-income countries (LMICs) have the highest rates of antimicrobial resistance (AMR) driven by high rates of antimicrobial utilization. This is a concern as AMR appreciably increases morbidity, mortality and costs. Pharmacogenetics (PGx) and precision medicine are emerging approaches to combat AMR. Consequently, as a first step there is a need to assess AMR knowledge and attitudes, and knowledge of PGx, among healthcare professionals and use the findings to guide future interventions.

Methodology: We conducted a cross-sectional study involving 304 healthcare professionals at tertiary hospitals in Lusaka, Zambia. Structural Equation Modeling (SEM) was used to analyze relationships among latent variables.

Results: Overall correctness of answers concerning AMR among healthcare professionals was 60.4% (7/11). Knowledge of pharmacogenetics was low (38%). SEM showed that high AMR knowledge score correlated with a positive attitude toward combating AMR (p < 0.001). Pharmacists had relatively higher AMR knowledge scores (mean = 7.67, SD = 1.1), whereas nurses had lower scores (mean = 5.57, SD = 1.9). A minority of respondents [31.5% (n = 95)] indicated that poor access to local antibiogram data promoted AMR, with the majority [56.5% (n = 190)] responding that poor adherence to prescribed antimicrobials can lead to AMR. Pharmacists had the highest scores for attitude (mean = 5.60, SD = 1.6) whereas nurses had the lowest scores (mean = 4.02, SD = 1.4).

Conclusion: AMR knowledge and attitudes, as well as knowledge on PGx among healthcare professionals in Zambia, is sub-optimal and has the potential to affect the uptake of precision medicine approaches to reduce AMR rates. Educational and positive behavioral change interventions are required to address this and in future, we will be seeking to introduce these to improve the use of antimicrobials.