bluuebunny/crossref_metadata_2025 huggingface dataset:
Exposure to Perfluoroalkyl Substances During Pregnancy and Fetal BDNF Level: A Prospective Cohort Study
Authors: Yu Guoqi , Luo Fei , Nian Min , Li Shuman , Liu Bin , Feng Liping , Zhang Jun
Published: June 2021

Background

Humans are widely exposed to environmental perfluoroalkyl substances (PFAS), which may affect fetal neurodevelopment. Brain-derived neurotrophic factor (BDNF) is an important factor in neurodevelopment, but its role in PFAS-induced neurotoxicity is unclear. We investigated the association between prenatal PFAS exposure and fetal BDNF level in the umbilical cord blood in a large prospective cohort.

Methods

A total of 725 pregnant women who participated in the Shanghai Birth Cohort were included. 10 PFAS were measured by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples of early pregnancy. The BDNF level was determined by ELISA. The concentration of total mercury (Hg) in the umbilical cord blood was tested by cold vapor atomic absorption spectrometry (AAS) and included as a main confounder, along with other covariates. Multiple linear regression was used to explore the associations between PFAS concentrations and BDNF level. Quantile-based g-computation was applied to explore the joint and independent effects of PFAS on BDNF level.

Results

The mean BDNF level in the total population was 10797 (±4713) pg/ml. Male fetuses had a higher level than female fetuses (P<0.001). A significant positive association was observed between PFHxS and BDNF level after adjusting for potential confounders [β=1285 (95% CI: 453, 2118, P=0.003)]. No association was observed between other PFAS congeners and BDNF level. Results of the mixed exposure model showed that the joint effects of PFAS mixture were not associated with BDNF [β=447 (95% CI: -83, 978, P=0.10)], while the positive association with PFHxS exposure remained significant after controlling for other PFAS [β=592 (95% CI: 226, 958, P=0.002)]. The above associations were more prominent in male [β=773 (95% CI: 25, 1520, P= 0.04)] than female fetuses [β=105 (95% CI: -791, 1002, P= 0.82)] for the mixed effects.

Conclusions

Prenatal exposure to PFHxS was associated with an increased BDNF level in the umbilical blood, especially in male fetuses.
Inhibition of the Renin-Angiotensin System Reduces Gene Expression of Inflammatory Mediators in Adipose Tissue Independent of Energy Balance
Authors: Mitchell Caitlin S. , Premaratna Shirmila D. , Bennett Garth , Lambrou Maria , Stahl Lauren A. , Jois Markandeya , Barber Elizabeth , Antoniadis Christopher P. , Woods Stephen C. , Cameron-Smith David , Weisinger Richard S. , Begg Denovan P.
Published: June 2021

Obesity is a growing health problem worldwide. The renin-angiotensin system (RAS) is present in adipose tissue, and evidence suggests that it is involved in both diet-induced obesity and the inflammation associated with obesity. The present experiments determined the effect of (1) different angiotensin-converting enzyme (ACE) inhibitors (captopril, perindopril, enalapril) and angiotensin receptor blockers (ARBs: telmisartan, losartan) on adiposity of mice fed a high-fat diet for 28 days (2); acute treatment with the ACE-inhibitor captopril on gene expression of inflammatory markers in mice fed a high-fat diet (HFD); and (3) short-term (2 days) and chronic (28 days) treatment of ACE-inhibition on energy expenditure (EE) and energy balance in mice fed HFD ad libitum (AL), as well as receiving HFD limited to the amount of calories eaten by controls (pair-fed (PF) group). Body weight, food intake, adiposity and plasma leptin were lower in ACE inhibitor or ARB-treated groups over 28 days compared with HFD untreated mice. Short-term treatment with captopril led to increased EE relative to the level in the PF group. After 28 days, EE was lower in both captopril-treated and PF mice compared with AL, but the effect was greater in the captopril-treated group. Adiponectin was elevated in captopril-treated mice, but not in PF mice, after both 2 and 28 days. Additionally, acute RAS blockade in HFD-fed mice reduced mRNA expression for MCP-1, IL-6, TLR4, and leptin in adipose tissue relative to values in untreated groups. These data demonstrate that ACE inhibition and angiotensin receptor blockade reduce food intake to produce weight loss and suggest that the anti-inflammatory effects of ACE inhibition may be independent of weight loss.
Roles of Cholecystokinin in the Nutritional Continuum. Physiology and Potential Therapeutics
Authors: Miller Laurence J. , Harikumar Kaleeckal G. , Wootten Denise , Sexton Patrick M.
Published: June 2021

Cholecystokinin is a gastrointestinal peptide hormone with important roles in metabolic physiology and the maintenance of normal nutritional status, as well as potential roles in the prevention and management of obesity, currently one of the dominant causes of direct or indirect morbidity and mortality. In this review, we discuss the roles of this hormone and its receptors in maintaining nutritional homeostasis, with a particular focus on appetite control. Targeting this action led to the development of full agonists of the type 1 cholecystokinin receptor that have so far failed in clinical trials for obesity. The possible reasons for clinical failure are discussed, along with alternative pharmacologic strategies to target this receptor for prevention and management of obesity, including development of biased agonists and allosteric modulators. Cellular cholesterol is a natural modulator of the type 1 cholecystokinin receptor, with elevated levels disrupting normal stimulus-activity coupling. The molecular basis for this is discussed, along with strategies to overcome this challenge with a corrective positive allosteric modulator. There remains substantial scope for development of drugs to target the type 1 cholecystokinin receptor with these new pharmacologic strategies and such drugs may provide new approaches for treatment of obesity.
Blood Sampling From Rat Ileal Mesenteric Vein Revealed a Major Role of Dietary Protein in Meal-Induced GLP-1 Response
Authors: Hira Tohru , Sekishita Madoka , Hara Hiroshi
Published: June 2021

The present study was conducted to examine region-dependent glucagon-like peptide-1 (GLP-1) responses to “meal ingestion” under physiological (conscious and unrestrained) conditions using rats with a catheter inserted into either the portal vein (PV) or the ileal mesenteric vein (ILMV). After recovery from the cannulation surgery, blood samples were collected from either PV or ILMV catheter before and after the voluntary ingestion of test diets. After an AIN-93G standard diet ingestion, GLP-1 concentration was higher in ILMV than in PV, and postprandial responses of peptide-YY (PYY) had similar trend, while that of glucose dependent-insulinotropic polypeptide showed an opposite trend to GLP-1/PYY responses. In a separated experiment, a protein-enriched diet containing casein at 25% wt/wt transiently increased GLP-1 concentration only in ILMV; however, a protein-free diet did not increase GLP-1 concentrations in PV or ILMV. These results indicate that postprandial GLP-1 is immediately released from the distal intestine under physiological conditions, and that dietary protein has a critical role in the enhancement of postprandial GLP-1 response.
Interferon Lambda 3/4 (IFNλ3/4) rs12979860 Polymorphisms Is Not Associated With Susceptibility to Systemic Lupus Erythematosus, Although It Regulates OASL Expression in Patients With SLE
Authors: Juárez-Vicuña Yaneli , Pérez-Ramos Julia , Adalid-Peralta Laura , Sánchez Fausto , Martínez-Martínez Laura Aline , Ortiz-Segura María del Carmen , Pichardo-Ontiveros Edgar , Hernández-Díazcouder Adrián , Amezcua-Guerra Luis M. , Ramírez-Bello Julian , Sánchez-Muñoz Fausto
Published: June 2021

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex etiology. Various genetic factors are associated with susceptibility to developing SLE and contribute to its onset and progression. Different single-nucleotide polymorphisms (SNPs) have been associated with SLE in several populations. The rs12979860 SNP in interferon lambda 3/4 (IFNλ3/4) is significantly associated with SLE susceptibility in patients negative for nephritis in Taiwanese people, and interferon-stimulated genes (ISGs) are differentially expressed in normal liver by the rs12979860 genotype. This study aimed to investigate whether rs12979860 is associated with the presence of SLE and lupus nephritis in Mexican individuals as well as with the expression of several ISGs in SLE patients. In total, 439 SLE patients and 358 healthy donors were genotyped for rs12979860 using real-time PCR, and allelic discrimination plots were constructed. Additionally, peripheral blood mononuclear cells (PBMCs) were isolated from the venous blood of SLE patients by centrifugation (n = 78). The mRNA levels of 2′-5′-oligoadenylate synthetase like (OASL), myxovirus resistance 1 (MX1), 2′5′-oligoadenylate synthetase 1 (OAS1), interferon-stimulated gene 15 (ISG15) and lymphocyte antigen 6 complex, locus E (LY6E) were determined using real-time PCR. The distributions of rs12979860 genotypes and allele frequencies were compared between SLE patients and healthy donors; case-control analysis revealed that rs12979860 was not associated with SLE susceptibility (OR 1.18, 95% CI 0.97–1.45, p = 0.08) or with the risk for lupus nephritis (OR 0.913, 95% CI 0.590–1.411, p = 0.682). However, OASL expression levels in PBMCs were significantly different between rs12979860 genotypes in SLE patients: median OASL mRNA levels were significantly higher in patients carrying the CC genotype (197.10, IQR 71.10–411.17) than in those with CT/TT genotypes (173.75, IQR 58.80–278.75, p = 0.016). Our results suggest that the SNP rs12979860 does not play a relevant role in susceptibility to SLE in Mexican individuals. However, IFNλ3/4 genotypes appear to be associated with OASL expression in PBMCs from patients with SLE.
Correlation Between Skin and Affected Organs in 52 Sclerodermic Patients Followed in a Diseases Management Team: Development of a Risk Prediction Model of Organ-Specific Complications
Authors: Cozzani Emanuele , Muracchioli Andrea , Murdaca Giuseppe , Beccalli Mirko , Caprioli Simone , Zentilin Patrizia , Ameri Pietro , Grosso Marco , Russo Rodolfo , Carmisciano Luca , Parodi Aurora
Published: June 2021

Objective

To identify the existence of a correlation among the various organs affected, focusing primarily on immuno-dermatological aspects, and to create a risk prediction model of organ-specific complications.

Material and Methods

Fifty-two patients with stable scleroderma, followed between 2015 and 2019, were investigated through an extensive multidisciplinary evaluation in the last year.

Results

Patients with lung involvement presented a worse degree of skin fibrosis than patients without it (p <0.001). No relationship was observed for the heart, kidney, and esophagus. Patients with pulmonary involvement had a lower pressure of the low esophagus sphincter and a higher Warrick score than patients without it (p <0.05). Age was significantly higher in patients with kidney involvement. Diffuse scleroderma patients had a worse pulmonary impairment than limited scleroderma patients (p <0.05). The manometric “sclerodermic” pattern was observed to be the most frequent (55.6%, p <0.05) in dcSSc patients while the sclerodermic and normal pattern were equally represented (41.2 and 32.4% respectively, p <0.05) in lcSSc patients. When compared to the negative serological groups, anti-Scl-70 positive patients presented a worse lung involvement while anti-centromere patients presented a better lung outcome (p <0.05). PM-Scl 100/75 positive patients presented mostly a pulmonary fibrotic pattern (p <0.05) and, also, heart complications were more likely associated with anti PM-Scl 100/75 positivity (p <0.05). The risk prediction model for organ-specific complications had an accuracy of 84.4% (95%CI 78, 89) in complication-site prediction, AUC of 0.871, 86% of sensitivity, and 83% of specificity, Cohen’s Kappa (k) of 0.68.

Conclusions

Out of all the organs studied, the skin is the one that correlates with the lung. Patients with a diffuse form of disease presented more frequently the anti Scl-70 antibody and had a worse lung and esophageal involvement (scleroderma pattern) than the negative group. Conversely, patients with limited disease presented all positive for the anti-centromere antibody with a better lung involvement than the negative group, without any difference among the esophageal manometric pattern. Anti PM-Scl 100/75 antibody patients were associated with pulmonary fibrosis and presented cardiac involvement. The model created has demonstrated excellent values of sensitivity, specificity, and accuracy, but further studies are needed for validation.
Immunothrombosis in Acute Respiratory Dysfunction of COVID-19
Authors: Fang Xiang-Zhi , Wang Ya-Xin , Xu Ji-Qain , He Ya-Jun , Peng Zhe-Kang , Shang You
Published: June 2021

COVID-19 is an acute, complex disorder that was caused by a new β-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on current reports, it was surprising that the characteristics of many patients with COVID-19, who fulfil the Berlin criteria for acute respiratory distress syndrome (ARDS), are not always like those of patients with typical ARDS and can change over time. While the mechanisms of COVID-19–related respiratory dysfunction in COVID-19 have not yet been fully elucidated, pulmonary microvascular thrombosis is speculated to be involved. Considering that thrombosis is highly related to other inflammatory lung diseases, immunothrombosis, a two-way process that links coagulation and inflammation, seems to be involved in the pathophysiology of COVID-19, including respiratory dysfunction. Thus, the current manuscript will describe the proinflammatory milieu in COVID-19, summarize current evidence of thrombosis in COVID-19, and discuss possible interactions between these two.
Interplay Between Gluten, HLA, Innate and Adaptive Immunity Orchestrates the Development of Coeliac Disease
Authors: Voisine Jordan , Abadie Valérie
Published: June 2021

Several environmental, genetic, and immune factors create a “perfect storm” for the development of coeliac disease: the antigen gluten, the strong association of coeliac disease with HLA, the deamidation of gluten peptides by the enzyme transglutaminase 2 (TG2) generating peptides that bind strongly to the predisposing HLA-DQ2 or HLA-DQ8 molecules, and the ensuing unrestrained T cell response. T cell immunity is at the center of the disease contributing to the inflammatory process through the loss of tolerance to gluten and the differentiation of HLA-DQ2 or HLA-DQ8-restricted anti-gluten inflammatory CD4+T cells secreting pro-inflammatory cytokines and to the killing of intestinal epithelial cells by cytotoxic intraepithelial CD8+lymphocytes. However, recent studies emphasize that the individual contribution of each of these cell subsets is not sufficient and that interactions between these different populations of T cells and the simultaneous activation of innate and adaptive immune pathways in distinct gut compartments are required to promote disease immunopathology. In this review, we will discuss how tissue destruction in the context of coeliac disease results from the complex interactions between gluten, HLA molecules, TG2, and multiple innate and adaptive immune components.
The Frequency and Effect of Granulocytic Myeloid-Derived Suppressor Cells on Mycobacterial Survival in Patients With Tuberculosis: A Preliminary Report
Authors: Davids Malika , Pooran Anil , Smith Liezel , Tomasicchio Michele , Dheda Keertan
Published: June 2021

Introduction

Protective host responses in those exposed to or infected with tuberculosis (TB) is thought to require a delicate balance between pro-inflammatory and regulatory immune responses. Myeloid-derived suppressor cells (MDSCs), regulatory cells that dampen T-cell function, have been described in cancer and other infectious diseases but there are limited data on their role in TB.

Methods

Peripheral blood was obtained from patients with active pulmonary TB and participants with presumed latent TB infection (LTBI) from Cape Town, South Africa. MDSC frequency was ascertained by flow cytometry. Purified MDSCs were used to assess (i) their suppressive effect on T-cell proliferation using a Ki67 flow cytometric assay and (ii) their effect on mycobacterial containment by co-culturing with H37Rv-infected monocyte-derived macrophages and autologous pre-primed effector T-cells with or without MDSCs. Mycobacterial containment was measured by plating colony forming units (CFU).

Results

MDSCs (CD15+HLA-DR-CD33+) had significantly higher median frequencies (IQR) in patients with active TB (n=10) versus LTBI (n= 10) [8.2% (6.8-10.7) versus 42.2% (27–56) respectively; p=0.001]. Compared to MDSC-depleted peripheral blood mononuclear and effector T cell populations, dilutions of purified MDSCs isolated from active TB patients suppressed T-cell proliferation by up to 72% (n=6; p=0.03) and significantly subverted effector T-cell-mediated containment of H37Rv in monocyte-derived macrophages (n=7; 0.6% versus 8.5%; p=0.02).

Conclusion

Collectively, these data suggest that circulating MDSCs are induced during active TB disease and can functionally suppress T-cell proliferation and subvert mycobacterial containment. These data may inform the design of vaccines and immunotherapeutic interventions against TB but further studies are required to understand the mechanisms underpinning the effects of MDSCs.
Transcriptome Profiling Reveals a Novel Mechanism of Antiviral Immunity Upon Sacbrood Virus Infection in Honey Bee Larvae (Apis cerana)
Authors: Guo Yulong , Zhang Zhengyi , Zhuang Mingsheng , Wang Liuhao , Li Kai , Yao Jun , Yang Huipeng , Huang Jiaxing , Hao Yue , Ying Fan , Mannan Hira , Wu Jie , Chen Yanping , Li Jilian
Published: June 2021

The honey bee is one of the most important pollinators in the agricultural system and is responsible for pollinating a third of all food we eat. Sacbrood virus (SBV) is a member of the virus family Iflaviridae and affects honey bee larvae and causes particularly devastating disease in the Asian honey bees, Apis cerana. Chinese Sacbrood virus (CSBV) is a geographic strain of SBV identified in China and has resulted in mass death of honey bees in China in recent years. However, the molecular mechanism underlying SBV infection in the Asian honey bee has remained unelucidated. In this present study, we employed high throughput next-generation sequencing technology to study the host transcriptional responses to CSBV infection in A. cerana larvae, and were able to identify genome-wide differentially expressed genes associated with the viral infection. Our study identified 2,534 differentially expressed genes (DEGs) involved in host innate immunity including Toll and immune deficiency (IMD) pathways, RNA interference (RNAi) pathway, endocytosis, etc. Notably, the expression of genes encoding antimicrobial peptides (abaecin, apidaecin, hymenoptaecin, and defensin) and core components of RNAi such as Dicer-like and Ago2 were found to be significantly upregulated in CSBV infected larvae. Most importantly, the expression of Sirtuin target genes, a family of signaling proteins involved in metabolic regulation, apoptosis, and intracellular signaling was found to be changed, providing the first evidence of the involvement of Sirtuin signaling pathway in insects’ immune response to a virus infection. The results obtained from this study provide novel insights into the molecular mechanism and immune responses involved in CSBV infection, which in turn will contribute to the development of diagnostics and treatment for the diseases in honey bees.
Identification and Characterization of the CRISPR/Cas System in Staphylococcus aureus Strains From Diverse Sources
Authors: Cruz-López Erick Adrian , Rivera Gildardo , Cruz-Hernández María Antonia , Martínez-Vázquez Ana Verónica , Castro-Escarpulli Graciela , Flores-Magallón Rebeca , Vázquez Karina , Cruz-Pulido Wendy Lizeth , Bocanegra-García Virgilio
Published: June 2021

The CRISPR-Cas [clustered regularly interspaced short palindromic repeats and the CRISPR-associated genes (Cas)] system provides defense mechanisms in bacteria and archaea vs. mobile genetic elements (MGEs), such as plasmids and bacteriophages, which can either be harmful or add sequences that can provide virulence or antibiotic resistance. Staphylococcus aureus is a Gram-positive bacterium that could be the etiological agent of important soft tissue infections that can lead to bacteremia and sepsis. The role of the CRISPR-Cas system in S. aureus is not completely understood since there is a lack of knowledge about it. We analyzed 716 genomes and 1 genomic island from GENOMES-NCBI and ENA-EMBL searching for the CRISPR-Cas systems and their spacer sequences (SSs). Our bioinformatic analysis shows that only 0.83% (6/716) of the analyzed genomes harbored the CRISPR-Cas system, all of them were subtype III-A, which is characterized by the presence of the cas10/csm1 gene. Analysis of SSs showed that 91% (40/44) had no match to annotated MGEs and 9% of SSs corresponded to plasmids and bacteriophages, indicating that those phages had infected those S. aureus strains. Some of those phages have been proposed as an alternative therapy in biofilm-forming or infection with S. aureus strains, but these findings indicate that such antibiotic phage strategy would be ineffective. More research about the CRISPR/Cas system is necessary for a bigger number of S. aureus strains from different sources, so additional features can be studied.
A Single Nucleotide Polymorphism in lptG Increases Tolerance to Bile Salts, Acid, and Staining of Calcofluor-Binding Polysaccharides in Salmonella enterica Serovar Typhimurium E40
Authors: Wahlig Taylor A. , Stanton Eliot , Godfrey Jared J. , Stasic Andrew J. , Wong Amy C. L. , Kaspar Charles W.
Published: June 2021

The outer membrane ofSalmonella entericaplays an important role in combating stress encountered in the environment and hosts. The transport and insertion of lipopolysaccharides (LPS) into the outer membrane involves lipopolysaccharide transport proteins (LptA-F) and mutations in the genes encoding for these proteins are often lethal or result in the transport of atypical LPS that can alter stress tolerance in bacteria. During studies of heterogeneity in bile salts tolerance,S. entericaserovar Typhimurium E40 was segregated into bile salts tolerant and sensitive cells by screening for growth in TSB with 10% bile salts. An isolate (E40V) with a bile salts MIC >20% was selected for further characterization. Whole-genome sequencing of E40 and E40V using Illumina and PacBio SMRT technologies revealed a non-synonymous single nucleotide polymorphism (SNP) inlptG. Leucine at residue 26 in E40 was substituted with proline in E40V. In addition to growth in the presence of 10% bile salts, E40V was susceptible to novobiocin while E40 was not. Transcriptional analysis of E40 and E40V, in the absence of bile salts, revealed significantly greater (p< 0.05) levels of transcript in three genes in E40V;yjbE(encoding for an extracellular polymeric substance production protein),yciE(encoding for a putative stress response protein), and an uncharacterized gene annotated as an acid shock protein precursor (ASPP). No transcripts of genes were present at a greater level in E40 compared to E40V. Corresponding with the greater level of these transcripts, E40V had greater survival at pH 3.35 and staining of Calcofluor-binding polysaccharide (CBPS). To confirm the SNP inlptGwas associated with these phenotypes, strain E40E was engineered from E40 to encode for the variant form of LptG (L26P). E40E exhibited the same differences in gene transcripts and phenotypes as E40V, including susceptibility to novobiocin, confirming the SNP was responsible for these differences.
Lentilactobacillus hilgardii Inoculum, Dry Matter Contents at Harvest and Length of Conservation Affect Fermentation Characteristics and Aerobic Stability of Corn Silage
Authors: Ferrero Francesco , Tabacco Ernesto , Borreani Giorgio
Published: June 2021

Heterofermentative Lentilactobacillus hilgardii isolated from sugarcane silage, has recently been proposed as a silage inoculant to increase aerobic stability. Various conditions can influence the activity of LAB and their ability to alter silage quality (e.g., DM content and length of conservation). The aim of this study has been to evaluate the effect of L. hilgardii on the fermentation quality and aerobic stability of whole crop corn silage with different DM contents (from 26 to 45%), conserved for various conservation lengths (13–272 days). The silages were analyzed for their DM content, pH, fermentative profile, microbial count, and aerobic stability. L. hilgardii showed a positive effect on improving the aerobic stability of silages, due its ability to produce acetic acid, and reduced the yeast count. The acetic acid content increased as the conservation period increased and decreased as the DM content increased. The yeast count was reduced during conservation in a DM dependent manner and the inoculation with LH determined a reduction in the count of 0.48 log cfu/g. The aerobic stability increased as the conservation period increased, and the treatment with LH on average increased the aerobic stability by 19 h. The results of this experiment suggest that higher aerobic stability could be achieved in corn silages by ensiling at medium or low DM contents, or by increasing the length of conservation if a higher DM content at ensiling is needed. The inoculation with LH helps to improve the aerobic stability of corn silages by reducing the yeast count.
YAP1 is a Prognostic Biomarker and Correlated with Immune Cell Infiltration in Pancreatic Cancer
Authors: Sun Kai , Zhang Xue-de , Liu Xiao-yang , Lu Pei
Published: June 2021

Yes-associated protein-1 (YAP1) is an important effector of the Hippo pathway and has crosstalk with other cancer signaling pathways. It induces an immunosuppressive tumor microenvironment by activating pathways in several cellular components. However, the mechanisms by which it drives immune infiltration in pancreatic cancer remain poorly understood. We analyzed the expression of YAP1 as well as its prognostic value and correlations with immune infiltrates in various cancers, with a focus on pancreatic cancer. In particular, using the Oncomine database and Gene Expression Profiling Interactive Analysis (GEPIA) database, we found that YAP1 is differentially expressed between tumor tissues and control tissues in a number of cancers and in particular, is elevated in pancreatic cancer. Using the Kaplan–Meier plotter, GEPIA, and Long-term Outcome and Gene Expression Profiling database of pan-cancers (LOGpc), we further established the prognostic value of YAP1. We found that YAP1 expression was significantly related to outcomes in multiple types of cancer based on data from The Cancer Genome Atlas, particularly in pancreatic cancer. Correlations between YAP1 and immune cell infiltration and immune cell marker expression were examined using Tumor Immune Estimation Resource and GEPIA. High expression levels of YAP1 were significantly associated with a variety of immune markers and immune cell subsets in pancreatic cancer. These results suggest that YAP1 is correlated with patient outcomes and tumor immune cell infiltration in multiple cancer types and is a valuable prognostic biomarker in pancreatic cancer.
Multiplex Immunofluorescence and Multispectral Imaging: Forming the Basis of a Clinical Test Platform for Immuno-Oncology
Authors: Hoyt Clifford C.
Published: June 2021

As immuno-oncology (I/O) emerges as an effective approach in the fight against cancer, multispectral imaging of multiplex immunofluorescence (mIF) is maturing as an analytical platform. The timing is fortuitous. Due to health economic considerations surrounding the use of I/O, there is an urgent need for tests that accurately predict response to the growing list of available therapies. Multispectral mIF provides several advantages over other biomarker modalities by enabling deeper interrogation of the intricate biology within the tumor microenvironment, including detection of cell-to-cell spatial interactions that correlate with clinical outcomes. It also provides a practical path for generating reliable and reproducible results in a clinically suitable, high-throughput workflow. In this article, we (1) describe the principles behind multispectral mIF; (2) provide advice and recommendations on assay development and optimization and highlight characteristics of a well-performing assay; and (3) discuss the requirements for translating this approach into clinical practice.
Robotic Assisted Upper Limb Training Post Stroke: A Randomized Control Trial Using Combinatory Approach Toward Reducing Workforce Demands
Authors: Budhota Aamani , Chua Karen S. G. , Hussain Asif , Kager Simone , Cherpin Adèle , Contu Sara , Vishwanath Deshmukh , Kuah Christopher W. K. , Ng Chwee Yin , Yam Lester H. L. , Loh Yong Joo , Rajeswaran Deshan Kumar , Xiang Liming , Burdet Etienne , Campolo Domenico
Published: June 2021

Post stroke upper limb rehabilitation is a challenging problem with poor outcomes as 40% of survivors have functionally useless upper limbs. Robot-aided therapy (RAT) is a potential method to alleviate the effort of intensive, task-specific, repetitive upper limb exercises for both patients and therapists. The present study aims to investigate how a time matched combinatory training scheme that incorporates conventional and RAT, using H-Man, compares with conventional training toward reducing workforce demands. In a randomized control trial (NCT02188628,www.clinicaltrials.gov), 44 subacute to chronic stroke survivors with first-ever clinical stroke and predominant arm motor function deficits were recruited and randomized into two groups of 22 subjects: Robotic Therapy (RT) and Conventional Therapy (CT). Both groups received 18 sessions of 90 min; three sessions per week over 6 weeks. In each session, participants of the CT group received 90 min of 1:1 therapist-supervised conventional therapy while participants of the RT group underwent combinatory training which consisted of 60 min of minimally-supervised H-Man therapy followed by 30 min of conventional therapy. The clinical outcomes [Fugl-Meyer (FMA), Action Research Arm Test and, Grip Strength] and the quantitative measures (smoothness, time efficiency, and task error, derived from two robotic assessment tasks) were independently evaluated prior to therapy intervention (week 0), at mid-training (week 3), at the end of training (week 6), and post therapy (week 12 and 24). Significant differences within group were observed at the end of training for all clinical scales compared with baseline [mean and standard deviation of FMA score changes between baseline and week 6; RT: Δ4.41 (3.46) and CT: Δ3.0 (4.0);p< 0.01]. FMA gains were retained 18 weeks post-training [week 24; RT: Δ5.38 (4.67) and week 24 CT: Δ4.50 (5.35);p< 0.01]. The RT group clinical scores improved similarly when compared to CT group with no significant inter-group at all time points although the conventional therapy time was reduced to one third in RT group. There were no training-related adverse side effects. In conclusion, time matched combinatory training incorporating H-Man RAT produced similar outcomes compared to conventional therapy alone. Hence, this study supports a combinatory approach to improve motor function in post-stroke arm paresis.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02188628.
Large-Scale Brain Functional Network Integration for Discrimination of Autism Using a 3-D Deep Learning Model
Authors: Yang Ming , Cao Menglin , Chen Yuhao , Chen Yanni , Fan Geng , Li Chenxi , Wang Jue , Liu Tian
Published: June 2021

Goal

Brain functional networks (BFNs) constructed using resting-state functional magnetic resonance imaging (fMRI) have proven to be an effective way to understand aberrant functional connectivity in autism spectrum disorder (ASD) patients. It is still challenging to utilize these features as potential biomarkers for discrimination of ASD. The purpose of this work is to classify ASD and normal controls (NCs) using BFNs derived from rs-fMRI.

Methods

A deep learning framework was proposed that integrated convolutional neural network (CNN) and channel-wise attention mechanism to model both intra- and inter-BFN associations simultaneously for ASD diagnosis. We investigate the effects of each BFN on performance and performed inter-network connectivity analysis between each pair of BFNs. We compared the performance of our CNN model with some state-of-the-art algorithms using functional connectivity features.

Results

We collected 79 ASD patients and 105 NCs from the ABIDE-I dataset. The mean accuracy of our classification algorithm was 77.74% for classification of ASD versus NCs.

Conclusion

The proposed model is able to integrate information from multiple BFNs to improve detection accuracy of ASD.

Significance

These findings suggest that large-scale BFNs is promising to serve as reliable biomarkers for diagnosis of ASD.
Correlation Between the Evolution of Somatic Alterations During Lymphatic Metastasis and Clinical Outcome in Penile Squamous Cell Carcinoma
Authors: Cao Jian , Yang Chun-He , Han Wei-Qing , Xie Yu , Liu Zhi-Zhong , Jiang Shu-Suan
Published: June 2021

Penile squamous cell carcinoma (PSCC) is a rare malignancy with poor survival after standard treatment. Although genomic alterations of PSCC have been characterized in several latest studies, the association between the formation of somatic landscape and regional lymph node metastasis (LNM), an important predictor for patient survival, has not been comprehensively investigated. Here, we collected formalin-fixed paraffin-embedded tumor tissue and matched normal samples of 32 PSCC patients, including 14 LNM patients and 18 clinically node-negative patients, to implement a whole-exome sequencing. Comparison of genomic features among different lymph node status subgroups was conducted after genomic profiling and its effects on patient survival were explored. Top-ranked recurrent gene mutants in our PSCC cohort were TP53 (13/32), NOTCH1 (12/32), CDKN2A (11/32), TTN (9/32) and FAT1 (8/32), mainly identified in the Notch, Hippo, cell cycle, TP53, RTK-RAS and PI3K pathways. While CDKN2A was confirmed to be the driver gene in all PSCC patients, certain gene mutants were significantly enriched in LNM involved patients, including TP53 (9/14 vs. 4/18, p = 0.029) and GBF1 (4/14 vs. 0/18, p = 0.028). Overall survival stratification of PSCC patients were found to be significantly correlated with mutations of three genes, including PIK3CA (Hazard ratio [HR] = 4.15, p = 0.029), CHD7 (HR = 4.82, p = 0.032) and LAMC3 (HR = 15.9, p < 0.001). PIK3CA and LAMC3 held a higher prevalence in patients with LNM compared to those without LNM (PIK3CA: 3/14 vs. 1/18, LAMC3: 2/14 vs. 1/18). Our finding demonstrated that genomic divergence exists across PSCC patients with different lymph node statuses, and it may be correlated with their survival outcome. It helps delineate somatic evolution during tumor progression and perfect potential therapeutic intervention in this disease.
Sandpile Models in the Large
Authors: Ruelle Philippe
Published: June 2021

This contribution is a review of the deep and powerful connection between the large-scale properties of critical systems and their description in terms of a field theory. Although largely applicable to many other models, the details of this connection are illustrated in the class of two-dimensional Abelian sandpile models. Bulk and boundary height variables, spanning tree–related observables, boundary conditions, and dissipation are all discussed in this context and found to have a proper match in the field theoretic description.
A Comparison of CVR Magnitude and Delay Assessed at 1.5 and 3T in Patients With Cerebral Small Vessel Disease
Authors: Stringer Michael S. , Blair Gordon W. , Shi Yulu , Hamilton Iona , Dickie David A. , Doubal Fergus N. , Marshall Ian M. , Thrippleton Michael J. , Wardlaw Joanna M.
Published: June 2021

Background

Cerebrovascular reactivity (CVR) measures blood flow change in response to a vasoactive stimulus. Impairment is associated with several neurological conditions and can be measured using blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI). Field strength affects the BOLD signal, but the effect on CVR is unquantified in patient populations.

Methods

We recruited patients with minor ischemic stroke and assessed CVR magnitude and delay time at 3 and 1.5 Tesla using BOLD MRI during a hypercapnic challenge. We assessed subcortical gray (GM) and white matter (WM) differences using Wilcoxon signed rank tests and scatterplots. Additionally, we explored associations with demographic factors, WM hyperintensity burden, and small vessel disease score.

Results

Eighteen of twenty patients provided usable data. At 3T vs. 1.5T: mean CVR magnitude showed less variance (WM 3T: 0.062 ± 0.018%/mmHg, range 0.035, 0.093; 1.5T: 0.057 ± 0.024%/mmHg, range 0.016, 0.094) but was not systematically higher (Wilcoxon signal rank tests, WM: r = −0.33, confidence interval (CI): −0.013, 0.003, p = 0.167); delay showed similar variance (WM 3T: 40 ± 12 s, range: 12, 56; 1.5T: 31 ± 13 s, range 6, 50) and was shorter in GM (r = 0.33, CI: −2, 9, p = 0.164) and longer in WM (r = −0.59, CI: −16, −2, p = 0.010). Patients with higher disease severity tended to have lower CVR at 1.5 and 3T.

Conclusion

Mean CVR magnitude at 3T was similar to 1.5T but showed less variance. GM/WM delay differences may be affected by low signal-to-noise ratio among other factors. Although 3T may reduce variance in CVR magnitude, CVR is readily assessable at 1.5T and reveals comparable associations and trends with disease severity.
Modeling the Glomerular Filtration Barrier and Intercellular Crosstalk
Authors: Ebefors Kerstin , Lassén Emelie , Anandakrishnan Nanditha , Azeloglu Evren U. , Daehn Ilse S.
Published: June 2021

The glomerulus is a compact cluster of capillaries responsible for blood filtration and initiating urine production in the renal nephrons. A trilaminar structure in the capillary wall forms the glomerular filtration barrier (GFB), composed of glycocalyx-enriched and fenestrated endothelial cells adhering to the glomerular basement membrane and specialized visceral epithelial cells, podocytes, forming the outermost layer with a molecular slit diaphragm between their interdigitating foot processes. The unique dynamic and selective nature of blood filtration to produce urine requires the functionality of each of the GFB components, and hence, mimicking the glomerular filter in vitro has been challenging, though critical for various research applications and drug screening. Research efforts in the past few years have transformed our understanding of the structure and multifaceted roles of the cells and their intricate crosstalk in development and disease pathogenesis. In this review, we present a new wave of technologies that include glomerulus-on-a-chip, three-dimensional microfluidic models, and organoids all promising to improve our understanding of glomerular biology and to enable the development of GFB-targeted therapies. Here, we also outline the challenges and the opportunities of these emerging biomimetic systems that aim to recapitulate the complex glomerular filter, and the evolving perspectives on the sophisticated repertoire of cellular signaling that comprise the glomerular milieu.
Guide to Plant-PET Imaging Using 11CO2
Authors: Mincke Jens , Courtyn Jan , Vanhove Christian , Vandenberghe Stefaan , Steppe Kathy
Published: June 2021

Due to its high sensitivity and specificity for tumor detection, positron emission tomography (PET) has become a standard and widely used molecular imaging technique. Given the popularity of PET, both clinically and preclinically, its use has been extended to study plants. However, only a limited number of research groups worldwide report PET-based studies, while we believe that this technique has much more potential and could contribute extensively to plant science. The limited application of PET may be related to the complexity of putting together methodological developments from multiple disciplines, such as radio-pharmacology, physics, mathematics and engineering, which may form an obstacle for some research groups. By means of this manuscript, we want to encourage researchers to study plants using PET. The main goal is to provide a clear description on how to design and execute PET scans, process the resulting data and fully explore its potential by quantification via compartmental modeling. The different steps that need to be taken will be discussed as well as the related challenges. Hereby, the main focus will be on, although not limited to, tracing 11CO2 to study plant carbon dynamics.
Genome Editing for Plasmodesmal Biology
Authors: Iswanto Arya Bagus Boedi , Shelake Rahul Mahadev , Vu Minh Huy , Kim Jae-Yean , Kim Sang Hee
Published: June 2021

Plasmodesmata (PD) are cytoplasmic canals that facilitate intercellular communication and molecular exchange between adjacent plant cells. PD-associated proteins are considered as one of the foremost factors in regulating PD function that is critical for plant development and stress responses. Although its potential to be used for crop engineering is enormous, our understanding of PD biology was relatively limited to model plants, demanding further studies in crop systems. Recently developed genome editing techniques such as Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associate protein (CRISPR/Cas) might confer powerful approaches to dissect the molecular function of PD components and to engineer elite crops. Here, we assess several aspects of PD functioning to underline and highlight the potential applications of CRISPR/Cas that provide new insight into PD biology and crop improvement.
Severe Air Pollution and Psychological Distress in China: The Interactive Effects of Coping and Perceived Controllability
Authors: Zhu Zhuoying , Zhao Yitong
Published: June 2021

The coping styles of focusing on a stressor (i.e., trauma focus), and moving beyond the emotional impact of a stressor (i.e., forward focus), have both been found beneficial to psychological adjustment. This study investigated whether these two coping styles are similarly associated with adjustment across levels of perceived controllability and beyond European-American contexts. During China’s peak of air pollution in 2014, we surveyed 250 young- to middle- aged adults online to measure their coping behaviors, smog perceptions, and psychological distress, and collected objective data of pollution severity in the respondents’ cities. Results showed that forward-focus coping was generally associated with lower distress and trauma-focus coping was associated with greater distress. Perceived controllability significantly moderated the associations between trauma focus (but not forward focus) and distress. These findings suggest that while forward focus correlated with beneficial adjustment outcomes in coping with air pollution, the extensive processing of event-related cognitions and emotions in trauma focus may be detrimental, especially for events perceived to be less controllable. We discussed the implications of our findings within an interdependent cultural context.
The Influence of Action Video Games on Attentional Functions Across Visual and Auditory Modalities
Authors: Wu Xia , Jiang Ying , Jiang Yunpeng , Chen Guodong , Chen Ying , Bai Xuejun
Published: June 2021

Attention can help an individual efficiently find a specific target among multiple distractors and is proposed to consist of three functions: alerting, orienting, and executive control. Action video games (AVGs) have been shown to enhance attention. However, whether AVG can affect the attentional functions across different modalities remains to be determined. In the present study, a group of action video game players (AVGPs) and a group of non-action video game players (NAVGPs) selected by a video game usage questionnaire successively participated in two tasks, including an attention network task-visual version (ANT-V) and an attention network task-auditory version (ANT-A). The results indicated that AVGPs showed an advantage in orienting under the effects of conflicting stimuli (executive control) in both tasks, and NAVGPs may have a reduced ability to disengage when conflict occurs in visual task, suggesting that the AVGs can improve guidance toward targets and inhibition of distractors with the function of executive control. AVGPs also showed more correlations among attentional functions. Importantly, the alerting functions of AVGPs in visual and auditory tasks were significantly related, indicating that the experience of AVGs could help us to generate a supramodal alerting effect across visual and auditory modalities.
Phonemic Training Modulates Early Speech Processing in Pre-reading Children
Authors: Bauch Anne , Friedrich Claudia K. , Schild Ulrike
Published: June 2021

Phonemic awareness and rudimentary grapheme knowledge concurrently develop in pre-school age. In a training study, we tried to disentangle the role of both precursor functions of reading for spoken word recognition. Two groups of children exercised with phonemic materials, but only one of both groups learnt corresponding letters to trained phonemes. A control group exercised finger-number associations (non-linguistic training). After the training, we tested how sensitive children were to prime-target variation in word onset priming. A group of young adults took part in the same experiment to provide data from experienced readers. While decision latencies to the targets suggested fine-grained spoken word processing in all groups, event-related potentials (ERPs) indicated that both phonemic training groups processed phonemic variation in more detail than the non-linguistic training group and young adults at early stages of speech processing. Our results indicate temporal plasticity of implicit speech processing in pre-school age as a function of explicit phonemic training.
Investigation of an MAA Test With Virtual Sound Synthesis
Authors: Meng Ruijie , Xiang Jingpeng , Sang Jinqiu , Zheng Chengshi , Li Xiaodong , Bleeck Stefan , Cai Juanjuan , Wang Jie
Published: June 2021

The ability to localize a sound source is very important in our daily life, specifically to analyze auditory scenes in complex acoustic environments. The concept of minimum audible angle (MAA), which is defined as the smallest detectable difference between the incident directions of two sound sources, has been widely used in the research fields of auditory perception to measure localization ability. Measuring MAAs usually involves a reference sound source and either a large number of loudspeakers or a movable sound source in order to reproduce sound sources at a large number of predefined incident directions. However, existing MAA test systems are often cumbersome because they require a large number of loudspeakers or a mechanical rail slide and thus are expensive and inconvenient to use. This study investigates a novel MAA test method using virtual sound source synthesis and avoiding the problems with traditional methods. We compare the perceptual localization acuity of sound sources in two experimental designs: using the virtual presentation and real sound sources. The virtual sound source is reproduced through a pair of loudspeakers weighted by vector-based amplitude panning (VBAP). Results show that the average measured MAA at 0° azimuth is 1.1° and the average measured MAA at 90° azimuth is 3.1° in a virtual acoustic system, meanwhile the average measured MAA at 0° azimuth is about 1.2° and the average measured MAA at 90° azimuth is 3.3° when using the real sound sources. The measurements of the two methods have no significant difference. We conclude that the proposed MAA test system is a suitable alternative to more complicated and expensive setups.