bluuebunny/crossref_metadata_2025 huggingface dataset:
Teaching and Learning Continuity Amid and Beyond the Pandemic
Authors: Dayagbil Filomena T. , Palompon Daisy R. , Garcia Laurence L. , Olvido Michelle Mae J.
Published: July 2021

The study explored the challenges and issues in teaching and learning continuity of public higher education in the Philippines as a result of the COVID-19 pandemic. The study employed the exploratory mixed-method triangulation design and analyzed the data gathered from 3, 989 respondents composed of students and faculty members. It was found out that during school lockdowns, the teachers made adjustments in teaching and learning designs guided by the policies implemented by the institution. Most of the students had difficulty complying with the learning activities and requirements due to limited or no internet connectivity. Emerging themes were identified from the qualitative responses to include the trajectory for flexible learning delivery, the role of technology, the teaching and learning environment, and the prioritization of safety and security. Scenario analysis provided the contextual basis for strategic actions amid and beyond the pandemic. To ensure teaching and learning continuity, it is concluded that higher education institutions have to migrate to flexible teaching and learning modality recalibrate the curriculum, capacitate the faculty, upgrade the infrastructure, implement a strategic plan and assess all aspects of the plan.
Convex Approximation Algorithm for AC/DC Distribution Network With Energy Router
Authors: Zhang Tao , Mu Yunfei , Wang Xiaoyu , Deng Youjun , Song Yi , Yuan Kai , Jia Hongjie
Published: July 2021

The optimal operation model of AC/DC distribution network with energy router (ER) is essentially a nonconvex nonlinear programming (NLP) problem. In order to improve the feasibility of solving the model, a convex approximation algorithm is proposed in this work. The steady-state model of ER is developed with considering the loss characteristics and multiport coordinated control strategy. It is embedded in the optimization formulations of AC/DC network as basic operating equations. Then, using second-order cone relaxation technology, the power flow equations of AC and DC distribution networks are convexly relaxed. On this basis, the highly nonlinear operating model of ER is linearized by introducing a successive approximation approach. Therefore, the original NLP problem is transformed into the convex programming problem and the solution efficiency is improved. Meanwhile, an iterative solution algorithm is developed to ensure the accuracy of the convex approximation approach. Simulation results verify the feasibility and efficiency of the proposed algorithm.
The Accumulating Costs Hypothesis—to Better Understand Delayed “Hidden” Costs of Seemingly Mild Disease and Other Moderate Stressors
Authors: Hasselquist Dennis , Tobler Michael
Published: July 2021

Mild diseases and moderate stressors are seemingly harmless and are therefore often assumed to have negligible impact on Darwinian fitness. Here we argue that the effects of “benign” parasites and other moderate stressors may have a greater impact on lifespan and other fitness traits than generally thought. We outline the “accumulating costs” hypothesis which proposes that moderate strains on the body caused by mild diseases and other moderate stressors that occur throughout life will result in small irreversible “somatic lesions” that initially are invisible (i.e., induce “hidden” costs). However, over time these somatic lesions accumulate until their summed effect reaches a critical point when cell senescence and malfunction begin to affect organ functionality and lead to the onset of degenerative diseases and aging. We briefly discuss three potential mechanisms through which the effects of moderate strains (e.g., mild diseases) could accumulate: Accelerated telomere shortening, loss of repetitious cell compartments and other uncorrected DNA damage in the genome. We suggest that telomere shortening may be a key candidate for further research with respect to the accumulating costs hypothesis. Telomeres can acquire lesions from moderate strains without immediate negative effects, lesions can be accumulated over time and lead to a critically short telomere length, which may eventually cause severe somatic malfunctioning, including aging. If effects of mild diseases, benign parasites and moderate stressors accrued throughout life can have severe delayed consequences, this might contribute to our understanding of life history strategies and trade-offs, and have important implications for medicine, including consideration of treatment therapies for mild (chronic) infections such as malaria.
Genetic Diversity and Population Structure of Medemia argun (Mart.) Wurttenb. ex H.Wendl. Based on Genome-Wide Markers
Authors: Elshibli Sakina , Korpelainen Helena
Published: July 2021

Medemia argun is a wild, dioecious palm, adapted to the harsh arid environment of the Nubian Desert in Sudan and southern Egypt. There is a concern about its conservation status, since little is known about its distribution, abundance, and genetic variation. M. argun grows on the floodplains of seasonal rivers (wadis). The continuing loss of suitable habitats in the Nubian Desert is threatening the survival of this species. We analyzed the genetic diversity, population genetic structure, and occurrence of M. argun populations to foster the development of conservation strategies for M. argun. Genotyping-by-sequencing (GBS) analyses were performed using a whole-genome profiling service. We found an overall low genetic diversity and moderate genetic structuring based on 40 single-nucleotide polymorphisms (SNPs) and 9,866 SilicoDArT markers. The expected heterozygosity of the total population (HT) equaled 0.036 and 0.127, and genetic differentiation among populations/groups (FST) was 0.052 and 0.092, based on SNP and SilicoDArT markers, respectively. Bayesian clustering analyses defined five genetic clusters that did not display any ancestral gene flow among each other. Based on SilicoDArT markers, the results of the analysis of molecular variance (AMOVA) confirmed the previously observed genetic differentiation among generation groups (23%; p < 0.01). Pairwise FST values indicated a genetic gap between old and young individuals. The observed low genetic diversity and its loss among generation groups, even under the detected high gene flow, show genetically vulnerable M. argun populations in the Nubian Desert in Sudan. To enrich and maintain genetic variability in these populations, conservation plans are required, including collection of seed material from genetically diverse populations and development of ex situ gene banks.
The Use of Synthetic Herbivory-Induced Plant Volatiles That Attract Specialist Parasitoid Wasps, Cotesia vestalis, for Controlling the Incidence of Diamondback Moth Larvae in Open Agricultural Fields
Authors: Uefune Masayoshi , Yoneya Kinuyo , Yamamoto Masaki , Takabayashi Junji
Published: July 2021

We evaluated the effectiveness of using a blend of volatiles that attract Cotesia vestalis, a specialist parasitoid wasp of diamondback moth (DBM) larvae, to control DBM larvae on cabbage plants under open field conditions. We set three dispensers of the synthetic C. vestalis attractant together with one sugary-food feeder in a cabbage plot (10 m × 1 m; the treated plot) on one side of a pesticide-free open agricultural field (approximately 20 m × 20 m) from June to September in 2010 and July to August in 2011. On the other side of the field, we created a control cabbage plot of the same size in which neither dispensers nor a feeder was set. The incidences of DBM larvae and C. vestalis cocoons in the control and treated plots were compared. In 2010, the incidence of DBM larvae in the treated plot was significantly lower than that in the control plot. Poisson regression analyses in 2010 showed that the rate of increase in the number of C. vestalis cocoons along with an increase in the number of DBM larvae in the treated plot was significantly higher than that in the control plot. In 2011, the incidence in both the treated and control plots remained low (five larvae per plant or less) with no significant difference between the plots. Poisson regression analyses in 2011 showed that the number of C. vestalis cocoons in the treated plot was significantly higher than that in the control plot, irrespective of the number of DBM larvae. This 2-year field study suggested that the dispensers recruited native C. vestalis from the surrounding environment to the treated plot, and the dispensers controlled the number of DBM larvae in 2010 when the density of DBM larvae exceeded the economic injury levels for the cabbage crop. We also compared the incidences of other arthropods in the control and treated plots. The incidences of Pieris rapae larvae and Plusiinae spp. were not affected by the treatments. The number of aphids in the treated and control plots was inconsistent between the 2 years. Based on these 2-year results, the possible use of C. vestalis attractants in open agricultural fields is discussed.
Stemflow Infiltration Hotspots Create Soil Microsites Near Tree Stems in an Unmanaged Mixed Beech Forest
Authors: Metzger Johanna Clara , Filipzik Janett , Michalzik Beate , Hildebrandt Anke
Published: July 2021

In stemflow, rainfall is collected and channeled to a concentrated soil water input. It can constitute up to 30% of incident precipitation in some ecosystems. However, the size of the zone influenced by stemflow is unclear, and statistically representative measurement of stemflow (on and in between sites) is scarce. Therefore, whether stemflow creates hotspots of infiltration and potential impacts on forest soils remain subject to controversy. In this study, we investigated the areal dimension of infiltrating stemflow fluxes as well as effects on near-stem soils. We measured throughfall, stemflow and soil properties in high-resolution statistical designs on a mixed forest plot in Germany receiving moderate stemflow. From this data, we modeled the spatial distribution of net precipitation infiltration depth on the plot. Furthermore, we examined soil chemical and physical properties around tree stems to test for and assess a stemflow impact. Results show that stemflow infiltration areas are much smaller than typically assumed and constitute strong infiltration hotspots compared to throughfall. This is also mirrored in soil properties, which are significantly altered near stems. Here, accelerated soil formation and enhanced translocation processes indicate increased soil water fluxes due to high inputs. Additionally, altered soil hydraulic properties enable quicker soil water fluxes near stems. Our findings attest that even comparatively low stemflow fractions (of gross precipitation) can generate strong hotspots of water and matter inputs, which are impactful to subsequent hydrological and biogeochemical processes and properties. Trees shape their direct soil environment, thereby establishing pathways of preferential water flow connecting the canopy and the deeper subsurface.
Genetically Predicted Fibroblast Growth Factor 23 and Major Cardiovascular Diseases, Their Risk Factors, Kidney Function, and Longevity: A Two-Sample Mendelian Randomization Study
Authors: Liang Ying , Luo Shan , Schooling C. Mary , Au Yeung Shiu Lun
Published: July 2021

Introduction

Fibroblast growth factor 23 (FGF23), a potential biomarker for kidney function, is related to cardiovascular disease (CVD) and diabetes, although it is unclear whether the relation is causal. This study evaluated the associations of genetically predicted FGF23 with major CVDs, their risk factors, kidney function, and longevity using Mendelian randomization (MR).

Methods

This is a two-sample MR study using summary statistics from large genome-wide association studies. Primary outcomes included coronary artery disease (CAD), myocardial infarction, heart failure, and atrial fibrillation. Secondary outcomes included cardiovascular risk factors, kidney function, and longevity. We used four single-nucleotide polymorphisms (SNPs) predicting FGF23, excluding rs2769071 in theABOgene, which likely violates the MR exclusion-restriction assumption. We used inverse-variance weighted (IVW) as the primary statistical method to assess associations of FGF23 with the outcomes. Sensitivity analyses included weighted median (WM) and MR-Egger. We repeated the analyses including all five SNPs. Last, we validated the positive findings from the main analyses in a smaller study, i.e., FinnGen.

Results

Using IVW, genetically predicted higher FGF23 was inversely associated with risk of CAD [odds ratio (OR): 0.69 per logtransformed FGF23 (pg/ml) increase, 95% confidence interval (CI): 0.52–0.91] and type 2 diabetes mellitus (T2DM) (OR: 0.70, 95% CI: 0.52–0.96), but not with the other outcomes. The WM and MR-Egger estimates were directionally consistent.

Conclusion

This study suggests that genetically predicted higher FGF23 may be protective against CAD and T2DM. Future studies should explore the underlying mechanisms related to the potential protective effect of FGF23. FGF23 was unlikely a cause of poorer renal function.
Metabolomics in the Diagnosis and Prognosis of COVID-19
Authors: Hasan Mohammad Rubayet , Suleiman Mohammed , Pérez-López Andrés
Published: July 2021

Coronavirus disease 2019 (COVID-19) pandemic triggered an unprecedented global effort in developing rapid and inexpensive diagnostic and prognostic tools. Since the genome of SARS-CoV-2 was uncovered, detection of viral RNA by RT-qPCR has played the most significant role in preventing the spread of the virus through early detection and tracing of suspected COVID-19 cases and through screening of at-risk population. However, a large number of alternative test methods based on SARS-CoV-2 RNA or proteins or host factors associated with SARS-CoV-2 infection have been developed and evaluated. The application of metabolomics in infectious disease diagnostics is an evolving area of science that was boosted by the urgency of COVID-19 pandemic. Metabolomics approaches that rely on the analysis of volatile organic compounds exhaled by COVID-19 patients hold promise for applications in a large-scale screening of population in point-of-care (POC) setting. On the other hand, successful application of mass-spectrometry to detect specific spectral signatures associated with COVID-19 in nasopharyngeal swab specimens may significantly save the cost and turnaround time of COVID-19 testing in the diagnostic microbiology and virology laboratories. Active research is also ongoing on the discovery of potential metabolomics-based prognostic markers for the disease that can be applied to serum or plasma specimens. Several metabolic pathways related to amino acid, lipid and energy metabolism were found to be affected by severe disease with COVID-19. In particular, tryptophan metabolism via the kynurenine pathway were persistently dysregulated in several independent studies, suggesting the roles of several metabolites of this pathway such as tryptophan, kynurenine and 3-hydroxykynurenine as potential prognostic markers of the disease. However, standardization of the test methods and large-scale clinical validation are necessary before these tests can be applied in a clinical setting. With rapidly expanding data on the metabolic profiles of COVID-19 patients with varying degrees of severity, it is likely that metabolomics will play an important role in near future in predicting the outcome of the disease with a greater degree of certainty.
CAR-NK Cells Effectively Target SARS-CoV-2-Spike-Expressing Cell Lines In Vitro
Authors: Ma Minh Tuyet , Badeti Saiaditya , Chen Chih-Hsiung , Kim James , Choudhary Alok , Honnen Bill , Reichman Charles , Calianese David , Pinter Abraham , Jiang Qingkui , Shi Lanbo , Zhou Renping , Xu Huanbin , Li Qingsheng , Gause William , Liu Dongfang
Published: July 2021

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious and presents a significant public health issue. Current therapies used to treat coronavirus disease 2019 (COVID-19) include monoclonal antibody cocktail, convalescent plasma, antivirals, immunomodulators, and anticoagulants. The vaccines from Pfizer and Moderna have recently been authorized for emergency use, which are invaluable for the prevention of SARS-CoV-2 infection. However, their long-term side effects are not yet documented, and populations with immunocompromised conditions (e.g., organ-transplantation and immunodeficient patients) may not be able to mount an effective immune response. In addition, there are concerns that wide-scale immunity to SARS-CoV-2 may introduce immune pressure that could select for escape mutants to the existing vaccines and monoclonal antibody therapies. Emerging evidence has shown that chimeric antigen receptor (CAR)- natural killer (NK) immunotherapy has potent antitumor response in hematologic cancers with minimal adverse effects in recent studies, however, the potentials of CAR-NK cells in treating COVID-19 has not yet been fully exploited. Here, we improve upon a novel approach for the generation of CAR-NK cells for targeting SARS-CoV-2 and its various mutants. CAR-NK cells were generated using the scFv domain of S309 (henceforward, S309-CAR-NK), a SARS-CoV and SARS-CoV-2 neutralizing antibody (NAbs) that targets the highly conserved region of SARS-CoV-2 spike (S) glycoprotein and is therefore more likely to recognize different variants of SARS-CoV-2 isolates. S309-CAR-NK cells can specifically bind to pseudotyped SARS-CoV-2 virus and its D614G, N501Y, and E484K mutants. Furthermore, S309-CAR-NK cells can specifically kill target cells expressing SARS-CoV-2 S protein in vitro and show superior killing activity and cytokine production, compared to that of the recently reported CR3022-CAR-NK cells. Thus, these results pave the way for generating ‘off-the-shelf’ S309-CAR-NK cells for treatment in high-risk individuals as well as provide an alternative strategy for patients unresponsive to current vaccines.
Analysis of Interleukin-1 Signaling Alterations of Colon Adenocarcinoma Identified Implications for Immunotherapy
Authors: Zhou Xiaogang , Liu Yu , Xiang Jing , Wang Yuntao , Wang Qiqian , Xia Jianling , Chen Yunfei , Bai Yifeng
Published: July 2021

Immune checkpoint inhibitors (ICIs) have made breakthrough progress in the treatment of various malignant tumors. However, only some patients receiving ICIs obtain long-lasting clinical effects, and some patients still do not achieve remission. Improving the treatment benefits of this part of the population has become a concern of clinicians. IL-1 signaling plays an important role in the tumor microenvironment (TME). However, the relationship between the IL-1 signaling mutation status and the prognosis of colon adenocarcinoma (COAD) patients receiving ICIs has not been reported. We downloaded the data of a COAD cohort receiving ICIs, including prognostic data and mutation data. Additionally, we downloaded the data of a COAD cohort from The Cancer Genome Atlas (TCGA) database, including clinical data, expression data and mutation data. Gene set enrichment analysis (GSEA) was used to assess differences in the activity of some key physiological pathways between the IL-1 signaling mutated-type (IL-1-MT) and IL-1 signaling wild-type (IL-1-WT) groups. The CIBERSORT algorithm was used to evaluate the contents of immune cells in the TME of COAD patients. The multivariate Cox regression model results suggested that IL-1-MT can be used as an independent predictor of a better prognosis in COAD patients receiving ICIs (P = 0.03, HR = 0.269, 95% CI: 0.082-0.883). Additionally, IL-1-MT COAD patients had significantly longer overall survival (OS) (log-rank P = 0.015). CIBERSORT analysis showed that the IL-1-MT group had high infiltration levels of activated dendritic cells (DCs), M1 macrophages, neutrophils, activated natural killer (NK) cells, activated CD4+ memory T cells and CD8+ T cells. Similarly, the IL-1-MT group had significantly upregulated immunogenicity, including in terms of the tumor mutation burden (TMB), neoantigen load (NAL) and number of mutations in DNA damage repair (DDR) signaling. GSEA showed that the IL-1-MT group was highly enriched in the immune response and proinflammatory mediators. Additionally, the expression levels of immune-related genes, immune checkpoint molecules and immune-related signatures were significantly higher in the IL-1-MT group than in the IL-1-WT group. IL-1-MT may be an independent predictor of a good prognosis in COAD patients receiving ICIs, with significantly longer OS in IL-1-MT COAD patients. Additionally, IL-1-MT was associated with significantly increased immunogenicity, activated immune cell and inflammatory mediator levels and immune response-related scores.
CAR Macrophages for SARS-CoV-2 Immunotherapy
Authors: Fu Wenyan , Lei Changhai , Ma Zetong , Qian Kewen , Li Tian , Zhao Jian , Hu Shi
Published: July 2021

Targeted therapeutics for the treatment of coronavirus disease 2019 (COVID-19), especially severe cases, are currently lacking. As macrophages have unique effector functions as a first-line defense against invading pathogens, we genetically armed human macrophages with chimeric antigen receptors (CARs) to reprogram their phagocytic activity against SARS-CoV-2. After investigation of CAR constructs with different intracellular receptor domains, we found that although cytosolic domains from MERTK (CARMERTK) did not trigger antigen-specific cellular phagocytosis or killing effects, unlike those from MEGF10, FcRγ and CD3ζ did, these CARs all mediated similar SARS-CoV-2 clearance in vitro. Notably, we showed that CARMERTK macrophages reduced the virion load without upregulation of proinflammatory cytokine expression. These results suggest that CARMERTK drives an ‘immunologically silent’ scavenger effect in macrophages and pave the way for further investigation of CARs for the treatment of individuals with COVID-19, particularly those with severe cases at a high risk of hyperinflammation.
Integrated Bioinformatics and Validation Reveal Potential Biomarkers Associated With Progression of Primary Sjögren’s Syndrome
Authors: Li Ning , Li Lei , Wu Mengyao , Li Yusi , Yang Jie , Wu Yicheng , Xu Haimin , Luo Danyang , Gao Yiming , Fei Xiaochun , Jiang Liting
Published: July 2021

Background

Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease of the exocrine glands characterized by specific pathological features. Previous studies have pointed out that salivary glands from pSS patients express a unique profile of cytokines, adhesion molecules, and chemokines compared to those from healthy controls. However, there is limited evidence supporting the utility of individual markers for different stages of pSS. This study aimed to explore potential biomarkers associated with pSS disease progression and analyze the associations between key genes and immune cells.

Methods

We combined our own RNA sequencing data with pSS datasets from the NCBI Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs)viabioinformatics analysis. Salivary gland biopsies were collected from 14 pSS patients, 6 non-pSS patients, and 6 controls. Histochemical staining and transmission electron micrographs (TEM) were performed to macroscopically and microscopically characterize morphological features of labial salivary glands in different disease stages. Then, we performed quantitative PCR to validate hub genes. Finally, we analyzed correlations between selected hub genes and immune cells using the CIBERSORT algorithm.

Results

We identified twenty-eight DEGs that were upregulated in pSS patients compared to healthy controls. These were mainly involved in immune-related pathways and infection-related pathways. According to the morphological features of minor salivary glands, severe interlobular and periductal lymphocytic infiltrates, acinar atrophy and collagen in the interstitium, nuclear shrinkage, and microscopic organelle swelling were observed with pSS disease progression. Hub genes based on above twenty-eight DEGs, including MS4A1, CD19, TCL1A, CCL19, CXCL9, CD3G, and CD3D, were selected as potential biomarkers and verified by RT-PCR. Expression of these genes was correlated with T follicular helper cells, memory B cells and M1 macrophages.

Conclusion

Using transcriptome sequencing and bioinformatics analysis combined with our clinical data, we identified seven key genes that have potential value for evaluating pSS severity.
Adapting Rapid Diagnostic Tests to Detect Historical Dengue Virus Infections
Authors: Echegaray Fernando , Laing Peter , Hernandez Samantha , Marquez Sully , Harris Amanda , Laing Ian , Chambers Adam , McLennan Neil , Sugiharto Victor A. , Chen Hua-Wei , Villagran Sandra Vivero , Collingwood Abigail , Montoya Magelda , Carrillo Fausto Bustos , Simons Mark P. , Cooper Philip J. , Lopez Andrea , Trueba Gabriel , Eisenberg Joseph , Wu Shuenn-Jue , Messer William , Harris Eva , Coloma Josefina , Katzelnick Leah C.
Published: July 2021

The only licensed dengue vaccine, Dengvaxia®, increases risk of severe dengue when given to individuals without prior dengue virus (DENV) infection but is protective against future disease in those with prior DENV immunity. The World Health Organization has recommended using rapid diagnostic tests (RDT) to determine history of prior DENV infection and suitability for vaccination. Dengue experts recommend that these assays be highly specific (≥98%) to avoid erroneously vaccinating individuals without prior DENV infection, as well as be sensitive enough (≥95%) to detect individuals with a single prior DENV infection. We evaluated one existing and two newly developed anti-flavivirus RDTs using samples collected >6 months post-infection from individuals in non-endemic and DENV and ZIKV endemic areas. We first evaluated the IgG component of the SD BIOLINE Dengue IgG/IgM RDT, which was developed to assist in confirming acute/recent DENV infections (n=93 samples). When evaluated following the manufacturer’s instructions, the SD BIOLINE Dengue RDT had 100% specificity for both non-endemic and endemic samples but low sensitivity for detecting DENV seropositivity (0% non-endemic, 41% endemic). Sensitivity increased (53% non-endemic, 98% endemic) when tests were allowed to run beyond manufacturer recommendations (0.5 up to 3 hours), but specificity decreased in endemic samples (36%). When tests were evaluated using a quantitative reader, optimal specificity could be achieved (≥98%) while still retaining sensitivity at earlier timepoints in non-endemic (44-88%) and endemic samples (31-55%). We next evaluated novel dengue and Zika RDTs developed by Excivion to detect prior DENV or ZIKV infections and reduce cross-flavivirus reactivity (n=207 samples). When evaluated visually, the Excivion Dengue RDT had sensitivity and specificity values of 79%, but when evaluated with a quantitative reader, optimal specificity could be achieved (≥98%) while still maintaining moderate sensitivity (48-75%). The Excivion Zika RDT had high specificity (>98%) and sensitivity (>93%) when evaluated quantitatively, suggesting it may be used alongside dengue RDTs to minimize misclassification due to cross-reactivity. Our findings demonstrate the potential of RDTs to be used for dengue pre-vaccination screening to reduce vaccine-induced priming for severe dengue and show how assay design adaptations as well quantitative evaluation can further improve RDTs for this purpose.
Circulating Interleukin-37 Levels in Healthy Adult Humans – Establishing a Reference Range
Authors: Santarelli Danielle M. , Vincent Fabien B. , Rudloff Ina , Nold-Petry Claudia A. , Nold Marcel F. , Russo Marc A.
Published: July 2021

Interleukin (IL)-37 has an important function in limiting excessive inflammation. Its expression is increased in numerous inflammatory and autoimmune conditions and correlates with disease activity, suggesting it could have potential as a disease biomarker. Nevertheless, a reference range has yet to be determined. Our aim was to establish the first reference range of circulating IL-37 levels in healthy adult humans. PubMed was searched for studies reporting blood IL-37 concentrations in healthy adult subjects as measured by enzyme-linked immunosorbent assay. Nineteen studies were included in the analysis. Mean IL-37 levels were weighted by sample sizes, and weighted mean lower and upper levels ( ± 2SD of means) were calculated to provide a weighted mean and reference range. IL-37 levels were quantified in either serum or plasma from a total of 1035 (647 serum; 388 plasma) healthy subjects. The serum, plasma and combined matrix weighted means (reference ranges) were 72.9 (41.5 – 104.4) pg/mL, 83.9 (41.1 – 126.8) pg/mL, and 77.1 (41.4 – 112.8) pg/mL, respectively. There were no significant differences between serum and plasma means and upper and lower limits. Study means and upper IL-37 levels were significantly higher in Chinese population studies. From our analysis, a preliminary reference range for circulating IL-37 levels in healthy human adults has been established. In order to determine a reliable reference range for clinical application, large, prospective, multi-ethnic, healthy population studies are necessary. In addition, demographics, sample matrix, collection, processing and storage methods potentially affecting IL-37 detection levels should be thoroughly investigated.
A Novel Anti-Infective Peptide BCCY-1 With Immunomodulatory Activities
Authors: Cai Jinyang , Cui Xianwei , Wang Xing , You Lianghui , Ji Chenbo , Cao Yan
Published: July 2021

Antibiotic resistance has been considered to be a global threat which underscores the need to develop novel anti-infective therapeutics. Modulation of innate immunity by synthetic peptides is an attractive strategy to overcome this circumstance. We recently reported that BCCY-1, a human β-casein-derived peptide displays regulatory activities on monocytes, thereby enhancing their actions in innate immune responses. However, the function of peptide BCCY-1 in host defense against infection remains unknown. In this study, we investigated the in vivo characteristics and effects of peptide BCCY-1 in mouse models of bacterial infection. Following intraperitoneal injection, the peptide BCCY-1 exhibited high level of cellular uptake by monocytes without obvious toxicities. Results revealed that peptide BCCY-1, but not the scrambled version, stimulated the chemokine production and monocyte recruitment in vivo. Treatment with BCCY-1 enhanced the pathogen clearance and protected mice against lethal infections. Because the anti-infective effects of BCCY-1 was abolished by in vivo depletion of monocytes/macrophages rather than lymphocytes and granulocytes, we conclude that monocytes/macrophages are key effector cells in BCCY-1-mediated anti-infective protection. Additionally, BCCY-1 lacks direct antimicrobial activity. To our knowledge, a human β-casein-derived peptide that counters infection by selective regulation of innate immunity has not been reported previously. These results suggest peptide BCCY-1 as a promising alternative approach and a valuable complement to current anti-infective strategy.
Type I Interferon Induction in Cutaneous DNA Damage Syndromes
Authors: Klein Benjamin , Günther Claudia
Published: July 2021

Type I interferons (IFNs) as part of the innate immune system have an outstanding importance as antiviral defense cytokines that stimulate innate and adaptive immune responses. Upon sensing of pattern recognition particles (PRPs) such as nucleic acids, IFN secretion is activated and induces the expression of interferon stimulated genes (ISGs). Uncontrolled constitutive activation of the type I IFN system can lead to autoinflammation and autoimmunity, which is observed in autoimmune disorders such as systemic lupus erythematodes and in monogenic interferonopathies. They are caused by mutations in genes which are involved in sensing or metabolism of intracellular nucleic acids and DNA repair. Many authors described mechanisms of type I IFN secretion upon increased DNA damage, including the formation of micronuclei, cytosolic chromatin fragments and destabilization of DNA binding proteins. Hereditary cutaneous DNA damage syndromes, which are caused by mutations in proteins of the DNA repair, share laboratory and clinical features also seen in autoimmune disorders and interferonopathies; hence a potential role of DNA-damage-induced type I IFN secretion seems likely. Here, we aim to summarize possible mechanisms of IFN induction in cutaneous DNA damage syndromes with defects in the DNA double-strand repair and nucleotide excision repair. We review recent publications referring to Ataxia teleangiectasia, Bloom syndrome, Rothmund–Thomson syndrome, Werner syndrome, Huriez syndrome, and Xeroderma pigmentosum. Furthermore, we aim to discuss the role of type I IFN in cancer and these syndromes.
Influence of Estuarine Water on the Microbial Community Structure of Patagonian Fjords
Authors: Tamayo-Leiva Javier , Cifuentes-Anticevic Jerónimo , Aparicio-Rizzo Pilar , Arroyo José Ignacio , Masotti Italo , Díez Beatriz
Published: July 2021

Fjords are sensitive areas affected by climate change and can act as a natural laboratory to study microbial ecological processes. The Chilean Patagonian fjords (41–56°S), belonging to the Subantarctic ecosystem (46–60°S), make up one of the world’s largest fjord systems. In this region, Estuarine Water (EW) strongly influences oceanographic conditions, generating sharp gradients of oxygen, salinity and nutrients, the effects of which on the microbial community structure are poorly understood. During the spring of 2017 we studied the ecological patterns (dispersal and oceanographic factors) underlying the microbial community distribution in a linear span of 450 km along the estuarine-influenced Chilean Patagonian fjords. Our results show that widespread microbial dispersion existed along the fjords where bacterioplankton exhibited dependence on the eukaryotic phytoplankton community composition. This dependence was particularly observed under the low chlorophyll-a conditions of the Baker Channel area, in which a significant relationship was revealed between SAR11 Clade III and the eukaryotic families Pyrenomonadaceae (Cryptophyte) and Coccomyxaceae (Chlorophyta). Furthermore, dissolved oxygen and salinity were revealed as the main drivers influencing the surface marine microbial communities in these fjords. A strong salinity gradient resulted in the segregation of the Baker Channel prokaryotic communities from the rest of the Patagonian fjords. Likewise, Microbacteriaceae, Burkholderiaceae and SAR11 Clade III, commonly found in freshwater, were strongly associated with EW conditions in these fjords. The direct effect of EW on the microbial community structure and diversity of the fjords exemplifies the significance that climate change and, in particular, deglaciation have on this marine region and its productivity.
Phononic Crystal Sensors: A New Class of Resonant Sensors—Chances and Challenges for the Determination of Liquid Properties
Authors: Lucklum Ralf , Mukhin Nikolay , Djafari Rouhani Bahram , Pennec Yan
Published: July 2021

Resonant mechanical sensors are often considered as mass balance, which responds to an analyte adsorbed on or absorbed in a thin sensitive (and selective) layer deposited on the surface of the resonant device. In a more general sense, the sensor measures properties at the interface of the mechanical resonator to the medium under inspection. A phononic crystal (PnC) sensor employs mechanical resonance as well; however, the working principle is fundamentally different. The liquid medium under inspection becomes an integral part of the PnC sensor. The liquid-filled compartment acts as a mechanical resonator. Therefore, the sensor probes the entire liquid volume within this compartment. In both sensor concepts, the primary sensor value is a resonant frequency. To become an attractive new sensing concept, specifically as a bio and chemical sensor, the PnC sensor must reach an extraordinary sensitivity. We pay attention to the liquid viscosity, which is an important factor limiting sensitivity. The main part of our analysis has been performed on 1D PnC sensors, since they underlie the same material-related acoustic dissipation mechanisms as 2D and 3D PnC sensors. We show that an optimal relation of frequency shift to bandwidth and amplitude of resonance is the key to an enhanced sensitivity of the sensor-to-liquid analyte properties. We finally address additional challenges of 2D and 3D PnC sensor design concept. We conclude that the sensor should seek for a frequency resolution close to 10−6 the probing frequency, or a resolution with speed of sound approaching 1 mm s−1, taking water-based analytes as an example.
The Role of Gulls as Reservoirs of Antibiotic Resistance in Aquatic Environments: A Scoping Review
Authors: Zeballos-Gross Danae , Rojas-Sereno Zulma , Salgado-Caxito Marília , Poeta Patricia , Torres Carmen , Benavides Julio A.
Published: July 2021

The role of wildlife with long-range dispersal such as gulls in the global dissemination of antimicrobial resistance (AMR) across natural and anthropogenic aquatic environments remains poorly understood. Antibiotic-resistant bacteria have been detected in resident and migratory gulls worldwide for more than a decade, suggesting gulls as either sentinels of AMR pollution from anthropogenic sources or independent reservoirs that could maintain and disperse AMR across aquatic environments. However, confirming either of these roles remains challenging and incomplete. In this review, we present current knowledge on the geographic regions where AMR has been detected in gulls, the molecular characterization of resistance genes, and the evidence supporting the capacity of gulls to disperse AMR across regions or countries. We identify several limitations of current research to assess the role of gulls in the spread of AMR including most studies not identifying the source of AMR, few studies comparing bacteria isolated in gulls with other wild or domestic species, and almost no study performing longitudinal sampling over a large period of time to assess the maintenance and dispersion of AMR by gulls within and across regions. We suggest future research required to confirm the role of gulls in the global dispersion of AMR including the standardization of sampling protocols, longitudinal sampling using advanced satellite tracking, and whole-genome sequencing typing. Finally, we discuss the public health implications of the spread of AMR by gulls and potential solutions to limit its spread in aquatic environments.
Management of Coronavirus Disease 2019 Patients With Lung Cancer: Experience From a Thoracic Oncology Center
Authors: Coelho David Barros , Santos Vanessa , Araújo David , Bastos Hélder Novais , Magalhães Adriana , Hespanhol Venceslau , Queiroga Henrique , Cruz-Martins Natália , Fernandes Maria Gabriela O.
Published: July 2021

Background

Cancer patients appear to be at a higher risk of complications from coronavirus disease 2019 (COVID-19). Specific data related to lung cancer (LC) patient management, active treatment, and/or recent diagnosis are still very limited. Here, we aimed to investigate the clinical presentation, baseline features, and clinical outcomes of LC patients with COVID-19.

Methods

A retrospective case study was performed at Centro Hospitalar Universitário de São Joao, a tertiary hospital in the North of Portugal. Data from LC patients diagnosed with COVID-19 were collected during the first 10 months of the COVID-19 pandemic (March 2020–January 2021).

Results

Twenty-eight patients with active LC were diagnosed with COVID-19, being adenocarcinoma the most common histological type present (n = 13, 46.4%). Sixteen patients had metastatic stage IV LC (61.5%). Twenty-five patients (89.3%) had relevant comorbidities including hypertension (39.3%) and chronic obstructive pulmonary disease (32.1%). For patients undergoing antineoplastic treatment, the median time from the last chemotherapy administration to COVID-19 diagnosis was of 16 days (interquartile range = 13–41 days). Half of patients were previously on corticosteroid therapy. Twenty patients (71.4%) needed hospitalization, 18 received oxygen therapy (64.3%), 3 (10.7%) of them received high-flow nasal cannula with good tolerability, and 1 (3.6%) needed non-invasive ventilation. Hydroxychloroquine and antibiotics were given to 4 (14.3%) and 12 (42.9%) patients, respectively. Seven patients (25%) died at a median time of 5 days following COVID-19 diagnosis.

Conclusion

This is one of the first studies reporting the adverse outcomes associated with COVID-19 in LC patients at same time that adds evidence regarding the need to create protocols and guidelines to reduce the infection risk in such patients.
Punishment on Pause: Preliminary Evidence That Mindfulness Training Modifies Neural Responses in a Reactive Aggression Task
Authors: Rahrig Hadley , Bjork James M. , Tirado Camila , Chester David S. , Creswell J. David , Lindsay Emily K. , Penberthy Jennifer Kim , Brown Kirk Warren
Published: July 2021

Reactive aggression, a hostile retaliatory response to perceived threat, has been attributed to failures in emotion regulation. Interventions for reactive aggression have largely focused on cognitive control training, which target top-down emotion regulation mechanisms to inhibit aggressive impulses. Recent theory suggests that mindfulness training (MT) improves emotion regulation via both top-down and bottom-up neural mechanisms and has thus been proposed as an alternative treatment for aggression. Using this framework, the current pilot study examined how MT impacts functional brain physiology in the regulation of reactive aggression. Participants were randomly assigned to 2 weeks of MT (n = 11) or structurally equivalent active coping training (CT) that emphasizes cognitive control (n = 12). Following training, participants underwent functional magnetic resonance imaging (fMRI) during a retaliatory aggression task, a 16-trial game in which participants could respond to provocation by choosing whether or not to retaliate in the next round. Training groups did not differ in levels of aggression displayed. However, participants assigned to MT exhibited enhanced ventromedial prefrontal cortex (vmPFC) recruitment during punishment events (i.e., the aversive consequence of losing) relative to those receiving active CT. Conversely, the active coping group demonstrated greater dorsomedial prefrontal cortex (dmPFC) activation when deciding how much to retaliate, in line with a bolstered top-down behavior monitoring function. The findings suggest that mindfulness and cognitive control training may regulate aggression via different neural circuits and at different temporal stages of the provocation-aggression cycle.

Trial Registration: identification no. NCT03485807.
Single Prolonged Stress Reduces Intrinsic Excitability and Excitatory Synaptic Drive Onto Pyramidal Neurons in the Infralimbic Prefrontal Cortex of Adult Male Rats
Authors: Nawreen Nawshaba , Baccei Mark L. , Herman James P.
Published: July 2021

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness marked by abnormal fear responses and deficits in extinction of fear memories. The pathophysiology of PTSD is linked to decreased activation of the ventromedial prefrontal cortex (vmPFC). This study aims to investigate underlying functional changes in synaptic drive and intrinsic excitability of pyramidal neurons in the rodent homolog of the vmPFC, the infralimbic cortex (IL), following exposure to single prolonged stress (SPS), a paradigm that mimics core symptoms of PTSD in rats. Rats were exposed to SPS and allowed 1 week of recovery, following which brain slices containing the PFC were prepared for whole-cell patch clamp recordings from layer V pyramidal neurons in the IL. Our results indicate that SPS reduces spontaneous excitatory synaptic drive to pyramidal neurons. In addition, SPS decreases the intrinsic membrane excitability of IL PFC pyramidal cells, as indicated by an increase in rheobase, decrease in input resistance, hyperpolarization of resting membrane potential, and a reduction in repetitive firing rate. Our results suggest that SPS causes a lasting reduction in PFC activity, supporting a body of evidence linking traumatic stress with prefrontal hypoactivity.
Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models
Authors: Kosillo Polina , Bateup Helen S.
Published: July 2021

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by altered social interaction and communication, and repetitive, restricted, inflexible behaviors. Approximately 1.5-2% of the general population meet the diagnostic criteria for ASD and several brain regions including the cortex, amygdala, cerebellum and basal ganglia have been implicated in ASD pathophysiology. The midbrain dopamine system is an important modulator of cellular and synaptic function in multiple ASD-implicated brain regions via anatomically and functionally distinct dopaminergic projections. The dopamine hypothesis of ASD postulates that dysregulation of dopaminergic projection pathways could contribute to the behavioral manifestations of ASD, including altered reward value of social stimuli, changes in sensorimotor processing, and motor stereotypies. In this review, we examine the support for the idea that cell-autonomous changes in dopaminergic function are a core component of ASD pathophysiology. We discuss the human literature supporting the involvement of altered dopamine signaling in ASD including genetic, brain imaging and pharmacologic studies. We then focus on genetic mouse models of syndromic neurodevelopmental disorders in which single gene mutations lead to increased risk for ASD. We highlight studies that have directly examined dopamine neuron number, morphology, physiology, or output in these models. Overall, we find considerable support for the idea that the dopamine system may be dysregulated in syndromic ASDs; however, there does not appear to be a consistent signature and some models show increased dopaminergic function, while others have deficient dopamine signaling. We conclude that dopamine dysregulation is common in syndromic forms of ASD but that the specific changes may be unique to each genetic disorder and may not account for the full spectrum of ASD-related manifestations.
Modulation of the Hypothalamic Nutrient Sensing Pathways by Sex and Early-Life Stress
Authors: Ruigrok Silvie R. , Stöberl Nina , Yam Kit-Yi , de Lucia Chiara , Lucassen Paul J. , Thuret Sandrine , Korosi Aniko
Published: July 2021

There are sex differences in metabolic disease risk, and early-life stress (ES) increases the risk to develop such diseases, potentially in a sex-specific manner. It remains to be understood, however, how sex and ES affect such metabolic vulnerability. The hypothalamus regulates food intake and energy expenditure by sensing the organism’s energy state via metabolic hormones (leptin, insulin, ghrelin) and nutrients (glucose, fatty acids). Here, we investigated if and how sex and ES alter hypothalamic nutrient sensing short and long-term. ES was induced in mice by limiting the bedding and nesting material from postnatal day (P)2-P9, and the expression of genes critical for hypothalamic nutrient sensing were studied in male and female offspring, both at P9 and in adulthood (P180). At P9, we observed a sex difference in both Ppargc1a and Lepr expression, while the latter was also increased in ES-exposed animals relative to controls. In adulthood, we found sex differences in Acacb, Agrp, and Npy expression, whereas ES did not affect the expression of genes involved in hypothalamic nutrient sensing. Thus, we observe a pervasive sex difference in nutrient sensing pathways and a targeted modulation of this pathway by ES early in life. Future research is needed to address if the modulation of these pathways by sex and ES is involved in the differential vulnerability to metabolic diseases.