bluuebunny/crossref_metadata_2025 huggingface dataset:
Restoration of Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice
Authors: Qaisar Rizwan , Pharaoh Gavin , Bhaskaran Shylesh , Xu Hongyang , Ranjit Rojina , Bian Jan , Ahn Bumsoo , Georgescu Constantin , Wren Jonathan D. , Van Remmen Holly
Published: December 2020

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction.
The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia
Authors: Koch Mirja , Scheel Constanze , Ma Hongwei , Yang Fan , Stadlmeier Michael , Glück Andrea F. , Murenu Elisa , Traube Franziska R. , Carell Thomas , Biel Martin , Ding Xi-Qin , Michalakis Stylianos
Published: December 2020

Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the Cnga3 knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in Cnga3 KO mice. Virus-mediated knockdown or genetic ablation of Prkg2 in Cnga3 KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in Cnga3 KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies.
Mechanical Stability of a Small, Highly-Luminescent Engineered Protein NanoLuc
Authors: Ding Yue , Apostolidou Dimitra , Marszalek Piotr
Published: December 2020

NanoLuc is a bioluminescent protein recently engineered for applications in molecular imaging and cellular reporter assays. Compared to other bioluminescent proteins used for these applications, like Firefly Luciferase and Renilla Luciferase, it is ~150 times brighter, more thermally stable, and smaller. Yet, no information is known with regards to its mechanical properties, which could introduce a new set of applications for this unique protein, such as a novel biomaterial or as a substrate for protein activity/refolding assays. Here, we generated a synthetic NanoLuc derivative protein that consists of three connected NanoLuc proteins flanked by two human titin I91 domains on each side and present our mechanical studies at the single molecule level by performing Single Molecule Force Spectroscopy (SMFS) measurements. Our results show each NanoLuc repeat in the derivative behaves as a single domain protein, with a single unfolding event occurring on average when approximately 72 pN is applied to the protein. Additionally, we performed cyclic measurements, where the forces applied to a single protein were cyclically raised then lowered to allow the protein the opportunity to refold: we observed the protein was able to refold to its correct structure after mechanical denaturation only 16.9% of the time, while another 26.9% of the time there was evidence of protein misfolding to a potentially non-functional conformation. These results show that NanoLuc is a mechanically moderately weak protein that is unable to robustly refold itself correctly when stretch-denatured, which makes it an attractive model for future protein folding and misfolding studies.
Identifying the p65-Dependent Effect of Sulforaphene on Esophageal Squamous Cell Carcinoma Progression via Bioinformatics Analysis
Authors: Han Sichong , Wang Zhe , Liu Jining , Yuan Qipeng
Published: December 2020

Understanding the mechanism by which sulforaphene (SFE) affects esophageal squamous cell carcinoma (ESCC) contributes to the application of this isothiocyanate as a chemotherapeutic agent. Thus, we attempted to investigate SFE regulation of ESCC characteristics more deeply. We performed gene set enrichment analysis (GSEA) on microarray data of SFE-treated ESCC cells and found that differentially expressed genes are enriched in TNFα_Signaling_via_the_NFκB_Pathway. Coupled with the expression profile data from the GSE20347 and GSE75241 datasets, we narrowed the set to 8 genes, 4 of which (C-X-C motif chemokine ligand 10 (CXCL10), TNF alpha induced protein 3 (TNFAIP3), inhibin subunit beta A (INHBA), and plasminogen activator, urokinase (PLAU)) were verified as the targets of SFE. RNA-sequence (RNA-seq) data of 182 ESCC samples from The Cancer Genome Atlas (TCGA) were grouped into two phenotypes for GSEA according to the expression of CXCL10, TNFAIP3, INHBA, and PLAU. The enrichment results proved that they were all involved in the NFκB pathway. ChIP-seq analyses obtained from the Cistrome database indicated that NFκB-p65 is likely to control the transcription of CXCL10, TNFAIP3, INHBA, and PLAU, and considering TNFAIP3 and PLAU are the most significantly differentially expressed genes, we used chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) to verify the regulation of p65 on their expression. The results demonstrated that SFE suppresses ESCC progression by down-regulating TNFAIP3 and PLAU expression in a p65-dependent manner.
Blood–Nerve Barrier (BNB) Pathology in Diabetic Peripheral Neuropathy and In Vitro Human BNB Model
Authors: Takeshita Yukio , Sato Ryota , Kanda Takashi
Published: December 2020

In diabetic peripheral neuropathy (DPN), metabolic disorder by hyperglycemia progresses in peripheral nerves. In addition to the direct damage to peripheral neural axons, the homeostatic mechanism of peripheral nerves is disrupted by dysfunction of the blood–nerve barrier (BNB) and Schwann cells. The disruption of the BNB, which is a crucial factor in DPN development and exacerbation, causes axonal degeneration via various pathways. Although many reports revealed that hyperglycemia and other important factors, such as dyslipidemia-induced dysfunction of Schwann cells, contributed to DPN, the molecular mechanisms underlying BNB disruption have not been sufficiently elucidated, mainly because of the lack of in vitro studies owing to difficulties in establishing human cell lines from vascular endothelial cells and pericytes that form the BNB. We have developed, for the first time, temperature-sensitive immortalized cell lines of vascular endothelial cells and pericytes originating from the BNB of human sciatic nerves, and we have elucidated the disruption to the BNB mainly in response to advanced glycation end products in DPN. Recently, we succeeded in developing an in vitro BNB model to reflect the anatomical characteristics of the BNB using cell sheet engineering, and we established immortalized cell lines originating from the human BNB. In this article, we review the pathologic evidence of the pathology of DPN in terms of BNB disruption, and we introduce the current in vitro BNB models.
Role of microRNAs in Pressure Ulcer Immune Response, Pathogenesis, and Treatment
Authors: Niemiec Stephen M. , Louiselle Amanda E. , Liechty Kenneth W. , Zgheib Carlos
Published: December 2020

Pressure ulcers are preventable, yet highly prevalent, chronic wounds that have significant patient morbidity and high healthcare costs. Like other chronic wounds, they are characterized by impaired wound healing due to dysregulated immune processes. This review will highlight key biochemical pathways in the pathogenesis of pressure injury and how this signaling leads to impaired wound healing. This review is the first to comprehensively describe the current literature on microRNA (miRNA, miR) regulation of pressure ulcer pathophysiology.
Mitochondrial Mechanisms of Necroptosis in Liver Diseases
Authors: Xue Chen , Gu Xinyu , Li Ganglei , Bao Zhengyi , Li Lanjuan
Published: December 2020

Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease. Necroptosis is a common form of programmed cell death in the liver. Necroptosis can be activated by ligands of death receptors, which then interact with receptor-interactive protein kinases 1 (RIPK1). RIPK1 mediates receptor interacting receptor-interactive protein kinases 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) and necrosome formation. Regarding the molecular mechanisms of mitochondrial-mediated necroptosis, the RIPK1/RIPK3/MLKL necrosome complex can enhance oxidative respiration and generate reactive oxygen species, which can be a crucial factor in the susceptibility of cells to necroptosis. The necrosome complex is also linked to mitochondrial components such as phosphoglycerate mutase family member 5 (PGAM5), metabolic enzymes in the mitochondrial matrix, mitochondrial permeability protein, and cyclophilin D. In this review, we focus on the role of mitochondria-mediated cell necroptosis in acute liver injury, chronic liver diseases, and hepatocellular carcinoma, and its possible translation into clinical applications.
Urea-Peptide Hybrids as VEGF-A165/NRP-1 Complex Inhibitors with Improved Receptor Affinity and Biological Properties
Authors: Puszko Anna K. , Sosnowski Piotr , Rignault-Bricard Rachel , Hermine Olivier , Hopfgartner Gérard , Pułka-Ziach Karolina , Lepelletier Yves , Misicka Aleksandra
Published: December 2020

Neuropilin-1 (NRP-1), the major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2), may also independently act with VEGF-A165 to stimulate tumour growth and metastasis. Therefore, there is great interest in compounds that can block VEGF-A165/NRP-1 interaction. Peptidomimetic type inhibitors represent a promising strategy in the treatment of NRP-1-related disorders. Here, we present the synthesis, affinity, enzymatic stability, molecular modeling and in vitro binding evaluation of the branched urea–peptide hybrids, based on our previously reported Lys(hArg)-Dab-Oic-Arg active sequence, where the Lys(hArg) branching has been modified by introducing urea units to replace the peptide bond at various positions. One of the resulting hybrids increased the affinity of the compound for NRP-1 more than 10-fold, while simultaneously improving resistance for proteolytic stability in serum. In addition, ligand binding to NRP-1 induced rapid protein stock exocytotic trafficking to the plasma membrane in breast cancer cells. Examined properties characterize this compound as a good candidate for further development of VEGF165/NRP-1 inhibitors.
The Many Faces of CD4+ T Cells: Immunological and Structural Characteristics
Authors: Chatzileontiadou Demetra S. M. , Sloane Hannah , Nguyen Andrea T. , Gras Stephanie , Grant Emma J.
Published: December 2020

As a major arm of the cellular immune response, CD4+ T cells are important in the control and clearance of infections. Primarily described as helpers, CD4+ T cells play an integral role in the development and activation of B cells and CD8+ T cells. CD4+ T cells are incredibly heterogeneous, and can be divided into six main lineages based on distinct profiles, namely T helper 1, 2, 17 and 22 (Th1, Th2, Th17, Th22), regulatory T cells (Treg) and T follicular helper cells (Tfh). Recent advances in structural biology have allowed for a detailed characterisation of the molecular mechanisms that drive CD4+ T cell recognition. In this review, we discuss the defining features of the main human CD4+ T cell lineages and their role in immunity, as well as their structural characteristics underlying their detection of pathogens.
The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potential in Oncology: Third Time’s a Charm
Authors: Lecocq Quentin , Keyaerts Marleen , Devoogdt Nick , Breckpot Karine
Published: December 2020

The blockade of immune checkpoints (ICPs), such as cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed death-1 (PD-1) and its ligand (PD-L1), has propelled the field of immuno-oncology into its current era. Drugs targeting these ICPs have improved clinical outcome in a number of patients with solid and hematological cancers. Nonetheless, some patients have no benefit from these ICP-blocking therapies. This observation has instigated research into alternative pathways that are responsible for the escape of cancer cells from anti-cancer immune responses. From this research, a number of molecules have emerged as promising therapeutic targets, including lymphocyte activating gene-3 (LAG-3), a next-generation ICP. We will review the current knowledge on the biological activity of LAG-3 and linked herewith its expression on activated immune cells. Moreover, we will discuss the prognostic value of LAG-3 and how LAG-3 expression in tumors can be monitored, which is an aspect that is of utmost importance, as the blockade of LAG-3 is actively pursued in clinical trials.
Correction: Cao, Z., et al. The Expression and Functional Significance of Runx2 in Hepatocellular Carcinoma: Its Role in Vasculogenic Mimicry and Epithelial—Mesenchymal Transition. Int. J. Mol. Sci. 2017, 18, 500
Authors: Cao Zi , Sun Baocun , Zhao Xiulan , Zhang Yanhui , Gu Qiang , Liang Xiaohui , Dong Xueyi , Zhao Nan
Published: December 2020

The author wishes to make the following corrections to this paper [...]
Alterations in the Genomic Distribution of 5hmC in In Vivo Aged Human Skin Fibroblasts
Authors: Kołodziej-Wojnar Paulina , Borkowska Joanna , Wicik Zofia , Domaszewska-Szostek Anna , Połosak Jacek , Cąkała-Jakimowicz Marta , Bujanowska Olga , Puzianowska-Kuznicka Monika
Published: December 2020

5-Hydroxymethylcytosine (5hmC) is a functionally active epigenetic modification. We analyzed whether changes in DNA 5-hydroxymethylation are an element of age-related epigenetic drift. We tested primary fibroblast cultures originating from individuals aged 22–35 years and 74–94 years. Global quantities of methylation-related DNA modifications were estimated by the dot blot and colorimetric methods. Regions of the genome differentially hydroxymethylated with age (DHMRs) were identified by hMeDIP-seq and the MEDIPS and DiffBind algorithms. Global levels of DNA modifications were not associated with age. We identified numerous DHMRs that were enriched within introns and intergenic regions and most commonly associated with the H3K4me1 histone mark, promoter-flanking regions, and CCCTC-binding factor (CTCF) binding sites. However, only seven DHMRs were identified by both algorithms and all of their settings. Among them, hypo-hydroxymethylated DHMR in the intron of Rab Escort Protein 1 (CHM) coexisted with increased expression in old cells, while increased 5-hydroxymethylation in the bodies of Arginine and Serine Rich Protein 1 (RSRP1) and Mitochondrial Poly(A) Polymerase (MTPAP) did not change their expression. These age-related differences were not associated with changes in the expression of any of the ten-eleven translocation (TET) enzymes or their activity. In conclusion, the distribution of 5hmC in DNA of in vivo aged human fibroblasts underwent age-associated modifications. The identified DHMRs are, likely, marker changes.
Ordinary Gasoline Emissions Induce a Toxic Response in Bronchial Cells Grown at Air-Liquid Interface
Authors: Cervena Tereza , Vojtisek-Lom Michal , Vrbova Kristyna , Ambroz Antonin , Novakova Zuzana , Elzeinova Fatima , Sima Michal , Beranek Vit , Pechout Martin , Macoun David , Klema Jiri , Rossnerova Andrea , Ciganek Miroslav , Topinka Jan , Rossner Pavel
Published: December 2020

Gasoline engine emissions have been classified as possibly carcinogenic to humans and represent a significant health risk. In this study, we used MucilAir™, a three-dimensional (3D) model of the human airway, and BEAS-2B, cells originating from the human bronchial epithelium, grown at the air-liquid interface to assess the toxicity of ordinary gasoline exhaust produced by a direct injection spark ignition engine. The transepithelial electrical resistance (TEER), production of mucin, and lactate dehydrogenase (LDH) and adenylate kinase (AK) activities were analyzed after one day and five days of exposure. The induction of double-stranded DNA breaks was measured by the detection of histone H2AX phosphorylation. Next-generation sequencing was used to analyze the modulation of expression of the relevant 370 genes. The exposure to gasoline emissions affected the integrity, as well as LDH and AK leakage in the 3D model, particularly after longer exposure periods. Mucin production was mostly decreased with the exception of longer BEAS-2B treatment, for which a significant increase was detected. DNA damage was detected after five days of exposure in the 3D model, but not in BEAS-2B cells. The expression of CYP1A1 and GSTA3 was modulated in MucilAir™ tissues after 5 days of treatment. In BEAS-2B cells, the expression of 39 mRNAs was affected after short exposure, most of them were upregulated. The five days of exposure modulated the expression of 11 genes in this cell line. In conclusion, the ordinary gasoline emissions induced a toxic response in MucilAir™. In BEAS-2B cells, the biological response was less pronounced, mostly limited to gene expression changes.
Lack of GABARAP-Type Proteins Is Accompanied by Altered Golgi Morphology and Surfaceome Composition
Authors: Sanwald Julia L. , Dobner Jochen , Simons Indra M. , Poschmann Gereon , Stühler Kai , Üffing Alina , Hoffmann Silke , Willbold Dieter
Published: December 2020

GABARAP (γ-aminobutyric acid type A receptor-associated protein) and its paralogues GABARAPL1 and GABARAPL2 comprise a subfamily of autophagy-related Atg8 proteins. They are studied extensively regarding their roles during autophagy. Originally, however, especially GABARAPL2 was discovered to be involved in intra-Golgi transport and homotypic fusion of post-mitotic Golgi fragments. Recently, a broader function of mammalian Atg8s on membrane trafficking through interaction with various soluble N-ethylmaleimide-sensitive factor-attachment protein receptors (SNAREs) was suggested. By immunostaining and microscopic analysis of the Golgi network, we demonstrate the importance of the presence of individual GABARAP-type proteins on Golgi morphology. Furthermore, triple knockout (TKO) cells lacking the whole GABARAP subfamily showed impaired Golgi-dependent vesicular trafficking as assessed by imaging of fluorescently labelled ceramide. With the Golgi apparatus being central within the secretory pathway, we sought to investigate the role of the GABARAP-type proteins for cell surface protein trafficking. By analysing the surfaceome composition of TKOs, we identified a subset of cell surface proteins with altered plasma membrane localisation. Taken together, we provide novel insights into an underrated aspect of autophagy-independent functions of the GABARAP subfamily and recommend considering the potential impact of GABARAP subfamily proteins on a plethora of processes during experimental analysis of GABARAP-deficient cells not only in the autophagic context.
Extracellular Vesicles-Encapsulated Yeast Prions and What They Can Tell Us about the Physical Nature of Propagons
Authors: Kabani Mehdi
Published: December 2020

The yeast Saccharomyces cerevisiae hosts an ensemble of protein-based heritable traits, most of which result from the conversion of structurally and functionally diverse cytoplasmic proteins into prion forms. Among these, [PSI+], [URE3] and [PIN+] are the most well-documented prions and arise from the assembly of Sup35p, Ure2p and Rnq1p, respectively, into insoluble fibrillar assemblies. Yeast prions propagate by molecular chaperone-mediated fragmentation of these aggregates, which generates small self-templating seeds, or propagons. The exact molecular nature of propagons and how they are faithfully transmitted from mother to daughter cells despite spatial protein quality control are not fully understood. In [PSI+] cells, Sup35p forms detergent-resistant assemblies detectable on agarose gels under semi-denaturant conditions and cytosolic fluorescent puncta when the protein is fused to green fluorescent protein (GFP); yet, these macroscopic manifestations of [PSI+] do not fully correlate with the infectivity measured during growth by the mean of protein infection assays. We also discovered that significant amounts of infectious Sup35p particles are exported via extracellular (EV) and periplasmic (PV) vesicles in a growth phase and glucose-dependent manner. In the present review, I discuss how these vesicles may be a source of actual propagons and a suitable vehicle for their transmission to the bud.
The Spatial Analysis of the Malicious Uniform Resource Locators (URLs): 2016 Dataset Case Study
Authors: Amin Raid W. , Sevil Hakki Erhan , Kocak Salih , Francia Guillermo , Hoover Philip
Published: December 2020

In this study, we aimed to identify spatial clusters of countries with high rates of cyber attacks directed at other countries. The cyber attack dataset was obtained from Canadian Institute for Cybersecurity, with over 110,000 Uniform Resource Locators (URLs), which were classified into one of 5 categories: benign, phishing, malware, spam, or defacement. The disease surveillance software SaTScanTM was used to perform a spatial analysis of the country of origin for each cyber attack. It allowed the identification of spatial and space-time clusters of locations with unusually high counts or rates of cyber attacks. Number of internet users per country obtained from the 2016 CIA World Factbook was used as the population baseline for computing rates and Poisson analysis in SaTScanTM. The clusters were tested for significance with a Monte Carlo study within SaTScanTM, where any cluster with p < 0.05 was designated as a significant cyber attack cluster. Results using the rate of the different types of malicious URL cyber attacks are presented in this paper. This novel approach of studying cyber attacks from a spatial perspective provides an invaluable relative risk assessment for each type of cyber attack that originated from a particular country.
Tracing the Invasion and Expansion Characteristics of the Flatid Planthopper, Metcalfa pruinosa (Hemiptera: Flatidae), in Korea Using Mitochondrial DNA Sequences
Authors: Lee Keon Hee , Jeong Jun Seong , Park Jeong Sun , Kim Min Jee , Jeong Na Ra , Jeong Su Yeon , Lee Gwan Seok , Lee Wonhoon , Kim Iksoo
Published: December 2020

The flatid planthopper, Metcalfa pruinosa (Hemiptera: Flatidae), which is an invasive species, is widespread in Korea. We sequenced a fragment of the COI from 536 individuals collected mainly in Korea and the European countries and combined these sequence data with the public data, totaling 830 individuals worldwide. The identification of one shared haplotype only between Korea and the USA, the presence of this haplotype only in the North-West region of Korea, and the highest haplotype diversity in this region suggested that the North-West region is another point of entry in addition to the South-East region, which is the presumed sole point of entry to Korea. Furthermore, it suggested that North-West entry involves the M. pruinosa originating from the USA. In an effort to find further variable regions in the mitochondrial genome, one region provided substantially increased variability compared to that of the fragment of COI. FST estimation, PCoA, and BAPS analysis, using the concatenated sequences of COI and the newly detected variable region to infer the expansion pattern in Korea, indicates that the main highway, running obliquely between the North-West and South-East regions, appears to be responsible for the current population genetic structure of M. pruinosa in Korea, facilitating gene flow through this highway traffic.
Polycystic Ovary Syndrome: Familiar to Millions?
Authors: Ott Johannes
Published: December 2020

Often, articles about polycystic ovary syndrome (PCOS) start with information about the condition’s high prevalence, the basic characteristics that define this endocrine disorder, and the manifold somatic and/or psychological consequences [...]
Gut Bacterial Dysbiosis in Children with Intractable Epilepsy
Authors: Lee Kihyun , Kim Namil , Shim Jung Ok , Kim Gun-Ha
Published: December 2020

A few published clinical studies have evaluated the association between gut microbiota in intractable epilepsy, but with inconsistent results. We hypothesized that the factors associated with the gut bacterial composition, such as age and geography, contributed to the discrepancies. Therefore, we used a cohort that was designed to minimize the effects of possible confounding factors and compared the gut microbiota between children with intractable epilepsy and healthy controls. Eight children with intractable epilepsy aged 1 to 7 years and 32 age-matched healthy participants were included. We collected stool samples and questionnaires on their diet and bowel habits at two time points and analyzed the gut microbiota compositions. In the epilepsy group, the amount of Bacteroidetes was lower (Mann–Whitney test, false discovery rate (FDR) < 0.01) and the amount of Actinobacteria was higher (FDR < 0.01) than in the healthy group. The epilepsy subjects were 1.6- to 1.7-fold lower in microbiota richness indices (FDR < 0.01) and harbored a distinct species composition (p < 0.01) compared to the healthy controls. Species biomarkers for intractable epilepsy included the Enterococcus faecium group, Bifidobacterium longum group, and Eggerthella lenta, while the strongest functional biomarker was the ATP-binding cassette (ABC) transporter. Our study identified gut bacterial dysbiosis associated with intractable epilepsy within the cohort that was controlled for the factors that could affect the gut microbiota.
Longitudinal Outcomes in Octogenarian Critically Ill Patients with a Focus on Frailty and Cardiac Surgery
Authors: Hill Aileen , Heyland Daren K. , Rossaint Rolf , Arora Rakesh C. , Engelman Daniel T. , Day Andrew G. , Stoppe Christian
Published: December 2020

Cardiac surgery (CSX) can be lifesaving in elderly patients (age ≥ 80 years) but may still be associated with complications and functional decline. Frailty represents a determinant to outcomes in critically ill patients, but little is known about its influence on elderly CSX-patients. This is a secondary exploratory analysis of a multi-center, prospective observational cohort study of 610 elderly patients admitted to the ICU and followed for one year to document long-term outcomes. CSX-ICU-patients (n = 49) were compared to surgical ICU patients (n = 184) with regard to demographics, frailty, and outcomes. Of all surgical patients, 102 (43%) were considered vulnerable or frail. The subdistribution hazard ratio (SHR) of time to discharge home (TTDH) for vulnerable/frail vs. fit/well patients was 0.54 (95% confidence interval (CI), 0.34, 0.86, p = 0.007). The p-value for effect modification between surgery group (CSX vs. surgical ICU patients) and Clinical Frailty Scale (CFS) group was not significant (p = 0.37) suggesting that the observed difference in the CFS effect between the CSX and surgical ICU patients is consistent with random error. A further subgroup analysis shows that among surgical ICU patients, the SHR of time to discharge home (TTDH) for vulnerable/frail vs. fit/well patients was 0.49 (95% CI, 0.29, 0.83) while the corresponding SHR for CSX patients was 0.77 (0.32–1.88). In conclusion, preoperative frailty reduced the rate of discharge to home in both surgical and CSX patients, but a larger sample of CSX patients is needed to adequately address this question in this patient group.
Cannabis Use, Cannabis Use Disorder, and Comorbid Psychiatric Illness: A Narrative Review
Authors: Hasin Deborah , Walsh Claire
Published: December 2020

Background: The landscape of attitudes, legal status and patterns of use of cannabis is rapidly changing in the United States and elsewhere. Therefore, the primary aim of this narrative review is to provide a concise overview of the literature on the comorbidity of cannabis use and cannabis use disorder (CUD) with other substance use and psychiatric disorders, and to use this information to accurately guide future directions for the field. Methods: A literature review of PubMed was conducted for studies relating to cannabis use, CUD, and a co-occurring psychiatric disorder. To provide an overview of representative data, the literature review focused on national-level, population-based work from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and National Survey on Drug Use and Health (NSDUH) surveys. Considering rapidly changing cannabis laws, recent (past five-year) studies were addressed. Results: A strong body of literature shows associations between cannabis use and CUD with other drug use, psychosis, mood disorders, anxiety disorders, and personality disorders. The strongest evidence of a potential causal relationship exists between cannabis use and psychotic disorders. While some evidence shows potential directionality between cannabis use and mood and anxiety disorders, results are inconsistent. Studies have established higher rates of CUD among those with personality disorders, but little about the specifics of this relationship is understood. Conclusions: Although the general population in the United States increasingly perceives cannabis to be a harmless substance, empirical evidence shows that cannabis use is associated both with CUD and comorbid psychiatric illness. However, there is mixed evidence regarding the role of cannabis in the etiology, course, and prognosis of a co-occurring disorder across all categories of psychiatric disorders. Future research should expand on the existing body of literature with representative, longitudinal data, in order to better understand the acute and long-term effects of cannabis on comorbid psychiatric illness.
Pharmacological and Parenteral Nutrition-Based Interventions in Microvillus Inclusion Disease
Authors: Leng Changsen , Rings Edmond H. H. M. , de Wildt Saskia N. , van IJzendoorn Sven C. D.
Published: December 2020

Microvillus inclusion disease (MVID) is a rare inherited and invariably fatal enteropathy, characterized by severe intractable secretory diarrhea and nutrient malabsorption. No cure exists, and patients typically die during infancy because of treatment-related complications. The need for alternative treatment strategies is evident. Several pharmacological interventions with variable successes have been tried and reported for individual patients as part of their clinical care. Unfortunately, these interventions and their outcomes have remained hidden in case reports and have not been reviewed. Further, recent advances regarding MVID pathogenesis have shed new light on the outcomes of these pharmacological interventions and offer suggestions for future clinical research and trials. Hence, an inventory of reported pharmacological interventions in MVID, their rationales and outcomes, and a discussion of these in the light of current knowledge is opportune. Together with a discussion on MVID-specific pharmacokinetic, -dynamic, and -genetic concerns that pose unique challenges regarding pharmacological strategies, we envision that this paper will aid researchers and clinicians in their efforts to develop pharmacological interventions to combat this devastating disease.
Cyanobacterial Extracellular Polymeric Substances for Heavy Metal Removal: A Mini Review
Authors: Yadav Ajit Pratap Singh , Dwivedi Vinay , Kumar Satyendra , Kushwaha Anamika , Goswami Lalit , Reddy Bezawada Sridhar
Published: December 2020

Heavy metals from various natural and anthropogenic sources are becoming a chief threat to the aquatic system owing to their toxic and lethal effect. The treatment of such contaminated wastewater is one of the prime concerns in this field. For decades, a huge array of innovative biosorbents is used for heavy metal removal. Though extensive microbes and their biomolecules have been experimented and have showed great potential but most of them have failed to have the substantial breakthrough for the practical application. The present review emphasis on the potential utilization of the cyanobacteria for the heavy metal removal along with the toxic effect imposed by the pollutant. Furthermore, the effect of significant parameters, plausible mechanistic insights of the heavy metal toxicity imposed onto the cyanobacteria is also discussed in detail. The role of extrapolymeric substances and metallothionein secreted by the microbes are also elaborated. The review was evident that the cyanobacterial species have a huge potential towards the heavy metal removal from the aqueous system ranging from very low to very high concentrations.
Polymorphisms within the TNFSF4 and MAPKAPK2 Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium
Authors: Sánchez-Maldonado Jose Manuel , Moñiz-Díez Ana , ter Horst Rob , Campa Daniele , Cabrera-Serrano Antonio José , Martínez-Bueno Manuel , Garrido-Collado María del Pilar , Hernández-Mohedo Francisca , Fernández-Puerta Laura , López-Nevot Miguel Ángel , Cunha Cristina , González-Sierra Pedro Antonio , Springer Jan , Lackner Michaela , Alcazar-Fuoli Laura , Fianchi Luana , Aguado José María , Pagano Livio , López-Fernández Elisa , Clavero Esther , Potenza Leonardo , Luppi Mario , Moratalla Lucia , Solano Carlos , Sampedro Antonio , Cuenca-Estrella Manuel , Lass-Flörl Cornelia ,   PCRAGA Study Group, Canzian Federico , Loeffler Juergen , Li Yang , Einsele Hermann , Netea Mihai G. , Vázquez Lourdes , Carvalho Agostinho , Jurado Manuel , Sainz Juan
Published: December 2020

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.
Ionizing Radiation Protein Biomarkers in Normal Tissue and Their Correlation to Radiosensitivity: Protocol for a Systematic Review
Authors: Dietz Anne , Gomolka Maria , Moertl Simone , Subedi Prabal
Published: December 2020

Background: Radiosensitivity is a significantly enhanced reaction of cells, tissues, organs or organisms to ionizing radiation (IR). During radiotherapy, surrounding normal tissue radiosensitivity often limits the radiation dose that can be applied to the tumour, resulting in suboptimal tumour control or adverse effects on the life quality of survivors. Predicting radiosensitivity is a component of personalized medicine, which will help medical professionals allocate radiation therapy decisions for effective tumour treatment. So far, there are no reviews of the current literature that explore the relationship between proteomic changes after IR exposure and normal tissue radiosensitivity systematically. Objectives: The main objective of this protocol is to specify the search and evaluation strategy for a forthcoming systematic review (SR) dealing with the effects of in vivo and in vitro IR exposure on the proteome of human normal tissue with focus on radiosensitivity. Methods: The SR framework has been developed following the guidelines established in the National Toxicology Program/Office of Health Assessment and Translation (NTP/OHAT) Handbook for Conducting a Literature-Based Health Assessment, which provides a standardised methodology to implement the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to environmental health assessments. The protocol will be registered in PROSPERO, an open source protocol registration system, to guarantee transparency. Eligibility criteria: Only experimental studies, in vivo and in vitro, investigating effects of ionizing radiation on the proteome of human normal tissue correlated with radio sensitivity will be included. Eligible studies will include English peer reviewed articles with publication dates from 2011–2020 which are sources of primary data. Information sources: The search strings will be applied to the scientific literature databases PubMed and Web of Science. The reference lists of included studies will also be manually searched. Data extraction and results: Data will be extracted according to a pre-defined modality and compiled in a narrative report following guidelines presented as a “Synthesis without Meta-analyses” method. Risk of bias: The risk of bias will be assessed based on the NTP/OHAT risk of bias rating tool for human and animal studies (OHAT 2019). Level of evidence rating: A comprehensive assessment of the quality of evidence for both in vivo and in vitro studies will be followed, by assigning a confidence rating to the literature. This is followed by translation into a rating on the level of evidence (high, moderate, low, or inadequate) regarding the research question. Registration: PROSPERO Submission ID 220064.
The Relict Ecosystem of Maytenus senegalensis subsp. europaea in an Agricultural Landscape: Past, Present and Future Scenarios
Authors: Mendoza-Fernández Antonio J. , Martínez-Hernández Fabián , Salmerón-Sánchez Esteban , Pérez-García Francisco J. , Teruel Blas , Merlo María E. , Mota Juan F.
Published: December 2020

Maytenus senegalensis subsp. europaea is a shrub belonging to the Celastraceae family, whose only European populations are distributed discontinuously along the south-eastern coast of the Iberian Peninsula, forming plant communities with great ecological value, unique in Europe. As it is an endangered species that makes up plant communities with great palaeoecological significance, the development of species distribution models is of major interest under different climatic scenarios, past, present and future, based on the fact that the climate could play a relevant role in the distribution of this species, as well as in the conformation of the communities in which it is integrated. Palaeoecological models were generated for the Maximum Interglacial, Last Maximum Glacial and Middle Holocene periods. The results obtained showed that the widest distribution of this species, and the maximum suitability of its habitat, occurred during the Last Glacial Maximum, when the temperatures of the peninsular southeast were not as contrasting as those of the rest of the European continent and were favored by higher rainfall. Under these conditions, large territories could act as shelters during the glacial period, a hypothesis reflected in the model’s results for this period, which exhibit a further expansion of M. europaea’s ecological niche. The future projection of models in around 2070, for four Representative Concentration Pathways according to the fifth report of the Intergovernmental Panel on Climate Change, showed that the most favorable areas for this species would be Campo de Dalías (southern portion of Almería province) as it presents the bioclimatic characteristics of greater adjustment to M. europaea’s ecological niche model. Currently, some of the largest specimens of the species survive in the agricultural landscapes in the southern Spain. These areas are almost totally destroyed and heavily altered by intensive agriculture greenhouses, also causing a severe fragmentation of the habitat, which implies a prospective extinction scenario in the near future.
Transition to Smart and Regenerative Urban Places (SRUP): Contributions to a New Conceptual Framework
Authors: Peponi Angeliki , Morgado Paulo
Published: December 2020

Modern urbanism is called to face current challenges ranging from intensive demographic growth, economic and social stagnation to resources salvation and climate changes. Under the broader scope of sustainability, we argue that the transition to a holistic perspective of smart and regenerative planning and design is the way to face and yet to prevent these urban challenges. In doing so, we adopt systematic thinking to study the complexity of urban metabolisms at an urban place scale, emphasizing the ongoing coevolution of social-cultural-technological and ecological processes. Focusing on urban places, we give a city or region the sense of a place of stability, security, cultural and social interactions, and a sense of uniqueness. We plan and design innovative urban places that improve the environment and the quality of urban life, able to adapt and mitigate climate changes and natural hazards, leverage community spirit, and power a green-based economy. Designing the conceptual framework of smart and regenerative urban places we contribute to the field of modern urban studies helping practitioners, policymakers, and decision-makers to vision and adopt more environmental-friendly policies and actions using a user-centered approach.
Numerical Simulation of Static Seal Contact Mechanics Including Hydrostatic Load at the Contacting Interface
Authors: Huang De , Yan Xiang , Larsson Roland , Almqvist Andreas
Published: December 2020

A finite element model of a static seal assembled in its housing has been built and is utilized to study how the seal deforms under varying loading conditions. The total contact load on the sealing surface is balanced by the sealed fluid pressure and the friction between the seal and the housing sidewall perpendicular to the sealing surface. The effect of the sealed fluid pressure between the sealing surfaces was investigated and the simulation showed that the surface profile is distorted due to the hydrostatic pressure. We study the distorted contact profile with varying sealed fluid pressure and propose five parameters to describe the corresponding contact pressure profile. One of these parameters, overshoot pressure, a measure of the difference between maximum contact pressure and the sealed fluid pressure, is an indicator of sealing performance. The simulations performed show different behaviors of the overshoot pressure with sealed fluid pressure for cosinusoidal and parabolic surfaces with the same peak to valley (PV) value.
Mechanical Behavior of GFRP Connection Using FRTP Rivets
Authors: Matsui Takayoshi , Matsushita Yoshiyuki , Matsumoto Yukihiro
Published: December 2020

In recent years, the application of fiber-reinforced plastics (FRPs) as structural members has been promoted. Metallic bolts and rivets are often used for the connection of FRP structures, but there are some problems caused by corrosion and stress concentration at the bearing position. Fiber-reinforced thermoplastics (FRTPs) have attracted attention in composite material fields because they can be remolded by heating and manufactured with excellent speed compared with thermosetting plastics. In this paper, we propose and evaluate the connection method using rivets produced of FRTPs for FRP members. It was confirmed through material tests that an FRTP rivet provides stable tensile, shear, and bending strength. Then, it was clarified that non-clearance connection could be achieved by the proposed connection method, so initial sliding was not observed, and connection strength linearly increased as the number of FRTP rivets increased through the double-lapped tensile shear tests. Furthermore, the joint strength of the beam using FRTP rivets could be calculated with high accuracy using the method for bolt joints in steel structures through a four-point beam bending test.
The Number of Subgrain Boundaries in the Airfoils of Heat-Treated Single-Crystalline Turbine Blades
Authors: Krawczyk Jacek , Bogdanowicz Włodzimierz , Sieniawski Jan
Published: December 2020

In the present study, the dendrites deflection mechanism from the mold walls were subjected to verification regarding its heat-treated turbine rotor blades. The number of macroscopic low-angle boundaries created on the cross-section of the blades’ airfoil near the tip was experimentally determined and compared to the number of low-angle boundaries calculated from a model based on the dendrites deflection mechanism. Based on the Laue patterns and geometrical parameters of airfoils, the number of low-angle boundaries occurring at the upper part of the blades airfoil after heat treatment was calculated. This number for the analyzed group of blades ranged from 5 to 9.