bluuebunny/crossref_metadata_2025 huggingface dataset:
The Potential Contribution of ABO, Lewis and Secretor Histo-Blood Group Carbohydrates in Infection by Toxoplasma gondii
Authors: De Mattos Luiz Carlos , Ferreira Ana Iara Costa , de Oliveira Karina Younan , Nakashima Fabiana , Brandão Cinara Cássia
Published: June 2021

The glycosyltransferases encoded by genes from the human ABO, Lewis, and Secretor histo-blood group systems synthesize part of the carbohydrate antigens in hematopoietic and non-hematopoietic tissues. The combined action of these glycosyltransferases strongly influences cell, tissue, mucosa, and exocrine secretion carbohydrate phenotypes, including those serving as habitat for mutualistic and pathogenic microorganisms. A set of reports investigated associations between Toxoplasma gondii infection and the ABO histo-blood group system, but the results are contradictory. As T. gondii uses the gastrointestinal tract as a route for infection, and in this organ, the expression of ABO, Lewis, and Secretor histo-blood group carbohydrates occurs, it is reasonable to suppose some biological relationship between them. This text reviewed association studies published in recent decades focusing on the potential contribution of the ABO, Lewis, and Secretor histo-blood group carbohydrates and infection by T. gondii.
Characterisation of Bacteriophage-Encoded Depolymerases Selective for Key Klebsiella pneumoniae Capsular Exopolysaccharides
Authors: Blundell-Hunter George , Enright Mark C. , Negus David , Dorman Matthew J. , Beecham Gemma E. , Pickard Derek J. , Wintachai Phitchayapak , Voravuthikunchai Supayang P. , Thomson Nicholas R. , Taylor Peter W.
Published: June 2021

Capsular polysaccharides enable clinically important clones of Klebsiella pneumoniae to cause severe systemic infections in susceptible hosts. Phage-encoded capsule depolymerases have the potential to provide an alternative treatment paradigm in patients when multiple drug resistance has eroded the efficacy of conventional antibiotic chemotherapy. An investigation of 164 K. pneumoniae from intensive care patients in Thailand revealed a large number of distinct K types in low abundance but four (K2, K51, K1, K10) with a frequency of at least 5%. To identify depolymerases with the capacity to degrade capsules associated with these common K-types, 62 lytic phage were isolated from Thai hospital sewage water using K1, K2 and K51 isolates as hosts; phage plaques, without exception, displayed halos indicative of the presence of capsule-degrading enzymes. Phage genomes ranged in size from 41–348 kb with between 50 and 535 predicted coding sequences (CDSs). Using a custom phage protein database we were successful in applying annotation to 30 - 70% (mean = 58%) of these CDSs. The largest genomes, of so-called jumbo phage, carried multiple tRNAs as well as CRISPR repeat and spacer sequences. One of the smaller phage genomes was found to contain a putative Cas type 1E gene, indicating a history of host DNA acquisition in these obligate lytic phage. Whole-genome sequencing (WGS) indicated that some phage displayed an extended host range due to the presence of multiple depolymerase genes; in total, 42 candidate depolymerase genes were identified with up to eight in a single genome. Seven distinct virions were selected for further investigation on the basis of host range, phage morphology and WGS. Candidate genes for K1, K2 and K51 depolymerases were expressed and purified as his6-tagged soluble protein and enzymatic activity demonstrated against K. pneumoniae capsular polysaccharides by gel electrophoresis and Anton-Paar rolling ball viscometry. Depolymerases completely removed the capsule in K-type-specific fashion from K. pneumoniae cells. We conclude that broad-host range phage carry multiple enzymes, each with the capacity to degrade a single K-type, and any future use of these enzymes as therapeutic agents will require enzyme cocktails for utility against a range of K. pneumoniae infections.
Is Fun For Wellness Engaging? Evaluation of User Experience of an Online Intervention to Promote Well-Being and Physical Activity
Authors: Scarpa Michael P. , Prilletensky Isaac , McMahon Adam , Myers Nicholas D. , Prilleltensky Ora , Lee Seungmin , Pfeiffer Karin A. , Bateman André G. , Brincks Ahnalee M.
Published: June 2021

Online well-being interventions demonstrate great promise in terms of both engagement and outcomes. Fun For Wellness (FFW) is a novel online intervention grounded in self-efficacy theory and intended to improve multidimensional well-being and physical activity through multi-modal methods. These strategies include capability-enhancing opportunities, learning experiences such as games, video vignettes, and self-assessments. RCT studies have suggested that FFW is efficacious in improving subjective and domain-specific well-being, and effective in improving mental health, physical health, physical activity, and self-efficacy in United States. adults who are overweight and in the general population. The present study uses qualitative and quantitative user experience data collected during two RCT trials to understand and evaluate engagement with FFW, its drivers, and its outcomes. Results suggest that FFW is enjoyable, moderately engaging, and easy to use; and contributes to positive outcomes including skill development and enhanced confidence, for both overweight individuals and the general adult population. Drivers of engagement appear to include rewards, gamification, scenario-based learning, visual tracking for self-monitoring, ease of use and simple communications, and the entertaining, interactive nature of program activities. Findings indicate that there are opportunities to streamline and simplify the experience. These results can help improve FFW and contribute to the science of engagement with online interventions designed to improve well-being.
Response of Peatland CO2 and CH4 Fluxes to Experimental Warming and the Carbon Balance
Authors: Li Qian , Gogo Sébastien , Leroy Fabien , Guimbaud Christophe , Laggoun-Défarge Fatima
Published: June 2021

The function of peatlands as a large carbon (C) reservoir results from the net C uptake under cold, wet, and acid environments. However, in the context of global warming, the balance between C input and release is expected to change, which may further alter the C sink of peatlands. To examine the response to climate warming of a temperate Sphagnum peatland which has been invaded by vascular plants, a mesocosm experiment was conducted with open top chambers (OTCs) to simulate a moderate temperature increase. Gross primary production (GPP), ecosystem respiration (ER), and methane (CH4) emissions were monitored for 2 years. The CO2 and CH4 fluxes were modeled by relating to abiotic and biotic factors, including temperature, water table depth (WTD), and vegetation, in order to calculate the annual C budget. Results showed that the annual cumulated GPP was significantly enhanced by the simulated warming (−602 compared to −501 gC m−2 yr−1 in OTC and control plots, respectively), mainly due to the increase of graminoid biomass by warming, while experimental warming had no significant effect on the annual ER and CH4 emissions (an output of 615 and 500 gC m−2 yr−1 for ER; 21 and 16 gC m−2 yr−1 for CH4 emissions in OTC and control plots, respectively). The annual NEE and C budget were not affected by the short-term experimental warming. The mesocosms under both treatments acted as a gaseous C source with 34 and 14 gC m−2 yr−1 output under OTC and control treatment, respectively. This C source was driven by the strong net carbon dioxide (CO2) release during a low WTD period in summer, as CH4 emissions only accounted for 0.9–2.2% of the total C fluxes. Our study identified the effect of moderate warming on the C fluxes, even on a short-term basis. Also, our findings highlighted that the response of C fluxes to warming largely depends on the WTD and vegetation composition. Thus, long-term monitoring of hydrology and vegetation change under climate warming is essential to examine their interactions in determining the C fluxes in peatlands.
School Professional Needs to Support Student Mental Health During the COVID-19 Pandemic
Authors: Rusch Amy , Rodriguez-Quintana Natalie , Choi Seo Youn , Lane Annalise , Smith Maureen , Koschmann Elizabeth , Smith Shawna N.
Published: June 2021

School closures due to COVID-19 left students in Michigan without physical access to school mental health professionals (SMHPs) and other supports typically available in schools. This report examines the needs of SMHPs across Michigan during the early months of the COVID-19 pandemic and how those needs informed programming and resources provided by a University of Michigan school mental health training and implementation program. In April 2020, a web-based survey asking about student and SMHP mental health was sent to 263 SMHPs who had previously participated in this program. 155 SMHPs (58.9%) responded. Nearly half of SMHPs reported their students’ most pressing needs were support for self-care, anxiety, depression, and traumatic stress. Some SMHPs also met screening criteria themselves for depression and/or anxiety. This survey provided an overview of SMHPs’ concerns early in the COVID-19 pandemic and drove development of new COVID-19-related resources designed to support SMHPs.
Testosterone Deficiency Is a Risk Factor for Severe COVID-19
Authors: Lanser Lukas , Burkert Francesco Robert , Thommes Lis , Egger Alexander , Hoermann Gregor , Kaser Susanne , Pinggera Germar Michael , Anliker Markus , Griesmacher Andrea , Weiss Günter , Bellmann-Weiler Rosa
Published: June 2021

Background

Male sex is related to increased COVID-19 severity and fatality although confirmed infections are similarly distributed between men and women. The aim of this retrospective analysis was to investigate the impact of sex hormones on disease progression and immune activation in men with COVID-19.

Patients and Methods

We studied for effects of sex hormones on disease severity and immune activation in 377 patients (230 men, 147 women) with PCR-confirmed SARS-CoV-2 infections hospitalized at the Innsbruck University Hospital between February and December 2020.

Results

Men had more severe COVID-19 with concomitant higher immune system activation upon hospital admission when compared to women. Men with a severe course of infection had lower serum total testosterone (tT) levels whereas luteinizing hormone (LH) and estradiol (E2) levels were within the normal range. tT deficiency was associated with elevated CRP (rs = - 0.567, p < 0.001), IL-6 levels (rs = - 0.563, p < 0.001), lower cholesterol levels (rs = 0.407, p < 0.001) and an increased morbidity and mortality. Men with tT levels < 100 ng/dL had a more than eighteen-fold higher in-hospital mortality risk (OR 18.243 [95%CI 2.301 – 144.639], p = 0.006) compared to men with tT levels > 230 ng/dL. Moreover, while morbidity and mortality showed a positive correlation with E2 levels at admission, we detected a negative correlation with the tT/E2 ratio upon hospital admission.

Conclusion

Hospitalized men with COVID-19 present with rather low testosterone levels linked to more advanced immune activation, severe clinical manifestations translating into an increased risk for ICU admission or death. The underlying mechanisms remain elusive but may include infection driven hypogonadism as well as inflammation mediated cholesterol reduction causing gonadotropin suppression and impaired androgen formation. Finally, in elderly late onset hypogonadism might also contribute to lower testosterone levels.
Litterfall Chemistry Is Modulated by Wet-Dry Seasonality and Leaf Phenology of Dominant Species in the Tropics
Authors: Tonin Alan M. , Lima Laís S. , Bambi Paulino , Figueiredo Monique L. , Rezende Renan S. , Gonçalves José F.
Published: June 2021

Litterfall has a large influence on carbon and nutrient cycling of ecosystems, particularly in light-limited forested streams, as most nutrients return in the form of litter. Although recent evidence points to the prevalence of seasonal litterfall in species-rich and evergreen tropical riparian forests, there is a limited understanding of how riparian plant diversity intersects with stream and riparian ecosystem functions. To explore this question, we investigate litterfall chemistry across wet and dry seasons and the congruence between litter traits and plant species composition of litterfall in the wet-dry tropics. Using generalized additive models, we observed consistent seasonal patterns of litterfall chemistry over 2 years, mostly influenced by dominant species in litterfall. While drier seasons showed litter lower in nutrients and structural compounds and higher in polyphenols, litter from wetter seasons were nutrient rich but lower in polyphenols. We also found contrasting seasonal patterns in litterfall chemistry, one showing that litterfall nutrient, structural compounds, and secondary metabolite concentrations declined in drier seasons while the other showed that mass-based litterfall inputs increased markedly in drier seasons. Our findings suggest that litterfall chemistry may be altered by shifts in the identity of dominant plant species and seasonality, possibly leading to changes in carbon and nutrient fluxes in tropical riparian ecosystems.
Patterns of Immune Infiltration in Endometriosis and Their Relationship to r-AFS Stages
Authors: Zhong Qiyu , Yang Fan , Chen Xiaochuan , Li Jinbo , Zhong Cailing , Chen Shuqin
Published: June 2021

Background: Endometriosis (EMS) is an estrogen-dependent disease in which endometrial glands and stroma arise outside the uterus. Current studies have suggested that the number and function of immune cells are abnormal in the abdominal fluid and ectopic lesion tissues of patients with EMS. The developed CIBERSORT method allows immune cell profiling by the deconvolution of gene expression microarray data.

Methods: By applying CIBERSORT, we assessed the relative proportions of immune cells in 68 normal endometrial tissues (NO), 112 eutopic endometrial tissues (EU) and 24 ectopic endometrial tissues (EC). The obtained immune cell profiles provided enumeration and activation status of 22 immune cell subtypes. We obtained associations between the immune cell environment and EMS r-AFS stages. Macrophages were evaluated by immunohistochemistry (IHC) in 60 patients with ovarian endometriomas.

Results: Total natural killer (NK) cells were significantly decreased in EC, while plasma cells and resting CD4 memory T cells were increased in EC. Total macrophages in EC were significantly increased compared to those of EU and NO, and M2 macrophages were the primary macrophages in EC. Compared to those of EC from patients with r-AFS stage I ~ II, M2 macrophages in EC from patients with stage III ~ IV were significantly increased. IHC experiments showed that total macrophages were increased in EC, with M2 macrophages being the primary subtype.

Conclusions: Our data demonstrate that deconvolution of gene expression data by CIBERSORT provides valuable information about immune cell composition in EMS.
Pembrolizumab-Induced Thyroiditis Shows PD-L1Expressing Histiocytes and Infiltrating T Cells in Thyroid Tissue - A Case Report
Authors: Jabkowski Jörg , Loidl Almute , Auinger Barbara , Kehrer Helmut , Sepp Norbert , Pichler Robert
Published: June 2021

Context

Immune-related adverse events frequently take place after initiation of immune checkpoint inhibitors (ICI) therapy. The thyroid gland is the endocrine organ most commonly affected by ICI therapy, the pathological mechanism is still poorly understood.

Case Description

A 60-year old Upper Austrian male melanoma patient under pembrolizumab therapy received thyroidectomy because of a suspicious FDG avid thyroid nodule. Histopathology showed a pattern comparable with thyroiditis de Quervain. The inflammatory process consisted predominantly of T lymphocytes with a dominance of CD4+ T helper cells. In addition CD68+ histiocytes co-expressing PD-L1 were observed.

Conclusion

Clusters of perifollicular histiocytes expressing PD-L1 were observed in this case of pembrolizumab induced thyroiditis - probably induced by the former ICI therapy. This finding might indicate the initial target for the breakdown of self tolerance. In context with other data the immunological process seems to be driven by CD3+ lymphocytes infiltrating the thyroid.
Molecular Level Characterization of Diatom and Coccolithophore-Associated Biopolymers That Are Binding 210Pb and 210Po in Seawater
Authors: Lin Peng , Xu Chen , Xing Wei , Santschi Peter H.
Published: June 2021

Through a combination of selective extractions and molecular characterization techniques including Isoelectric Focusing Chromatography and Electrospray Ionization Fourier-Transform Ion Cyclotron Resonance Mass spectrometry, molecular structures of diatom (Phaeodactylum tricornutum) and coccolithophore (Emiliania huxleyi)-associated biopolymers that are responsible for the distinct partitioning behavior between 210Pb and 210Po were determined. Our results show that diatom-derived biopolymers have distinctive elemental grouping distributions as compared to those excreted by the coccolithophore, with the former consisting of more heterogeneous elements (i.e., nitrogen, sulfur and phosphorus-containing organic compounds). For the coccolithophore culture, two 210Pb-enriched biopolymers (non-attached exopolymeric substances and coccosphere shell-associated biopolymers) have a higher abundance of CHO-type compounds, suggesting CHO-only-type compounds as the main binding moieties for 210Pb. In contrast, such association was not evident in the diatom culture. Different with 210Pb, 210Po enrichment in coccolithophore-derived attached exopolymeric substances and Fe-Mn-associated metabolites coincided with the higher abundance of nitrogen/sulfur-containing organic compounds in these two biopolymer fractions, suggesting the strong parallel of Po with the production of nitrogen-rich organic matter as well as sulfur-containing amino acids. These different associations between 210Pb/210Po and organic functional groups were further explored by separating 210Pb or 210Po-labeled coccolithophore-derived biopolymers via isoelectric focusing. This technique suggests that phosphate group-containing molecules but not the other molecules that contain heterogeneous elements (e.g., CHONS, CHON, and CHOS) as the strongest binding agents for 210Pb, while the more hydrophobic (high protein to carbohydrate ratio) nitrogen/sulfur-enriched organic moieties acted as the main 210Po-binding ligands. It is concluded that the deficiency of 210Po with respect to 210Pb can be influenced by the relative abundance of nitrogen/sulfur-enriched organic moieties to the nitrogen/sulfur-depleted organic compounds in the water column. This behavior constrains the application of 210Po-210Pb approach to quantify the particulate organic carbon (POC) export flux in the ocean. It also explains that differences in chemical binding of the 210Po as compared to those of other radionuclides (e.g., thorium-234) as the main factor. That suggests that differences in decay half-lives or physical factors are less important when these nuclides are applied to estimate the POC flux in the ocean.
Energy Down-Conversion Cs3Cu2Cl5 Nanocrystals for Boosting the Efficiency of UV Photodetector
Authors: Liu Chengjun , Wang Lixi , Fang Fan , Zhao Zihan , Pan Jiangyong , Akram Javed , Shafie Suhaidi Bin , Talaighil Razika Zair , Li Qing , Zhao Zhiwei , Wu Jun , Zhu Zhuoya , Lei Wei , Zhang Xiaobing , Chen Jing
Published: June 2021

Zero-dimension (0-D) lead halide perovskite nanocrystals (NCs) have attracted a sight of interest in the field of optoelectronic devices due to their outstanding properties, such as high photoluminescence quantum yield (PLQY) and size- and composition-controlled tunable emission wavelengths. However, the toxicity of lead (Pb) element in the lead perovskite NCs is the bottleneck for the commercial application of perovskite NCs. Herein, we report a facile ligand-assisted synthesis to achieve lead-free Cs3Cu2Cl5 NCs with a high PLQY of ∼70% and good stability against environmental oxygen/moisture as a promising down-conversion material. It has good merits of high PLQY and large Stokes shift (∼300 nm) originated from the effect of Jahn–Teller distortion and self-trapped excitons (STEs). Furthermore, the Cs3Cu2Cl5 NCs embedded composite films (NCCFs) were utilized to enhance the ultraviolet (UV) response of silicon (Si) photodetectors. External quantum efficiency (EQE) measurements show that the UV response can be greatly improved from 3.3 to 19.9% @ 295 nm based on NCCFs combined with Si photodiodes. Our work offers an effective approach to develop highly efficient and stable lead-free Cs3Cu2Cl5 NCs for the application in the solar-blind UV photodetector.
Clinical Aspects of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis With Severe Ocular Complications in Brazil
Authors: Wakamatsu Tais Hitomi , dos Santos Myrna Serapião , Barreiro Telma Pereira , Sant'Anna Ana Estela Besteti Pires Ponce , Murta Fabíola , da Costa Alexandre Xavier , Marculino Leonardo Guedes C. , de Alcântara Rafael Jorge Alves , de Farias Charles Costa , Gomes José Álvaro Pereira
Published: June 2021

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute and potentially fatal inflammatory vesiculobullous reactions that affect the skin and mucous membranes, and which are most often triggered by particular medications and infections. In Brazil, the drugs most frequently associated with TEN and SJS include cold medicine such as dipyrone and NSAIDs, followed by carbamazepine, phenobarbital, penicillin, and allopurinol. Genetic variations have been found to increase the risk of SJS/TEN in response to triggering factors such as medications. The most closely associated genes found in Brazilian cold-medicine-related SJS/TEN patients with severe ocular complications are HLA-A*66:01 in those of mixed African and European ancestry and HLA-B*44:03 and HLA-C*12:03 in those of solely European ancestry. Our classification system for grading ocular surface complication severity in SJS/TEN patients revealed the most severe complications to be limbal stem cell deficiency and dry eye. Changes to the conjunctival flora have also been observed in SJS/TEN patients. Our group identified bacterial colonization in 95% of the eyes (55.5% of which were gram-positive cocci, 25.5% of which were gram-negative bacilli, and 19% of which were gram-positive bacilli). Several new treatment options in the acute and chronic ocular management of the SJS/TEN patients have been described. This article highlights some Brazilian institutions' contributions to ocular surface care in both the acute phase (including the use of amniotic membrane transplantation) and the chronic phase (such as eyelid margin and fornix reconstruction, minor salivary gland transplantation, amniotic membrane and limbal transplantation, scleral contact lenses, anti-angiogenic eyedrops for corneal neovascularization, ex-vivo cultivated limbal epithelium transplantation, conjunctival-limbal autografting, oral mucosa transplantation, and keratoprosthesis).
Harnessing the Endogenous 2μ Plasmid of Saccharomyces cerevisiae for Pathway Construction
Authors: Yang Jing , Tian Yujuan , Liu Huayi , Kan Yeyi , Zhou Yi , Wang Ying , Luo Yunzi
Published: June 2021

pRS episomal plasmids are widely used in Saccharomyces cerevisiae, owing to their easy genetic manipulations and high plasmid copy numbers (PCNs). Nevertheless, their broader application is hampered by the instability of the pRS plasmids. In this study, we designed an episomal plasmid based on the endogenous 2μ plasmid with both improved stability and increased PCN, naming it p2μM, a 2μ-modified plasmid. In the p2μM plasmid, an insertion site between the REP1 promoter and RAF1 promoter was identified, where the replication (ori) of Escherichia coli and a selection marker gene of S. cerevisiae were inserted. As a proof of concept, the tyrosol biosynthetic pathway was constructed in the p2μM plasmid and in a pRS plasmid (pRS423). As a result, the p2μM plasmid presented lower plasmid loss rate than that of pRS423. Furthermore, higher tyrosol titers were achieved in S. cerevisiae harboring p2μM plasmid carrying the tyrosol pathway-related genes. Our study provided an improved genetic manipulation tool in S. cerevisiae for metabolic engineering applications, which may be widely applied for valuable product biosynthesis in yeast.
Diversity and Eco-Evolutionary Associations of Endosymbiotic Astome Ciliates With Their Lumbricid Earthworm Hosts
Authors: Obert Tomáš , Rurik Ivan , Vd’ačný Peter
Published: June 2021

Coevolution of endosymbionts with their hosts plays an important role in the processes of speciation and is among the most fascinating topics in evolutionary biology. Astome ciliates represent an interesting model for coevolutionary studies because they are so tightly associated with their host organisms that they completely lost the cell oral apparatus. In the present study, we used five nuclear markers (18S rRNA gene, ITS1–5.8S–ITS2 region, and 28S rRNA gene) and two mitochondrial genes (16S rRNA gene and cytochromecoxidase subunit I) to explore the diversity of astomes inhabiting the digestive tract of lumbricid earthworms at temperate latitudes in Central Europe and to cast more light on their host specificity and coevolution events that shaped their diversification. The present coevolutionary and phylogenetic interaction-adjusted similarity analyses suggested that almost every host switch leads to speciation and firm association with the new host. Nevertheless, the suggested high structural host specificity of astomes needs to be tested with increased earthworm sampling, as only 52 out of 735 lumbricid earthworms (7.07%) were inhabited by ciliates. On the other hand, the diversification of astomes associated with megascolecid and glossoscolecid earthworms might have been driven by duplication events without host switching.
In vitro Studies and Clinical Observations Imply a Synergistic Effect Between Epstein-Barr Virus and Dengue Virus Infection
Authors: Deng Xiao-Mei , Zhao Ling-Zhai , Liang Xue-Ying , Li Dan , Yu Lei , Zhang Fu-Chun , Zhang Hua , Liu Zhong-Yu , Xu Pei
Published: June 2021

Dengue virus (DENV) infection can lead to a complex spectrum of clinical outcomes, ranging from asymptomatic infection to life-threatening severe dengue. The reasons for thus drastically varying manifestations of the disease remain an enigma. Herein, we reported an original discovery of the synergistic effect between preexisting Epstein–Barr virus (EBV) infection and DENV superinfection in vitro and of a strong correlation of these two viruses in the clinical samples from dengue patients. We showed that (I) DENV-2 infection of an EBV-positive cell line (EBV + Akata cell) reactivated EBV, and it could be blocked by wortmannin treatment. (II) Examination of human peripheral blood mononuclear cell (PBMC) samples from dengue patients revealed significantly elevated cell-associated EBV DNA copy number at the time of hospitalization vs. at the time of disease recovery in most individuals. (III) EBV infection promoted DENV propagation in both EBV-hosting B cells and indirectly in THP-1 cells, supported by the following evidence: (A) EBV + Akata cells were more permissive to DENV-2 infection compared with Akata cells harboring no EBV virus (EBV- Akata cells). (B) Low-molecular weight fraction secreted from EBV + Akata cells could enhance DENV-2 propagation in monocytic THP-1 cells. (C) While reactivation of EBV in EBV + Akata cells further increased DENV-2 yield from this cell line, pharmacological inhibition of EBV replication by acyclovir had the opposite effect. To our knowledge, this is the first investigation demonstrating a positive correlation between EBV and DENV in vitro and in human biospecimens.
The First Molecular Characterization of Serbian SARS-CoV-2 Isolates From a Unique Early Second Wave in Europe
Authors: Miljanovic Danijela , Milicevic Ognjen , Loncar Ana , Abazovic Dzihan , Despot Dragana , Banko Ana
Published: June 2021

March 6, 2020 is considered as the official date of the beginning of the COVID-19 epidemic in Serbia. In late spring and early summer 2020, Europe recorded a decline in the rate of SARS-CoV-2 infection and subsiding of the first wave. This trend lasted until the fall, when the second wave of the epidemic began to appear. Unlike the rest of Europe, Serbia was hit by the second wave of the epidemic a few months earlier. Already in June 2020, newly confirmed cases had risen exponentially. As the COVID-19 pandemic is the first pandemic in which there has been instant sharing of genomic information on isolates around the world, the aim of this study was to analyze whole SARS-CoV-2 viral genomes from Serbia, to identify circulating variants/clade/lineages, and to explore site-specific mutational patterns in the unique early second wave of the European epidemic. This analysis of Serbian isolates represents the first publication from Balkan countries, which demonstrates the importance of specificities of local transmission especially when preventive measures differ among countries. One hundred forty-eight different genome variants among 41 Serbian isolates were detected in this study. One unique and seven extremely rare mutations were identified, with locally specific continuous dominance of the 20D clade. At the same time, amino acid substitutions of newly identified variants of concern were found in our isolates from October 2020. Future research should be focused on functional characterization of novel mutations in order to understand the exact role of these variations.
Dose-Response Effects of Acute Aerobic Exercise Intensity on Inhibitory Control in Children With Attention Deficit/Hyperactivity Disorder
Authors: Tsai Yu-Jung , Hsieh Shu-Shih , Huang Chung-Ju , Hung Tsung-Min
Published: June 2021

The present study aimed to examine whether the effect of acute aerobic exercise on inhibitory control of children with attention-deficit/hyperactivity disorder (ADHD) is moderated by exercise intensity. Using a within-subjects design, 25 children with ADHD completed a flanker task with concurrent collection of electroencephalography (EEG) data after three different intensities of treadmill running. The results showed that low- and moderate-intensity exercises resulted in shorter reaction times (RTs) relative to vigorous-intensity exercise during the incompatible condition of the flanker task regardless of task congruency. A P3 congruency effect was observed following low- and vigorous-intensity exercises but not after moderate-intensity exercise. The mean alpha power, a measure of cortical arousal, increased following low- and moderate-intensity exercises but decreased following vigorous-intensity exercise. In addition, the change in arousal level after moderate-intensity exercise was negatively correlated with RT during incompatible flanker tasks. The current findings suggest that children with ADHD have better inhibitory control following both low- and moderate-intensity exercises relative to vigorous aerobic exercise, which could be characterized by an optimal state of cortical arousal.
Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers
Authors: Limbocker Ryan , Staats Roxine , Chia Sean , Ruggeri Francesco S. , Mannini Benedetta , Xu Catherine K. , Perni Michele , Cascella Roberta , Bigi Alessandra , Sasser Liam R. , Block Natalie R. , Wright Aidan K. , Kreiser Ryan P. , Custy Edward T. , Meisl Georg , Errico Silvia , Habchi Johnny , Flagmeier Patrick , Kartanas Tadas , Hollows Jared E. , Nguyen Lam T. , LeForte Kathleen , Barbut Denise , Kumita Janet R. , Cecchi Cristina , Zasloff Michael , Knowles Tuomas P. J. , Dobson Christopher M. , Chiti Fabrizio , Vendruscolo Michele
Published: June 2021

The aberrant aggregation of proteins is a key molecular event in the development and progression of a wide range of neurodegenerative disorders. We have shown previously that squalamine and trodusquemine, two natural products in the aminosterol class, can modulate the aggregation of the amyloid-β peptide (Aβ) and of α-synuclein (αS), which are associated with Alzheimer’s and Parkinson’s diseases. In this work, we expand our previous analyses to two squalamine derivatives, des-squalamine and α-squalamine, obtaining further insights into the mechanism by which aminosterols modulate Aβ and αS aggregation. We then characterize the ability of these small molecules to alter the physicochemical properties of stabilized oligomeric species in vitro and to suppress the toxicity of these aggregates to varying degrees toward human neuroblastoma cells. We found that, despite the fact that these aminosterols exert opposing effects on Aβ and αS aggregation under the conditions that we tested, the modifications that they induced to the toxicity of oligomers were similar. Our results indicate that the suppression of toxicity is mediated by the displacement of toxic oligomeric species from cellular membranes by the aminosterols. This study, thus, provides evidence that aminosterols could be rationally optimized in drug discovery programs to target oligomer toxicity in Alzheimer’s and Parkinson’s diseases.
Real-World Data on Outcomes in Metastatic Castrate-Resistant Prostate Cancer Patients Treated With Abiraterone or Enzalutamide: A Regional Experience
Authors: Raju Rachel , Sahu Arvind , Klevansky Myron , Torres Javier
Published: June 2021

Background

Both abiraterone and enzalutamide have shown to improve overall survival (OS), progression-free survival (PFS) and prostate-specific antigen (PSA) response in patients with metastatic castration-resistant prostate cancer (mCRPC) regardless of previous treatment with chemotherapy (COU-AA3011, COU-AA3022, AFFIRM3 and PREVAIL4). The data regarding the impact of these treatments in the real world setting is scarce. This study assessed the real world survival and disease outcomes in mCRPC patients in a regional health service in Victoria with the use of abiraterone and enzalutamide.

Methods

This retrospective clinical audit included 75 patients with diagnosis of mCRPC treated with either abiraterone or enzalutamide between January 1, 2014, and December 31, 2019, at Goulburn Valley Health. Patients were stratified according to the drug received, Eastern Cooperative Oncology Group (ECOG) performance status, Gleason score, burden of disease at diagnosis, presence of visceral metastases and use of previous chemotherapy. The primary end point was PSA response (defined as a reduction in the PSA level from baseline by 50% or more). The secondary outcomes were PSA PFS, radiographic PFS, and OS.

Results

Thirty-seven patients received enzalutamide, and the other 38 received abiraterone. Only 20% of patients in either group had visceral metastases. 32% of patients receiving enzalutamide had a high burden of disease, compared to 53% receiving abiraterone. 38% of patients in the enzalutamide group and 53% in the abiraterone group had received prior chemotherapy. PSA response rates were higher in the enzalutamide group than abiraterone group (70.3% vs 37.8%). Both PSA and radiographic PFS were longer in the enzalutamide group than abiraterone group; 7 months vs 5 months for both end points. OS was also found to be longer in patients receiving enzalutamide; 30 months compared to only 13 months in patients receiving abiraterone.

Conclusion

Both abiraterone and enzalutamide have shown to result in significant PSA response rates, as well as PFS and OS benefit in mCRPC patients in the real world setting. The difference in responses and survival benefit are probably impacted by the unbalanced burden of disease.
Bilirubin Restrains the Anticancer Effect of Vemurafenib on BRAF-Mutant Melanoma Cells Through ERK-MNK1 Signaling
Authors: Tan Yufan , Zhong Xiaoyu , Wen Xizhi , Yao Leyi , Shao Zhenlong , Sun Wenshuang , Wu Jiawen , Wen Guanmei , Tang Daolin , Zhang Xiaoshi , Liao Yuning , Liu Jinbao
Published: June 2021

Melanoma, the most threatening cancer in the skin, has been considered to be driven by the carcinogenic RAF-MEK1/2-ERK1/2 signaling pathway. This signaling pathway is usually mainly dysregulated by mutations in BRAF or RAS in skin melanomas. Although inhibitors targeting mutant BRAF, such as vemurafenib, have improved the clinical outcome of melanoma patients with BRAF mutations, the efficiency of vemurafenib is limited in many patients. Here, we show that blood bilirubin in patients with BRAF-mutant melanoma treated with vemurafenib is negatively correlated with clinical outcomes. In vitro and animal experiments show that bilirubin can abrogate vemurafenib-induced growth suppression of BRAF-mutant melanoma cells. Moreover, bilirubin can remarkably rescue vemurafenib-induced apoptosis. Mechanically, the activation of ERK-MNK1 axis is required for bilirubin-induced reversal effects post vemurafenib treatment. Our findings not only demonstrate that bilirubin is an unfavorable for patients with BRAF-mutant melanoma who received vemurafenib treatment, but also uncover the underlying mechanism by which bilirubin restrains the anticancer effect of vemurafenib on BRAF-mutant melanoma cells.
Creative Music Therapy and Neurodevelopmental Outcomes in Pre-term Infants at 2 Years: A Randomized Controlled Pilot Trial
Authors: Haslbeck Friederike Barbara , Bucher Hans Ulrich , Bassler Dirk , Hagmann Cornelia , Natalucci Giancarlo
Published: June 2021

Impaired neurodevelopment is increasingly recognized as a major health issue in children born prematurely. Creative music therapy (CMT) intends to prevent and or reduce neurobehavioral deficits in pre-term infants using musical stimulation and socio-emotional co-regulation. We conducted a randomized, clinical pilot CMT trial to test feasibility and to examine long-term neurodevelopmental outcomes in pre-term infants (NCT02434224: https://clinicaltrials.gov/ct2/show/NCT02434224). Eighty-two pre-term infants were randomized either to CMT or standard care. A specially trained music therapist provided family-integrating CMT via infant-directed singing during hospitalization. Fifty-six infants underwent follow-up at 2 years of corrected age. No significant beneficial nor adverse effects of CMT were identified in routine clinical neurodevelopmental measures (Bayley-III Scales of Infant and Toddler Development and the standardized neurological examination). Longer term follow-up (5 years) and larger future studies are recommended to elucidate possible long-term effects of music in relation to more sensitive outcomes including executive function, detailed language processing and social-emotional development.
Juvenile Idiopathic Arthritis With Epstein-Barr Virus-Associated Smooth Muscle Tumor in a 6-Year-Old Girl: A Rare Case Report
Authors: Kang Zhijuan , Xu Juan , Li Zhihui
Published: June 2021

Herein, we reported a rare case of Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) combined with juvenile idiopathic arthritis (JIA) in a 6-year old girl without HIV, organ transplantation, or congenital immunodeficiency. The patient suffered from pain in the bilateral hip joints, which drastically affected her physical activity. Consequently, she was diagnosed with JIA (September 2019). She was given methotrexate and methylprednisolone pills via oral route and a subcutaneous injection of Recombinant Human Tumor Necrosis Factor-α Receptor II;lgG Fc Fusion Protein for 4 weeks that successfully relieved the pain. In May 2020, the pain reoccurred and was accompanied by occasional headaches. After extensive pathological examination, the patient was diagnosed with EBV-SMT. The imaging examinations after admission showed multiple lesions in the skull, lungs, and vertebral body. Biopsy of the L2 vertebral body was then performed to clarify the diagnosis. Finally, the in-situ hybridization of the tumor of the lumbar vertebrae suggested a non-HIV/transplantation-related EBV-SMT. Consequently, the patient received surgery without chemotherapy and radiotherapy, after which her conditions improved.
Light-Responsive Micelles Loaded With Doxorubicin for Osteosarcoma Suppression
Authors: Chen Jiayi , Qian Chenhong , Ren Peng , Yu Han , Kong Xiangjia , Huang Chenglong , Luo Huanhuan , Chen Gang
Published: June 2021

The enhancement of tumor targeting and cellular uptake of drugs are significant factors in maximizing anticancer therapy and minimizing the side effects of chemotherapeutic drugs. A key challenge remains to explore stimulus-responsive polymeric nanoparticles to achieve efficient drug delivery. In this study, doxorubicin conjugated polymer (Poly-Dox) with light-responsiveness was synthesized, which can self-assemble to form polymeric micelles (Poly-Dox-M) in water. As an inert structure, the polyethylene glycol (PEG) can shield the adsorption of protein and avoid becoming a protein crown in the blood circulation, improving the tumor targeting of drugs and reducing the cardiotoxicity of doxorubicin (Dox). Besides, after ultraviolet irradiation, the amide bond connecting Dox with PEG can be broken, which induced the responsive detachment of PEG and enhanced cellular uptake of Dox. Notably, the results of immunohistochemistry in vivo showed that Poly-Dox-M had no significant damage to normal organs. Meanwhile, they showed efficient tumor-suppressive effects. This nano-delivery system with the light-responsive feature might hold great promises for the targeted therapy for osteosarcoma.
Exercise Capacity, Ventilatory Response, and Gas Exchange in COPD Patients With Mild to Severe Obstruction Residing at High Altitude
Authors: Gonzalez-Garcia Mauricio , Barrero Margarita , Maldonado Dario
Published: June 2021

Background

Exercise intolerance, desaturation, and dyspnea are common features in patients with chronic obstructive pulmonary disease (COPD). At altitude, the barometric pressure (BP) decreases, and therefore the inspired oxygen pressure and the partial pressure of arterial oxygen (PaO2) also decrease in healthy subjects and even more in patients with COPD. Most of the studies evaluating ventilation and arterial blood gas (ABG) during exercise in COPD patients have been conducted at sea level and in small populations of people ascending to high altitudes. Our objective was to compare exercise capacity, gas exchange, ventilatory alterations, and symptoms in COPD patients at the altitude of Bogotá (2,640 m), of all degrees of severity.

Methods

Measurement during a cardiopulmonary exercise test of oxygen consumption (VO2), minute ventilation (VE), tidal volume (VT), heart rate (HR), ventilatory equivalents of CO2 (VE/VCO2), inspiratory capacity (IC), end-tidal carbon dioxide tension (PETCO2), and ABG. For the comparison of the variables between the control subjects and the patients according to the GOLD stages, the non-parametric Kruskal–Wallis test or the one-way analysis of variance test was used.

Results

Eighty-one controls and 525 patients with COPD aged 67.5 ± 9.1 years were included. Compared with controls, COPD patients had lower VO2 and VE (p < 0.001) and higher VE/VCO2 (p = 0.001), A-aPO2, and VD/VT (p < 0.001). In COPD patients, PaO2 and saturation decreased, and delta IC (p = 0.004) and VT/IC increased (p = 0.002). These alterations were also seen in mild COPD and progressed with increasing severity of the obstruction.

Conclusion

The main findings of this study in COPD patients residing at high altitude were a progressive decrease in exercise capacity, increased dyspnea, dynamic hyperinflation, restrictive mechanical constraints, and gas exchange abnormalities during exercise, across GOLD stages 1–4. In patients with mild COPD, there were also lower exercise capacity and gas exchange alterations, with significant differences from controls. Compared with studies at sea level, because of the lower inspired oxygen pressure and the compensatory increase in ventilation, hypoxemia at rest and during exercise was more severe; PaCO2 and PETCO2 were lower; and VE/VO2 was higher.
Quantifying the Speed of Chromatophore Activity at the Single-Organ Level in Response to a Visual Startle Stimulus in Living, Intact Squid
Authors: Hadjisolomou Stavros P. , El-Haddad Rita W. , Kloskowski Kamil , Chavarga Alla , Abramov Israel
Published: June 2021

The speed of adaptive body patterning in coleoid cephalopods is unmatched in the natural world. While the literature frequently reports their remarkable ability to change coloration significantly faster than other species, there is limited research on the temporal dynamics of rapid chromatophore coordination underlying body patterning in living, intact animals. In this exploratory pilot study, we aimed to measure chromatophore activity in response to a light flash stimulus in seven squid, Doryteuthis pealeii. We video-recorded the head/arms, mantle, and fin when squid were presented with a light flash startle stimulus. Individual chromatophores were detected and tracked over time using image analysis. We assessed baseline and response chromatophore surface area parameters before and after flash stimulation, respectively. Using change-point analysis, we identified 4,065 chromatophores from 185 trials with significant surface area changes elicited by the flash stimulus. We defined the temporal dynamics of chromatophore activity to flash stimulation as the latency, duration, and magnitude of surface area changes (expansion or retraction) following the flash presentation. Post stimulation, the response’s mean latency was at 50 ms (± 16.67 ms), for expansion and retraction, across all body regions. The response duration ranged from 217 ms (fin, retraction) to 384 ms (heads/arms, expansion). While chromatophore expansions had a mean surface area increase of 155.06%, the retractions only caused a mean reduction of 40.46%. Collectively, the methods and results described contribute to our understanding of how cephalopods can employ thousands of chromatophore organs in milliseconds to achieve rapid, dynamic body patterning.
The Release of Nitric Oxide Is Involved in the β-Arrestin1-Induced Antihypertensive Effect in the Rostral Ventrolateral Medulla
Authors: Sun Jia-Cen , Tan Xing , Ge Lian-Jie , Xu Ming-Juan , Wang Wei-Zhong
Published: June 2021

β-Arrestin1 is a multifunctional scaffold protein with the ability to interact with diverse signaling molecules independent of G protein-coupled receptors. We previously reported that overexpression of β-arrestin1 in the rostral ventrolateral medulla (RVLM) decreased blood pressure (BP) and renal sympathetic nerve activity (RSNA) in spontaneously hypertensive rats (SHRs). Nitric oxide (NO) is widely reported to be involved in central cardiovascular regulation. The goal of this study was to investigate whether NO signaling contributes to the β-arrestin1-mediated antihypertensive effect in the RVLM. It was found that bilateral injection of adeno-associated virus containingArrb1gene (AAV-Arrb1) into the RVLM of SHRs significantly increased NO production and NO synthase (NOS) activity. Microinjection of the non-selective NOS inhibitorN-nitro-L-arginine methyl ester (L-NAME; 10 nmol) into the RVLM prevented the β-arrestin1-induced cardiovascular inhibitory effect. Furthermore, β-arrestin1 overexpression in the RVLM significantly upregulated the expression of phosphorylated neuronal NOS (nNOS) by 3.8-fold and extracellular regulated kinase 1/2 (ERK1/2) by 5.6-fold in SHRs. The β-arrestin1-induced decrease in BP and RSNA was significantly abolished by treatment with ERK1/2 small interfering RNA (ERK1/2 siRNA). Moreover, ERK1/2 siRNA attenuated the β-arrestin1-induced NO production, NOS activity, and nNOS phosphorylation in the RVLM. Taken together, these data demonstrate that the antihypertensive effect of β-arrestin1 in the RVLM is mediated by nNOS-derived NO release, which is associated with ERK1/2 activation.