bluuebunny/crossref_metadata_2025 huggingface dataset:
Recommendation for use of diphtheria and tetanus toxoids and acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b conjugate, and hepatitis B vaccine in infants
Authors: Cho Hye-Kyung , Park Su Eun , Kim Yae-Jean , Jo Dae Sun , Kim Yun-Kyung , Eun Byung-Wook , Lee Taek-Jin , Lee Jina , Lee Hyunju , Kim Ki Hwan , Cho Eun Young , Ahn Jong Gyun , Choi Eun Hwa ,   The Committee on Infectious Diseases of the Korean Pediatric Society
Published: June 2021

In April 2020, the Ministry of Food and Drug Safety licensed a hexavalent combined diphtheria and tetanus toxoids and acellular pertussis (DTaP), inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib) conjugated to tetanus protein, and hepatitis B (HepB) (recombinant DNA) vaccine, DTa-PIPV-Hib-HepB (Hexaxim, Sanofi Pasteur), for use as a 3-dose primary series in infants aged 2, 4, and 6 months. The DTaP-IPVHib-HepB vaccine is highly immunogenic and safe and provides a long-term immune response based on studies performed in a variety of settings in many countries, including Korea. This report summarizes the Committee on Infectious Diseases of the Korean Pediatric Society guidelines for the use of this newly introduced hexavalent combination vaccine.
Using movement, diet, and genetic analyses to understand Arctic charr responses to ecosystem change
Authors: Cote D , Dempson JB , Piersiak M , Layton K , Roul S , Laing R , Angnatok J , Bradbury I
Published: June 2021

Arctic charr Salvelinus alpinus are a commercially and culturally valued species for northern Indigenous peoples. Climate shifts could have important implications for charr and those that rely on them, but studies that evaluate responses to ecosystem change and the spatial scales at which they occur are rare. We compare marine-phase habitat use, long-term diet patterns, and trends in effective population size of Arctic charr from 2 areas (Nain and Saglek) of Nunatsiavut, Labrador, Canada. Tagged charr in both areas frequently occupied estuaries but some also used other habitats that extended to the headland environments outside of their natal fjords. Despite the relatively small distances separating these study areas (<200 km), we observed differences in habitat use and diet. Northern stocks (including Saglek) were more reliant on invertebrates than southern stocks (e.g. Nain), for which capelin and sand lance were important prey. The use of coastal headlands also varied, with Saglek charr occupying these environments more frequently than those from Nain, which only used these habitats in 1 year of the study. Long-term commercial catches also indicate that the tendency for Nain charr to stay within fjords varies annually and relates to capelin availability. Despite the demonstrated capacity to alter diet and habitat use to changing environmental conditions, notable declines in effective population size were associated with the regime shift of the 1990s in the northwest Atlantic. Collectively, these results demonstrate that behavioral plasticity of Arctic charr may be insufficient to deal with the large environmental perturbations expected to arise from a changing climate.
Evaluation of Developmental Structures and Cenopulation State Cerastium davuricum Fisch. ex Spreng. in the Highlands of the Lesser Caucasus
Authors: Guliyeva R.
Published: June 2021

On the highlands of the north – eastern part of the Lesser Caucasus were investigated ontogenetic characteristics Cerastium davuricum in different type of plants. There are found that cenopopulation spices goes through a 4- and 10-year periods. Age composition cenopopulations species is very variable and is associated with the biological characteristics of species composition of the sward, the economic use of pastures. In research found the following types of cenopopulation: normal, invasive, regressive. Meanwhile, the predominance of vegetative individuals in the population in the first case indicates the weakness of cenopopulation, and in the second case, the high number of generative individuals indicates the sustainability of cenopopulation. This arrangement of population under less favorable conditions compared with another one.
Disorders of metabolism in lysosomes in oncopathology as marker of nutritional prognosis
Authors: Varvanina G. G. , Kostyuchenko L. N.
Published: June 2021

With oncopathology, the role of Katepsin L in proteolysis is not sufficiently studied, in particular, its connection with the nutritional status and the nutritional forecast.The purpose of the study. To determine the effect of impaired metabolism in lysosomes and its connection with the development of nutritional failure.Material and methods. The study includes 156 patients (65 with pancreatic cancer, 69 with СP). In the serum, MMP-9, TIMP-1 and GC were determined by the ELISA method. Statistical analysis was carried out by the criterion of Mann–Whitney. The results were presented in the form of medians (intercomdlic range). The reliability of differences was considered essential at p < 0.05.Results. It was revealed that the dynamics of changes in the epidermal-mezenchymal transition markers indicates an increase in the level of cystatin C (inhibitor of cathepsins), a decrease in the level of RSB in relations with the Catencin L, which is subsequently reflected in the reduction of the level of prehalet (marker of somatic protein deficiency). Cathepsin L in the complex with RSB determines one of the mechanisms for the development of nutritional failure and can predict it.Conclusions. The definition in the colprix of the RSB, cathepsin L and prehaletbin can serve as an early prognostic marker of nutritional insufficiency.
Features of gastroenterologist’s work in COVID‑19 pandemic
Authors: Butov M. A. , Vasilevskaya A. S. , Shelukhina S. V. , Kuznetsov P. S. , Borisova M. V. , Markova E. V.
Published: June 2021

The aim of the study was to determine the prevalence of organic and functional pathology at an outpatient appointment with a gastroenterologist before and during the COVID-19 pandemic. An assessment of 428 outpatient clinical cases over two periods was carried out. The analysis revealed a significant increase in functional gastrointestinal pathology. During the first study period, 36% of all applied patients had functional gastrointestinal diseases, in the second period the number of patients increased to 57%.The results obtained allow us to conclude that, despite the fact that COVID-19 affects the digestive organs along with the respiratory tract, the forced isolation that arose during the pandemic and general anxiety significantly increased the growth of the functional pathology of the gastrointestinal tract, which should be taken into account when developing treatment regimens and managing gastroenterological patients.
Difficulties in differential diagnosis of inflammatory bowel diseases in patient with overlapping autoimmune hepatitis and primary sclerosing cholangitis
Authors: Krolevets T. S. , Livzan M. A. , Plinder M. I.
Published: June 2021

The article presents a clinical case of cross-syndrome of autoimmune hepatitis type 1 with primary sclerosing cholangitis. The main symptoms, laboratory and instrumental criteria of these diseases are discussed. Detection of specific antibodies is necessary for an accurate diagnosis. Interpretation of changes in the colon obtained by stepwise biopsy requires special attention. The described morphological picture does not allow to make an accurate diagnosis, it can be regarded as initial manifestations of Crohn's disease, microscopic or eosinophilic colitis, signs of worm-parasitic invasion. An example of a differential diagnostic search in such a situation is discussed.
ANALISIS PEMILIHAN SUPPLIER DAN PENENTUAN JUMLAH PEMBELIAN BAHAN BAKU DENGAN MENGGUNAKAN METODE ANALYTIC NETWORK PROCESS (ANP)
Authors: Asmarawati Citra Indah , Wibowo Sadiq Ardo
Published: June 2021

PT. Guna Kemas Indah in determining the supplier of raw materials, but the existing criteria are not sufficient to meet the expected criteria. By using Analytical networking process (ANP) and goal programming in determining quality. In addition, it can also be seen how much raw material purchases are based on the selected supplier. Selection of suppliers is based on several criteria using vendor performance indicators, which are arranged based on sub-criteria. Where the existing subcriteria can influence each criterion. Based on the weight calculation for the criteria are success-quality (0.3868), cost (0.3668), delivery (0.1256), flexibility (0.0619), responsiveness (0.0586) so that 3 supplier candidates will be obtained.
PERBANDINGAN METODE SINGLE EXPONENTIAL SMOOTHING DAN MOVING AVERAGE PADA PERAMALAN PENJUALAN PRODUK MINYAK GORENG DI PT TUNAS BARU LAMPUNG
Authors: Chaerunnisa Niken , Momon Ade
Published: June 2021

PT Tunas Baru Lampung is a company that produces palm cooking oil products under the Rose Brand brand. In product sales, companies sometimes experience ups and downs. Based on the sales data from Rose Brand Cooking Oil, the size of 1 L has fluctuated or in each period it changes and is not always boarding. Even though product sales are one of the important things to be evaluated from time to time on an ongoing basis. To predict future sales, forecasting is done. The forecasting method used is Double Exponential Smoothing and Moving Average. The method of accuracy will be compared using MSE, MAD, and MAPE. The results showed a comparison of the accuracy and the smallest error value in each method. By using the weight values ​​0.1, 0.3, 0.4, 0.5, 0.6, 0.7, and 0.8 on the Single Exponential Smoothing method the weight value is 0.8 or α = 0.8, namely MSE of 250,570,764.80, MAD of 12,922.32 and MAPE of 33.55 Then, using the movement value n = 3 in the Moving Average method has an accuracy of 438,980,942.75 MSE, 18,142.14 MAD, and 41.37 MAPE. After comparing the accuracy of the two methods, the Single Exponential Smoothing method is the best method to predict sales of Rose Brand 1 L Cooking Oil products.
N-Glycosylation Network Construction and Analysis to Modify Glycans on the Spike (S) Glycoprotein of SARS-CoV-2
Authors: Krishnan Sridevi , Krishnan Giri P.
Published: June 2021

Background: The N-glycan structure and composition of the spike (S) protein of SARS-CoV-2 are pertinent to vaccine development and efficacy.

Methods: We reconstructed the glycosylation network based on previously published mass spectrometry data using GNAT, a glycosylation network analysis tool. Our compilation of the network tool had 26 glycosyltransferase and glucosidase enzymes and could infer the pathway of glycosylation machinery based on glycans in the virus spike protein. Once the glycan biosynthesis pathway was generated, we simulated the effect of blocking specific enzymes—swainsonine or deoxynojirimycin for blocking mannosidase-II and indolizidine for blocking alpha-1,6-fucosyltransferase—to see how they would affect the biosynthesis network and the glycans that were synthesized.

Results: The N-glycan biosynthesis network of SARS-CoV-2 spike protein shows an elaborate enzymatic pathway with several intermediate glycans, along with the ones identified by mass spectrometric studies. Of the 26 enzymes, the following were involved—Man-Ia, MGAT1, MGAT2, MGAT4, MGAT5, B3GalT, B4GalT, Man-II, SiaT, ST3GalI, ST3GalVI, and FucT8. Blocking specific enzymes resulted in a substantially modified glycan profile of SARS-CoV-2.

Conclusion: Variations in the final N-glycan profile of the virus, given its site-specific microheterogeneity, are factors in the host response to the infection, vaccines, and antibodies. Heterogeneity in the N-glycan profile of the spike (S) protein and its potential effect on vaccine efficacy or adverse reactions to the vaccines remain unexplored. Here, we provide all the resources we generated—the glycans in the glycoCT xml format and the biosynthesis network for future work.
Subgroups of Foot-Ankle Movement Patterns Can Influence the Responsiveness to a Foot-Core Exercise Program: A Hierarchical Cluster Analysis
Authors: Watari Ricky , Suda Eneida Y. , Santos João P. S. , Matias Alessandra B. , Taddei Ulisses T. , Sacco Isabel C. N.
Published: June 2021

The purpose of this study is to identify homogenous subgroups of foot-ankle (FA) kinematic patterns among recreational runners and further investigate whether differences in baseline movement patterns can influence the mechanical responses to a foot-core exercise intervention program. This is a secondary analysis of data from 85 participants of a randomized controlled trial (clinicaltrials.gov – NCT02306148) investigating the effects of an exercise-based therapeutic approach focused on FA complex. A validated skin marker-based multi-segment foot model was used to acquire kinematic data during the stance phase of treadmill running. Kinematic features were extracted from the time-series data using a principal component analysis, and the reduced data served as input for a hierarchical cluster analysis to identify subgroups of FA movement patterns. FA angle time series were compared between identified clusters and the mechanical effects of the foot-core exercise intervention was assessed for each subgroup. Two clusters of FA running patterns were identified, with cluster 1 (n = 36) presenting a pattern of forefoot abduction, while cluster 2 (n = 49) displayed deviations in the proximal segments, with a rearfoot adduction and midfoot abduction throughout the stance phase of running. Data from 29 runners who completed the intervention protocol were analyzed after 8-weeks of foot-core exercises, resulting in changes mainly in cluster 1 (n = 16) in the transverse plane, in which we observed a reduction in the forefoot abduction, an increase in the rearfoot adduction and an approximation of their pattern to the runners in cluster 2 (n = 13). The findings of this study may help guide individual-centered treatment strategies, taking into account their initial mechanical patterns.
Long Non-coding RNA 332443 Inhibits Preadipocyte Differentiation by Targeting Runx1 and p38-MAPK and ERK1/2-MAPK Signaling Pathways
Authors: Xiao Fen , Tang Chen-Yi , Tang Hao-Neng , Wu Hui-Xuan , Hu Nan , Li Long , Zhou Hou-De
Published: June 2021

Long non-coding RNAs (lncRNAs) have emerged as integral regulators of pathophysiological processes, but their specific roles and mechanisms in adipose tissue development remain largely unknown. Here, through microarray analysis, co-expression, and tissue specific analysis of adipocyte tissues after fasting for 72 h, we found that Lnc-FR332443 expression was dramatically decreased, as well as the expression of Runx1. The UCSC database and Ensembl database indicated that Lnc-FR332443 is the antisense lncRNA of Runx1. Lnc-FR332443 and Runx1 are highly enriched in adipose tissue and downregulated during adipogenic differentiation. Adipose tissue-specific knockdown of Lnc-FR332443 increased fat mass in vivo, and specific knockdown of Lnc-FR332443 in 3T3-L1 preadipocytes promoted adipogenic differentiation. In this process, Runx1 expression was decreased when Lnc-FR332443 was downregulated in adipocytes or 3T3-L1 preadipocytes, and vice versa, when Lnc-FR332443 was upregulated, the expression of Runx1 was increased. However, overexpression of Runx1 decreased the expression of the adipocyte cell marker genes PPARγ, C/EBPα and FABP4 significantly, while not affected the expression of Lnc-FR332443. Mechanistically, Lnc-FR332443 positively regulates Runx1 expression in mouse adipocytes and suppresses adipocyte differentiation by attenuating the phosphorylation of MAPK-p38 and MAPK-ERK1/2 expression. Thus, this study indicated that Lnc-FR332443 inhibits adipogenesis and which might be a drug target for the prevention and treatment of obesity.
AMPK and Pulmonary Hypertension: Crossroads Between Vasoconstriction and Vascular Remodeling
Authors: Zhao Qiang , Song Ping , Zou Ming-Hui
Published: June 2021

Pulmonary hypertension (PH) is a debilitating and life-threatening disease characterized by increased blood pressure within the pulmonary arteries. Adenosine monophosphate-activated protein kinase (AMPK) is a heterotrimeric serine-threonine kinase that contributes to the regulation of metabolic and redox signaling pathways. It has key roles in the regulation of cell survival and proliferation. The role of AMPK in PH is controversial because both inhibition and activation of AMPK are preventive against PH development. Some clinical studies found that metformin, the first-line antidiabetic drug and the canonical AMPK activator, has therapeutic efficacy during treatment of early-stage PH. Other study findings suggest the use of metformin is preferentially beneficial for treatment of PH associated with heart failure with preserved ejection fraction (PH-HFpEF). In this review, we discuss the “AMPK paradox” and highlight the differential effects of AMPK on pulmonary vasoconstriction and pulmonary vascular remodeling. We also review the effects of AMPK activators and inhibitors on rescue of preexisting PH in animals and include a discussion of gender differences in the response to metformin in PH.
Gastrointestinal Distension by Pectin-Containing Carbonated Solution Suppresses Food Intake and Enhances Glucose Tolerance via GLP-1 Secretion and Vagal Afferent Activation
Authors: Ohbayashi Kento , Oyama Yukiko , Yamaguchi Chiharu , Asano Toshiki , Yada Toshihiko , Iwasaki Yusaku
Published: June 2021

Diet-induced gastrointestinal distension is known to evoke satiation and suppress postprandial hyperglycemia; however, the underlying mechanisms remain poorly understood. This study explored how gastrointestinal distension regulates energy homeostasis by using inflating stomach formulation (ISF), the carbonated solution containing pectin that forms stable gel bubbles under acidic condition in the stomach. Here we show that, in mice, oral administration of ISF induced distension of stomach and proximal intestine temporarily, stimulated intestinal glucagon-like peptide-1 (GLP-1) secretion, and activated vagal afferents and brainstem. ISF suppressed food intake and improved glucose tolerance via enhancing insulin sensitivity. The anorexigenic effect was partially inhibited, and the beneficial glycemic effect was blunted by pharmacological GLP-1 receptor blockade and chemical denervation of capsaicin-sensitive sensory nerves. In HFD-fed obese mice showing arrhythmic feeding and obesity, subchronic ISF treatment at the light period (LP) onset for 10 days attenuated LP hyperphagia and visceral fat accumulation. These results demonstrate that gastrointestinal distension by ISF stimulates GLP-1 secretion and the vagal afferent signaling to the brain, thereby regulating feeding behavior and glucose tolerance. Furthermore, subchronic ISF treatment ameliorates HFD-induced visceral obesity. We propose the diet that induces gastrointestinal distension as a novel treatment of hyperphagic obesity and diabetes.
Considerations on Forest Changes of Northwest China in Past Seven Decades
Authors: Guojing Yang , Junhao Li , Lihua Zhou
Published: June 2021

Forests cover four billion hectares (31%) of the Earth’s landmass and contain over 75% of all carbon in vegetation. They provide renewable raw materials and natural amenities, protect land and water resources, harbor biological diversity, and mitigate climate change. However, due to less precipitation, the forest coverage rate is only 5.86% in Northwest China. The forests in these arid areas are mainly distributed in alpine areas, which play a key role in runoff regulation and ensure the ecological and economic development of the middle and lower reaches of the inland basins. In the past several decades, China had experienced large-scale deforestation and reforestation. What were the changes of the few forest areas and growing stock in arid Northwest China? Has forest quality been restored? Changes of that had been analyzed in this article. The results showed that the forest area and growing stock decreased greatly from the 1950s to 1970s; the artificial forest area increased clearly; the natural forest area stabilized from the 1980s, growing stock of forest per unit area was still lower than that in the 1950s; and the forest quality had not yet been restored. Results of the analysis of influencing factors showed that the policy-led human activities in different periods were the efficient cause of forest changes in Northwest China. With the development of forestry science, more and more attention has been paid to forest ecological restoration. “Three-North Shelter Forest Program (TNSFP)” in 1978 had made great progress on forest areas by afforestation, and the ecological benefits and economic benefits also increased remarkably owing to the increase in the artificial forest area. In recent years, great progress on forest areas has been made by afforestation, and the forests also contribute significantly to the ecology and economy. However, large-scale afforestation in the Loess Plateau had caused a phenomenon of large investment and little effect on water conservation in some afforestation areas, which showed that afforestation initiated under different polices, which were not always scientifically based, resulted in unintended consequences. Clear ecological principles should be used to ensure best environmental and forest ecology outcomes.
Whole Genome Level Analysis of the Wnt and DIX Gene Families in Mice and Their Coordination Relationship in Regulating Cardiac Hypertrophy
Authors: Gai Zhongchao , Wang Yujiao , Tian Lu , Gong Guoli , Zhao Jieqiong
Published: June 2021

The Wnt signaling pathway is an evolutionarily conserved signaling pathway that plays essential roles in embryonic development, organogenesis, and many other biological activities. Both Wnt proteins and DIX proteins are important components of Wnt signaling. Systematic studies of Wnt and DIX families at the genome-wide level may provide a comprehensive landscape to elucidate their functions and demonstrate their relationships, but they are currently lacking. In this report, we describe the correlations between mouse Wnt and DIX genes in family expansion, molecular evolution, and expression levels in cardiac hypertrophy at the genome-wide scale. We observed that both the Wnt and DIX families underwent more expansion than the overall average in the evolutionarily early stage. In addition, mirrortree analyses suggested that Wnt and DIX were co-evolved protein families. Collectively, these results would help to elucidate the evolutionary characters of Wnt and DIX families and demonstrate their correlations in mediating cardiac hypertrophy.
St. Louis Encephalitis Virus in the Southwestern United States: A Phylogeographic Case for a Multi-Variant Introduction Event
Authors: Ridenour Chase L. , Cocking Jill , Poidmore Samuel , Erickson Daryn , Brock Breezy , Valentine Michael , Roe Chandler C. , Young Steven J. , Henke Jennifer A. , Hung Kim Y. , Wittie Jeremy , Stefanakos Elene , Sumner Chris , Ruedas Martha , Raman Vivek , Seaton Nicole , Bendik William , Hornstra O’Neill Heidie M. , Sheridan Krystal , Centner Heather , Lemmer Darrin , Fofanov Viacheslav , Smith Kirk , Will James , Townsend John , Foster Jeffrey T. , Keim Paul S. , Engelthaler David M. , Hepp Crystal M.
Published: June 2021

Since the reemergence of St. Louis Encephalitis (SLE) Virus (SLEV) in the Southwest United States, identified during the 2015 outbreak in Arizona, SLEV has been seasonally detected within Culex spp. populations throughout the Southwest United States. Previous work revealed the 2015 outbreak was caused by an importation of SLEV genotype III, which had only been detected previously in Argentina. However, little is known about when the importation occurred or the transmission and genetic dynamics since its arrival into the Southwest. In this study, we sought to determine whether the annual detection of SLEV in the Southwest is due to enzootic cycling or new importations. To address this question, we analyzed 174 SLEV genomes (142 sequenced as part of this study) using Bayesian phylogenetic analyses to estimate the date of arrival into the American Southwest and characterize the underlying population structure of SLEV. Phylogenetic clustering showed that SLEV variants circulating in Maricopa and Riverside counties form two distinct populations with little evidence of inter-county transmission since the onset of the outbreak. Alternatively, it appears that in 2019, Yuma and Clark counties experienced annual importations of SLEV that originated in Riverside and Maricopa counties. Finally, the earliest representatives of SLEV genotype III in the Southwest form a polytomy that includes both California and Arizona samples. We propose that the initial outbreak most likely resulted from the importation of a population of SLEV genotype III variants, perhaps in multiple birds, possibly multiple species, migrating north in 2013, rather than a single variant introduced by one bird.
High Purity Isolation of Low Density Neutrophils Casts Doubt on Their Exceptionality in Health and Disease
Authors: Hardisty Gareth R. , Llanwarne Frances , Minns Danielle , Gillan Jonathan L. , Davidson Donald J. , Gwyer Findlay Emily , Gray Robert D.
Published: June 2021

Low density neutrophils (LDNs) are described in a number of inflammatory conditions, cancers and infections and associated with immunopathology, and a mechanistic role in disease. The role of LDNs at homeostasis in healthy individuals has not been investigated. We have developed an isolation protocol that generates high purity LDNs from healthy donors. Healthy LDNs were identical to healthy normal density neutrophils (NDNs), aside from reduced neutrophil extracellular trap formation. CD66b, CD16, CD15, CD10, CD54, CD62L, CXCR2, CD47 and CD11b were expressed at equivalent levels in healthy LDNs and NDNs and underwent apoptosis and ROS production interchangeably. Healthy LDNs had no differential effect on CD4+ or CD8+ T cell proliferation or IFNγ production compared with NDNs. LDNs were generated from healthy NDNs in vitro by activation with TNF, LPS or fMLF, suggesting a mechanism of LDN generation in disease however, we show neutrophilia in people with Cystic Fibrosis (CF) was not due to increased LDNs. LDNs are present in the neutrophil pool at homeostasis and have limited functional differences to NDNs. We conclude that increased LDN numbers in disease reflect the specific pathology or inflammatory environment and that neutrophil density alone is inadequate to classify discrete functional populations of neutrophils.
Neutrophil Extracellular Traps Activate Proinflammatory Functions of Human Neutrophils
Authors: Dömer Daniel , Walther Tabea , Möller Sonja , Behnen Martina , Laskay Tamás
Published: June 2021

Neutrophil extracellular traps (NETs) consist of decondensed nuclear chromatin that is associated with proteins and are released by neutrophils during an inflammatory response. Released NETs are able to capture pathogens, prevent their dissemination and potentially kill them via antimicrobial peptides and proteins that are associated with the decondensed chromatin. In addition to their antimicrobial functions, NETs have also been shown to exert immunomodulatory effects by activation and differentiation of macrophages, dendritic cells and T cells. However, the effect of NETs on neutrophil functions is poorly understood. Here we report the first comprehensive study regarding the effects of NETs on human primary neutrophils in vitro. NETs were isolated from cultures of PMA-exposed neutrophils. Exposure of neutrophils to isolated NETs resulted in the activation of several neutrophil functions in a concentration-dependent manner. NETs induced exocytosis of granules, the production of reactive oxygen species (ROS) by the NADPH oxidase NOX2, NOX2-dependent NET formation, increased the phagocytosis and killing of microbial pathogens. Furthermore, NETs induced the secretion of the proinflammatory chemokine IL-8 and the B-cell-activating cytokine BAFF. We could show that the NET-induced activation of neutrophils occurs by pathways that involve the phosphorylation of Akt, ERK1/2 and p38. Taken together our results provide further insights into the proinflammatory role of NETs by activating neutrophil effector function and further supports the view that NETs can amplify inflammatory events. On the one hand the amplified functions enhance the antimicrobial defense. On the other hand, NET-amplified neutrophil functions can be involved in the pathophysiology of NET-associated diseases. In addition, NETs can connect the innate and adaptive immune system by inducing the secretion of the B-cell-activating cytokine BAFF.
Bridging Computational Vaccinology and Vaccine Development Through Systematic Identification, Characterization, and Downselection of Conserved and Variable Circumsporozoite Protein CD4 T Cell Epitopes From Diverse Plasmodium falciparum Strains
Authors: Noe Amy R. , Terry Frances E. , Schanen Brian C. , Sassano Emily , Hindocha Pooja , Phares Timothy W. , Moise Leonard , Christen Jayne M. , Tucker Kenneth D. , Kotraiah Vinayaka , Drake Donald R. , Martin William D. , De Groot Anne S. , Gutierrez Gabriel M.
Published: June 2021

An effective malaria vaccine must prevent disease in a range of populations living in regions with vastly different transmission rates and protect against genetically-diversePlasmodium falciparum(Pf) strains. The protective efficacy afforded by the currently licensed malaria vaccine, Mosquirix™, promotes strong humoral responses to Pf circumsporozoite protein (CSP) 3D7 but protection is limited in duration and by strain variation. Helper CD4 T cells are central to development of protective immune responses, playing roles in B cell activation and maturation processes, cytokine production, and stimulation of effector T cells. Therefore, we took advantage of recent in silico modeling advances to predict and analyze human leukocyte antigen (HLA)-restricted class II epitopes from PfCSP – across the entire PfCSP 3D7 sequence as well as in 539 PfCSP sequence variants – with the goal of improving PfCSP-based malaria vaccines. Specifically, we developed a systematic workflow to identify peptide sequences capable of binding HLA-DR in a context relevant to achieving broad human population coverage utilizing cognate T cell help and with limited T regulatory cell activation triggers. Through this workflow, we identified seven predicted class II epitope clusters in the N- and C-terminal regions of PfCSP 3D7 and an additional eight clusters through comparative analysis of 539 PfCSP sequence variants. A subset of these predicted class II epitope clusters was synthesized as peptides and assessed for HLA-DR bindingin vitro. Further, we characterized the functional capacity of these peptides to prime and activate human peripheral blood mononuclear cells (PBMCs), by monitoring cytokine response profiles using MIMIC®technology (Modular IMmuneIn vitroConstruct). Utilizing this decision framework, we found sufficient differential cellular activation and cytokine profiles among HLA-DR-matched PBMC donors to downselect class II epitope clusters for inclusion in a vaccine targeting PfCSP. Importantly, the downselected clusters are not highly conserved across PfCSP variants but rather, they overlap a hypervariable region (TH2R) in the C-terminus of the protein. We recommend assessing these class II epitope clusters within the context of a PfCSP vaccine, employing a test system capable of measuring immunogenicity across a broad set of HLA-DR alleles.
Higher Prevalence of Bacteroides fragilis in Crohn’s Disease Exacerbations and Strain-Dependent Increase of Epithelial Resistance
Authors: Becker Heike E. F. , Jamin Casper , Bervoets Liene , Boleij Annemarie , Xu Pan , Pierik Marie J. , Stassen Frank R. M. , Savelkoul Paul H. M. , Penders John , Jonkers Daisy M. A. E.
Published: June 2021

Bacteroides fragilis has previously been linked to Crohn’s disease (CD) exacerbations, but results are inconsistent and underlying mechanisms unknown. This study investigates the epidemiology of B. fragilis and its virulence factors bft (enterotoxin) and ubiquitin among 181 CD patients and the impact on the intestinal epithelial barrier in vitro. The prevalence of B. fragilis was significantly higher in active (n = 69/88, 78.4%) as compared to remissive (n = 58/93, 62.4%, p = 0.018) CD patients. Moreover, B. fragilis was associated with intestinal strictures. Interestingly, the intestinal barrier function, as examined by transepithelial electrical resistance (TEER) measurements of Caco-2 monolayers, increased when exposed to secretomes of bft-positive (bft-1 and bft-2 isotype; increased TEER ∼160%, p < 0.001) but not when exposed to bft-negative strains. Whole metagenome sequencing and metabolomics, respectively, identified nine coding sequences and two metabolites that discriminated TEER-increasing from non-TEER-increasing strains. This study revealed a higher B. fragilis prevalence during exacerbation. Surprisingly, bft-positive secretomes increased epithelial resistance, but we excluded Bft as the likely causative factor.
Prevalence and Characterization of Food-Borne Vibrio parahaemolyticus From African Salad in Southern Nigeria
Authors: Igbinosa Etinosa O. , Beshiru Abeni , Igbinosa Isoken H. , Ogofure Abraham G. , Uwhuba Kate E.
Published: June 2021

The demand for minimally processed vegetables (African salad) has increased partly due to its inclusion in ready-to-eat foods. Nevertheless, the associated risk of the presence of emergent foodborne pathogens, such asVibrio parahaemolyticusmight be underestimated. The present study was designed to isolate and characterize foodborneV. parahaemolyticusfrom minimally processed vegetables using culture-based methods and molecular approach. A total of 300 samples were examined from retail outlets between November 2018 and August 2019 from Southern Nigeria. The prevalence of vibrios from the overall samples based on the colonial proliferation of yellow, blue-green and/or green colonies on thiosulfate citrate bile salts sucrose agar was 74/300 (24.6%). An average of two green or blue-green colonies from respective plates was screened forV. parahaemolyticususing analytical profile index (API) 20 NE. Polymerase chain reaction further confirmed the identity of positiveV. parahaemolyticus. The counts ofV. parahaemolyticusranged from 1.5 to 1,000 MPN/g. A total of 63 recoveredV. parahaemolyticuswere characterized further. The resistance profile of the isolates include ampicillin 57/63 (90.5%), cefotaxime 41/63 (65.1%), ceftazidime 30/63 (47.6%), amikacin 32/63 (50.8%), kanamycin 15/63 (23.8%), and oxytetracycline 16/63 (25.4%). The multiple antibiotic index ranged from 0–0.81. The formation of biofilm by the isolates revealed the following: strong formation 15/63 (23.8%), moderate formation 31/63 (49.2%), weak formation 12/63 (19.1%), and no formation 5/63 (7.9%). A total of 63/63 (100%), 9/63 (14.3%), and 20/63 (31.8%) of the isolates harbored thetox Rgene, TDH-related hemolysin (trh) and thermostable direct hemolysin (tdh) determinants respectively. The isolates with O2 serogroup were most prevalentviaPCR. Isolates that were resistant to tetracycline, kanamycin, and chloramphenicol possessed resistant genes. The presence of multidrug-resistant vibrios in the minimally processed vegetables constitutes a public health risk and thus necessitates continued surveillance.
Severity of Lesions Involving the Cortical Cholinergic Pathways May Be Associated With Cognitive Impairment in Subacute Ischemic Stroke
Authors: Zhong Huo-Hua , Qu Jian-feng , Xiao Wei-Min , Chen Yang-kun , Liu Yong-lin , Wu Zhi-qiang , Qiu Dong-hai , Liang Wen-cong
Published: June 2021

Purpose: Impairment of cortical cholinergic pathways (CCP) is an important risk factor for chronic vascular cognitive impairment. However, this phenomenon has rarely been studied in post-stroke cognitive impairment (PSCI). We investigated the relationship between PSCI and CCP lesions assessed by structural magnetic resonance imaging (MRI).

Patients and methods: We prospectively enrolled 103 patients within 7 days of ischemic stroke onset. CCP was measured by the cholinergic pathways hyperintensities scale (CHIPS), which semiquantitatively grades MR lesions strategically located on the CCP identified in human brains. We also measured other MRI parameters, including the location and volumes of acute infarcts, cerebral microbleeds, medial temporal lobe atrophy, and white matter lesions. Neuropsychological assessments were performed using the 60-min modified vascular dementia battery (VDB) at 3 months after the index stroke, and PSCI was defined according to VDB as well as ADL.

Results: Of all 103 patients, 69 men (67.0%) and 34 women (33.0%) with a mean age of 57.22 ± 12.95 years, 55 patients (53.4%) were judged to have PSCI at 3 months, including 43 (41.7%) patients with PSCI-no dementia and 12 (11.7%) patients with poststroke dementia. According to the VBD assessment, the most commonly impaired cognitive domain was visuomotor speed (27.2%) followed by verbal memory (25.2%). Univariate analysis showed that patients with PSCI were older; had higher informant questionnaire on cognitive decline in the elderly (IQCODE) scores; had more frequent previous stroke history and atrial fibrillation; and had higher CHIPS scores, more severe white matter lesions, and medial temporal lobe atrophy. PSCI patients also had higher depression scores at 3 months. In the multivariate regression analysis, age, IQCODE score, CHIPS score, and Hamilton depression rating scale score were independent predictors of PSCI. Ordinal regression analysis for risk factors of poor functional outcomes revealed that IQCODE scores and cognitive function status were related to mRS score at 3 months after stroke.

Conclusion: In patients with early subacute ischemic stroke, the severity of lesions involving the CCP may be associated with cognitive impairment at 3 months.

Clinical Trial Registration: Chinese Clinical Trial Registry, identifier: ChiCTR1800014982.
Blood-Based Biomarkers: A Forgotten Friend of Hyperacute Ischemic Stroke
Authors: Liu Zhilan , Yang Cui , Wang Xiaoming , Xiang Yang
Published: June 2021

Ischemic stroke (IS) is the second leading cause of death worldwide. Multimodal neuroimaging techniques that have significantly facilitated the diagnosis of hyperacute IS are not widely used in underdeveloped areas and community hospitals owing to drawbacks such as high cost and lack of trained operators. Moreover, these methods do not have sufficient resolution to detect changes in the brain at the cellular and molecular levels after IS onset. In contrast, blood-based biomarkers can reflect molecular and biochemical alterations in both normal and pathophysiologic processes including angiogenesis, metabolism, inflammation, oxidative stress, coagulation, thrombosis, glial activation, and neuronal and vascular injury, and can thus provide information complementary to findings from routine examinations and neuroimaging that is useful for diagnosis. In this review, we summarize the current state of knowledge on blood-based biomarkers of hyperacute IS including those associated with neuronal injury, glial activation, inflammation and oxidative stress, vascular injury and angiogenesis, coagulation and thrombosis, and metabolism as well as genetic and genomic biomarkers. Meanwhile, the blood sampling time of the biomarkers which are cited and summarized in the review is within 6 h after the onset of IS. Additionally, we also discuss the diagnostic and prognostic value of blood-based biomarkers in stroke patients, and future directions for their clinical application and development.
Why Are Stroke Rehabilitation Trial Recruitment Rates in Single Digits?
Authors: Geed Shashwati , Feit Preethy , Edwards Dorothy F. , Dromerick Alexander W.
Published: June 2021

Background: Recruitment of patients in early subacute rehabilitation trials (<30 days post-stroke) presents unique challenges compared to conventional stroke trials recruiting individuals >6 months post-stroke. Preclinical studies suggest treatments be initiated sooner after stroke, thus requiring stroke rehabilitation trials be conducted within days post-stroke. How do specific inclusion and exclusion criteria affect trial recruitment rates for early stroke rehabilitation trials?

Objectives: Provide estimates of trial recruitment based on screening and enrollment data from a phase II early stroke rehabilitation trial.

Methods: CPASS, a phase II intervention trial screened ischemic stroke patients in acute care (18-months, N = 395) and inpatient rehabilitation (22-months, N = 673). Patients were stratified by upper extremity (UE) impairment into mild (NIHSS motor arm = 0, 1); moderate (NIHSS = 2, 3); severe (NIHSS = 4) and numbers of patients disqualified due to CPASS exclusion criteria determined. We also examined if a motor-specific evaluation (Action Research Arm Test, ARAT) increases the pool of eligible patients disqualified by the NIHSS motor arm item.

Results: CPASS recruitment in acute care (5.3%) and inpatient rehabilitation (5%) was comparable to prior trials. In acute care, a short stay (7–17-days), prior stroke (13.5% in moderately; 13.2% in severely impaired) disqualified the majority. In inpatient rehabilitation, the majority (40.8%) were excluded for “too mild” impairment. The next majority were disqualified for reaching inpatient rehabilitation “too late” to participate in an early stroke trial (15% in moderately; 24% in severely impaired). Mean ARAT in the “too mild” showed significant impairment and potential to benefit from participation in select UE rehabilitation trials.

Conclusions: Screening of ischemic stroke patients while they are still in acute care is crucial to successful recruitment for early stroke rehabilitation trials. A significant proportion of eligible patients are lost to “short length of stay” in acute care, and arrive to inpatient rehabilitation “too late” for an early rehabilitation trial. Additional screening of mildly impaired patients using a motor function specific scale will benefit the trial recruitment and generalizability.

Trial Registration Number:http://www.clinicaltrials.gov Identifier: NCT02235974.
Artificial Intelligence Can Cut Costs While Maintaining Accuracy in Colorectal Cancer Genotyping
Authors: Kacew Alec J. , Strohbehn Garth W. , Saulsberry Loren , Laiteerapong Neda , Cipriani Nicole A. , Kather Jakob N. , Pearson Alexander T.
Published: June 2021

Rising cancer care costs impose financial burdens on health systems. Applying artificial intelligence to diagnostic algorithms may reduce testing costs and avoid wasteful therapy-related expenditures. To evaluate the financial and clinical impact of incorporating artificial intelligence-based determination of mismatch repair/microsatellite instability status into the first-line metastatic colorectal carcinoma setting, we developed a deterministic model to compare eight testing strategies: A) next-generation sequencing alone, B) high-sensitivity polymerase chain reaction or immunohistochemistry panel alone, C) high-specificity panel alone, D) high-specificity artificial intelligence alone, E) high-sensitivity artificial intelligence followed by next generation sequencing, F) high-specificity artificial intelligence followed by next-generation sequencing, G) high-sensitivity artificial intelligence and high-sensitivity panel, and H) high-sensitivity artificial intelligence and high-specificity panel. We used a hypothetical, nationally representative, population-based sample of individuals receiving first-line treatment for de novo metastatic colorectal cancer (N = 32,549) in the United States. Model inputs were derived from secondary research (peer-reviewed literature and Medicare data). We estimated the population-level diagnostic costs and clinical implications for each testing strategy. The testing strategy that resulted in the greatest project cost savings (including testing and first-line drug cost) compared to next-generation sequencing alone in newly-diagnosed metastatic colorectal cancer was using high-sensitivity artificial intelligence followed by confirmatory high-specificity polymerase chain reaction or immunohistochemistry panel for patients testing negative by artificial intelligence ($400 million, 12.9%). The high-specificity artificial intelligence-only strategy resulted in the most favorable clinical impact, with 97% diagnostic accuracy in guiding genotype-directed treatment and average time to treatment initiation of less than one day. Artificial intelligence has the potential to reduce both time to treatment initiation and costs in the metastatic colorectal cancer setting without meaningfully sacrificing diagnostic accuracy. We expect the artificial intelligence value proposition to improve in coming years, with increasing diagnostic accuracy and decreasing costs of processing power. To extract maximal value from the technology, health systems should evaluate integrating diagnostic histopathologic artificial intelligence into institutional protocols, perhaps in place of other genotyping methodologies.
circ0093740 Promotes Tumor Growth and Metastasis by Sponging miR-136/145 and Upregulating DNMT3A in Wilms Tumor
Authors: Cao Juan , Huang Zhongying , Ou Shunling , Wen Feiqiu , Yang Guocheng , Miao Qiuling , Zhang Huang , Wang Yue , He Xiaoxiao , Shan Yingying , Liu Sixi , Jiang Lijuan
Published: June 2021

As a research hotspot, circular RNAs (circRNAs) is one type of non-coding RNAs which have many different functions in biological processes. However, there is lack of study investigating the underlying molecular mechanism and the potential roles of circRNAs in Wilms tumor. We conducted a high-throughput microarray sequencing to screen differentially expressed circRNAs in Wilms tumor. A novel circRNA (circ0093740) was identified as a frequently upregulated circRNA in Wilms tumor cells and tissues. Suppression of circ0093740 remarkably inhibited the proliferation and migration ability in Wilms tumor, validated by several experiments. The molecular mechanism of circ0093740 was investigated by luciferase assays and RNA immunoprecipitation assays. The results revealed that circ0093740 promotes the growth and migration ability by sponging miR-136/145 and upregulating DNMT3A. In conclusion, our study discovered the biological role of the circ0093740-miR-136/145-DNMT3A axis in Wilms tumor growth and metastasis which is important for developing new treatment strategy.
Single-Cell RNA-seq Identification of the Cellular Molecular Characteristics of Sporadic Bilateral Clear Cell Renal Cell Carcinoma
Authors: Yu Zhenyuan , Lu Wenhao , Su Cheng , Lv Yufang , Ye Yu , Guo Bingqian , Liu Deyun , Yan Haibiao , Mi Hua , Li Tianyu , Zhang Qingyun , Cheng Jiwen , Mo Zengnan
Published: June 2021

Bilateral renal cell carcinoma (RCC) is a rare disease that can be classified as either familial or sporadic. Studying the cellular molecular characteristics of sporadic bilateral RCC is important to provide guidance for clinical treatment. Cellular molecular characteristics can be expressed at the RNA level, especially at the single-cell degree. Single-cell RNA sequencing (scRNA-seq) was performed on bilateral clear cell RCC (ccRCC). A total of 3,575 and 3,568 high-quality single-cell transcriptome data were captured from the left and right tumour tissues, respectively. Gene characteristics were identified by comparing left and right tumours at the scRNA level. The complex cellular environment of bilateral ccRCC was presented by using scRNA-seq. Single-cell transcriptomic analysis revealed high similarity in gene expression among most of the cell types of bilateral RCCs but significant differences in gene expression among different site tumour cells. Additionally, the potential biological function of different tumour cell types was determined by gene ontology (GO) analysis. The transcriptome characteristics of tumour tissues in different locations at the single-cell transcriptome level were revealed through the scRNA-seq of bilateral sporadic ccRCC. This work provides new insights into the diagnosis and treatment of bilateral RCC.