bluuebunny/crossref_metadata_2025 huggingface dataset:
Public Model of Intellectual Property Management for AR4D-Systems (Agricultural Research for Development)
Authors: Lytvynchuk Iryna L. , Molodetska Kateryna V. , Skydan Oleh V. , Zaburanna Lesia V.
Published: August 2021

The paper attempts to define the trends of the intellectual property (ІР) management in the framework of an agrarian economy. The object of the investigation are the controversies of intellectual property relations in the systems of agricultural research for development (AR4D-systems) that testify to the difficulties in ІР management. Taking into account a global trend of changing the correlation of private and public interests to the benefit of the latter in terms of managing intellectual property in AR4D-systems, the paper aims to develop a comprehensive model of intellectual property public management (that guarantees fair balance of interests) and to clarify how to evaluate the integral efficiency of such model. The theoretical basis of the study were existing analytical investigations of the intellectual property policies (conventional policy standard; open innovation policy; mixed policies of combining intellectual property rights regimes). The main obtained result of the study is a general concept of the comprehensive model of intellectual property public management for the AR4D systems based on 5 managing clusters. The integral efficiency monitoring of the proposed model was tested on the example of Ukraine with the help of the methods of multicriteria optimization of the vector criterion. The results show that the integral efficiency of the Ukrainian model is higher than average, but it can be increased by improving the tools of the information and communication support cluster and the cluster of organizational and technical assistance and capacity building such as the availability of the mobilization fund, the availability of the specialized electronic credit and investment platforms, the level of awareness of the users, the number of users of the system's electronic services. The practical value of the obtained results is their strategic impact on a sustainable development policy.
Ensuring the Marketing Activities of Agricultural Enterprises: Strategic and Tactical Decisions
Authors: Riabchyk Alla , Babicheva Olena , Nahorna Olena , Korchynska Olena , Bilousko Tamila
Published: August 2021

The strategy of agricultural enterprises is transformed under the influence of external requirements. Limited opportunities for agricultural enterprises to adapt to harsh economic and environmental conditions, especially in developing countries, determine strategic opportunities and decisions. The purpose of an article was to study the features of the strategy and tactics of marketing activities of agricultural enterprises to identify their effectiveness in order to support the development of activities. The methodology is based on the theory of strategic decision-making and the concept of sustainable agriculture to identify the effectiveness of strategies and tactics of marketing activities of agricultural firms in Hungary, Poland, Romania, Slovenia. The results show a low level of strategic orientation of rural enterprises. State support does little effort to stimulate differentiation and niche specialization of agricultural producers, as evidenced by the constant dynamics of agricultural production. Investing in physical assets is the most effective tool to support the agricultural sector. Cooperation and collaboration among enterprises is not widespread and single-owner farming is the most common organizational form in the agricultural sector. Producers' pricing policies remain stable and depend on market conditions: product prices fluctuated slightly. The practical value of the results lies in taking into account the identified effective ways of state support for agricultural producers in promoting the strategy of differentiation of agricultural products.
Natural Resource Potential of Industrial Development of The Tashkent Economic District
Authors: Nazarov Mamatkodir I. , Rakhmanov Bekzod B. , Yanchuk Sergey L. , Kurbanov Shuxrat B. , Tashtayeva Saida K. , Abdalova Zulhumor T.
Published: August 2021

The key factors in the production development and location, including industrial production, in any region, are the territorial structure of natural resources and the level of production infrastructure development. At present, the industry is one of the leading sectors of the developed countries' economy. Therefore, the Government of Uzbekistan, from the first days of state independence, prioritises the industry development, its modernisation and diversification when reforming the national economy. Due to this, over the past ten years, the industrial production share in the country's GDP has grown significantly and amounts to almost 1/3 of it. However, the participation of regions in gross industrial output is very uneven, and a number of them, in the presence of high natural resource potential, still retain agricultural specialisation. The paper presents an economic and geographical analysis of natural resources as a factor of industrial development in the Tashkent economic district. The general characteristic of mineral and raw material balance of the Tashkent region in the context of administrative districts (rural areas) is given. The paper describes the current development state of the territorial and sectoral structure of the Tashkent region and Tashkent city. The study analyses reserves and the involvement level of mineral resources in the context of administrative districts. The authors of this paper considered the issues and prospects of territorial and sectoral structure establishment and development in Tashkent economic district industry.
Activation of Pancreatic Stellate Cells Is Beneficial for Exocrine but Not Endocrine Cell Differentiation in the Developing Human Pancreas
Authors: Li Jinming , Chen Bijun , Fellows George F. , Goodyer Cynthia G. , Wang Rennian
Published: August 2021

Pancreatic stellate cells (PaSCs) are non-endocrine, mesenchymal-like cells that reside within the peri-pancreatic tissue of the rodent and human pancreas. PaSCs regulate extracellular matrix (ECM) turnover in maintaining the integrity of pancreatic tissue architecture. Although there is evidence indicating that PaSCs are involved in islet cell survival and function, its role in islet cell differentiation during human pancreatic development remains unclear. The present study examines the expression pattern and functional role of PaSCs in islet cell differentiation of the developing human pancreas from late 1st to 2nd trimester of pregnancy. The presence of PaSCs in human pancreata (8–22 weeks of fetal age) was characterized by ultrastructural, immunohistological, quantitative RT-PCR and western blotting approaches. Using human fetal PaSCs derived from pancreata at 14–16 weeks, freshly isolated human fetal islet-epithelial cell clusters (hIECCs) were co-cultured with active or inactive PaSCs in vitro. Ultrastructural and immunofluorescence analysis demonstrated a population of PaSCs near ducts and newly formed islets that appeared to make complex cell-cell dendritic-like contacts. A small subset of PaSCs co-localized with pancreatic progenitor-associated transcription factors (PDX1, SOX9, and NKX6-1). PaSCs were highly proliferative, with significantly higher mRNA and protein levels of PaSC markers (desmin, αSMA) during the 1st trimester of pregnancy compared to the 2nd trimester. Isolated human fetal PaSCs were identified by expression of stellate cell markers and ECM. Suppression of PaSC activation, using all-trans retinoic acid (ATRA), resulted in reduced PaSC proliferation and ECM proteins. Co-culture of hIECCs, directly on PaSCs or indirectly using Millicell® Inserts or using PaSC-conditioned medium, resulted in a reduction the number of insulin+ cells but a significant increase in the number of amylase+ cells. Suppression of PaSC activation or Notch activity during the co-culture resulted in an increase in beta-cell differentiation. This study determined that PaSCs, abundant during the 1st trimester of pancreatic development but decreased in the 2nd trimester, are located near ductal and islet structures. Direct and indirect co-cultures of hIECCs with PaSCs suggest that activation of PaSCs has opposing effects on beta-cell and exocrine cell differentiation during human fetal pancreas development, and that these effects may be dependent on Notch signaling.
Anatase-Wrapped Rutile Nanorods as an Effective Electron Collector in Hybrid Photoanodes for Visible Light-Driven Oxygen Evolution
Authors: Gong Ruihao , Mitoraj Dariusz , Leiter Robert , Mundszinger Manuel , Mengele Alexander K. , Krivtsov Igor , Biskupek Johannes , Kaiser Ute , Beranek Radim , Rau Sven
Published: August 2021

Arrays of single crystal TiO2 rutile nanorods (RNRs) appear highly promising as electron-collecting substrates in hybrid photoanodes as the RNRs offer direct charge carriers transport pathways, contrary to the conventional electrodes prepared from TiO2 powders that suffer from the numerous charge traps at the grain boundaries. However, the specific surface area of the nanorods is highly limited by their smooth morphology, which might be detrimental in view of utilizing the RNR as a substrate for immobilizing other functional materials. In this study, we developed a novel anatase-wrapped RNR (ARNR) material fabricated by a facile seed layer-free hydrothermal method. The ARNR comprises polycrystalline anatase nanoparticles formed on the surface of RNR, resulting in a large surface area that provides more deposition sites compared to the bare nanorods. Herein, we functionalize ARNR and RNR electrodes with polymeric carbon nitride (CNx) coupled with a CoO(OH)x cocatalyst for dioxygen evolution. The anatase wrapping of the rutile nanorod scaffold is found to be crucial for effective deposition of CNx and for improved photoanode operation in visible light-driven (λ > 420 nm) oxygen evolution, yielding a significant enhancement of photocurrent (by the factor of ∼3.7 at 1.23 V vs. RHE) and faradaic efficiency of oxygen evolution (by the factor of ∼2) as compared to photoanodes without anatase interlayer. This study thus highlights the importance of careful interfacial engineering in constructing photoelectrocatalytic systems for solar energy conversion and paves the way for the use of ARNR-based electron collectors in further hybrid and composite photochemical architectures for solar fuel production.
Wide Application of Minimally Processed Saliva on Multiple RT-qPCR Kits for SARS-CoV-2 Detection in Indonesia
Authors: Mahendra Caroline , Kaisar Maria Mardalena Martini , Vasandani Suraj Rajan , Surja Sem Samuel , Tjoa Enty , Chriestya Febie , Junusmin Kathleen Irena , Widowati Tria Asri , Irwanto Astrid , Ali Soegianto
Published: August 2021

Saliva as a sample matrix has been an attractive alternative for the detection of SARS-CoV-2. However, due to potential variability in collection and processing steps, evaluating a proposed workflow amongst the local population is recommended. Here, we aim to validate the collection and treatment of human saliva as a direct specimen for RT-qPCR-based detection of SARS-CoV-2 in Indonesia. We demonstrated that SARS-CoV-2 target genes were detected in saliva specimens and remained stable for five days either refrigerated or stored at room temperature. The method of processing saliva specimens described in this report bypasses the need for an RNA-extraction process, thereby reducing the cost, time, and manpower required for processing samples. The developed method was tested across nine commercial kits, including the benchmark, to demonstrate its wide applicability on multiple existing workflows. Our developed method achieved an 86% overall agreement rate compared to paired nasopharyngeal and oropharyngeal swab specimens (NPOP). With the assistance of a saliva sampling device, the collection was found to be more convenient for individuals and improved the overall agreement rate to 97%.
The Clinical Potential of Oral Microbiota as a Screening Tool for Oral Squamous Cell Carcinomas
Authors: Zhou Xinxuan , Hao Yu , Peng Xian , Li Bolei , Han Qi , Ren Biao , Li Mingyun , Li Longjiang , Li Yi , Cheng Guo , Li Jiyao , Ma Yue , Zhou Xuedong , Cheng Lei
Published: August 2021

Introduction

The oral squamous cell carcinoma (OSCC) is detrimental to patients’ physical and mental health. The prognosis of OSCC depends on the early diagnosis of OSCC in large populations.

Objectives

Here, the present study aimed to develop an early diagnostic model based on the relationship between OSCC and oral microbiota.

Methods

Overall, 164 samples were collected from 47 OSCC patients and 48 healthy individuals as controls, including saliva, subgingival plaque, the tumor surface, the control side (healthy mucosa), and tumor tissue. Based on 16S rDNA sequencing, data from all the five sites, and salivary samples only, two machine learning models were developed to diagnose OSCC.

Results

The average diagnostic accuracy rates of five sites and saliva were 98.17% and 95.70%, respectively. Cross-validations showed estimated external prediction accuracies of 96.67% and 93.58%, respectively. The false-negative rate was 0%. Besides, it was shown that OSCC could be diagnosed on any one of the five sites. In this model, Actinobacteria, Fusobacterium, Moraxella, Bacillus, and Veillonella species exhibited strong correlations with OSCC.

Conclusion

This study provided a noninvasive and inexpensive way to diagnose malignancy based on oral microbiota without radiation. Applying machine learning methods in microbiota data to diagnose OSCC constitutes an example of a microbial assistant diagnostic model for other malignancies.
MiR-3064 in Epicardial Adipose-Derived Exosomes Targets Neuronatin to Regulate Adipogenic Differentiation of Epicardial Adipose Stem Cells
Authors: Yang Wenkai , Tu Hanjian , Tang Kai , Huang Haozhong , Ou Shi , Wu Jianguo
Published: August 2021

Backgroud: The metabolism of epicardial adipose tissue (EAT) is closely related to coronary atherosclerotic heart disease (CAHD), but the specific mechanism is not fully understood. In this study, we investigated the effects of EAT microenvironment on adipose metabolism from the viewpoint of EAT-derived exosomes and epicardial adipose stem cells (EASCs).

Methods: EAT samples from CAHD patients and non-CAHD patients were collected to obtain exosomes via tissue culture. MiRNA sequencing was performed to analyze differences in miRNA expression in exosomes between groups. Luciferase reporter assay was then performed to verify the miRNA target gene. EAT was digested by collagenase to obtain EASCs, which were induced to mature adipocytes in vitro. Immunochemical staining and western blotting were performed to detect protein expression levels.

Results: The results showed that CAHD patients had higher levels of EASCs in EAT, and no significant difference in the adipogenic differentiation ability of EASCs was observed between CAHD and non-CAHD patients in vitro. This indicates that the EAT microenvironment is a key factor affecting the adipogenic differentiation of EASCs. The EAT-derived exosomes from CAHD patients inhibited adipogenic differentiation of EASCs in vitro. Sequencing analysis showed that miR-3064-5p was highly expressed in EAT-derived exosomes in CAHD patients, and its inhibitor could improve the adipogenic differentiation of EASCs. Luciferase reporter assay results showed that the target gene of miR-3064-5p is neuronatin (Nnat). Nnat remained silent in EASCs and was less expressed in EAT of CAHD patients.

Conclusion: Abovementioned results suggest that Nnat is the key to regulating the adipogenic differentiation of EASCs, and miR-3064-5p in EAT-derived exosomes can inhibit the expression of Nnat by targeting its mRNA, thereby affecting the adipogenic differentiation of EASCs.
Impact of Uterine Adenomyosis on Pregnancy Outcomes in Women Undergoing In Vitro Fertilization Treated With a Long-Term Pituitary Downregulation Protocol
Authors: Zhang Jiaxin , Hu Linli , Bu Zhiqin , Sun Yingpu
Published: August 2021

Background

Some studies have demonstrated that adenomyosis patients can achieve a comparable pregnancy outcome with women with normal uteruses, while there is no unanimous conclusion at present.

Method

We recruited 65 adenomyosis patients and 260 frequency-matched control women with endometriosis at a ratio of 1:4 according to age. Clinical pregnancy rate, spontaneous abortion rate, and live birth rate were compared between these two groups after controlling other factors.

Results

Compared with endometriosis patients, adenomyosis patients had a higher antral follicle count (AFC) (12.71 vs 11.65, P=0.027). Though the two groups had the same number of embryos transferred, adenomyosis patients had an obviously declined implantation rate (31.91% vs 46.74%, P=0.005), clinical pregnancy rate (47.06% vs 64.42%, P=0.028), live birth rate (31.37% vs 54.81%, P=0.004), and significantly increased spontaneous abortion rate (33.33% vs 13.43%, P=0.034). Multivariate logistic regression analysis showed that adenomyosis had adverse influences on pregnancy outcome when age and the number of embryo transfers were controlled (adjusted OR=0.361, P=0.003).

Conclusion

Even after being matched with age, adenomyosis still had adverse influences on the pregnancy outcome of IVF in patients undergoing the long protocol.
A Review of Human Exposure to Microplastics and Insights Into Microplastics as Obesogens
Authors: Kannan Kurunthachalam , Vimalkumar Krishnamoorthi
Published: August 2021

The ubiquitous exposure of humans to microplastics (MPs) through inhalation of particles in air and ingestion in dust, water, and diet is well established. Humans are estimated to ingest tens of thousands to millions of MP particles annually, or on the order of several milligrams daily. Available information suggests that inhalation of indoor air and ingestion of drinking water bottled in plastic are the major sources of MP exposure. Little is known on the occurrence of MPs in human diet. Evidence is accumulating that feeding bottles and medical devices can contribute to MP exposure in newborns and infants. Biomonitoring studies of human stool, fetus, and placenta provide direct evidence of MP exposure in infants and children. MPs <20 µm were reported to cross biological membranes. Although plastics were once perceived as inert materials, MP exposure in laboratory animals is linked to various forms of inflammation, immunological response, endocrine disruption, alteration of lipid and energy metabolism, and other disorders. Whereas exposure to MPs itself is a concern, MPs can also be sources of exposure to plastic additives and other toxicants. Exposure of human cell lines to MP additives such as phthalates, bisphenols, and organotins causes adverse effects through the activation of nuclear receptors, peroxisome proliferator-activated receptors (PPARs) α, β, and γ, and retinoid X receptor (RXR), leading to oxidative stress, cytotoxicity, immunotoxicity, thyroid hormone disruption, and altered adipogenesis and energy production. The size, shape, chemical composition, surface charge, and hydrophobicity of MPs influence their toxicity. Maternal transfer of MPs to the developing fetus has been demonstrated in exposed laboratory animals and through the analysis of human placenta. In laboratory animal studies, maternal exposure to MPs altered energy and lipid metabolism in offspring and subsequent generations. Moreover, concomitant with the global increase in plastics production, the prevalence of overweight and obesity in human populations has increased over the past five decades, and there is evidence to support the hypothesis that MPs and their additives are potential obesogens. Even though MP exposures are ubiquitous and toxic effects from such exposures are a concern, systematic studies on this topic remain urgently needed.
Mapping Transcriptome Data to Protein–Protein Interaction Networks of Inflammatory Bowel Diseases Reveals Disease-Specific Subnetworks
Authors: Maden Sefika Feyza , Acuner Saliha Ece
Published: August 2021

Inflammatory bowel disease (IBD) is the common name for chronic disorders associated with the inflammation of the gastrointestinal tract. IBD is triggered by environmental factors in genetically susceptible individuals and has a significant number of incidences worldwide. Crohn’s disease (CD) and ulcerative colitis (UC) are the two distinct types of IBD. While involvement in ulcerative colitis is limited to the colon, Crohn’s disease may involve the whole gastrointestinal tract. Although these two disorders differ in macroscopic inflammation patterns, they share various molecular pathogenesis, yet the diagnosis can remain unclear, and it is important to reveal their molecular signatures in the network level. Improved molecular understanding may reveal disease type-specific and even individual-specific targets. To this aim, we determine the subnetworks specific to UC and CD by mapping transcriptome data to protein–protein interaction (PPI) networks using two different approaches [KeyPathwayMiner (KPM) and stringApp] and perform the functional enrichment analysis of the resulting disease type-specific subnetworks. TP63 was identified as the hub gene in the UC-specific subnet and p63 tumor protein, being in the same family as p53 and p73, has been studied in literature for the risk associated with colorectal cancer and IBD. APP was identified as the hub gene in the CD-specific subnet, and it has an important role in the pathogenesis of Alzheimer’s disease (AD). This relation suggests that some similar genetic factors may be effective in both AD and CD. Last, in order to understand the biological meaning of these disease-specific subnets, they were functionally enriched. It is important to note that chemokines—special types of cytokines—and antibacterial response are important in UC-specific subnets, whereas cytokines and antimicrobial responses as well as cancer-related pathways are important in CD-specific subnets. Overall, these findings reveal the differences between IBD subtypes at the molecular level and can facilitate diagnosis for UC and CD as well as provide potential molecular targets that are specific to disease subtypes.
Case Report: Identification of a Novel Homozygous Mutation in GPD1 Gene of a Chinese Child With Transient Infantile Hypertriglyceridemia
Authors: Lin Haihua , Fang Youhong , Han Lin , Chen Jie , Lou Jingan , Yu Jindan
Published: August 2021

Transient infantile hypertriglyceridemia is a rare autosomal recessive disorder characterized by hypertriglyceridemia, hypohepatia, hepatomegaly, hepatic steatosis and fibrosis in infancy. Mutations in GPD1 gene are considered the causative factor but the underlying mechanism of this disorder is still enigmatic. To date, only 24 different GPD1 mutations have been reported in the literature worldwide with transient infantile hypertriglyceridemia or relevant conditions. Here we report a Chinese girl who developed hepatomegaly hepatic steatosis, elevated transaminase and hypertriglyceridemia from the age of 4 months. A novel homozygous variant c.454C>T (p.Q152*) was found in GPD1 gene by next-generation sequencing. This patient is the 3rd Asian reported with transient infantile hypertriglyceridemia. We summarized the clinical presentations of transient infantile hypertriglyceridemia and also expanded the spectrum of disease-causing mutations in GPD1.
Recombinant Protein Filovirus Vaccines Protect Cynomolgus Macaques From Ebola, Sudan, and Marburg Viruses
Authors: Lehrer Axel T. , Chuang Eleanore , Namekar Madhuri , Williams Caitlin A. , Wong Teri Ann S. , Lieberman Michael M. , Granados Alex , Misamore John , Yalley-Ogunro Jake , Andersen Hanne , Geisbert Joan B. , Agans Krystle N. , Cross Robert W. , Geisbert Thomas W.
Published: August 2021

Ebola (EBOV), Marburg (MARV) and Sudan (SUDV) viruses are the three filoviruses which have caused the most fatalities in humans. Transmission from animals into the human population typically causes outbreaks of limited scale in endemic regions. In contrast, the 2013-16 outbreak in several West African countries claimed more than 11,000 lives revealing the true epidemic potential of filoviruses. This is further emphasized by the difficulty seen with controlling the 2018-2020 outbreak of EBOV in the Democratic Republic of Congo (DRC), despite the availability of two emergency use-approved vaccines and several experimental therapeutics targeting EBOV. Moreover, there are currently no vaccine options to protect against the other epidemic filoviruses. Protection of a monovalent EBOV vaccine against other filoviruses has never been demonstrated in primate challenge studies substantiating a significant void in capability should a MARV or SUDV outbreak of similar magnitude occur. Herein we show progress on developing vaccines based on recombinant filovirus glycoproteins (GP) from EBOV, MARV and SUDV produced using the Drosophila S2 platform. The highly purified recombinant subunit vaccines formulated with CoVaccine HT™ adjuvant have not caused any safety concerns (no adverse reactions or clinical chemistry abnormalities) in preclinical testing. Candidate formulations elicit potent immune responses in mice, guinea pigs and non-human primates (NHPs) and consistently produce high antigen-specific IgG titers. Three doses of an EBOV candidate vaccine elicit full protection against lethal EBOV infection in the cynomolgus challenge model while one of four animals infected after only two doses showed delayed onset of Ebola Virus Disease (EVD) and eventually succumbed to infection while the other three animals survived challenge. The monovalent MARV or SUDV vaccine candidates completely protected cynomolgus macaques from infection with lethal doses of MARV or SUDV. It was further demonstrated that combinations of MARV or SUDV with the EBOV vaccine can be formulated yielding bivalent vaccines retaining full efficacy. The recombinant subunit vaccine platform should therefore allow the development of a safe and efficacious multivalent vaccine candidate for protection against Ebola, Marburg and Sudan Virus Disease.
Polarized Secretion of APRIL by the Tonsil Epithelium Upon Toll-Like Receptor Stimulation
Authors: Sturm Nathalie , Quinterot Melanie , Guyot Jean-Philippe , Righini Christian , Daamen Willeke F. , van Kuppevelt Toin H. , Huard Bertrand
Published: August 2021

In mucosa such as tonsil, antibody-producing plasmocytes (PCs) lie in sub-epithelium space, which is thought to provide a suitable environment for their survival. A proliferation inducing ligand (APRIL) is one key survival factor for PCs present in this area. According to in situ staining, apical epithelial cells produced APRIL, and the secreted product had to migrate all through the stratified surface epithelium to reach basal cells. A similar process also occurred in the less-organized crypt epithelium. Tonsil epithelial cells captured secreted APRIL, thanks to their surface expression of the APRIL coreceptor, either syndecan-1 or -4 depending on their differentiation stage. In the most basal epithelial cells, secreted APRIL accumulated inside secretory lamp-1+ vesicles in a polarized manner, facing the sub-epithelium. The tonsil epithelium upregulated APRIL production by apical cells and secretion by basal cells upon Toll-like receptor stimulation. Furthermore, LPS-stimulated epithelial cells sustained in vitro PC survival in a secreted APRIL-dependent manner. Taken together, our study shows that the tonsil epithelium responds to pathogen sensing by a polarized secretion of APRIL in the sub-epithelial space, wherein PCs reside.
Achieving Precision Medicine in Allergic Disease: Progress and Challenges
Authors: Proper Steven P. , Azouz Nurit P. , Mersha Tesfaye B.
Published: August 2021

Allergic diseases (atopic dermatitis, food allergy, eosinophilic esophagitis, asthma and allergic rhinitis), perhaps more than many other traditionally grouped disorders, share several overlapping inflammatory pathways and risk factors, though we are still beginning to understand how the relevant patient and environmental factors uniquely shape each disease. Precision medicine is the concept of applying multiple levels of patient-specific data to tailor diagnoses and available treatments to the individual; ideally, a patient receives the right intervention at the right time, in order to maximize effectiveness but minimize morbidity, mortality and cost. While precision medicine in allergy is in its infancy, the recent success of biologics, development of tools focused on large data set integration and improved sampling methods are encouraging and demonstrates the utility of refining our understanding of allergic endotypes to improve therapies. Some of the biggest challenges to achieving precision medicine in allergy are characterizing allergic endotypes, understanding allergic multimorbidity relationships, contextualizing the impact of environmental exposures (the “exposome”) and ancestry/genetic risks, achieving actionable multi-omics integration, and using this information to develop adequately powered patient cohorts and refined clinical trials. In this paper, we highlight several recently developed tools and methods showing promise to realize the aspirational potential of precision medicine in allergic disease. We also outline current challenges, including exposome sampling and building the “knowledge network” with multi-omics integration.
Supplementing Chitosan Oligosaccharide Positively Affects Hybrid Grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂) Fed Dietary Fish Meal Replacement With Cottonseed Protein Concentrate: Effects on Growth, Gut Microbiota, Antioxidant Function and Immune Response
Authors: Chen Guofeng , Yin Bin , Liu Hongyu , Tan Beiping , Dong Xiaohui , Yang Qihui , Chi Shuyan , Zhang Shuang
Published: August 2021

Oligosaccharides have recently received much attention from researchers owing to their multiple biological activities. This study was conducted to investigate the effects of a diet with reduced fish meal and chitosan oligosaccharide (COS) supplementation on a hybrid grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂). Seven isonitrogenous and isolipidic types of diet were formulated to feed the groupers for 56 days. To prepare the feed, a reference diet (FM group) containing 55% fish meal was used. Concentrated cottonseed protein (CPC) was used to replace 45% of the fish meal protein, and different COS supplementation levels (0, 0.2%, 0.4, 0.6, 0.8, and 1%) were added. After an 8-week breeding trial, Vibrio harveyi bacteria were injected into the groupers for a 7-day challenge test. The results showed that the FM and COS0.4 groups showed the best growth performance among the groups (p < 0.05); however, there was no significant difference in the survival rate (p > 0.05). Unlike in the FM group, adhesion and breakage of the intestinal plica occurred in the COS0 group. The height and width of the gut fold reached maximum values in the COS0.4 group (p < 0.05). Microbiome sequencing suggested that there was a stable microbiota core in the gut of the groupers. With increasing COS levels, the abundance of both beneficial bacteria and conditional pathogens increased; the activities of serum glucose oxidase, catalase, and total superoxide dismutase also increased (p < 0.05). In the gut tissue, the activities of glutathione peroxidase, glutathione reductase, and glutamine increased first but then decreased (p < 0.05); the contents of lysozyme, acid phosphatase, complements C3 and C4, and IgM showed upward trends (p < 0.05). Compared with that in the FM group, the expression of IL-1β and TNF-α in the COS0 group was upregulated. Gene expression levels of TLR22, TGF-β, and Nrf2 increased first but then decreased with COS supplementation levels (p < 0.05). COS supplementation reduced the cumulative mortality of the groupers in the challenge test (p < 0.05). In general, the results of this study demonstrated that dietary COS supplementation enhanced growth performance, intestinal health, and antioxidant and immune responses of groupers fed with a low-fish meal diet. The optimal and acceptable levels of COS supplement were 0.45 and 0.4–0.6%, respectively; these values can provide a reference for developing aquatic prebiotics.
The Role of Atopy in COPD and Asthma
Authors: Karakioulaki Meropi , Papakonstantinou Eleni , Goulas Antonios , Stolz Daiana
Published: August 2021

Common to several allergic diseases is the generation of immunoglobulin E (IgE) by plasma cells, when exposed to an innocuous antigen. Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent chronic airway inflammatory diseases. Asthma is mediated in some patients through eosinophilic inflammatory mechanisms that include allergic sensitization and Th2-mediated immune airway response. COPD, on the other hand is mainly considered a Th1-mediated inflammatory process with neutrophilic predominance or a non-Th2 inflammation, occasionally associated with the presence of airway bacteria or viruses. IgE production appears to play an important role in the development of both COPD and asthma, as it has been associated to respiratory symptoms, lung function, bacterial and viral infections, airway remodeling and bronchial hyperreactivity in both diseases. The aim of this review is to summarize all current data concerning the role of specific and total IgE in COPD and asthma and to highlight similarities and differences in view of possible therapeutic interventions.
Containing the Transmission of COVID-19: A Modeling Study in 160 Countries
Authors: Niu Yan , Rui Jia , Wang Qiupeng , Zhang Wei , Chen Zhiwei , Xie Fang , Zhao Zeyu , Lin Shengnan , Zhu Yuanzhao , Wang Yao , Xu Jingwen , Liu Xingchun , Yang Meng , Zheng Wei , Chen Kaixin , Xia Yilan , Xu Lijuan , Zhang Shi , Ji Rongrong , Jin Taisong , Chen Yong , Zhao Benhua , Su Yanhua , Song Tie , Chen Tianmu , Hu Guoqing
Published: August 2021

Background: It is much valuable to evaluate the comparative effectiveness of the coronavirus disease 2019 (COVID-19) prevention and control in the non-pharmacological intervention phase of the pandemic across countries and identify useful experiences that could be generalized worldwide.

Methods: In this study, we developed a susceptible–exposure–infectious–asymptomatic–removed (SEIAR) model to fit the daily reported COVID-19 cases in 160 countries. The time-varying reproduction number (Rt) that was estimated through fitting the mathematical model was adopted to quantify the transmissibility. We defined a synthetic index (IAC) based on the value of Rt to reflect the national capability to control COVID-19.

Results: The goodness-of-fit tests showed that the SEIAR model fitted the data of the 160 countries well. At the beginning of the epidemic, the values of Rt of countries in the European region were generally higher than those in other regions. Among the 160 countries included in the study, all European countries had the ability to control the COVID-19 epidemic. The Western Pacific Region did best in continuous control of the epidemic, with a total of 73.76% of countries that can continuously control the COVID-19 epidemic, while only 43.63% of the countries in the European Region continuously controlled the epidemic, followed by the Region of Americas with 52.53% of countries, the Southeast Asian Region with 48% of countries, the African Region with 46.81% of countries, and the Eastern Mediterranean Region with 40.48% of countries.

Conclusion: Large variations in controlling the COVID-19 epidemic existed across countries. The world could benefit from the experience of some countries that demonstrated the highest containment capabilities.
The Influence of Cesarean Section on the Composition and Development of Gut Microbiota During the First 3 Months of Life
Authors: Long Gao , Hu Yuting , Tao Enfu , Chen Bo , Shu Xiaoli , Zheng Wei , Jiang Mizu
Published: August 2021

The intestinal microbiota has emerged as a critical regulator of growth and development in the early postnatal period of life. Cesarean section (CS) delivery is one of the strongest disrupting factors of the normal colonization process and has been reported as a risk factor for disorders in later life. In this study, we dynamically and longitudinally evaluated the impact of CS on the initial colonization pattern and development of gut microbiota by 16 healthy Chinese infants with fecal samples collected at 9 time points (day 5, day 8, day 11, week 2, week 4, week 6, week 7, month 2, and month 3) during the first 3 months of life. The V3–V4 regions of 16S rRNA gene were analyzed by Illumina sequencing. In comparison with vaginally delivered (VD) infants, infants born by CS showed decreased relative abundance of Bacteroides and Parabacteroides and enrichment of Clostridium_sensu_stricto_1, Enterococcus, Klebsiella, Clostridioides, and Veillonella. Most interestingly, Firmicutes/Bacteroidetes ratio was found to be significantly higher in the CS group than in the VD group from day 5 until month 3. Besides, the results of microbial functions showed that the VD group harbored significantly higher levels of functional genes in vitamin B6 metabolism at day 5, day 8, week 2, week 4, week 6, week 7, month 2, and month 3 and taurine and hypotaurine metabolism at day 5, while the phosphotransferase system and starch and sucrose metabolism involved functional genes were plentiful in the CS group at day 11, week 2, week 4, week 6, week 7, and month 2 and at week 2, week 7, and month 2, respectively. Our results establish a new evidence that CS affected the composition and development of gut microbiota in the first 3 months and provide a novel insight into strategies for CS-related disorders in later life.
Characterization of Campylobacter spp. Strains Isolated From Wild Birds in Turkey
Authors: Kürekci Cemil , Sakin Fatih , Epping Lennard , Knüver Marie-Theres , Semmler Torsten , Stingl Kerstin
Published: August 2021

Turkey is an important stopover site for many migrating birds between Europe, Asia and Africa. Campylobacter spp. are frequently found in wildlife, in particular waterfowl, and distinct strains are disseminated within this reservoir. In this study, 183 wild birds of hunting areas in Turkey were collected and thermophilic Campylobacter spp. from cloacal swabs were isolated at a prevalence of 5.2% from song thrushes (6/116) and 93% from Eurasian coots (41/44). After PCR species differentiation and flaA restriction profiles determination, C. jejuni and C. coli strains were further investigated by whole genome sequencing. PCR target amplification of the ceuE gene, commonly used for C. coli species-identification was inefficient and even hampered in one isolate. A close look on the ceuE sequence revealed that various mismatches in the ceuE oligo annealing sites caused less efficient diagnostic detection. All C. coli isolates belonged to the environmental clade II and clade III, for which thirty-six novel MLST types were identified. Further single nucleotide polymorphism (SNP) analysis showed a high genomic divergence between the C. coli isolates. High variability was also implicated for putative plasmid-located genes detected in 51% of the C. coli isolates. Distinct gene variants in clades II and III C. coli were identified by a k-mer analysis. After substracting k-mers in common with C. coli clade I database, 11 and 35 distinct genes were identified in clades II and III isolates, mainly involved in surface structures and modifications as well as signal transduction, suggesting niche adaptation of C. coli strains in wild birds. All strains were susceptible against (fluoro-)quinolones, erythromycin, tetracycline, gentamicin and only one isolate was resistant against streptomycin, suggesting that the sensitive phenotype was due to absence of selective pressure and niche separation in wild birds in Turkey. We conclude that Campylobacter spp. isolates from wildlife and environmental sources are still scarce in the databases and that there is a need for more studies on thermophilic Campylobacter spp. from different places all over the world in order to complement our understanding on dissemination and adaptation to distinct niches of this global food-borne pathogen.
A Unique Gene Module in Thermococcales Archaea Centered on a Hypervariable Protein Containing Immunoglobulin Domains
Authors: Makarova Kira S. , Wolf Yuri I. , Karamycheva Svetlana , Koonin Eugene V.
Published: August 2021

Molecular mechanisms involved in biological conflicts and self vs nonself recognition in archaea remain poorly characterized. We apply phylogenomic analysis to identify a hypervariable gene module that is widespread among Thermococcales. These loci consist of an upstream gene coding for a large protein containing several immunoglobulin (Ig) domains and unique combinations of downstream genes, some of which also contain Ig domains. In the large Ig domain containing protein, the C-terminal Ig domain sequence is hypervariable, apparently, as a result of recombination between genes from different Thermococcales. To reflect the hypervariability, we denote this gene module VARTIG (VARiable Thermococcales IG). The overall organization of the VARTIG modules is similar to the organization of Polymorphic Toxin Systems (PTS). Archaeal genomes outside Thermococcales encode a variety of Ig domain proteins, but no counterparts to VARTIG and no Ig domains with comparable levels of variability. The specific functions of VARTIG remain unknown but the identified features of this system imply three testable hypotheses: (i) involvement in inter-microbial conflicts analogous to PTS, (ii) role in innate immunity analogous to the vertebrate complement system, and (iii) function in self vs nonself discrimination analogous to the vertebrate Major Histocompatibility Complex. The latter two hypotheses seem to be of particular interest given the apparent analogy to the vertebrate immunity.
The Perception of Rhizosphere Bacterial Communication Signals Leads to Transcriptome Reprogramming in Lysobacter capsici AZ78, a Plant Beneficial Bacterium
Authors: Bejarano Ana , Perazzolli Michele , Pertot Ilaria , Puopolo Gerardo
Published: August 2021

The rhizosphere is a dynamic region governed by complex microbial interactions where diffusible communication signals produced by bacteria continuously shape the gene expression patterns of individual species and regulate fundamental traits for adaptation to the rhizosphere environment. Lysobacter spp. are common bacterial inhabitants of the rhizosphere and have been frequently associated with soil disease suppressiveness. However, little is known about their ecology and how diffusible communication signals might affect their behavior in the rhizosphere. To shed light on the aspects determining rhizosphere competence and functioning of Lysobacter spp., we carried out a functional and transcriptome analysis on the plant beneficial bacterium Lysobacter capsici AZ78 (AZ78) grown in the presence of the most common diffusible communication signals released by rhizosphere bacteria. Mining the genome of AZ78 and other Lysobacter spp. showed that Lysobacter spp. share genes involved in the production and perception of diffusible signal factors, indole, diffusible factors, and N-acyl-homoserine lactones. Most of the tested diffusible communication signals (i.e., indole and glyoxylic acid) influenced the ability of AZ78 to inhibit the growth of the phytopathogenic oomycete Pythium ultimum and the Gram-positive bacterium Rhodococcus fascians. Moreover, RNA-Seq analysis revealed that nearly 21% of all genes in AZ78 genome were modulated by diffusible communication signals. 13-Methyltetradecanoic acid, glyoxylic acid, and 2,3-butanedione positively influenced the expression of genes related to type IV pilus, which might enable AZ78 to rapidly colonize the rhizosphere. Moreover, glyoxylic acid and 2,3-butanedione downregulated tRNA genes, possibly as a result of the elicitation of biological stress responses. On its behalf, indole downregulated genes related to type IV pilus and the heat-stable antifungal factor, which might result in impairment of twitching motility and antibiotic production in AZ78. These results show that diffusible communication signals may affect the ecology of Lysobacter spp. in the rhizosphere and suggest that diffusible communication signals might be used to foster rhizosphere colonization and functioning of plant beneficial bacteria belonging to the genus Lysobacter.
The Cognitive Connectome in Healthy Aging
Authors: Garcia-Cabello Eloy , Gonzalez-Burgos Lissett , Pereira Joana B. , Hernández-Cabrera Juan Andres , Westman Eric , Volpe Giovanni , Barroso José , Ferreira Daniel
Published: August 2021

Objectives: Cognitive aging has been extensively investigated using both univariate and multivariate analyses. Sophisticated multivariate approaches such as graph theory could potentially capture unknown complex associations between multiple cognitive variables. The aim of this study was to assess whether cognition is organized into a structure that could be called the “cognitive connectome,” and whether such connectome differs between age groups.

Methods: A total of 334 cognitively unimpaired individuals were stratified into early-middle-age (37–50 years, n = 110), late-middle-age (51–64 years, n = 106), and elderly (65–78 years, n = 118) groups. We built cognitive networks from 47 cognitive variables for each age group using graph theory and compared the groups using different global and nodal graph measures.

Results: We identified a cognitive connectome characterized by five modules: verbal memory, visual memory—visuospatial abilities, procedural memory, executive—premotor functions, and processing speed. The elderly group showed reduced transitivity and average strength as well as increased global efficiency compared with the early-middle-age group. The late-middle-age group showed reduced global and local efficiency and modularity compared with the early-middle-age group. Nodal analyses showed the important role of executive functions and processing speed in explaining the differences between age groups.

Conclusions: We identified a cognitive connectome that is rather stable during aging in cognitively healthy individuals, with the observed differences highlighting the important role of executive functions and processing speed. We translated the connectome concept from the neuroimaging field to cognitive data, demonstrating its potential to advance our understanding of the complexity of cognitive aging.
Update in Autoimmune Movement Disorders: Newly Described Antigen Targets in Autoimmune and Paraneoplastic Cerebellar Ataxia
Authors: Garza Madeline , Piquet Amanda L.
Published: August 2021

Movement disorders are a common feature of many antibody-associated neurological disorders. In fact, cerebellar ataxia is one of the most common manifestations of autoimmune neurological diseases. Some of the first autoantibodies identified against antigen targets include anti-neuronal nuclear antibody type 1 (ANNA-1 or anti-Hu) and Purkinje cell cytoplasmic antibody (PCA-1) also known as anti-Yo have been identified in paraneoplastic cerebellar degeneration. Historically these antibodies have been associated with an underlying malignancy; however, recently discovered antibodies can occur in the absence of cancer as well, resulting in the clinical syndrome of autoimmune cerebellar ataxia. The pace of discovery of new antibodies associated with autoimmune or paraneoplastic cerebellar ataxia has increased rapidly over the last few years, and pathogenesis and potential treatment options remains to be explored. Here we will review the literature on recently discovered antibodies associated with autoimmune and paraneoplastic cerebellar ataxia including adaptor protein-3B2 (AP3B2); inositol 1,4,5-trisphophate receptor type 1 (ITPR1); tripartite motif-containing (TRIM) proteins 9, 67, and 46; neurochondrin; neuronal intermediate filament light chain (NIF); septin 5; metabotropic glutamate receptor 2 (mGluR2); seizure-related 6 homolog like 2 (SEZ6L2) and homer-3 antibodies. We will review their clinical characteristics, imaging and CSF findings and treatment response. In addition, we will discuss two clinical case examples of autoimmune cerebellar ataxia.