bluuebunny/crossref_metadata_2025 huggingface dataset:
The incidence of public security policies on political risk
Authors: Hernández Gutiérrez José Carlos
Published: December 2020

The aim of this work is to make explicit the relationship between political risk
and public security policies. The theory through which such a link is established
is the theory of dangerous places. These places are characterized by high levels
of unemployment, poverty, high demographic density, etc. These phenomena
are also threats to security. That there are territories that have such characteristics
is, in a way, the responsibility of governments. Thus, they are also responsible
for the thousands of companies that annually incur millions in losses due
to business victimization. For this reason, it seems essential to take into account
the current or future governments’ crime prevention public policy approaches,
since their decisions can minimize the losses borne by the victimized companies.
Gull Alpha Power of the Chen Type
Authors: Clement Boateng Ampadu
Published: December 2020

In they introduced the Chen distribution, and in they extended the distribution to include its “normalized version”. In this paper, we introduce a variant of the Gull Alpha Power distribution by modifying Chen-G of and show the new family is good in fitting real life data.
Penerapan Senam Rematik terhadap Penurunan Skala Nyeri pada Asuhan Keperawatan Rheumatoid Arthritis di Kelurahan Gebangrejo
Authors: Suharto Dewi Nurviana , Agusrianto Agusrianto , Rantesigi Nirva , Tasnim Tasnim
Published: December 2020

Pendahuluan: Rheumatoid arthritis merupakan kelainan autoimun yang menyebabkan inflamasi sendi yang berlangsung kronik dan mengenai lebih dari lima sendi (poliartritis). Gejala yang sering muncul ialah kekakuan di pagi hari. Pengobatan secara nonfarmakologi dapat dilakukan dengan mengubah gaya hidup yang lebih sehat dan melakukan terapi fisik (senam rematik) yang bisa dilakukan setiap hari. Tujuan: Menggambarkan penerapan Teknik Senam Rematik Terhadap Nyeri Sendi Pada Asuhan Keperawatan Gerontik Dengan Rheumatoid arthritis. Metode Penelitian: yaitu dengan menggunakan metode pendekatan observasional deskriptif dengan desain penelitian studi kasus. Hasil Penelitian: Setelah dilakukan penerapan senam rematik selama 7 hari pada Ny. S didapatkan hasil nyeri pada kaki berkurang. Penerapan senam rematik dapat menurunkan skala nyeri yang dirasakan Ny. S dari (skala 8 (0-10) menjadi 6 (0-10). Saran: Diharapkan klien mampu melakukan terapi fisik (senam rematik) ketika pasien mengalami atau merakan nyeri pada bagian ektremitas.
Phase Transition and Electronic Structures of All-d-Metal Heusler-Type X2MnTi Compounds (X = Pd, Pt, Ag, Au, Cu, and Ni)
Authors: Wu Mengxin , Zhou Feng , Khenata Rabah , Kuang Minquan , Wang Xiaotian
Published: December 2020

In this work, we investigated the phase transition and electronic structures of some newly designed all-d-metal Heusler compounds, X2MnTi (X = Pd, Pt, Ag, Au, Cu, and Ni), by means of the first principles. The competition between the XA and L21 structures of these materials was studied, and we found that X2MnTi favors to feature the L21-type structure, which is consistent with the well-known site-preference rule (SPR). Under the L21 structure, we have studied the most stable magnetic state of these materials, and we found that the ferromagnetic state is the most stable due to its lower energy. Through tetragonal deformation, we found that the L21 structure is no longer the most stable structure, and a more stable tetragonal L10 structure appeared. That is, under the tetragonal strain, the material enjoys a tetragonal phase transformation (i.e., from cubic L21 to tetragonal L10 structure). This mechanism of L21-L10 structure transition is discussed in detail based on the calculated density of states. Moreover, we found that the energy difference between the most stable phases of L10 and L21, defined as ΔEM (ΔEM = ECubic-ETetragonal), can be adjusted by the uniform strain. Finally, the phonon spectra of all tetragonal X2MnTi (X = Pd, Pt, Ag, Au, Cu, and Ni) phases are exhibited, which provides a powerful evidence for the stability of the tetragonal L10 state. We hope that our research can provide a theoretical guidance for future experimental investigations.
E. coli NF73-1 Isolated From NASH Patients Aggravates NAFLD in Mice by Translocating Into the Liver and Stimulating M1 Polarization
Authors: Zhang Yifan , Jiang Weiwei , Xu Jun , Wu Na , Wang Yang , Lin Tianyu , Liu Yun , Liu Yulan
Published: December 2020

Objective

The gut microbiota is associated with nonalcoholic fatty liver disease (NAFLD). We isolated the Escherichia coli strain NF73-1 from the intestines of a NASH patient and then investigated its effect and underlying mechanism.

Methods

16S ribosomal RNA (16S rRNA) amplicon sequencing was used to detect bacterial profiles in healthy controls, NAFLD patients and NASH patients. Highly enriched E. coli strains were cultured and isolated from NASH patients. Whole-genome sequencing and comparative genomics were performed to investigate gene expression. Depending on the diet, male C57BL/6J mice were further grouped in normal diet (ND) and high-fat diet (HFD) groups. To avoid disturbing the bacterial microbiota, some of the ND and HFD mice were grouped as “bacteria-depleted” mice and treated with a cocktail of broad-spectrum antibiotic complex (ABX) from the 8th to 10th week. Then, E. coli NF73-1, the bacterial strain isolated from NASH patients, was administered transgastrically for 6 weeks to investigate its effect and mechanism in the pathogenic progression of NAFLD.

Results

The relative abundance of Escherichia increased significantly in the mucosa of NAFLD patients, especially NASH patients. The results from whole-genome sequencing and comparative genomics showed a specific gene expression profile in E. coli strain NF73-1, which was isolated from the intestinal mucosa of NASH patients. E. coli NF73-1 accelerates NAFLD independently. Only in the HFD-NF73-1 and HFD-ABX-NF73-1 groups were EGFP-labeled E. coli NF73-1 detected in the liver and intestine. Subsequently, translocation of E. coli NF73-1 into the liver led to an increase in hepatic M1 macrophages via the TLR2/NLRP3 pathway. Hepatic M1 macrophages induced by E. coli NF73-1 activated mTOR-S6K1-SREBP-1/PPAR-α signaling, causing a metabolic switch from triglyceride oxidation toward triglyceride synthesis in NAFLD mice.

Conclusions

E. coli NF73-1 is a critical trigger in the progression of NAFLD. E. coli NF73-1 might be a specific strain for NAFLD patients.
A Metagenome-Wide Association Study of Gut Microbiome in Patients With Multiple Sclerosis Revealed Novel Disease Pathology
Authors: Kishikawa Toshihiro , Ogawa Kotaro , Motooka Daisuke , Hosokawa Akiko , Kinoshita Makoto , Suzuki Ken , Yamamoto Kenichi , Masuda Tatsuo , Matsumoto Yuki , Nii Takuro , Maeda Yuichi , Nakamura Shota , Inohara Hidenori , Mochizuki Hideki , Okuno Tatsusada , Okada Yukinori
Published: December 2020

While microbiome plays key roles in the etiology of multiple sclerosis (MS), its mechanism remains elusive. Here, we conducted a comprehensive metagenome-wide association study (MWAS) of the relapsing-remitting MS gut microbiome (ncase = 26, ncontrol = 77) in the Japanese population, by using whole-genome shotgun sequencing. Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis, and pathway analysis). Phylogenetic case-control association tests showed discrepancies of eight clades, most of which were related to the immune system (false discovery rate [FDR] < 0.10; e.g., Erysipelatoclostridium_sp. and Gemella morbillorum). Gene association tests found an increased abundance of one putative dehydrogenase gene (Clo1100_2356) and one ABC transporter related gene (Mahau_1952) in the MS metagenome compared with controls (FDR < 0.1). Molecular pathway analysis of the microbiome gene case-control comparisons identified enrichment of multiple Gene Ontology terms, with the most significant enrichment on cell outer membrane (P = 1.5 × 10−7). Interaction between the metagenome and host genome was identified by comparing biological pathway enrichment between the MS MWAS and the MS genome-wide association study (GWAS) results (i.e., MWAS-GWAS interaction). No apparent discrepancies in alpha or beta diversities of metagenome were found between MS cases and controls. Our shotgun sequencing-based MWAS highlights novel characteristics of the MS gut microbiome and its interaction with host genome, which contributes to our understanding of the microbiome’s role in MS pathophysiology.
Non-invasive Technology Advances in Cancer—A Review of the Advances in the Liquid Biopsy for Endometrial and Ovarian Cancers
Authors: Openshaw Mark R. , McVeigh Terri P.
Published: December 2020

Improving cancer survival rates globally requires improvements in disease detection and monitoring, with the aim of improving early diagnosis and prediction of disease relapse. Traditional means of detecting and monitoring cancers rely largely on imaging and, where possible, blood-based protein biomarkers, many of which are non-specific. Treatments are being improved by identification of inherited and acquired genomic aberrations in tumors, some of which can be targeted by newly developed therapeutic interventions. Treatment of gynecological malignancy is progressively moving toward personalized therapy, as exemplified by application of PARP-inhibition for patients with BRCA-deficient tubo-ovarian cancers, or checkpoint inhibition in patients with mismatch repair-deficient disease. However, the more recent discovery of a group of biomarkers described under the umbrella term of “liquid biopsy” promises significant improvement in our ability to detect and monitor cancers. The term “liquid biopsy” is used to describe an array of tumor-derived material found in blood plasma and other bodily fluids such as ascites, pleural fluid, saliva, and urine. It includes circulating tumors cells (CTCs), circulating nucleic acids including DNA, messenger RNA and micro RNAs, and extracellular vesicles (EVs). In this review, we discuss recent advancements in liquid biopsy for biomarker detection to help in diagnosis, prognosis, and planning of treatment of ovarian and endometrial cancer.
Student and Parent Perspectives of the Transition From Primary to Secondary School for Students With Autism Spectrum Disorder
Authors: Stack Karen , Symonds Jennifer E. , Kinsella William
Published: December 2020

Objective: Transition from primary school to secondary school is an important point in a young person's development. Children's experiences at transition have been found to have an enduring impact on their social and academic performance and potentially their success or failure at secondary school. This primary-secondary transition frequently presents challenges for children with Autism Spectrum Disorder (ASD), resulting in uncertainty and anxiety. The objective of this study was to explore the perceptions of children with ASD, on the topic of which features of school environment fit more or less well with their needs, as they transferred from primary to secondary schools.

Method: Semi-structured interviews were used to gather the experiences of 6 students with ASD, and their parents, before and after the transition to secondary school. A thematic analysis of these data identified common themes that captured the fits and misfits between the children's needs and their primary and secondary school environments.

Result: Overall, participants voiced more positive perspectives of secondary school than primary school. Data analysis identified themes of feelings about school, peer relationships, relationship with school staff, curriculum, school organization, and accommodations.

Conclusion: Inclusion and integration of students with ASD in mainstream secondary schools at transition can be a positive experience when the school environments are a good fit with the individual needs of each child with ASD. The transition can be challenging for children when a one size fits all approach is taken.
Reporting Genetic Findings to Individual Research Participants: Guidelines From the Swiss Personalized Health Network
Authors: Blasimme Alessandro , Brall Caroline , Vayena Effy
Published: December 2020

In 2017 the Swiss federal government established the Swiss Personalized Health Network (SPHN), a nationally coordinated data infrastructure for genetic research. The SPHN advisory group on Ethical, Legal, and Social Implications (ELSI) was tasked with the creation of a recommendation to ensure ethically responsible reporting of genetic research findings to research participants in SPHN-funded studies. Following consultations with expert stakeholders, including geneticists, pediatricians, sociologists, university hospitals directors, patient representatives, consumer protection associations, and insurers, the ELSI advisory group issued its recommendation on “Reporting actionable genetic findings to research participants” in May 2020. In this paper we outline the development of this recommendation and the provisions it contains. In particular, we discuss some of its key features, namely: (1) that participation in SPHN-funded studies as a research subject is conditional to accepting that medically relevant genetic research findings will be reported; (2) that a Multidisciplinary Expert Panel (MEP) should be created to support researchers’ decision-making processes about reporting individual genetic research findings; (3) that such Multidisciplinary Expert Panel will make case-by-case decisions about whether to allow reporting of genetic findings, instead of relying on a pre-defined list of medically relevant variants; (4) that research participants shall be informed of the need to disclose genetic mutations when applying for private insurance, which may influence individual decisions about participation in research. By providing an account of the procedural background and considerations leading to the SPHN recommendation on “Reporting actionable genetic findings to research participants,” we seek to promote a better understanding of the proposed guidance, as well as to contribute to the global dialog on the reporting of genetic research findings.
Signaling Pathways Implicated in Carbon Nanotube-Induced Lung Inflammation
Authors: Dong Jie
Published: December 2020

Inflammation is a tissue response to a variety of harmful stimuli, such as pathogens, irritants, and injuries, and can eliminate insults and limit tissue damage. However, dysregulated inflammation is recognized as a cause of many human diseases, exemplified by organ fibrosis and cancer. In this regard, inflammation-promoted fibrosis is commonly observed in human lung diseases, such as idiopathic pulmonary fibrosis and pneumoconiosis. Carbon nanotubes (CNTs) are a type of nanomaterials with unique properties and various industrial and commercial applications. On the other hand, certain forms of CNTs are potent inducers of inflammation and fibrosis in animal lungs. Notably, acute inflammation is a remarkable phenotype elicited by CNTs in the lung during the early acute phase post-exposure; whereas a type 2 immune response is evidently activated and dominates during the late acute and chronic phases, leading to type 2 inflammation and lung fibrosis. Numerous studies demonstrate that these immune responses involve distinct immune cells, various pathologic factors, and specific functions and play crucial roles in the initiation and progression of inflammation and fibrosis in the lung exposed to CNTs. Thus, the mechanistic understanding of the immune responses activated by CNTs has drawn great attention in recent years. This article reviews the major findings on the cell signaling pathways that are activated in immune cells and exert functions in promoting immune responses in CNT-exposed lungs, which would provide new insights into the understanding of CNT-induced lung inflammation and inflammation-driven fibrosis, the application of CNT-induced lung inflammation and fibrosis as a new disease model, and the potential of targeting immune cells as a therapeutic strategy for relevant human lung diseases.
Human Commensal Prevotella histicola Ameliorates Disease as Effectively as Interferon-Beta in the Experimental Autoimmune Encephalomyelitis
Authors: Shahi Shailesh K. , Jensen Samantha N. , Murra Alexandra C. , Tang Na , Guo Hui , Gibson-Corley Katherine N. , Zhang Jian , Karandikar Nitin J. , Murray Joseph A. , Mangalam Ashutosh K.
Published: December 2020

Gut microbiota has emerged as an important environmental factor in the pathobiology of multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Both genetic and environmental factors have been shown to play an important role in MS. Among genetic factors, the human leukocyte antigen (HLA) class II allele such as HLA-DR2, DR3, DR4, DQ6, and DQ8 show the association with the MS. We have previously used transgenic mice expressing MS susceptible HLA class II allele such as HLA-DR2, DR3, DQ6, and DQ8 to validate significance of HLA alleles in MS. Although environmental factors contribute to 2/3 of MS risk, less is known about them. Gut microbiota is emerging as an imporatnt environmental factor in MS pathogenesis. We and others have shown that MS patients have distinct gut microbiota compared to healthy control (HC) with a lower abundance of Prevotella. Additionally, the abundance of Prevotella increased in patients receiving disease-modifying therapies (DMTs) such as Copaxone and/or Interferon-beta (IFNβ). We have previously identified a specific strain of Prevotella (Prevotella histicola), which can suppress experimental autoimmune encephalomyelitis (EAE) disease in HLA-DR3.DQ8 transgenic mice. Since Interferon-β-1b [IFNβ (Betaseron)] is a major DMTs used in MS patients, we hypothesized that treatment with the combination of P. histicola and IFNβ would have an additive effect on the disease suppression. We observed that treatment with P. histicola suppressed disease as effectively as IFNβ. Surprisingly, the combination of P. histicola and IFNβ was not more effective than either treatment alone. P. histicola alone or in combination with IFNβ increased the frequency and number of CD4+FoxP3+ regulatory T cells in the gut-associated lymphoid tissue (GALT). Treatment with P. histicola alone, IFNβ alone, and in the combination decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4+ T cells in the CNS. Additionally, P. histicola alone or IFNβ alone or the combination treatments decreased CNS pathology, characterized by reduced microglia and astrocytic activation. In conclusion, our study indicates that the human gut commensal P. histicola can suppress disease as effectively as commonly used MS drug IFNβ and may provide an alternative treatment option for MS patients.
IL-2-Agonist-Induced IFN-γ Exacerbates Systemic Anaphylaxis in Food Allergen-Sensitized Mice
Authors: Link Christopher W.M. , Rau Christina N. , Udoye Christopher C. , Ragab Mohab , Korkmaz Rabia Ü. , Comdühr Sara , Clauder Ann-Katrin , Lindemann Timo , Frehse Britta , Hofmann Katharina , Almeida Larissa N. , Laumonnier Yves , Beidaq Asmaa El , Finkelman Fred D. , Manz Rudolf A.
Published: December 2020

Food allergies are common, costly and potentially life-threatening disorders. They are driven by Th2, but inhibited by Th1 reactions. There is also evidence indicating that IL-2 agonist treatment inhibits allergic sensitization through expansion of regulatory T cells. Here, we tested the impact of an IL-2 agonist in a novel model for food allergy to hen´s egg in mice sensitized without artificial adjuvants. Prophylactic IL-2 agonist treatment expanded Treg populations and inhibited allergen-specific sensitization. However, IL-2 agonist treatment of already sensitized mice increased mast cell responses and allergic anaphylaxis upon allergen re-challenge. These effects depended on allergen-specific IgE and were mediated through IFN-γ, as shown by IgE transfer and blockade of IFN-γ with monoclonal antibodies. These results suggest that although shifting the allergic reaction toward a Treg/Th1 response inhibits allergic sensitization, the prototypic Th1 cytokine IFN-γ promotes mast cell activation and allergen-induced anaphylaxis in individuals that are already IgE-sensitized. Hence, while a Th1 response can prevent the development of food allergy, IFN-γ has the ability to exacerbate already established food allergy.
IgE and IgG Antibodies as Regulators of Mast Cell and Basophil Functions in Food Allergy
Authors: Kanagaratham Cynthia , El Ansari Yasmeen S. , Lewis Owen L. , Oettgen Hans C.
Published: December 2020

Food allergy is a major health issue, affecting the lives of 8% of U.S. children and their families. There is an urgent need to identify the environmental and endogenous signals that induce and sustain allergic responses to ingested allergens. Acute reactions to foods are triggered by the activation of mast cells and basophils, both of which release inflammatory mediators that lead to a range of clinical manifestations, including gastrointestinal, cutaneous, and respiratory reactions as well as systemic anaphylaxis. Both of these innate effector cell types express the high affinity IgE receptor, FcϵRI, on their surface and are armed for adaptive antigen recognition by very-tightly bound IgE antibodies which, when cross-linked by polyvalent allergen, trigger degranulation. These cells also express inhibitory receptors, including the IgG Fc receptor, FcγRIIb, that suppress their IgE-mediated activation. Recent studies have shown that natural resolution of food allergies is associated with increasing food-specific IgG levels. Furthermore, oral immunotherapy, the sequential administration of incrementally increasing doses of food allergen, is accompanied by the strong induction of allergen-specific IgG antibodies in both human subjects and murine models. These can deliver inhibitory signalsviaFcγRIIb that block IgE-induced immediate food reactions. In addition to their role in mediating immediate hypersensitivity reactions, mast cells and basophils serve separate but critical functions as adjuvants for type 2 immunity in food allergy. Mast cells and basophils, activated by IgE, are key sources of IL-4 that tilts the immune balance away from tolerance and towards type 2 immunity by promoting the induction of Th2 cells along with the innate effectors of type 2 immunity, ILC2s, while suppressing the development of regulatory T cells and driving their subversion to a pathogenic pro-Th2 phenotype. This adjuvant effect of mast cells and basophils is suppressed when inhibitory signals are delivered by IgG antibodies signalingviaFcγRIIb. This review summarizes current understanding of the immunoregulatory effects of mast cells and basophils and how these functions are modulated by IgE and IgG antibodies. Understanding these pathways could provide important insights into innovative strategies for preventing and/or reversing food allergy in patients.
Friction and Wear Behaviors of Reduced Graphene Oxide- and Carbon Nanotube-Reinforced Hydroxyapatite Bioceramics
Authors: Hu Huanlong , Li Zhong , Sun Wen , Li Ruitao , Li Hua , Khor Khiam Aik
Published: December 2020

Friction and wear properties play an important role in the long-term in vivo performance of load-bearing bioceramic implants. In this study, the friction and wear behaviors of hydroxyapatite (HA) reinforced with reduced graphene oxide (rGO) and rGO + carbon nanotube (CNT) hybrids were studied by ball-on-disk tests to understand the effects of nanocarbon content and morphology on the composites’ tribological behaviors. The intact and worn surfaces were characterized by optical microscopy, nanoindentation, field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, and Raman spectroscopy. We found that the incorporation of rGO and rGO + CNT hybrids in HA bioceramic both improved the friction and wear behaviors, and the highest wear resistance was achieved by employing 1 wt% rGO and 1 wt% CNT as reinforcements. The major reinforcing mechanism was the formation of carbonaceous films between the composite surfaces and counterbody, which served as solid lubrication films that resulted in a lower coefficient of friction, higher hardness, and increased hardness/modulus ratio. Importantly, CNT addition facilitated the uniform distribution of the reinforcements in the HA matrix and the pinning effects of CNT enhanced the connection between rGO and HA.
Phenotypic and Molecular Biological Analysis of Polymycovirus AfuPmV-1M From Aspergillus fumigatus: Reduced Fungal Virulence in a Mouse Infection Model
Authors: Takahashi-Nakaguchi Azusa , Shishido Erika , Yahara Misa , Urayama Syun-ichi , Ninomiya Akihiro , Chiba Yuto , Sakai Kanae , Hagiwara Daisuke , Chibana Hiroji , Moriyama Hiromitsu , Gonoi Tohru
Published: December 2020

The filamentous fungal pathogen Aspergillus fumigatus is one of the most common causal agents of invasive fungal infection in humans; the infection is associated with an alarmingly high mortality rate. In this study, we investigated whether a mycovirus, named AfuPmV-1M, can reduce the virulence of A. fumigatus in a mouse infection model. AfuPmV-1M has high sequence similarity to AfuPmV-1, one of the polymycovirus that is a capsidless four-segment double-stranded RNA (dsRNA) virus, previously isolated from the genome reference strain of A. fumigatus, Af293. However, we found the isolate had an additional fifth dsRNA segment, referred to as open reading frame 5 (ORF5), which has not been reported in AfuPmV-1. We then established isogenic lines of virus-infected and virus-free A. fumigatus strains. Mycovirus infection had apparent influences on fungal phenotypes, with the virus-infected strain producing a reduced mycelial mass and reduced conidial number in comparison with these features of the virus-free strain. Also, resting conidia of the infected strain showed reduced adherence to pulmonary epithelial cells and reduced tolerance to macrophage phagocytosis. In an immunosuppressed mouse infection model, the virus-infected strain showed reduced mortality in comparison with mortality due to the virus-free strain. RNA sequencing and high-performance liquid chromatography (HPLC) analysis showed that the virus suppressed the expression of genes for gliotoxin synthesis and its production at the mycelial stage. Conversely, the virus enhanced gene expression and biosynthesis of fumagillin. Viral RNA expression was enhanced during conidial maturation, conidial germination, and the mycelial stage. We presume that the RNA or translation products of the virus affected fungal phenotypes, including spore formation and toxin synthesis. To identify the mycovirus genes responsible for attenuation of fungal virulence, each viral ORF was ectopically expressed in the virus-free KU strain. We found that the expression of ORF2 and ORF5 reduced fungal virulence in the mouse model. In addition, ORF3 affected the stress tolerance of host A. fumigatus in culture. We hypothesize that the respective viral genes work cooperatively to suppress the pathogenicity of the fungal host.
Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria
Authors: Zhong Qifeng , Kobe Bostjan , Kappler Ulrike
Published: December 2020

Mononuclear molybdoenzymes are highly versatile catalysts that occur in organisms in all domains of life, where they mediate essential cellular functions such as energy generation and detoxification reactions. Molybdoenzymes are particularly abundant in bacteria, where over 50 distinct types of enzymes have been identified to date. In bacterial pathogens, all aspects of molybdoenzyme biology such as molybdate uptake, cofactor biosynthesis, and function of the enzymes themselves, have been shown to affect fitness in the host as well as virulence. Although current studies are mostly focused on a few key pathogens such asEscherichia coli, Salmonella enterica, Campylobacter jejuni, andMycobacterium tuberculosis, some common themes for the function and adaptation of the molybdoenzymes to pathogen environmental niches are emerging. Firstly, for many of these enzymes, their role is in supporting bacterial energy generation; and the corresponding pathogen fitness and virulence defects appear to arise from a suboptimally poised metabolic network. Secondly, all substrates converted by virulence-relevant bacterial Mo enzymes belong to classes known to be generated in the host either during inflammation or as part of the host signaling network, with some enzyme groups showing adaptation to the increased conversion of such substrates. Lastly, a specific adaptation to bacterial in-host survival is an emerging link between the regulation of molybdoenzyme expression in bacterial pathogens and the presence of immune system-generated reactive oxygen species. The prevalence of molybdoenzymes in key bacterial pathogens including ESKAPE pathogens, paired with the mounting evidence of their central roles in bacterial fitness during infection, suggest that they could be important future drug targets.
Fetal Metabolomic Alterations Following Porcine Reproductive and Respiratory Syndrome Virus Infection
Authors: Malgarin Carolina M. , MacPhee Daniel J. , Harding John C. S.
Published: December 2020

PRRSV infection in third-trimester pregnant sows can lead to fetal death and abortions, although the mechanisms triggering these effects are not well understood. Since resistant and susceptible fetuses can coexist in the same litter, we propose that there may be differential mechanisms used by some fetuses to evade infection and/or disease progression. Our objectives were to investigate possible differences in the metabolome of PRRSV-infected and non-infected fetuses, as well as the interaction of altered intrauterine growth development and PRRSV infection to elucidate possible causes of fetal death following PRRSV infection. Near-term serum samples collected from fetuses on gestation day 106, 21 days post PRRSV-2 infection, were processed by direct flow injection mass spectrometry (DI-MS) and nuclear magnetic resonance (NMR) techniques. Experiment one investigated disease progression with 24 fetuses selected from each of four phenotypic groups: fetuses from non-inoculated gilts (CTRL); fetuses from inoculated gilts that escaped infection (UNINF); infected high viral load viable fetuses (INF); and infected high viral load meconium-stained fetuses (MEC). Experiment two investigated the interaction of intrauterine growth retardation (IUGR) and PRRSV infection by analyzing differences among: non-infected normal development (CON-N); CON-IUGR; PRRS infected normal development (PRRS-N); and PRRS-IUGR. Univariate and multivariate (PCA, PLS-DA) statistics determined group differences among various contrasts, and the most important metabolites associated with disease progression and fetal development. Significant differences in the metabolome were observed, especially between PRRSV-negative fetuses (CTRL and UNINF) and MEC fetuses, while INF fetuses appear to span both groups. The two metabolites with highest variable importance in projection (VIP) scores related to disease progression were alpha-aminoadipic acid (alpha-AAA) and kynurenine (KYN), having the highest concentration in MEC and INF fetuses, respectively, compared to CTRL and UNINF. In experiment two, non-IUGR fetuses were found to have increased levels of lysoPCs, PCs and amino acids compared to IUGR fetuses, while the near complete absence of lysoPCs and PCs in IUGR fetuses, even during infection, indicate a distinctive response to infection compared to non-growth retarded fetuses. Possible markers of PRRSV fetal susceptibility, such as alpha-AAA, kynurenine and lysoPCs, are presented and discussed.
AChRs Degeneration at NMJ in Aging-Associated Sarcopenia–A Systematic Review
Authors: Bao Zhengyuan , Cui Can , Chow Simon Kwoon-Ho , Qin Ling , Wong Ronald Man Yeung , Cheung Wing-Hoi
Published: December 2020

Sarcopenia is an aging process with a decline of skeletal muscle mass and function, which is a challenging public health problem with reduced quality of life in patients. The endplate, the post-synaptic part of the neuromuscular junction (NMJ), occupies 0.1% of the myofiber surface area only, but is composed of millions of acetylcholine receptors (AChRs) that are efficient in binding to acetylcholine (ACh) and triggering skeletal muscle contraction. This systematic review aims to examine aging-associated alterations of post-synaptic AChRs, including morphology, function and related gene expression. A systematic literature search was conducted in PubMed, Embase and Web of Science with relevant keywords by two independent reviewers. Original pre-clinical and clinical studies regarding AChRs changes during aging with available full text and written in English were included. Information was extracted from the included studies for further review. In total, 30 articles were included. Various parameters assessing AChRs alterations by radioassay, immunofluorescence, electrophysiology and mechanical test were reported. Endplate fragmentation and denervation were common in old skeletal muscles during aging. To ensure efficient NMJ transmission and force generation, type I or IIb muscle fibers tended to have increased ACh quanta releasing after electrical stimulations, while type IIa muscle fibers tended to have stronger binding between ACh and AChRs, but the overall function of AChRs was reduced during aging. Alterations of AChRs area depended on muscle type, species and the progress of muscle atrophy and type I muscles fibers tended to demonstrate enlarging AChRs areas. Myogenic regulator factors (MRFs) can regulate the expression of AChRs subunits, while decreased MRF4 may lead to expression changes of AChRs subunits during aging. Sarcoglycan-α can delay low-density lipoprotein receptor-related protein 4 (LRP4) degradation. This protein was increased in old muscles but still cannot suppress the degradation of LRP4. Investigating the role of these AChRs-related genes in the process of aging may provide a potential target to treat sarcopenia.
LesionQuant for Assessment of MRI in Multiple Sclerosis—A Promising Supplement to the Visual Scan Inspection
Authors: Brune Synne , Høgestøl Einar A. , Cengija Vanja , Berg-Hansen Pål , Sowa Piotr , Nygaard Gro O. , Harbo Hanne F. , Beyer Mona K.
Published: December 2020

Background and Goals: Multiple sclerosis (MS) is a central nervous system inflammatory disease where magnetic resonance imaging (MRI) is an important tool for diagnosis and disease monitoring. Quantitative measurements of lesion volume, lesion count, distribution of lesions, and brain atrophy have a potentially significant value for evaluating disease progression. We hypothesize that utilizing software designed for evaluating MRI data in MS will provide more accurate and detailed analyses compared to the visual neuro-radiological evaluation.

Methods: A group of 56 MS patients (mean age 35 years, 70% females and 96% relapsing-remitting MS) was examined with brain MRI one and 5 years after diagnosis. The T1 and FLAIR brain MRI sequences for all patients were analyzed using the LesionQuant (LQ) software. These data were compared with data from structured visual evaluations of the MRI scans performed by neuro-radiologists, including assessments of atrophy, and lesion count. The data from LQ were also compared with data from other validated research methods for brain segmentation, including assessments of whole brain volume and lesion volume. Correlations with clinical tests like the timed 25-foot walk test (T25FT) were performed to explore additional value of LQ analyses.

Results: Lesion count assessments by LQ and by the neuro-radiologist were significantly correlated one year (cor = 0.92, p = 2.2 × 10−16) and 5 years (cor = 0.84, p = 2.7 × 10−16) after diagnosis. Analyzes of the intra- and interrater variability also correlated significantly (cor = 0.96, p < 0.001, cor = 0.97, p < 0.001). Significant positive correlation was found between lesion volume measured by LQ and by the software Cascade (cor = 0.7, p < 0.001. LQ detected a reduction in whole brain percentile >10 in 10 patients across the time-points, whereas the neuro-radiologist assessment identified six of these. The neuro-radiologist additionally identified five patients with increased atrophy in the follow-up period, all of them displayed decreasing low whole brain percentiles (median 11, range 8–28) in the LQ analysis. Significant positive correlation was identified between lesion volume measured by LQ and test performance on the T25FT both at 1 and 5 years after diagnosis.

Conclusion: For the number of MS lesions at both time-points, we demonstrated strong correlations between the assessments done by LQ and the neuro-radiologist. Lesion volume evaluated with LQ correlated with T25FT performance. LQ-analyses classified more patients to have brain atrophy than the visual neuro-radiological evaluation. In conclusion, LQ seems like a promising supplement to the evaluation performed by neuro-radiologists, providing an automated tool for evaluating lesions in MS patients and also detecting early signs of atrophy in both a longitudinal and cross-sectional setting.
Aberrant Hippocampal Network Connectivity Is Associated With Neurocognitive Dysfunction in Patients With Moderate and Severe Obstructive Sleep Apnea
Authors: Zhou Li , Liu Guiqian , Luo Hong , Li Huabing , Peng Yating , Zong Dandan , Ouyang Ruoyun
Published: December 2020

Objectives: This work aims to explore the changes of functional connectivity (FC) within the hippocampus network in patients with moderate and severe obstructive sleep apnea (OSA) and its correlation with neurocognitive dysfunction to explore the potential neurophysiological mechanism.

Methods: A total of 32 treatment-naïve patients with moderate or severe OSA and 26 healthy controls (HCs), matched in age, gender, and education, underwent the evaluations of Epworth Sleep Scale, neurocognitive function, full-night polysomnography, and resting-state functional magnetic resonance imaging. The FC map of the hippocampus to other brain areas was compared among 15 OSA patients and 15 HCs with little head motion. Finally, the correlation between hippocampus FC strength and respiratory sleep parameters and neurocognitive assessments was analyzed.

Results: Compared with HCs, the right hippocampus showed a significantly decreased FC with the bilateral insular lobe, right thalamus, and right anterior cingulate gyrus (ACG) and an increased FC with the right superior and middle temporal gyrus, left posterior cingulate gyrus, and left angular gyrus in the patients with OSA. The left hippocampus presented a significantly decreased FC with the left anterior cerebellum in patients with OSA. In addition, the aberrant right hippocampal FC with the right ACG was significantly correlated with disease severity and disrupted sleep architecture in the OSA group. Furthermore, after adjusting the related confounding factors, the FC strength between the right hippocampus, right insular lobe, and right thalamus was positively associated with the scores of Stroop Color–Word Test (SCWT) or Hopkins Verbal Learning Test—Revised (HVLT-R), while the FC between the right hippocampus and the right middle temporal gyrus was negatively correlated with the scores of HVLT-R. The right hippocampus FC with right superior temporal gyrus, left angular gyrus, and ACG were all negatively related to the scores of the symbol coding test (r = −0.642, p = 0.045; r = −0.638, p = 0.047; r = −0.753, p = 0.012), respectively. The FC between the left hippocampal and the left anterior cerebellar lobe showed a positive relationship with the scores of HVLT-R (r = 0.757, p = 0.011) and CPT-3D (r = −0.801, p = 0.005).

Conclusion: The hippocampus presented abnormal FC with the cerebral and cerebellar regions extensively in OSA, and the correlation between abnormal hippocampal network FC and neurocognitive dysfunction in OSA suggests a promising insight to explore the potential biomarker and pathophysiologic mechanism of neurocognitive dysfunction of OSA.
SARS-CoV-2 Is Not Detected in the Cerebrospinal Fluid of Encephalopathic COVID-19 Patients
Authors: Placantonakis Dimitris G. , Aguero-Rosenfeld Maria , Flaifel Abdallah , Colavito John , Inglima Kenneth , Zagzag David , Snuderl Matija , Louie Eddie , Frontera Jennifer Ann , Lewis Ariane
Published: December 2020

Neurologic manifestations of the novel coronavirus SARS-CoV-2 infection have received wide attention, but the mechanisms remain uncertain. Here, we describe computational data from public domain RNA-seq datasets and cerebrospinal fluid data from adult patients with severe COVID-19 pneumonia that suggest that SARS-CoV-2 infection of the central nervous system is unlikely. We found that the mRNAs encoding the ACE2 receptor and the TMPRSS2 transmembrane serine protease, both of which are required for viral entry into host cells, are minimally expressed in the major cell types of the brain. In addition, CSF samples from 13 adult encephalopathic COVID-19 patients diagnosed with the viral infection via nasopharyngeal swab RT-PCR did not show evidence for the virus. This particular finding is robust for two reasons. First, the RT-PCR diagnostic was validated for CSF studies using stringent criteria; and second, 61% of these patients had CSF testing within 1 week of a positive nasopharyngeal diagnostic test. We propose that neurologic sequelae of COVID-19 are not due to SARS-CoV-2 meningoencephalitis and that other etiologies are more likely mechanisms.
Lactobacillus delbrueckii Interfere With Bile Acid Enterohepatic Circulation to Regulate Cholesterol Metabolism of Growing–Finishing Pigs via Its Bile Salt Hydrolase Activity
Authors: Hou Gaifeng , Peng Wei , Wei Liangkai , Li Rui , Yuan Yong , Huang Xingguo , Yin Yulong
Published: December 2020

Microbiota-targeted therapies for hypercholesterolemia get more and more attention and are recognized as an effective strategy for preventing and treating cardiovascular disease. The experiment was conducted to investigate the cholesterol-lowering mechanism of Lactobacillus delbrueckii in a pig model. Twelve barrows (38.70 ± 5.33 kg) were randomly allocated to two groups and fed corn–soybean meal diets with either 0% (Con) or 0.1% Lactobacillus delbrueckii (Con + LD) for 28 days. L. delbrueckii–fed pigs had lower serum contents of total cholesterol (TC), total bile acids (TBAs), and triglyceride, but higher fecal TC and TBA excretion. L. delbrueckii treatment increased ileal Lactobacillus abundance and bile acid (BA) deconjugation and affected serum and hepatic BA composition. Dietary L. delbrueckii downregulated the gene expression of ileal apical sodium-dependent bile acid transporter (ASBT) and ileal bile acid binding protein (IBABP), and hepatic farnesoid X receptor (FXR), fibroblast growth factor (FGF19), and small heterodimer partner (SHP), but upregulated hepatic high-density lipoprotein receptor (HDLR), low-density lipoprotein receptor (LDLR), sterol regulatory element binding protein-2 (SREBP-2), and cholesterol-7α hydroxylase (CYP7A1) expression. Our results provided in vivo evidence that L. delbrueckii promote ileal BA deconjugation with subsequent fecal TC and TBA extraction by modifying ileal microbiota composition and induce hepatic BA neosynthesis via regulating gut–liver FXR–FGF19 axis.
Glioblastoma Distance From the Subventricular Neural Stem Cell Niche Does Not Correlate With Survival
Authors: Mistry Akshitkumar M. , Mummareddy Nishit , Salwi Sanjana , Davis Larry T. , Ihrie Rebecca A.
Published: December 2020

Objective

To determine the relationship between survival and glioblastoma distance from the ventricular-subventricular neural stem cell niche (VSVZ).

Methods

502 pre-operative gadolinium-enhanced, T1-weighted MRIs with glioblastoma retrieved from an institutional dataset (n = 252) and The Cancer Imaging Atlas (n=250) were independently reviewed. The shortest distance from the tumor contrast enhancement to the nearest lateral ventricular wall, the location of the VSVZ, was measured (GBM-VSVZDist). The relationship of GBM-VSVZDist with the proportion of glioblastomas at each distance point and overall survival was explored with a Pearson’s correlation and Cox regression model, respectively, adjusting for the well-established glioblastoma prognosticators.

Results

244/502 glioblastomas had VSVZ contact. The proportion of non-VSVZ-contacting glioblastomas correlated inversely with GBM-VSVZDist (partial Pearson’s correlation adjusted for tumor volume R=-0.79, p=7.11x10-7). A fit of the Cox regression model adjusted for age at diagnosis, Karnofsky performance status score, post-operative treatment with temozolomide and/or radiotherapy, IDH1/2 mutation status, MGMT promoter methylation status, tumor volume, and extent of resection demonstrated a significantly decreased overall survival only when glioblastoma contacted the VSVZ. Overall survival did not correlate with GBM-VSVZDist.

Conclusions

In the two independent cohorts analyzed, glioblastomas at diagnosis were found in close proximity or in contact with the VSVZ with a proportion that decreased linearly with GBM-VSVZDist. Patient survival was only influenced by the presence or absence of a gadolinium-enhanced glioblastoma contact with the VSVZ. These results may guide analyses to test differential effectiveness of VSVZ radiation in VSVZ-contacting and non-contacting glioblastomas and/or inform patient selection criteria in clinical trials of glioblastoma radiation.
Durable Response to Sintilimab and Chidamide in a Patient With Pegaspargase- and Immunotherapy-Resistant NK/T-Cell Lymphoma: Case Report and Literature Review
Authors: Yan Zheng , Yao Shuna , Liu Yanyan , Zhang Jianbo , Li Peng , Wang Haiying , Chu Junfeng , Zhao Shuang , Yao Zhihua
Published: December 2020

The prognosis of patients with relapsed/refractory NK/T-cell lymphoma (NKTCL) is dismal. Immunotherapy has showed encouraging anti-tumor activity in patients with asparaginase-resistant NKTCL; however, only a portion of patients benefit and the median response duration is rather short. Treatment strategies have not been identified for immunotherapy-resistant NKTCL. We describe a patient with primary cutaneous NKTCL experienced disease progression after pegaspargase-based chemotherapy and PD-1 inhibitor (sintilimab)-based immunotherapy. Following a combined treatment of sintilimab and the HDAC inhibitor chidamide, the patient achieved a durable complete molecular response with mild toxicity. This case indicates that the combination of PD-1 inhibitor and HDAC inhibitor might be a treatment choice for immunotherapy-resistant NKTCL.