niryuu/sni-each-converted huggingface dataset:
The mucus-dwelling parasite Ostertagia ostertagi is one of the most important gastrointestinal nematodes in cattle. Our group has previously demonstrated the protective capacity of a vaccine against this parasite based on a native activation-associated secreted protein ASP1 (nASP) in combination with the saponin adjuvant QuilA. The aim of the current study was to analyse the effect of both antigen and adjuvant on the cellular and humoral vaccine-induced immune responses by comparing the native ASP to a recombinant version expressed in Pichia pastoris (pASP) and replacing QuilA by Al(OH) 3 . Immunization of cattle with the protective nASP+QuilA vaccine was associated with antigen-induced proliferation of natural killer (NK) cells combined with IFN-γ secretion and the induction of a mixed IgG1/IgG2 antibody response. ASP-specific activation and proliferation of NK cells was also observed in mice following the same vaccination regime. Replacing QuilA by Al(OH) 3 or nASP by pASP significantly decreased the capacity of the vaccines to trigger both NK cell activation and antibody responses and failed to induce protection against a challenge infection. Reduction of the structurally anchoring disulphide bonds of the nASP completely abolished its ability to induce NK cell activation and antibody responses, highlighting the importance of protein conformation for the immunostimulatory activity.
Output: Host protective ASP-based vaccine against the parasitic nematode Ostertagia ostertagi triggers NK cell activation and mixed IgG1-IgG2 response
Hand-foot-and-mouth disease (HFMD) is generally considered as a mild exanthematous disease to infants and young children worldwide. HFMD cases are usually mild and self-limiting but for few cases leads to complicated severe clinical outcomes, and even death. Previous studies have indicated that serum Ang II levels in patients with H7N9 infection were related to the severity of infection. However, the mechanisms underlying the pathogenesis of severe HFMD remain unclear. This study was undertaken to clarify the role of the reninangiotensin system (RAS) in the progression of severe HFMD.
Output: Involvement of the renin-angiotensin system in the progression of severe hand-foot-and- mouth disease
Typically not assisted by proofreading, the RNAdependent RNA polymerases (RdRPs) encoded by the RNA viruses may need to independently control its fidelity to fulfill virus viability and fitness. However, the precise mechanism by which the RdRP maintains its optimal fidelity level remains largely elusive. By solving 2.1-2.5Å resolution crystal structures of the classical swine fever virus (CSFV) NS5B, an RdRP with a unique naturally fused N-terminal domain (NTD), we identified high-resolution intramolecular interactions between the NTD and the RdRP palm domain. In order to dissect possible regulatory functions of NTD, we designed mutations at residues Y471 and E472 to perturb key interactions at the NTD-RdRP interface. When crystallized, some of these NS5B interface mutants maintained the interface, while the others adopted an 'open' conformation that no longer retained the intra-molecular interactions. Data from multiple in vitro RdRP assays indicated that the perturbation of the NTD-RdRP interactions clearly reduced the fidelity level of the RNA synthesis, while the processivity of the NS5B elongation complex was not affected. Collectively, our work demonstrates an explicit and unique mode of polymerase fidelity modulation and provides a vivid example of co-evolution in multi-domain enzymes.
Output: A unique intra-molecular fidelity-modulating mechanism identified in a viral RNA-dependent RNA polymerase
The mitochondrial protein repertoire varies depending on the cellular state. Protein component modifications caused by mitochondrial DNA (mtDNA) depletion are related to a wide range of human diseases; however, little is known about how nuclear-encoded mitochondrial proteins (mt proteome) changes under such dysfunctional states. In this study, we investigated the systemic alterations of mtDNA-depleted (r 0 ) mitochondria by using network analysis of gene expression data. By modularizing the quantified proteomics data into protein functional networks, systemic properties of mitochondrial dysfunction were analyzed. We discovered that up-regulated and down-regulated proteins were organized into two predominant subnetworks that exhibited distinct biological processes. The down-regulated network modules are involved in typical mitochondrial functions, while up-regulated proteins are responsible for mtDNA repair and regulation of mt protein expression and transport. Furthermore, comparisons of proteome and transcriptome data revealed that r 0 cells attempted to compensate for mtDNA depletion by modulating the coordinated expression/transport of mt proteins. Our results demonstrate that mt protein composition changed to remodel the functional organization of mitochondrial protein networks in response to dysfunctional cellular states. Human mt protein functional networks provide a framework for understanding how cells respond to mitochondrial dysfunctions. Citation: Jeon J, Jeong JH,
Output: Network Clustering Revealed the Systemic Alterations of Mitochondrial Protein Expression
Although coronavirus tropism is most often ascribed to receptor availability, increasing evidence suggests that for the neurotropic strains of the murine coronavirus mouse hepatitis virus (MHV), spike-receptor interactions cannot fully explain neurovirulence. The canonical MHV receptor CEACAM1a and its spike-binding site have been extensively characterized. However, CEACAM1a is poorly expressed in neurons, and the extremely neurotropic MHV strain JHM.SD infects ceacam1a S/S mice and spreads among ceacam1a S/S neurons. Two proposed alternative MHV receptors, CEACAM2 and PSG16, also fail to account for neuronal spread of JHM.SD in the absence of CEACAM1a. It has been reported that JHM.SD has an unusually labile spike protein, enabling it to perform receptor-independent spread (RIS), but it is not clear if the ability to perform RIS is fully responsible for the extremely neurovirulent phenotype. We propose that the extreme neurovirulence of JHM.SD is multifactorial and might include as yet unidentified neuron-specific spread mechanisms.
Output: Pathogenesis of neurotropic murine coronavirus is multifactorial
Glycosylation is a ubiquitous post-translational modification responsible for a multitude of crucial biological roles. As obligate parasites, viruses exploit host-cell machinery to glycosylate their own proteins during replication. Viral envelope proteins from a variety of human pathogens including HIV-1, influenza virus, Lassa virus, SARS, Zika virus, dengue virus, and Ebola virus have evolved to be extensively glycosylated. These hostcell derived glycans facilitate diverse structural and functional roles during the viral life-cycle, ranging from immune evasion by glycan shielding to enhancement of immune cell infection. In this review, we highlight the imperative and auxiliary roles glycans play, and how specific oligosaccharide structures facilitate these functions during viral pathogenesis. We discuss the growing efforts to exploit viral glycobiology in the development of anti-viral vaccines and therapies.
Output: Exploitation of glycosylation in enveloped virus pathobiology
Objective: To provide cutting-edge information for the management of community-acquired pneumonia in children under 5 years, based on the latest evidence published in the literature. Data source: A comprehensive search was conducted in PubMed, by using the expressionsAll articles retrieved had the title and the abstract read, when the papers reporting the latest evidence on each subject were identified and downloaded for complete reading. Data synthesis: In the era of largely implemented bacterial conjugate vaccines and widespread use of amplification nucleic acid techniques, respiratory viruses have been identified as the most frequent causative agents of community-acquired pneumonia in patients under 5 years. Hypoxemia (oxygen saturation ≤96%) and increased work of breathing are signs most associated with community-acquired pneumonia. Wheezing detected on physical examination independently predicts viral infection and the negative predictive value (95% confidence interval) of normal chest X-ray and serum procalcitonin <0.25 ng/dL was 92% (77---98%) and 93% (90---99%), respectively. Inability to drink/feed, vomiting everything, convulsions, lower chest indrawing, central cyanosis, lethargy, nasal flaring, grunting, head nodding, and oxygen saturation <90% are predictors of death and can be used as indicators for hospitalization. Moderate/large pleural effusions and multilobar infiltrates are predictors of severe disease. Orally administered amoxicillin is the first line outpatient treatment, while ampicillin, aqueous penicillin G, or amoxicillin (initiated initially by intravenous route) are the first line options to treat inpatients. Conclusions: Distinct aspects of childhood community-acquired pneumonia have changed during the last three decades.
Output: Community-acquired pneumonia among children: the latest evidence for an updated management ଝ
A multiplex quantitative real-time polymerase chain reaction (mqPCR) assay was developed and validated for the detection and differentiation of porcine circovirus type 3 (PCV3) and type 2 (PCV2) strains. The assay coverage was 97.9% (184/188) for PCV3 and 99.1% (1889/1907) for PCV2 sequences that were available from the current GenBank database. The PCR amplification efficiencies were 98-99% for plasmids, and 92-96% for diagnostic samples, with correlation coefficients all greater than 0.99. The limit of detection (LOD) determined as plasmid copies per reaction was 17 for PCV3 and 14 for PCV2. The assay specifically detected the targeted viruses without cross reacting to each other or to other common porcine viruses. Among 336 swine clinical samples collected in 2018, 101 (30.1%) were PCV3 positive, 56 (16.7%) were PCV2 positive and 18 (5.4%) were co-positives. Sixty selected PCV3 positives were confirmed by Sanger sequencing, and 53 of the 56 PCV2 positive samples were tested positive by another validated PCR assay.
Output: A multiplex real-time PCR assay for the detection and differentiation of the newly emerged porcine circovirus type 3 and continuously evolving type 2 strains in the United States
The renin-angiotensin system plays an important role in the maintenance of blood pressure homeostasis. The angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II, which binds the angiotensin II type-1 receptor (AT1R), is a potent vasoconstrictor. On a pathophysiological basis, both ACE I/D and AT1R A1166C polymorphism lead to an enhanced activity of the angiotensin II-AT1R axis, thereby possibly contributing to circulatory disturbances. A mutually facilitatory effect may be presumed between the two polymorphisms. We examined whether this synergistic effect is involved in the evolution of different types of ischemic stroke. Genetic and clinical data on 308 consecutive patients with acutely developing ischemic stroke were analyzed. A total of 272 stroke and neuroimaging alteration-free subjects served as a control group. Univariate and logistic regression statistical approaches were used. The ACE D allele combined with the AT1R 1166C allele did not yield a risk of ischemic stroke. However, the co-occurrence of the homozygous ACE D/D and at least one AT1R 1166C allele was more frequent in the ischemic stroke group than in the control group (22.4 vs 11%, p < 0.005, OR, 2.33; 95% CI, 1.46-3.7). After specific subgroup analysis, this synergistic association was even stronger for small-vessel ischemic stroke (OR, 3.44; 95% CI, 1.9-6.24; p < 0.0005). Multivariate logistic regression analysis of the data confirmed this association (adjusted OR, 3.54, 95% CI, 1.88-7.16; p < 0.0005). Our results demonstrate that ACE D/D and AT1R 1166C NeuroMolecular Medicine
Output: Coexistence of Angiotensin II Type-1 Receptor A1166C and Angiotensin-Converting Enzyme D/D Polymorphism Suggests Susceptibility for Small-Vessel-Associated Ischemic Stroke
The objectives were to determine the median infective dose (ID 50 ) of Cryptosporidium parvum and to describe the dose-response relationship including associated clinical illness in experimentally challenged dairy calves. Within the first 24 h of life, 27 test calves were experimentally challenged with C. parvum oocysts and 3 control calves were sham dosed. Test calves received 1 of 8 possible doses (25, 50, 100, 500, 1 × 10 3 , 1 × 10 4 , 1 × 10 5 , and 1 × 10 6 oocysts). All 27 test calves developed diarrhea. Fecal oocyst shedding occurred in 25 (92.6%) test calves and in 0 control calves. The 2 non-shedding test calves both received 25 oocysts. There was an inverse relationship between dose and time to onset of fecal oocyst shedding (P = 0.005). There was no relationship found between dose and duration (P = 0.2) or cessation (P = 0.3) of fecal oocyst shedding. In addition, there was not a significant relationship between log-dose and the log-peak oocysts (P = 0.2) or log-total oocysts (P = 0.5) counted/g of feces across the dose groups. There was a positive dose-response relationship between log-dose and diarrhea (P = 0.01). However, when controlling for other factors, such as onset and cessation of fecal oocyst shedding, dose was not a significant predictor of diarrhea (P = 0.5). Onset and cessation of fecal oocyst shedding were found to be the best predictors of diarrhea (P = 0.0006 and P = 0.04, respectively). The ID 50 for fecal oocyst shedding was 5.8 oocysts, for diarrhea was 9.7 oocysts, and for fecal oocyst shedding with diarrhea was 16.6 oocysts. Given that the ID 50 of C. parvum is far less than would be excreted into the environment by a naturally infected calf, prevention and control of cryptosporidiosis is a formidable challenge.
Output: Cryptosporidium parvum: Determination of ID 50 and the dose-response relationship in experimentally challenged dairy calves
In this study, a multi-pathogens survey was conducted to verify the sanitary status of two Italian wolf packs of Majella National Park. Twenty fecal samples (10/pack) were collected using a sampling protocol, based on the combining data from radio-collared wolves with geographic information system (GIS) analysis, allowing to mark off the home range of packs and to recover groupspecific and high-quality specimens. Virological screening against the most prevalent canine viruses (protoparvovirus, distemper virus, adenoviruses, and coronaviruses) was carried out by molecular methods, while parasites were detected by means of copromicroscopic and molecular analysis. Canine parvovirus type 2b (CPV-2b) is the most prevalent virus in both packs (7/20), followed by canine adenovirus type 2 (CAdV-2), while no sequences of canine distemper virus and coronaviruses were detected. The sequence analysis of the viruses demonstrated the domestic origin of the infection, highlighting the importance of vaccination of local dogs in order to reduce the risk of exposure of wildlife to these pathogens. Fourteen samples resulted positive for parasites. Capillaria aerophila (sin. Eucoleus aerophilus), Ancylostoma/Uncinaria, Trichuris vulpis eggs, Sarcocystis spp., Cystoisospora canis, and Angiostrongylus vasorum larvae were identified. Echinococcus granulosus sensu stricto (ovine genotype G1) and Giardia duodenalis(canid-specific Assemblage C) were also characterized, providing insights into the wolves' diet and their effects on environmental contamination. The sampling protocol applied in this study, based on a multidisciplinary approach, represents an innovative tool for the survey of Apennine wolf, able to integrate sanitary data with the ecological and demographic features of this population.
Output: Detection of selected pathogens in Apennine wolf (Canis lupus italicus) by a non-invasive GPS-based telemetry sampling of two packs from Majella National Park, Italy
N ot since the threat of a potential SARS (severe acute respiratory syndrome) pandemic (in 2003) has medical news captured as much national media attention as in the recent few weeks. Tuberculosis (TB) has been in the public eye since news broke that Andrew Speaker, a 31year-old US citizen and attorney from Atlanta, Ga, was a passenger on international commercial airline flights while infected with a very resistant strain of TB and that he has since been placed in isolation by US health authorities. This case has focused attention on important public health issues: the global TB epidemic and the risk of spread of infectious agents either knowingly or unknowingly via air travel. The purpose of this editorial is to provide background information on the epidemiology of TB in the world, the problem of drug-resistant TB, the risks of acquiring infections from air travel, and the role of health authorities in minimizing risk to the public.
Output: Dealing With Threat of Drug-Resistant Tuberculosis: Background Information for Interpreting the Andrew Speaker and Related Cases
Feline foamy virus (FFV) and feline leukemia virus (FeLV) belong to the Retroviridae family. While disease has not been reported for FFV infection, FeLV infection can cause anemia and immunosuppression (progressive infection). Co-infection with FFV/FeLV allows evaluation of the pathogenic potential and epidemiology of FFV infection in cats with FeLV pathology. Blood and buccal swab samples from 81 cats were collected in Rio de Janeiro. Plasma was serologically tested for FeLV. DNA extracted from peripheral blood mononuclear cells and buccal swabs was used to PCR detect FFV and FeLV. A qPCR was developed to detect and measure FFV proviral loads (pVLs) in cats. FeLV qPCR was performed using previous methods. The median log10 pVL of FFV mono-infected individuals was lower than found in FFV/FeLV co-infected cats in buccal swabs (p = 0.003). We found 78% of cats had detectable buccal FFV DNA in FFV mono-infected and FFV co-infected FeLV-progressive cats, while in FeLV-regressive cats (those without signs of disease) 22% of cats had detectable buccal FFV DNA (p = 0.004). Our results suggest that regressive FeLV infection may reduce FFV saliva transmission, the main mode of FV transmission. We did not find evidence of differences in pathogenicity in FFV mono-and -dually infected cats. In summary, we show that FVs may interact with FeLV within the same host. Our study supports the utility of cats naturally co-infected with retroviruses as a model to investigate the impact of FV on immunocompromised mammalian hosts.
Output: Clinical and Molecular Features of Feline Foamy Virus and Feline Leukemia Virus Co-Infection in Naturally-Infected Cats
Background: Overcrowding, reduced nurse to patient ratio, limited distance between incubators and absence of microbiological surveillance have been shown to promote spread of multidrug-resistant gram-negative organisms (MDRGN) in patients with birthweight < 1500 g. Patients > 1500 g treated on an intermediate care unit are unrepresented in recent literature. We therefore intended to present data obtained from a short-term overcrowded neonatal intermediate care unit (NIMCU) at a level III (international categorization) perinatal center at University Hospital Frankfurt, Germany. Methods: During a 25 day overcrowding (OV) and 28 day post-overcrowding period (POST-OV) on NIMCU, epidemiological data obtained from continuously hold microbiological surveillance were investigated and compared to the last 12 months of ward-regular bed occupancy preceding OV (PRAE-OV). Results: During OV, the number of patients simultaneously treated at the NIMCU increased from 18 to 22, resulting in a reduced bed-to-bed space. Nurse: patient ratio was 4:22 during OV compared to 3:18 during PRAE-OV. Cumulative incidence of MDRGN was 4.7% in OV and 2.4% POST-OV compared to 4.8% to PRAE-OV, respectively, without any significant variations. During OV and POST-OV, septic episodes due to MDRGN were not observed. In one case, potential nosocomial transmission of Enterobacter cloacae resistant to Piperacillin and 3rd/4th generation cephalosporins was observed. Conclusions: Prevention of nosocomial spread of MDRGN in an overcrowded NIMCU is based on staff's diligent training and adequate staffing. Concise microbiological surveillance should be guaranteed to escort through overcrowding periods. In our setting, impact of bed-to-bed distance on MDRGN transmission seemed to be less strong.
Output: Overcrowding in a neonatal intermediate care unit: impact on the incidence of multidrug-resistant gram-negative organisms
a b s t r a c t H1N1 is an infectious virus which, when spread affects a large volume of the population. It is an airborne disease that spreads easily and has a high death rate. Development of healthcare support systems using cloud computing is emerging as an effective solution with the benefits of better quality of service, reduced costs and flexibility. In this paper, an effective cloud computing architecture is proposed which predicts H1N1 infected patients and provides preventions to control infection rate. It consists of four processing components along with secure cloud storage medical database. The random decision tree is used to initially assess the infection in any patient depending on his/her symptoms. Social Network Analysis (SNA) is used to present the state of the outbreak. The proposed architecture is tested on synthetic data generated for two million users. The system provided 94% accuracy for the classification and around 81% of the resource utilization on Amazon EC2 cloud. The key point of the paper is the use of SNA graphs to calculate role of an infected user in spreading the outbreak known as Outbreak Role Index (ORI). It will help government agencies and healthcare departments to present, analyze and prevent outbreak effectively.
Output: Smart monitoring and controlling of Pandemic Influenza A (H1N1) using Social Network Analysis and cloud computing
The plaque assay has long served as the "gold standard" to measure virus infectivity and test antiviral drugs, but the assay is labor-intensive, lacks sensitivity, uses excessive reagents, and is hard to automate. Recent modification of the assay to exploit flow-enhanced virus spread with quantitative imaging has increased its sensitivity. Here we performed flow-enhanced infection assays in microscale channels, employing passive fluid pumping to inoculate cell monolayers with virus and drive infection spread. Our test of an antiviral drug (5-fluorouracil) against vesicular stomatitis virus infections of BHK cell monolayers yielded a two-fold improvement in sensitivity, relative to the standard assay based on plaque counting. The reduction in scale, simplified fluid handling, imagebased quantification, and higher assay sensitivity will enable infection measurements for high-throughput drug screening, sero-conversion testing, and patient-specific diagnosis of viral infections.
Output: Infection on a chip: a microscale platform for simple and sensitive cell-based virus assays
The uses of antiviral agents are increasing in the new era along with the development of vaccines for the effective control of viral diseases. The main aims of antiviral agents are to minimize harm to the host system and eradicate deadly viral diseases. However, the replications of viruses in host system represent a massive therapeutic challenge than bacteria and fungi. Antiviral drugs not just penetrate to disrupt the virus' cellular divisions but also have a negative impact on normal physiological pathways in the host. Due to these issues, antiviral agents have a narrow therapeutic index than antibacterial drugs. Nephrotoxicity is the main adverse reaction of antiviral drugs in human and animals. In this chapter, we summarize the antiviral agents' past, present and future perspectives with the main focus on the brief history of antiviral in animals, miscellaneous drugs, natural products, herbal and repurposing drugs. Virus · Therapy · Bacteria · DNA · RNA
Output: Antivirals: Past, Present and Future
The nasal septa of fetal rabbits at 26 days of gestation were harvested by cesarean section of the does while under anesthesia and then exposed to Bordetella bronchiseptica or its lipopolysaccharide (LPS) for periods of 2 and 4 hours. A total of 240 explants were used. The tissues were examined using the Hematoxylin & Eosin technique. Then, semithin sections (0.5 m) were stained with toluidine blue and examined with indirect immunoperoxidase (IPI) and lectin histochemistry. The most frequent and statistically significant findings were as follows: (1) cell death and increased goblet cell activity when exposed to bacteria and (2) cell death, cytoplasmic vacuolation and infiltration of polymorphonuclear leukocytes when exposed to LPS. The lesions induced by the bacterium were more severe than with LPS alone, except for the cytoplasmic vacuolation in epithelial cells. IPI stained the ciliated border of the epithelium with the bacterium more intensely, while LPS lectin histochemistry preferentially labeled the cytoplasm of goblet cell. These data indicate that B. bronchiseptica and its LPS may have an affinity for specific glycoproteins that would act as adhesion receptors in both locations.
Output: Interaction of Bordetella bronchiseptica and Its Lipopolysaccharide with In Vitro Culture of Respiratory Nasal Epithelium
The interferon-inducible transmembrane (Ifitm/Fragilis) genes encode homologous proteins that are induced by IFNs. Here, we show that IFITM proteins regulate murine CD4 + Th cell differentiation. Ifitm2 and Ifitm3 are expressed in wild-type (WT) CD4 + T cells. On activation, Ifitm3 was downregulated and Ifitm2 was upregulated. Resting Ifitm-family-deficient CD4 + T cells had higher expression of Th1-associated genes than WT and purified naive Ifitm-family-deficient CD4 + T cells differentiated more efficiently to Th1, whereas Th2 differentiation was inhibited. Ifitm-family-deficient mice, but not Ifitm3-deficient mice, were less susceptible than WT to induction of allergic airways disease, with a weaker Th2 response and less severe disease and lower Il4 but higher Ifng expression and IL-27 secretion. Thus, the Ifitm family is important in adaptive immunity, influencing Th1/Th2 polarization, and Th2 immunopathology. Keywords: Allergic airway disease r IFN-γ r Interferon-inducible transmembrane (IFITM) protein r T helper 1 (Th1) r T helper 2 (Th2) Additional supporting information may be found online in the Supporting Information section at the end of the article.
Output: Basic Adaptive immunity Research Article IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation
Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl-1-␤-d-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K.transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78,[3572][3573][3574][3575][3576][3577]. Ribavirin given at 75 mg/kg 4 h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1␣, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response thought to contribute to the pathogenesis of the infection. Our data do not support the use of ribavirin or other IMP dehydrogenase inhibitors for treating SARS infections in humans.
Output: Prior infection and passive
Up to November 2014, Middle East respiratory syndrome coronavirus (MERS-CoV) has infected 935 individuals and killed 371, all originating in or with links to the Middle East. The mechanisms of transmission of the disease are not fully understood, but MERS-CoV seems to sustain itself in the human population through repeated re-introduction from a camel reservoir and is able to cause nosocomial outbreaks. The risk of a global spread of MERS-CoV is low. Epidemiological, serological and phylogenetic research, combined with one health surveillance, dynamic case definitions, active case finding, rigorous infection control, culturally sensitive risk communication and a continuous re-evaluation of new evidence will enable to better understand the disease, limit its spread and quantify its risk in order to better prepare for a hypothetical spread.
Output: What needs to be done to control the spread of Middle East respiratory syndrome coronavirus?
Automated nucleic acid extraction from primary (raw) sputum continues to be a significant technical challenge for molecular diagnostics. In this work, we developed a prototype openarchitecture, automated nucleic acid workstation that includes a mechanical homogenization and lysis function integrated with heating and TruTip purification; optimized an extraction protocol for raw sputum; and evaluated system performance on primary clinical specimens. Eight samples could be processed within 70 min. The system efficiently homogenized primary sputa and doubled nucleic acid recovery relative to an automated protocol that did not incorporate sample homogenization. Nucleic acid recovery was at least five times higher from raw sputum as compared to that of matched sediments regardless of smear or culture grade, and the automated workstation reproducibly recovered PCR-detectable DNA to at least 80 CFU mL -1 raw sputum. M. tuberculosis DNA was recovered and detected from 122/123 (99.2%) and 124/124 (100%) primary sputum and sediment extracts, respectively. There was no detectable cross-contamination across 53 automated system runs and amplification or fluorescent inhibitors (if present) were not detectable. The open fluidic architecture of the prototype automated workstation yields purified sputum DNA that can be used for any molecular diagnostic test. The ability to transfer TruTip protocols between personalized, on-demand pipetting tools and the fully automated workstation also affords public health agencies an opportunity to standardize sputum nucleic acid sample preparation procedures, reagents, and quality control across multiple levels of the health care system.
Output: Automated TruTip nucleic acid extraction and purification from raw sputum
Middle East respiratory syndrome coronavirus (MERS-CoV) is continuously spreading and causing severe and fatal acute respiratory disease in humans. Prophylactic and therapeutic strategies are therefore urgently needed to control MERS-CoV infection. Here, we generated a humanized monoclonal antibody (mAb), designated hMS-1, which targeted the MERS-CoV receptor-binding domain (RBD) with high affinity. hMS-1 significantly blocked MERS-CoV RBD binding to its viral receptor, human dipeptidyl peptidase 4 (hDPP4), potently neutralized infection by a prototype MERS-CoV, and effectively crossneutralized evolved MERS-CoV isolates through recognizing highly conserved RBD epitopes. Notably, single-dose treatment with hMS-1 completely protected hDPP4 transgenic (hDPP4-Tg) mice from lethal infection with MERS-CoV. Taken together, our data suggest that hMS-1 might be developed as an effective immunotherapeutic agent to treat patients infected with MERS-CoV, particularly in emergent cases.
Output: Single-dose treatment with a humanized neutralizing antibody affords full protection of a human transgenic mouse model from lethal Middle East respiratory syndrome (MERS)-coronavirus infection-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Bidens pilosa L. is an edible herb and has been traditionally used for a wide range of ailments in many countries. The aim of this review is to present comprehensive information of the chemical constituents, nutraceutical and ethnomedical uses as well as the biological and pharmacological effects and toxicity of this plant based on 218 literary sources reported over 40 years. Major chemical constituents (including 301 compounds) belonging to polyacetylenes, polyacetylene glycosides, flavonoids, flavone glycosides, aurones, chalcones, okanin glycosides, phenolic acids, terpenes, pheophytins, fatty acids and phytosterols have been identified or isolated from the different parts of this plant. Many of them have been considered as the bioactive compounds which are potentially responsible for the pharmacological actions. Various types of preparations, extracts and individual compounds derived from this plant have been found to possess biological and pharmacological activities such as anti-malarial, anti-allergy, antihypertensive and smooth muscle relaxant, anti-cancerogenic, anti-diabetic, anti-inflammatory, anti-microbial, antioxidant. The results of data analysis on the chemicals, pharmacological and toxicological characteristics of B. pilosa validate the view of its folk worldwide-medicinal uses. This herb has a great beneficial therapeutic property and is possibly used for complement or alternative to pharmaceutical drugs in some specific cases. However, this herb is known as hyperaccumulator and as-excluder; therefore, harvesting the herb for medicinal uses should be judiciously cautioned.
Output: Chemistry and pharmacology of Bidens pilosa: an overview
We describe the association of caspase-dependent and caspase-independent mechanisms in macrophage apoptosis induced by LpqH, a 19 kDa Mycobacterium tuberculosis lipoprotein. LpqH triggered TLR2 activation, with upregulation of death receptors and ligands, which was followed by a death receptor signaling cascade with activation of initiator caspase 8 and executioner caspase 3. In this caspase-mediated phase, mitochondrial factors were involved in loss of mitochondrial transmembrane potential (ΔΨm), release of cytochrome c, and caspase 9 activation. Interestingly, a caspase-independent pathway was also identified; by immunoblot, the mitochondrial apoptosis inducing factor (AIF) was demonstrated in nuclei and cytosol of LpqH-treated macrophages. Confocal microscopy revealed translocation of AIF to the nuclei of the majority of apoptotic cells. These findings emphasize the complex and redundant nature of the macrophage death response to mycobacteria.
Output: Mycobacterium tuberculosis Lipoprotein (LpqH) Induces Macrophage Apoptosis through Extrinsic and Intrinsic Pathways: A Role for the Mitochondrial Apoptosis-Inducing Factor
Pet owners frequently administer antimicrobials to their pets and therefore have an important role to play in promoting antimicrobial stewardship in veterinary medicine. However, best methods of educating pet owners about antimicrobial stewardship have yet to be defined. While visual materials such as brochures and posters are often used in health promotion campaigns, their effectiveness in veterinary medicine is unknown. The objective of this study was to determine whether pet owners noticed and retained the message of a poster with an antimicrobial stewardship message placed in veterinary clinic exam rooms. A total of 111 pet owners from five veterinary clinics (three general practices, two low-cost clinics) in the greater Philadelphia area participated in the study. Participants completed a survey asking whether they noticed the poster and if they could paraphrase its message. In a follow-up survey, an antibiotic knowledge score was calculated from answers to questions assessing their knowledge of the poster message. Baseline knowledge was assessed by asking participants to define antibiotic resistance. At the end of the study, veterinarians at participating clinics were interviewed about their experiences with the poster. Only 51 (46.4%) participants noticed the poster, and only 11 (9.9%) could partially or completely reproduce its message. No demographic or clinic-level factors were significantly associated with noticing the poster or recalling its message. Antibiotic knowledge scores were highly correlated (ρ = 0.87, p < 0.001) with baseline knowledge and not affected by viewing the poster (p = 0.955). Veterinarians expressed skepticism that the poster was effective in conveying a message of judicious antibiotic use to clients and noted no difference in the frequency with which they discussed antibiotic resistance or felt pressured to prescribe antibiotics by their clients. Posters alone will likely have limited impact in conveying a message of judicious antibiotic use to pet owners. However, they might be useful as part of an active, multi-modal education strategy, especially if complemented by veterinarian actions.
Output: Posters Have Limited Utility in Conveying a Message of Antimicrobial Stewardship to Pet Owners
Sanekata, T., Kishimoto, E., Sato, K., Honma, H., Otsuki, K. and Tsubokura, M., 1991. Detection of poricine rotavirus in stools by a latex agglutination test. Vet. Microbiol., 27:245-251. We developed a simple agglutination test for the detection of porcine rotavirus in stools from pigs with diarrhea. The virus was detected with high sensitivity and specificity by a slide agglutination test using latex particles coated with antibody against the porcine rotavirus strain OSU (LA-antiOSU). The agglutination of LA-antiOSU with OSU on a glass slide was evident macroscopically within 2 rain. The sensitivity of this latex agglutination (LA) test was four times higher than that of the electron microscope method. The LA test is available for the rapid diagnosis of porcine rotavirus infections.
Output: Detection of porcine rotavirus in stools by a latex agglutination test
Flavonols are an important class of natural products isolated from plants. Some glycosylated flavonols showed very interesting biological activities. A library of flavonols has been made through Algar-Flynn-Oyamada reaction from 2 0 -hydroxyacetophenones and benzaldehydes. Glycosylation of these flavonols with various glycosyl donors affords a library of glycosylated flavonols. These compounds are potentially useful pharmacologically active compounds and will be studied for biological activities.
Output: Synthesis of a library of glycosylated flavonols
Bacterial pathogens use siderophores to obtain iron from the host in order to survive and grow. The host defends against siderophore-mediated iron acquisition by producing siderocalins. Siderocalins are a siderophore binding subset of the lipocalin family of proteins. The design of the siderophore binding pocket gives siderocalins the ability to bind a wide variety of siderophores and protect the host against several pathogens. Siderocalins have been identified in humans, chickens, and quail, among other animals. The differences in the respective siderocalins suggest that each was developed in response to the most serious pathogens encountered by that animal. Additionally, siderocalins have been observed in many roles unrelated to pathogen defense including differentiation, embryogenesis, inflammation, and cancer.
Output: Customized Siderocalins for Host Defense and Beyond
Autophagy is the bulk degradation of proteins and organelles, a process essential for cellular maintenance, cell viability, differentiation and development in mammals. Autophagy has significant associations with neurodegenerative diseases, cardiomyopathies, cancer, programmed cell death, and bacterial and viral infections. During autophagy, a cup-shaped structure, the preautophagosome, engulfs cytosolic components, including organelles, and closes, forming an autophagosome, which subsequently fuses with a lysosome, leading to the proteolytic degradation of internal components of the autophagosome by lysosomal lytic enzymes. During the formation of mammalian autophagosomes, two ubiquitylation-like modifications are required, Atg12-conjugation and LC3-modification. LC3 is an autophagosomal ortholog of yeast Atg8. A lipidated form of LC3, LC3-II, has been shown to be an autophagosomal marker in mammals, and has been used to study autophagy in neurodegenerative and neuromuscular diseases, tumorigenesis, and bacterial and viral infections. The other Atg8 homologues, GABARAP and GATE-16, are also modified by the same mechanism. In non-starved rats, the tissue distribution of LC3-II differs from those of the lipidated forms of GABARAP and GATE-16, GABARAP-II and GATE-16-II, suggesting that there is a functional divergence among these three modified proteins. Delipidation of LC3-II and GABARAP-II is mediated by hAtg4B. We review the molecular mechanism of LC3-modification, the crosstalk between LC3-modification and mammalian Atg12-conjugation, and the cycle of LC3-lipidation and delipidation mediated by hAtg4B, as well as recent findings concerning the other two Atg8 homologues, GABARAP and GATE-16. We also highlight recent findings regarding the pathobiology of LC3-modification, including its role in microbial infection, cancer and neuromuscular diseases.
Output: LC3 conjugation system in mammalian autophagy
Objectives. Over time, quarantine has become a classic public health intervention and has been used repeatedly when newly emerging infectious diseases have threatened to spread throughout a population. Here, we weigh the economic costs and benefits associated with implementing widespread quarantine in Toronto during the SARS outbreaks of 2003. Methods. We compared the costs of two outbreak scenarios: in Scenario A, SARS is able to transmit itself throughout a population without any significant public health interventions. In Scenario B, quarantine is implemented early on in an attempt to contain the virus. By evaluating these situations, we can investigate whether or not the use of quarantine is justified by being either cost-saving, life saving, or both. Results. Our results indicate that quarantine is effective in containing newly emerging infectious diseases, and also cost saving when compared to not implementing a widespread containment mechanism. Conclusions. This paper illustrates that it is not only in our humanitarian interest for public health and healthcare officials to remain aggressive in their response to newly emerging infections, but also in our collective economic interest. Despite somewhat daunting initial costs, quarantine saves both lives and money.
Output: c Ann Arbor Veterans Affairs Hospital
Human metapneumovirus (HMPV) is a single negativestranded RNA-enveloped virus in the Paramyxoviridae family [1] . HMPV is known to cause respiratory tract infections. HMPV-induced encephalitis has only sporadically been documented, mostly in children [2] . In adults only three former reports exist [1, 3, 4 ]. An 78-year-old Caucasian male patient presented at the emergency department because of agitation and confusion. His wife reported myoclonic jerks and urinary incontinence during sleep. Glasgow coma scale was 9/15. He had not taken any psychotropic drugs. Clinical examination showed no lateralisation, plantar reflexes were in flexion. The right eye was red and slightly swollen. Cardiovascular parameters were normal. Temperature was 38.9 °C. Medical history revealed diabetes mellitus type 1, arterial hypertension, hypercholesterolemia, nicotine abuse and glaucoma. Laboratory results showed leucocytosis of 12.600 white blood cells, a normal CRP of 1 mg/l (N < 5), slightly elevated lactate 20.3 mg/dl (N < 19.8) and glucose 161 m/dl (N < 110). Creatinine, electrolytes, enzymes, TSH and carboxy-hemoglobin were within normal limits. EEG showed a generalized slowing of the basal rhythm slightly more pronounced bitemporal, indicative for encephalopathy or encephalitis (Fig. 1 ). There were no signs of epilepsy. CT scan of the brain was normal. Chest radiography showed accentuated bronchopulmonary markings as seen in viral respiratory infections. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Output: An adult case of metapneumovirus-induced acute encephalitis
SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). Here, using polymerase extension experiments, we have demonstrated that the active triphosphate form of Sofosbuvir (a key component of the FDA approved hepatitis C drug EPCLUSA), is incorporated by SARS-CoV-2 RdRp, and blocks further incorporation. Using the same molecular insight, we selected the active triphosphate forms of three other anti-viral agents, Alovudine, AZT (an FDA approved HIV/AIDS drug) and Tenofovir alafenamide (TAF, an FDA approved drug for HIV and hepatitis B) for evaluation as inhibitors of SARS-CoV-2 RdRp. We demonstrated the ability of these three viral polymerase inhibitors, 3'-fluoro-3'-deoxythymidine triphosphate, 3'-azido-3'deoxythymidine triphosphate and Tenofovir diphosphate (the active triphosphate forms of Alovudine, AZT and TAF, respectively) to be incorporated by SARS-CoV-2 RdRp, where they also terminate further polymerase extension. These results offer a strong molecular basis for these nucleotide analogues to be evaluated as potential therapeutics for COVID-19.
Output: Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase
Porcine epidemic diarrhoea (PED) is a contagious enteric disease of pigs caused by a coronavirus. A double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) based on the use of monoclonal antibodies was developed for the detection of porcine epidemic diarrhoea virus (PEDV). The DAS-ELISA was compared with RT-PCR in the examination of 506 specimens collected during 2006-2007 from pigs originating from different farms located in the Po valley. Both faecal samples obtained directly from the rectum of live animals showing clinical signs and intestinal samples collected from the caecum of deceased pigs were included in the study. The correlation between the two methods was higher when testing faecal samples (K = 0.97, 95% CI: 0.94-1.00) than testing intestinal samples (K = 0.62, 95% CI: 0.35-0.89). The use of ELISA technology provided an efficient and effective mean of evaluating the presence of coronavirus PED antigen in field samples and indicates that this procedure is a very useful tool in epidemiological studies.
Output: Comparison of enzyme-linked immunosorbent assay and RT-PCR for the detection of porcine epidemic diarrhoea virus