niryuu/sni-each-converted huggingface dataset:
Background: Cumulating reports suggest that acute phase proteins (APPs) do not only play a role as systemic inflammatory mediators, but are also expressed in different tissues as local reaction to inflammatory stimuli. The present study aimed to evaluate presence and changes in luminal lung concentrations of the APPs haptoglobin (Hp), lipopolysaccharide binding protein (LBP), C-reactive protein (CRP), and lactoferrin (Lf) in calves with an acute respiratory disease experimentally induced by Chlamydia (C.) psittaci. Results: Intra-bronchial inoculation of the pathogen resulted in a consistent respiratory illness. In venous blood of the infected calves (n = 13), concentrations of plasma proteins and serum LBP were assessed (i) before exposure and (ii) 8 times within 14 days after inoculation (dpi). Increasing clinical illness correlated significantly with increasing LBP-and decreasing albumin concentrations in blood, both verifying a systemic acute phase response. Broncho-alveolar lavage fluid (BALF) was obtained from all 13 calves experimentally infected with C. psittaci at 4, 9 and 14 dpi, and from 6 uninfected healthy calves. Concentrations of bovine serum albumin (BSA), Hp, LBP, CRP and Lf in BALF were determined by ELISA. In infected animals, absolute concentrations of LBP and Hp in BALF correlated significantly with the respiratory score. The quotient [LBP]/[BSA] in BALF peaked significantly in acutely infected animals (4 dpi), showed a time-dependent decrease during the recovery phase (9-14 dpi), and was significantly higher compared to healthy controls. Concentrations of Hp and Lf in BALF as well as [Hp]/[BSA]-and [Lf]/[BSA]-quotients decreased during the study in infected animals, but were never higher than in healthy controls. CRP concentrations and [CRP]/[BSA]-quotient did not express significant differences between infected and healthy animals or during the course of infection. Conclusion: In conclusion, absolute concentrations of LBP in blood and BALF as well as the quotient [LBP]/[BSA] in BALF perfectly paralleled the clinical course of respiratory illness after infection. Beside LBP, the suitability of Hp and Lf as local biomarkers of respiratory infections in cattle and their role in the local response to pathogens is worth further investigation, while CRP does not seem to play a role in local defense mechanisms of the bovine lung.
Output: Acute phase proteins as local biomarkers of respiratory infection in calves
The unfolded protein response (UPR) adjusts the cell's protein folding capacity in the endoplasmic reticulum (ER) according to need. IRE1 is the most conserved UPR sensor in eukaryotic cells. It has remained controversial, however, whether mammalian and yeast IRE1 use a common mechanism for ER stress sensing. Here, we show that similar to yeast, human IRE1a's ER-lumenal domain (hIRE1a LD) binds peptides with a characteristic amino acid bias. Peptides and unfolded proteins bind to hIRE1a LD's MHC-like groove and induce allosteric changes that lead to its oligomerization. Mutation of a hydrophobic patch at the oligomerization interface decoupled peptide binding to hIRE1a LD from its oligomerization, yet retained peptide-induced allosteric coupling within the domain. Importantly, impairing oligomerization of hIRE1a LD abolished IRE1's activity in living cells. Our results provide evidence for a unifying mechanism of IRE1 activation that relies on unfolded protein binding-induced oligomerization.
Output: An unfolded protein-induced conformational switch activates mammalian IRE1
, produce more severe disease in the elderly, yet the molecular mechanisms governing age-related susceptibility remain poorly studied. Advanced age was significantly associated with increased SARS-related deaths, primarily due to the onset of early-and late-stage acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Infection of aged, but not young, mice with recombinant viruses bearing spike glycoproteins derived from early human or palm civet isolates resulted in death accompanied by pathological changes associated with ARDS. In aged mice, a greater number of differentially expressed genes were observed than in young mice, whose responses were significantly delayed. Differences between lethal and nonlethal virus phenotypes in aged mice could be attributed to differences in host response kinetics rather than virus kinetics. SARS-CoV infection induced a range of interferon, cytokine, and pulmonary wound-healing genes, as well as several genes associated with the onset of ARDS. Mice that died also showed unique transcriptional profiles of immune response, apoptosis, cell cycle control, and stress. Cytokines associated with ARDS were significantly upregulated in animals experiencing lung pathology and lethal disease, while the same animals experienced downregulation of the ACE2 receptor. These data suggest that the magnitude and kinetics of a disproportionately strong host innate immune response contributed to severe respiratory stress and lethality. Although the molecular mechanisms governing ARDS pathophysiology remain unknown in aged animals, these studies reveal a strategy for dissecting the genetic pathways by which SARS-CoV infection induces changes in the host response, leading to death.
Output: Early Upregulation of Acute Respiratory Distress Syndrome-Associated Cytokines Promotes Lethal Disease in an Aged-Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Infection ᰔ
As the prevalence of cancer and transmittable disease persists, the development of new and more advanced therapies remains a priority in medical research. An emerging platform for the treatment of these illnesses is the use of materials formed via peptide assembly where the bulk material itself acts as the therapeutic. Higher ordered peptide structures with defined chemistry are capable of cellular targeting, recognition, and internalization. Recent design efforts are being made to exploit the nanoscale definition of the materials formed by assembling peptides to target cancer and microbial cells and to function as vaccines. This review focuses on assembled peptide materials that actively participate in the biological processes important to cancer and transmittable diseases to exert an anticipated functional outcome.
Output: Materials from peptide assembly: towards the treatment of cancer and transmittable disease
Spongiform degeneration is characterized by vacuolation in nervous tissue accompanied by neuronal death and gliosis. Although spongiform degeneration is a hallmark of prion diseases, this pathology is also present in the brains of patients suffering from Alzheimer's disease, diffuse Lewy body disease, human immunodeficiency virus (HIV) infection, and Canavan's spongiform leukodystrophy. The shared outcome of spongiform degeneration in these diverse diseases suggests that common cellular mechanisms must underlie the processes of spongiform change and neurodegeneration in the central nervous system. Immunohistochemical analysis of brain tissues reveals increased ubiquitin immunoreactivity in and around areas of spongiform change, suggesting the involvement of ubiquitin-proteasome system dysfunction in the pathogenesis of spongiform neurodegeneration. The link between aberrant ubiquitination and spongiform neurodegeneration has been strengthened by the discovery that a null mutation in the E3 ubiquitin-protein ligase mahogunin ring finger-1 (Mgrn1) causes an autosomal recessively inherited form of spongiform neurodegeneration in animals. Recent studies have begun to suggest that abnormal ubiquitination may alter intracellular signaling and cell functions via proteasome-dependent and proteasome-independent mechanisms, leading to spongiform degeneration and neuronal cell death. Further elucidation of the pathogenic pathways involved in spongiform neurodegeneration should facilitate the development of novel rational therapies for treating prion diseases, HIV infection, and other spongiform degenerative disorders. transmissible spongiform encephalopathy (TSE); retroviral infection; mahogunin ring finger-1 (Mgrn1); oxidative stress; autophagy; endocytic trafficking NIH Public Access
Output: The ubiquitin-proteasome system in spongiform degenerative disorders
To provide optimal cut-off values of anti-Middle East respiratory syndrome coronavirus (MERS-CoV) serologic tests, we evaluated performance of ELISA IgG, ELISA IgA, IFA IgM, and IFA IgG using 138 serum samples of 49 MERS-CoV-infected patients and 219 serum samples of 219 rRT-PCR-negative MERS-CoV-exposed healthcare personnel and patients. The performance analysis was conducted for two different purposes: (1) prediction of neutralization activity in MERS-CoV-infected patients, and (2) epidemiologic surveillance of MERS-CoV infections among MERS-CoV-exposed individuals. To evaluate performance according to serum collection time, we used 'days post onset of illness (dpoi)' and 'days post exposure (dpex)' assessing neutralization activity and infection diagnosis, respectively. Performance of serologic tests improved with delayed sampling time, being maximized after a seroconversion period. In predicting neutralization activity, ELISA IgG tests showed optimal performance using sera collected after 21 dpoi at cut-off values of OD ratio 0.4 (sensitivity 100% and specificity 100%), and ELISA IgA showed optimal performance using sera collected after 14 dpoi at cut-off value of OD ratio 0.2 (sensitivity 85.2% and specificity 100%). In diagnosis of MERS-CoV infection, ELISA IgG exhibited optimal performance using sera collected after 28 dpex, at a cut-off value of OD ratio 0.2 (sensitivity 97.3% and specificity 92.9%). These new breakpoints are markedly lower than previously suggested values (ELISA IgG OD ratio 1.1, sensitivity 34.8% and specificity 100% in the present data set), and the performance data help serologic tests to be practically used in the field of MERS management.
Output: Suggested new breakpoints of anti-MERS-CoV antibody ELISA titers: performance analysis of serologic tests
The nitric oxide synthase (NOS) activity in the haemocytes of shrimps Fenneropenaeus chinensis (Osbeck) and Marsupenaeus japonicus (Bate) was studied after white spot syndrome virus (WSSV) infection to determine its characteristics in response to virus infection. First, the NOS activity in haemocytes of shrimps was determined by the means of NBT reduction and changes in cell conformation. And the variations of NOS activity in shrimps after challenge with WSSV intramuscularly were evaluated through the analysis of L-citrulline and total nitrite/nitrate (both as NO derivates) concentrations. The result showed that NOS activity in the haemocytes of F. chinensis increased slightly from 0 to 12 h postchallenge, indicated by the variations of L-citrulline (from 11.15 § 0.10 to 12.08 § 0.64 M) and total nitrite/nitrate concentrations (from 10.45 § 0.65 to 12.67 § 0.52 M). Then it decreased sharply till the end of the experiment (84 h postchallenge), the concentrations of L-citrulline and total nitrite/nitrate at 84 h were 1.58 § 0.24 and 2.69 § 0.70 M, respectively. The LPSstimulated NOS activity kept constant during the experiment. However, in M. japonicus, the NOS activity kept increasing during the Wrst 72 h postchallenge, the concentrations of L-citrulline and total nitrite/nitrate increased from 7.82 § 0.77 at 0 h to 10.79 § 0.50 M at 72 h, and from 8.98 § 0.43 at 0 h to 11.20 § 0.37 M at 72 h, respectively. Then it decreased till the end of the experiment (216 h postchallenge), and the concentrations of L-citrulline and total nitrite/nitrate at 216 h were 5.66 § 0.27 and 4.68 § 0.16 M, respectively. More importantly, an apparent increase of LPS-stimulated NOS activity was observed in M. japonicus at 48 h postchallenge, which was about 4 times higher than that in the control group of health shrimps. In correspondence with the diVerence of NOS activity between the two species of shrimps, the cumulative mortalities of the shrimps were also diVerent. All shrimps of F. chinensis in the mortality experiment died in 66 h, much more quickly than M. japonicus, whose accumulative mortality reached 100% after 240 h. Data here reported let us hypothesize that NOS activity in the haemocytes of shrimps F. chinensis and M. japonicus responses to WSSV infection diVerently, and this might be one of the reasons for the diVerent susceptibility of F. chinensis and M. japonicus to WSSV infection.
Output: Studies on nitric oxide synthase activity in haemocytes of shrimps Fenneropenaeus chinensis and Marsupenaeus japonicus after white spot syndrome virus infection
Basic and translational research on lung biology has discovered multiple progenitor cell types, specialized or facultative, responsible for turnover, renewal, and repair. Isolation of populations of resident lung progenitor cells (LPCs) has been described by multiple protocols, and some have been successfully applied to healthy human lung tissue. We aimed at understanding how different cell culture conditions may affect, in vitro, the phenotype of LPCs to create an ideal niche-like microenvironment. The influence of different substrates (i.e., fibronectin, gelatin, laminin) and the impact of a three-dimensional/two-dimensional (3D/2D) culture switch on the biology of LPCs isolated as lung spheroids (LSs) from normal adult human lung biopsy specimens were investigated. We applied a spheroid culture system as the selective/inductive step for progenitor cell culture, as described in many biological systems. The data showed a niche-like proepithelial microenvironment inside the LS, highly sensitive to the 3D culture system and significantly affecting the phenotype of adult LPCs more than culture substrate. LSs favor epithelial phenotypes and LPC maintenance and contain cells more responsive to specific commitment stimuli than 2D monolayer cultures, while secreting a distinctive set of paracrine factors. We have shown for the first time, to our knowledge, how culture as 3D LSs can affect LPC epithelial phenotype and produce strong paracrine signals with a distinctive secretomic profile compared with 2D monolayer conditions. These findings suggest novel approaches to maintain ex vivo LPCs for basic and translational studies. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1-11 SIGNIFICANCE A lung niche-like microenvironment was created ex vivo inside the pneumosphere. Pneumospheres have a distinctive secretomic profile compared with two-dimensional culture. Three-dimensional culture switch significantly affects lung progenitor phenotype. Lung progenitors in pneumospheres were more committed toward epithelial lineages.
Output: Tissue-Specific Progenitor and Stem Cells Human Lung Spheroids as In Vitro Niches of Lung Progenitor Cells With Distinctive Paracrine and Plasticity Properties
Glycyrrhizin (GL) is known to have various immunomodulating activities and has long been used clinically as an antiallergic and anti-hepatitis agent. While the potency of GL against lung inflammatory diseases has been expected, the effect of GL on the lung has been poorly understood. Lung fibroblasts are known as a potent producer of inflammatory chemokines, IL-8 and eotaxin 1, by which neutrophils and eosinophils are strongly attracted during inflammation. Therefore, we studied the effects of GL on the production of these chemokines using a human fetal lung fibroblast cell line, HFL-1, stimulated with TNFa and IL-4. Moreover, we examined the structure-activity relationships of GL to explore more beneficial compounds. 18a,h-GL inhibited IL-8 dose-dependently and inhibited eotaxin 1 slightly. 18a,h-Glycyrrhetic acid (GA) did not inhibit IL-8 but inhibited eotaxin 1. The effect of 18a,h-glycyrrhetic acid monoglucuronide (MGA) resembled that of 18a,h-GL but was weaker. Both 3h-[(2-O-h-d-glucopyranuronosyl-h-d-glucopyranuronosyl)oxy]-18h-11-deoxo-olean-12-en-30-oic acid (11deoxo-GL) and 3h-[(2-O-h-d-glucopyranuronosyl-h-d-glucopyranuronosyl)oxy]-olean-11,13(18)-dien-30-oic acid (hetero-GL) exhibited inhibitory activity with significant cytotoxicity. 3h-[(2-O-h-d-Glucopyranuronosyl-h-d-glucopyranuronosyl)oxy]-18h-olean-9,12-dien-30-oic acid (homo-GL) did not have cytotoxicity but its activity was mild like that of 18a,h-GL. 3h-[(2-O-h-d-Glucopyranuronosyl-h-d-glucopyranuronosyl)oxy]-olean-11,13(18)-dien-30-ol (hetero-30-OH-GL) and 3h- [(2-O-h-d-glucopyranuronosyl-h-d-glucopyranuronosyl)oxy]-18h-olean-9,12-dien-30-ol (homo-30-OH-GL) showed potent inhib-1567-5769/$ -see front matter D itory effects, at concentrations lower than 18a,h-GL with no significant cytotoxicity. These results suggest that GL-related compounds are effective in reducing chemokine production and that GL-modified compounds including hetero-30-OH-GL and homo-30-OH-GL appear most beneficial in view of their inhibitory capacity with less cytotoxicity. D
Output: Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line
Steroid-associated osteonecrosis (SAON) might induce bone collapse and subsequently lead to joint arthroplasty. Core decompression (CD) is regarded as an effective therapy for early-stage SAON, but the prognosis is unsatisfactory due to incomplete bone repair. Parathyroid hormone[1-34] (PTH ) has demonstrated positive efficacy in promoting bone formation. We therefore evaluated the effects of PTH on improving the effects of CD in Early-Stage SAON. Distal femoral CD was performed two weeks after osteonecrosis induction or vehicle injection, with ten of the ON-induced rabbits being subjected to six-week PTH [1-34] treatment and the others, including ON-induced and non-induced rabbits, being treated with vehicle. MRI confirmed that intermittent PTH administration improved SAON after CD therapy. Micro-CT showed increased bone formation within the tunnel. Bone repair was enhanced with decreased empty osteocyte lacunae and necrosis foci area, resulting in enhanced peak load and stiffness of the tunnel. Additionally, PTH enlarged the mean diameter of vessels in the marrow and increased the number of vessels within the tunnels, as well as elevated the expression of BMP-2, RUNX2, IGF-1, bFGF and VEGF, together with serum OCN and VEGF levels. Therefore, PTH[1-34] enhances the efficacy of CD on osteogenesis and neovascularization, thus promoting bone and blood vessels repair in the SAON model. OPEN ACCESS Citation: Zhou C-h, Meng J-h, Zhao C-c, Ye C-y, Zhu H-x, Hu B, et al. (2017) PTH[1-34] improves the effects of core decompression in early-stage steroid-associated osteonecrosis model by enhancing bone repair and revascularization. PLoS ONE 12(5): e0178781. https://doi.org/10.
Output: PTH[1-34] improves the effects of core decompression in early-stage steroid- associated osteonecrosis model by enhancing bone repair and revascularization
The ongoing novel coronavirus disease pandemic has rapidly spread in early 2020, causing tens of thousands of deaths, over a million cases and widespread socioeconomic disruption. With no vaccine available and numerous national healthcare systems reaching or exceeding capacity, interventions to limit transmission are urgently needed. While there is broad agreement that travel restrictions and closure of non-essential businesses and schools are beneficial in limiting local and regional spread, recommendations around the use of face masks for the general population are less consistent internationally. In this study, we examined the role of face masks in mitigating the spread of COVID-19 in the general population, using epidemic models to estimate the total reduction of infections and deaths under various scenarios. In particular, we examined the optimal deployment of face masks when resources are limited, and explored a range of supply and demand dynamics. We found that face masks, even with a limited protective effect, can reduce infections and deaths, and can delay the peak time of the epidemic. We consistently found that a random distribution of masks in the population was a suboptimal strategy when resources were limited. Prioritizing coverage among the elderly was more beneficial, while allocating a proportion of available resources for diagnosed infected cases provided further mitigation under a range of scenarios. In summary, face mask use, particularly for a pathogen with relatively common asymptomatic carriage, can effectively provide some mitigation of transmission, while balancing provision between vulnerable healthy persons and symptomatic persons can optimize mitigation efforts when resources are limited. The rapid global spread of SARS-CoV-2 and the resulting coronavirus disease pandemic has led to urgent efforts to contain and mitigate transmission, leading to significant and widespread socioeconomic disruption. As of April 3rd 2020, over one million cases have been reported worldwide, as well as over 60,000 deaths, with ongoing spread in most parts of the world [1]. While infection is frequently asymptomatic, or associated with only mild symptoms in many people [2, 3] , it can cause severe and life-threatening illness in the immunocompromised and the elderly, with a case fatality ratio of over 10% in the latter group [3] [4] [5] . The rapid spread of the virus has raised concerns that healthcare systems lack sufficient resources and will be unable to bear the burden of accommodating patients suffering from COVID-19, resulting in significantly increased morbidity and mortality. There is an urgent need . CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) The copyright holder for this preprint .
Output: Face mask use in the general population and optimal resource allocation during the COVID-19 pandemic
Background: The Kingdom of Saudi Arabia has experienced a prolonged outbreak of Middle East Respiratory Syndrome (MERS) coronavirus since 2012. Healthcare workers (HCWs) form a significant risk group for infection. Objectives: The aim of this survey was to assess the knowledge, attitudes, infection control practices and educational needs of HCWs in the Kingdom of Saudi Arabia to MERS coronavirus and other emerging infectious diseases. Methods: 1500 of HCWs from Saudi Ministry of Health were invited to fill a questionnaire developed to cover the survey objectives from 9 September 2015 to 8 November 2015. The response rate was about 81%. Descriptive statistics was used to summarise the responses. Results: 1216 HCWs were included in this survey. A total of 56.5% were nurses and 22% were physicians. The most common sources of MERS-coronavirus (MERS-CoV) information were the Ministry of Health (MOH) memo (74.3%). Only (47.6%) of the physicians, (30.4%) of the nurses and (29.9%) of the other HCWs were aware that asymptomatic MERS-CoV was described. Around half of respondents who having been investigated for MERS-CoV reported that their work performance decreased while they have suspicion of having MERS-CoV and almost two thirds reported having psychological problems during this period. Almost two thirds of the HCWs (61.2%) reported anxiety about contracting MERS-CoV from patients. Conclusions: The knowledge about emerging infectious diseases was poor and there is need for further education and training programs particularly in the use of personal protective equipment, isolation and infection control measures. The self-reported infection control practices were sub-optimal and seem to be overestimated.
Output: Knowledge, Attitudes and Behaviours of Healthcare Workers in the Kingdom of Saudi Arabia to MERS Coronavirus and Other Emerging Infectious Diseases
We studied the course of demyelination and subsequent remyelination of nerve fibers after heat injury in the dorsal funiculus of the rat spinal cord. Four weeks after heat treatment, we observed, in addition to normally remyelinated axons, a few aberrantly remyelinated axons which had both CNS-and PNS-type myelin sheaths: the CNS-type myelin sheaths were always situated inside the PNS-type sheaths. This finding indicates that in some conditions Schwann cells can form myelin sheaths around those formed by oligodendrocytes.
Output: Ileurol tholog a Aberrant remyelination of axons after heat injury in the dorsal funiculus of rat spinal cord
Background: The role of disulfide bond remodeling in HIV-1 infection is well described, but the process still remains incompletely characterized. At present, the data have been predominantly obtained using established cell lines and/or CXCR4-tropic laboratory-adapted virus strains. There is also ambiguity about which disulfide isomerases/ reductases play a major role in HIV-1 entry, as protein disulfide isomerase (PDI) and/or thioredoxin (Trx) have emerged as the two enzymes most often implicated in this process. We have extended our previous findings and those of others by focusing on CCR5-using HIV-1 strains and their natural targets -primary human macrophages and CD4 + T lymphocytes. We found that the nonspecific thiol/ disulfide exchange inhibitor, 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), significantly reduced HIV-1 entry and infection in cell lines, human monocyte-derived macrophages (MDM), and also phytohemagglutinin (PHA)stimulated peripheral blood mononuclear cells (PBMC). Subsequent studies were performed using specific anti-PDI or Trx monoclonal antibodies (mAb) in HIV-1 envelope pseudotyped and wild type (wt) virus infection systems. Although human donor-to-donor variability was observed as expected, Trx appeared to play a greater role than PDI in HIV-1 infection of MDM. In contrast, PDI, but not Trx, was predominantly involved in HIV-1 entry and infection of the CD4 + /CCR5 + T cell line, PM-1, and PHA-stimulated primary human T lymphocytes. Intriguingly, both PDI and Trx were present on the surface of MDM, PM-1 and PHA-stimulated CD4 + T cells. However, considerably lower levels of Trx were detected on freshly isolated CD4 + lymphocytes, compared to PHA-stimulated cells. Conclusions: Our findings clearly demonstrate the role of thiol/disulfide exchange in HIV-1 entry in primary T lymphocytes and MDM. They also establish a cell-type specificity regarding the involvement of particular disulfide isomerases/reductases in this process and may provide an explanation for differences among previously published studies. More importantly, from an in vivo perspective, the preferential utilization of PDI may be relevant to the HIV-1 entry and establishment of virus reservoirs in resting CD4 + cells, while the elevated levels of Trx reported in the chronic stages of HIV-1 infection may facilitate the virus entry in macrophages and help to sustain high viremia during the decline of T lymphocytes.
Output: Cell-type specific requirements for thiol/disulfide exchange during HIV-1 entry and infection
Single-stranded RNA (ssRNA) is the simplest form of genetic molecule and constitutes the genome in some viruses and presumably in primitive life-forms. However, an innate and unsolved problem regarding the ssRNA genome is formation of inactive doublestranded RNA (dsRNA) during replication. Here, we addressed this problem by focusing on the secondary structure. We systematically designed RNAs with various structures and observed dsRNA formation during replication using an RNA replicase (Q␤ replicase). From the results, we extracted a simple rule regarding ssRNA genome replication with less dsRNA formation (less GC number in loops) and then designed an artificial RNA that encodes a domain of the ␤-galactosidase gene based on this rule. We also obtained evidence that this rule governs the natural genomes of all bacterial and most fungal viruses presently known. This study revealed one of the structural design principles of an ssRNA genome that replicates continuously with less dsRNA formation.
Output: A design principle for a single-stranded RNA genome that replicates with less double-strand formation
Introduction-HIV-1 uses a programmed -1 ribosomal frameshift to generate Gag-Pol, the precursor of its enzymes, when its full-length mRNA is translated by the ribosomes of the infected cells. This change in the reading frame occurs at a so-called slippery sequence that is followed by a specific secondary structure, the frameshift stimulatory signal. This signal controls the frameshift efficiency. The synthesis of HIV-1 enzymes is critical for the virus replication and therefore, the -1 ribosomal frameshift could be the target of novel antiviral drugs. Areas covered-This review examines various approaches used to select drugs interfering with the -1 frameshift of HIV-1. These include the selection and modification of chemical compounds that specifically bind to the frameshift stimulatory signal, the use of antisense oligonucleotides targeting this signal and the selection of compounds that modulate HIV-1 frameshift, by using bicistronic reporters where the expression of the second cistron depends upon HIV-1 frameshift. Expert opinion-The most promising approach is the selection and modification of compounds specifically targeting HIV-1 frameshift stimulatory signal. The use of antisense oligonucleotides binding to the frameshift stimulatory signal is still questionable. The use of bicistronic reporters preferentially selects compounds that modulate the frameshift by targeting the ribosomes, which is less promising.
Output: Targeting frameshifting in the human immunodeficiency virus
Among the causes for pregnancy loss, viruses and non-infectious factors are among the most important. In both dogs and cats, research and clinical evidence provide proof that there is an increasing incidence of pregnancy loss associated with infectious diseases like herpesvirus, as well as the presence of toxicants or chemicals in the animal's diet and environment. Endocrine causes must be taken into consideration when dealing with pregnancy loss. This review will cover the most recent knowledge regarding viral and non-infectious of pregnancy losses in the dog and cat. #
Output: Canine and feline pregnancy loss due to viral and non-infectious causes: A review
Geographical variations in cardiovascular disease rates have been linked to individual air pollutants. Investigating the relation between cardiovascular disease and exposure to a complex mixture of air pollutants requires holistic approaches. We assessed the relationship between exposure to multiple air pollutants and the incidence of coronary heart disease (CHD) in a general population sample. We collected data in the Lille MONICA registry (2008-2011) on 3268 incident cases (age range: 35-74). Based on 20 indicators, we derived a composite environmental score (SEnv) for cumulative exposure to air pollution. Poisson regression models were used to analyse associations between CHD rates on one hand and SEnv and each single indicator on the other (considered in tertiles, where T3 is the most contaminated). We adjusted models for age, sex, area-level social deprivation, and neighbourhood spatial structure. The incidence of CHD was a spatially heterogeneous (p=0.006). There was a significant positive association between SEnv and CHD incidence (trend p=0.0151). The relative risks [95%CI] of CHD were 1.08 [0.98-1.18] and 1.16 [1.04-1.29] for the 2nd and 3rd tertile of SEnv exposure. In the single pollutant analysis, PM 10 , NO 2 , cadmium, copper, nickel, and palladium were significantly associated with CHD rates. Multiple air pollution was associated with an increased risk of CHD. Single pollutants reflecting road traffic pollution were the most strongly associated with CHD. Our present results are consistent with the literature data on the impact of road traffic on the CHD risk in urban areas.
Output: Exposure to multiple air pollutants and the incidence of coronary heart disease: A fine-scale geographic analysis
The origins and evolutionary history of the Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV) remain an issue of uncertainty and debate. Based on evolutionary analyses of coronavirus DNA sequences, encompassing an approximately 13 kb stretch of the SARS-TOR2 genome, we provide evidence that SARS-CoV has a recombinant history with lineages of types I and III coronavirus. We identified a minimum of five recombinant regions ranging from 83 to 863 bp in length and including the polymerase, nsp9, nsp10, and nsp14. Our results are consistent with a hypothesis of viral host jumping events, concomitant with the reassortment of bird and mammalian coronaviruses, a scenario analogous to earlier outbreaks of influenzae.
Output: Evidence from the evolutionary analysis of nucleotide sequences for a recombinant history of SARS-CoV
Background: COVID-19 diagnosis is a critical problem, mainly due to the lack or delay in the test results. We aimed to obtain a model to predict SARS-CoV-2 infection in suspected patients reported to the Brazilian surveillance system. Methods: We analyzed suspected patients reported to the National Surveillance System that corresponded to the following case definition: patients with respiratory symptoms and fever, who traveled to regions with local or community transmission or who had close contact with a suspected or confirmed case. Based on variables routinely collected, we obtained a multiple model using logistic regression. The area under the receiver operating characteristic curve (AUC) and accuracy indicators were used for validation. Results: We described 1468 COVID-19 cases (confirmed by RT-PCR) and 4271 patients with other illnesses. With a data subset, including 80% of patients from Sao Paulo (SP) and Rio Janeiro (RJ), we obtained a function which reached an AUC of 95.54% (95% CI: 94.41% -96.67%) for the diagnosis of COVID-19 and accuracy of 90.1% (sensitivity 87.62% and specificity 92.02%). In a validation dataset including the other 20% of patients from SP and RJ, this model exhibited an AUC of 95.01% (92.51% -97.5%) and accuracy of 89.47% (sensitivity 87.32% and specificity 91.36%). Conclusion: We obtained a model suitable for the clinical diagnosis of COVID-19 based on routinely collected surveillance data. Applications of this tool include early identification for specific treatment and isolation, rational use of laboratory tests, and input for modeling epidemiological trends.
Output: A model to predict SARS-CoV-2 infection based on the first three- month surveillance data in Brazil
By focusing on the Masters of Public Health course, this study took a pragmatic approach to exploring the interface between public health education and public health practice. The commonly utilized 'three domains of practice' framework could provide a robust and explicit link between educational provision and practice for public health. This model provides the workforce, the university, the students and the potential funders of the course with an easily comprehensible framework for understanding how the modules of an MSc can support the development of competency within the context of practice.
Output: The three domains of public health: An internationally relevant basis for public health education?
The pathogenesis of SARS-CoV remains largely unknown. To study the function of the SARS-CoV nucleocapsid protein, we have conducted a yeast twohybrid screening experiment to identify cellular proteins that may interact with the SARS-CoV nucleocapsid protein. Pyruvate kinase (liver) was found to interact with SARS-CoV nucleocapsid protein in this experiment. The binding domains of these two proteins were also determined using the yeast two-hybrid system. The physical interaction between the SARS-CoV nucleocapsid and cellular pyruvate kinase (liver) proteins was further confirmed by GST pull-down assay, co-immunoprecipitation assay and confocal microscopy. Cellular pyruvate kinase activity in hepatoma cells was repressed by SARS-CoV nucleocapsid protein in either transiently transfected or stably transfected cells. PK deficiency in red blood cells is known to result in human hereditary non-spherocytic hemolytic anemia. It is reasonable to assume that an inhibition of PKL activity due to interaction with SARS-CoV N protein is likely to cause the death of the hepatocytes, which results in the elevation of serum alanine aminotransferase and liver dysfunction noted in most SARS patients. Thus, our results suggest that SARS-CoV could reduce pyruvate kinase activity via its nucleocapsid protein, and this may in turn cause disease.
Output: SARS-CoV nucleocapsid protein interacts with cellular pyruvate kinase protein and inhibits its activity
This bibliography is compiled by immunologists from the journals listed at the end of this publication. It is based on literature entered into our database between 1st April 1991 and 31st March 1992 (articles are generally added to the database about two and a half months after publication). In addition, the bibliography contains every paper annotated by reviewers; these references were obtained from a variety of bibliographic databases and published between the beginning of the review period and the time of going to press. The bibliography has been grouped into topics that relate to the reviews in this issue. 9 Papers considered by the reviewers to be of special interest. 0 9 Papers considered by the reviewers to be of outstanding interest. The number in square brackets following a selected paper, e.g. [7], refers to its number in the annotated references of the corresponding review.
Output: Bibliography of the current world literature
The leader RNA of the 5′ untranslated region (UTR) of coronaviral genomes contains two stem-loop structures denoted SL1 and SL2. Herein, we show that SL1 is functionally and structurally bipartite. While the upper region of SL1 is required to be paired, we observe strong genetic selection against viruses that contain a deletion of A35, an extrahelical nucleotide that destabilizes SL1, in favor of genomes that contain a diverse panel of destabilizing second-site mutations, due to introduction of a noncanonical base pair near A35. Viruses containing destabilizing SL1-ΔA35 mutations also contain one of two specific mutations in the 3′ UTR. Thermal denaturation and imino proton solvent exchange experiments reveal that the lower half of SL1 is unstable and that second-site SL1-ΔA35 substitutions are characterized by one or more features of the wild-type SL1. We propose a "dynamic SL1" model, in which the base of SL1 has an optimized lability required to mediate a physical interaction between the 5′ UTR and the 3′ UTR that stimulates subgenomic RNA synthesis. Although not conserved at the nucleotide sequence level, these general structural characteristics of SL1 appear to be conserved in other coronaviral genomes.
Output: Structural Lability in Stem-Loop 1 Drives a 5′ UTR-3′ UTR Interaction in Coronavirus Replication
Objective: We examined the relationship between hospital structural characteristics and system-level activities for patient safety and infection control, for use in designing an incentive structure to promote patient safety. Methods: This study utilized a questionnaire to collect institutional data about hospital infrastructure and volume of patient safety activities from all 1039 teaching hospitals in Japan. The patient safety activities were focused on meetings and conferences, internal audits, staff education and training, incident reporting and infection surveillance. Generalized linear modeling was used. Results: Of the 1039 hospitals surveyed, 418 (40.2%) hospitals participated. The amount of activities significantly increased by over 30% in hospitals with dedicated patient safety and infection control full-time staff (P < 0.001 and P < 0.01, respectively). High profit margins also predicted the increase of patient safety programs (P < 0.01). Perceived lack of administrative leadership was associated with reduced volume of activities (P < 0.05), and the economic burden of safety programs was found to be disproportionately large for small hospitals (P < 0.05). Conclusions: Hospitals with increased resources had greater spread of patient safety and infection control activities. To promote patient safety programs in hospitals, it is imperative that policy makers require the assignment of dedicated full-time staff to patient safety. Economic support for hospitals will also be required to assure that safety programs are sustainable.
Output: Factors associated with system-level activities for patient safety and infection control
Phylogenetic analyses have provided strong evidence that amino acid changes in spike (S) protein of animal and human SARS coronaviruses (SARS-CoVs) during and between two zoonotic transfers (2002/03 and 2003/04) are the result of positive selection. While several studies support that some amino acid changes between animal and human viruses are the result of inter-species adaptation, the role of neutralizing antibodies (nAbs) in driving SARS-CoV evolution, particularly during intraspecies transmission, is unknown. A detailed examination of SARS-CoV infected animal and human convalescent sera could provide evidence of nAb pressure which, if found, may lead to strategies to effectively block virus evolution pathways by broadening the activity of nAbs. Here we show, by focusing on a dominant neutralization epitope, that contemporaneousand cross-strain nAb responses against SARS-CoV spike protein exist during natural infection. In vitro immune pressure on this epitope using 2002/03 strain-specific nAb 80R recapitulated a dominant escape mutation that was present in all 2003/ 04 animal and human viruses. Strategies to block this nAb escape/naturally occurring evolution pathway by generating broad nAbs (BnAbs) with activity against 80R escape mutants and both 2002/03 and 2003/04 strains were explored. Structure-based amino acid changes in an activation-induced cytidine deaminase (AID) ''hot spot'' in a light chain CDR (complementarity determining region) alone, introduced through shuffling of naturally occurring non-immune human VL chain repertoire or by targeted mutagenesis, were successful in generating these BnAbs. These results demonstrate that nAb-mediated immune pressure is likely a driving force for positive selection during intra-species transmission of SARS-CoV. Somatic hypermutation (SHM) of a single VL CDR can markedly broaden the activity of a strain-specific nAb. The strategies investigated in this study, in particular the use of structural information in combination of chain-shuffling as well as hot-spot CDR mutagenesis, can be exploited to broaden neutralization activity, to improve anti-viral nAb therapies, and directly manipulate virus evolution. Citation: Sui J, Aird DR, Tamin A, Murakami A, Yan M, et al. (2008) Broadening of Neutralization Activity to Directly Block a Dominant Antibody-Driven SARS-Coronavirus Evolution Pathway. PLoS Pathog 4(11): e1000197. This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Output: Broadening of Neutralization Activity to Directly Block a Dominant Antibody-Driven SARS-Coronavirus Evolution Pathway
Acute respiratory distress syndrome presents as hypoxia and bilateral pulmonary infi ltrates on chest imaging in the absence of heart failure suffi cient to account for this clinical state. Management is largely supportive, and is focused on protective mechanical ventilation and the avoidance of fl uid overload. Patients with severe hypoxaemia can be managed with early short-term use of neuromuscular blockade, prone position ventilation, or extracorporeal membrane oxygenation. The use of inhaled nitric oxide is rarely indicated and both β 2 agonists and late corticosteroids should be avoided. M ortality remains at approximately 30%.
Output: Acute respiratory distress syndrome
Influenza viruses are a major public health problem worldwide. Although influenza has been extensively researched, there are still many aspects that are not fully understood such as the effects of within and between-hosts dynamics and their impact on behavior change. Here, we develop mathematical models with multiple infection stages and estimate parameters based on within-host data to investigate the impact of behavior change on influenza dynamics. We divide the infected population into three and four groups based on the age of the infection, which corresponds to viral load shedding. We consider within-host data on viral shedding to estimate the length and force of infection of the different infectivity stages. Our results show that behavior changes, due to exogenous events (e.g., media coverage) and disease symptoms, are effective in delaying and lowering an epidemic peak. We show that the dynamics of viral shedding and symptoms, during the infection, are key features when considering epidemic prevention strategies. This study improves our understanding of the spread of influenza virus infection in the population and provides information about the impact of emergent behavior and its connection to the within and between-hosts dynamics.
Output: Connecting within and between-hosts dynamics in the influenza infection-staged epidemiological models with behavior change
In the endoplasmic reticulum (ER), the sugar chain is initially introduced onto newly synthesized proteins as a triantennary tetradecasaccharide (Glc3Man9GlcNAc2). The attached oligosaccharide chain is subjected to stepwise trimming by the actions of specific glucosidases and mannosidases. In these processes, the transiently expressed N-glycans, as processing intermediates, function as signals for the determination of glycoprotein fates, i.e., folding, transport, or degradation through interactions of a series of intracellular lectins. The monoglucosylated glycoforms are hallmarks of incompletely folded states of glycoproteins in this system, whereas the outer mannose trimming leads to ER-associated glycoprotein degradation. This review outlines the recently emerging evidence regarding the molecular and structural basis of this glycoprotein quality control system, which is regulated through dynamic interplay among intracellular lectins, glycosidases, and glycosyltransferase. Structural snapshots of carbohydrate-lectin interactions have been provided at the atomic level using X-ray crystallographic analyses. Conformational ensembles of uncomplexed triantennary high-mannose-type oligosaccharides have been Molecules 2015, 20 2476 characterized in a quantitative manner using molecular dynamics simulation in conjunction with nuclear magnetic resonance spectroscopy. These complementary views provide new insights into glycoprotein recognition in quality control coupled with N-glycan processing.
Output: molecules Emerging Structural Insights into Glycoprotein Quality Control Coupled with N-Glycan Processing in the Endoplasmic Reticulum
Lassa virus (LASV) causes Lassa hemorrhagic fever in humans and poses a significant threat to public health in West Africa. Current therapeutic treatments for Lassa fever are limited, making the development of novel countermeasures an urgent priority. In this study, we identified losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, from 102 screened compounds as an inhibitor of LASV infection. Losmapimod exerted its inhibitory effect against LASV after p38 MAPK down-regulation, and, interestingly, had no effect on other arenaviruses capable of causing viral hemorrhagic fever. Mechanistic studies showed that losmapimod inhibited LASV entry by affecting the stable signal peptide (SSP)-GP2 subunit interface of the LASV glycoprotein, thereby blocking pH-dependent viral fusion. As an aryl heteroaryl bis-carboxyamide derivative, losmapimod represents a novel chemical scaffold with anti-LASV activity, and it provides a new lead structure for the future development of LASV fusion inhibitors.
Output: Identification of a clinical compound losmapimod that blocks Lassa virus entry