niryuu/sni-each-converted huggingface dataset:
Fast simulation tools for the prediction of transient particle transport are critical in designing the air distribution indoors to reduce the exposure to indoor particles and associated health risks. This investigation proposed a combined fast fluid dynamics (FFD) and Markov chain model for fast predicting transient particle transport indoors. The solver for FFD-Markov-chain model was programmed in OpenFOAM, an open-source CFD toolbox. This study used two cases from the literature to validate the developed model and found well agreement between the transient particle concentrations predicted by the FFD-Markov-chain model and the experimental data. This investigation further compared the FFD-Markov-chain model with the CFD-Eulerian model and CFD-Lagrangian model in terms of accuracy and efficiency. The accuracy of the FFD-Markov-chain model was similar to that of the other two models. For the two studied cases, the FFD-Markovchain model was 4.7 and 6.8 times faster, respectively, than the CFD-Eulerian model, and it was 137.4 and 53.3 times faster than the CFD-Lagrangian model in predicting the steady-state airflow and transient particle transport. Therefore, the FFD-Markov-chain model is able to greatly reduce the computing cost for predicting transient particle transport in indoor environments. computational fluid dynamics, indoor environment, Eulerian model, Lagrangian model, particle dispersion, aerosol dynamics Article History
Output: Modeling transient particle transport by fast fluid dynamics with the Markov chain method
The SARS 3C-like proteinase (SARS-3CLpro), which is the main proteinase of the SARS coronavirus, is essential to the virus life cycle. This enzyme has been shown to be active as a dimer in which only one protomer is active. However, it remains unknown how the dimer structure maintains an active monomer conformation. It has been observed that the Ser139-Leu141 loop forms a short 3 10 -helix that disrupts the catalytic machinery in the inactive monomer structure. We have tried to disrupt this helical conformation by mutating L141 to T in the stable inactive monomer G11A/R298A/Q299A. The resulting tetra-mutant G11A/L141T/R298A/Q299A is indeed enzymatically active as a monomer. Molecular dynamics simulations revealed that the L141T mutation disrupts the 3 10 -helix and helps to stabilize the active conformation. The coil-3 10 -helix conformational transition of the Ser139-Leu141 loop serves as an enzyme activity switch. Our study therefore indicates that the dimer structure can stabilize the active conformation but is not a required structure in the evolution of the active enzyme, which can also arise through simple mutations.
Output: Conformational Flexibility of a Short Loop near the Active Site of the SARS-3CLpro is Essential to Maintain Catalytic Activity OPEN
A stray female cat of unknown age, presenting bright red watery diarrhea, was submitted to the Animal and Plant Quarantine Agency for diagnosis. In the small intestines extracted from the necropsied cat, numerous white ovalshaped organisms were firmly embedded in the mucosa and there was thickening of intestinal wall. Histopathological analysis revealed severe necrotizing enteritis, together with atrophied intestinal villi, exfoliated enterocytes, and parasitic worms. Recovered worms were identified as Pharyngostomum cordatum by morphological observation and genetic analysis. Although P. cordatum is known to occur widely in Korea, this is the first clinical description of an infection by P. cordatum causing severe feline enteritis.
Output: Necrotizing Enteritis Caused by Pharyngostomum cordatum Infection in a Stray Cat
With the high pervasiveness of viral diseases, the battle against viruses has never ceased. Here we discuss five cellular processes, namely "autophagy", "programmed cell death", "immune response", "cell cycle alteration", and "lipid metabolic reprogramming", that considerably guide viral replication after host infection in an orchestrated manner. On viral infection, "autophagy" and "programmed cell death" are two dynamically synchronized cell survival programs; "immune response" is a cell defense program typically suppressed by viruses; "cell cycle alteration" and "lipid metabolic reprogramming" are two altered cell housekeeping programs tunable in both directions. We emphasize on their functionalities in modulating viral replication, strategies viruses have evolved to tune these processes for their benefit, and how these processes orchestrate and govern cell fate upon viral infection. Understanding how viruses hijack host networks has both academic and industrial values in providing insights toward therapeutic strategy design for viral disease control, offering useful information in applications that aim to use viral vectors to improve human health such as gene therapy, and providing guidelines to maximize viral particle yield for improved vaccine production at a reduced cost. ARTICLE HISTORY
Output: Orchestrated efforts on host network hijacking: Processes governing virus replication
In this two-part series of reviews, we have invited experts in their fields to contribute articles on the status of vaccine research and development for emerging pathogens. This topic has been brought into sharp focus in recent years following significant outbreaks of viral diseases such as those causing severe acute respiratory syndrome and Middle East respiratory syndrome, as well as devastating outbreaks of diseases caused by the Ebola, Marburg, Zika and Lassa fever viruses, to name only a few examples. Additionally, bacterial infections leading to bubonic and pneumonic plague, most notably in Madagascar in 2018, as well as malaria in many tropical countries, melioidosis in south east Asia and tularaemia in northern Europe and North America, have incurred significant morbidity and mortality. In this review series, the life cycle of these pathogens and the epidemiology of disease have been reviewed in the context of potential points of intervention for the prevention of human infection. Many of the emerging pathogens are zoonoses and, as such, there is scope for intervention at the animal/insect/environmental reservoir. Other pathogens covered in this review series are considered to be re-emerging, such as multi-drug resistant tuberculosis.
Output: Vaccines for emerging pathogens: from research to the clinic
As the Coronavirus (COVID-19) expands its impact from China, expanding its catchment into surrounding regions and other countries, increased national and international measures are being taken to contain the outbreak. The placing of entire cities in 'lockdown' directly affects urban economies on a multi-lateral level, including from social and economic standpoints. This is being emphasised as the outbreak gains ground in other countries, leading towards a global health emergency, and as global collaboration is sought in numerous quarters. However, while effective protocols in regard to the sharing of health data is emphasised, urban data, on the other hand, specifically relating to urban health and safe city concepts, is still viewed from a nationalist perspective as solely benefiting a nation's economy and its economic and political influence. This perspective paper, written one month after detection and during the outbreak, surveys the virus outbreak from an urban standpoint and advances how smart city networks should work towards enhancing standardization protocols for increased data sharing in the event of outbreaks or disasters, leading to better global understanding and management of the same. Healthcare 2020, 8, 46 7 of 9 As the world increases in its ready adoption of the smart city concept, and its related technological tools, these tools need to be tailored to ensure that liveability dimensions are adequately catered for, including the thematic of urban health. On this front, it is argued that the lack of standardization between smart city technology suppliers can lead and is leading to noncommunication between cities and data platforms. Such can, and is, resulting in a non-productive system in the case of virus outbreaks because early detection and management of the same can become increasingly dependent upon the technological backbone of smart cities. This paper thus highlights the urgent need to work towards the standardization of protocols for enhanced smart city communication and the need to democratize the smart city technology sphere to encourage equity and transparency amongst stakeholders, thereby providing more possible cooperation in the case of disasters.
Output: On the Coronavirus (COVID-19) Outbreak and the Smart City Network: Universal Data Sharing Standards Coupled with Artificial Intelligence (AI) to Benefit Urban Health Monitoring and Management
Novel infectious diseases continue to emerge within human populations. Predictive studies have begun to identify pathogen traits associated with emergence. However, emerging pathogens vary widely in virulence, a key determinant of their ultimate risk to public health. Here, we use structured literature searches to review the virulence of each of the 214 known human-infective RNA virus species. We then use a machine learning framework to determine whether viral virulence can be predicted by ecological traits, including human-tohuman transmissibility, transmission routes, tissue tropisms, and host range. Using severity of clinical disease as a measurement of virulence, we identified potential risk factors using predictive classification tree and random forest ensemble models. The random forest approach predicted literature-assigned disease severity of test data with mean accuracy of 89.4% compared to a null accuracy of 74.2%. In addition to viral taxonomy, the ability to cause systemic infection was the strongest predictor of severe disease. Further notable predictors of severe disease included having neural and/or renal tropism, direct contact or respiratory transmission, and limited (0 < R 0 � 1) human-to-human transmissibility. We present a novel, to our knowledge, comparative perspective on the virulence of all currently known human RNA virus species. The risk factors identified may provide novel perspectives in understanding the evolution of virulence and elucidating molecular virulence mechanisms. These risk factors could also improve planning and preparedness in public health strategies as part of a predictive framework for novel human infections.
Output: Tissue tropism and transmission ecology predict virulence of human RNA viruses
Background: Governments are preparing for a potential influenza pandemic. Therefore they need data to assess the possible impact of interventions. Face-masks worn by the general population could be an accessible and affordable intervention, if effective when worn under routine circumstances. We assessed transmission reduction potential provided by personal respirators, surgical masks and homemade masks when worn during a variety of activities by healthy volunteers and a simulated patient. Principal Findings: All types of masks reduced aerosol exposure, relatively stable over time, unaffected by duration of wear or type of activity, but with a high degree of individual variation. Personal respirators were more efficient than surgical masks, which were more efficient than home-made masks. Regardless of mask type, children were less well protected. Outward protection (mask wearing by a mechanical head) was less effective than inward protection (mask wearing by healthy volunteers).
Output: Professional and Home-Made Face Masks Reduce Exposure to Respiratory Infections among the General Population
The most recent Ebola virus outbreak in West Africa -unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected -highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae 1 . No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we describe the discovery of a novel anti-EBOV small molecule antiviral, GS-5734, a monophosphoramidate prodrug of an adenosine analog. GS-5734 exhibits antiviral activity against multiple variants of EBOV in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternate substrate and RNAchain terminator in primer-extension assays utilizing a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com
Output: Therapeutic Efficacy of the Small Molecule GS-5734 against Ebola Virus in Rhesus Monkeys
Porcine hemagglutinating encephalomyelitis virus (PHEV) is a member of the genus betacoronavirus within the family coronaviridae, which invades the central nervous system (CNS) via peripheral nervous system and causes encephalomyelitis or vomiting and wasting disease (VWD) in sucking piglets. Up to now, although few complete nucleotide sequences of PHEV have been reported, they are not annotated. This study aimed to illuminate genome characterization, phylogenesis and pathogenicity of the PHEV/2008 strain. The full length of the PHEV/2008 strain genome was 30,684 bp, with a G + C content of 37.27%. The genome included at a minimum of 11 predicted open reading frames (ORFs) flanked by 5′ and 3′ untranslated regions (UTR) of 211 and 289 nucleotides. The replicase polyproteins pp1a and pp1ab, which had 4382 and 7094 amino acid residues, respectively, were predicted to be cleaved into 16 subunits by two viral proteinases. Phylogenetic analysis based on the complete genome sequence revealed that PHEV/2008 strain was genetically different from other known PHEV types, which represented a novel genotype (GI-1). In addition, we found that PHEV/2008 was neurotropic and highly pathogenic to 4-week-old BALB/c mice. Taken together, this is the first detailed annotated, complete genomic sequence of a new genotype PHEV strain in China.
Output: Genomic characterization and pathogenicity of a porcine hemagglutinating encephalomyelitis virus strain isolated in China
Vaccines that elicit a protective broadly neutralizing antibody (bNAb) response and monoclonal antibody therapies are critical for the treatment and prevention of viral infections. However, isolation of protective neutralizing antibodies has been challenging for some viruses, notably those with high antigenic diversity or those that do not elicit a bNAb response in the course of natural infection. Here, we discuss recent work that employs protein engineering strategies to design immunogens that elicit bNAbs or engineer novel bNAbs. We highlight the use of rational, computational, and combinatorial strategies and assess the potential of these approaches for the development of new vaccines and immunotherapeutics.
Output: Protein Engineering Strategies for the Development of Viral Vaccines and Immunotherapeutics
A substantial proportion of hitherto unexplained respiratory tract illnesses is associated with human metapneumovirus (hMPV) infection. This virus also was found in patients with severe acute respiratory syndrome (SARS). To determine the dynamics and associated lesions of hMPV infection, six cynomolgus macaques (Macaca fascicularis) were inoculated with hMPV and examined by pathological and virological assays. They were euthanized at 5 (n ‫؍‬ 2) or 9 (n ‫؍‬ 2) days post-infection (dpi), or monitored until 14 dpi (n ‫؍‬ 2). Viral excretion peaked at 4 dpi and decreased to zero by 10 dpi. Viral replication was restricted to the respiratory tract and associated with minimal to mild, multi-focal erosive and inflammatory changes in conducting airways, and increased numbers of macrophages in alveoli. Viral expression was seen mainly at the apical surface of ciliated epithelial cells throughout the respiratory tract, and less frequently in type 1 pneumocytes and alveolar macrophages. Both cell tropism and respiratory lesions were distinct from those of SARS-associated coronavirus infection, excluding hMPV as the primary cause of SARS. This study demonstrates that hMPV is a respiratory pathogen and indicates that viral replication is short-lived, polarized to the apical surface, and occurs primarily in ciliated respiratory epithelial cells.
Output: Short Communication Experimental Human Metapneumovirus Infection of Cynomolgus Macaques (Macaca fascicularis) Results in Virus Replication in Ciliated Epithelial Cells and Pneumocytes with Associated Lesions throughout the Respiratory Tract
Oncolytic virus therapy is based on the ability of viruses to effectively infect and kill tumor cells without destroying the normal tissues. While some viruses seem to have a natural preference for tumor cells, most viruses require the modification of their tropism to specifically enter and replicate in such cells. This review aims to describe the transductional targeting strategies currently employed to specifically redirect viruses towards surface receptors on tumor cells. Three major strategies can be distinguished; they involve (i) the incorporation of new targeting specificity into a viral surface protein, (ii) the incorporation of a scaffold into a viral surface protein to allow the attachment of targeting moieties, and (iii) the use of bispecific adapters to mediate targeting of a virus to a specified moiety on a tumor cell. Of each strategy key features, advantages and limitations are discussed and examples are given. Because of their potential to cause sustained, multiround infection-a desirable characteristic for eradicating tumorsparticular attention is given to viruses engineered to become self-targeted by the genomic expression of a bispecific adapter protein.
Output: Retargeting of Viruses to Generate Oncolytic Agents
Databases and computational tools for mimotopes have been an important part of phage display study. Five special databases and eighteen algorithms, programs and web servers and their applications are reviewed in this paper. Although these bioinformatics resources have been widely used to exclude target-unrelated peptides, characterize small molecules-protein interactions and map protein-protein interactions, a lot of problems are still waiting to be solved. With the improvement of these tools, they are expected to serve the phage display community better.
Output: molecules Bioinformatics Resources and Tools for Phage Display
The current COVID-19 pandemic is rapidly spreading around the world. The first doctor to report this new disease was an ophthalmologist: this exemplifies the role of ophthalmologists in an infectious disease pandemic. Here we review how SARS-Cov2 affects the eye and discuss implications for ophthalmologists. and will never be medically evaluated. (II) To date we have no data regarding how many patients with conjunctivitis (who did or didn't attended the eye emergency department) developed COVID-19 in the following days. (III) During the COVID-19 epidemic ophthalmologists may have to deal with patients affected by conjunctivitis of other nature and have no guidelines on how to make a differential diagnosis. J o u r n a l P r e -p r o o f 3 Furthermore, recent studies suggest that the conjunctiva may represent a possible transmission route [5, 6] . The presence of the SARS-CoV-2 in the conjunctival sac of affected patients is also reported by a nonpeer-reviewed retrospective cohort study [7] . Anecdotal reports further suggested that when no eye protection was worn, the virus could also possibly be transmitted by aerosol contact with conjunctiva and cause infection II [7] . However, the possible transmission of SARS-CoV-2 by conjunctiva is controversial. Nevertheless, the WHO and the American Academy of Ophthalmology (AAO) III recommend wearing eye protection (e.g., goggles or shield) when treating patients (potentially) infected with COVID-19 to prevent droplet transmission. It can't be stated enough that, before the ophthalmological check, it is mandatory to know if the patient has COVID-19 symptoms and if the patient has recently been in contact with a confirmed COVID-19 case. A strategy to prevent transmission in ophthalmology outpatient clinics adopted in all public hospitals in Hong Kong during the COVID-19 outbreak should serve as templates for other ophthalmologic practices [8] . Installation of protective shields on slit lamps were implemented and surgical masks were worn by both ophthalmologists and patients. The adoption of strict hand hygiene and wearing goggles or face masks is highly recommended for every ophthalmologist. Because of the proximity to patients' nose and mouth and the potential exposure to tears, which might contain the virus, ophthalmologists are especially at risk to contracting the disease. In 2006 during a major SARS outbreak in Hong Kong. Ophthalmic practices took similar preventive measures (frequent hand washing with the use of chlorhexidine alcoholic handrub; wearing surgical/N95 respirator masks, as well as gloves and water-resistant gowns and visors) to prevent contracting or spreading the SARS infection [9] . Considering that these measures prevented staff and patients from being infected during the SARS epidemic, we recommend that these measures should be adopted in a notdeferrable ophthalmological examination also during this pandemic. In addition to that, the patient should wear mask and gloves during the examination.
Output: Journal Pre-proof The COVID-19 pandemic from an ophthalmologist's perspective The COVID-19 pandemic from an ophthalmologist's perspective
Polyoxometalate (POM) has promising antiviral activities. It shows broad-spectrum inhibiting ability, high efficiency, and low toxicity. Experimental assays show that titanium containing polyoxotungstates have anti-influenza-virus activity. In this paper, the binding mechanisms of five isomers of di-Ti-substituted polyoxotungstate, [α-1,2-PTi 2 W 10 O 40 ] 7-(α-1,2), [α-1,6-PTi 2 W 10 O 40 ] 7-(α-1,6), [α-1,5-PTi 2 W 10 O 40 ] 7-(α-1,5), [α-1,4-PTi 2 W 10 O 40 ] 7-(α-1,4) and [α-1,11-PTi 2 W 10 O 40 ] 7-(α-1,11), to five subtypes of influenza virus A neuraminidase (FluV-A NA) were investigated in the context of aqueous solution by using molecular docking and molecular dynamics studies. The results show that the isomer α-1,2 is superior to other isomers as a potential inhibitor to neuraminidase. The positively charged arginine residues around the active site of NA could be induced by negatively charged POM to adapt themselves and could form salt bridge interactions and hydrogen bond interactions with POM. The binding free energies of POM/NA complexes range from -5.36 to -8.31 kcal mol -1 . The electrostatic interactions are found to be the driving force during the binding process of POM to NA. The conformational analysis shows that POM tends to bind primarily with N1 and N8 at the edge of the active pocket, which causes the conformational change of the pincers structure comprising residue 347 and loop 150. Whereas, the active pockets of N2, N9 and N4 are found to be more spacious, which allows POM to enter into the active pockets directly and anchor there firmly. This study shows that negatively charged ligand as POM could induce the reorganization of the active site of NA and highlights POM as a promising inhibitor to NA despite the ever increasing mutants of NA. influenza virus A, neuraminidase, polyoxometalate, docking, molecular dynamics Citation: Wang J P, Hu D H, Su Z M. Molecular simulation study of the binding mechanism of [α-PTi 2 W 10 O 40 ] 7for its promising broad-spectrum inhibitory activity to FluV-A neuraminidase.
Output: Article Molecular simulation study of the binding mechanism of [α-PTi 2 W 10 O 40 ] 7-for its promising broad-spectrum inhibitory activity to FluV-A neuraminidase
Respiratory viruses of human origin infect wild apes across Africa, sometimes lethally. Here we report simultaneous outbreaks of two distinct human respiratory viruses, human metapneumovirus (MPV; Pneumoviridae: Metapneumovirus) and human respirovirus 3 (HRV3; Paramyxoviridae; Respirovirus, formerly known as parainfluenza virus 3), in two chimpanzee (Pan troglodytes schweinfurthii) communities in the same forest in Uganda in December 2016 and January 2017. The viruses were absent before the outbreaks, but each was present in ill chimpanzees from one community during the outbreak period. Clinical signs and gross pathologic changes in affected chimpanzees closely mirrored symptoms and pathology commonly observed in humans for each virus. Epidemiologic modelling showed that MPV and HRV3 were similarly transmissible (R 0 of 1.27 and 1.48, respectively), but MPV caused 12.2% mortality mainly in infants and older chimpanzees, whereas HRV3 caused no direct mortality. These results are consistent with the higher virulence of MPV than HRV3 in humans, although both MPV and HRV3 cause a significant global disease burden. Both viruses clustered phylogenetically within groups of known human variants, with MPV closely related to a lethal 2009 variant from mountain gorillas (Gorilla beringei beringei), suggesting two independent and simultaneous reverse zoonotic origins, either directly from humans or via intermediary hosts. These findings expand our knowledge of human origin viruses threatening wild chimpanzees and suggest that such viruses might be differentiated by their comparative epidemiological dynamics and pathogenicity in wild apes. Our results also caution against assuming common causation in coincident outbreaks.
Output: Simultaneous outbreaks of respiratory disease in wild chimpanzees caused by distinct viruses of human origin
Porcine hemagglutinating encephalomyelitis (PHE) is caused by the coronavirus hemagglutinating encephalomyelitis virus (PHE-CoV), and the recent, rapid spread of PHE-CoV in piglets from many countries emphasizes the urgent need for a PHE-CoV vaccine. Here we use a murine model for evaluation of the induction of humoral and cellular immune responses by inactivated and PHE-CoV DNA vaccines in order to define the immune correlates for protection against PHE-CoV. The inactivated vaccine was composed of purified PHE-CoV and aluminum hydroxide gel (alum), which was chosen as an adjuvant because of its long history of safety for human use. The PHE-CoV DNA vaccine was constructed by subcloning the S1 gene of PHE-CoV into the pVAX1 vector to create the recombinant plasmid pV-S1. Our results showed that the inactivated PHE-CoV vaccine (IPV) elicited a high level of humoral immunity, resulting in good protection efficacy against PHE-CoV challenge. The IPV induced the IgG1 subclass of serum antibodies and expression of the cytokine interleukin-4 (IL-4), suggesting that the IPV generated a predominantly Th2-type immune response. The DNA vaccine was found to mediate primarily a cellular immune response with high levels of IgG2a and the cytokines IL-2 and gamma interferon (IFN-␥). However, mice that were vaccinated twice with the DNA vaccine and boosted with the IPV could mount a sufficient neutralizing antibody response against live PHE-CoV, with little variation in IgG1 and IgG2a levels, and showed high levels of IL-2 and IL-4. This response may activate both B and T cells to mount a specific humoral and cellular immune response that could, in turn, elicit a phagocyte-mediated defense against PHE-CoV infections to achieve viral clearance.
Output: Comparative Evaluation of Two Hemagglutinating Encephalomyelitis Coronavirus Vaccine Candidates in Mice
Immunoglobulins (Igs), also called antibodies, are present in milk and colostrum of all lactating species. Igs are divided into classes having different physico-chemical structures and biological activities. The major Ig classes in bovine and human milk are IgA, IgG and IgM. Bovine colostral Igs provide the newborn calf with passive immune protection against microbial infections until the calf's own immune system matures. Colostral Ig preparations designed for farm animals have been commercially available for many years. Potential health benefi ts attributed to bovine colostrum have increased manufacture and marketing of colostral Ig-based dietary supplements also for human use. Furthermore, specifi c anti-microbial antibodies can be produced into colostrum by immunizing cows with vaccines made of pathogenic microorganisms. These antibodies can be concentrated and used to formulate so-called immune milk preparations. Such preparations have proven effective in prevention of animal and human infections caused, e.g. by rotavirus, Shigella fl exneri, Escherichia coli, Clostridium diffi cile, Streptococcus mutans, Cryptosporidium parvum and Helicobacter pylori. Their therapeutic effi cacy, however, seems limited. A few immune milk products have been commercialized and more can be expected in the future for use, e.g. as a supportive means in antibiotic treatments and for prevention of hospital infections.
Output: Bovine milk immunoglobulins against microbial human diseases
Background: Many outbreaks of Middle East respiratory syndrome coronavirus (MERS-CoV) have occurred in health care settings and involved health care workers (HCWs). We describe the occurrence of an outbreak among HCWs and attempt to characterize at-risk exposures to improve future infection control interventions. Methods: This study included an index case and all HCW contacts. All contacts were screened for MERS-CoV using polymerase chain reaction. Results: During the study period in 2015, the index case was a 30-year-old Filipino nurse who had a history of unprotected exposure to a MERS-CoV-positive case on May 15, 2015, and had multiple negative tests for MERS-CoV. Weeks later, she was diagnosed with pulmonary tuberculosis and MERS-CoV infection. A total of 73 staff were quarantined for 14 days, and nasopharyngeal swabs were taken on days 2, 5, and 12 postexposure. Of those contacts, 3 (4%) were confirmed positive for MERS-CoV. An additional 18 staff were quarantined and had MERS-CoV swabs. A fourth case was confirmed positive on day 12. Subsequent contact investigations revealed a fourth-generation transmission. Only 7 (4.5%) of the total 153 contacts were positive for MERS-CoV. Conclusions: The role of HCWs in MERS-CoV transmission is complex. Although most MERS-CoVinfected HCWs are asymptomatic or have mild disease, fatal infections can occur and HCWs can play a major role in propagating health care facility outbreaks. This investigation highlights the need to continuously review infection control guidance relating to the role of HCWs in MERS-CoV transmission in health care outbreaks, especially as it relates to the complex questions on definition of risky exposures, who to test, and the frequency of MERS-CoV testing; criteria for who to quarantine and for how long; and clearance and return to active duty criteria.
Output: Middle East respiratory syndrome coronavirus transmission among health care workers: Implication for infection control
Healthcare settings have played a major role in propagation of Ebola virus (EBOV) outbreaks. Healthcare workers (HCWs) have elevated risk of contact with EBOV-infected patients, particularly if safety precautions are not rigorously practiced. We conducted a serosurvey to determine seroprevalence against multiple EBOV antigens among HCWs of Boende Health Zone, Democratic Republic of the Congo, the site of a 2014 EBOV outbreak. Interviews and specimens were collected from 565 consenting HCWs. Overall, 234 (41.4%) of enrolled HCWs were reactive to at least 1 EBOV protein: 159 (28.1%) were seroreactive for anti-glycoprotein immunoglobulin G (IgG), 89 (15.8%) were seroreactive for anti-nucleoprotein IgG, and 54 (9.5%) were VP40 positive. Additionally, sera from 16 (2.8%) HCWs demonstrated neutralization capacity. These data demonstrate that a significant proportion of HCWs have the ability to neutralize virus, despite never having developed Ebola virus disease symptoms, highlighting an important and poorly documented aspect of EBOV infection and progression.
Output: The Journal of Infectious Diseases Serologic Markers for Ebolavirus Among Healthcare Workers in the Democratic Republic of the Congo
Human torovirus (HTV) and Breda virus (BRV), members of the genus torovirus in the family Coronaviridae, are established infectious agents of humans and cattle, respectively. The hemagglutinin-esterase (HE) gene of Breda virus serotype 2 (BRV-2) has been identified and the nucleotide sequence for BRV serotype 1 (BRV-1) genome which contains the open reading frames for the viral structural proteins has been reported revealing the presence of a 1.25 kb gene whose nucleotide sequence is identical to that of the BRV-2 HE gene. In this study, we amplified the 1.2kb HE gene from the HTV genome using long RT-PCR and sequenced the amplicon directly. At the nucleotide level, the HTV HE gene manifests 85% sequence identity to the HE genes of BRV-1 and BRV-2 and 89% identity with the X pseudogene sequence of BEV. The 1.25 kb amplicons which contained the HE genes of BRV-1 and HTV were cloned and expressed in a baculovirus system and the proteins purified by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Hyperimmune sera prepared in guinea pigs against these proteins were reactive with both bovine torovirus (BTV) and human torovirus (HTV) antigens. By immunoblot, they reacted specifically with a 65 kDa protein corresponding in size to the torovirus HE protein. Furthermore, the hyperimmune sera but not the preimmune sera reacted with a series of BTV-positive and HTV-positive fecal specimens by immunoblot and dot blot analysis. By immunoelectron microscopy (IEM) torovirus particles from BTV-positive specimens from calves with diarrhea and HTV-positive specimens from patients were aggregated by the hyperimmune sera. Human convalescent sera and gnotobiotic calf post-infection sera reacted by immunoblot with the expressed 65 kDa protein. The expressed HE protein of HTV has important diagnostic potential. : S 0 1 6 8 -1 7 0 2 ( 9 9 ) 0 0 0 8 8 -X
Output: The novel hemagglutinin-esterase genes of human torovirus and Breda virus
Little is known about the correlation between microbiological yield and radiographic activity, on chest computed tomography (CT), in suspected pulmonary tuberculosis (PTB) cases, despite CT being widely used, clinically. We used multicenter retrospective data, obtained from medical records, focusing on the diagnostic performance for definite PTB. We categorized patients into four groups, by radiographic activity: definitely active, probably active, indeterminate activity, and probably inactive. Of the 650 patients included, 316 had culture-confirmed PTB; 190 (29.2%), 323 (49.7%), 70 (10.8%), and 67 (10.3%) were classified into the definitely active, probably active, indeterminate activity, and probably inactive groups, respectively. The corresponding observed culture rates for CT radiographic activity were 61.6%, 60.7%, 4.3% and 0%, respectively. When not only culture rates but TB-PCR and histological results were taken into consideration as definite PTB, it showed 66.6%, 67.2%, 14.3%, and 0% of each CT radiographic activity, respectively. Regarding the diagnostic performance for definite PTB, radiographic PLOS ONE | https://doi.
Output: Correlation of microbiological yield with radiographic activity on chest computed tomography in cases of suspected pulmonary tuberculosis
The trichothecene mycotoxin deoxynivalenol (DON), a known translational inhibitor, induces ribosomal RNA (rRNA) cleavage. Here, we characterized this process relative to (1) specific 18S and 28S ribosomal RNA cleavage sites and (2) identity of specific upstream signaling elements in this pathway. Capillary electrophoresis indicated that DON at concentrations as low as 200 ng/ml evoked selective rRNA cleavage after 6 h and that 1000 ng/ml caused cleavage within 2 h. Northern blot analysis revealed that DON exposure induced six rRNA cleavage fragments from 28S rRNA and five fragments from 18S rRNA. When selective kinase inhibitors were used to identify potential upstream signals, RNAactivated protein kinase (PKR), hematopoietic cell kinase (Hck), and p38 were found to be required for rRNA cleavage, whereas c-Jun N-terminal kinase and extracellular signal-regulated kinase were not. Furthermore, rRNA fragmentation was suppressed by the p53 inhibitors pifithrin-a and pifithrin-m as well as the pan caspase inhibitor Z-VAD-FMK. Concurrent apoptosis was confirmed by acridine orange/ethidium bromide staining and flow cytometry. DON activated caspases 3, 8, and 9, thus suggesting the possible coinvolvement of both extrinsic and intrinsic apoptotic pathways in rRNA cleavage. Satratoxin G (SG), anisomycin, and ricin also induced specific rRNA cleavage profiles identical to those of DON, suggesting that ribotoxins might share a conserved rRNA cleavage mechanism. Taken together, DON-induced rRNA cleavage is likely to be closely linked to apoptosis activation and appears to involve the sequential activation of PKR/Hck /p38/p53/caspase 8/ 9/caspase 3.
Output: Targets and Intracellular Signaling Mechanisms for Deoxynivalenol-Induced Ribosomal RNA Cleavage
A novel coronavirus (the SARS-CoV-2) has been identified in January 2020 as the causal pathogen for COVID-19 pneumonia, an outbreak started near the end of 2019 in Wuhan, China. The SARS-CoV-2 was found to be closely related to the SARS-CoV, based on the genomic analysis. The Angiotensin converting enzyme 2 protein (ACE2) utilized by the SARS-CoV as a receptor was found to facilitate the infection of SARS-CoV-2, initiated by the binding of the spike protein to the human ACE2. Using homology modeling and molecular dynamics (MD) simulation methods, we report here the detailed structure of the ACE2 in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The predicted model is highly consistent with the experimentally determined complex structures. Besides the binding interface reported in the crystal structures, new plausible binding poses were revealed from all-atom MD simulations. The simulation data helped identify critical residues at the complex interface and provided more details about the interactions between the SARS-CoV-2 RBD and human ACE2. Two mutants mimicking rat ACE2 were modeled to study the mutation effects on RBD binding to ACE2. The simulations showed that the N-terminal helix and the K353 are very important for the tight binding of the complex, the mutants were found to alter the binding modes of the CoV2-RBD to ACE2.
Output: Computational simulations reveal the binding dynamics between human ACE2 and the receptor binding domain of SARS-CoV-2 spike protein
The immunoglobulin-like family of CD66 antigens, present on human neutrophils and epithelial cells, are used as receptors for adhesins expressed by the pathogenic Neisseriae . N . gonorrhoeae strain MS11 can express 11 isoforms of these adhesins, called opacity-related (Opa) proteins. Each MS11 Opa protein recognizes a distinct spectrum of CD66 receptors. CD66-Opa binding is mediated by the NH 2 -terminal domain of the receptor and occurs through protein-protein interactions. In this report, we have investigated the molecular basis for the binding between the CD66 and Opa protein families by mapping amino acids in CD66 receptors that determine Opa protein binding. We performed homologue scanning mutagenesis between CD66e, which binds multiple Opa variants, and CD66b, which binds none, and tested both loss-offunction by CD66e and gain-of-function by CD66b in solution assays and in assays involving full-length receptors expressed by epithelial cells. We found that three residues in the CD66e N-domain are required for maximal Opa protein receptor activity. Opa proteins that recognize the same spectrum of native CD66 molecules showed differential binding of receptors with submaximal activity, indicating that the binding characteristics of these Opa proteins are actually slightly different. These data provide a first step toward resolving the structural requirements for Opa-CD66 interaction.
Output: Homologue Scanning Mutagenesis Reveals CD66 Receptor Residues Required for Neisserial Opa Protein Binding
Background: Timely identification of respiratory virus infection is essential to mitigate inappropriate antibiotic use and to implement appropriate treatment and/or infection control procedures. As such, multiplexed PCR assays have become standard in many virology laboratories. Objectives: To compare the Seeplex RV15 (test of record) with two newer generation multiplex assays, the Anyplex II RV16 and the xTAG respiratory virus panels. Study design: Two hundred and three retrospective and 36 prospective respiratory samples were tested by all three assays. Samples were deemed to be positive if they tested positive for a virus by at least two of the three respective assays. Negative samples also had to test negative by at least two of the three assays. Inconclusive samples were those that showed band signal intensity between 0 and 100 on the RV15, but had not been previously tested on the RV16 or xTAG. Results and conclusions: Overall sensitivity and specificity of all three assays were similar (∼85% and 100%, respectively). Given each assay can identify multiple different viruses, the targets reported by one assay did not always agree with each target from another assay. Partial discordant rates were 47% and 21% for positive and negative samples, respectively. These higher than expected partial discordant rates may be due to primer or chemistry differences amongst the three multiplex assays.
Output: Evaluation of three commercial multiplex assays for the detection of respiratory viral infections
We have previously shown that immunotherapy directed against the protein Nogo-A leads to recovery on a skilled forelimb reaching task in rats after sensorimotor cortex stroke, which correlated with axonal and dendritic plasticity. Here we investigated anti-Nogo-A immunotherapy as an intervention to improve performance on a spatial memory task in aged rats after stroke, and whether cognitive recovery was correlated with structural plasticity. Aged rats underwent a unilateral distal permanent middle cerebral artery occlusion and one week later were treated with an anti-Nogo-A or control antibody. Nine weeks post-stroke, treated rats and normal aged rats were tested on the Morris water maze task. Following testing rats were sacrificed and brains processed for the Golgi-Cox method. Hippocampal CA3 and CA1 pyramidal and dentate gyrus granule cells were examined for dendritic length and number of branch segments, and CA3 and CA1 pyramidal cells were examined for spine density and morphology. Anti-Nogo-A immunotherapy given one week following stroke in aged rats improved performance on the reference memory portion of the Morris water maze task. However, this improved performance was not correlated with structural changes in the hippocampal neurons examined. Our finding of improved performance on the Morris water maze in aged rats after stroke and treatment with anti-Nogo-A immunotherapy demonstrates the promising therapeutic potential for anti-Nogo-A immunotherapy to treat cognitive deficits after stroke. The identification of sites of axonal and dendritic plasticity in the aged brain after stroke and treatment with anti-Nogo-A immunotherapy is still under investigation.
Output: Corresponding Author) Research Service 151 Building 1 Hines VA Hospital 5000 S. Fifth Avenue Hines, IL, USA Behav Brain Res
We evaluated the usefulness of a serum Aspergillus PCR assay for the diagnosis and prognosis of invasive aspergillosis in a study involving 941 patients for a total of 5146 serum samples. Fifty-one patients had proven/probable aspergillosis. We compared galactomannan (GM), PCR and mycologic analysis of pulmonary samples in both neutropenic and nonneutropenic patients. PCR performed in serum yielded 66.7% sensitivity, 98.7% specificity, 75.6% positive predictive value and 98.0% negative predictive value, while the GM index yielded 78.4% sensitivity, 87.5% specificity, 27% positive predictive value and 98.6% negative predictive value. The inclusion of PCR in the European Organization for Research and Treatment of Cancer (EORTC) and the Mycosis Study Group (MSG) mycologic criteria permitted the reclassification of nine other cases from possible to probable aspergillosis and increased the sensitivity to 71.7%. Combining the GM index with serum PCR increased the detection rate of invasive aspergillosis with 88.2% sensitivity. PCR was systematically negative in 16 patients with noninvasive forms of aspergillosis (namely aspergilloma and chronic aspergillosis). Remaining PCR positive after a period of 14 to 20 days of treatment was related to poor outcome at 30 and 90 days. Our results also indicate that, unlike the determination of the GM index, the initial fungus load as determined by PCR was highly predictive of 90-day mortality, with the rate of the latter being 15.8% for patients with <150 copies/mL vs. 73.2% for patients at or above that cutoff (p <0.0001). Therefore, PCR appears to be a powerful and interesting tool for the identification of patients with invasive aspergillosis who might benefit from more intense care.
Output: Aspergillus PCR in serum for the diagnosis, follow-up and prognosis of invasive aspergillosis in neutropenic and nonneutropenic patients
This chapter looks at the use of microlithographically fabricated biochip platforms for DNA diagnostics and prognostics, although protein and RNA biochips are also briefly considered. Biodetection methods such as ion-selective electrodes (ISEs), microelectromechanical systems (MEMS) devices such as microcantilevers, optical, piezoelectric-based acoustic wave, and mass spectrometry are briefly discussed. Emphasis is given to label-free electrochemical (impedimetric, voltammetric, and amperometric) detection. The production of DNA biochips is highlighted as are the operation and design of the experiments to reveal gene expression and SNP data. Applications discussed include the monitoring of microbes, cancer classification studies, and patient stratification in drug development. Finally, challenges and issues facing the development of diagnostic and prognostic biochips are discussed in detail.
Output: Biochip Platforms for DNA Diagnostics
a b s t r a c t a r t i c l e i n f o Purpose: COVID-19 (coronavirus disease 2019) is a public health emergency of international concern. As of this time, there is no known effective pharmaceutical treatment, although it is much needed for patient contracting the severe form of the disease. The aim of this systematic review was to summarize the evidence regarding chloroquine for the treatment of COVID-19. Methods: PubMed, EMBASE, and three trial Registries were searched for studies on the use of chloroquine in patients with COVID-19. Results: We included six articles (one narrative letter, one in-vitro study, one editorial, expert consensus paper, two national guideline documents) and 23 ongoing clinical trials in China. Chloroquine seems to be effective in limiting the replication of SARS-CoV-2 (virus causing COVID-19) in vitro. Conclusions: There is rationale, pre-clinical evidence of effectiveness and evidence of safety from long-time clinical use for other indications to justify clinical research on chloroquine in patients with COVID-19. However, clinical use should either adhere to the Monitored Emergency Use of Unregistered Interventions (MEURI) framework or be ethically approved as a trial as stated by the World Health Organization. Safety data and data from high-quality clinical trials are urgently needed.
Output: A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19