Unknown Agents Research Articles

Use of glucocorticoids and azithromycin in the therapy of COVID-19.

In December 2019, a new variant coronavirus, SARS-CoV-2, emerged in China, which was initially described as a pneumonia of an unknown agent. The new coronavirus spreads mainly by person-to-person transmission through close contact. The pathophysiology of COVID-19 is related to a complex immune system response that varies between people and, in severe cases of the disease, is characterized by excessive responses called “cytokine storms,” which are associated with complications that can lead to a state of hypercoagulation and death. Glucocorticoids and azithromycin are drugs that may be effective in the treatment. This review aims to highlight the clinical findings that demonstrate the effectiveness of glucocorticoid and azithromycin therapy in the treatment of COVID-19. To date, many drugs have been studied for use in combination therapy, and the rapid expansion of knowledge about the virology of SARS-CoV-2 generates a more accurate direction in therapy.

Contemporary evolution of the innate immune receptor gene TLR3 in an isolated vertebrate population.

Understanding where genetic variation exists, and how it influences fitness within populations is important from an evolutionary and conservation perspective. Signatures of past selection suggest that pathogen-mediated balancing selection is a key driver of immunogenetic variation, but studies tracking contemporary evolution are needed to help resolve the evolutionary forces and mechanism at play. Previous work in a bottlenecked population of Seychelles warblers (Acrocephalus sechellensis) show that functional variation has been maintained at the viral-sensing Toll-like receptor 3 (TLR3) gene, including one nonsynonymous SNP, resulting in two alleles. Here, we characterise evolution at this TLR3 locus over a 25-year period within the original remnant population of the Seychelles warbler, and in four other derived, populations. Results show a significant and consistent temporal decline in the frequency of the TLR3C allele in the original population, and that similar declines in the TLR3C allele frequency occurred in all the derived populations. Individuals (of both sexes) with the TLR3CC genotype had lower survival, and males - but not females - that carry the TLR3C allele had significantly lower lifetime reproductive success than those with only the TLR3A allele. These results indicate that positive selection on the TLR3A allele, caused by an as yet unknown agent, is driving TLR3 evolution in the Seychelles warbler. No evidence of heterozygote advantage was detected. However, whether the positive selection observed is part of a longer-term pattern of balancing selection (through fluctuating selection or rare-allele advantage) cannot be resolved without tracking the TLR3C allele over an extended time period.

Whole genome analysis of Aichivirus A, isolated from a child, suffering from gastroenteritis, in Pakistan

Viruses are the primary cause of acute gastroenteritis in children all over the world. Understanding the emergence and genetic variation of these viruses may help to prevent infections. Aichivirus (AiV) is a member of the Kobuvirus genus, which currently contains six officially recognized species: Aichivirus A-F. The species AiV A contains six types including Aichivirus 1 (AiV 1) and eventually, three genotypes have been identified in the human AiV 1 (named A to C). The present study describes the identification and sequencing of the polyprotein gene of a human AiV 1 strain PAK419 via NGS in Pakistani children with acute gastroenteritis. Our study strain PAK419 was classified as AiV 1 genotype A, most commonly found in Japan and Europe, and closely related to non-Japanese and European strains on the phylogenetic tree. PAK419 showed 95–98 % nucleotide sequence identity with strains isolated from Ethiopia (ETH/2016/P4), Australia (FSS693) and China (Chshc7). On phylogenetic observation PAK419 formed a distinct cluster in the AiV 1 genotype A with the above mentioned and other human AiV strains detected around the world (Germany, Brazil, Japan, Thailand, Korea and Vietnam). The data clearly showed that Pakistani AiV strains and human strains identified from all over the world are distinct from Aichivirus strains found in bovine, swine, canine, feline, caprine, ferret, bat, and environmental samples. The distinguishing characteristics of the AiV genome showed a lower probability of inter-genotypic recombination events, which may support the lack of AiV serotypes. PAK419 also had a high content of C nucleotide (37.4 %), as found in previous studies, which could also restrict the possible genetic variation of AiV. This study demonstrate the power of NGS in uncovering unknown gastroenteric etiological agents circulating in the population.

Do pregnant women living in endemic regions of chronic kidney disease of unknown origin (CKDu) show pathological changes in the placenta?

There had not been much research to find possible involvement of other organs other than the kidney in CKDu. The effects on pregnancy due to renal impairment in general is known2,3 but what other damage could be inflicted by the unknown aetiology of CKDu on feto placental unit remains unknown.This injury could precede overt renal impairment. One such vulnerable organ is the placenta as both kidneys and placenta share similar function as filtration barriers. It is logical to assume if an agent could affect the interstitium of the kidney, similar adverse effects could be imposed on the interstitium of haemochorionic human placenta. This study was designed with the objective of analysing possible effects on human placental structure of patients who have been exposed to the probable aetiological factor responsible for CKDu. Obviously, anything affecting placenta would adversely affect fetus, its growth and organ development. If the agent passed through to the fetus, there could be similar direct damage to fetal kidneys too. 240 placental samples of women who had lived at least 10 years in a highly endemic area were compared with a similar number from those who were not so exposed. All samples were processed at the department of pathology and reported on by the second author. There was statistically insufficient evidence to conclude that population proportions of two categories were significantly different. The differences between categories and abnormalities were statistically insignificant. Since there was no noticeable Light Microscopic changes observed attributable to an unknown pathological agent, it was concluded that during a 9-months period of exposure of the placenta, no significant changes occurred even in the most endemic areas. This data was useful as women attending antenatal clinics could be reassured that no ill effect of the agent is known and it would be unnecessary to abandon home during pregnancy for safety of the fetus.

The unknown agents of European cooperation, and their future

Since the Maastricht Treaty, the EU has created 37 agencies and bodies covering nearly every aspect of our daily lives. However, agencies have always played a supporting role, serving national interests as well as those of Brussels, and their pivotal role in bringing those interests together is often overlooked. As agencies have increasingly been used as a solution for addressing the challenges facing Europe, their relationship with the European Commission, the Member States and EU citizens also needs to evolve as a model for European cooperation. A few guiding principles are relevant for this purpose, and have already been set out in a performance audit entitled “Future of EU agencies – Potential for more flexibility and cooperation” for which I had the pleasure to serve as the reporting Member to the European Parliament.

International Rickettsia Disease Surveillance: An Example of Cooperative Research to Increase Laboratory Capability and Capacity for Risk Assessment of Rickettsial Outbreaks Worldwide.

Cooperative research that addresses infectious disease surveillance and outbreak investigations relies heavily on availability and effective use of appropriate diagnostic tools, including serological and molecular assays, as exemplified by the current COVID-19 pandemic. In this paper, we stress the importance of using these assays to support collaborative epidemiological studies to assess risk of rickettsial disease outbreaks among international partner countries. Workforce development, mentorship, and training are important components in building laboratory capability and capacity to assess risk of and mitigate emerging disease outbreaks. International partnerships that fund cooperative research through mentoring and on-the-job training are successful examples for enhancing infectious disease surveillance. Cooperative research studies between the Naval Medical Research Center's Rickettsial Diseases Research Program (RDRP) and 17 institutes from nine countries among five continents were conducted to address the presence of and the risk for endemic rickettsial diseases. To establish serological and molecular assays in the collaborative institutes, initial training and continued material, and technical support were provided by RDRP. The laboratory methods used in the research studies to detect and identify the rickettsial infections included (1) group-specific IgM and IgG serological assays and (2) molecular assays. Twenty-six cooperative research projects performed between 2008 and 2020 enhanced the capability and capacity of 17 research institutes to estimate risk of rickettsial diseases. These international collaborative studies have led to the recognition and/or confirmation of rickettsial diseases within each of the partner countries. In addition, with the identification of specific pathogen and non-pathogen Rickettsia species, a more accurate risk assessment could be made in surveillance studies using environmental samples. The discoveries from these projects reinforced international cooperation benefiting not only the partner countries but also the scientific community at large through presentations (n = 40) at international scientific meetings and peer-reviewed publications (n = 18). The cooperative research studies conducted in multiple international institutes led to the incorporation of new SOPs and trainings for laboratory procedures; biosafety, biosurety, and biosecurity methods; performance of rickettsia-specific assays; and the identification of known and unknown rickettsial agents through the introduction of new serologic and molecular assays that complemented traditional microbiology methods.

The Pandemic of COVID-19: Current Scheme of Iraq (24 February- 8 August 2020)

Late in December 2019, the Wuhan City of China faced an outbreak of the unknown etiological agent of COVID-19, which spread rapidly in China and then worldwide to include 188 countries or regions of Africa, Oceania, Australia, Europe, America and Asia including Iraq. There are 31,132,906 of infected people over the world and 962,008 of global death, whereas the infection numbers increase rapidly. Several methods have been considered worldwide in order to control COVID-19. In spite of limited resources in Iraq. The Iraqi government has also taken demanding measures includes safety guides during Ramadan in the context of Covid-19. In addition, several strategies are used for that purpose such as designed particular hospitals, laboratories for testing, quarantine facilities, and movement restrictions to control viral spread all over the country. This review highlights the efforts of the Iraqi government to contain this deadly pneumonia inside it as well as travellers from Turkey, Iran and other neighbour countries.

How Cooperative Engagement Programs Strengthen Sequencing Capabilities for Biosurveillance and Outbreak Response.

The threat of emerging and re-emerging infectious diseases continues to be a challenge to public and global health security. Cooperative biological engagement programs act to build partnerships and collaborations between scientists and health professionals to strengthen capabilities in biosurveillance. Biosurveillance is the systematic process of detecting, reporting, and responding to especially dangerous pathogens and pathogens of pandemic potential before they become outbreaks, epidemics, and pandemics. One important tool in biosurveillance is next generation sequencing. Expensive sequencing machines, reagents, and supplies make it difficult for countries to adopt this technology. Cooperative engagement programs help by providing funding for technical assistance to strengthen sequencing capabilities. Through workshops and training, countries are able to learn sequencing and bioinformatics, and implement these tools in their biosurveillance programs. Cooperative programs have an important role in building and sustaining collaborations among institutions and countries. One of the most important pieces in fostering these collaborations is trust. Trust provides the confidence that a successful collaboration will benefit all parties involved. With sequencing, this enables the sharing of pathogen samples and sequences. Obtaining global sequencing data helps to identify unknown etiological agents, track pathogen evolution and infer transmission networks throughout the duration of a pandemic. Having sequencing technology in place for biosurveillance generates the capacity to provide real-time data to understand and respond to pandemics. We highlight the need for these programs to continue to strengthen sequencing in biosurveillance. By working together to strengthen sequencing capabilities, trust can be formed, benefitting global health in the face of biological threats.

Chemokine CCL5 promotes robust optic nerve regeneration and mediates many of the effects of CNTF gene therapy.

Ciliary neurotrophic factor (CNTF) is a leading therapeutic candidate for several ocular diseases and induces optic nerve regeneration in animal models. Paradoxically, however, although CNTF gene therapy promotes extensive regeneration, recombinant CNTF (rCNTF) has little effect. Because intraocular viral vectors induce inflammation, and because CNTF is an immune modulator, we investigated whether CNTF gene therapy acts indirectly through other immune mediators. The beneficial effects of CNTF gene therapy remained unchanged after deleting CNTF receptor alpha (CNTFRα) in retinal ganglion cells (RGCs), the projection neurons of the retina, but were diminished by depleting neutrophils or by genetically suppressing monocyte infiltration. CNTF gene therapy increased expression of C-C motif chemokine ligand 5 (CCL5) in immune cells and retinal glia, and recombinant CCL5 induced extensive axon regeneration. Conversely, CRISPR-mediated knockdown of the cognate receptor (CCR5) in RGCs or treating wild-type mice with a CCR5 antagonist repressed the effects of CNTF gene therapy. Thus, CCL5 is a previously unrecognized, potent activator of optic nerve regeneration and mediates many of the effects of CNTF gene therapy.

The ghosts of parasitism past: lingering frontline anti-brood parasite defenses in a former host.

Coevolutionary arms races between brood parasites and hosts provide tractable systems for understanding antagonistic coevolution in nature; however, little is known about the fate of frontline antiparasite defenses when the host “wins” the coevolutionary arms race. By recreating bygone species interactions, using artificial parasitism experiments, lingering defensive behaviors that evolved in the context of parasitism can be understood and may even be used to identify the unknown agent of parasitism past. Here we present the first study of this type by evaluating lingering “frontline” nest defenses that have evolved to prevent egg laying in a former brood parasite host. The Australian reed warbler Acrocephalus australis is currently not parasitized but is known to exhibit fine-tuned egg discrimination—a defensive behavior indicative of a past brood parasite–host arms race and common in closely related parasitized species. Here, using 3D-printed models of adult brood parasites, we examined whether the Australian reed warbler also exhibits frontline defenses to adult brood parasites, and whether we could use these defenses to identify the warbler’s “ghost of parasitism past.” Our findings provide evidence that the Australian reed warbler readily engages in frontline defenses that are considered adaptive specifically in the context of brood parasitism. However, individuals were unable to discriminate between adults of different brood parasite species at their nest. Overall, our results demonstrate that despite a relaxation in selection, defenses against brood parasitism can be maintained across multiple stages of the host’s nesting cycle, and further suggest that, in accordance with previous findings, that learning may be important for fine-tuning frontline defense.

COVID-19: Molecular and Cellular Response.

In late December 2019, a vtiral pneumonia with an unknown agent was reported in Wuhan, China. A novel coronavirus was identified as the causative agent. Because of the human-to-human transmission and rapid spread; coronavirus disease 2019 (COVID-19) has rapidly increased to an epidemic scale and poses a severe threat to human health; it has been declared a public health emergency of international concern (PHEIC) by the World Health Organization (WHO). This review aims to summarize the recent research progress of COVID-19 molecular features and immunopathogenesis to provide a reference for further research in prevention and treatment of SARS coronavirus2 (SARS-CoV-2) infection based on the knowledge from researches on SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV).

Advanced emotion understanding: Children's and adults' knowledge that minds generalize from prior emotional events.

We examined an advanced form of emotion understanding in 4- to 10-year-olds and adults (N = 264): Awareness that people's minds generalize from past emotional episodes to bias how they feel, think, and make decisions in new situations. Participants viewed scenarios on an eye tracker, each featuring an initial perpetrator who caused a character to feel positively (P) and/or negatively (N) in 2-event sequences (NN, PP, NP, PN). Later, the character encountered a new agent who was highly similar to the initial perpetrator. Participants predicted the character's affective reactions (emotions, thoughts, decisions) to the unknown agent while we recorded their eye movements to past episodes. Participants also judged characters' emotions upon seeing additional agents, who differed in degree of similarity to the initial perpetrator. Four- to 5-year-olds discounted pasts with initial perpetrators-believing instead that characters would feel happy, anticipate good, and approach new agents. In contrast, adults exhibited robust beliefs that people generalize from past emotional experiences: They attributed more positive responses to new agents following PP > NP > PN > NN pasts, and they expected characters to have biased emotional reactions to even somewhat dissimilar new agents. Between 6 and 10 years, children increasingly assumed that the past would have a biasing impact; however, they drew stricter boundaries than did adults. Eye-tracking analyses revealed that all age groups attended to characters' emotional past histories when reasoning about reactions to new agents (especially negative events), adults prioritized recent negative events in PN pasts, and participants' attention biases to past event information correlated with their reasoning about emotion generalization. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Herding Through Booms and Busts

This paper explores whether rational herding can generate endogenous aggregate fluctuations. We embed a tractable model of rational herding into a business cycle framework. In the model, technological innovations arrive with unknown qualities and agents have dispersed information about how productive the technology really is. Rational investors decide whether to invest based on their private information and the investment behavior of others. Herd-driven boom-bust cycles arise endogenously in this environment when the technology is unproductive but investors' initial information is unusually optimistic. Their overoptimism leads to high investment rates, which investors mistakenly attribute to good fundamentals, leading to a self-reinforcing pattern of higher optimism and higher investment until the economy reaches a peak, followed by a crash when agents ultimately realize their mistake. We calibrate the model to the U.S. economy and show that it can explain boom-and-bust cycles in line with episodes like the dot-com bubble of the 1990s.

The ecology of a translocated population of a medium-sized marsupial in an urban vegetation remnant

Although urbanisation can result in habitat loss, some species persist within urban vegetation remnants. Due to urban development, these species are often the targets of mitigation translocation; for example, the Quenda (Isoodon fusciventer, Marsupialia, Peramelidae), native to southwestern Australia. We assessed the foraging patterns and habitat preferences of a population of Quenda recently introduced by unknown agents to Kings Park, a large urban bushland remnant. Quenda foraged actively throughout our study area, but foraged most intensively in dense, low vegetation, with a significant preference for communities dominated by Banksia sessilis. This study joins other literature indicating that Quenda are able to persist in modified urban vegetation remnants despite the presence of predators, and human activity. Given the Quenda’s clear adaptability to introduction into this urban remnant, we suggest that the greatest threat to continued persistence of urban populations of this species within remnants is likely to relate to difficulties in dispersing through surrounding urban areas. Nevertheless, the successful return of Quenda to a site that has traditionally been discounted from translocation programs suggests that other reserves in the region could also host introductions. Further research is required to determine whether Quenda can disperse through the surrounding suburbs, and whether it is possible to modify novel habitats to support Quenda populations within urban areas. Additionally, further research on facilitating dispersal through managing meta-populations in urban areas is required. Nevertheless, Quenda have successfully established at Kings Park, surrounded by dense urban areas. With ongoing management, urban remnants may be useful in Australia’s protected area network.

Challenges and considerations on quality control and evaluation of pathogen metagenomic next-generation sequencing

Metagenomic next-generation sequencing (mNGS) could be used for pathogen detection from nearly all types of clinical samples. Especially, the unique diagnostic capability of pathogen mNGS detecting unknown causative agent of infectious diseases makes this method become an importation complement and irreplaceable component for conventional routine laboratory test. However, the complexity of the testing process, the rapid product update, and the insufficiency in quality control and evaluation methods that all make clinical transformation, industry development, and regulation of this technology full of challenge and uncertainty. This review briefly introduces the technical advantages and challenges, and describes the general workflow and quality control steps in details. Finally, it focuses on current considerations regarding quality evaluation methods and standards for pathogen mNGS.

Resiliency in dynamic leader–follower multiagent systems

Resilient control of multiagent systems (MASs) in the presence of dynamic leaders is studied in this paper. We consider a network of agents consisting of a leader, a set of healthy agents, and a set of attacked malicious agents. The objective is developing a control strategy for the healthy agents to follow the trajectory of the leader, while they are in interaction with the unknown malicious agents. The main contribution of this paper is resilient leader–follower control of MASs when a dynamic leader determines a continuous time-varying trajectory for the MAS. By defining the concept of r-robust leader–follower graphs, we propose and analyze sufficient conditions on interaction among the agents such that the mentioned objective is achieved. Numerical examples verify the accuracy of the proposed control scheme.

Unveiling Viruses Associated with Gastroenteritis Using a Metagenomics Approach.

Acute infectious gastroenteritis is an important illness worldwide, especially on children, with viruses accounting for approximately 70% of the acute cases. A high number of these cases have an unknown etiological agent and the rise of next generation sequencing technologies has opened new opportunities for viral pathogen detection and discovery. Viral metagenomics in routine clinical settings has the potential to identify unexpected or novel variants of viral pathogens that cause gastroenteritis. In this study, 124 samples from acute gastroenteritis patients from 2012–2014 previously tested negative for common gastroenteritis pathogens were pooled by age and analyzed by next generation sequencing (NGS) to elucidate unidentified viral infections. The most abundant sequences detected potentially associated to acute gastroenteritis were from Astroviridae and Caliciviridae families, with the detection of norovirus GIV and sapoviruses. Lower number of contigs associated to rotaviruses were detected. As expected, other viruses that may be associated to gastroenteritis but also produce persistent infections in the gut were identified including several Picornaviridae members (EV, parechoviruses, cardioviruses) and adenoviruses. According to the sequencing data, astroviruses, sapoviruses and NoV GIV should be added to the list of viral pathogens screened in routine clinical analysis.

Pandemics, Power, and Conspiracy Theories

Pandemics, Power, and Conspiracy Theories

Granulomatous peritonitis

The term granulomatous peritonitis encompasses a wide range of unusual forms of inflammation of the peritoneum that have simmilar clinical, pathological, and imaging features. Infectious agents such as mycobacteria, fungi, foreign substances such as talc and barium; meconium; intestinal contents; contents of a ruptured ovarian cyst; gall stones; nematode eggs or unknown agents can cause granulomatous peritonitis. Most of the listed nosological forms of peritoneal lesions are not described, whereas vessels, lung tissue, intestines, kidneys, liver, lymph nodes are often the target organs. So far there are very fewpapers in the medical literature covering questions such as the spreading of granulomatous peritonitis, methods of their diagnosis, differential diagnosis and treatment. This review is an attempt to fill this gap.

Granulomatous peritonitis

The term granulomatous peritonitis encompasses a wide range of unusual forms of inflammation of the peritoneum that have simmilar clinical, pathological, and imaging features. Infectious agents such as mycobacteria, fungi, foreign substances such as talc and barium; meconium; intestinal contents; contents of a ruptured ovarian cyst; gall stones; nematode eggs or unknown agents can cause granulomatous peritonitis. Most of the listed nosological forms of peritoneal lesions are not described, whereas vessels, lung tissue, intestines, kidneys, liver, lymph nodes are often the target organs. So far there are very fewpapers in the medical literature covering questions such as the spreading of granulomatous peritonitis, methods of their diagnosis, differential diagnosis and treatment. This review is an attempt to fill this gap.