37 research outputs found
Identification of evolutionary trajectories shared across human betacoronaviruses
Comparing the evolution of distantly related viruses can provide insights into common adaptive processes related to shared ecological niches. Phylogenetic approaches, coupled with other molecular evolution tools, can help identify mutations informative on adaptation, whilst the structural contextualization of these to functional sites of proteins may help gain insight into their biological properties. Two zoonotic betacoronaviruses capable of sustained human-to-human transmission have caused pandemics in recent times (SARS-CoV-1 and SARS-CoV-2), whilst a third virus (MERS-CoV) is responsible for sporadic outbreaks linked to animal infections. Moreover, two other betacoronaviruses have circulated endemically in humans for decades (HKU1 and OC43). To search for evidence of adaptive convergence between established and emerging betacoronaviruses capable of sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1 and SARS-CoV-2), we developed a methodological pipeline to classify shared non-synonymous mutations as putatively denoting homoplasy (repeated mutations that do not share direct common ancestry) or stepwise evolution (sequential mutations leading towards a novel genotype). In parallel, we look for evidence of positive selection, and draw upon protein structure data to identify potential biological implications. We find 30 candidate mutations, from which four [codon sites 18121 (nsp14/residue 28), 21623 (spike/21), 21635 (spike/25) and 23948 (spike/796); SARS-CoV-2 genome numbering] further display evolution under positive selection and proximity to functional protein regions. Our findings shed light on potential mechanisms underlying betacoronavirus adaptation to the human host and pinpoint common mutational pathways that may occur during establishment of human endemicity
Identification of Evolutionary Trajectories Shared across Human Betacoronaviruses
Comparing the evolution of distantly related viruses can provide insights into common adaptive processes related to shared ecological niches. Phylogenetic approaches, coupled with other molecular evolution tools, can help identify mutations informative on adaptation, although the structural contextualization of these to functional sites of proteins may help gain insight into their biological properties. Two zoonotic betacoronaviruses capable of sustained human-to-human transmission have caused pandemics in recent times (SARS-CoV-1 and SARS-CoV-2), although a third virus (MERS-CoV) is responsible for sporadic outbreaks linked to animal infections. Moreover, two other betacoronaviruses have circulated endemically in humans for decades (HKU1 and OC43). To search for evidence of adaptive convergence between established and emerging betacoronaviruses capable of sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1, and SARS-CoV-2), we developed a methodological pipeline to classify shared nonsynonymous mutations as putatively denoting homoplasy (repeated mutations that do not share direct common ancestry) or stepwise evolution (sequential mutations leading towards a novel genotype). In parallel, we look for evidence of positive selection and draw upon protein structure data to identify potential biological implications. We find 30 candidate mutations, from which 4 (codon sites 18121 [nsp14/residue 28], 21623 [spike/21], 21635 [spike/25], and 23948 [spike/796]; SARS-CoV-2 genome numbering) further display evolution under positive selection and proximity to functional protein regions. Our findings shed light on potential mechanisms underlying betacoronavirus adaptation to the human host and pinpoint common mutational pathways that may occur during establishment of human endemicity
Mycobacterial glycolipids di-O-acylated trehalose and tri-O-acylated trehalose downregulate inducible nitric oxide synthase and nitric oxide production in macrophages
Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study
Background:
The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.
Methods:
This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.
Findings:
Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.
Interpretation:
This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.
Funding:
Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research
Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study
Background
The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility.
Methods
We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates.
Findings
From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant.
Interpretation
The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant.
Funding
Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society
Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission
AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p
Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission
Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16–20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement
Di-o-acil-trealosa, tri-o-acil-trealosa (DAT, TAT) y la glicolipoproteína de 19 KDA (LPQH) de Mycobacterium tuberculosis inhiben la producción de óxido nítrico por macrófagos
Vampir Fledermaus Virom: Evolutions Auswirkungen in einem immunologischen Kontext
The adaptation of bats to different environments has resulted in the evolution
of unique phenotypic and genotypic characteristics such as flight,
echolocation and highly specialized diets. Bats have also been increasingly
recognized as reservoirs for viruses which can cross species barriers. Among
the Neotropical bats, vampire bats (Desmodontinae subfamily) are the only
mammals that feed exclusively on the blood from other animals. Because of such
an exceptional adaptation to hematophagy these species exhibit a unique set of
behavioral, physiological, and morphological characteristics distinct among
all other bats. The common vampire bat (Desmodus rotundus) is a known
reservoir for rabies-causing lyssaviruses considered to be a major constraint
on the cattle industry since bat-transmitted rabies is a primary problem in
livestock from Latin America. Nonetheless, the presence of other viruses in
this species has hardly been explored. Although bats can be persistently
infected with many viruses, they rarely display clinical symptoms and it has
been suggested that they might have evolved specific immune strategies to
control viral replication. Toll like-receptors (TLRs) are a class of innate
immune receptors considered to be the first-line defense mechanism against
invading pathogens. The mammalian TLRs 3, 7, 8 and 9 play an important role in
triggering acquired immunity as they are activated by nucleic acid ligands.
TLRs are of interest from an evolutionary point of view since there is
evidence that the ligand binding properties of these receptors may vary among
different species thereby having an impact on the evolutionary ecology of
infectious diseases. Thus, the analysis of the bat immune variation at a
molecular level could reveal patterns of resistance or susceptibility to
pathogens within different species and at different taxonomic levels. However,
the study of the genetic variability of the immune system in bats has been
restricted to a few species and to a few genes. The hypothesis that vampire
bats carry viruses common to other mammals was tested based on the premise
that their exclusive adaptation to hematophagy could have resulted in viral
spill-over events among taxa throughout evolutionary history. Particular focus
was made on Retroviruses, given that this viral group is primarily transmitted
via body fluid exchange, and thus might have been particularly prone to jump
between vampire bats and other taxa. A novel endogenous betaretrovirus (DrERV)
was described with an evolutionary pattern that suggests multiple cross-
species transmissions among different species throughout their evolutionary
history. It was further hypothesized that given the unique adaptations within
the Chiroptera, bats as a taxonomic group would have acquired distinctive
mutations fixed within the nucleic-acid sensing TLRs with potential
consequences on their ligand recognition properties. The nucleic acid sensing
TLRs (3, 7, 8 and 9) of the common vampire bat were characterized and the
genetic variation of these receptors within different bats species and among
other mammals was compared by further testing for ongoing and episodic
diversifying selection acting upon specific lineages. Our results provide
evidence for potential functional differences between the bat and other
mammalian TLRs in terms of recognition of foreign nucleic acids. This project
was carried out in close collaboration with several European and Mexican
institutions contributing to the development of research on emerging zoonotic
diseases and wildlife surveillance.Anpassungen von Fledermäusen an verschiedene Umgebungen haben zu der
Entwicklung Die Anpassung von Fledermäusen an ihre Umwelt hat zu der
Entwicklung von besonderen phänotypischen und genotypischen Eigenschaften wie
Flugfähigkeit, Echoortung und spezifischen Ernährungsweisen geführt. Diese
Anpassungen haben auch zur evolutionären Entwicklung potentieller
Krankheitserreger beigetragen. So werden Fledermäuse zunehmend als Wirte für
Viren erkannt, welche auch interspezifisch übertragen werden können. Unter den
Fledermäusen der Neuen Welt sind die Vampirfledermäuse (Unterfamilie
Desmodontinae) als die einzigen Säugetiere bekannt, die sich ausschließlich
vom Blut anderer Tiere ernähren können. Wegen dieser ungewöhnlichen Anpassung
an Hämatophagie, zeigen diese Arten besondere Eigenschaften in ihrem
Verhalten, ihrer Physiologie und ihrer Morphologie, die sie von allen anderen
Fledermausarten unterscheidet. Der Gemeine Vampir (Desmodus rotundus) ist ein
bekannter Wirt für Tollwut-verursachende Lyssaviren und stellt eine große
Einschränkung für die Rinderhaltung in Lateinamerika dar. Der Einfluss anderer
Virentypen in dieser Art ist bisher kaum erforscht. Obwohl Fledermäuse
dauerhaft von vielen Viren infiziert sein können, zeigen sie selten klinische
Symptome. Es wird deshalb angenommen dass sie spezifische Immunstrategien
entwickelt haben um die Virusreplikation zu kontrollieren. Die Toll like-
receptors (TLRs) gehören zu den Immunrezeptoren, die als Bestandteil der
primäreren Abwehrantwort gegen eindringende Pathogene angesehen werden.
Abhängig von der Tierart unterscheidet man bis zu 13 verschiedene TLRs.
Insbesondere die Nukleinsäure-bindenden TLRs 3, 7, 8 und 9 spielen eine
wichtige Rolle in der erworbenen Immunreaktion, weil sie diese durch Liganden
in Form von Nukleinsäuren aktivieren. Die TLRs sind aus evolutionsbiologischer
Sicht besonders interessant, da die Bindungseigenschaften dieser Rezeptoren
unter verschiedenen Tierarten variieren können und deshalb einen Einfluss auf
die Evolutionsökologie von Infektionskrankheiten haben. Daher könnte die
Analyse der Immunvariation bei Fledermäusen auf molekularer Ebene Resistenz-
oder Anfälligkeitsmuster gegenüber Pathogenen innerhalb verschiedener Arten
und auf unterschiedlichen taxonomischen Ebenen offenlegen. Bisher wurde die
genetische Variabilität des Immunsystems von Fledermäusen nur bei wenigen
Arten und Genen erforscht. Unserer Hypothese zur Folge könnten
Vampirfledermäusen Viren in sich tragen, die auch in anderen Säugetieren
vorkommen, da ihre Fähigkeit zur Hämatophagie zu einer Virusübertragung
zwischen verschiedenen Taxa in der Evolutionsgeschichte geführt haben könnte.
Beispielsweise werden Retroviren hauptsächlich über den Austausch von
Körperflüssigkeiten übertragen, weswegen Viren dieser Gruppe leicht zwischen
Vampirfledermäusen und Tieren andere Taxa übertragen werden können. Ziel
unserer Arbeit war es, neue und bereits bekannte Retroviren in D. rotundus mit
Hilfe molekularevolutionärer Methoden zu untersuchen, um interspezifische
Übertragungen zu identifizieren. Wir konnten zeigen, dass ein neues endogenes
Betaretrovirus (DrERV) in D. rotundus ein Evolutionsmuster aufweist, das auf
mehrere interspezifische Übertragungen zwischen verschiedenen Taxa im Laufe
der Stammesentwicklung hindeutet. Außerdem sind wir davon ausgegangen dass
sich in Fledermäuse, auf Grund ihrer Anpassungen, spezielle Mutationen in den
Nukleinsäure-bindenden TLRs fixiert haben, welche wahrscheinlich Auswirkungen
auf die Bindungseigenschaften von Liganden haben. Wir haben die Nukleinsäure-
bindenden TLRs 3, 7, 8 und 9 des Gemeinen Vampirs grundlegend untersucht und
die genetischen Variationen dieser Rezeptoren innerhalb verschiedener
Fledermausarten und anderen Säugetieren verglichen. Wir untersuchten ob sich
die diversifizierende Selektion fortlaufend oder punktuell auf die Fledermaus-
TLRs ausgewirkt hat, um das evolutionäre Muster über lange und kurze Zeiträume
beschreiben zu können. Anschließende Analysen der Evolution auf molekularer
Ebene ließen spezielle Anpassungsmuster bei den TLRs verschiedener
Fledermausarten erkennen. Unsere Ergebnisse konnten außerdem funktionelle
Unterschiede in den Bindungseigenschaften von wirtsfremden Nucleinsäuren
zwischen den TLRs von Fledermäusen und denen anderer Säugetiere zeigen und
lieferten somit entscheidende Hinweise über die Anpassung von Fledermäuse an
Viren als potentielle Krankheitserreger. Dieses Projekt wurde in enger
Zusammenarbeit mit einigen europäischen und mexikanischen Instituten
durchgeführt, die zur Entwicklung von Forschungsbereichen wie Zoonosen und
Wildtierüberwachung beitragen
Gestión contable para disminuir la evasión tributaria en una empresa importadora de productos ópticos, Lima 2017
TesisLa gestión contable para disminuir la evasión tributaria en una empresa importadora de productos ópticos tuvo como finalidad proponer un plan de gestión contable para incentivar la formalización y generar una cultura tributaria lo que traerá como consecuencia la reducción de la evasión tributaria.
La investigación utilizó el sintagma holístico, el enfoque mixto que abarca lo cuantitativo y cualitativo, de tipo proyectiva, ya que plantea una propuesta para reducir la evasión tributaria a través de la gestión contable, se utilizó una muestra de 30 personas del área contable y se entrevistó a 3 contadores para realizar una triangulación de datos para la obtención del diagnóstico final.
La propuesta trata de dar solución al problema planteado debido a que los resultados de la investigación reflejan que existe un bajo nivel de conocimiento sobre la gestión contable y las normas tributarias, cuáles deben ser realizadas de manera eficiente para evitar sanciones innecesarias; por lo tanto se deben cumplir con las formalidades que estable la administración tributaria para que se reconozca el crédito fiscal. Así como los gastos con límite permitido para su deducción en el cálculo del impuesto a la renta