Background. Volunteer challenge studies have provided detailed data on viral shedding from the respiratory tract before and through the course of experimental influenza virus infection. There are no ...comparable quantitative data to our knowledge on naturally acquired infections. Methods. In a community-based study in Hong Kong in 2008, we followed up initially healthy individuals to quantify trends in viral shedding on the basis of cultures and reverse-transcription polymerase chain reaction (RT-PCR) through the course of illness associated with seasonal influenza A and B virus infection. Results. Trends in symptom scores more closely matched changes in molecular viral loads measured with RT-PCR for influenza A than for influenza B. For influenza A virus infections, the replicating viral loads determined with cultures decreased to undetectable levels earlier after illness onset than did molecular viral loads. Most viral shedding occurred during the first 2–3 days after illness onset, and we estimated that 1%–8% of infectiousness occurs prior to illness onset. Only 14% of infections with detectable shedding at RT-PCR were asymptomatic, and viral shedding was low in these cases. Conclusions. Our results suggest that “silent spreaders” (ie, individuals who are infectious while asymptomatic or presymptomatic) may be less important in the spread of influenza epidemics than previously thought.
Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other ...post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins encoded by the PARP (also called ARTD) gene family. The majority of the 17 human PARP genes are poorly characterized. However, one PARP protein, PARP13/ZAP, has broad antiviral activity and has evolved under positive (diversifying) selection in primates. Such evolution is typical of domains that are locked in antagonistic 'arms races' with viral factors. To identify additional PARP genes that may be involved in host-virus interactions, we performed evolutionary analyses on all primate PARP genes to search for signatures of rapid evolution. Contrary to expectations that most PARP genes are involved in 'housekeeping' functions, we found that nearly one-third of PARP genes are evolving under strong recurrent positive selection. We identified a >300 amino acid disordered region of PARP4, a component of cytoplasmic vault structures, to be rapidly evolving in several mammalian lineages, suggesting this region serves as an important host-pathogen specificity interface. We also found positive selection of PARP9, 14 and 15, the only three human genes that contain both PARP domains and macrodomains. Macrodomains uniquely recognize, and in some cases can reverse, protein mono-ADP-ribosylation, and we observed strong signatures of recurrent positive selection throughout the macro-PARP macrodomains. Furthermore, PARP14 and PARP15 have undergone repeated rounds of gene birth and loss during vertebrate evolution, consistent with recurrent gene innovation. Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, our evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts.
Influenza A viruses are believed to spread between humans through contact, large respiratory droplets and small particle droplet nuclei (aerosols), but the relative importance of each of these modes ...of transmission is unclear. Volunteer studies suggest that infections via aerosol transmission may have a higher risk of febrile illness. Here we apply a mathematical model to data from randomized controlled trials of hand hygiene and surgical face masks in Hong Kong and Bangkok households. In these particular environments, inferences on the relative importance of modes of transmission are facilitated by information on the timing of secondary infections and apparent differences in clinical presentation of secondary infections resulting from aerosol transmission. We find that aerosol transmission accounts for approximately half of all transmission events. This implies that measures to reduce transmission by contact or large droplets may not be sufficient to control influenza A virus transmission in households.
Poly(2-oxazoline)s have been investigated for decades as biomaterials. Pioneering early work suggested that hydrophilic poly(2-oxazoline)s are comparable to poly(ethylene glycol) regarding their ...potential as biomaterials, but the ready commercial availability of the latter has led to its meteoric rise to become the gold standard of hydrophilic synthetic biomaterials. In contrast, poly(2-oxazoline)s almost fell into oblivion. However, in the last decade, this family of polymers has gained much more interest in general and as biomaterials in particular. The rich chemistry and comparably straightforward synthesis of poly(2-oxazoline)s gives many opportunities for tailoring the properties of the resulting biomaterials, allowing the chemist to explore new conjugation chemistry, and to fine-tune the molar mass, hydrophilic-lipophilic balance as well as architecture. Thus, the wide range of demands for various applications of biomaterials can be suitably addressed.
This review aims to give a comprehensive and critical update of the development of poly(2-oxazoline) based biomaterials, focusing on the last 5 years, which have seen an explosive increase of interest. We believe that the research regarding this diverse family of polymers will remain strong and will keep growing, in particular after the promising first-in-human studies of a poly(2-oxazoline) drug conjugate. This review aims at researchers and students new to this polymer family and seasoned poly(2-oxazoline) experts alike and attempts to showcase how the chemical diversity of poly(2-oxazoline)s allows a relatively facile and broad access to biomaterials of all kinds.
Selfishness is pervasive and manifests at all scales of biology, from societies, to individuals, to genetic elements within a genome. The relentless struggle to seek evolutionary advantages drives ...perpetual cycles of adaptation and counter-adaptation, commonly referred to as Red Queen interactions. In this review, we explore insights gleaned from molecular and genetic studies of such genetic conflicts, both extrinsic (between genomes) and intrinsic (within genomes or cells). We argue that many different characteristics of selfish genetic elements can be distilled into two types of advantages: an over-replication advantage (e.g. mobile genetic elements in genomes) and a transmission distortion advantage (e.g. meiotic drivers in populations). These two general categories may help classify disparate types of selfish genetic elements.
Individuals with the 2019 coronavirus disease (COVID-19) show varying severity of the disease, ranging from asymptomatic to requiring intensive care. Although monoclonal antibodies specific to the ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been identified, we still lack an understanding of the overall landscape of B cell receptor (BCR) repertoires in individuals with COVID-19. We use high-throughput sequencing of bulk and plasma B cells collected at multiple time points during infection to characterize signatures of the B cell response to SARS-CoV-2 in 19 individuals. Using principled statistical approaches, we associate differential features of BCRs with different disease severity. We identify 38 significantly expanded clonal lineages shared among individuals as candidates for responses specific to SARS-CoV-2. Using single-cell sequencing, we verify the reactivity of BCRs shared among individuals to SARS-CoV-2 epitopes. Moreover, we identify the natural emergence of a BCR with cross-reactivity to SARS-CoV-1 and SARS-CoV-2 in some individuals. Our results provide insights important for development of rational therapies and vaccines against COVID-19.
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•Analysis of B cell repertoires with SARS-CoV-2 epitope-sorted B cell receptors•Differential sequence features of B cell receptors are associated with disease severity•Expansion of B cell clonal lineages in response to SARS-CoV-2•Shared B cell receptors emerge with cross-reactivity to SARS-CoV-1 and SARS-CoV-2
It is unclear how the dynamics of the humoral immune response to SARS-CoV-2 vary across individuals with different disease severity. Montague et al. develop a principled statistical approach based on time-course, high-throughput B cell repertoire sequences to identify shared, expanding, rare clonal B cell lineages as candidates for responses specific to SARS-CoV-2.
Rotavirus diarrhea is the major cause of death of millions of children in developing countries besides causing economically significant malady in neonates of many domestic animals. In neonates, the ...infection is non-viremic, have very short incubation period, and manifests profuse diarrhea and severe dehydration. Concurrent infection with secondary pathogens may augment the disease severity. Diarrhea occurs due to virus-mediated destruction of absorption efficient enterocytes, activation of enteric nervous system, or due to a rotavirus enterotoxin. Diagnosis of the infection relies on conventional techniques like isolation in MA 104 cell lines, electron microscopy, electro-pherotyping, and various serological tests. Presently, diagnosis and molecular typing is performed using serotype specific RT-PCR, sequencing or genomic hybridization techniques. As the rotaviruses are known to exhibit extreme genetic diversity and outplay disinfection procedures, eradication of the pathogen is often difficult. Hence, for prevention, good management practices coupled with vaccination of dam for protecting young ones, has to be practiced. Recently, new generation prophylactic strategies including DNA vaccines, subunit vaccines, virus-like particles (VLPs) and edible vaccines have been found to induce sufficient levels of passive immunity. Aside to the infection in animals, zoonotic significance of the animal rotaviruses has to be further unearthed. In this review, efforts have been made to highlight the importance and prevalence of the disease in bovines, its pathogenesis along with preventive measures, salient features of rotaviruses and their inter-species transmission abilities, zoonotic implications, and a concise account of the infection in various domestic animals and poultry.
Retroelements comprise a major fraction of most mammalian genomes. To protect their fitness and stability, hosts must keep retroelements in check in their germline. In most tissues mobile element ...insertions are decorated with chromatin modifications suggestive of transcriptional silencing. However, germline cells undergo massive chromatin reprogramming events, which erase repressive chromatin marks and necessitate de novo re-establishment of silencing. How do host genomes achieve the discrimination necessary for this de novo silencing? A series of recent studies have revealed aspects of the multi-pronged strategy that mammalian genomes use to identify and silence retroelements. These strategies include the use of small RNA-guides, of specialized DNA-binding protein adaptors and of proteins that repair chromatin discontinuities caused by retroelement insertions. Genetic analyses reveal the importance of these mechanisms of protection, each of which specializes in silencing retroelements of different evolutionary ages. Together, these strategies allow mammalian genomes to withstand the high burden of their parasites.
NLR (nucleotide-binding domain NBD- and leucine-rich repeat LRR-containing) proteins mediate innate immune sensing of pathogens in mammals and plants. How NLRs detect their cognate stimuli remains ...poorly understood. Here, we analyzed ligand recognition by NLR apoptosis inhibitory protein (NAIP) inflammasomes. Mice express multiple highly related NAIP paralogs that recognize distinct bacterial proteins. We analyzed a panel of 43 chimeric NAIPs, allowing us to map the NAIP domain responsible for specific ligand detection. Surprisingly, ligand specificity was mediated not by the LRR domain, but by an internal region encompassing several NBD-associated α-helical domains. Interestingly, we find that the ligand specificity domain has evolved under positive selection in both rodents and primates. We further show that ligand binding is required for the subsequent co-oligomerization of NAIPs with the downstream signaling adaptor NLR family, CARD-containing 4 (NLRC4). These data provide a molecular basis for how NLRs detect ligands and assemble into inflammasomes.
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•The LRR domain of NAIPs is not utilized for discrimination of bacterial ligands•The NBD-associated helical domains of NAIPs dictate specific ligand recognition•The ligand specificity domain has evolved under positive selection•Ligand binding is required for NAIP assembly into inflammasomes
Upon detection of bacterial or viral infection, inflammasomes initiate immune responses. Here, Tenthorey et al. determine how the NAIP/NLRC4 family of inflammasomes detect specific bacterial ligands and suggest that NAIP/NLRC4 inflammasomes are changing quickly in order to detect rapidly evolving bacterial ligands.
To examine the long-term relationship between changes in water and beverage intake and weight change.
Prospective cohort studies of 50013 women aged 40-64 years in the Nurses' Health Study (NHS, ...1986-2006), 52987 women aged 27-44 years in the NHS II (1991-2007) and 21988 men aged 40-64 years in the Health Professionals Follow-up Study (1986-2006) without obesity and chronic diseases at baseline.
We assessed the association of weight change within each 4-year interval, with changes in beverage intakes and other lifestyle behaviors during the same period. Multivariate linear regression with robust variance and accounting for within-person repeated measures were used to evaluate the association. Results across the three cohorts were pooled by an inverse-variance-weighted meta-analysis.
Participants gained an average of 1.45 kg (5th to 95th percentile: -1.87 to 5.46) within each 4-year period. After controlling for age, baseline body mass index and changes in other lifestyle behaviors (diet, smoking habits, exercise, alcohol, sleep duration, TV watching), each 1 cup per day increment of water intake was inversely associated with weight gain within each 4-year period (-0.13 kg; 95% confidence interval (CI): -0.17 to -0.08). The associations for other beverages were: sugar-sweetened beverages (SSBs) (0.36 kg; 95% CI: 0.24-0.48), fruit juice (0.22 kg; 95% CI: 0.15-0.28), coffee (-0.14 kg; 95% CI: -0.19 to -0.09), tea (-0.03 kg; 95% CI: -0.05 to -0.01), diet beverages (-0.10 kg; 95% CI: -0.14 to -0.06), low-fat milk (0.02 kg; 95% CI: -0.04 to 0.09) and whole milk (0.02 kg; 95% CI: -0.06 to 0.10). We estimated that replacement of 1 serving per day of SSBs by 1 cup per day of water was associated with 0.49 kg (95% CI: 0.32-0.65) less weight gain over each 4-year period, and the replacement estimate of fruit juices by water was 0.35 kg (95% CI: 0.23-0.46). Substitution of SSBs or fruit juices by other beverages (coffee, tea, diet beverages, low-fat and whole milk) were all significantly and inversely associated with weight gain.
Our results suggest that increasing water intake in place of SSBs or fruit juices is associated with lower long-term weight gain.
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