bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel biopolymer for mucosal adjuvant against respiratory pathogens
Authors: Hoover Ashley R. , More Sunil , Liu Kaili , West Connor L. , Valerio Trisha I. , Furrer Coline L. , Yu Ningli , Villalva Crystal , Kumar Amit , Alleruzzo Lu , Lam Samuel S. K. , Hode Tomas , Zhao Meng , Papin James F. , Chen Wei R.
Published: September 2022

Mucosal vaccinations for respiratory pathogens provide effective protection as they stimulate localized cellular and humoral immunities at the site of infection. Currently, the major limitation of intranasal vaccination is using effective adjuvants capable of withstanding the harsh environment imposed by the mucosa. Herein, we describe the efficacy of using a novel biopolymer, N-dihydrogalactochitosan (GC), as a nasal mucosal vaccine adjuvant against respiratory infections. Specifically, using COVID as an example, we mixed GC with recombinant SARS-CoV-2 trimeric spike (S) and nucleocapsid (NC) proteins to intranasally vaccinate K18-hACE2 transgenic mice, in comparison with Addavax (AV), an MF-59 equivalent. In contrast to AV, intranasal application of GC induces a robust, systemic antigen-specific antibody response and increases the number of T cells in the cervical lymph nodes. Moreover, GC+S+NC-vaccinated animals were largely resistant to the lethal SARS-CoV-2 challenge and experienced drastically reduced morbidity and mortality, with animal weights and behavior returning to normal 22 days post-infection. In contrast, animals intranasally vaccinated with AV+S+NC experienced severe weight loss, mortality, and respiratory distress, with none surviving beyond 6 days post-infection. Our findings demonstrate that GC can serve as a potent mucosal vaccine adjuvant against SARS-CoV-2 and potentially other respiratory viruses.
Aerosolized Desert Dusts Collected Near a Drying Lake and Pulmonary Inflammation in Mice: Implications for Environmental Exposures and Asthma
Authors: Biddle Trevor A. , Yisrael Keziyah , Drover Ryan , Li Qi , Maltz Mia R. , Topacio Talyssa M. , Yu Jasmine , Del Castillo Diana , Gonzales Daniel , Freund Hannah M. , Swenson Mark P. , Shapiro Malia L. , Botthoff Jon K. , Aronson Emma , Cocker David R. , Lo David D.
Published: September 2022

Background

A high incidence of asthma is prevalent among residents near the Salton Sea, a large inland terminal lake in southern California. This arid region has high levels of ambient particulate matter (PM); yet while high PM levels are often associated with asthma in many environments, it is possible that the rapidly retreating lake may contribute components with a specific role in promoting asthma symptoms.

Objectives

Our hypothesis is that asthma may be higher in residents closest to the Salton Sea due to chronic exposures to playa dust. Playa emissions may be concentrating dissolved material from the lake, with microbial components capable of inducing pulmonary innate immune responses. Such inflammatory responses may contribute to the development of asthma-like symptoms in residents. To test this hypothesis, we used a mouse model of aerosol exposures to assess the effects of playa dust.

Methods

From dust collected around the Salton Sea region, aqueous extracts were used to generate aerosols, which were injected into an environmental chamber for mouse exposure studies. We compared the effects of exposure to Salton Sea aerosols, as well as to known immunostimulatory reference materials. Acute 48-hour and chronic 7-day exposures were compared, with lungs analyzed for inflammatory cell recruitment and gene expression.

Results

Dust from sites nearest to the Salton Sea triggered lung neutrophil inflammation that was stronger at 48-hours but reduced at 7-days. This acute inflammatory profile and kinetics resembled the response to innate immune ligands LTA and LPS while distinct from the classic allergic response to Alternaria.

Conclusion

Lung inflammatory responses to Salton Sea dusts are similar to acute innate immune responses, raising the possibility that microbial components are entrained in the dust, promoting inflammation. This effect highlights the health risks at drying terminal lakes from inflammatory components in dust emissions from exposed lakebed.
Seasonality of pollinators in Mediterranean montane habitats: cool-blooded bees for early-blooming plants
Authors: Herrera Carlos M. , Núñez Alejandro , Aguado Luis O. , Alonso Conchita
Published: September 2022

Understanding the factors that drive community-wide assembly of plant-pollinator systems along environmental gradients has considerable evolutionary, ecological and applied significance. Variation in thermal environments combined with intrinsic differences among pollinators in thermal biology (tolerance limits, thermal optima, thermoregulatory ability) have been proposed as drivers of community-wide pollinator gradients, but this suggestion remains largely speculative. We test the hypothesis that seasonality in bee pollinator composition in montane habitats of southeastern Spain, which largely reflects the prevalence during the early flowering season of mining bees (Andrena), is a consequence of the latter’s thermal biology. Quantitative information on seasonality ofAndrenabees in the whole plant community (275 plant species) was combined with field and laboratory data on key aspects of the thermal biology of 30 species ofAndrena(endothermic ability, warming constant, relationships of body temperature with ambient and operative temperatures).Andrenabees were a conspicuous, albeit strongly seasonal component of the pollinator assemblage of the regional plant community, visiting flowers of 153 different plant species (57% of total). Proportion ofAndrenarelative to all bees reached a maximum among plant species which flowered in late winter and early spring, and declined precipitously from May onwards.Andrenawere recorded only during the cooler segment of the annual range of air temperatures experienced at flowers by the whole bee assemblage. These patterns can be explained by features ofAndrena’s thermal biology: null or negligible endothermy; ability to forage at much lower body temperature than endothermic bees (difference ~10°C); low upper tolerable limit of body temperature, beyond which thermal stress presumably precluded foraging at the warmest period of year; weak thermoregulatory capacity; and high warming constant enhancing ectothermic warming. Our results demonstrate the importance of lineage-specific pollinator traits as drivers of seasonality in community-wide pollinator composition; show that exploitation of cooler microclimates by bees does not require endothermy; falsify the frequent assumption that endothermy and thermoregulation apply to all bees; and suggest that medium- and large-sized ectothermic bees with low upper thermal limits and weak thermoregulatory ability can actually be more adversely affected by climate warming than large endothermic species.
Engineering High-Quality Cartilage Microtissues using Hydrocortisone Functionalised Microwells
Authors: Burdis Ross , Kronemberger Gabriela Soares , Kelly Daniel J.
Published: September 2022

Engineering clinically-relevant musculoskeletal tissues at a human scale is a considerable challenge. Developmentally-inspired scaffold-free approaches for engineering cartilage tissues have shown great promise in recent years, enabling the generation of highly biomimetic tissues. Despite the relative success of these approaches, the absence of a supporting scaffold or hydrogel creates challenges in the development of large scale tissues. Combining numerous scaled-down tissue units (herein termed microtissues) into a larger macrotissue represents a promising strategy to address this challenge. The overall success of such approaches, however, relies on the development of strategies to support the robust and consistent chondrogenic differentiation of clinically relevant cell sources such as mesenchymal stem/stromal cells (MSCs) within microwell arrays to biofabricate numerous microtissues rich in cartilage-specific extracellular matrix components. In this paper, we first describe a simple method to manufacture cartilage microtissues at various scales using novel microwell array stamps. This system allows the rapid and reliable generation of cartilage microtissues, and can be used as a platform to study microtissue phenotype and development. Based on the unexpected discovery that Endothelial Growth Medium (EGM) enhanced MSC aggregation and chondrogenic capacity within the microwell arrays, this work also sought to identify soluble factors within the media capable of supporting robust differentiation using heterogeneous MSC populations. Hydrocortisone was found to be the key factor within EGM that enhanced the chondrogenic capacity of MSCs within these microwell arrays. This strategy represents a promising means of generating large numbers of high-quality, scaffold-free cartilage microtissues for diverse biofabrication applications.
Population Normalization in SARS-CoV-2 Wastewater-Based Epidemiology: Implications from Statewide Wastewater Monitoring in Missouri
Authors: Li Chenhui , Bayati Mohamed , Hsu Shu-Yu , Hsieh Hsin-Yeh , Lindsi Wilfing , Belenchia Anthony , Zemmer Sally A. , Klutts Jessica , Samuelson Mary , Reynolds Melissa , Semkiw Elizabeth , Johnson Hwei-Yiing , Foley Trevor , Wieberg Chris G. , Wenzel Jeff , Lyddon Terri D. , LePique Mary , Rushford Clayton , Salcedo Braxton , Young Kara , Graham Madalyn , Suarez Reinier , Ford Anarose , Antkiewicz Dagmara S. , Janssen Kayley H. , Shafer Martin M. , Johnson Marc C. , Lin Chung-Ho
Published: September 2022

Abstract Figure

The primary objective of this study was to identify a universal wastewater biomarker for population normalization for SARS-CoV-2 wastewater-based epidemiology (WBE). A total of 2,624 wastewater samples (41 weeks) were collected weekly during May 2021-April 2022 from 64 wastewater facilities across Missouri, U.S. Three wastewater biomarkers, caffeine and its metabolite, paraxanthine, and pepper mild mottle virus (PMMoV), were compared for the population normalization effectiveness for wastewater SARS-CoV-2 surveillance. Paraxanthine had the lowest temporal variation and strongest relationship between population compared to caffeine and PMMoV. This result was confirmed by data from ten different Wisconsin’s WWTPs with gradients in population sizes, indicating paraxanthine is a promising biomarker of the real-time population across a large geographical region. The estimated real-time population was directly compared against the population patterns with human movement mobility data. Of the three biomarkers, population normalization by paraxanthine significantly strengthened the relationship between wastewater SARS-CoV-2 viral load and COVID-19 incidence rate the most (40 out of 61 sewersheds). Caffeine could be a promising population biomarker for regions where no significant exogenous caffeine sources (e.g., discharges from food industries) exist. In contrast, PMMoV showed the highest variability over time, and therefore reduced the strength of the relationship between sewage SARS-CoV-2 viral load and the COVID-19 incidence rate, as compared to wastewater data without population normalization and the population normalized by either recent Census population or the population estimated based on the number of residential connections and average household size for that municipality from the Census. Overall, the findings of this long-term surveillance study concluded that the paraxanthine has the best performance as a biomarker for population normalization for SARS-CoV-2 wastewater-based epidemiology.
Cell cycle progression defects and impaired DNA damage signaling drive enlarged cells into senescence
Authors: Manohar Sandhya , Estrada Marianna E. , Uliana Federico , Neurohr Gabriel E.
Published: September 2022

Cellular senescence plays an important role in development, ageing, and cancer biology. Senescence is associated with increased cell size, but how this contributes to permanent cell cycle exit is poorly understood. Using reversible G1 cell cycle arrests combined with growth rate modulation, we examined the effects of excess cell size on cell cycle progression in human cells. We show that enlarged cells paradoxically have high levels of G1/S regulators relative to cells that were maintained at physiological size but also induce p21, which restrains cell cycle entry and protects against cell division failure. Furthermore, we find that enlarged cells bear an increased propensity for DNA breakage and concomitant DNA damage repair defects that are established during G1. Based on these observations, we propose that impaired DNA damage repair pathways prime enlarged cells for persistent replication-acquired damage, ultimately leading to catastrophic cell cycle failure and permanent cell cycle exit.
Prefrontal network engagement by deep brain stimulation in limbic hubs
Authors: Allawala Anusha , Bijanki Kelly R , Oswalt Denise , Mathura Raissa K , Adkinson Joshua , Pirtle Victoria , Shofty Ben , Robinson Meghan , Harrison Matthew T , Mathew Sanjay J , Goodman Wayne K , Pouratian Nader , Sheth Sameer A , Borton David A
Published: September 2022

Background

Prefrontal circuits in the human brain play an important role in cognitive and affective processing. Neuromodulation therapies delivered to certain key hubs within these circuits are being used with increasing frequency to treat a host of neuropsychiatric disorders. However, the detailed neurophysiological effects of stimulation to these hubs are largely unknown.

Methods

Here, we performed intracranial recordings across prefrontal networks while delivering electrical stimulation to two well-established white matter hubs involved in cognitive regulation and depression: the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS).

Results

We demonstrate a shared frontotemporal circuit consisting of the ventromedial PFC, amygdala, and lateral orbitofrontal cortex where gamma oscillations are differentially modulated by stimulation target. Additionally, we found subject-specific responses to stimulation in the dorsal anterior cingulate cortex and demonstrate the capacity for further tuning of neural activity using current-steered stimulation.

Conclusions

Our findings indicate a potential neurophysiological mechanism for the dissociable therapeutic effects seen across the SCC and VC/VS DBS targets for psychiatric neuromodulation and our results lay the groundwork for personalized, network-guided neurostimulation therapy.
Variation in morphology among populations of threespine stickleback (Gasterosteus aculeatus) from western Newfoundland, Canada
Authors: Scott RJ , Haines GE , Biedak NR , Baker JA
Published: September 2022

Freshwater populations of threespine stickleback (Gasterosteus aculeatus) have diverged from their marine ancestor and show extensive variation among populations throughout most of their range. However, phenotypes of freshwater populations from the east coast of North America does not appear to demonstrate extensive variability observed throughout the rest of the species’ range. The relative young age of east coast North American populations may explain the apparent lack of freshwater variability. On the other hand, populations in this part of the species’ range have not received the level of attention as have populations throughout the rest of its range and the low level of variability observed may simply reflect lack of data for this region. We examined morphological traits (including linear measurements of body armor and body shape) of stickleback from 52 locations representing marine and freshwater populations along the west coast of Newfoundland, Canada. We found that variability in morphological traits among freshwater populations was much more extensive than previously assumed and similar to patterns observed throughout the rest of the species’ range.
The evolution of host resistance to a virus is determined by resources, historical contingency, and time scale
Authors: Visher Elisa , Mahjoub Hannah , Soufi Khadija , Pascual Nilbert , Hoang Vivian , Bartlett Lewis J. , Roberts Katherine , Meaden Sean , Boots Mike
Published: September 2022

Hosts can often evolve resistance to parasites (and other stressors), but such resistance is generally thought to be constrained by trade-offs with other traits. These trade-offs determine the host’s optimal resistance strategy and whether resistance cycles, diversifies, and/or is maintained in the absence of parasite. However, trade-offs are often inconsistently measured across experiments and can depend on environmental conditions. Here, we extend a selection experiment evolving resistance to viral infection under variable resource quality in thePlodia interpunctellamodel system to explore the evolutionary conditions leading to an incongruent earlier measurement of costless resistance. We find that environmental resource quality, historical contingency, and the time scale of selection all affect trade-offs in our long-term selection experiment. Specifically, populations selected for resistance with the dual stressor of low resource quality are slowed, but not prevented, from evolving resistance. Second, variation in starting populations or early sampled adaptations led to contingency towards context-dependent resistance. Finally, some costs to resistance observed at early time points were compensated over longer evolutionary time scales. Our work therefore informs perspectives for the predictability of adaptation and how variation in specific evolutionary conditions can alter the evolutionary trajectories of a population towards costly or costless resistance strategies.
When good species have porous boundaries: weak reproductive isolation and extensive gene flow between Mimulus glaucescens and M. guttatus in northern California
Authors: Ivey C. T. , Habecker N. M. , Bergmann J. P. , Ewald J. , Coughlan J. M.
Published: September 2022

Barriers to reproduction are often how progress in speciation is measured. Nonetheless, a key unresolved question is the extent to which reproductive barriers diminish gene flow in incipient species in nature. The Sierra Nevada foothill endemic Mimulus glaucescens and the widespread M. guttatus are considered to be distinct species based on contrasting vegetative traits, but barriers to reproduction are not readily apparent, although these species are not known to hybridize in nature. To explore boundaries between taxa, we examined 15 potential reproductive barriers between species in a Northern California area of broad sympatry. Most barriers, with the exception of ecogeographic isolation, were weak, and total isolation for each species was estimated to be incomplete. Population genomic analyses of range-wide and broadly sympatric accessions revealed that gene flow between these taxa is common across the range, and rampant within areas of sympatry. Thus, despite fairly strong ecological differentiation - which may be involved in maintenance of vegetative differences - ecological isolation is a weak barrier to gene flow in this system. This work underscores the value of combining classical measures of reproductive isolation with estimates of natural gene flow for studies of speciation in natural communities.
Use of the particle agglutination/particle agglutination-inhibition test for antigenic analysis of SARS-CoV-2
Authors: Kobayashi Jun , Matsuyama Shutoku , Shirakura Masayuki , Arita Tomoko , Suzuki Yasushi , Asanuma Hideki , Watanabe Shinji , Hasegawa Hideki , Nakamura Kazuya
Published: September 2022

The antigenicity of SARS-CoV-2 is a critical issue for the effectiveness of the vaccine, and thus it should be phenotypically evaluated by serological assays as new field isolates emerge. The hemagglutination/hemagglutination-inhibition (HA/HI) tests are well-known as a representative method for antigenic analysis of influenza viruses, but SARS-CoV-2 is unlikely to agglutinate to human or guinea pig red blood cells. Therefore, the antigenic analysis requires complicated enzyme-linked immunosorbent assay (ELISA) or cell-based assays such as the microneutralization assay. In this study, we developed the particle agglutination/particle agglutination-inhibition (PA/PAI) test to easily and rapidly quantify the virus and antibody using human angiotensin-converting enzyme 2 (hACE2)-bound latex beads. The PA titer was positively correlated with the plaque-forming units. The PAI titer using post-infection Syrian hamster antisera clearly revealed the antigenic difference between the omicron and previous variants. The results show the PAI test is useful for easy and rapid antigenic analysis of SARS-CoV-2.
Comparative analysis of macroalgae supplementation on the rumen microbial community: Asparagopsis taxiformis inhibits major ruminal methanogenic, fibrolytic, and volatile fatty acid-producing microbes in vitro
Authors: O’Hara E , Moote P , Terry S , Beauchemin KA , McAllister TA , Abbott DW , Gruninger RJ
Published: September 2022

1.

Seaweeds have received a great deal of attention recently for their potential as methane-suppressing feed additives in ruminants. To date, Asparagopsis taxiformis has proven a potent enteric methane inhibitor, but it is a priority to identify local seaweed varieties that may hold similar properties. It is essential that any methane inhibitor does not compromise the function of the rumen microbiome. In this study, we conducted an in vitro experiment using the RUSITEC system to evaluate the impact of A. taxiformis, Palmaria mollis, and Mazzaella japonica on rumen prokaryotic communities. 16S rRNA sequencing showed that A. taxiformis had a profound effect on the microbiome, particularly on methanogens. Weighted Unifrac distances showed significant separation of A. taxiformis samples from the control and other seaweeds (P<0.05). Neither P. mollis nor M. japonica had a substantial effect on the microbiome (P>0.05). A. taxiformis reduced the abundance of all major archaeal species (P<0.05), leading to an almost total disappearance of the methanogens. Prominent fibre-degrading and volatile fatty acid (VFA)-producing bacteria including Fibrobacter and Ruminococcus were also inhibited by A. taxiformis (P<0.05), as were other genera involved in propionate production. However, the abundance of many other major bacteria (e.g. Prevotella) was increased by A. taxiformis suggesting the rumen microbiome adapted to an initial perturbation. Our study provides baseline knowledge of microbial dynamics in response to seaweed feeding over an extended period and suggests that feeding A. taxiformis to cattle to reduce methane may directly or indirectly inhibit important fibre-degrading and VFA-producing bacteria.
Oral health literacy, oral health behavior, and oral health status among dental patients and associated factors
Authors: An Ran , Li Qianqian , Luo Yuan , Chen Wenfeng , Sohaib Muhammad , Liu Meizi , Wu Zitong
Published: September 2022

Background

Oral health plays an important role in overall health. Little is known about oral health literacy, oral health behavior, and oral health status in dental patients.

Purpose

This study aimed to assess oral health literacy (OHL), oral health behavior, oral health status, and associated factors in dental patients.

Methods

This cross-sectional study was conducted between June,13, 2022 and July, 26, 2022 in a tertiary general hospital, in Hebei, China. A total of 184 patients participated in the study. OHL was assessed by the Chinese version of the Health Literacy Dental Scale (HeLD-14). Trained interviewers performed face-to-face interviews for oral health-related behavior information. Data were analyzed using SPSS version 24. Mann–Whitney U-tests, chi-square tests, and binary logistic regression analysis were performed.

Results

Participants were 184 dental patients which consisted of 78.3% men and a mean age of 28.36 ± 10.72 years old. The mean oral health literacy score was 43.07±9.920 (out of 56). There were significant associations between inadequate OHL and economic burden (odds ratio [OR]=2.636, P = 0.003), mouthwash (OR=2.433, P = 0.006), gum bleeding (OR=3.798, P = 0.030), and dental visiting (OR=1.885, P = 0.049).

Conclusion

The oral health literacy of dental patients is at a medium level overall. Patients with inadequate OHL had a higher frequency of bleeding gums and less frequent dental visiting. Health care providers should consider improving oral health literacy among dental patients.
Distinct and joint effects of low and high levels of Aβ and tau deposition on cortical thickness
Authors: Hojjati Seyed Hani , Butler Tracy A. , Chiang Gloria C. , Habeck Christian , RoyChoudhury Arindam , Feiz Farnia , Shteingart Jacob , Nayak Siddharth , Ozoria Sindy , Fernández Antonio , Stern Yaakov , Luchsinger José A. , Devanand Davangere P. , Razlighi Qolamreza R.
Published: September 2022

Alzheimer’s disease (AD) is defined by the presence of Amyloid-β (Aβ), tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Prior studies have suggested that Aβ deposition can be associated with both cortical thinning and thickening. These contradictory results may be due to small sample sizes, the presence versus absence of tau, and limited detectability in the earliest phase of protein deposition, which may begin in young adulthood and cannot be captured in studies enrolling only older subjects. In this study, we aimed to find the distinct and joint effects of Aβ and tau on neurodegeneration during the progression from normal to abnormal stages of pathologies that remain incompletely understood. We used 18F-MK6240 and 18F-Florbetaben/18F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aβ, and cortical thickness in 529 participants ranging in age from 20 to 90. We applied a novel partial volume correction technique based on the absence of proteinopathy in young controls to optimize spatial resolution. Aβ/tau abnormality was defined at 95th percentile of the normal distribution of global Ab/tau observed in young participants. We performed multiple regression analyses to assess the distinct and joint effects of Aβ and tau on cortical thickness. Using 529 participants (83 young, 394 healthy older, 52 MCI) we showed that normal levels of Aβ deposition were significantly associated with increased cortical thickness regardless of the amount of tau (e.g., left entorhinal cortex with t>3.241). The relationship between tau deposition and neurodegeneration was more complex: abnormal levels of tau were associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t<-2.80 and left insula with t<-3.202), as expected based on prior neuroimaging and neuropathological studies. Surprisingly, however, normal levels of tau were found to be associated with cortical thickening. Moreover, at abnormal levels of Aβ and tau, the resonance between them, defined as their correlation throughout the cortex, was associated strongly with cortical thinning when controlling for their additive effect. We confirm prior findings of an association between Aβ deposition and cortical thickening and suggest this may also be the case in the earliest stages of deposition in normal aging. We discuss potential pathophysiologic processes underlying this effect such as inflammation and hyperactivation (excitotoxicity). We also illustrate that resonance between high levels of Aβ and tau uptake is strongly associated with cortical thinning, emphasizing the effects of Aβ/tau synergy in AD pathogenesis.
Using Lambda phages as a proxy for pathogen transmission in hospitals
Authors: Burke Kylie B. , Berryhill Brandon A. , Garcia Rodrigo , Goldberg David A. , Manuel Joshua A. , Gannon Paige , Levin Bruce R. , Kraft Colleen S. , Mumma Joel
Published: September 2022

One major concern in hospitalized patients is infections with pathogens borne on surfaces, patients, and healthcare workers. Fundamental to controlling nosocomial infections is identifying the sources of pathogens, monitoring the processes responsible for their transmission, and evaluating the efficacy of the procedures employed for restricting their transmission. Here we present a method using the bacteriophage Lambda (λ) to achieve these ends. Defined densities of multiple genetically marked λ phages were inoculated at known hotspots for contamination on high-fidelity mannequins. Healthcare workers (HCWs) then entered a pre-sanitized simulated hospital room and performed a series of patient care tasks on the mannequins. Sampling occurred on the scrubs and hands of the HCWs, as well as previously defined high-touch surfaces in hospital rooms. Following sampling, the rooms were decontaminated using procedures designed and demonstrated to be effective. Following the conclusion of the simulation, the samples were tested for the presence, identity, and densities of these Lambda phages.

The data generated enabled the determination of the sources and magnitude of contamination caused by the breakdown of established infection prevention practices by HCW. This technique enabled the standardized tracking of multiple contaminants during a single episode of patient care. While our application of these methods focused on nosocomial infections and the role of HCW behaviors in their spread, these methods could be employed for identifying the sources and sites of microbial contamination in other settings.
Estimating the cost-effectiveness of maternal vaccination and monoclonal antibodies for respiratory syncytial virus in Kenya and South Africa
Authors: Koltai Mihaly , Moyes Jocelyn , Nyawanda Bryan , Nyiro Joyce , Munywoki Patrick , Tempia Stefano , Li Xiao , Antillon Marina , Bilcke Joke , Flasche Stefan , Beutels Philippe , Nokes D. James , Cohen Cheryl , Jit Mark
Published: September 2022

Background

Respiratory syncytial virus (RSV) causes a substantial burden of acute lower respiratory infection in children under 5 years, particularly in low- and middle-income countries (LMICs). Maternal vaccine (MV) and next-generation monoclonal antibody (mAb) candidates have been shown to reduce RSV disease in infants in phase III clinical trials. The cost-effectiveness of these biologics has been estimated using disease burden data from global meta-analyses, but these are sensitive to the detailed age breakdown of paediatric RSV disease, for which there have previously been limited data.

Methods

We use original hospital-based incidence data from South Africa and Kenya collected between 2010 and 2018 of RSV-associated acute respiratory infection (ARI), influenza-like illness (ILI), severe acute respiratory infection (SARI) as well as deaths with monthly age-stratification, supplemented with data on healthcare-seeking behaviour and costs to the healthcare system and households. We estimated the incremental cost per DALY averted (incremental cost-effectiveness ratio or ICER) of public health interventions by MV or mAb for a plausible range of prices (3-30 USD for vaccines and 6-60 USD for monoclonals), using an adapted version of a previously published health economic model (McMarcel) of RSV immunisation.

Results

Our data show higher disease incidence for infants younger than 6 months of age in the case of Kenya and South Africa than suggested by earlier projections from community incidence-based meta-analyses of LMIC data. Since MV and mAb provide protection for these youngest age groups, this leads to a substantially larger reduction of disease burden and therefore, more favourable cost-effectiveness of both interventions in both countries. Specifically, using published efficacy data, our mean estimate for reducing RSV-associated deaths in children under 5 years of age is 9% for MV and 28% for mAb in Kenya. In South Africa, the reduction is larger, with the mean estimate of 14% for MV and 48% for mAb.

In the case of the lowest dose prices (3 USD for MV and 6 USD for mAb), the healthcare system perspective ICERs per DALY averted drop to 144 USD (mAb) and 397 USD (MV) in Kenya, whereas it is net cost-saving from the perspective of the South African healthcare system. At the highest assumed dose prices of 30 USD for MV and 60 USD for mAb, the median estimates for the ICER are 4528 USD for MV and 2748 USD for mAb in Kenya, while in South Africa, it is 4694 USD for MV and 2566 USD for mAb.

Conclusion

Interventions against RSV disease may be more cost-effective than previously estimated following the incorporation of new data indicating that the disease burden is highly concentrated in the first 6 months of life in two African settings.
HexSE: Simulating evolution in overlapping reading frames
Authors: Muñoz-Baena Laura , Wade Kaitlyn E. , Poon Art F. Y.
Published: September 2022

Motivation

Gene overlap occurs when two or more genes are encoded by the same nucleotides. This phenomenon is found in all taxonomic domains, but is particularly common in viruses, where it may provide a mechanism to increase the information content of compact genomes. The presence of overlapping reading frames (OvRFs) can skew estimates of selection based on the rates of non-synonymous and synonymous substitutions, since a substitution that is synonymous in one reading frame may be non-synonymous in another, and vice versa.

Results

To understand the impact of OvRFs on molecular evolution, we implemented a versatile simulation model of nucleotide sequence evolution along a phylogeny with any distribution of open reading frames in linear or circular genomes. We use a custom data structure to track the substitution rates at every nucleotide site, which is determined by the stationary nucleotide frequencies, transition bias, and the distribution of selection biases (dN/dS) in the respective reading frames.

Availability and implementation

Our simulation model is implemented in the Python scripting language. All source code is released under the GNU General Public License (GPL) version 3, and is available at https://github.com/PoonLab/HexSE.
Molecular mechanism of substrate recognition by folate transporter SLC19A1
Authors: Dang Yu , Zhou Dong , Du Xiaojuan , Zhao Hongtu , Lee Chia-Hsueh , Yang Jing , Wang Yijie , Qin Changdong , Guo Zhenxi , Zhang Zhe
Published: September 2022

Folate (vitamin B9) is the coenzyme involved in one-carbon transfer biochemical reactions essential for cell survival and proliferation, with its inadequacy causing developmental defects or severe diseases. Notably, mammalian cells lack the ability tode novosynthesize folate but instead rely on its intake from extracellular sources via specific transporters or receptors, among which SLC19A1 is the ubiquitously expressed one in tissues. However, the mechanism of substrate recognition by SLC19A1 has been unclear. Here we report the cryo-EM structures of human SLC19A1 and its complex with 5-methyltetrahydrofolate at 3.5-3.6 Å resolution and elucidate the critical residues for substrate recognition. In particular, we reveal that two variant residues among SLC19 subfamily members would designate the specificity for folate. Moreover, we identify intracellular thiamine pyrophosphate as the favorite coupled substrate for folate transport by SLC19A1. Together, this work has established the molecular basis of substrate recognition by this central folate transporter.
Your turn, my turn. Neural synchrony in mother-infant proto-conversation
Authors: Nguyen Trinh , Zimmer Lucie , Hoehl Stefanie
Published: September 2022

Even before infants utter their first words, they engage in highly coordinated vocal exchanges with their caregivers. During these so-called proto-conversations, caregiver-infant dyads use a presumably universal communication structure - turn-taking, which has been linked to favourable developmental outcomes. However, little is known about potential mechanisms involved in early turn-taking. Previous research pointed to interpersonal synchronisation of brain activity between adults and preschool-aged children during turn-taking. Here, we assessed caregivers and infants at 4-6 months of age (N=55) during a face-to-face interaction. We used functional-near infrared spectroscopy hyperscanning to measure dyads’ brain activity and microcoded their turn-taking. We also measured infants’ inter-hemispheric connectivity as an index for brain maturity and later vocabulary size and attachment security as developmental outcomes potentially linked to turn-taking. The results showed that more frequent turn-taking was related to interpersonal neural synchrony, but the strength of the relation decreased over the course of the proto-conversation. Importantly, turn-taking was positively associated with infant brain maturity and later vocabulary size, but not with later attachment security. Taken together, these findings shed light on mechanisms facilitating preverbal turn-taking and stress the importance of emerging turn-taking for child brain and language development.
In-silico comparative modeling and interaction studies of PRSV proteins - Accelerated towards dissection of structure based evolutionary divergence and functional interaction of virus within the host
Authors: Saleem Anam , Ali Zahid , Naseem Saadia
Published: September 2022

Function based structure analysis of viral proteins reinforce their distinctive and unanticipated role within the host. The interaction dynamics of virus protein and host which is prerequisite for complete infectivity as well as systemic spread of invading virus demands to explore viral proteins in framework of their interacting partners. Papaya ringspot virus strain from Pakistan (PRSV-PK) spreading as atypical variant and causes drastic reduction in papaya production. The in-depth knowledge of the virus variant and effective management is obligatory. The desired objective is achievable once the evolutionary dynamics, molecular characterization and physicochemical structural properties conceived from the 3D protein structures are comprehended. Although the diversity studies on PRSV-PK strain been established but still there is a niche regarding structural based evolutionary dynamics of virus proteins and their probable interaction mode inside the host. The present investigations provided insights into the in-silico analysis of the functionally significant genes Coat protein (CP), Helper component proteinase (HC-Pro) and Nuclear Inclusion b protein (NIb) of PRSV-PK. The protein structure has been modeled using Phyre2, Swiss-Model and i-TASSER. Phyre2 built model showed 100% confidence for 67%, 63% and 20% sequence identity residues for PRSV CP, HC-Pro and NIb proteins respectively. The Swiss model showed identity values of 63.40%, 62.42% and 16.49% for CP, HC-Pro and NIb protein. whereas, i-TASSER server exhibited identity values of 67%, 63% and 19% for CP, HC-Pro and NIb proteins respectively. These structures provided a base line for functional analysis of experimentally derived crystal structures. The predicted models were validated using protein structure checking tools PROCHECK. Further the PRSV-PK-CP structures were compared with the PRSV-CP structures of representative isolates from different geographical regions. Nevertheless, the comparative modeling provides the insight into the evolutionary characteristics and proposed genetic diversity of PRSV based on protein structures. In addition, the conserved functional motifs have been mapped on aligned protein sequences of CP, HC-Pro and NIb, and their critical function within the host has been highlighted. Eventually, the interaction of papaya protein with the invading PRSV-CP has been predicted through in-silico protein-protein docking to elucidate their possible role in virus inhibition. The established structural-functional relation provided a basis to propose probable host-virus interactions in terms of virus infectivity, resultant host adaptability, and host defense response activation to counteract the virus invasion.
Human commensalCandida albicansstrains demonstrate substantial within-host diversity and retained pathogenic potential
Authors: Anderson Faith M , Visser Noelle , Amses Kevin , Hodgins-Davis Andrea , Weber Alexandra M , Metzner Katura M , McFadden Michael J , Mills Ryan E , O’Meara Matthew J , James Timothy Y , O’Meara Teresa R
Published: September 2022

Candida albicansis a frequent colonizer of human mucosal surfaces as well as an opportunistic pathogen.C. albicansis remarkably versatile in its ability to colonize diverse host sites with differences in oxygen and nutrient availability, pH, immune responses, and resident microbes, among other cues. It is unclear how the genetic background of a commensal colonizing population can influence the shift to pathogenicity. Therefore, we undertook an examination of commensal isolates from healthy donors with a goal of identifying site-specific phenotypic adaptation and genetic variation associated with these phenotypes. We demonstrate that healthy people are reservoirs for genotypically and phenotypically diverseC. albicansstrains, and that this genetic diversity includes both SNVs and structural rearrangements. Using limited diversity exploitation, we identified a single nucleotide change in the uncharacterizedZMS1transcription factor that was sufficient to drive hyper invasion into agar. However, our commensal strains retained the capacity to cause disease in systemic models of infection, including outcompeting the SC5314 reference strain during systemic competition assays. This study provides a global view of commensal strain variation and within-host strain diversity ofC. albicansand suggests that selection for commensalism in humans does not result in a fitness cost for invasive disease.
Mucosal vaccination for SARS-CoV-2 elicits superior systemic T central memory function and cross-neutralizing antibodies against variants of concern
Authors: O’Neill Aled , Kala Monica Palanichamy , Wah Tan Chee , Saron Wilfried A.A. , Mantri Chinmay Kumar , Rathore Abhay P.S. , Wang Lin-Fa , St. John Ashley L.
Published: September 2022

COVID-19 vaccines used in humans are highly effective in limiting disease and death caused by the SARS-CoV-2 virus, yet improved vaccines that provide greater protection at mucosal surfaces, which could reduce break-through infections and subsequent transmission, are still needed. Here we show that intranasal (I.N.) vaccination with the receptor binding domain of Spike antigen of SARS-CoV-2 (S-RBD) in combination with the mucosal adjuvant mastoparan-7 improved systemic T cell responses compared to an equivalent dose of antigen delivered by the sub-cutaneous (S.C.) route, adjuvanted by either M7 or the gold-standard adjuvant, alum. T cell phenotypes induced by I.N. vaccine administration included enhanced polyfunctionality (combined IFN-γ and TNF expression) and greater numbers of T central memory (TCM) cells. These phenotypes were T cell-intrinsic and could be recalled in the lungs and/or brachial LNs upon antigen challenge after adoptive T cell transfer to naïve recipients. Furthermore, mucosal vaccination induced antibody responses that were similarly effective in neutralizing the binding of the parental strain of S-RBD to its ACE2 receptor, but showed greater cross-neutralizing capacity against multiple variants of concern (VOC), compared to S.C. vaccination. These results highlight the role of nasal vaccine administration in imprinting an immune profile associated with long-term T cell retention and diversified neutralizing antibody responses, which could be applied to improve vaccines for COVID-19 and other infectious diseases.
Cellular stress modulates severity of the acute respiratory distress syndrome in COVID-19
Authors: Rico-Llanos Gustavo , Porras-Perales Óscar , Escalante Sandra , Vázquez Daniel , Valiente Lucía , Castillo María I. , Pérez-Tejeiro José Miguel , Baglietto-Vargas David , Becerra José , Reguera José María , Duran Ivan , Csukasi Fabiana
Published: September 2022

Inflammation is a central pathogenic feature of the acute respiratory distress syndrome (ARDS) in COVID-19. Previous pathologies such as diabetes, autoimmune or cardiovascular diseases become risk factors for the severe hyperinflammatory syndrome. A common feature among these risk factors is the subclinical presence of cellular stress, a finding that has gained attention after the discovery that BiP (GRP78), a master regulator of stress, participates in the SARS-CoV-2 recognition. Here, we show that BiP serum levels are higher in COVID-19 patients who present certain risk factors. Moreover, early during the infection, BiP levels predict severe pneumonia, supporting the use of BiP as a prognosis biomarker. Using a mouse model of pulmonary inflammation, we demonstrate that cell surface BiP (cs-BiP) responds by increasing its levels in leukocytes. Neutrophiles show the highest levels of cs-BiP and respond by increasing their population, whereas alveolar macrophages increase their levels of cs-BiP. The modulation of cellular stress with the use of a clinically approved drug, 4-PBA, resulted in the amelioration of the lung hyperinflammatory response, supporting the anti-stress therapy as a valid therapeutic strategy for patients developing ARDS. Finally, we identified stress-modulated proteins that shed light into the mechanism underlying the cellular stress-inflammation network in lungs.
Protein secretion zones within the Gram-positive cell wall
Authors: Strach Manuel , Koch Felicitas , Fiedler Svenja , Liebeton Klaus , Graumann Peter L.
Published: September 2022

Whereas the translocation of proteins across the cell membrane has been thoroughly investigated, it is still unclear how proteins cross the cell wall in Gram positive bacteria, which are widely used for industrial applications. We have studied secretion of α-amylase AmyE within two different Bacillus strains. We show that a C-terminal fusion of AmyE with the fluorescent reporter mCherry is secreted via discrete patches with very low dynamics that are visible at many places within the lateral cell wall, for many minutes. Expression from a high copy number plasmid was required to be able to see these structures we term “secretion zones”. Zones corresponded to visualized AmyE activity on the surface of cells, and frequently overlapped with SecA signals, but did not necessarily co-localize with the secretion ATPase. Single particle tracking showed much higher dynamics of SecA and of SecDF, involved in AmyE secretion, at the cell membrane than AmyE. These experiments suggest that SecA initially translocates AmyE molecules through the cell membrane, and then diffuses to a different translocon. Single molecule tracking of SecA show changes in distinct diffusion states of SecA, but suggest that AmyE overexpression does not overwhelm the system. Because secretion zones were only found during the transition to and within stationary phase, diffusion rather than passive transport based on cell wall growth from inside to outside, releases AmyE and thus probably secreted proteins in general. Our findings suggest active transport through the cell membrane and slow, passive transition through the cell wall in Gram positive bacteria.