bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiological causes and biogeographic consequences of thermal optima in the hypoxia tolerance of marine ectotherms
Authors: Endress Martin-Georg A. , Boag Thomas H. , Burford Benjamin P. , Penn Justin L. , Sperling Erik A. , Deutsch Curtis A.
Published: February 2022

The minimum O2 needed to fuel the demand of aquatic animals is commonly observed to increase with temperature, driven by accelerating metabolism. However, recent measurements of critical O2 thresholds (‘Pcrit’) reveal more complex patterns, including those with a minimum at an inter-mediate thermal ‘optimum’. To discern the prevalence, physiological drivers, and biogeographic manifestations of such curves, we analyze new experimental and biogeographic data using a general dynamic model of aquatic water breathers. The model simulates the transfer of oxygen from ambient water, through a boundary layer and into animal tissues driven by temperature-dependent rates of metabolism, diffusive gas exchange, and ventilatory and circulatory systems with O2-protein binding. We find that a thermal optimum in Pcrit can arise even when all physiological rates increase steadily with temperature. This occurs when O2 supply at low temperatures is limited by a process that is more temperature sensitive than metabolism, but becomes limited by a less sensitive process at warmer temperatures. Analysis of species respiratory traits suggests this scenario is not uncommon in marine biota, with ventilation and circulation limiting supply under cold conditions and diffusion limiting supply at high temperatures. Using biogeographic data, we show that species with these physiological traits inhabit lowest O2 waters near the optimal temperature for hypoxia tolerance, and are restricted to higher O2 at temperatures above and below this optimum. Our results imply that O2 tolerance can decline under both cold and warm conditions, and thus may influence both poleward and equatorward species range limits.

Significance Statement

Physiology shapes the ecology, biogeography, and climate responses of marine species. In aquatic ectotherms, accelerating metabolism and lowered oxygen availability generally result in increasing oxygen limitation with warming. Here we present evidence for thermal optima in hypoxia tolerance of diverse species that is explained by a dynamical model of organismal physiology. Our results indicate that this potentially widespread bidirectional pattern explains species biogeographic limits in cold and warm waters. It can be understood using a generalized Metabolic Index of O2 supply to demand, which captures the variable observed trends between temperature and species hypoxia sensitivity. Oxygen limitation of aerobic metabolism in cold water has far-reaching implications for marine biogeography and species migrations under climate change.
A scalable and unbiased discordance metric with H+
Authors: Dyjack Nathan , Baker Daniel N. , Braverman Vladimir , Langmead Ben , Hicks Stephanie C.
Published: February 2022

A standard unsupervised analysis is to cluster observations into discrete groups using a dissimilarity measure, such as Euclidean distance. If there does not exist a ground-truth label for each observation necessary for external validity metrics, then internal validity metrics, such as the tightness or consistency of the cluster, are often used. However, the interpretation of these internal metrics can be problematic when using different dissimilarity measures as they have different magnitudes and ranges of values that they span. To address this problem, previous work introduced the ‘scale-agnostic’ G+ discordance metric, however this internal metric is slow to calculate for large data. Furthermore, we show that G+ varies as a function of the proportion of observations in the predicted cluster labels (group balance), which is an undesirable property.

To address this problem, we propose a modification of G+, referred to as H+, and demonstrate that H+ does not vary as a function of group balance using a simulation study and with public single-cell RNA-sequencing data. Finally, we provide scalable approaches to estimate H+, which are available in the fasthplus R package.
Priority effects determine how dispersal affects biodiversity in seasonal metacommunities
Authors: Zou Heng-Xing , Rudolf Volker H. W.
Published: February 2022

The arrival order of species frequently determines the outcome of their interactions. This phenomenon, called the priority effect, is ubiquitous in nature and determines local community structure, but we know surprisingly little about how it influences biodiversity across different spatial scales. Here, we use a seasonal metacommunity model to show that biodiversity patterns and the homogenizing effect of high dispersal depend on the specific mechanisms underlying priority effects. When priority effects are only driven by positive frequency dependence, dispersal-diversity relationships are sensitive to initial conditions but generally show a hump-shaped relationship: biodiversity declines when dispersal rates become high and allow the dominant competitor to exclude other species across patches. When spatiotemporal variation in phenological differences alters species’ interaction strengths (trait-dependent priority effects), local, regional, and temporal diversity are surprisingly insensitive to variation in dispersal, regardless of the initial numeric advantage. Thus, trait-dependent priority effects can strongly reduce the effect of dispersal on biodiversity, preventing the homogenization of metacommunities. Our results suggest an alternative mechanism that maintains local and regional diversity without environmental heterogeneity, highlighting that accounting for the mechanisms underlying priority effects is fundamental to understanding patterns of biodiversity.
Developmental emergence of sleep rhythms enables long-term memory capabilities in Drosophila
Authors: Poe Amy R. , Zhu Lucy , McClanahan Patrick D. , Szuperak Milan , Anafi Ron C. , Thum Andreas S. , Cavanaugh Daniel J. , Kayser Matthew S.
Published: February 2022

In adulthood, sleep-wake rhythms are one of the most prominent behaviors under circadian control. However, during early life, sleep is spread across the 24-hour day (1–4). The mechanism through which sleep rhythms emerge, and the consequent advantage conferred to a juvenile animal, are unknown. In 2nd instar Drosophila larvae (L2), like human infants, sleep is not under circadian control (5). Here, we identify the precise developmental timepoint when the circadian clock begins to regulate sleep in Drosophila, leading to the emergence of sleep rhythms at the early 3rd instar stage (L3). At this stage, a cellular connection forms between DN1a clock neurons and arousalpromoting Dh44 neurons, bringing arousal under clock control to drive the emergence of circadian sleep. Finally, we demonstrate that L3 but not L2 larvae exhibit long-term memory (LTM) of an aversive cue, and that this LTM depends upon deep sleep generated once sleep rhythms begin. We propose that the developmental emergence of circadian sleep enables more complex cognitive processes, including the onset of enduring memories.
Spatial Organization of Neuron-Astrocyte Interactions in the Somatosensory Cortex
Authors: Baraibar Andrés M. , Belisle Lindsey , Marsicano Giovanni , Matute Carlos , Mato Susana , Araque Alfonso , Kofuji Paulo
Published: February 2022

Microcircuits in the neocortex are functionally organized along layers and columns, which are the fundamental modules of cortical information processing. While the function of cortical microcircuits has focused on neuronal elements, much less is known about the functional organization of astrocytes and their bidirectional interaction with neurons. Here we show that CB1R-mediated astrocyte activation by neuron-released endocannabinoids elevate astrocyte Ca2+ levels, stimulate ATP/adenosine release as gliotransmitters, and transiently depress synaptic transmission in layer 5 pyramidal neurons at relatively distant synapses (>20 µm) from the stimulated neuron. This astrocyte-mediated heteroneuronal synaptic depression occurred between pyramidal neurons within a cortical column and was absent in neurons belonging to adjacent cortical columns. Moreover, this form of heteroneuronal synaptic depression occurs between neurons located in particular layers, following a specific connectivity pattern that depends on a layer-specific neuron-to-astrocyte signaling. These results unravel the existence of astrocyte-mediated non-synaptic communication between cortical neurons, and that this communication is column- and layer-specific, which adds further complexity to the intercellular signaling processes in the cortex.
Monotreme-specific conserved proteins derived from retroviral reverse transcriptase
Authors: Kitao Koichi , Miyazawa Takayuki , Nakagawa So
Published: February 2022

Endogenous retroviruses (ERVs) have played an essential role in the evolution of mammals. Many ERV-derived genes are reported in the therians that are involved in placental development. However, the contribution of the ERV-derived genes in monotremes, which are oviparous mammals, remains to be uncovered. Here, we conducted a comprehensive search for possible ERV-derived genes in platypus and echidna genomes and identified three reverse transcriptase-like genes named RTOM1, 2, and 3. They were found to be clustered in the GRIP2 intron. Phylogenetic analysis revealed that RTOM1, 2, and 3 are strongly conserved between these species, and they were generated by tandem duplications before the divergence of platypus and echidna. The RTOM transcripts were specifically expressed in the testis, suggesting the physiological importance of RTOM genes. This is the first study reporting monotreme-specific de novo gene candidates derived from ERVs, which provides new insights into the unique evolution of monotremes.
Investigations into the emergent properties of gene-to-phenotype networks across cycles of selection: A case study of shoot branching in plants
Authors: Powell Owen M. , Barbier Francois , Voss-Fels Kai P. , Beveridge Christine , Cooper Mark
Published: February 2022

Predictive breeding is now widely practised in crop improvement programs and has accelerated selection response (i.e., the amount of genetic gain between breeding cycles) for complex traits. However, world food production needs to increase further to meet the demands of the growing human population. The prediction of complex traits with current methods can be inconsistent across different genetic, environmental, and agronomic management contexts because the complex relationships between genomic and phenotypic variation are not well accounted for. Therefore, developing gene-to-phenotype network models for traits that integrate the knowledge of networks from systems biology, plant and crop physiology with population genomics has been proposed to close this gap in predictive modelling. Here, we develop a gene-to-phenotype network for shoot branching, a critical developmental pathway underpinning harvestable yield for many crop species, as a case study to explore the value of developing gene-to-phenotype networks to enhance understanding of selection responses. We observed that genetic canalization is an emergent property of the complex interactions among shoot branching gene-to-phenotype network components, leading to the accumulation of cryptic genetic variation, reduced selection responses, and large variation in selection trajectories across populations. As genetic canalization is expected to be pervasive in traits, such as grain yield, that result from interactions among multiple genes, traits, environments, and agronomic management practices, the need to model traits in crop improvement programs as outcomes of gene-to-phenotype networks is highlighted as an emerging opportunity to advance our understanding of selection response and the efficiency of developing resilient crops for future climates.
Effective high-throughput RT-qPCR screening for SARS-CoV-2 infections in children
Authors: Dewald Felix , Suárez Isabelle , Johnen Ronja , Grossbach Jan , Moran-Tovar Roberto , Steger Gertrud , Joachim Alexander , Rubio Gibran Horemheb , Fries Mira , Behr Florian , Kley Joao , Lingnau Andreas , Kretschmer Alina , Gude Carina , Beazes-Flores Guadelupe , del Valle David Laveaga , Roblero-Hernandez Alberto , Magana-Cerino Jesus , Hernandez Adriana Torres , Ruiz-Quinones Jesus , Schega Konstantin , Linne Viktoria , Junker Lena , Wunsch Marie , Heger Eva , Knops Elena , Di Cristanziano Veronica , Meyer Meike , Hünseler Christoph , Weber Lutz T. , Lüers Jan-Christoffer , Quade Gustav , Wisplinghoff Hilmar , Tiemann Carsten , Zotz Rainer , Jomaa Hassan , Pranada Arthur , Herzum Ileana , Cullen Paul , Schmitz Franz-Josef , Philipsen Paul , Kirchner Georg , Knabbe Cornelius , Hellmich Martin , Buess Michael , Wolff Anna , Kossow Annelene , Niessen Johannes , Jeworutzki Sebastian , Schräpler Jörg-Peter , Lässig Michael , Dötsch Jörg , Fätkenheuer Gerd , Kaiser Rolf , Beyer Andreas , Rybniker Jan , Klein Florian
Published: February 2022

Systematic SARS-CoV-2 testing is a valuable tool for infection control and surveillance. However, broad application of high sensitive RT-qPCR testing in children is often hampered due to unpleasant sample collection, limited RT-qPCR capacities and high costs. Here, we developed a high-throughput approach (‘Lolli-Method’) for SARS-CoV-2 detection in children, combining non-invasive sample collection with an RT-qPCR-pool testing strategy. SARS-CoV-2 infections were diagnosed with sensitivities of 100% and 93.9% when viral loads were >106 copies/ml and >103 copies/ml in corresponding Naso-/Oropharyngeal-swabs, respectively. For effective application of the Lolli-Method in schools and daycare facilities, SEIR-modeling indicated a preferred frequency of two tests per week. The developed test strategy was implemented in 3,700 schools and 698 daycare facilities in Germany, screening over 800,000 individuals twice per week. In a period of 3 months, 6,364 pool-RT-qPCRs tested positive (0.64%), ranging from 0.05% to 2.61% per week. Notably, infections correlated with local SARS-CoV-2 incidences and with a school social deprivation index. Moreover, in comparison with the alpha variant, statistical modeling revealed a 36.8% increase for multiple (≥2 children) infections per class following infections with the delta variant. We conclude that the Lolli-Method is a powerful tool for SARS-CoV-2 surveillance and infection control in schools and daycare.
Measuring patient centeredness with German language Patient-Reported Experience Measures (PREM) – a systematic review and qualitative analysis according to COSMIN
Authors: Mihaljevic André L. , Dörr-Harim Colette , Kalkum Eva , Strunk Guido
Published: February 2022

Background

Patient centeredness is an integral part of the quality of care. Patient-reported experience measures (PREMs) are assumed to be an appropriate tool to assess patient-centredness. An evaluation of German-speaking PREMs is lacking.

Objective

To perform a systematic review and qualitative analysis of psychometric measurement qualities of German-speaking PREMs.

Methods

A systematic literature search was performed in Medline, PsycInfo, CINHAL, Embase, Cochrane database (last search 9th November 2021) for studies describing generic, surgery-or cancer-specific PREMs. Subsequently, questionnaires that were not in German or for which no German translation exists were excluded. Furthermore, questionnaires, that are for healthcare professionals rather than patients as well as disease-specific questionnaires were excluded. Baseline data for all studies was extracted by two independent reviewers. Psychometric measurement qualities of the questionnaires were assessed according to the COSMIN guidelines.

Results

In total, 3457 abstracts were screened, of which 3345 were excluded. The remaining 112 articles contained 51 PREMs, of which 12 were either developed in or translated into German: 8 generic (NORPEQ, PPE-15, PEACS, HCAHPS, QPPS, DUQUE, PEQ-G, Schoenfelder et al.), 4 cancer-specific (EORTC IN-PATSAT32, PSCC-G, Danish National Cancer Questionnaire, SCCC) and no surgery-specific PREM. None of the PREMs covered all 16 domains patient-centeredness. Overall rating of structural validity was adequate only for PEACS and HCAHPS. High ratings for internal consistency were given for NORPEQ, Schoenfelder et al., PSCC-G and the SCCC. Cross-cultural validity for translated questionnaires was adequate only for the PSCC-G, while reliability was adequately assessed only for the EORTC IN-PATSAT32. Due to a lack of measurement gold standard and minimal important change, criterion validity and measurement invariance could not be assessed Most PREMs showed the expected outcomes for hypotheses testing for construct validity.

Conclusion

None of the PREMs has been fully evaluated in German. Based on current evidence, the EORTC IN-PATSAT32 and PSCC-G can be recommended for cancer patients, while HCAHPS, NORPEQ, PPE-15 and PEACS might be used as generic PREMs. Compared to other languages PREM development in German is rudimentary and no comprehensive PREM system is currently available.

Registration

PROSPERO CRD42021276827

Funding

None
Profiling of humoral immune responses to norovirus in children across Europe
Authors: Villabruna Nele , Izquierdo-Lara Ray , Schapendonk Claudia M.E. , de Bruin Erwin , Chandler Felicity , Thao Tran Thi Nhu , Westerhuis Brenda M. , van Beek Janko , Sigfrid Louise , Giaquinto Carlo , Goossens Herman , Bielicki Julia A. , Vasconcelos Malte Kohns , Fraaij Pieter L.A. , Koopmans Marion P.G. , de Graaf Miranda
Published: February 2022

Human noroviruses are a major cause of gastroenteritis outbreaks worldwide. The majority of outbreaks and sporadic cases are caused by norovirus genotype GII.4 but 48 capsid genotypes and 60 polymerase genotypes (P-types) have been described, some of which are frequently reported while others are rarely detected. Little is known about the circulation and reservoirs of the less common genotypes. In this study, we have investigated whether children could pose a possible reservoir for undetected circulation of norovirus diversity. We, therefore, tested IgG and IgA responses of sera obtained from 287 children aged <1-month to 5.5-years on a protein microarray against P particles representing 30 norovirus GI and GII genotypes. We further profiled immune responses against the P-type by assessing antigenicity and seroprevalence of the non-structural proteins. The overall seroprevalence was 95.3% in children up to six months old (maternal antibodies), followed by a decrease to 59.6% up to 12 months, and an increase to 84.7% by the age of 5.5 years. We detected antibody responses against all tested genotypes, with the most specific IgG and IgA responses directed against the GII.2, GII.3, GII.4, and GII.6 capsid genotypes, which are the most frequently reported noroviruses in outbreaks. We also detected antibodies against the non-structural proteins p48 and p22 in sera of older children, predominantly against GII genotypes.

While we found no evidence to suggest that rarely detected genotypes widely circulate in children, this is the first study to investigate seroprevalence against such a wide variety of human norovirus capsid and polymerase genotypes.

Importance

Norovirus is a leading cause of epidemic acute gastroenteritis, causing severe disease in children, the elderly, and immunocompromised individuals. Although norovirus is a diverse genus of viruses, the majority of reported cases are caused by viruses of the GII.4 genotype. Many of the genotypes are rarely detected and it is unknown where they circulate between outbreaks. Here we investigated the possibility of children posing a reservoir for undetected circulation. While previous serological studies have tested antibodies against a limited set of capsid genotypes, we profiled the antibody repertoire of children against the capsid and the non-structural proteins, representing the known diversity of human noroviruses. While we detected high seroprevalence in children older than one year, we found no evidence to suggest a wide circulation of rare genotypes in children in Europe.
Appropriately smoothing prevalence data to inform estimates of growth rate and reproduction number
Authors: Eales Oliver , Ainslie Kylie E. C. , Walters Caroline E. , Wang Haowei , Atchison Christina , Ashby Deborah , Donnelly Christl A. , Cooke Graham , Barclay Wendy , Ward Helen , Darzi Ara , Elliott Paul , Riley Steven
Published: February 2022

The time-varying reproduction number (Rt) can change rapidly over the course of a pandemic due to changing restrictions, behaviours, and levels of population immunity. Many methods exist that allow the estimation of Rt from case data. However, these are not easily adapted to point prevalence data nor can they infer Rt across periods of missing data. We developed a Bayesian P-spline model suitable for fitting to a wide range of epidemic time-series, including point-prevalence data. We demonstrate the utility of the model by fitting to periodic daily SARS-CoV-2 swab-positivity data in England from the first 7 rounds (May 2020 – December 2020) of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Estimates of Rt over the period of two subsequent rounds (6-8 weeks) and single rounds (2-3 weeks) inferred using the Bayesian P-spline model were broadly consistent with estimates from a simple exponential model, with overlapping credible intervals. However, there were sometimes substantial differences in point estimates. The Bayesian P-spline model was further able to infer changes in Rt over shorter periods tracking a temporary increase above one during late-May 2020, a gradual increase in Rt over the summer of 2020 as restrictions were eased, and a reduction in Rt during England’ s second national lockdown followed by an increase as the Alpha variant surged. The model is robust against both under-fitting and over-fitting and is able to interpolate between periods of available data; it is a particularly versatile model when growth rate can change over small timescales, as in the current SARS-CoV-2 pandemic. This work highlights the importance of pairing robust methods with representative samples to track pandemics.
The Simple One-step stool processing method for detection of Pulmonary tuberculosis: a study protocol to assess the robustness, stool storage conditions and sampling strategy for global implementation and scale-up
Authors: de Haas Petra , Yenew Bazezew , Diriba Getu , Amare Misikir , Slyzkyi Andrii , Demissie Yohannes , Sherefdin Bihil , Bedru Ahmed , Mengesha Endale , Dememew Zewdu Gashu , Kebede Abebaw , Getahun Muluwork , Tiemersma Edine , Jerene Degu
Published: February 2022

Background

Xpert MTB/RIF Ultra (Xpert-Ultra) provides timely results with good sensitivity and acceptable specificity with stool samples in children for bacteriological confirmation of tuberculosis (TB). This study aims to optimize the Simple One-Step (SOS) stool processing method for testing stool samples using the Xpert-Ultra in children and adults in selected health facilities in Addis Ababa, Ethiopia. The study is designed to assess the robustness of the SOS stool method, to help fine-tune the practical aspects of performing the test and to provide insights in stool storage conditions and sampling strategies before the method can be implemented and scaled in routine settings in Ethiopia as well as globally.

Methods and design

The project “painless optimized diagnosis of TB in Ethiopian children” (PODTEC) will be a cross sectional study where three key experiments will be carried out focusing on 1) sampling strategy to investigate if the Xpert-UltraM.tuberculosis(MTB) -positivity rate depends on stool consistency, and if sensitivity can be increased by taking more than one stool sample from the same participant, or doing multiple tests from the same stool sample, 2) storage conditions to determine how long and at what temperature stool can be stored without losing sensitivity, and 3) optimization of sensitivity and robustness of the SOS stool processing method by varying sample processing steps, stool volume, and sampling from the stool-sample reagent mixture.

Stool samples will be collected from participants (children and adults) who are either sputum or naso-gastric aspiration (NGA) and/or stool Xpert-Ultra MTB positive depending on the experiment. Stool samples from these participants, recruited from 22 sites for an ongoing related study, will be utilized for the PODTEC experiments. The sample size is estimated will be 50 participants.

We will use EpiData for data entry and Stata for data analysis purposes. The main analyses will include computing the loss or gain in the Xpert-Ultra MTB positivity rate, and rates of unsuccessful test results. The differences in the positivity rate regarding testing more than one sample per child, different storage, and processing conditions, will be compared to the baseline (on-site) Xpert-Ultra result.

Ethics and dissemination

The protocol was reviewed and approved by the Ethical Review Board of the Ethiopian Public Health Institute (EPHI-IRB) (Protocol no EPHI-IRB-234-2020). The study results will be shared with the national TB program and stakeholders to the benefit of further roll out of the test in a routine Ethiopian setting. The results will also be disseminated in peer-reviewed scientific journals.
Establishing a marine monitoring programme to assess antibiotic resistance: a case study from the Gulf Cooperation Council (GCC) region
Authors: Light Edel , Baker-Austin Craig , Card Roderick M. , Ryder David , Alves Mickael Teixeira , Al-Sarawi Hanan A. , Abdulla Khalil Hasan , Stahl Henrik , AL-Ghabshi Aliya , Ghoribi Majed Al , Balkhy Hanan H. , Joseph Andrew , Hughes Alexandra , Verner-Jeffreys David W. , Lyons Brett P. , Le Quesne Will J.F.
Published: February 2022

The World Health Organization considers antimicrobial resistance as one of the most pressing global issues which poses a fundamental threat to human health, development, and security. Due to demographic and environmental factors, the marine environment of the Gulf Cooperation Council (GCC) region may be particularly susceptible to the threat of antimicrobial resistance. However, there is currently little information on the presence of AMR in the GCC marine environment to inform the design of appropriate targeted surveillance activities. The objective of this study was to develop, implement and conduct a rapid regional baseline monitoring survey of the presence of AMR in the GCC marine environment, through the analysis of seawater collected from high-risk areas across four GCC states: (Bahrain, Oman, Kuwait, and the United Arab Emirates). 560 Escherichia coli strains were analysed as part of this monitoring programme between December 2018 and May 2019. Multi-drug resistance (resistance to three or more structural classes of antimicrobials) was observed in 32.5% of tested isolates. High levels of reduced susceptibility to ampicillin (29.6%), nalidixic acid (27.9%), tetracycline (27.5%), sulfamethoxazole (22.5%) and trimethoprim (22.5%) were observed. Reduced susceptibility to the high priority critically important antimicrobials: azithromycin (9.3%), ceftazidime (12.7%), cefotaxime (12.7%), ciprofloxacin (44.6%), gentamicin (2.7%) and tigecycline (0.5%), was also noted. A subset of 173 isolates was whole genome sequenced, and high carriage rates of qnrS1 (60/173) and blaCTX-M-15 (45/173) were observed, correlating with reduced susceptibility to the fluoroquinolones and third generation cephalosporins, respectively. This study is important because of the resistance patterns observed, the demonstrated utility in applying genomic-based approaches to routine microbiological monitoring, and the overall establishment of a transnational AMR surveillance framework focussed on coastal and marine environments.
Minimizing school disruption under high incidence conditions due to the Omicron variant in early 2022
Authors: Colosi Elisabetta , Bassignana Giulia , Barrat Alain , Lina Bruno , Vanhems Philippe , Bielicki Julia , Colizza Vittoria
Published: February 2022

As record cases due to the Omicron variant are currently registered in Europe, schools remain a vulnerable setting suffering large disruption. Extending previous modeling of SARS-CoV-2 transmission in schools in France, we estimate that at high incidence rates reactive screening protocols (as currently applied in France) require comparable test resources as weekly screening (as currently applied in some Swiss cantons), for considerably lower control. Our findings can be used to define incidence levels triggering school protocols and optimizing their cost-effectiveness.
From Volume to Value: Comparative value, quality, and cost between three treatment modalities for early childhood caries
Authors: Okuji David , Jivraj Ashiana , Wu Yinxiang
Published: February 2022

Context

In recent decades there has been a shift from a reimbursement system based upon treatment “volume” to “value.”

Aims

To compare value, quality, and cost of three treatment modalities for early childhood caries: surgical care with and without general anesthesia, and non-surgical care with disease management.

Settings and Design

Through an analytical, observational, cross-sectional design, data was collected from 487 pediatric subjects treated at health centers in seven states. Nearly 95% of the subjects were beneficiaries of the United States government Medicaid health insurance program, which supports families with low socioeconomic status.

Methods and Material

Quality was measured with a Parental-Reported Symptom and Service Quality questionnaire, adapted from the validated Early Child Oral Health Impact Scale, Child-Oral Impacts on Daily Performance, and Dental Consumer Assessments of Healthcare Providers and Systems surveys. Cost was measured by the labor cost for clinicians and adjusted by total relative value units for all treatment procedures. Value was calculated as the quotient of the weighted quality score and the adjusted cost, multiplied by a coefficient.

Statistical Analysis

Value comparisons were analyzed using chi-square, ANOVA, and likelihood ratio tests.

Results

Children treated with non-surgical, disease management had significantly higher parental-perceived quality, lower cost, and higher value when compared to the two surgical treatment modalities.

Conclusions

Dentists should consider that non-surgical treatment yields higher “value” than surgical treatments for the management of early childhood caries. Payers and consumers would benefit by comparing treatment “value” when choosing institutions and providers for the management of early childhood caries.
Tissue specific dual RNA-seq defines host-parasite interplay in murine visceral leishmaniasis caused by Leishmania donovani and Leishmania infantum
Authors: Forrester Sarah , Goundry Amy , Dias Bruna Torres , Leal-Calvo Thyago , Moraes Milton Ozório , Kaye Paul M. , Mottram Jeremy C. , Lima Ana Paula C. A.
Published: February 2022

Visceral leishmaniasis is associated with hepato-splenomegaly and altered immune and haematological parameters in both pre-clinical animal models and humans. We studied mouse experimental visceral leishmaniasis caused by Leishmania infantum and Leishmania donovani in BALB/c mice using dual RNA-seq to investigate the transcriptional response of host and parasite in liver and spleen. We identified only 4 species-specific parasite expressed genes (SSPEGs; log2FC >1, FDR <0.05) in the infected spleen, and none in the infected liver. For the host transcriptome, we found 789 differentially expressed genes (DEGs; log2FC >1, FDR <0.05) in the spleen that were common to both infections, with IFNγ signaling and complement and coagulation cascade pathways highly enriched, and an additional 286 and 186 DEGs that were selective to L. donovani and L. infantum infection respectively. Among those, there were network interactions between genes of amino acid metabolism and PPAR signaling in L. donovani infection and increased IL1β and positive regulation of fatty acid transport in L. infantum infection, although no pathway enrichment was observed. In the liver, there were 1939 DEGs in mice infected with either L. infantum or L. donovani in comparison to uninfected mice, and the most enriched pathways were IFNγ signaling, neutrophil mediated immunity, complement and coagulation, cytokine-chemokine responses and hemostasis. Additionally, 221 DEGs were selective in L. donovani and 429 DEGs in L. infantum infections. These data show that the host response for these two visceral leishmaniasis infection models is broadly similar, and ∼10% of host DEGs vary in infections with either parasite species.

Importance

Visceral leishmaniasis (VL) is caused by two species of Leishmania parasites, L. donovani in the Old World and L. infantum in the New World and countries bordering the Mediterranean. Although cardinal features such as hepato-splenomegaly and alterations in blood and immune function are evident, clinical presentation may vary by geography, with for example severe bleeding often associated with VL in Brazil. Although animal models of both L. donovani and L. infantum have been widely used to study disease pathogenesis, a direct side-by-side comparison of how these parasites species impact the infected host and/or how they might respond to the stresses of mammalian infection has not been previously reported. Identifying common and distinct pathways to pathogenesis will be important to ensure that new therapeutic or prophylactic approaches will be applicable across all forms of VL.
Regulation of mannitol metabolism inEnterococcus faecalisand association withparEF0409toxin-antitoxin locus function
Authors: Anbalagan Srivishnupriya , Sadlon Jessie , Weaver Keith
Published: February 2022

TheparEF0409type I toxin-antitoxin locus is situated between genes for two paralogous mannitol-family phosphoenolpyruvate phosphotransferase systems (PTS). In order to address the possibility thatparEF0409function was associated with sugar metabolism, genetic and phenotypic analyses were performed on the flanking genes. It was found that the genes were transcribed as two operons; the downstream operon essential for mannitol transport and metabolism and the upstream operon performing a regulatory function. In addition to genes for the PTS components, the upstream operon encodes a gene similar tomtlR, the key regulator of mannitol metabolism in other Gram-positive bacteria. We confirmed that this gene is essential for regulation of the downstream operon and identified putative phosphorylation sites required for carbon catabolite repression and mannitol-specific regulation. Genomic comparisons revealed that this dual operon organization of mannitol utilization genes is uncommon in enterococci and that association with a toxin-antitoxin system is unique toE. faecalis. Finally, we consider possible links betweenparEF0409function and mannitol utilization.

Importance

Enterococcus faecalisis both a common member of the human gut microbiota and an opportunistic pathogen. Its evolutionary success is partially due to its metabolic flexibility: in particular, its ability to import and metabolize a wide variety of sugars. While a large number of phosphoenolpyruvate phosphotransferase sugar transport systems have been identified in theE. faecalisgenome bioinformatically, the specificity and regulation of most of these systems remains undetermined. Here we characterize a complex system of two operons flanking a type I toxin-antitoxin system required for the transport and metabolism of the common dietary sugar mannitol. We also determine the phylogenetic distribution of mannitol utilization genes in the enterococcal genus and discuss the significance of association with toxin-antitoxin systems.
Wastewater Surveillance of U.S. Coast Guard Installations and Seagoing Military Vessels to Mitigate the Risk of COVID-19 Outbreaks
Authors: Hall Gregory J. , Page Eric J. , Rhee Min , Hay Clara , Krause Amelia , Langenbacher Emma , Ruth Allison , Grenier Steve , Duran Alexander P. , Kamara Ibrahim , Iskander John K. , Thomas Dana L. , Bock Edward , Porta Nicholas , Pharo Jessica , Osterink Beth A. , Zelmanowitz Sharon , Fleischmann Corinna M. , Liyanage Dilhara , Gray Joshua P.
Published: February 2022

Military training centers may be high risk environments for the spread of disease such as COVID-19. Individuals arrive after traveling from many parts of the country, live in communal settings, and undergo high-interaction training. A pilot study of wastewater testing was initiated in February, 2021 to determine its feasibility as a sentinel surveillance tool in the U.S. Coast Guard for SARS-CoV-2. Wastewater was analyzed for the presence of two viral genes, N and E, and quantified relative to levels of a fecal indicator virus, Pepper Mild Mottle Virus (PMMoV). A stability control, Bovine Syncytial Respiratory Virus vaccine, was added to samples to assess sample stability and degradation. Wastewater data was validated by comparison with concomitant screening and surveillance programs that identified asymptomatic individuals infected with SARS-CoV-2 by diagnostic testing at on site medical clinics using PCR. Elevated levels of SARS-CoV-2 in wastewater were frequently associated with diagnosed cases, and in several instances, led to screenings of asymptomatic individuals that identified infected personnel, mitigating the risk of spread of disease. Wastewater screening also successfully indicated the presence of breakthrough cases in vaccinated individuals. A method for assessing blackwater from Coast Guard vessels was also developed, allowing detection of SARS-CoV-2 virus in shipboard populations. In one instance, virus was detected in the blackwater four weeks following the diagnosis of a single person on a Coast Guard cutter. These data show that wastewater testing is an effective tool for measuring the presence and prevalence of SARS-CoV-2 in military populations so that mitigation can occur and suggest other diseases may be assessed similarly. As a result, the Coast Guard has established three laboratories with wastewater testing capability at strategic locations and is actively continuing its wastewater testing program.
Rtt105 configurationally staples RPA and blocks facilitated exchange and interactions with RPA-interacting proteins
Authors: Kuppa Sahiti , Deveryshetty Jaigeeth , Chadda Rahul , Mattice Jenna , Pokhrel Nilisha , Kaushik Vikas , Patterson Angela , Dhingra Nalini , Pangeni Sushil , Sadauskas Marisa K. , Shiekh Sajad , Balci Hamza , Ha Taekjip , Zhao Xiaolan , Bothner Brian , Antony Edwin
Published: February 2022

Replication Protein A (RPA) binds to single-stranded DNA (ssDNA) and recruits over three dozen RPA-interacting proteins (RIPs) to coordinate multiple aspects of DNA metabolism including DNA replication, repair, and recombination. Rtt105 is a molecular chaperone that regulates nuclear localization of RPA. Whether and how Rtt105 regulates the activities of RPA is poorly understood. Here, we show that Rtt105 binds to multiple DNA binding and protein-interaction domains of RPA and configurationally staples the complex. In the absence of ssDNA, Rtt105 inhibits RPA binding to Rad52, thus preventing spurious binding to RPA-interacting proteins (RIPs). When ssDNA is available, Rtt105 promotes formation of high-density RPA nucleoprotein filaments and dissociates during this process. Free Rtt105 further stabilizes the RPA-ssDNA filaments by inhibiting RPA facilitated exchange. Collectively, our data suggest that Rtt105 sequesters free RPA in the nucleus to prevent untimely RIP interaction, while stabilizing RPA-ssDNA filaments at DNA lesion sites.
Profiling Unbinding Events to Identify Near-Native RNA-Ligand Poses
Authors: Liu Yichen , Frank Aaron T.
Published: February 2022

Predicting the structure (or pose) of RNA-ligand complexes is an important problem in RNA structural biology and drug discovery. Although one could use molecular docking procedures to rapidly sample putative poses of RNA-ligand complexes, accurately dis-criminating the native-like poses from non-native, decoy structures remains a formidable challenge. Here, we started from the assumption that native-like RNA-ligand poses are less likely to dissociate during molecular dynamics simulations, and then we used enhanced simulations to promote ligand for diverse poses of a handful of RNA-ligand complexes. By fitting unbinding profiles obtained from the simulations to a single-exponential, we identified the characteristic decay time (τ) as particularly effective at resolving native poses from decoys. Remarkably, a simple regression model trained to predict the simulation-derived parameters directly from structure could also discriminate poses. As such, when molecular dynamics simulations are feasible, one could use them to simulate ligand unbinding to aid in the identification of near-native poses. On the other hand, when speed is more important, one could use a simple structure-based regression model, like the ones described in this study, to analyze and filter RNA-ligand poses.
The conserved Pelado/ZSWIM8 protein regulates actin dynamics by promoting linear actin filament polymerization
Authors: Pelayo Claudia Molina , Olguin Patricio , Mlodzik Marek , Glavic Alvaro
Published: February 2022

Actin filament polymerization can be branched or linear, which depends on the associated regulatory proteins. Competition for Actin monomers occurs between proteins that induce branched or linear actin polymerization. Cell specialization requires the regulation of actin filaments to allow the formation of cell-type specific structures, like cuticular hairs inDrosophila, formed by linear actin filaments. Here, we report the functional analysis of CG34401/pelado, a gene encoding a SWIM domain containing protein, conserved throughout the animal kingdom. Mutantpeladoepithelial cells display actin hair elongation defects. This phenotype is reversed by increasing Actin monomer levels or by either pushing linear actin polymerization or reducing branched actin polymerization. The same behavior occurs in hemocytes, where Pelado is essential to induce filopodia, a linear actin-based structure. We further show that this function of Pelado, ZSWIM8 in mammals, is conserved in human cells, where Pelado inhibits branched actin polymerization in a cell migration context. In summary, our data indicate that the function of Pelado/ZSWIM8 in regulating actin cytoskeletal dynamics is conserved, favoring linear actin polymerization at the expense of branched filaments.
IS SHORT-TERM ACYCLOVIR TREATMENT RELATED WITH MORE UNFAVOURABLE OUTCOMES IN PATIENTS WITH HSV-1 ENCEPHALITIS?
Authors: Arslan Ferhat , Akgündüz Ravza , Ermiş Abdülkadir , Bektaş Begüm , Erbayat Ebru , Vahaboğlu Haluk
Published: February 2022

Background

Herpes simplex encephalitis (HSE) is the most common form of sporadic encephalitis which is caused by herpes simplex virus type 1 (HSV-1). Current guidelines recommend intravenous Acyclovir for 14–21 days in cases of HSE.

Objectives

Optimizing the Acyclovir treatment duration is important in regards to preventing Acyclovir-related neurotoxicity and nephrotoxicity.

Study design

We retrospectively evaluated 13 patients, who were diagnosed with HSE by molecular testing (HSV-1 PCR positivity in cerebrospinal fluid), in two university hospitals in Istanbul, between 2010 and 2021. The patients were treated either 10 days or less as a short-term treatment regimen of Acyclovir or for 14 days or more as long-term treatment regimen

Results

The median age was 58 years (range 24–82 years) and 54% of them were male. The median follow-up time was 79 days (range 20-670 days) after discharge. Long-term treatment was used in 6 and a short-term treatment regimen was used in 7 cases. One of the patients died on the 4th day of Acyclovir treatment. One patient never received Acyclovir treatment. Of the 5 patients who received long-term treatment, 3 (21-28 days) had amnesia and orientation-cooperation restriction, one (21 days) died on the 2nd day of treatment, while the other (14 days) had no sequelae. There were no sequelae in three out of 5 patients who received short-term treatment.

Conclusions

We believe that it is necessary to determine the optimal Acyclovir therapy duration should be evaluated in a prospective randomized clinical trial in large patient population.
A phasevarion controls multiple virulence traits, including expression of vaccine candidates, in Streptococcus pneumoniae
Authors: Phillips Zachary N. , Trappetti Claudia , Van Den Bergh Annelies , Martin Gael , Calcutt Ainslie , Ozberk Victoria , Guillon Patrice , Pandey Manisha , von Itzstein Mark , Swords W. Edward , Paton James C. , Jennings Michael P. , Atack John M.
Published: February 2022

Streptococcus pneumoniae is the most common cause of bacterial illness worldwide. Current vaccines based on the polysaccharide capsule (PCV-13 and PPSV-23) are only effective against a limited number of the >100 capsular serotypes. A universal vaccine based on conserved protein antigens requires a thorough understanding of gene expression in S. pneumoniae. Restriction-Modification (R-M) systems, classically described as a defence against bacteriophage, are almost ubiquitous in the bacterial domain, and roles other than phage defence. All S. pneumoniae strains encode the SpnIII R-M system. This system contains a phase-variable methyltransferase that randomly switches specificity, and controls expression of multiple genes; a phasevarion. We aimed to determine the role of the SpnIII phasevarion during pneumococcal pathobiology and determine if phase-variation resulted in differences in expression of protein antigens that are being investigated as vaccine candidates. Using ‘locked’ S. pneumoniae strains that express a single SpnIII methyltransferase specificity, we found significant differences in clinically relevant traits, including survival in blood, and adherence to and invasion of human cells. Crucially, we also observed differences in expression of numerous proteinaceous vaccine candidates, which complicates selection of protein antigens for inclusion in a universal protein-based pneumococcal vaccine. This study will inform future vaccine design against S. pneumoniae by ensuring only stably expressed candidates are included in a rationally designed vaccine.

Significance Statement

S. pneumoniae is the world’s foremost bacterial pathogen. S. pneumoniae encodes a randomly expressed epigenetic regulator, a phasevarion (phase-variable regulon), that results in random expression of multiple genes. Previous work demonstrated that the pneumococcal SpnIII phasevarion switches between six different expression states, generating six unique phenotypic variants in a pneumococcal population. Here, we show that this phasevarion generates multiple phenotypic differences relevant to pathobiology. Importantly, expression of conserved protein antigens varies with phasevarion switching. As capsule expression, a major pneumococcal virulence factor, is also controlled by the phasevarion, our work will inform the selection of the best candidates to include in a rationally designed, universal pneumococcal vaccine.