bluuebunny/crossref_metadata_2025 huggingface dataset:
Adolescent Development of Biological Rhythms: Estradiol Dependence and Effects of Combined Contraceptives
Authors: Grant Azure D. , Wilbrecht Linda , Kriegsfeld Lance J.
Published: July 2021

Purpose

Adolescence is a period of continuous development, including the maturation of endogenous rhythms across systems and timescales. Although these dynamic changes are well recognized, their continuous structure and hormonal dependence have not been systematically characterized. Given the well-established link between core body temperature (CBT) and reproductive hormones in adults, we hypothesized that high-resolution CBT can be applied to passively monitor pubertal development and disruption with high fidelity.

Methods

To examine this possibility, we used signal processing to investigate the trajectory of CBT rhythms at the within-day (ultradian), daily (circadian), and ovulatory timescales, their dependence on estradiol, and the effects of hormonal contraceptives.

Results

Puberty onset was marked by a rise in fecal estradiol (fE2), followed by an elevation in CBT and circadian power. This time period marked the commencement of 4-day rhythmicity in fE2, CBT, and ultradian power marking the onset of the estrous cycle. The rise in circadian amplitude was accelerated by E2 treatment, indicating a role for this hormone in rhythmic development. Contraceptive administration in later adolescence reduced CBT and circadian power and resulted in disruption to 4-day cycles that persisted after discontinuation.

Conclusions

Our data reveal with precise temporal resolution how biological rhythms change across adolescence and demonstrate a role for E2 in the emergence and preservation of multiscale rhythmicity. These findings also demonstrate how hormones delivered exogenously in a non-rhythmic pattern can disrupt rhythmic development. These data lay the groundwork for a future in which temperature metrics provide an inexpensive, convenient method for monitoring pubertal maturation and support the development of hormone therapies that better mimic and support human chronobiology.
A model of actin-driven endocytosis explains differences of endocytic motility in budding and fission yeast
Authors: Nickaeen Masoud , Berro Julien , Pollard Thomas D. , Slepchenko Boris M.
Published: July 2021

A comparative study (Sun et al., eLife, 2019) showed that the abundance of proteins at sites of endocytosis in fission and budding yeast is more similar in the two species than previously thought, yet membrane invaginations in fission yeast elongate two-fold faster and are nearly twice as long as in budding yeast. Here we use a three-dimensional model of a motile endocytic invagination (Nickaeen et al., MBoC, 2019) to investigate factors affecting elongation of the invaginations. We found that differences in turgor pressure in the two yeast species can largely explain the paradoxical differences observed experimentally in endocytic motility.
Defining the prototypical DNA replication fork trap in bacteria
Authors: Toft Casey J. , Moreau Morgane J. J. , Perutka Jiri , Mandapati Savitri , Enyeart Peter , Sorenson Alanna E. , Ellington Andrew D. , Schaeffer Patrick M.
Published: July 2021

InEscherichia coli, DNA replication termination is orchestrated by two clusters ofTersites forming a DNA replication fork trap when bound by Tus proteins. The formation of a ‘locked’ Tus-Tercomplex is essential for halting incoming DNA replication forks. However, the absence of replication fork arrest at someTersites raised questions about their significance. In this study, we examined the genome-wide distribution of Tus and found that only the six innermostTersites (TerA-EandG) were significantly bound by Tus. We also found that a single ectopic insertion ofTerBin its non-permissive orientation could not be achieved, advocating against a need for ‘back-up’Tersites. Finally, examination of the genomes of a variety of Enterobacterales revealed a new replication fork trap architecture exclusively found outside the Enterobacteriaceae family. Taken together, our data enabled the delineation of a narrow prototypical Tus-dependent DNA replication fork trap consisting of only twoTersites.

Graphical Abstract
SGLT2-Inhibition reverts urinary peptide changes associated with severe COVID-19: anin-silicoproof-of-principle of proteomics-based drug repurposing
Authors: Latosinska Agnieszka , Siwy Justyna , Cherney David Z. , Perkins Bruce A. , Mischak Harald , Beige Joachim
Published: July 2021

Severe COVID-19 is reflected by significant changes in multiple urine peptides. Based on this observation, a clinical test based on urinary peptides predicting COVID-19 severity, CoV50, was developed and registered as IVD in Germany. We have hypothesized that molecular changes displayed by CoV50, to a large degree likely reflective of endothelial damage, can be significantly reversed by specific drugs. To test this hypothesis, we have collected urinary peptide data from patients without COVID-19 prior and after drug treatment. The drugs chosen were selected based on availability of sufficient number of participants in the dataset (n>20) and potential value of drug therapies in the treatment of COVID-19 based on reports in the literature. In these participants without COVID-19, while spironolactone did not demonstrate a significant impact on CoV50 scoring, empagliflozin treatment resulted in a significant change in CoV50 scoring, indicative of a potential therapeutic benefit. The results serve as a proof-of-principle for a drug repurposing approach based on human urinary peptide signatures and support the initiation of a randomised control trial testing a potential positive effect of empagliflozin in the treatment of severe COVID-19, possibly via endothelial protective mechanisms.

Significance of the study

COVID-19 pandemic has imposed a heavy burden on society, health care and economics. Although multiple drugs have been tested in the context of COVID-19, effective treatments for patients experiencing severe disease are still missing, with some drugs demonstrating benefit only at earlier disease stage. Computational drug repurposing emerged as a promising approach to boost drug development, allowing to predict drug efficacy based on the molecular signature of drug impact, mainly using transcriptomics data from cell lines.

Recently we demonstrated that urinary proteomics profiles significantly differ between patients with severe COVID-19 course and those with mild/ moderate disease. This resulted in the development of a molecular signature associated with COVID-19 severity (CoV50), allowing to predict COVID-19 course, and enabling guiding intervention.

Here we report on the first study demonstrating the application of clinical proteomics data (from clinical trial participants) in a drug repurposing approach. We used the CoV50 signature to examine if the molecular changes associated with COVID-19 severity in patients without COVID-19 might be altered by existing drugs. In a study population without COVID-19, empagliflozin demonstrated a partial, yet significant reversion of the CoV50 signature, indicating a potential benefit in the context of severe COVID-19.
Spread of infection and treatment interruption among Japanese workers during the COVID-19 pandemic: a cross-sectional study
Authors: Akashi Jun , Hino Ayako , Tateishi Seiichiro , Nagata Tomohisa , Tsuji Mayumi , Ogami Akira , Matsuda Shinya , Kataoka Masaharu , Fujino Yoshihisa ,   CORoNaWork Project
Published: July 2021

Objectives

This study aimed to examine the relationship between regional infection level and treatment interruption for chronic diseases.

Methods

A cross-sectional Internet monitoring survey was performed between December 22 and 26, 2020. Data from 9,510 (5,392 males and 4,118 females) participants needing regular treatment or hospital visits were analyzed. We determined the age-sex- and multivariate-adjusted odds ratios (ORs) of treatment interruption associated with various indices of infection level by nesting multilevel logistic models in prefecture of residence. In the multivariate model, sex, age, marital status, job type, equivalent household income, education, self-rated health, and anxiety were adjusted.

Results

The ORs of treatment interruption for the lowest versus highest levels of infection were 1.32 (95% CI: 1.09–1.59) for the overall incidence rate (per 1,000 population), 1.34 (95% CI: 1.10–1.63) for the overall number of people infected, 1.28 (95% CI: 1.06–1.54) for the monthly incidence rate (per 1,000 population), and 1.38 (95% CI: 1.14–1.67) for the number of people infected per month. For each index of infection level, higher infection was linked to more workers experiencing treatment interruption.

Conclusion

Higher local infection levels were linked to more workers experiencing treatment interruption. Our results suggest that apart from individual characteristics such as socioeconomic and health status, treatment interruptions during the pandemic were also subject to contextual effects related to regional infection levels. Preventing community spread of COVID-19 may thus protect individuals from indirect effects of the pandemic, such as treatment interruption.
Concentration of SARS-CoV-2 from large volumes of raw wastewater is enhanced with the inuvai R180 system
Authors: Monteiro Silvia , Rente Daniela , Cunha Mónica V. , Marques Tiago A. , Cardoso Eugénia , Álvaro Pedro , Vilaça João , Ribeiro Jorge , Silva Marco , Coelho Norberta , Brôco Nuno , Carvalho Marta , Santos Ricardo
Published: July 2021

Wastewater-based epidemiology (WBE) for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) is a powerful tool to complement syndromic surveillance: first, as an early-warning system for the spread of the virus in the community, second, to find hotspots of infection, and third, to aid in the early detection and follow-up of circulating virus variants.

Although detection of SARS-CoV-2 in raw wastewater may be prompted with good recoveries during periods of high community prevalence, in the early stages of population outbreaks concentration procedures are required to overcome low viral concentrations. Several methods have become available for the recovery of SARS-CoV-2 from raw wastewater, generally involving filtration. However, these methods are limited to small sample volumes, possibly missing the early stages of virus circulation, and restrained applicability across different water matrices. The aim of this study was thus to evaluate the performance of three methods enabling the concentration of SARS-CoV-2 from large volumes of wastewater: i) hollow fiber filtration using the inuvai R180, with an enhanced elution protocol and polyethylene glycol (PEG) precipitation; ii) PEG precipitation; and iii) skimmed milk flocculation. The performance of the three approaches was evaluated in wastewater from multiple wastewater treatment plants (WWTP) with distinct singularities, according to: i) effective volume; ii) percentage of recovery; iii) extraction efficiency; iv) inhibitory effect; and v) the limits of detection and quantification (The inuvai R180 system had the best performance, with detection of spiked controls across all samples, average recovery percentages of 64% for SARS-CoV-2 control and 68% for porcine epidemic diarrhea virus (PEDV), with low variability.

The inuvai R180 enables the scalability of volumes without negative impact on the costs, time for analysis, and recovery/inhibition. Moreover, hollow fiber filters favor the concentration of different microbial taxonomic groups. Such combined features make this technology attractive for usage in environmental waters monitoring.
Accounting for the Role of Asymptomatic Patients in Understanding the Dynamics of the COVID-19 Pandemic: A Case Study from Singapore
Authors: Teck Liew Fu , Ghosh Palash , Chakraborty Bibhas
Published: July 2021

Objectives

To forecast the true growth of COVID-19 cases in Singapore after accounting for asymptomatic infections, we study and make modifications to the SEIR (Susceptible-Exposed-Infected-Recovered) epidemiological model by incorporating hospitalization dynamics and the presence of asymptomatic cases. We then compare the simulation results of our three epidemiological models of interest against the daily reported COVID-19 case counts across the time period from 23rd January to 6th April 2020. Finally, we compare and evaluate on the performance and accuracy of the aforementioned models’ simulations.

Methods

Three epidemiological models are used to forecast the true growth of COVID-19 case counts by accounting for asymptomatic infections in Singapore. They are the exponential model, SEIR model with hospitalization dynamics (SEIHRD), and the SEIHRD model with inclusion of asymptomatic cases (SEAIHRD).

Results

Simulation results of all three models reflect underestimation of COVID-19 cases in Singapore during the early stages of the pandemic. At a 40% asymptomatic proportion, we report basic reproduction number R0 = 3.28 and 3.74 under the SEIHRD and SEAIHRD models respectively. At a 60% asymptomatic proportion, we report R0 = 3.48 and 3.96 under the SEIHRD and SEAIHRD models respectively.

Conclusions

Based on the results of different simulation scenarios, we are highly confident that the number of COVID-19 cases in Singapore was underestimated during the early stages of the pandemic. This is supported by the exponential increase of COVID-19 cases in Singapore as the pandemic developed.
The infinite alleles model revisited: a Gibbs sampling approach
Authors: Manceau Marc
Published: July 2021

The SARS-CoV-2 outbreak started in late 2019 in the Hubei province in China and the first viral sequence was made available to the scientific community on early January 2020. From there, viral genomes from all over the world have followed at an outstanding rate, reaching already more than 105on early May 2020, and more than 106by early March 2021. Phylodynamics methods have been designed in recent years to process such datasets and infer population dynamics and sampling intensities in the past. However, the unprecedented scale of the SARS-CoV-2 dataset now calls for new methodological developments, relying e.g. on simplifying assumptions of the mutation process.

In this article, I build on theinfinite alleles modelstemming from the field of population genetics to develop a new Bayesian statistical method allowing the joint reconstruction of the outbreak’s effective population sizes and sampling intensities through time. This relies on prior conjugacy properties that prove useful both to develop a Gibbs sampler and to gain intuition on the way different parameters of the model are linked and inferred. I finally illustrate the use of this method on SARS-CoV-2 genomes sequenced during the first wave of the outbreak in four distinct European countries, thus offering a new perspective on the evolution of the sampling intensity through time in these countries from genetic data only.
Spatial and Temporal Organization of Composite Receptive Fields in the Songbird Auditory Forebrain
Authors: Vahidi Nasim W.
Published: July 2021

The mechanisms underlying how single auditory neurons and neuron populations encode natural and acoustically complex vocal signals, such as human speech or bird songs, are not well understood. Classical models focus on individual neurons, whose spike rates vary systematically as a function of change in a small number of simple acoustic dimensions. However, neurons in the caudal medial nidopallium (NCM), an auditory forebrain region in songbirds that is analogous to the secondary auditory cortex in mammals, have composite receptive fields (CRFs) that comprise multiple acoustic features tied to both increases and decreases in firing rates. Here, we investigated the anatomical organization and temporal activation patterns of auditory CRFs in European starlings exposed to natural vocal communication signals (songs). We recorded extracellular electrophysiological responses to various bird songs at auditory NCM sites, including both single and multiple neurons, and we then applied a quadratic model to extract large sets of CRF features that were tied to excitatory and suppressive responses at each measurement site. We found that the superset of CRF features yielded spatially and temporally distributed, generalizable representations of a conspecific song. Individual sites responded to acoustically diverse features, as there was no discernable organization of features across anatomically ordered sites. The CRF features at each site yielded broad, temporally distributed responses that spanned the entire duration of many starling songs, which can last for 50 s or more. Based on these results, we estimated that a nearly complete representation of any conspecific song, regardless of length, can be obtained by evaluating populations as small as 100 neurons. We conclude that natural acoustic communication signals drive a distributed yet highly redundant representation across the songbird auditory forebrain, in which adjacent neurons contribute to the encoding of multiple diverse and time-varying spectro-temporal features.
Genome-Wide Identification and Characterization of Fusarium circinatum-Responsive lncRNAs in Pinus radiata
Authors: Zamora-Ballesteros C. , Martín-García J. , Suárez-Vega A. , Diez J.J.
Published: July 2021

One of the most promising strategies of Pine Pitch Canker (PPC) management is the use of reproductive plant material resistant to the disease. Understanding the complexity of plant transcriptome that underlies the defence to the causal agent Fusarium circinatum, would greatly facilitate the development of an accurate breeding program. Long non-coding RNAs (lncRNAs) are emerging as important transcriptional regulators under biotic stresses in plants. However, to date, characterization of lncRNAs in conifer trees has not been reported. In this study, transcriptomic identification of lncRNAs was carried out using strand-specific paired-end RNA sequencing, from Pinus radiata samples inoculated with F. circinatum at an early stage of infection. Overall, 13,312 lncRNAs were predicted through a bioinformatics approach, including long intergenic non-coding RNAs (92.3%), antisense lncRNAs (3.3%) and intronic lncRNAs (2.9%). Compared with protein-coding RNAs, pine lncRNAs are shorter, have lower expression, lower GC content and harbour fewer and shorter exons. A total of 164 differentially expressed (DE) lncRNAs were identified in response to F. circinatum infection in the inoculated versus mock-inoculated P. radiata seedlings. The predicted cis-regulated target genes of these pathogen-responsive lncRNAs were related to defence mechanisms such as kinase activity, phytohormone regulation, and cell wall reinforcement. Co-expression network analysis of DE lncRNAs, DE protein-coding RNAs and lncRNA target genes also indicated a potential network regulating pectinesterase activity and cell wall remodelling. This study presents the first analysis of conifer lncRNAs involved in the regulation of defence network and provides the basis for future functional characterizations of lncRNAs in relation to pine defence responses against F. circinatum.
Contribution of genome scale metabolic modeling to niche theory
Authors: Régimbeau Antoine , Budinich Marko , Larhlimi Abdelhalim , Karlusich Juan Jose Pierella , Aumont Olivier , Memery Laurent , Bowler Chris , Eveillard Damien
Published: July 2021

Standard niche modeling is based on probabilistic inference from organismal occurrence data but does not benefit yet from genome-scale descriptions of these organisms. This study over-comes this shortcoming by proposing a new conceptual niche that encompasses the whole metabolic capabilities of an organism. The so-called metabolic niche resumes well-known traits such as nutrient needs and their dependencies for survival. Despite the computational challenge, its implementation allows the detection of traits and the formal comparison of niches of different organisms, emphasizing that the presence-absence of functional genes is not enough to approximate the phenotype. Further statistical exploration of an organism’s niche sheds light on genes essential for the metabolic niche and their role in understanding various biological experiments, such as transcriptomics, paving the way for incorporating better the genome-scale description in ecological studies.
Short-chain fatty acids activate acetyltransferase p300
Authors: Thomas Sydney P. , Denu John M.
Published: July 2021

Short-chain fatty acids (SCFAs) acetate, propionate, and butyrate are produced in large quantities by the gut microbiome and contribute to a wide array of physiological processes. While the underlying mechanisms are largely unknown, many effects of SCFAs have been traced to changes in the cell’s epigenetic state. Here, we systematically investigate how SCFAs alter the epigenome. Using quantitative proteomics of histone modification states, we identified rapid and sustained increases in histone acetylation after addition of butyrate or propionate, but not acetate. While decades of prior observations would have suggested that hyperacetylation induced by SCFAs are attributed to inhibition of histone deacetylases (HDACs), we found that propionate and butyrate instead activate the acetyltransferase p300. Propionate and butyrate are rapidly converted to the corresponding acyl-CoAs which are then used by p300 to catalyze auto-acylation of the autoinhibitory loop, activating the enzyme for histone/protein acetylation. This data challenges the long-held belief that SCFAs mainly regulate chromatin by inhibiting HDACs, and instead reveals a previously unappreciated mechanism of HAT activation that can explain how even low levels of SCFAs alter global chromatin states.

Summary Figure
Microbial association networks in cheese: a meta-analysis
Authors: Parente Eugenio , Zotta Teresa , Ricciardi Annamaria
Published: July 2021

Interactions among starter and non-starter microorganisms (starter bacteria, naturally occurring or intentionally added non-starter bacteria, yeasts and filamentous fungi, spoilage and pathogenic microorganisms and, finally bacteriophages and even arthropods) deeply affect the dynamics of cheese microbial communities and, as a consequence, multiple aspects of cheese quality, from metabolites affecting the taste, aroma and flavour, to body, texture and colour. Understanding and exploiting microbial interactions is therefore key to managing cheese quality. This is true for the simplest systems (fresh cheeses produced from pasteurized milk using defined starters composed solely of Lactic Acid Bacteria) and the more so for complex, dynamic systems, like surface ripened cheese produced from raw milk, in which a dynamic succession of diverse microorganisms is essential for obtained the desired combination of sensory properties while guaranteeing safety. Positive (commensalism, protocooperation) and negative (competition, amensalism, predation and parasitism) among members of the cheese biota have been reviewed multiple times. Although the complex, multidimensional datasets generated by multi-omic approaches to cheese microbiology and biochemistry are ideally suited for the representation of biotic and metabolic interactions as networks, network science concepts and approaches are rarely applied to cheese microbiology.

In this review we first illustrate concepts relevant to the description of microbial interaction networks using network science concepts. Then, we briefly review methods used for the inference and analysis of microbial association networks and their potential use in the interpretation of the cheese interactome. Since these methods can only be used for mining microbial associations, a review of the experimental methods used to confirm the nature of microbial interactions among cheese microbes. Finally, we demonstrate the potential of microbial association network inference by mining metataxonomic data stored in the public database DairyFMBN, a specialized version of FoodMicrobionet which collates data on 74 metataxonomic studies on dairy products. Microbial association networks were inferred from 34 studies on cheese with up to 4 different methods and the results discussed to evaluate several aspects (choice of method, level of taxonomic resolution for the analysis, network, node and edge properties) which provide insight on the usefulness of this approach as explorative tool in the detection of microbial interactions in cheese.

Highlights

Approaches for inference of association networks from metataxonomic data were reviewed

A metastudy on association networks in cheese was carried out using 34 recent studies

Inference method and taxonomic resolution should be chosen carefully

SPIEC-EASI may be used as a conservative method for microbial association inference

Edge and node properties support the formulation of testable hypotheses for microbial interactions
MyD88-dependent TLR signaling oppositely regulates hematopoietic progenitor and stem cell formation in the embryo
Authors: Bennett Laura F. , Mumau Melanie D. , Li Yan , Speck Nancy A.
Published: July 2021

Hemogenic endothelial (HE) cells in the dorsal aorta undergo an endothelial to hematopoietic transition (EHT) to form lympho-myeloid biased progenitors (LMPs), pre-hematopoietic stem cells (pre-HSCs) and adult-repopulating HSCs. These briefly accumulate in intra-arterial hematopoietic clusters (IAHCs) before being released into the circulation. It is generally assumed that the number of IAHC cells correlates with the number of HSCs. Here we show that changes in the number of IAHC cells, LMPs, and HSCs can be uncoupled. Mutations impairing MyD88-dependent toll-like receptor (TLR) signaling decreased the number of IAHC cells and LMPs but increased the number of HSCs in the aorta-gonad-mesonephros region of mouse embryos. TLR4 -deficient embryos generated normal numbers of HE cells but the proliferation of IAHC cells was decreased. Loss of MyD88-dependent TLR signaling in innate immune myeloid cells had no effect on IAHC cell numbers. Instead, TLR4 deletion in endothelial cells recapitulated the phenotype observed with germline deletion, demonstrating that MyD88-dependent TLR signaling in endothelial cells and/or in IAHCs regulates the balance between generating LMPs and HSCs.

Summary Statement

Toll-like receptor signaling in endothelial cells restricts the number of hematopoietic stem cells but increases the number of committed progenitors and intra-arterial hematopoietic cluster cells by promoting their proliferation.
Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice
Authors: Gul Seref , Akyel Yasemin Kubra , Gul Zeynep Melis , Isin Safak , Korkmaz Tuba , Selvi Saba , Danis Ibrahim , Ipek Ozgecan Savlug , Aygenli Fatih , Taskin Ali Cihan , Ozturk Nuri , Ozturk Narin , Ünal Durişehvar Özer , Guzel Mustafa , Turkay Metin , Okyar Alper , Kavakli Ibrahim Halil
Published: July 2021

Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous level of the CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis is unknown. Here, we discovered a molecule that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The small molecule, called M47, selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and the period of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 enhanced degradation rate of the CRY1 level in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced cisplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Finally, systemic repetitive administration of M47 increased the median lifespan of p53−/− mice by ~25%. Collectively our data suggest that M47 is a very promising molecule to treat forms of cancer depending on the p53 mutation.
Emergence of growth and dormancy from a kinetic model of theEscherichia colicentral carbon metabolism
Authors: Himeoka Yusuke , Mitarai Namiko
Published: July 2021

Physiological states of bacterial cells exhibit a wide spectrum of timescale. Under nutrient-rich conditions, most of the cells in an isogenic bacterial population grow at certain rates, while a small subpopulation sometimes falls into a dormant state where the growth rates slow down by orders of magnitude. The dormant cells have unique characteristics: The metabolic activity is quite slow, and the dormant cells typically exhibit a high tolerance for a range of stresses, such as antibiotics applications. To reveal the origins of such heterogeneity of timescales, we constructed a kinetic model ofEscherichia colicentral carbon metabolism, including the dynamics of the energy currency molecules, and asked if perturbations of the metabolites’ concentrations lead to the distinct metabolic states. By numerically studying the relaxation dynamics, we found that the model robustly exhibits two qualitatively distinct relaxation dynamics depending on the initial conditions generated by the perturbations. In the first type, the concentrations of metabolites reach the steady-state quickly, resembling the growing dynamics. On the other hand, the other type of dynamics takes a much longer time to reach the steady-state, and during the relaxation, cell growth almost halts, reminding us of the dormant cells. In order to unveil the mechanism of distinct behaviors, we reduced the metabolic network model into a minimal model without losing the emergence of distinct dynamics. Analytical and numerical studies of the 2-variable minimal model revealed the necessary conditions for the distinct behavior, namely, the depletion of energy due to the futile cycle and its non-uniform impact on the kinetics because of the coexistence of the energy currency-coupled and uncoupled reactions as well as branching of the network. The result is consistent with the experimental reports that the dormant cells commonly exhibit low ATP levels and provides a possible explanation for the appearance of dormant cells that causes antibiotic persistence.
Modelling the spatiotemporal spread of beneficial alleles using ancient genomes
Authors: Muktupavela Rasa , Petr Martin , Ségurel Laure , Korneliussen Thorfinn , Novembre John , Racimo Fernando
Published: July 2021

Ancient genome sequencing technologies now provide the opportunity to study natural selection in unprecedented detail. Rather than making inferences from indirect footprints left by selection in present-day genomes, we can directly observe whether a given allele was present or absent in a particular region of the world at almost any period of human history within the last 10,000 years. Methods for studying selection using ancient genomes often rely on partitioning individuals into discrete time periods or regions of the world. However, a complete understanding of natural selection requires more nuanced statistical methods which can explicitly model allele frequency changes in a continuum across space and time. Here we introduce a method for inferring the spread of a beneficial allele across a landscape using two-dimensional partial differential equations. Unlike previous approaches, our framework can handle time-stamped ancient samples, as well as genotype likelihoods and pseudohaploid sequences from low-coverage genomes. We apply the method to a panel of published ancient West Eurasian genomes to produce dynamic maps showcasing the inferred spread of candidate beneficial alleles over time and space. We also provide estimates for the strength of selection and diffusion rate for each of these alleles. Finally, we highlight possible avenues of improvement for accurately tracing the spread of beneficial alleles in more complex scenarios.
A single oral immunization with a replication-competent adenovirus-vectored vaccine protects mice from influenza respiratory infection
Authors: Goffin Emeline , Hemmi Silvio , Machiels Bénédicte , Gillet Laurent
Published: July 2021

The development of effective and flexible vaccine platforms is a major public health challenge as recently highlighted by the COVID-19 pandemic. Adenoviruses (AdVs) are easy to produce and have a good safety and efficacy profile when administered orally as demonstrated by the long-term use of oral AdV 4 and 7 vaccines in the US military. These viruses therefore appear to be the ideal backbone for the development of oral replicative vector vaccines. However, research on these vaccines is limited by the ineffective replication of human AdVs in laboratory animals. The use of mouse AdV type 1 (MAV-1) in its natural host allows infection to be studied under replicative conditions. Here, we orally vaccinated mice with MAV-1 vectors expressing the full length or the “headless” hemagglutinin (HA) of influenza to assess the protection conferred against an intranasal challenge of influenza. We showed that while the headless HA vector did not generate a significant humoral or cellular immune response to influenza, a single oral immunisation with the full-length HA vaccine generated influenza-specific and neutralizing antibodies and completely protected the mice against clinical signs and viral replication.

Importance

Given the constant threat of pandemics and the need for annual vaccination against influenza and possibly emerging agents such as SARS-CoV-2, new types of vaccines that are easier to produce and administer and therefore more widely accepted are a critical public health need. Here, using a relevant animal model, we have shown that replicative oral AdV vaccine vectors can help make vaccination against major respiratory diseases more available, better accepted and therefore more effective. These results could be of major importance in the coming years in the fight against emerging diseases such as COVID-19.
Dual projecting cells linking thalamic and cortical communication routes between the medial prefrontal cortex and hippocampus
Authors: Schlecht Maximilian , Jayachandran Maanasa , Rasch Gabriela E. , Allen Timothy A.
Published: July 2021

The interactions between the medial prefrontal cortex (mPFC) and the hippocampus (HC) are critical for memory and decision making and have been specifically implicated in several neurological disorders including schizophrenia, epilepsy, frontotemporal dementia, and Alzheimer’s disease. The ventral midline thalamus (vmThal), and lateral entorhinal cortex and perirhinal cortex (LEC/PER) constitute major communication pathways that facilitate mPFC-HC interactions in memory. Although vmThal and LEC/PER circuits have been delineated separately we sought to determine whether these two regions share cell-specific inputs that could influence both routes simultaneously. To do this we used a dual fluorescent retrograde tracing approach using cholera toxin subunit-B (CTB-488 and CTB-594) with injections targeting vmThal and the LEC/PER in rats. Retrograde cell body labeling was examined in key regions of interest within the mPFC-HC system including: (1) mPFC, specifically anterior cingulate cortex (ACC), dorsal and ventral prelimbic cortex (dPL, vPL), and infralimbic cortex (IL); (2) medial and lateral septum (MS, LS); (3) subiculum (Sub) along the dorsal-ventral and proximal-distal axes; and (4) LEC and medial entorhinal cortex (MEC). Results showed that dual vmThal-LEC/PER-projecting cell populations are found in MS, vSub, and the shallow layers II/III of LEC and MEC. We did not find any dual projecting cells in mPFC or in the cornu ammonis (CA) subfields of the HC. Thus, mPFC and HC activity is sent to vmThal and LEC/PER via non-overlapping projection cell populations. Importantly, the dual projecting cell populations in MS, vSub, and EC are in a unique position to simultaneously influence both cortical and thalamic mPFC-HC pathways critical to memory.

Significance Statement

The interactions between mPFC and HC are critical for learning and memory, and dysfunction within this circuit is implicated in various neurodegenerative and psychiatric diseases. mPFC-HC interactions are mediated through multiple communication pathways including a thalamic hub through the vmThal and a cortical hub through lateral entorhinal cortex and perirhinal cortex. Our data highlight newly identified dual projecting cell populations in the septum, Sub, and EC of the rat brain. These dual projecting cells may have the ability to modify the information flow within the mPFC-HC circuit through synchronous activity, and thus offer new cell-specific circuit targets for basic and translational studies in memory.
Analysis of genotype by environment interactions in a maize mapping population
Authors: Hudson Asher I. , Odell Sarah G. , Dubreuil Pierre , Tixier Marie-Helene , Praud Sébastien , Runcie Daniel E. , Ross-Ibarra Jeffrey
Published: July 2021

Genotype by environment interactions are a significant challenge for crop breeding as well as being important for understanding the genetic basis of environmental adaptation. In this study, we analyzed genotype by environment interaction in a maize multi-parent advanced generation intercross population grown across five environments. We found that genotype by environment interactions contributed as much as genotypic effects to the variation in some agronomically important traits. In order to understand how genetic correlations between traits change across environments, we estimated the genetic variance-covariance matrix in each environment. Changes in genetic covariances between traits across environments were common, even among traits that show low genotype by environment variance. We also performed a genome-wide association study to identify markers associated with genotype by environment interactions but found only a small number of significantly associated markers, possibly due to the highly polygenic nature of genotype by environment interactions in this population.
Single worm transcriptomics identifies a developmental core network of oscillating genes with deep conservation across nematodes
Authors: Sun Shuai , Rödelsperger Christian , Sommer Ralf J.
Published: July 2021

High-resolution spatial and temporal maps of gene expression have facilitated a comprehensive understanding of animal development and evolution. In nematodes, the small body size represented a major challenge for such studies, but recent advancements have helped overcome this limitation. Here, we have implemented single worm transcriptomics (SWT) in the nematode model organism Pristionchus pacificus to provide a high-resolution map of the developmental transcriptome. We selected 38 time points from hatching of the J2 larvae to young adults to perform transcriptome analysis over 60 h of postembryonic development. A mean sequencing depth of 4.5 million read pairs allowed the detection of more than 23,135 (80%) of all genes. Nearly 3000 (10%) genes showed oscillatory expression with discrete expression levels, phases, and amplitudes. Gene age analysis revealed an overrepresentation of ancient gene classes among oscillating genes, and around one-third of them have 1:1 orthologs in C. elegans. One important gene family overrepresented among oscillating genes is collagens. Several of these collagen genes are regulated by the developmental switch gene eud-1, indicating a potential function in the regulation of mouth-form plasticity, a key developmental process in this facultative predatory nematode. Together, our analysis provides (1) an updated protocol for SWT in nematodes that is applicable to many microscopic species, (2) a 1- to 2-h high-resolution catalog of P. pacificus gene expression throughout postembryonic development, and (3) a comparative analysis of oscillatory gene expression between the two model organisms P. pacificus and C. elegans and associated evolutionary dynamics.
Serial crystallography using automated drop dispensing
Authors: Su Zhen , Cantlon Joshua , Douthit Lacey , Wiedorn Max , Boutet Sébastien , Kern Jan , Yoon Chun Hong , DePonte Daniel
Published: July 2021

Automated, pulsed liquid-phase sample delivery has the potential to greatly improve the efficiency of both sample and photon use at pulsed X-ray facilities. In this work, an automated drop on demand (DOD) system that accelerates sample exchange for serial femtosecond crystallography (SFX) is demonstrated. Four different protein crystal slurries were tested, and this technique is further improved here with an automatic sample-cycling system whose effectiveness was verified by the indexing results. Here, high-throughput SFX screening is shown to be possible at free-electron laser facilities with very low risk of cross contamination and minimal downtime. The development of this technique will significantly reduce sample consumption and enable structure determination of proteins that are difficult to crystallize in large quantities. This work also lays the foundation for automating sample delivery.
Public health interventions in English local authorities: constructing the facts, (re)imagining the future
Authors: Brackley James , Tuck Penelope , Exworthy Mark
Published: July 2021

Purpose

This paper examines the contested value of healthy life and wellbeing in a context of severe austerity, exploring how the value of “Public Health” is constructed through and with material-discursive practices and accounting representations. It seeks to explore the political and ethical implications of constructing the valuable through a shared consensus over the “facts” when addressing complex, multi-agency problems with long time horizons and outcomes that are not always easily quantifiable.

Design/methodology/approach

The theorisation, drawing on science and technology studies (STS) scholars and Karen Barad's (2007) agential realism, opens up the analysis to the performativity of both material and discursive practices in the period following a major re-organisation of activity. The study investigates two case authorities in England and the national regulator through interviews, observations and documentary analysis.

Findings

The paper demonstrates the deeply ethical and political entanglements of accounting representations as objectivity, consensus and collective action are constructed and resisted in practice. It goes on to demonstrate the practical challenges of constructing “alternative accounts” and “intelligent accountabilities” through times of austerity towards a shared sense of public value and suggests austerity measures make such aims both more challenging and all the more essential.

Originality/value

Few studies in the accounting literature have explored the full complexity of valuation practices in non-market settings, particularly in a public sector context; this paper, therefore, extends familiar conceptual vocabulary of STS inspired research to further explore how value(s), ethics and identity all play a crucial role in making things valuable.
Segmentation at Sticks Kebob Shop
Authors: Venkatesan Rajkumar
Published: July 2021

This case is used in the Marketing Analytics elective at Darden. A Sticks executive team is interested in opening a second quick-service restaurant in Richmond, Virginia. But before doing so, the team wanted to gain a better sense of who were Sticks' customers, which location would attract the best customers, and how to best connect with customers. An opportunity to gather survey data presented itself. Would the demographic and psychographic assumptions the team had gathered from talking to people in stores align with the survey answers? And what would the data suggest about where to locate new stores and about what marketing channels and messages to use to promote them?
Demystifying the role of internal dynamics in the path of innovative competitiveness: a serial mediation model of international joint ventures
Authors: Aggarwal Vijita , Kapoor Madhavi
Published: July 2021

Purpose

The study proposes and evaluates a parsimonious research framework by integrating the major strategic theories related to an international firm's internal dynamics. This research's essence lies in the proposition that organizational competencies, knowledge resources and processes, absorptive capacity and innovativeness form the underlying base for sustainable competitive advantage in this dynamic world.

Design/methodology/approach

A cross-sectional explanatory research design is adopted. Using the quantitative data obtained from the sample of Indian international joint ventures (IJVs), partial least squares structural equation modeling (PLS-SEM) is deployed to confirm the proposed relationships among the research constructs. Finally, qualitative interviews helped in triangulating the primary survey's results.

Findings

A well-established relationship between knowledge transfer and innovation is negated by the Indian IJVs' data, which is delved deeper with cross-industry qualitative analysis. The novel hierarchical model with multiple mediations has nurtured quite exciting results for the business world with some significant theoretical and managerial implications.

Research limitations/implications

This study has investigated the nexus between multi-dimensional organizational competencies, knowledge transfer, absorptive capacity and venture innovativeness in the context of Indian IJVs. It has emphasized the role of internal dynamics in cross-cultural joint ventures to attain sustainable competitiveness through strategic and technological efficiency.

Originality/value

The study has addressed the specific research gap of under-investigation of dynamic capabilities and sustainable competitiveness in international joint ventures. It has investigated a complex model of multiple mediations, yielding interesting quantitative results with qualitative insights; which is rare to match in literature.
The dark side of teamwork–the relationship between social stressors, social resources and team member well-being in monocultural and multicultural work teams
Authors: Leifels Katrin , Bowen Paul
Published: July 2021

Purpose

The purpose of this paper is to explore the relationship between cultural diversity in teams and team members' individual well-being. The paper further explores the relationship between social resources, social stressors, team member well-being and the influence of the type of team individuals are working in (mono- vs. multicultural), gender and individualism/collectivism (IC).

Design/methodology/approach

Using data collected via an online survey, the authors analyzed 659 responses from individuals working in mono- and multicultural work teams. A theoretical model explaining the influence of social stressors, social resources, and social and demographic variables was proposed and tested using structural equation modeling.

Findings

The results indicate that members of multicultural work teams perceive significantly more social stressors and lower levels of social resources than do members of monocultural teams. Higher levels of social stressors suggest decreased psychological well-being, while social resources have an indirect positive effect on psychological well-being. Furthermore, personal characteristics, namely, individualism and gender, have direct effects on the perception of social stressors and indirect effects on team member well-being.

Originality/value

This paper demonstrates that cultural diversity in teams can influence the social stressors and resources that individual team members experience. Moreover, the pivotal role of social resources in the facilitation of team member well-being is highlighted primarily through its direct effect on social stressors and its concomitant indirect effect on well-being.