bluuebunny/crossref_metadata_2025 huggingface dataset:
The diversity and functional capacity of microbes associated with coastal phototrophs
Authors: Miranda Khashiff , Weigel Brooke L. , Fogarty Emily C. , Veseli Iva A. , Giblin Anne E. , Eren A. Murat , Pfister Catherine A.
Published: January 2022

Coastal marine phototrophs exhibit some of the highest rates of primary productivity in the world. They have been found to host a diverse set of microbes, many of which may impact the biology of their phototroph hosts through metabolisms that are unique to microbial taxa. Here we characterized the metabolic functions of phototroph-associated microbial communities using metagenomes collected from 2 species of kelp (Laminaria setchelliiandNereocystis luetkeana) and 3 marine angiosperms (Phyllospadix scouleri, P. serrulatusandZostera marina), including the rhizomes of two surfgrass species (Phyllospadixspp.) and the seagrassZostera marina, and the sediments surroundingP. scouleriandZ. marina. Using metagenomic sequencing, we describe 72 metagenome assembled genomes (MAGs) that potentially benefit from being associated with macrophytes and may contribute to macrophyte fitness through their metabolic gene content. All host-associated metagenomes contained genes for the use of dissolved organic matter from hosts and vitamin (B1, B2, B7, B12) biosynthesis. Additionally, we found a range of nitrogen metabolism genes that transform dissolved inorganic nitrogen into forms that may be more available to the host. The rhizosphere of surfgrass and seagrass contained genes for anaerobic microbial metabolisms, includingnifHgenes associated with nitrogen fixation, despite residing in a well-mixed and oxygenated environment. The range of oxygen environments engineered by macrophytes likely explains the diversity of both oxidizing and reducing microbial metabolisms, and contributes to the functional capabilities of microbes and their influence on carbon and nitrogen cycling in nearshore ecosystems.

Importance

Kelps, seagrasses and surfgrasses are ecosystem engineers on rocky shorelines where they show remarkably high levels of primary production. Through analysis of their associated microbial communities, we found a variety of microbial metabolisms that may benefit the host, including nitrogen metabolisms and the production of B vitamins. In turn, these microbes have the genetic capability to assimilate the dissolved organic compounds released by their phototroph hosts. We describe a range of oxygen environments associated with surfgrass, including low-oxygen microhabitats in their rhizomes that host genes for nitrogen fixation. The tremendous productivity of coastal phototrophs is likely due in part to the activities of associated microbes and an increased understanding of these associations is needed.
Characterization of ultrapotent chemogenetic ligands for research applications in non-human primates
Authors: Raper Jessica , Eldridge Mark A. G. , Sternson Scott. M. , Shim Jalene Y. , Fomani Grace P. , Richmond Barry J. , Wichmann Thomas , Galvan Adriana
Published: January 2022

Chemogenetics is a technique for obtaining selective pharmacological control over a cell population by expressing an engineered receptor that is selectively activated by an exogenously administered ligand. A promising approach for neuronal modulation involves the use of “Pharmacologically Selective Actuator Modules” (PSAMs); these chemogenetic receptors are selectively activated by ultrapotent “Pharmacologically Selective Effector Molecules” (uPSEMs). To extend the use of PSAM/PSEMs to studies in nonhuman primates it is necessary to thoroughly characterize the efficacy and safety of these tools. We describe the time course and brain penetrance in rhesus monkeys of two compounds with promising binding specificity and efficacy profiles in in vitro studies, uPSEM792 and uPSEM817, after systemic administration. Rhesus macaques received subcutaneous (s.c.) or intravenous (i.v.) administration of uPSEM817(0.064 mg/kg) or uPSEM792 (0.87 mg/kg) and plasma and CSF samples were collected over the course of 48 hours. Both compounds exhibited good brain penetrance, relatively slow washout and negligible conversion to potential metabolites - varenicline or hydroxyvarenicline. In addition, we found that neither of these uPSEMs significantly altered heart rate or sleep. Our results indicate that both compounds are suitable candidates for neuroscience studies using PSAMs in nonhuman primates.
Translational buffering by ribosome stalling in upstream open reading frames
Authors: Bottorff Ty , Geballe Adam P. , Subramaniam Arvind Rasi
Published: January 2022

Upstream open reading frames (uORFs) are present in over half of all human mRNAs. uORFs can potently regulate the translation of downstream open reading frames by several mechanisms: siphoning away scanning ribo-somes, regulating re-initiation, and allowing interactions between scanning and elongating ribosomes. However, the consequences of these different mechanisms for the regulation of protein expression remain incompletely understood. Here, we performed systematic measurements on the uORF-containing 5’ UTR of the cytomegaloviral UL4 mRNA to test alternative models of uORF-mediated regulation in human cells. We find that a terminal diproline-dependent elongating ribosome stall in the UL4 uORF prevents decreases in main ORF translation when ribosome loading onto the mRNA is reduced. This uORF-mediated buffering is insensitive to the location of the ribosome stall along the uORF. Computational kinetic modeling based on our measurements suggests that scanning ribosomes dissociate rather than queue when they collide with stalled elongating ribosomes within the UL4 uORF. We identify several human uORFs that repress main ORF translation via a similar terminal diproline motif. We propose that ribosome stalls in uORFs provide a general mechanism for buffering against reductions in main ORF translation during stress and developmental transitions.
Sulfane sulfur post-translationally modifies the global regulator AdpA to influence actinorhodin production and morphological differentiation of Streptomyces coelicolor
Authors: Lu Ting , Wu Xiaohua , Cao Qun , Xia Yongzhen , Xun Luying , Liu Huaiwei
Published: January 2022

The transcription factor AdpA is a key regulator controlling both secondary metabolism and morphological differentiation in Streptomyces. Due to its critical functions, its expression undergoes multi-level regulations at transcriptional, post-transcriptional, and translational levels, yet no post-translational regulation has been reported. Sulfane sulfur, such as organic polysulfide (RSnH, n≥2), is common inside microorganisms, but its physiological functions are largely unknown. Herein, we discovered that sulfane sulfur post-translationally modifies AdpA in S. coelicolor via specifically reacting with Cys62 of AdpA to form a persulfide (Cys62-SSH). This modification decreases the affinity of AdpA to its self-promoter PadpA, allowing increased expression of adpA, further promoting the expression of its target genes actII-4 and wblA. ActII-4 activates actinorhodin biosynthesis and WblA regulates morphological development. Bioinformatics analyses indicated that AdpA-Cys62 is highly conserved in Streptomyces, suggesting the prevalence of such modification in this genus. Thus, our study unveils a new type of regulation on the AdpA activity and sheds a light on how sulfane sulfur stimulates the production of antibiotics in Streptomyces.

IMPORTANCE

Streptomyces produce myriad of polyketide compounds having (potential) clinical applications. While the database of polyketide gene clusters are quickly expanding, the regulation mechanisms of them are rarely known. Sulfane sulfur species are commonly present in microorganisms with unclear functions. Herein, we discovered that sulfane sulfur increases actinorhodin (ACT) production in S. coelicolor. The underlying mechanism is sulfane sulfur specifically reacts with AdpA, a global transcription factor controlling both ACT gene cluster and morphological differentiation related genes, to form sulfhydrated AdpA. This modification changes dynamics of AdpA-controlled gene network and leads to high expression of ACT biosynthetic genes. Given the wide prevalence of AdpA and sulfane sulfur in Streptomyces, this mechanism may represent a common regulating pattern of polyketide gene clusters. Thus, this finding provides a new strategy for mining and activating valuable polyketide gene clusters.
Epidemiological waves - types, drivers and modulators in the COVID-19 pandemic
Authors: Harvey John , Chan Bryan , Srivastava Tarun , Zarebski Alexander E. , Dłotko Paweł , Błaszczyk Piotr , Parkinson Rachel H. , White Lisa J. , Aguas Ricardo , Mahdi Adam
Published: January 2022

Introduction

A discussion of ‘waves’ of the COVID-19 epidemic in different countries is a part of the national conversation for many, but there is no hard and fast means of delineating these waves in the available data and their connection to waves in the sense of mathematical epidemiology is only tenuous.

Methods

We present an algorithm which processes a general time series to identify substantial, significant and sustained periods of increase in the value of the time series, which could reasonably be described as ‘observed waves’. This provides an objective means of describing observed waves in time series.

Results

The output of the algorithm as applied to epidemiological time series related to COVID-19 corresponds to visual intuition and expert opinion. Inspecting the results of individual countries shows how consecutive observed waves can differ greatly with respect to the case fatality ratio. Furthermore, in large countries, a more detailed analysis shows that consecutive observed waves have different geographical ranges. We also show how waves can be modulated by government interventions and find that early implementation of non-pharmaceutical interventions correlates with a reduced number of observed waves and reduced mortality burden in those waves.

Conclusion

It is possible to identify observed waves of disease by algorithmic methods and the results can be fruitfully used to analyse the progression of the epidemic.
Infectious disease dynamics and restrictions on social gathering size
Authors: Boyer Christopher B , Rumpler Eva , Kissler Stephen M , Lipsitch Marc
Published: January 2022

Social gatherings can be an important locus of transmission for many pathogens including SARS-CoV-2. During an outbreak, restricting the size of these gatherings is one of several non-pharmaceutical interventions available to policy-makers to reduce transmission. Often these restrictions take the form of prohibitions on gatherings above a certain size. While it is generally agreed that such restrictions reduce contacts, the specific size threshold separating “allowed” from “prohibited” gatherings often does not have a clear scientific basis, which leads to dramatic differences in guidance across location and time. Building on the observation that gathering size distributions are often heavy-tailed, we develop a theoretical model of transmission during gatherings and their contribution to general disease dynamics. We find that a key, but often overlooked, determinant of the optimal threshold is the distribution of gathering sizes. Using data on pre-pandemic contact patterns from several sources as well as empirical estimates of transmission parameters for SARS-CoV-2, we apply our model to better understand the relationship between restriction threshold and reduction in cases. We find that, under reasonable transmission parameter ranges, restrictions may have to be set quite low to have any demonstrable effect on cases due to relative frequency of smaller gatherings. We compare our conceptual model with observed changes in reported contacts during lockdown in March of 2020.
Exploring the health impacts and inequalities of the new way of working: findings from a cross-sectional study
Authors: Griffiths Melda Lois , Gray Benjamin J , Kyle Richard G , Davies Alisha R
Published: January 2022

Aim

To explore the working Welsh adult population’s ability to work from home, their preferences for the future, and the self-reported health impacts of home-working.

Subject and Methods

A nationally-representative household survey was undertaken across Wales (Public Health Wales’ COVID-19, Employment and Health in Wales study), with cross-sectional data on home-working being collected between November 2020 and January 2021 from 615 employed working-aged adults in Wales (63.7% female, 32.7% aged 50-59). Respondents were asked about their ability to work from home, their perceptions of its impact on their health and their preferences for time spent home-working in future.

Results

Over 50% were able to work from home, and showed a preference towards home-working to some capacity, with over a third wishing to work from home at least half the time. However, those living in the most deprived areas, in atypical employment, with high wage precarity or with limiting pre-existing conditions were less likely to report being able to work from home. Of those that could work from home, over 40% reported that it worsened their mental well-being and loneliness, and for people in poorer health, home-working negatively impacted their diet, physical activity, smoking and alcohol use. People aged 30 to 39 and those who lived alone were more likely to report wanting to spend some time working in an office/base instead of at home.

Conclusion

The inequity in the ability to work from home reflects underlying inequalities in Wales, with those facing the greatest insecurity (e.g. those living in most deprived areas, those with more precarious work or financial circumstances) being less able to participate in home-working. Working from home offers greater flexibility, reduces the financial and time costs associated with commuting, and protects individuals from exposure to communicable diseases. However, working from home presents an enormous challenge to preserving the mental-wellbeing of the workforce, particularly for younger individuals and those with low mental well-being. Younger respondents and those in poorer health who could work from home were also more likely to engage in health-harming behaviours, and reduce their engagement in health-protective behaviours such as eating well and moving more. Reflecting on the future, providing pathways for accessing work from home arrangements, integrating hybrid models and preparing targeted health support for at risk groups may be best suited to the working population’s preferences and needs.
The combined impact of persistent infections and human genetic variation on C-reactive protein levels
Authors: Hodel F. , Naret O. , Bonnet C. , Brenner N. , Bender N. , Waterboer T. , Marques-Vidal P. , Vollenweider P. , Fellay J.
Published: January 2022

Multiple human pathogens establish chronic, sometimes life-long infections. Even if they are often latent, these infections can trigger some degree of local or systemic immune response, resulting in chronic low-grade inflammation. There remains an incomplete understanding of the potential contribution of both persistent infections and human genetic variation on chronic low-grade inflammation. We searched for potential associations between seropositivity for 13 persistent pathogens and the plasma levels of the inflammatory biomarker C-reactive protein (CRP), using data collected in the context of the UK Biobank and the CoLaus|PsyCoLaus Study, two large population-based cohorts. We performed backward stepwise regression starting with the following potential predictors: serostatus for each pathogen, polygenic risk score for CRP, as well as demographic and clinical factors known to be associated with CRP. We found evidence for an association between Chlamydia trachomatis (P-value = 5.04e-3) and Helicobacter pylori (P-value = 8.63e-4) seropositivity and higher plasma levels of CRP. We also found an association between pathogen burden and CRP levels (P-value = 4.12e-4). These results improve our understanding of the relationship between persistent infections and chronic inflammation, an important determinant of long-term morbidity in humans.
Estimation of excess all-cause mortality due to COVID-19 in Thailand
Authors: Wilasang Chaiwat , Modchang Charin , Lincharoen Thanchanok , Chadsuthi Sudarat
Published: January 2022

Thailand has experienced the most prominent COVID-19 outbreak, resulting in a new record for COVID-19 cases and deaths in 2021. To assess the influence of the COVID-19 outbreak on mortality, we estimated excess all-cause and pneumonia mortality in Thailand during the COVID-19 outbreak from April to October 2021. We used the previous five years’ mortality to estimate the baseline number of deaths using generalized linear mixed models (GLMMs). The models were adjusted for seasonality and demographics. We found that the estimated cumulative excess death was 14.3% (95% CI: 8.6%-18.8%) higher than the baseline. The results also showed that the excess deaths in males were higher than in females by approximately 26.3%. The excess deaths directly caused by the COVID-19 infections accounted for approximately 75.0% of the all-cause excess deaths. Furthermore, excess pneumonia deaths were also found to be 26.2% (95% CI: 4.8%-46.0%) above baseline. There was a significant rise in excess fatalities, especially in the older age groups. Therefore, the age and sex structure of the population are essential to assessing the mortality impact of COVID-19. Our modeling results could potentially provide insights into the COVID-19 outbreaks and provide a guide for outbreak control and intervention.
COVID-19 vaccine effectiveness among healthcare workers in Portugal: results from a hospital-based cohort study, December 2020 to November 2021
Authors: Gaio Vânia , Silva Adriana , Amaral Palmira , Viana João Faro , Leite Pedro Pinto , Dias Carlos Matias , Kislaya Irina , Nunes Baltazar , Machado Ausenda
Published: January 2022

Introduction

Healthcare workers (HCW) were amongst the first prioritized for COVID-19 vaccination but data on COVID-19 vaccine effectiveness among HCW is still limited. This study aims to estimate the COVID-19 vaccine effectiveness (VE) against SARS-CoV-2 symptomatic infection among HCW from Portuguese hospitals.

Methods

In this prospective cohort study, we analysed data from HCW (all professional categories) from two central hospitals in the Lisbon and Tagus Valley and Centre regions of mainland Portugal between December 2020 and November 2021. VE against symptomatic SARS-CoV-2 infection was estimated as one minus the confounder adjusted hazard ratios by Cox models considering age group, sex, presence of chronic disease and occupational exposure to patients diagnosed with COVID-19 as adjustment variables.

Results

During the 11 months of follow up, the 2213 HCW contributed a total of 1950 person-years at risk and 171 SARS-CoV-2 events occurred. The COVID-19 incidence rate for unvaccinated HCW was 348.7 per 1000 person-years while for fully vaccinated HCW was 43.0 per 1000 person-years. We observed a VE against symptomatic SARS-CoV-2 infection of 73.9% (95% CI: 26.2–90.8%) for complete vaccination status.

Conclusion

This cohort study found a high COVID-19 VE against symptomatic SARS-CoV-2 infection in Portuguese HCW, which is in concordance with previous studies from other countries. Monitoring of VE in this HCW cohort continues during the winter 2021/2022 to evaluate potential VE decay and booster vaccine effect.
Mendelian gene identification through mouse embryo viability screening
Authors: Cacheiro Pilar , Westerberg Carl Henrik , Mager Jesse , Dickinson Mary E. , Nutter Lauryl M.J. , Muñoz-Fuentes Violeta , Hsu Chih-Wei , Van den Veyver Ignatia B. , Flenniken Ann M. , McKerlie Colin , Murray Stephen A. , Teboul Lydia , Heaney Jason D. , Lloyd K. C. Kent , Lanoue Louise , Braun Robert E. , White Jacqueline K. , Creighton Amie K. , Laurin Valerie , Guo Ruolin , Qu Dawei , Wells Sara , Cleak James , Bunton-Stasyshyn Rosie , Stewart Michelle , Harrisson Jackie , Mason Jeremy , Mashhadi Hamed Haseli , Parkinson Helen , Mallon Ann-Marie ,   International Mouse Phenotyping Consortium,   Genomics England Research Consortium, Smedley Damian
Published: January 2022

The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful.

A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid or late gestation lethal.

We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes, and found that the members of the early gestation lethal category show distinctive characteristics and a strong enrichment for genes linked with recessive forms of inherited metabolic disease.

Based on these findings, we explored a gene similarity approach for novel gene discovery focused on this subset of lethal genes. Finally, we investigated unsolved cases from the 100,000 Genomes Project recruited under this disease category to look for signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes and highlight two novel candidates with phenotypic overlap between the patients and the mouse knockout.
Inpatient COVID-19 Mortality Rates: What are the predictors?
Authors: Al-Amin Mona , Islam Md Nazmul , Li Kate , Sheils Natalie E. , Buresh John
Published: January 2022

Objective

This study aims to investigate the relationship between registered nurses and hospital-based medical specialties staffing levels with inpatient COVID-19 mortality rates.

Methods

We rely on data from AHA Annual Survey Database, Area Health Resource File, and UnitedHealth Group Clinical Discovery Database. We use linear regression to analyze the association between hospital staffing levels and bed capacity with inpatient COVID-19 mortality rates from March 1, 2020, through December 31, 2020.

Results

Higher staffing levels of registered nurses, hospitalists, and emergency medicine physicians were associated with lower COVID-19 mortality rates. Moreover, a higher number of ICU and skilled nursing beds were associated with better patient outcomes. Hospitals located in urban counties with high infection rates had the worst patient mortality rates.

Conclusion

Higher staffing levels are associated with lower inpatient mortality rates for COVID-19 patients. A future assessment is needed to establish benchmarks on the minimum staffing levels for nursing and hospital-based medical specialties during pandemics.
Outcomes of COVID-19 infection in patients with chronic kidney disease on maintenance hemodialysis at a COVID hospital in India
Authors: Singh Ram , Krishnasamy Sudarsan , Meena Jitendra Kr , Sirohiya Prashant , Kumar Balbir , Ratre Brajesh kumar , Vig Saurabh , Pandit Anuja , Sagiraju Hari , Gupta Raghav , Bhatnagar Sushma
Published: January 2022

Background

Patients with chronic kidney disease (CKD) on hemodialysis are highly vulnerable to COVID-19 infection with a mortality rate higher than the rest of the population. There are several clinical and laboratory parameters that can predict the course and the outcomes in this group of population.

Methods

We retrospectively collected the baseline demographic, clinical, in-hospital, and laboratory data of the patients with CKD on maintenance hemodialysis who were admitted to our COVID-19 hospital during the first and the second wave.

Results

We obtained data for 35 patients from the first and 5 patients from the second wave. The analysis of the data for 35 patients from the first wave revealed shortness of breath (62.9%), and fever (54.3%) being the most common presenting symptoms, and the majority of the patients (57.2 %) presented with moderate to severe disease at admission with 57 % had bilateral lung infiltrates, and required oxygen support (65.7%) at admission. The comparison of clinical and laboratory markers between survivors (27 patients, 77.1%) and non-survivors (8 patients, 22.9%) revealed an older age, severe disease at presentation, invasive mechanical ventilation, baseline severe lymphocytopenia, high serum glutamic oxaloacetic transaminase, blood urea, and inflammatory markers like Interleukin-6 and procalcitonin, fibrinogen and low albumin in non survivors.

Conclusions

The older age, severe disease at presentation, the requirement of invasive mechanical ventilation, raised baseline Interleukin-6, procalcitonin, serum glutamic oxaloacetic transaminase, blood urea and a low albumin level could be valuable predictors of poor outcomes.
Generalized Michaelis–Menten rate law with time-varying molecular concentrations
Authors: Lim Roktaek , Martin Thomas L. P. , Chae Junghun , Kim WooJoong , Ghim Cheol-Min , Kim Pan-Jun
Published: January 2022

The Michaelis–Menten (MM) rate law has been the dominant paradigm of modeling biochemical rate processes for over a century with applications in biochemistry, biophysics, cell biology, systems biology, and chemical engineering. The MM rate law and its remedied form stand on the assumption that the concentration of the complex of interacting molecules, at each moment, approaches an equilibrium (quasi-steady state) much faster than the molecular concentrations change. Yet, this assumption is not always justified. Here, we relax this quasi-steady state requirement and propose the generalized MM rate law for the interactions of molecules with active concentration changes over time. Our approach for time-varying molecular concentrations, termed the effective time-delay scheme (ETS), is based on rigorously estimated time-delay effects in molecular complex formation. With particularly marked improvements in protein–protein and protein–DNA interaction modeling, the ETS provides an analytical framework to interpret and predict rich transient or rhythmic dynamics (such as autogenously-regulated cellular adaptation and circadian protein turnover), which goes beyond the quasi-steady state assumption.
Hexosamine pathway activation improves memory but does not extend lifespan in mice
Authors: Allmeroth Kira , Hartman Matías D. , Purrio Martin , Mesaros Andrea , Denzel Martin S.
Published: January 2022

Glucosamine feeding and genetic activation of the hexosamine biosynthetic pathway (HBP) have been linked to improved protein quality control and lifespan extension in various species. Thus, there is considerable interest in the potential health benefits of dietary supplementation with glucosamine or other HBP metabolites in people. The HBP is a sensor for energy availability and its activation has been implicated in tumor progression and diabetes in higher organisms. As the activation of the HBP has been linked to longevity in lower animals, it is imperative to explore the long-term effects of chronic HBP activation in mammals, which has not been examined so far. To address this issue, we activated the HBP in mice both genetically and through metabolite supplementation, and evaluated metabolism, memory, and survival. GlcNAc supplementation in the drinking water had no adverse effect on weight gain in males but increased weight in young female mice. Glucose or insulin tolerance were not affected up to 20 months of age. Of note, we observed improved memory in the Morris water maze in young male mice supplemented with GlcNAc. Survival was not changed by GlcNAc supplementation. To assess the effects of genetic HBP activation we overexpressed the key enzyme GFAT1 as well as a constitutively activated point mutant form in all mouse tissues. We detected elevated UDP-GlcNAc levels in mouse brains, but did not find any effects on behavior, memory, or survival. Together, while dietary GlcNAc supplementation did not extend survival in mice, it positively affected memory and is generally well tolerated.
Homologous BHLH transcription factors induce distinct deformations of torsionally-stressed DNA: a potential transcription regulation mechanism
Authors: Hörberg Johanna , Moreau Kevin , Reymer Anna
Published: January 2022

Changing torsional restraints on DNA is essential for the regulation of transcription. Torsional stress, introduced by RNA polymerase, can propagate along chromatin facilitating topological transitions and modulating the specific binding of transcription factors (TFs) to DNA. Despite the importance, the mechanistic details on how torsional stress impacts the TFs-DNA complexation remain scarce. Herein we address the impact of torsional stress on DNA complexation with homologous human basic-helix-loop-helix (BHLH) hetero- and homodimers: MycMax, MadMax, and MaxMax. The three TF dimers exhibit specificity towards the same DNA consensus sequences, the E-box response element, while regulating different transcriptional pathways. Using microseconds-long atomistic molecular dynamics simulations together with the torsional restraint that controls DNA total helical twist, we gradually over- and underwind naked and complexed DNA to a maximum of ±5°/b.p. step. We observe that the binding of the BHLH dimers results in a similar increase in DNA torsional rigidity. However, under torsional stress the BHLH dimers induce distinct DNA deformations, characterised by changes in DNA grooves geometry and a significant asymmetric DNA bending. Supported by bioinformatics analyses, our data suggest that torsional stress may contribute to the execution of differential transcriptional programs of the homologous TFs by modulating their collaborative interactions.
Resolving Protein Conformational Plasticity and Substrate Binding Through the Lens of Machine-Learning
Authors: Ahalawat Navjeet , Mondal Jagannath
Published: January 2022

A long-standing target in elucidating the biomolecular recognition process is the identification of binding-competent conformations of the receptor protein. However, protein conformational plasticity and the stochastic nature of the recognition processes often preclude the assignment of a specific protein conformation to an individual ligand-bound pose. In particular, we consider multi-microsecond long Molecular dynamics simulation trajectories of ligand recognition process in solvent-inaccessible cavity of two archtypal systems: L99A mutant of T4 Lysozyme and Cytochrome P450. We first show that if the substrate-recognition occurs via long-lived intermediate, the protein conformations can be automatically classified into substrate-bound and unbound state through an unsupervised dimensionality reduction technique. On the contrary, if the recognition process is mediated by selection of transient protein conformation by the ligand, a clear correspondence between protein conformation and binding-competent macrostates can only be established via a combination of supervised machine learning (ML) and unsupervised dimension reduction approach. In such scenario, we demonstrate that an a priori random forest based supervised classification of the simulated trajectories recognition process would help characterize key amino-acid residue-pairs of the protein that are deemed sensitive for ligand binding. A subsequent unsupervised dimensional reduction via time-lagged independent component analysis of the selected residue-pairs would delineate a conformational landscape of protein which is able to demarcate ligand-bound pose from the unbound ones. As a key breakthrough, the ML-based protocol would identify distal protein locations which would be allosterically important for ligand binding and characterise their roles in recognition pathways.
A kinase translocation reporter reveals real-time dynamics of ERK activity in Drosophila
Authors: Yuen Alice C. , Prasad Anadika R. , Fernandes Vilaiwan M. , Amoyel Marc
Published: January 2022

Extracellular Signal-Regulated Kinase (ERK) lies downstream of a core signalling cascade that controls all aspects of development and adult homeostasis. Recent developments have led to new tools to image and manipulate the pathway. However, visualising ERK activityin vivowith high temporal resolution remains a challenge in Drosophila. We adapted a kinase translocation reporter (KTR) for use in Drosophila, which shuttles out of the nucleus when phosphorylated by ERK. We show that ERK-KTR faithfully reports endogenous ERK signalling activity in developing and adult tissues, and that it responds to genetic perturbations upstream of ERK. Using ERK-KTR in time-lapse imaging, we made two novel observations: firstly, sustained hyperactivation of ERK by expression of dominant-active Epidermal Growth Factor Receptor raised the overall level but did not alter the kinetics of ERK activity; secondly, heterogeneity in ERK activity in retinal basal glia correlated with the direction of migration of individual cells. Our results show that KTR technology can be applied in Drosophila to monitor ERK activity in real-time and suggest that this modular tool can be further adapted to study other kinases.

Summary Statement

We describe a reporter to study the dynamics of ERK signalling in Drosophila, use it to measure signalling in individual cells over time, and monitor development.
Features of smaller ribosomes in Candidate Phyla Radiation (CPR) bacteria revealed with a molecular evolutionary analysis
Authors: Tsurumaki Megumi , Saito Motofumi , Tomita Masaru , Kanai Akio
Published: January 2022

The Candidate Phyla Radiation (CPR) is a large bacterial group consisting mainly of uncultured lineages. They have small cells and small genomes, and often lack ribosomal proteins L1, L9, and/or L30, which are basically ubiquitous in ordinary (non-CPR) bacteria. Here, we comprehensively analyzed the genomic information of CPR bacteria and identified their unique properties. In the distribution of protein lengths in CPR bacteria, the peak was at around 100–150 amino acids, whereas the position of the peak varies in the range of 100–300 amino acids in free-living non-CPR bacteria, and at around 100–200 amino acids in most symbiotic non-CPR bacteria. These results show that CPR bacteria have smaller proteins on average, like symbiotic non-CPR bacteria. We found that ribosomal proteins L28, L29, L32, and L33 are also deleted in CPR bacteria, in a lineage-specific manner. Moreover, the sequences of approximately half of all ribosomal proteins in CPR differ, in part, from those of non-CPR bacteria, with missing regions or specific added region. We also found that several regions of the 16S, 23S, and 5S rRNAs are lacking in CPR bacteria and that the total predicted length of the three rRNAs in CPR bacteria is smaller than that in non-CPR bacteria. The regions missing in the CPR ribosomal proteins and rRNAs are located near the surface of the ribosome, and some are close to one another. These observations suggest that ribosomes are smaller in CPR bacteria than in free-living non-CPR bacteria, with simplified surface structures.
Sustained upregulation of widespread hippocampal-neocortical coupling following memory encoding
Authors: Folvik Line , Sneve Markus H. , Ness Hedda T. , Vidal-Piñeiro Didac , Raud Liisa , Geier Oliver M. , Walhovd Kristine B. , Fjell Anders M.
Published: January 2022

Systems consolidation of new experiences into lasting episodic memories involves interactions between hippocampus and the neocortex. Evidence of this process is seen already during early awake post-encoding rest periods. Functional MRI (fMRI) studies have demonstrated increased hippocampal coupling with task-relevant perceptual regions and reactivation of stimulus-specific encoding patterns following intensive encoding tasks. Here we investigate the spatial and temporal characteristics of these hippocampally anchored post-encoding neocortical modulations. Eighty-nine adults participated in an experiment consisting of interleaved memory task- and resting-state periods. As expected, we observed increased post-encoding functional connectivity between hippocampus and individually localized neocortical regions responsive to stimulus categories encountered during memory encoding. Post-encoding modulations were however not restricted to stimulus-selective cortex, but manifested as a nearly system-wide upregulation in hippocampal coupling with all major functional networks. The spatial configuration of these extensive modulations resembled hippocampal-neocortical interaction patterns estimated from active encoding operations, suggesting hippocampal post-encoding involvement by far exceeds reactivation of perceptual aspects. This reinstatement of encoding patterns during immediate post-encoding rest was not observed in resting-state scans collected 12 hours later, nor in control analyses estimating post-encoding neocortical modulations in functional connectivity using other candidate seed regions. The broad similarity in hippocampal functional coupling between online memory encoding and offline post-encoding rest suggests reactivation in humans may involve a spectrum of cognitive processes engaged during experience of an event.

Significance statement

Stabilization of newly acquired information into lasting memories occurs through systems consolidation – a process which gradually spreads the locus of memory traces from hippocampus to more distributed neocortical representations. One of the earliest signs of consolidation is the upregulation of hippocampal-neocortical interactions during periods of awake rest following an active encoding task. We here show that these modulations involve much larger parts of the brain than previously reported in humans. Comparing changes in hippocampal coupling during post-encoding rest with those observed under active encoding, we find evidence for encoding-like hippocampal reinstatement throughout cortex during task-free periods. This suggests early systems consolidation of an experience involves reactivating not only core sensory details but multiple additional aspects of the encoding event.
Collision response and obstacle avoidance of the tethered-space net robot system with non-target objects
Authors: Zhu Weiliang , Pang Zhaojun , Si Jiyue , Du Zhonghua
Published: January 2022

Purpose

This paper aims to study the encounter issues of the Tethered-Space Net Robot System (TSNRS) with non-target objects on orbit during the maneuver, including the collision issues with small space debris and the obstacle avoidance from large obstacles.

Design/methodology/approach

For the collision of TSNRS with small debris, the available collision model of the tethered net and its limitation is discussed, and the collision detection method is improved. Then the dynamic response of TSNRS is studied and a closed-loop controller is designed. For the obstacle avoidance, the variable enveloping circle of the TSNRS has coupled with the artificial potential field (APF) method. In addition, the APF is improved with a local trajectory correction method to avoid the overbending segment of the trajectory.

Findings

The collision model coupled with the improved collision detection method solves the detection failure and speeds up calculation efficiency by 12 times. Collisions of TSNRS with small debris make the local thread stretch and deforms finally making the net a mess. The boundary of the disturbance is obtained by a series of collision tests, and the designed controller not only achieved the tracking control of the TSNRS but also suppressed the disturbance of the net.

Practical implications

This paper fills the gap in the research on the collision of the tethered net with small debris and makes the collision model more general and efficient by improving the collision detection method. And the coupled obstacle avoidance method makes the process of obstacle avoidance safer and smoother.

Originality/value

The work in this paper provides a reference for the on-orbit application of TSNRS in the active space debris removal mission.
A review on modelling and dynamic analysis of viscoelastic rotor systems
Authors: Ganguly Krishanu , Chandraker Saurabh , Roy Haraprasad
Published: January 2022

Purpose

The purpose of this study is to bring down collective information about various issues encountered in modelling of rotor systems.

Design/methodology/approach

The most important and basic part of “rotor dynamics” is the study related to its different modelling techniques which further involves the analysis of shaft for understanding the system potential, competence and reliability. The issues addressed in this study are classified mainly into two parts: the initial part gives out a vast overview of significant problems as well as different techniques applied to encounter modelling of rotor systems, while the latter part of the study describes the post-processing problem that occurs while performing the dynamic analysis.

Findings

The review incorporates the most important research works that have already placed a benchmark right from the beginning as well as the recent works that are still being carried out to further produce better outcomes. The review concludes with the modal analysis of rotor shaft to show the importance of mathematical model through its dynamic behaviour.

Originality/value

A critical literature review on the modelling techniques of rotor shaft systems is provided from earliest to latest along with its real-time application in different research and industrial fields.
Allergen's labeling of food products: regulatory practices in Morocco
Authors: Guennouni Morad , Admou Brahim , El Khoudri Noureddine , Bourrouhouat Aicha , Machraoui Safaa , Jasny El Khansaa , Hilali Abderraouf
Published: January 2022

Purpose

Allergenic substances cause food allergy, which represents a major health issue in most countries. This underlines the importance of considering the products' labeling as well as applying related regulatory practices. The objective of this study was to assess the labeling practices of allergens in food products in Morocco.

Design/methodology/approach

This cross-sectional survey was conducted on 156 food products collected from four supermarkets in a Moroccan megacity. The data related to the allergen substances (allergen declared, emphasis characters, precautionary allergen labeling) were collected from labels of food products.

Findings

The number of foods included in this research was 156, of which 7 (4.5%) did not mention the allergy alert. The analysis of the allergy alert in the others sample (149) showed 266 nonconformities, noticed in 112 (71.8%) products. The labeling emphasis characters were observed in 33.3% of products, and only 13.5% mentioned “contains allergen” as a mandatory statement to declare the presence of allergens. Allergic alerts found in places concealed, removable by the opening of the seal or difficult to see were observed in 28.9%. The use of a precautionary allergen labeling statement was noticed in 40.4% of products.

Originality/value

Moroccan regulations on food allergens are demanding like those of the European Union and more demanding than those of most African countries. However, the application of this regulation remains unsatisfactory and 266 non-conformities were found in 112 (71.8%) products. The absence of emphasis characters and the declaration in inappropriate places represent the most observed non-conformities. Therefore, Moroccan manufacturers must strictly adhere to regulations to avoid exposure of predisposed consumers to potentially threatening allergenic substances.
My job is to hide it! A role strain perspective
Authors: Sinha Sweta , Pandey Agrata
Published: January 2022

Purpose

The study presents a framework of knowledge hiding (KH) driven by positive and negative intentions. The study also highlights the impact of KH on the employee’s role-related responsibility to engage in KH.

Design/methodology/approach

We review the literature on KH from the perspective of role strain theory and propose a conceptual framework.

Findings

The study proposes a conceptual framework of KH practices driven by positive and negative intent, further segregated into organizational and personal causes of KH. The framework also depicts the positive and negative impact of KH on the employees and highlights the impact of role-related responsibility of KH.

Originality/value

This paper provides a framework to understand how role-related KH responsibilities (organization driven) and personal motives map to employee outcomes.
Designing metadata schema for a human library: a prototype
Authors: Jana Anupta , Rout Rosalien
Published: January 2022

Purpose

In the absence of a working model for describing, managing and archiving the human library resources, this study aims to attempt a practical approach that will provide all the necessary information to the library users, library professionals and researchers.

Design/methodology/approach

Initially, different metadata standards, archival projects and attributes of the human books were reviewed to identify appropriate metadata standards that accurately describe the resources of the human library. A free and open-source software; DSpace was considered for implementing newly defined metadata schema in this study. Thereafter, a set of new subject entries was incorporated to standardize the contents of the human library.

Findings

This study finds that the widely used metadata schema – Dublin Core (DC) is not appropriate to describe the contents of the human book. It shows that selected metadata elements from the types – person and event of schema.org can be used for describing, organizing and archiving the resources of the human library. It further highlights that existing subject entries are not sufficient to standardize the contents of these types of resources.

Research limitations/implications

Two metadata fields in DSpace are strongly recommended by the DSpace community to consider in the input-forms.xml file, that is why the study could not completely omit DC metadata elements in describing human books.

Originality/value

The study provides a roadmap to the library professionals on the inclusion of new metadata schemas in describing the uniquely featured resources of the library.
Y-Mat: an improved hybrid finite-discrete element code for addressing geotechnical and geological engineering problems
Authors: Liu Gang , Ma Fengshan , Zhang Maosheng , Guo Jie , Jia Jun
Published: January 2022

Purpose

Continua and discontinua coexist in natural rock materials. This paper aims to present an improved approach for addressing the mechanical response of rock masses based on the combined finite-discrete element method (FDEM) proposed by Munjiza.

Design/methodology/approach

Several algorithms have been programmed in the new approach. The algorithms include (1) a simpler and more efficient algorithm to calculate the contact force; (2) An algorithm for tangential contact force closer to the actual physical process; (3) a plastic yielding criterion (e.g. Mohr-Coulomb) to modify the elastic stress for fitting the mechanical behavior of elastoplastic materials; and (4) a complete code for the mechanical calculation to be implemented in Matrix Laboratory (MATLAB).

Findings

Three case studies, including two standard laboratory experiments (uniaxial compression and Brazilian split test) and one engineering-scale anti-dip slop model, are presented to illustrate the feasibility of the Y-Mat code and its ability to deal with multi-scale rock mechanics problems. The results, including the progressive failure process, failure mode and trajectory of each case, are acceptable compared to other corresponding studies. It is shown that, the code is capable of modeling geotechnical and geological engineering problems.

Originality/value

This article gives an improved FDEM-based numerical calculation code. And, feasibility of the code is verified through three cases. It can effectively solve the geotechnical and geological engineering problems.