bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis B virus infection in the Lao PDR: A systematic review
Authors: Hefele Lisa , Nouanthong Phonethipsavanh , Hübschen Judith M. , Muller Claude P , Black Antony P
Published: January 2022

Introduction

Even though hepatitis B is endemic in the Lao PDR, the understanding of the epidemiology of hepatitis B infection is incomplete. This article reviews the available literature about hepatitis B seroprevalence, risk factors and genotypes in the Lao population in order to provide an up- to date summary of the HBV epidemiology in the Lao PDR, identify knowledge gaps and provide public health recommendations.

Methods

Using PubMed/Medline and ScienceDirect, all studies reporting the prevalence of hepatitis B markers or genotype distribution in the Lao PDR published were systematically reviewed.

Results

The 21 studies included focused on the general population, blood donors, women, children, health care workers and garment factory workers. The studies varied extensively in sample size, target population, methods, study location and time periods. The prevalence of the hepatitis B surface antigen (HBsAg) in blood donors was reported to be 8.7%-9.6% in 2003-2006. In the years 2011-2012, the reported HBsAg prevalence among women (including pregnant women) ranged from 0%-9.5% and among children aged 5-9 years from 1.7%-8.7%, depending on study location and age. The majority of strains characterized in Lao PDR belonged to genotypes B and C.

Conclusion

Studies displayed considerable heterogeneity in populations, design and laboratory methods. A high HBsAg prevalence was reported in adults including pregnant women. Low infant vaccination coverage and compromised vaccine immunogenicity were found. Only two studies focused on HBV in risk populations, emphasizing the need for further studies to characterize hepatitis B epidemiology in potentially vulnerable groups. Hepatitis B infection continues to represent a substantial public health threat in the Lao PDR and needs to be monitored to inform health authorities and to counteract over-burdening of the health care system. In order to end mother to child transmission, vaccination coverage with the hepatitis B birth dose should be increased.
Are allergic diseases a risk factor for systemic side effects after COVID-19 vaccines?
Authors: Atayik Emel , Aytekіn Gökhan
Published: January 2022

Background/ aim

Mass vaccination seems to be the most effective way to turn back to the pre-pandemic period and end the pandemic. Unfortunately, COVID-19 vaccines have some side effects. In phase studies of currently-approved COVID-19 vaccines, patients with a known allergy or a history of anaphylaxis were excluded from the studies. This situation creates doubts about the course of atopy and the presence of allergic disease related to the side effects of COVID-19 vaccines in patients with allergic diseases. Therefore, our aim with this study was to evaluate local side effects (LSE) and systemic side effects (SSE) after COVID-19 vaccines in patients with allergic diseases and to determine possible risk factors.

Materials and Methods

Six hundred forty-eight adult patients who received any COVID-19 vaccine between April 1, 2021 and September 30, 2021 and agreed to participate in the study were included in this case-control retrospective study.

Results

Six hundred forty-eight adult patients [Female: 446 (68.8%), Male: 202 (32.2%)] participated in the study. After the 1st dose of COVID-19 vaccine, 24.1% of patients reported SSE. After the 2nd dose of COVID-19 vaccine, 67 patients (12.3%) developed SSE. Female gender (OR: 1.757, 95%Cl: 1.143-2.702, p: 0.010), history of previous COVID-19 infection (OR: 1.762, 95%Cl: 1.068-2.906, p: 0.026), and COVID-19 vaccine type administered (OR: 4.443, 95% CI: 2.640-7.476, p<0.001) were found to be independent risk factors for SSE after COVID-19 vaccines. Premedication (OR: 0.454, 95% Cl: 0.281-0.733, p<0.001), was found to be a protective factor for SSE developing after COVID-19 vaccines.

Conclusion

CoronoVac and Pfizer-BioNTech COVID-19 vaccines are shown to be well tolerated. Patients with allergic disease do not have an increased risk for SSE that may develop after COVID-19 vaccines. Moreover, doubts or fears about possible side effects in the allergic patient group should not be an obstacle to COVID-19 vaccination.
Evidence on the role of journal editors in the COVID19 infodemic: metascientific study analyzing COVID19 publication rates and patterns
Authors: Grisi Gabriel , Barreto Segundo Joao de Deus , Freire Camila Veronica , Matias Denise , Cruz Mariana , Laporte Larrie Rabelo , Medina Daniel , Taniguchi Thiago Masashi , Requiao Leticia , Goes Bruno , Correia Luis Claudio Lemos
Published: January 2022

ABSTRACT

Objective: Infodemic, a neologism characterizing an excess of fast-tracked low quality publications, has been employed to depict the scientific research response to the COVID19 crisis. The concept relies on the presumed exponential growth of research output. This study aimed to test the COVID19 infodemic claim by assessing publication rates and patterns of COVID19-related research and a control, a year prior.

Design: A Reproduction Number of Publications (Rp) was conceived. It was conceptualized as a division of a week incidence of publications by the average of publications of the previous week. The publication growth rates of preprint and MEDLINE-indexed peer-reviewed literature on COVID19 were compared using the correspondent Influenza output, a year prior, as control. Rp for COVID19 and Influenza papers and preprints were generated and compared and then analyzed in light of the respective growth patterns of their papers and preprints.

Main outcomes: Output growth rates and Reproduction Number of Publications (Rp).

Results: COVID19 peer-reviewed papers showed a fourteen fold increase compared to Influenza papers. COVID19 papers and preprints displayed an exponential growth curve until the 20th week. COVID19 papers displayed Rp=3.17±0.72, while the control group presented Rp=0.97±0.12. Their preprints exhibited Rp=2.18±0.54 and Rp=0.97±0.27 respectively, with no evidence of exponential growth in the control group, as its Rp remained approximately one.

Conclusions: COVID19 publications displayed an epidemic pattern. As the growth patterns of COVID19 peer-reviewed articles and preprints were similar, and the majority of the COVID19 output came from indexed journals, not only authors but also editors appear to had played a significant part on the infodemic.

Review protocol: https://osf.io/q3zkw/?view_only=ff540dc4630b4c6e9a2639d732047324

Ethical aspects: No ethical clarence was required as all analyzed data were publicly available.
A brain atlas of the camouflaging dwarf cuttlefish,Sepia bandensis
Authors: Montague Tessa G. , Rieth Isabelle J. , Gjerswold-Selleck Sabrina , Garcia-Rosales Daniella , Aneja Sukanya , Elkis Dana , Zhu Nanyan , Kentis Sabrina , Rubino Frederick A. , Nemes Adriana , Wang Katherine , Hammond Luke A. , Emiliano Roselis , Ober Rebecca A. , Guo Jia , Axel Richard
Published: January 2022

The coleoid cephalopods (cuttlefish, octopus, and squid) are a group of soft-bodied marine mollusks that exhibit an array of interesting biological phenomena, including dynamic camouflage, complex social behaviors, prehensile regenerating arms, and large brains capable of learning, memory, and problem-solving [1–10]. The dwarf cuttlefish,Sepia bandensis, is a promising model cephalopod species due to its small size, substantial egg production, short generation time, and dynamic social and camouflage behaviors [11]. Cuttlefish dynamically camouflage to their surroundings by changing the color, pattern and texture of their skin. Camouflage is optically-driven, and is achieved by expanding and contracting hundreds of thousands of pigment-filled saccules (chromatophores) in the skin, which are controlled by motor neurons emanating from the brain. We generated a dwarf cuttlefish brain atlas using magnetic resonance imaging (MRI), deep learning, and histology, and we built an interactive web tool (cuttlebase.org) to host the data. Guided by observations in other cephalopods [12–20], we identified 32 brain lobes, including two large optic lobes (75% the total volume of the brain), chromatophore lobes whose motor neurons directly innervate the chromatophores of the color-changing skin, and a vertical lobe that has been implicated in learning and memory. This brain atlas provides a valuable tool for exploring the neural basis of cuttlefish behavior.
Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case
Authors: Tatham Lee , Kipar Anja , Sharp Joanne , Kijak Edyta , Herriott Joanne , Neary Megan , Box Helen , Gallardo Toledo Eduardo , Valentijn Anthony , Cox Helen , Pertinez Henry , Curley Paul , Arshad Usman , Rajoli Rajith KR , Rannard Steve , Stewart James , Owen Andrew
Published: January 2022

Background

Ronapreve demonstrated clinical application in post-exposure prophylaxis, mild/moderate disease and in the treatment of seronegative patients with severe COVID19 prior to the emergence of the Omicron variant in late 2021. Numerous reports have described loss ofin vitroneutralisation activity of Ronapreve and other monoclonal antibodies for BA.1 Omicron and subsequent sub-lineages of the Omicron variant. With some exceptions, global policy makers have recommended against the use of existing monoclonal antibodies in COVID19. Gaps in knowledge regarding the mechanism of action of monoclonal antibodies are noted, and further preclinical study will help understand positioning of new monoclonal antibodies under development.

Objectives

The purpose of this study was to investigate the impact of Ronapreve on compartmental viral replication as a paradigm for a monoclonal antibody combination. The study also sought to confirm absence ofin vivoactivity against BA.1 Omicron (B.1.1.529) relative to the Delta (B.1.617.2) variant.

Methods

Virological efficacy of Ronapreve was assessed in K18-hACE2 mice inoculated with either the SARS-CoV-2 Delta or Omicron variants. Viral replication in tissues was quantified using qRT-PCR to measure sub-genomic viral RNA to the E gene (sgE) as a proxy. A histological examination in combination with staining for viral antigen served to determine viral spread and associated damage.

Results

Ronapreve reduced sub-genomic viral RNA levels in lung and nasal turbinate, 4 and 6 days post infection, for the Delta variant but not the Omicron variant of SARS-CoV-2 at doses 2-fold higher than those shown to be active against previous variants of the virus. It also appeared to block brain infection which is seen with high frequency in K18-hACE2 mice after Delta variant infection. At day 6, the inflammatory response to lung infection with the Delta variant was altered to a mild multifocal granulomatous inflammation in which the virus appeared to be confined. A similar tendency was also observed in Omicron infected, Ronapreve-treated animals.

Conclusions

The current study provides evidence of an altered tissue response to the SARS-CoV-2 after treatment with a monoclonal antibody combination that retains neutralization activity. These data also demonstrate that experimental designs that reflect the treatment use case are achievable in animal models for monoclonal antibodies deployed against susceptible variants. Extreme caution should be taken when interpreting prophylactic experimental designs when assessing plausibility of monoclonal antibodies for treatment use cases.
Structural basis for the neurotropic AAV9 and the engineered AAVPHP.eB recognition with cellular receptors
Authors: Xu Guangxue , Zhang Ran , Li Huapeng , Yin Kaixin , Ma Xinyi , Lou Zhiyong
Published: January 2022

Clade F adeno-associated virus (AAV) 9 has been utilized as therapeutic gene delivery vector, and it is capable of crossing blood brain barrier (BBB). Recently, an AAV9 based engineering serotype with enhanced BBB crossing ability, AAVPHP.eB, further expand clade F AAVs’ usages in the central nervous system (CNS) gene delivery. In this study, we determined the cryo-electron microscopy (cryo-EM) structures of the AAVPHP.eB, and its parental serotype AAV9 alone or in complex with their essential receptor Adeno-associated virus receptor (AAVR). These structures reveal the molecular details of their AAVR recognition, where the polycystic kidney disease (PKD) repeat domain 2 (PKD2) of AAVR interact to the 3-fold protrusions and the raised capsid regions between the 2- and 5-fold axes termed the 2/5-fold wall of both AAV9 and AAVPHP.eB virions. The interacting patterns of AAVR to AAV9 and AAVPHP.eB are similar with what was observed in AAV1/AAV2-AAVR complexes. Moreover, we found that AAVPHP.eB variable region VIII (VR-VIII) may independently facilitate the new receptor recognition responsible for enhanced CNS transduction. Our study provides insights into different receptor recognition for engineered AAVPHP.eB and parental serotype AAV9, and further reveal the potential molecular basis underlying their different tropism.
Latent circuit inference from heterogeneous neural responses during cognitive tasks
Authors: Langdon Christopher , Engel Tatiana A.
Published: January 2022

Higher cortical areas carry a wide range of sensory, cognitive, and motor signals supporting complex goal-directed behavior. These signals are mixed in heterogeneous responses of single neurons tuned to multiple task variables. Dimensionality reduction methods used to analyze neural responses rely merely on correlations, leaving unknown how heterogeneous neural activity arises from connectivity to drive behavior. Here we present a framework for inferring a low-dimensional connectivity structure—the latent circuit—from high-dimensional neural response data. The latent circuit captures mechanistic interactions between task variables and their mixed representations in single neurons. We apply the latent circuit inference to recurrent neural networks trained to perform a context-dependent decision-making task and find a suppression mechanism in which contextual representations inhibit irrelevant sensory responses. We validate this mechanism by confirming the behavioral effects of patterned connectivity perturbations predicted by the latent circuit structure. Our approach can reveal interpretable and causally testable circuit mechanisms from heterogeneous neural responses during cognitive tasks.
Quantitative clonal analysis reveals vast heterogeneity among fallopian tube cells for ovarian cancer-initiation and progression
Authors: Zeng Jianhao , Alvarez-Yela Astrid Catalina , Casarez Eli , Jiang Ying , Wang Lixin , Kelly Brianna E. , Ke Eugene , Jenkins Taylor , Atkins Kristen A. , Janes Kevin A. , Slack-Davis Jill K. , Zong Hui
Published: January 2022

Different cellular compartments within a tissue present distinct cancer-initiating capacities. Current approaches to delineate cancer-initiating heterogeneity require a well-understood lineage hierarchy and cell-specific genetic tools, which are lacking for many tissues. Here, we circumvented this hurdle and investigated the capacity of fallopian tube cells in initiating serous ovarian cancer, utilizing a mouse genetic system that generates scattered GFP-labeled mutant cells. Through quantitative tracing of clonal expansion of individual mutant cells, we revealed that only a rare primitive subset enriched in the distal fallopian tube is capable of clonal expansion whereas others stall immediately upon acquiring oncogenic mutations. Expanded clones from this subset then encountered further attrition: many stalled shortly after while others sustained small cluster of proliferative cells and biased differentiation toward primitive fate. Taken together, our study showcases quantitative clonal tracing as a powerful approach to investigate cancer-initiating heterogeneity and clonal trajectory in tissues with limited prior knowledge.
A qualitative study exploring the impact of the COVID-19 pandemic on People Who Inject Drugs (PWID) and drug service provision in the UK: PWID and service provider perspectives
Authors: May Tom , Dawes Jo , Fancourt Daisy , Burton Alexandra
Published: January 2022

Background

People Who Inject Drugs (PWID) are subject to distinct socio-structural inequalities that can expose them to high risks of COVID-19 transmission and related health and social complications. In response to COVID-19 mitigation strategies, these vulnerabilities are being experienced in the context of adapted drug treatment service provision, including reduced in-person support and increased regulatory flexibility in opioid substitution therapy (OST) guidelines. This study aimed to explore the longer-term impact of the pandemic on the health and wellbeing of PWID in the UK, including provider and client experiences of treatment changes.

Methods

Interviews were conducted with 19 PWID and 17 drug treatment providers between May – September 2021, recruited from third-sector drug services in the UK. Data were analysed using reflexive thematic analysis.

Results

Most participants expressed ongoing fears of COVID-19 transmission, although socio-structural inequalities limited the contexts in which physical distancing could be practised. In addition, virus mitigation strategies altered the risk environment for PWID, resulting in ongoing physical (e.g. changing drug use patterns, including transitions to crack cocaine, benzodiazepine and pregabalin use) and socio-economic harms (e.g. limited opportunities for sex work engagement and income generation). Finally, whilst clients reported some favourable experiences from service adaptations prompted by COVID-19, including increased regulatory flexibility in OST guidelines, there was continued scepticism and caution among providers toward sustaining any treatment changes beyond the pandemic period.

Conclusions

Whilst our findings emphasize the importance of accessible harm reduction measures attending to changing indices of drug-related harm during this period, there is a need for additional structural supports to ensure pre-existing disparities and harms impacting PWID are not exacerbated further by the conditions of the pandemic. In addition, any sustained policy and service delivery adaptations prompted by COVID-19 will require further attention if they are to be acceptable to both service users and providers.
Prediction of Hospital Outpatient Attendance in UK Hospitals: A Retrospective Study Applying Machine Learning to Routinely Collected Data for Patients of All Ages
Authors: Holdship Jonathan , Dhanoa Harpreet , Hopper Adrian , Steves Claire J. , Butler Mark , Wolfe Ingrid , Tucker Katie , Cooper Carolyn , Yates Jeremy
Published: January 2022

Objectives

Patient non-attendance at outpatient appointments is a major concern for healthcare providers. Non-attendances increase waiting lists, reduce access to care and may be detrimental not for the patient who did not attend. We aim to produce a model which can accurately predict which appointments will be attended.

Setting

A teaching hospital in London, UK combining secondary and tertiary care.

Participants

A set of 9.6 million outpatient appointments between April 2015 and September 2019 including all ages and specialities.

Primary and secondary outcome measures

Area under the receiver operating characteristic curve (AU-ROC) for prediction of outpatient appointment non-attendances.

Results

The model uses 27 predictors to achieve an AUROC score of 0.768 (95% CI: 0.767-0.769) and accuracy of 89.2% (95% CI: 89.16%-89.24%) on test data. We find that the waiting period between booking and the appointment, the patient’s past attendance behaviour, and the levels of deprivation in their local area are important factors in predicting future attendance.

Conclusion

Our model successfully predicts patient attendance at outpatient appointments. Its performance on both patients who did not appear in the training data and appointments from a different time period which covers the Covid-19 pandemic indicate it generalized well across both face to face and virtual appointments and could be used to target resources and intervention towards those patients who are likely to miss an appointment. Moreover, it highlights the impact of deprivation on patient access to healthcare

Strengths and Limitation of this Study

We make use of a large dataset which enables us to use complex machine learning algorithms.

We validate the model on two large, distinct datasets giving high confidence in our model performance.

An unknown amount of patient data is missing due to a nearby hospital which shares patients with the study setting.
SARS-CoV-2 viremia precedes an IL6 response in severe COVID-19 patients: results of a longitudinal prospective cohort
Authors: Roy-Vallejo Emilia , Cardeñoso Laura , Triguero-Martínez Ana , Llano Marta Chicot , Zurita Nelly , Ávalos Elena , Barrios Ana , Hernando Julia , Ortiz Javier , Rodríguez-García Sebastián C. , Sañudo Marianela Ciudad , Marcos Celeste , Castillo Elena García , García-Rodrigo Leticia Fontán , González Begoña , Méndez Rosa , Iturrate Isabel , Sanz-García Ancor , Villa Almudena , Azofra Ana Sánchez , Quicios Begoña , Arribas David , Rodríguez Jesús Álvarez , Patiño Pablo , Trigueros Marina , Uriarte Miren , Martín-Ramírez Alexandra , Arévalo Román Cristina , Galván-Román José María , García-Vicuña Rosario , Ancochea Julio , Calleja Cecilia Muñoz , Fernández-Ruiz Elena , de la Cámara Rafael , Fernández Carmen Suárez , Álvaro Isidoro González , Rodríguez Serrano Diego A.
Published: January 2022

Background

Interleukin 6 (IL6) levels and SARS-CoV-2 viremia have been correlated with COVID-19 severity. The association over time between them has not been assessed in a prospective cohort. Our aim was to evaluate the relationship between SARS-CoV-2 viremia and time evolution of IL6 levels in a COVID-19 prospective cohort.

Methods

Secondary analysis from a prospective cohort including COVID-19 hospitalized patients from Hospital Universitario La Princesa between November 2020 and January 2021. Serial plasma samples were collected from admission until discharge. Viral load was quantified by Real-Time Polymerase Chain Reaction and IL6 levels with an enzyme immunoassay. To represent the evolution over time of both variables we used the graphic command twoway of Stata.

Results

A total of 57 patients were recruited, with median age of 63 years (IQR [53-81]), 61.4% male and 68.4% caucasian. The peak of viremia appeared shortly after symptom onset in patients with persistent viremia (more than 1 sample with >1.3 log10 copies/ml) and also in those with at least one IL6>30 pg/ml, followed by a progressive increase in IL6 around 10 days later. Persistent viremia in the first week of hospitalization was associated with higher levels of IL6. Both IL6 and SARS-CoV-2 viral load were higher in males, with a quicker increase with age.

Conclusions

In those patients with worse outcomes, an early peak of SARS-CoV-2 viral load precedes an increase in IL6 levels. Monitoring SARS-CoV-2 viral load during the first week after symptom onset may be helpful to predict disease severity in COVID-19 patients.
The Choice of Response Alternatives in COVID-19 Social Science Surveys
Authors: Wright Daniel B. , Wolff Sarah M. , Jaspal Rusi , Barnett Julie , Breakwell Glynis M.
Published: January 2022

Social science research is key for understanding and for predicting compliance with COVID-19 guidelines, and much of this research relies on survey data. While much focus is on the survey question stems, less is on the response alternatives presented that both constrain responses and convey information about the assumed expectations of the survey designers. The focus here is on the choice of response alternatives for the types of behavioral frequency questions used in many COVID-19 and other health surveys. We examine issues with two types of response alternatives. The first are vague quantifiers, like “rarely” and ‘frequently.” Using data from 30 countries from the Imperial COVID data hub, we show that the interpretation of these vague quantifiers (and their translations) depends on the norms in that country. If the mean amount of hand washing in your country is high, it is likely “frequently” corresponds to a higher numeric value for hand washing than if the mean in your country is low. The second type are precise numeric response alternatives and they can also be problematic. Using a US survey, respondents were randomly allocated to receive either response alternatives where most of the scale corresponds to low frequencies or where most of the scale corresponds to high frequencies. Those given the low frequency set provided lower estimates of the health behaviors. The choice of response alternatives for behavioral frequency questions can affect the estimates of health behaviors. How the response alternatives mold the responses should be taken into account for epidemiological modeling. We conclude with some recommendations for response alternatives for health behavioral frequency questions in surveys.
Modelling preventive measures and their effect on generation times in emerging epidemics
Authors: Favero Martina , Tomba Gianpaolo Scalia , Britton Tom
Published: January 2022

Abstract

We present a stochastic epidemic model to study the effect of various preventive measures, such as uniform reduction of contacts and transmission, vaccination, isolation, screening and contact tracing, on a disease outbreak in a homogeneously mixing community. The model is based on an infectivity process, which we define through stochastic contact and infectiousness processes, so that each individual has an independent infectivity profile. In particular, we monitor variations of the reproduction number and of the distribution of generation times. We show that some interventions, i.e. uniform reduction and vaccination, affect the former while leaving the latter unchanged, whereas other interventions, i.e. isolation, screening and contact tracing, affect both quantities. We provide a theoretical analysis of the variation of these quantities, and we show that, in practice, the variation of the generation time distribution can be significant and that it can cause biases in the estimation of basic reproduction numbers. The framework, because of its general nature, captures the properties of many infectious diseases, but particular emphasis is on COVID-19, for which numerical results are provided.
The Hyaloperanospora arabidopsidis effector HaRxL77 is hypermobile between cells and manipulates host defence
Authors: Liu Xiaokun , Bellandi Annalisa , Johnston Matthew G. , Faulkner Christine
Published: January 2022

Multicellular organisms require dynamic communication between cells, tissues and organs to integrate responses to external and internal signals. In plants, cell-to-cell communication relies in part on plasmodesmata, which connect adjacent cells and allow the exchange of signals and resources. Upon infection by pathogens, plants act to isolate infected cells from non-infected cells by closing plasmodesmata but pathogens can suppress this defence and maintain plasmodesmata in an open state. To address the question of what a pathogen might gain from keeping plasmodesmata open, we screened effectors from the biotrophic Arabidopsis pathogen Hyaloperonospora arabidopsidis (Hpa) for the ability to move cell-to-cell via plasmodesmata in plant tissues. We quantified the mobility of cytoplasmic effectors and identified six that were hypermobile, i.e., can move further than expected for a protein of that size. Of these, HaRxL77 indirectly modifies plasmodesmatal permeability to facilitate hypermobility and suppresses the flg22-induced ROS burst, suggesting that cell-to-cell mobility of effectors allows defence manipulation ahead of the infection front. Thus, this study provides novel insights into how Hpa exploits plasmodesmata-mediated intercellular connectivity to promote infection, characterising a poorly explored element of plant-pathogen interaction.

Author Summary

During infection, pathogens secrete effectors into host cells to manipulate them for their benefit. Plant cells are connected via plasmodesmata, and pathogen effectors can use these connections to reach uninfected cells. We asked what a pathogen might gain by having effectors that can travel between cells and thus screened Arabidopsis downy mildew effectors for this capability. We found downy mildew produces many cell-to-cell mobile effectors, and that some of these can move further than we might expect. One ‘hypermobile’ effector, HaRxL77, can open plasmodesmata to allow this increased mobility, although how it does this is not clear. HaRxL77 interferes with several host defence mechanisms, suggesting that cell- to-cell mobility allows effectors to perturb host defence ahead of the infection front.
Post-embryonic maturation of the C. elegans motor circuit
Authors: Mulcahy Ben , Witvliet Daniel , Mitchell James , Schalek Richard , Berger Daniel , Wu Yuelong , Holmyard Doug , Lu Yangning , Ahamed Tosif , Samuel Aravinthan , Chisholm Andrew D , Lichtman Jeff , Zhen Mei
Published: January 2022

During development, animals can maintain behavioral output even as the underlying circuits structurally remodel. After hatching, C. elegans undergoes substantial motor neuron expansion and synapse re-wiring while the animal continuously moves with an undulatory pattern. To understand how the circuit transitions from its juvenile to mature configuration without disrupting functional output, we reconstructed the C. elegans motor circuit by electron microscopy across larval development. We observed: 1) Embryonic motor neurons transiently interact with the developing post-embryonic motor neurons prior to remodeling of their juvenile wiring; 2) Post-embryonic neurons initiate synapse development with their future partners as their neurites navigate through the juvenile nerve cords; 3) Embryonic and post-embryonic neurons sequentially build structural machinery needed for the adult circuit before the embryonic neurons relinquish their roles to post-embryonic neurons; 4) This transition is repeated region by region along the body in an anterior to posterior sequence, following the birth order of post-embryonic neurons. Through this orchestrated, programmed and gradual rewiring, the motor circuit transforms from asymmetric to symmetric wiring. These maturation strategies support the continuous maintenance of motor patterns as the juvenile circuit develops into the adult configuration.

Highlights

Post-embryonic motor circuit maturation was reconstructed by synapse-resolution serial EM.

Motor patterns are maintained as the circuit matures from asymmetric to symmetric configuration.

Programmed rewiring gradually and sequentially transforms the circuit structure.

Preparatory and communicative wiring-rewiring allows maturation without functional disruption.
Species-informative SNP markers for characterising freshwater prawns of genus Macrobrachium in Cameroon
Authors: Makombu Judith G. , Cheruiyot Evans K. , Stomeo Francesca , Thuo David N. , Oben Pius M. , Oben Benedicta O. , Zango Paul , Mialhe Eric , Ngueguim Jules Romain , Mujibi Fidalis D. N.
Published: January 2022

Single Nucleotide Polymorphisms (SNPs) are now popular for a myriad of applications in animal and plant species including, ancestry assignment, conservation genetics, breeding, and traceability of animal products. The objective of this study was to develop a customized cost-effective SNP panel for genetic characterisation of Macrobrachium species in Cameroon. The SNPs identified in a previous characterization study were screened as viable candidates for the reduced panel. Starting from a full set of 1,814 SNPs, a total of 72 core SNPs were chosen using conventional approaches: a) allele frequency differentials, minor allele frequency (MAF) profiles, and Wright’s Fst statistics. The discriminatory power of reduced set of informative SNPs were then tested using the admixture analysis, principal component analysis (PCA), and discriminant analysis of principal components (DAPC). The panel of prioritised SNP markers (i.e., N = 72 SNPs) distinguished Macrobrachium species with 100% accuracy. However, large sample size is needed to identify more informative SNPs for discriminating genetically closely related species, including M. macrobrachion versus M. vollenhovenii and M. sollaudii versus M. dux. Overall, the findings in this study show that we can accurately characterise Macrobrachium using a small set of core SNPs which could be useful for commercial breeding operations, conservation, and species assignment of this economically important species in Cameroon. Given the results obtained in this study, a larger independent validation sample set will be needed to confirm the discriminative capacity of this SNP panel for wider commercial and research applications.
Single cell profiling reveals functional heterogeneity and serial killing in human peripheral and ex vivo-generated CD34+ progenitor derived Natural Killer cells
Authors: Subedi Nikita , Verhagen Liesbeth Petronella , de Jonge Paul , Van Eyndhoven Laura , van Turnhout Mark C. , Koomen Vera , Baudry Jean , Eyer Klaus , Dolstra Harry , Tel Jurjen
Published: January 2022

Increasing evidence suggest that Natural killer (NK) cells are composed of distinct functional subsets. This multi-functional role displayed by NK cells have made them an attractive choice for anti-cancer immunotherapy. A functional NK cell repertoire is generated through cellular education, resulting in heterogeneous NK cell population with distinct capabilities to respond to different stimuli. The application of a high-throughput droplet-based microfluidic platform allows monitoring of NK cell-target cell interactions at single-cell level and in real-time. Through fluorescence-based screening of around 80,000 droplets, with different Effector:Target ratios, a fully automated image analysis allows for the assessment of individual killing events in each droplet over time. We observed a variable response of single NK cells towards different target cells and identified a distinct population of NK cells capable of inducing multiple target lysis, coined as serial killers. To meet the increasing clinical demand for NK cells several sources, such as umbilical cord blood (UCB), have successfully been explored. By assessing the cytotoxic dynamics, we showed that single UCB-derived CD34+ hematopoietic progenitor (HPC)-NK cells display superior anti-tumor cytotoxicity. Additionally, with an integrated analysis of cytotoxicity and cytokine secretion we showed that target cell interactions augmented cytotoxic as well as secretory behavior of NK cells. By providing an in-depth assessment over NK cell functions, this study provides crucial information on diversity and functional characteristics of peripheral blood NK cells and ex vivo-generated HPC-NK cells to develop and improve of NK cell-based cancer immunotherapy.
Evolutionary conserved aspects of animal nutrient uptake and transport in sea anemone vitellogenesis
Authors: Lebouvier Marion , Miramón-Puértolas Paula , Steinmetz Patrick R. H.
Published: January 2022

Vitellogenesis, the accumulation of egg yolk, relies on the transport of dietary nutrients from the gut to the ovary through the circulatory system in many bilaterians (e.g. vertebrates, arthropods). How these dietary nutrients and yolk precursors are absorbed and transported in cnidarians (e.g. corals, sea anemones, jellyfish), which are bi-layered and lack a circulatory system, is however only poorly understood. Here, we studied the tissues and molecules that facilitate the uptake and transport of dietary nutrients, especially lipids, towards the oocytes in the sea anemone Nematostella vectensis to better understand the evolution of systemic nutrient transport in animals. We identified the somatic gonad epithelium as one of several gastrodermal tissues specialized in phagocytosis, micropinocytosis and intracellular digestion. We showed more specifically that dietary fatty acids are absorbed by the ApolipoproteinB- and Vitellogenin-expressing somatic gonad epithelium. Their subsequent, rapid transport into the extracellular matrix (ECM) and endocytosis into oocytes is likely mediated by an evolutionary conserved Vitellogenin (Vtg)-Very Low-Density Lipoprotein Receptor (VLDLR) ligand/receptor pair. We propose that ECM-based, Vtg/VLDLR-mediated lipoprotein transport during vitellogenesis predates the cnidarian-bilaterian split and provided a mechanistic basis to evolve sophisticated circulatory systems in bilaterians.
Lysophosphatidic acid, a CSF marker in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1
Authors: Toft-Bertelsen Trine Lisberg , Barbuskaite Dagne , Heerfordt Eva Kjer , Lolansen Sara Diana , Andreassen Søren Norge , Rostgaard Nina , Olsen Markus Harboe , Norager Nicolas H. , Capion Tenna , Rath Martin Fredensborg , Juhler Marianne , MacAulay Nanna
Published: January 2022

A range of neurological pathologies can cause secondary hydrocephalus. For decades, treatment has been limited to surgical CSF diversion, as still no pharmacological options exist due to the elusive molecular nature of the CSF secretion apparatus and its regulatory properties. We have now identified phospholipid lysophosphatidic acid (LPA) as a biomarker for posthemorrhagic hydrocephalus (PHH) in patients with subarachnoid hemorrhage (SAH) and mimicked our results in an animal model of intraventricular hemorrhage (IVH). Intraventricular administration of LPA caused elevated brain water content and ventriculomegaly in experimental rats, via its action as an agonist of the choroidal transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4 was revealed as a novel regulator of ICP in experimental rats via its ability to modulate the CSF secretion rate through its direct activation of the Na+, K+, 2Cl- cotransporter (NKCC1) implicated in CSF secretion. Together, our data reveal that a biomarker present in brain pathologies with hemorrhagic events promotes CSF hypersecretion and ensuing brain water accumulation via its direct action on TRPV4 and its downstream regulation of NKCC1. TRPV4 may therefore be a promising future pharmacological target for pathologies involving disturbed brain fluid dynamics.
The central clock suffices to drive the majority of circulatory metabolic rhythms
Authors: Petrus Paul , Smith Jacob G. , Koronowski Kevin B. , Chen Siwei , Sato Tomoki , Greco Carolina M. , Mortimer Thomas , Welz Patrick-Simon , Zinna Valentina , Shimaji Kohei , Cervantes Marlene , Baldi Pierre , Muñoz-Cánoves Pura , Sassone-Corsi Paolo , Benitah Salvador Aznar
Published: January 2022

Life on Earth anticipates recurring 24-h environmental cycles via genetically-encoded molecular clocks active in all mammalian organs. Communication between these clocks is believed to control circadian homeostasis. Metabolism can be considered a form of inter- tissue communication language that results in temporal coordination of systemic metabolism between tissues. Here we characterize the extent to which clocks in different organs employ this means of communication, an area which remains largely unexplored. For this, we analysed the metabolome of serum from mice with tissue-specific expression of the clock gene Bmal1. Notably, having functional hepatic and muscle clocks can only drive a minority (13%) of the oscillating metabolites in circulation. Conversely, limiting Bmal1 expression to Syt10- expressing neurons (which are enriched in the suprachiasmatic nucleus [SCN], the master pacemaker that regulates circadian rhythms) restores rhythms to 57% of circulatory metabolites and 28% of liver transcripts, and rescues glucose intolerance. Importantly, these parameters were also restored in clock-less mice upon rhythmic feeding, indicating that the central clock mainly regulates metabolic rhythms via behavior. These findings explicate the circadian communication between tissues and highlight the importance of the central clock in governing those signals.
Multilevel Development of Cognitive Abilities in an Artificial Neural Network
Authors: Volzhenin Konstantin , Changeux Jean-Pierre , Dumas Guillaume
Published: January 2022

Several neuronal mechanisms have been proposed to account for the formation of cognitive abilities through postnatal interactions with the physical and socio-cultural environment. Here, we introduce a three-level computational model of information processing and acquisition of cognitive abilities. We propose minimal architectural requirements to build these levels and how the parameters affect their performance and relationships. The first sensorimotor level handles local nonconscious processing, here during a visual classification task. The second level or cognitive level globally integrates the information from multiple local processors via long-ranged connections and synthesizes it in a global, but still nonconscious manner. The third and cognitively highest level handles the information globally and consciously. It is based on the Global Neuronal Workspace (GNW) theory and is referred to as conscious level. We use trace and delay conditioning tasks to, respectively, challenge the second and third levels. Results first highlight the necessity of epigenesis through selection and stabilization of synapses at both local and global scales to allow the network to solve the first two tasks. At the global scale, dopamine appears necessary to properly provide credit assignment despite the temporal delay between perception and reward. At the third level, the presence of interneurons becomes necessary to maintain a self-sustained representation within the GNW in the absence of sensory input. Finally, while balanced spontaneous intrinsic activity facilitates epigenesis at both local and global scales, the balanced excitatory-inhibitory ratio increases performance. Finally, we discuss the plausibility of the model in both neurodevelopmental and artificial intelligence terms.
DciA helicase operators exhibit diversity across bacterial phyla
Authors: Blaine Helen C. , Burke Joseph T. , Ravi Janani , Stallings Christina L.
Published: January 2022

A fundamental requirement for life is the replication of an organism’s DNA. Studies inEscherichia coliandBacillus subtilishave set the paradigm for DNA replication in bacteria. During replication initiation inE. coliandB. subtilis, the replicative helicase is loaded onto the DNA at the origin of replication by an ATPase helicase loader. However, most bacteria do not encode homologs to the helicase loaders inE. coliandB. subtilis. Recent work has identified the DciA protein as a predicted helicase operator that may perform a function analogous to the helicase loaders inE. coliandB. subtilis. DciA proteins, which are defined by the presence of a DUF721 domain (termed the DciA domain herein), are conserved in most bacteria but have only been studied in mycobacteria and γ-proteobacteria (Pseudomonas aeruginosaandVibrio cholerae). Sequences outside of the DciA domain inMycobacterium tuberculosisDciA are essential for protein function but are not conserved in theP. aeruginosaandV. choleraehomologs, raising questions regarding the conservation and evolution of DciA proteins across bacterial phyla. To comprehensively define the DciA protein family, we took a computational evolutionary approach and analyzed domain architectures and sequence properties of DciA-domain containing proteins across the tree of life. These analyses identified lineage-specific domain architectures amongst DciA homologs as well as broadly conserved sequence-structural motifs. The diversity of DciA proteins represents the evolution of helicase operation in bacterial DNA replication and highlights the need for phylum-specific analyses of this fundamental biological process.

IMPORTANCE

Despite the fundamental importance of DNA replication for life, this process remains understudied in bacteria outside ofEscherichia coliandBacillus subtilis. In particular, most bacteria do not encode the helicase loading proteins that are essential inE. coliandB. subtilisfor DNA replication. Instead, most bacteria encode a DciA homolog that likely constitutes the predominant mechanism of helicase operation in bacteria. However, it is still unknown how DciA structure and function compare across diverse phyla that encode DciA proteins. In this study, we perform computational evolutionary analyses to uncover tremendous diversity amongst DciA homologs. These studies provide a significant advance in our understanding of an essential component of the bacterial DNA replication machinery.
Impaired glutamate reuptake induces synaptic mistuning in rat hippocampal slices, that can be counteracted by ketamine
Authors: Juarez Erika Vazquez , Srivastava Ipsit , Lindskog Maria
Published: January 2022

Mistuning of synaptic transmission has been proposed to underlie many psychiatric disorders, with decreased reuptake of the excitatory neurotransmitter glutamate as one contributing factor. Synaptic tuning occurs through several diverging and converging forms of plasticity. By recording evoked field postsynaptic potentials in the CA1 area in hippocampal slices, we found that inhibiting glutamate transporters using DL-TBOA causes retuning of synaptic transmission, resulting in a new steady state with reduced synaptic strength and a lower threshold for inducing long-term synaptic potentiation (LTP). Moreover, we also found reduced threshold for LTP in a rat model of depression that has decreased levels of glutamate transporters. Most importantly, we found that the antidepressant ketamine counteracts the effects of increased glutamate on the various steps involved in synaptic retuning. We therefore propose that ketamine’s mechanism of action as an antidepressant is to restore adequate synaptic tuning.
Real space in cryo-EM: the future is local
Authors: Palmer Colin M. , Aylett Christopher H. S.
Published: January 2022

Cryo-EM images have extremely low signal-to-noise levels because biological macromolecules are highly radiation-sensitive, requiring low-dose imaging, and because the molecules are poor in contrast. Confident recovery of the signal requires the averaging of many images, the iterative optimization of parameters and the introduction of much prior information. Poor parameter estimates, overfitting and variations in signal strength and resolution across the resulting reconstructions remain frequent issues. Because biological samples are real-space phenomena, exhibiting local variations, real-space measures can be both more reliable and more appropriate than Fourier-space measures. Real-space measures can be calculated separately over each differing region of an image or volume. Real-space filters can be applied according to the local need. Powerful prior information, not available in Fourier space, can be introduced in real space. Priors can be applied in real space in ways that Fourier space precludes. The treatment of biological phenomena remains highly dependent on spatial frequency, however, which would normally be handled in Fourier space. We believe that measures and filters based around real-space operations on extracted frequency bands, i.e. a series of band-pass filtered real-space volumes, and over real-space densities of striding (sequentially increasing or decreasing) resolution through Fourier space are the best way to address this and will perform better than global Fourier-space-based approaches. Future developments in image processing within the field are generally expected to be based on a mixture of both rationally designed and deep-learning approaches, and to incorporate novel prior information from developments such as AlphaFold. Regardless of approach, it is clear that `locality', through real-space measures, filters and processing, will become central to image processing.