bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Restraint Device to Improve Safety and Efficacy of Blood Collection During Non-Terminal Sampling of Bats
Authors: Morgan Clint N. , Mauldin Matthew R. , Jones Jeremy , Collier Brian , Nakazawa Yoshinori
Published: March 2022

There are a variety of blood collection techniques described in the literature for unanesthetized bats, which typically require multiple sharps (e.g., needles, lancets, etc.), competent animal handling for prolonged periods, and usually involve two individuals. With the challenges inherent to non-terminal sampling of blood from bats, as well as the growing need for the use of this technique across multiple disciplines and industries, an improved blood collection method is needed. We report the creation of a bat restraint device specifically designed for a single individual to safely collect blood from anesthetized or non-anesthetized bats. The utility of this restraint device is multifaceted, serving as a safety measure for both animal and handler, as well as increasing the efficiency of blood collection. The restraint device was tested during two laboratory bat studies, Afterwards, the users of the restraint device were provided with a 10-question survey questionnaire to record their opinions on its usage. In total 80% of responses were considered positive, 15% considered neutral, and 5% considered negative. Survey questions that all participants responded to positively when in comparison to the traditional method of blood collection from bats include “easier to perform”, “safer to bats”, and “safer to the individual”. While using the restraint devices during the laboratory studies, no needle sticks, bites, or scratches to laboratorians occurred, and no observable health issues or complication due to blood collection in the bats bled using the restraint devices.
Fewer non-native insects in freshwater than in terrestrial habitats across continents
Authors: Sendek Agnieszka , Baity-Jesi Marco , Altermatt Florian , Bader Martin K.-F. , Liebhold Andrew M. , Turner Rebecca , Roques Alain , Seebens Hanno , Spaak Piet , Vorburger Christoph , Brockerhoff Eckehard G.
Published: March 2022

Aim

Biological invasions are a major threat to biodiversity in both aquatic and terrestrial habitats. Insects represent an important group of species in freshwater and terrestrial habitats, and they constitute a large proportion of non-native species. However, while many non-native insects are known from terrestrial ecosystems, it remains unclear how they are represented in freshwater habitats. Comparisons of the richness of invaders relative to the richness of native species between freshwater and terrestrial habitats are scarce, which hinders syntheses of invasion processes. Here, we used data from three regions on different continents to determine whether non-native insects are under- or overrepresented in freshwater compared to terrestrial assemblages.

Location

Europe, North America, New Zealand

Methods

We compiled a comprehensive inventory of the native and non-native insect species established in freshwater and terrestrial habitats of the three study regions. We then contrasted the richness of non-native and native species among freshwater and terrestrial insects for all insect orders in each region. Using binomial regression, we analysed the proportions of non-native species in freshwater and terrestrial habitats across the three regions.

Results

In most insect orders living in freshwater, non-native species were under-represented, while they were over-represented in a number of terrestrial orders. This pattern occurred in purely aquatic orders as well as in orders with both freshwater and terrestrial species. Overall, the proportion of non-native species was significantly lower in freshwater than in terrestrial species.

Main conclusions

Despite the numerical and ecological importance of insects among all non-native species, non-native insect species are surprisingly rare in freshwater habitats, and this pattern is consistent across the three investigated study regions. We briefly review hypotheses concerning species traits and invasion pathways that are most likely to explain these patterns. Our findings contribute to a growing appreciation of drivers and impacts of biological invasions.
A cellular and molecular analysis of SoxB-driven neurogenesis in a cnidarian
Authors: Chrysostomou Eleni , Flici Hakima , Gornik Sebastian G , Salinas-Saavedra Miguel , Gahan James M , McMahon Emma T , Thompson Kerry , Hanley Shirley , Kilcoyne Michelle , Schnitzler Christine E. , Gonzalez Paul , Baxevanis Andreas D , Frank Uri
Published: March 2022

Neurogenesis is the generation of neurons from stem cells, a process that is regulated by SoxB transcription factors (TFs) in many animals. Although the roles of these TFs are well understood in bilaterians, how their neural function evolved is unclear. Here, we use Hydractinia symbiolongicarpus, a member of the early-branching phylum Cnidaria, to provide insight into this question. Using a combination of mRNA in situ hybridization, transgenesis, gene knockdown, transcriptomics, and in-vivo imaging, we provide a comprehensive molecular and cellular analysis of neurogenesis during embryogenesis, homeostasis, and regeneration in this animal. We show that SoxB genes act sequentially. Stem cells expressing Piwi1 and Soxb1, which have a broad developmental potential, become neural progenitors that express Soxb2 before differentiating into mature neural cells. Knockdown of SoxB genes resulted in complex defects in embryonic neurogenesis. Hydractinia neural cells differentiate while migrating from the aboral to the oral end of the animal, but it is unclear whether migration per se or exposure to different microenvironments is the main driver of their fate determination. Our data constitute a rich resource for studies aiming at addressing this question, which is at the heart of understanding neurological disorders in all animals, including humans.
Ontology-Aware Biomedical Relation Extraction
Authors: Aghaebrahimian Ahmad , Anisimova Maria , Gil Manuel
Published: March 2022

Motivation

Automatically extracting relationships from biomedical texts among multiple sorts of entities is an essential task in biomedical natural language processing with numerous applications, such as drug development or repurposing, precision medicine, and other biomedical tasks requiring knowledge discovery. Current Relation Extraction (RE) systems mostly use one set of features, either as text, or more recently, as graph structures. The state-of-the-art systems often use resource-intensive hence slow algorithms and largely work for a particular type of relationship. However, a simple yet agile system that learns from different sets of features has the advantage of adaptability over different relationship types without an extra burden required for system re-design.

Results

We model RE as a classification task and propose a new multi-channel deep neural network designed to process textual and graph structures in separate input channels. We extend a Recurrent Neural Network (RNN) with a Convolutional Neural Network (CNN) to process three sets of features, namely, tokens, types, and graphs. We demonstrate that entity type and ontology graph structure provide better representations than simple token-based representations for RE. We also experiment with various sources of knowledge, including data resources in the Unified Medical Language System (UMLS) to test our hypothesis. Extensive experiments on four well-studied biomedical benchmarks with different relationship types show that our system outperforms earlier ones. Thus, our system has state-of-the-art performance and allows processing millions of full-text scientific articles in a few days on one typical machine.
Crimp: fast and scalable cluster relabeling based on impurity minimization
Authors: Lautenschlager Ulrich
Published: March 2022

Motivation

To analyze population structure based on multilocus geno-type data, a variety of popular tools perform model-based clustering, as-signing individuals to a prespecified number of ancestral populations. Since such methods often involve stochastic components, it is a common practice to perform multiple replicate analyses based on the same input data and parameter settings. Their results are typically affected by the label-switching phenomenon, which complicates their comparison and summary. Available tools allow to mitigate this problem, but leave room for improvements, in particular, regarding large input datasets.

Results

In this work, I present Crimp, a lightweight command-line tool, which offers a relatively fast and scalable heuristic to align clusters across multiple replicate clusterings consisting of the same number of clusters. For small problem sizes, an exact algorithm can be used as alternative. Additional features include row-specific weights, input and output files similar to those of CLUMPP (Jakobsson & Rosenberg, 2007), and the evaluation of a given solution in terms of either CLUMPP’s and its own objective functions. Benchmark analyses show that Crimp, especially when applied to larger datasets, tends to outperform alternative tools considering runtime requirements and various quality measures.

Availability

Crimp’s source code along with precompiled binaries for Linux and Windows, usage guidelines and benchmark code are freely available at https://github.com/ulilautenschlager/crimp.

Contact

ulrich.lautenschlager@ur.de
Neural activity in the anterior cingulate cortex is required for effort-based decision making
Authors: Kashay Adrienne Q. , Cheung Jovian Y. , Vaknalli Rahil N. , Delaney Molly J. , Navarro Michael B. , Junaidi Christabelle , Veenker Faith , Neuwirth Morgan E. , Gabriel Christopher J. , DeNardo Laura A. , Wilke Scott A.
Published: March 2022

Adaptive decision making requires the evaluation of cost-benefit tradeoffs to guide action selection. Effort-based decision making (EBD) involves weighing predicted gains against effort costs and is disrupted in several neuropsychiatric disorders. The anterior cingulate cortex (ACC) is postulated to control effort-based choice via its role in encoding the value of overcoming effort costs in rodent EBD assays. However, temporally precise methods of manipulating neural activity have rarely been applied to EBD. We developed and validated a mouse version of the barrier T-maze EBD task, in which action selection is spatiotemporally segregated from surmounting an effortful obstacle and effort is minimally confounded with time cost. Optogenetic silencing of ACC excitatory neurons during action selection, rapidly and reversibly impaired preference to exert greater effort for a larger reward, when a less effortful alternative was available. Detailed analysis of mouse choice trajectories revealed that silencing ACC disrupts kinematics, especially prior to high effort choices. However, there were no effects on overall mobility or tendency to exert effort in non-choice assays. These findings establish causality between ACC neural activity and effortful action selection during spatial cost-benefit decision making.

SIGNIFICANCE STATEMENT

Disturbances in evaluating effort-based costs during decision making occur in depression, schizophrenia, addiction and Parkinson’s disease. Precisely resolving the function of prefrontal brain regions in mediating these processes will reveal key loci of dysfunction and potential therapeutic intervention in these disorders.
Marked regional glial heterogeneity in the human white matter of the central nervous system
Authors: Seeker Luise A. , Bestard-Cuche Nadine , Jäkel Sarah , Kazakou Nina-Lydia , Bøstrand Sunniva M. K. , Kilpatrick Alastair M. , Van Bruggen David , Kabbe Mukund , Pohl Fabio Baldivia , Moslehi Zahra , Henderson Neil C. , Vallejos Catalina A. , Manno Gioele La , Castelo-Branco Gonçalo , Williams Anna
Published: March 2022

The myelinated white matter tracts of the central nervous system (CNS) are essential for fast transmission of electrical impulses and are commonly affected in neurodegenerative diseases. However, these often uniquely human diseases differentially affect white matter regions, at various ages and between males and females, and we hypothesised that this is secondary to physiological variation in white matter glia with region, age and sex. Using single nucleus RNA sequencing of healthy human post-mortem samples, we find marked glial heterogeneity with tissue region (primary motor cortex, cerebellum, cervical spinal cord), with tissue-specific cell populations of oligodendrocyte precursor cells and astrocytes, and a spinal cord-enriched oligodendrocyte type that appears human-specific. Spinal cord microglia but not astrocytes show a more activated phenotype compared to brain. These regional effects, with additional differentially expressed genes with age and sex in all glial lineages, help explain pathological patterns of disease – essential knowledge for therapeutic strategies.
The genomics and physiology of abiotic stressors associated with global elevation gradients inArabidopsis thaliana
Authors: Gamba Diana , Lorts Claire , Haile Asnake , Sahay Seema , Lopez Lua , Xia Tian , Takou Margarita , Kulesza Evelyn , Elango Dinakaran , Kerby Jeffrey , Yifru Mistire , Bulafu Collins E. , Wondimu Tigist , Glowacka Katarzyna , Lasky Jesse R.
Published: March 2022

Phenotypic and genetic diversity inArabidopsis thalianamay be associated with adaptation along its wide elevational range. We took a multi-regional view of elevational adaptation and in a diverse panel of ecotypes measured plant responses to high elevation stressors: low partial CO2pressure, high light, and night freezing. We conducted genome-wide association studies (GWAS) and found evidence of contrasting locally adaptive clines between regions. Western Mediterranean ecotypes showed low δ13C/early flowering at low elevations to high δ13C/late flowering at high elevations, while Asian ecotypes showed the opposite pattern. We mapped different candidate genes for each region, and trait-associated SNPs often showed elevational clines likely maintained by selection. Antioxidants and pigmentation showed regional differentiation but rarely elevational clines. GWAS for antioxidants identified an ascorbate transporterPHT4;4(AT4G00370), which we show alters non-photochemical quenching kinetics under high light and may be involved in local adaptation to Moroccan mountains. The low-antioxidantPHT4;4GWAS allele was associated with lowerPHT4;4expression and this haplotype was characterized by binding sites of a transcription factor family, DOF, involved in light response. Our results highlight how physiological and genomic elevational clines in different regions can be unique, underlining the complexity of local adaptation in widely distributed species.
Influenza infection in ferrets with SARS-CoV-2 infection history
Authors: de Melo Caroline Vilas Boas , Peters Florence , van Dijken Harry , Lenz Stefanie , van de Ven Koen , Wijsman Lisa , Gommersbach Angéla , Schouten Tanja , van Kasteren Puck B. , Judith van den Brand , de Jonge Jørgen
Published: March 2022

Non-pharmaceutical interventions (NPIs) to contain the SARS-CoV-2 pandemic drastically reduced human-to-human interactions, decreasing the circulation of other respiratory viruses as well. As a consequence, influenza virus circulation – normally responsible for 3-5 million hospitalizations per year globally – was significantly reduced. With downscaling the NPI countermeasures, there is a concern for increased influenza disease, particularly in individuals suffering from post-acute effects of SARS-CoV-2 infection. To investigate this possibility, we performed a sequential influenza H1N1 infection 4 weeks after an initial SARS-CoV-2 infection in the ferret model. Upon H1N1 infection, ferrets that were previously infected with SARS-CoV-2 showed an increased tendency to develop clinical symptoms compared to the control H1N1 infected animals. Histopathological analysis indicated only a slight increase for type II pneumocyte hyperplasia and bronchitis. The effects of the sequential infection thus appeared minor. However, ferrets were infected with B.1.351-SARS-CoV-2, the beta variant of concern, which replicated poorly in our model. The histopathology of the respiratory organs was mostly resolved 4 weeks after SARS-CoV-2 infection, with only reminiscent histopathological features in the upper respiratory tract. Nevertheless, SARS-CoV-2 specific cellular and humoral responses were observed, confirming an established infection. Thus, there may likely be a SARS-CoV-2 variant-dependent effect on the severity of disease upon a sequential influenza infection as we observed mild effects upon a mild infection. It, however, remains to be determined what the impact is of more virulent SARS-CoV-2 variants.

Importance

During the COVID-19 pandemic, the use of face masks, social distancing and isolation were not only effective in decreasing the circulation of SARS-CoV-2, but also in reducing other respiratory viruses such as influenza. With less restrictions, influenza is slowly returning. In the meantime, people still suffering from long-COVID, could be more vulnerable to an influenza virus infection and develop more severe influenza disease. This study provides directions to the effect of a previous SARS-CoV-2 exposure on influenza disease severity in the ferret model. This model is highly valuable to test sequential infections under controlled settings for translation to humans. We could not induce clear long-term COVID-19 effects as SARS-CoV-2 infection in ferrets was mild. However, we still observed a slight increase in influenza disease severity compared to ferrets that had not encountered SARS-CoV-2 before. It may therefore be advisable to include long-COVID patients as a risk group for influenza vaccination.
Does contrast-enhancement improve visualisation of lenticulostriate arteries in cerebral small vessel disease using time-of-flight magnetic resonance angiography at 7 Tesla?
Authors: Osuafor Christopher N. , Rua Catarina , Mackinnon Andrew D. , Egle Marco , Benjamin Philip , Tozer Daniel J. , Rodgers Christopher T. , Markus Hugh S.
Published: March 2022

Background And Purpose

7 Tesla-field-strength (7T) Magnetic Resonance Imaging (MRI) allows the small perforating arteries in the brain to be visualised, and this modality may allow visualisation of the arterial pathology in cerebral small vessel disease (cSVD). Most studies have used standard Time-of-Flight (ToF) Magnetic Resonance Angiography (MRA). Whether the use of contrast enhancement improves perforating artery visualisation at 7T remains unclear.

Materials And Methods

In a prospective study, we compared standard ToF MRA with contrast-enhanced (CE) ToF MRA at 7T for the visualisation of the lenticulostriate arteries (LSAs). Ten patients with symptomatic lacunar stroke were recruited (mean age, SD, 64±9.9 years). Visualisation was assessed using a visual rating scale administered by two independent expert readers and length of the LSAs visible.

Results

Visualisation of the LSAs was improved with CE ToF MRA. The mean Visibility and Sharpness Score was higher for CE ToF MRA over standard ToF MRA (2.55±0.64 vs 1.75±0.68; P=0.0008). The mean length of LSA visualised was significantly longer with CE ToF MRA compared to standard ToF MRA (24.4±4.5 vs 21.9±4.0 mm; P=0.01).

Conclusion

CE ToF MRA offers improved visualisation of the LSAs over standard ToF MRA. The addition of contrast may improve the ability to visualise cerebral small vessel disease arterial pathology.
Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer’s disease
Authors: Hu Jin , Zhu Hongrui , Yang Qihua , Shen Huidan , Chai Guolin , Zhang Boxin , Chen Shaoxuan , Chen Qiang , Cai Zhiyu , Li Xuewen , Hong Fan , Li Hongda , Hou Lichao , Mo Wei
Published: March 2022

The pathology of Alzheimer’s disease (AD) is associated with the extracellular amyloid-β (Aβ) plaques that perturb the mechanical properties of brain tissue. Microglia sense and integrate biochemical cues in their local microenvironment, intimate linking with AD progress. However, neither the microglial mechanosensing pathway nor its impact on AD pathogenesis is well studied. Here, we showed that the mechanosensitive ion channel Piezo1 is increased in microglia upon stiffness stimuli of Aβ fibrils. The upregulation of Piezo1 in Aβ plaque-associated microglia was observed in AD mouse models and human patients. Microglia lacking Piezo1 disturbed microglial clustering, phagocytosis, and compaction of Aβ plaques, resulting in the exacerbation of Aβ and neurodegenerative pathologies in AD. Conversely, pharmacological activation of Piezo1 ameliorated brain Aβ burden and cognitive impairment in the 5×FAD mouse. Together, our results reveal Piezo1, as a mechanosensor of Aβ fibrils stiffness in microglia, could represent a promising therapeutic target for AD.
Genetics of Fertility Restoration in A1 Cytoplasmic Genetic Male Sterility (CGMS) Systems in Sorghum (Sorghum bicolor L. Moench)
Authors: Narkhede Gopal W , Mehtre Shivaji P , Ingle Krishnananda P , Romana Kirandeep Kaur , Vinutha KS , Deshpande Santosh P
Published: March 2022

The cause of Cytoplasmic Genetic Male Sterility (CGMS) is specific nuclear and mitochondrial interactions. Almost all commercial sorghum hybrids were developed using the A1 cytoplasmic genetic male sterility system. Understanding the inheritance of fertility restoration in sorghum for A1 cytoplasm, for example, can improve the selection efficiency of restorer lines for increased seed production. In a cross of male sterile line 296A with A1 cytoplasm and restorer lines comprised of a set of Recombinant Inbred Lines (RILs), the inheritance pattern of fertility restoration of sorghum was studied. The F1 hybrid was completely fertile, revealing the dominant nature of fertility restoration, which is controlled by one or two major genes with modifiers. In this study, the genetics of fertility restoration of the A1 cytoplasmic nuclear male sterility system (CGMS) in sorghum were investigated in segregating F2 and BC1 populations of A1 cytoplasm crosses. Fertility restoration was governed by a monogenic inheritance (3F:1S) mechanism represented by a single dominant gene responsible for fertility restoration in all of the crosses studied.
Successor-like representation guides the prediction of future events in human visual cortex and hippocampus
Authors: Ekman Matthias , Kusch Sarah , de Lange Floris P.
Published: March 2022

Human agents build models of their environment, which enable them to anticipate and plan upcoming events. However, little is known about the properties of such predictive models. Recently, it has been proposed that hippocampal representations take the form of a predictive map-like structure, the so-called successor representation. Here we used human fMRI to probe whether activity in the early visual cortex (V1) and hippocampus adhere to the postulated properties of the successor representation after visual sequence learning. Participants were exposed to an arbitrary spatiotemporal sequence consisting of four items (A-B-C-D). We found that after repeated exposure to the sequence, merely presenting single sequence items (e.g., - B - -) resulted in V1 activation at the successor locations of the full sequence (e.g., C-D), but not at the predecessor locations (e.g., A). This highlights that visual representations are skewed toward future states, in line with the successor representation. Similar results were also found in the hippocampus. Moreover, the hippocampus developed a tuning profile that showed sensitivity to the temporal distance in sequence-space, with fading representations for sequence events in the more distant past and future. V1, in contrast, showed a tuning profile that was only sensitive to spatial distance in stimulus-space. Together, these results provide empirical evidence for the proposition that both visual and hippocampal cortex represent a predictive map of the visual world akin to the successor representation.
The gender gap in academic career achievements and the mediation effect of work-family conflict and partner support
Authors: Zheng Xiang , Yuan Haimiao , Ni Chaoqun
Published: March 2022

Parenthood has long been associated with gender disparities in academia. Yet, the underlying mechanism of how parenting is associated with career achievement gaps of academics remains unclear. Using data from a large-scale survey distributed to 7,764 scholars and their publication profiles from the Web of Science database, we analyze the gender differences in parenthood, academic achievements, and the mediation effect of work-family conflict and partner support in these gender gaps. Our results suggest that gender gaps in academic achievements are in fact “parenthood gaps”. Specifically, we found significant gender gaps exist in all measures of objective and subjective career achievements of academics in the parent group but not in the non-parent group. Additionally, mothers are more likely than fathers to experience higher levels of work-family conflict, and receive lower levels of partner support, contributing significantly to the gender gaps in objective and subjective career achievements for the parent group. Findings from this study identify the forms and the impact of parenthood on gender disparities in career achievements of academics and shed light on possible interventions and actions for mitigating gender inequalities in academia.
Examination of genome-wide ortholog variation in clinical and environmental isolates of the fungal pathogen Aspergillus fumigatus
Authors: Horta Maria Augusta , Steenwyk Jacob , Mead Matthew E. , dos Santos Luciano H. Braz , Zhao Shu , Gibbons John G. , Marcet-Houben Marina , Gabaldón Toni , Rokas Antonis , Goldman Gustavo H.
Published: March 2022

Aspergillus fumigatus is both an environmental saprobe and an opportunistic human fungal pathogen. Knowledge of genomic variation across A. fumigatus isolates is essential for understanding the evolution of pathogenicity, virulence, and resistance to antifungal drugs. Here, we investigated 206 A. fumigatus isolates (133 clinical and 73 environmental isolates) aiming to identify genes with variable presence across isolates and test whether this variation was related to the clinical or environmental origin of isolates. The PanCore genome of A. fumigatus constitutes 13,085 ortholog groups, of which 7,773 (59.4%) are shared by all isolates (CORE) and 5,312 (40.6%) vary in their gene presence across isolates (ACCESSORY). Despite differences in the distribution of orthologs across all isolates, no significant differences were observed among clinical vs. environmental isolates when accounting for phylogeny. Orthologs that differ in their distribution across isolates tend to occur in low frequency and/or be restricted to specific isolates; thus, the degree of genomic conservation between orthologs of A. fumigatus is high. These results suggest that differences in the distribution of orthologs within A. fumigatus cannot be associated with the clinical or environmental origin of isolates.

Importance

Aspergillus fumigatus is a cosmopolitan species of fungi responsible for thousands of cases of invasive disease. Clinical and environmental isolates of A. fumigatus exhibit extensive phenotypic differences, including differences related to virulence and antifungal drug resistance. A comprehensive survey of the genomic diversity present in A. fumigatus and its relationship to the clinical or environmental origin of isolates can contribute to the prediction of the mechanisms of evolution and infection of the species. Our results suggest that there is no significant variation in ortholog distribution between clinical and environmental isolates when accounting for evolutionary history. The work supports the hypothesis that environmental and clinical isolates of A. fumigatus do not differ in their gene contents.
Long-term cellular cargo tracking reveals intricate trafficking through active cytoskeletal networks
Authors: Park Jin-Sung , Lee Il-Buem , Moon Hyeon-Min , Hong Seok-Cheol , Cho Minhaeng
Published: March 2022

A eukaryotic cell is a microscopic world within which efficient material transport is essential. To examine cargo transport in a crowded cellular environment, we tracked unlabeled cargos in directional motion in a massively parallel fashion using the interferometric scattering microscopy. Our label-free, cargo-tracing method revealed not only dynamic cargo transportation but also the fine architecture of the actively used cytoskeletal highways and the long-term evolution of the associated traffic at sub-diffraction resolution via a myriad of molecular strokes. Cargos experience a traffic jam, but they have an effective strategy to circumvent it: moving together in tandem or migrating collectively. All taken together, a cell is an incredibly complex and busy space where the principle and practice in transportation intriguingly parallel those of our macroscopic world.
International comparison of the impact of the pandemic and vaccination measures adopted on children and adolescent population
Authors: Rajmil Luis , Pinzón-Segura María-Camila , Yaw Appiah Seth Christopher , Ekpenyong Bernadine , González Fernando , Gündoğdu Zuhal , Oncel Selim , Çakıcı Özlem
Published: March 2022

Background

The objectives of this study were to compare the cumulative incidence, hospitalizations and mortality, by country and age group, in child and young people (CYP) from the beginning of the pandemic to January 2022, and to describe the differences and similarities and justification in the measures adopted in relation to CYP vaccination against SARS-CoV-2.

Methods

A descriptive quantitative summary of the available data on the impact of the COVID-19 on children and adolescents (<18y) from 7 countries (Chile, Colombia, Paraguay, Nigeria, Ghana, Spain) or regions (Kocaeli, Turkey), based on official published data was performed. Outcome measures were: available data on incidence, admission to hospital and to intensive care units (ICU), and deaths, by country or region; vaccination plans, including age, type of vaccine and official justification about the proposal.

Results

All countries analyzed data showed variable incidence rate, and relatively low ICU hospitalizations and deaths. Vaccines used and age at starting were also variable, i.e. starting at 3-5y in some Latin American countries, while in other countries proposal starts at 15y old. Almost all justifications were based on the idea to promote collective protection, and that vaccination is important as it -directly and indirectly-protect the rest of the population.

Conclusions

The results reinforce the idea of the urgent need to prioritize globally and equitably distribution of vaccines in the population at greatest risk, and to apply the precautionary principle in CYP before deciding to massively vaccinate it.

What is known

The child population has less severe infections and seems to transmit the infection less than the adult population.

Published data from the Randomized Clinical Trials (RCT) of vaccines in minors presented short follow-up than in the adult population and basically studied the incidence of infection as the main endpoint

What this study adds

Mortality in the child population due to COVID-19 since the start of the pandemic has been low in all the countries analyzed

The vaccines used as well as the vaccination guidelines shows high variability in these countries

The results of the study reinforce the need to establish global and equitable mechanisms for the distribution of vaccines and prioritize the population at greatest risk, such as older people.

In the child population, it is necessary to apply the precautionary principle before establishing massive vaccination plans
The scope and needs related to training, research, and mentorship among early-career addiction medicine professionals: an online global survey followed by expert group discussions
Authors: Bhad Roshan , Achab Sophia , Rafei Parnian , Kathiresan Preethy , Ardabili Hossein Mohaddes , Butner Jenna L. , Orsolini Laura , Melby Katrine , Farokhnia Mehdi , Narasimha Venkata Lakshmi , Ridley Kelly , Tolomeo Serenella , Kanabar Mitika , Matanje Beatrice , Grandinetti Paolo ,   ISAM NExT Consortium, Potenza Marc N. , Ekhtiari Hamed , Baldacchino Alexander
Published: March 2022

Addiction medicine is a developing field, with many young professionals opting for a career in this area. However, globally, early-career professionals often face challenges in this field, such as lack of competency-based training due to a shortage of trainers, low availability of institutions with appropriate infrastructure, and limited resources for adequate training, particularly in developing countries. On the other hand, in developed countries, early career professionals may struggle with mentorship, limited job opportunities, and challenges with establishing a suitable research area.

The International Society of Addiction Medicine (ISAM) New Professionals Exploration, Training & Education (NExT) committee, a global platform for early-career addiction medicine professionals (ECAMPs), conducted an online survey using a modified Delphi-based approach among ECAMPs across 56 countries to assess and understand the need and scope for standardized training, research opportunities, and mentorship. The survey was conducted in 2 phases. A total of 110 respondents participated in Phase I (online key informant survey), and 28 respondents participated in Phase II (online expert group discussions on the three themes identified in Phase I). Most participants agreed with the lack of standardized training, structured mentorship programmes, research funding, and research opportunities in addiction medicine for ECAMPs. There is a need for standardized training programmes, improving research opportunities, and effective mentorship programmes to promote the next generation of addiction medicine professionals and further development to the entire field. The efforts of ISAM-NExT are well-received and give a template of how this gap can be addressed.
A screening tool enhances home-based identification of adolescents (aged 10-14) living with HIV in Zambia and South Africa: HPTN 071 (PopART) Study
Authors: Chaila Mwate Joseph , Macleod David , Vermund Sten H , Thornicroft Moomba Mbolongwe , Mbewe Madalitso , Mubekapi-Musadaidzwa Constance , Harper Abigail , Schaap Albertus , Floyd Sian , Hoddinott Graeme , Hayes Richard , Fidler Sarah , Ayles Helen , Shanaube Kwame
Published: March 2022

Introduction

The HPTN071 (PopART) for Youth (P-ART-Y) study evaluated the acceptability and uptake of a community-level combination HIV prevention package including universal testing and treatment (UTT) among young people in Zambia and South Africa (SA). We determined whether a four-question primary care level screening tool, validated for use in clinical settings, could enhance community (door-to-door) identification of undiagnosed HIV-positive younger adolescents (aged 10-14) who are frequently left out of HIV interventions.

Method

Community HIV-care Providers (CHiPs) contacted and consented adolescents in their homes and offered them participation in the PopART intervention. CHiPs used a four question-screening tool, which included: history of hospital admission; recurring skin problems; poor health in last 3 months; and death of at least one parent. A “yes” response to one or more questions was classified as being “at risk” of being HIV-positive. The data were captured through an electronic data capturing device from August 2016 to December 2017. Proportions of adolescents who were deemed “at risk” were calculated and the association of screening “at risk” with age, sex and community was tested using a chi-squared test. The adjusted odds ratio (OR) comparing the odds of testing HIV-positive if “at risk” with the odds of testing positive if “not at risk” was estimated using logistic regression.

Results

In our 14 study sites, 33,283 adolescents aged 10-14 in Zambia and 8,610 in SA participated in the study. About 1.3% (427/33,710) and 1.2% (106/8,610) self-reported to be HIV positive. Excluding the self-reported HIV-positive, we classified 11.3% (3,746/33,283) of adolescents in Zambia and 17.5% (1,491/8,504) in SA as “at risk”. In Zambia and SA, the “at risk” adolescents were 4.6 and nearly 16.7 times more likely to test HIV-positive compared to the “not at risk”, respectively (both p<0.001). Using the screening tool, one-third of HIV-positive adolescents could be diagnosed using just a tenth of the number of HIV tests compared to universal testing.

Conclusion

The screening tool may be of some value where UTT is not possible and limited resources must be prioritised toward adolescents who are more likely to be living with HIV. Further, the tool is of greater value in settings where there are more adolescents living with HIV who are undiagnosed. However, given our goal is to identify and treat all ALHIV, as well as link all HIV uninfected young people to prevention services, this screening tool should not be a substitute for UTT in community settings.

Clinical Trial Number

NCT01900977
Vaccine Effectiveness Against Hospitalization Among Adolescent and Pediatric SARS-CoV-2 Cases in Ontario, Canada
Authors: Simmons Alison E. , Amoako Afia , Grima Alicia , Murison Kiera , Buchan Sarah A , Tuite Ashleigh , Fisman David
Published: March 2022

Background: Vaccines against SARS-CoV-2 have been shown to reduce risk of infection, as well as severe disease among those with breakthrough infection, in adults. The latter effect is particularly important as Immune evasion by Omicron variants appears to have made vaccines less effective for prevention of infection. There is currently little available information on the protection conferred by vaccination against severe illness due to SARS-CoV-2 in children. Methods: To minimize confounding by changing vaccination practices and dominant circulating viral variants, we performed an age- and time-matched nested case-control design. Reported SARS-CoV-2 case records in Ontario children and adolescents aged 4 to 17 were linked to vaccination records. We used multivariable logistic regression to estimate the effectiveness of one and two vaccine doses against hospitalization. Results: We identified 130 hospitalized SARS-CoV-2 cases and 1,300 non-hospitalized, age- and time-matched controls, with disease onset between May 28, 2021 and January 9, 2022. One vaccine dose was shown to be 34% effective against hospitalization among SARS-CoV-2 cases (aOR = 0.66 [95% CI: 0.34, 1.21]). In contrast, two doses were 56% (aOR = 0.44 [95% CI: 0.23, 0.83]) effective at preventing hospitalization among SARS-CoV-2 cases. Exploratory instrumental variable analyses, and calculation of E-values, suggested that these effects are unlikely to be explained by unmeasured confounding. Conclusions: Even with immune evasion by SARS-CoV-2 variants, two vaccine doses continue to provide protection against hospitalization among adolescent and pediatric SARS-CoV-2 cases, even when the vaccines do not prevent infection.
Vimentin intermediate filaments organize organellar architecture in response to ER stress
Authors: Cremer Tom , Voortman Lenard M. , Bos Erik , van Elsland Daphne M. , ter Haar Laurens R. , Koning Roman I. , Berlin Ilana , Neefjes Jacques
Published: March 2022

Compartmentalization of organelles in space and time affects their functional state and enables higher order regulation of essential cellular processes. How organellar residence is maintained in a defined area of the cell remains poorly understood. In this study, we uncover a new role for intermediate filaments in the maintenance of organellar architecture and dynamics, which is executed through a functional connection between Vimentin and the ER-embedded ubiquitin ligase ring finger protein 26 (RNF26). While the ubiquitin ligase function of RNF26 promotes perinuclear positioning of endolysosomes, its catalytically inactive mutant I382R preferentially binds Vimentin through the RNF26 C-terminal tail. Loss of either RNF26 or Vimentin redistributes endolysosomes throughout the cytosol and mobilizes ER membranes from the perinuclear ER towards the periphery. Furthermore, RNF26 and Vimentin control changes in ER morphology and organelle compartmentalization during ER stress. Collectively, we define a new function for Vimentin-containing intermediate filaments as anchors of a dynamic interplay between the ER and endosomes, critical to the integrity of the perinuclear ER and corresponding perinuclear endosomal cloud during homeostatic and stress conditions.

Synopsis

The perinuclear area hosts a wide variety of cellular organelles, and their interaction with the ER governs essential cellular processes. To spatiotemporally organize endosomes and ER in the perinuclear region, the ER-embedded E3 ubiquitin ligase RNF26 interacts with Vimentin to physically link the perinuclear ER membrane with the intermediate filament cytoskeleton. As a result, Vimentin ensures perinuclear RNF26 retention, which in turn controls the perinuclear location of ER membranes and endosomes, which can be affected during stressed conditions.

Vimentin interacts with inactive RNF26 in the ER membrane

RNF26 by virtue of the Vimentin interaction controls perinuclear organization of ER membranes and the endosomal system

Vimentin immobilizes ER membranes in the perinuclear area

Vimentin and RNF26 compartmentalize organelles in the perinuclear region during ER stress

We define a new function of Vimentin intermediate filaments in the control of the perinuclear endosomal and ER organization
Patient-derived parathyroid organoids as tracer and drug-screening application model
Authors: Noltes Milou E. , Sondorp Luc H.J. , Kracht Laura , Antunes Inês F. , Wardenaar René , Kelder Wendy , Kemper Annelies , Szymanski Wiktor , Zandee Wouter T. , Jansen Liesbeth , Brouwers Adrienne H. , Coppes Robert P. , Kruijff Schelto
Published: March 2022

Parathyroid diseases are characterized by dysregulation of calcium homeostasis and alterations in parathyroid hormone (PTH) excretion. The understanding of parathyroid hyperplastic growth and the development of parathyroid-targeted treatment and imaging tracers could benefit from in vitro models. Therefore, we aim to establish stem cell-derived, three-dimensional organoids representing human parathyroid tissue in vitro. Patient-derived hyperplastic parathyroid tissue was dispersed and parathyroid organoids (PTO) were cultured and characterized. PTO-derived cells were shown to exhibit in vitro self-renewal over several passages, indicative of the presence of putative stem cells. Immunofluorescence and RNA-sequencing confirm that PTO phenocopy hyperplastic parathyroid tissue. Exposure of PTO to increasing calcium concentrations and to PTH-lowering drugs resulted in a significantly reduced PTH excretion. Next to this, the PTO showed specific binding of 11C-methionine to the targeted receptor. Additionally, when organoids were incubated with 99mTc-sestamibi, we observed a higher uptake in PTOs from patients with a 99mTc-sestamibi positive scan compared to patients with a negative scan. These data show functionality of PTOs resembling the parathyroid. In conclusion, we present a patient-derived PTO culture, that recapitulates the originating tissue on gene and protein expression and functionality. This PTO model paves the way for future physiology studies and therapeutic target and tracer discovery.
FKS1 is required for Cryptococcus neoformans fitness in vivo: application of copper-regulated gene expression to mouse models of cryptococcosis
Authors: Beattie Sarah R. , Jezewski Andrew J. , Ristow Laura C. , Wellington Melanie , Krysan Damian J.
Published: March 2022

There is an urgent need for new antifungals to treat cryptococcal meningoencephalitis, a leading cause of mortality in people living with HIV/AIDS. An important aspect of antifungal drug development is the validation of targets to determine whether they are required for the survival of the organism in animal models of disease. In Cryptococcus neoformans, a copper-regulated promoter (pCTR4-2) has been used to modulate gene expression in vivo previously. The premise for these experiments is that copper concentrations vary depending on the host niche. Here, we directly test this premise and confirm that the expression of CTR4, the promoter used to regulate gene expression, is much lower in the mouse lung compared to the brain. To further explore this approach, we applied to the gene encoding 1,3-β-glucan synthase, FKS1. In vitro, reduced expression of FKS1 has little effect on growth but does activate the cell wall integrity stress response and increase susceptibility to caspofungin, a direct inhibitor of Fks1. These data suggest that compensatory pathways that reduce C. neoformans resistance do so through post-transcriptional effects. In vivo, however, a less pronounced reduction in FKS1 expression leads to a much more significant reduction in lung fungal burden (~1 log10 CFU), indicating that the compensatory responses to a reduction in FKS1 expression are not as effective in vivo as they are in vitro. In summary, use of copper-regulated expression of putative drug targets in vitro and in vivo can provide insights into the biological consequences of reduced activity of the target during infection.

Importance

Conditional expression systems are widely used to genetically validate antifungal drug targets in mouse models of infection. Copper-regulated expression using the promoter of the CTR4 gene has been sporadically used for this purpose in C. neoformans. Here, we show that CTR4 expression is low in the lung and high in the brain, establishing the basic premise behind this approach. We applied it to the study of FKS1, the gene encoding for the target of the echinocandin class of 1,3-β-glucan synthase inhibitors. Our in vitro and in vivo studies indicate that C. neoformans tolerates extremely low levels of FKS1 expression. This observation provides a potential explanation for the poor activity of 1,3-β-glucan synthase inhibitors toward C. neoformans.
Effects of mucin and DNA concentrations in airway mucus on Pseudomonas aeruginosa biofilm recalcitrance
Authors: Rouillard Kaitlyn R. , Kissner William J. , Markovetz Matthew R. , Hill David B.
Published: March 2022

The pathological properties of airway mucus in cystic fibrosis (CF) are dictated by mucus concentration and composition, with mucins and DNA being responsible for mucus viscoelastic properties. As CF pulmonary disease progresses, the concentrations of mucins and DNA increase and are associated with increased mucus viscoelasticity and decreased transport. Similarly, the biophysical properties of bacterial biofilms are heavily influenced by the composition of their extracellular polymeric substances (EPS). While the roles of polymer concentration and composition in mucus and biofilm mechanical properties have been evaluated independently, the relationship between mucus concentration and composition and the biophysical properties of biofilms grown therein remains unknown. Pseudomonas aeruginosa biofilms were grown in airway mucus as a function of overall concentration and DNA concentration to mimic healthy and CF physiology and biophysical properties were evaluated with macro- and microrheology. Biofilms were also characterized after exposure to DNase or DTT to examine the effects of DNA and mucin degradation, respectively. Identifying critical targets in biofilms for disrupting mechanical stability in highly concentrated mucus may lead to the development of efficacious biofilm therapies and ultimately improve CF patient outcomes. Overall mucus concentration was the predominant contributor to biofilm viscoelasticity and both DNA degradation and mucin reduction resulted in compromised biofilm mechanical strength.