bluuebunny/crossref_metadata_2025 huggingface dataset:
The challenge of controlling an auditory BCI in the case of severe motor disability
Authors: Séguin Perrine , Maby Emmanuel , Fouillen Mélodie , Otman Anatole , Luauté Jacques , Giraux Pascal , Morlet Dominique , Mattout Jérémie
Published: January 2023

Background

The locked-in syndrome (LIS), due to a lesion in the pons, impedes communication. This situation can also be met after some severe brain injury or in advanced Amyotrophic Lateral Sclerosis (ALS). In the most severe condition, the persons cannot communicate at all because of a complete oculomotor paralysis (Complete LIS or CLIS). This even prevents the detection of consciousness. Some studies suggest that auditory brain-computer interface (BCI) could restore a communication through a « yes-no » code.

Methods

We developed an auditory EEG-based interface which makes use of voluntary modulations of attention, to restore a yes-no communication code in non-responding persons. This binary BCI uses repeated speech sounds (alternating “yes” on the right ear and “no” on the left ear) corresponding to either frequent (short) or rare (long) stimuli. Users are instructed to pay attention to the relevant stimuli only. We tested this BCI with 18 healthy subjects, and 7 people with severe motor disability (3 “classical” persons with locked-in syndrome and 4 persons with ALS).

Results

We report online BCI performance and offline event-related potential analysis. On average in healthy subjects, online BCI accuracy reached 86% based on 50 questions. Only one out of 18 subjects could not perform above chance level. Ten subjects had an accuracy above 90%. However, most patients could not produce online performance above chance level, except for two people with ALS who obtained 100% accuracy. We report individual event-related potentials and their modulation by attention. In addition to the classical P3b, we observed a signature of sustained attention on responses to frequent sounds, but in healthy subjects and patients with good BCI control only.

Conclusions

Auditory BCI can be very well controlled by healthy subjects, but it is not a guarantee that it can be readily used by the target population of persons in LIS or CLIS. A conclusion that is supported by a few previous findings in BCI and should now trigger research to assess the reasons of such a gap in order to propose new and efficient solutions.

Clinical trial registrations

N°NCT02567201(2015) andNCT03233282(2013)
Bayesian sequential approach to monitor COVID-19 variants through positivity rate from wastewater
Authors: Montesinos-López J. Cricelio , Daza–Torres Maria L. , García Yury E. , Herrera César , Bess C. Winston , Bischel Heather N. , Nuño Miriam
Published: January 2023

Trends in COVID-19 infection have changed throughout the pandemic due to myriad factors, including changes in transmission driven by social behavior, vaccine development and uptake, mutations in the virus genome, and public health policies. Mass testing was an essential control measure for curtailing the burden of COVID-19 and monitoring the magnitude of the pandemic during its multiple phases. However, as the pandemic progressed, new preventive and surveillance mechanisms emerged. Implementing vaccine programs, wastewater (WW) surveillance, and at-home COVID-19 tests reduced the demand for mass severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. This paper proposes a sequential Bayesian approach to estimate the COVID-19 positivity rate (PR) using SARS-CoV-2 RNA concentrations measured in WW through an adaptive scheme incorporating changes in virus dynamics. PR estimates are used to compute thresholds for WW data using the CDC thresholds for low, substantial, and high transmission. The effective reproductive number estimates are calculated using PR estimates from the WW data. This approach provides insights into the dynamics of the virus evolution and an analytical framework that combines different data sources to continue monitoring the COVID-19 trends. These results can provide public health guidance to reduce the burden of future outbreaks as new variants continue to emerge. The proposed modeling framework was applied to the City of Davis and the campus of the University of California Davis.
Covariates of success in quitting smoking in the community and secondary acute or mental health care services: a rapid systematic review
Authors: Hock Emma S. , Franklin Matthew , Baxter Susan , Clowes Mark , Chilcott Jim , Gillespie Duncan
Published: January 2023

Objectives

To identify a comprehensive set of variables associated with quitting success among tobacco smokers contacting secondary healthcare services in the United Kingdom (UK) who are offered support to quit smoking and subsequently set a quit date.

Design

Rapid systematic literature review of five electronic databases.

Setting

Studies eligible for inclusion investigated quitting success in one of three contexts: (a) the general population in the UK; (b) people with a mental health condition; (c) quit attempts initiated within a secondary care setting.

Interventions

Smoking cessation intervention in a secondary care setting.

Primary and secondary outcome measures

Parameters from statistical analysis showing the effects of covariates on quitting success with a statistically significant (i.e., p-value <0.05) association.

Results

The review identified 29 relevant studies and 14 covariates of quitting success, which we grouped into four categories: demographics (age; sex; ethnicity; socio-economic conditions; relationship status, cohabitation and social network), individual health status and healthcare setting (physical health, mental health), tobacco smoking variables (current tobacco consumption, smoking history, nicotine dependence; motivation to quit; quitting history), and intervention characteristics (reduction in amount smoked prior to quitting, the nature of behavioural support, tobacco dependence treatment duration, pharmacological aids).

Conclusions

Fourteen data fields were identified that should be considered for inclusion in datasets and statistical analysis plans for evaluating the quitting outcomes of smoking cessation interventions initiated in secondary care contexts in the UK.

Trial registration

PROSPERO CRD42021254551

STRENGTHS AND LIMITATIONS OF THIS STUDY

The strengths of this review lie in the rapid but systematic approach taken and in the design of the research question and population restrictions to identify data fields important to consider in plans for the statistical analysis of the quitting outcomes of smoking cessation interventions initiated in secondary care contexts in the UK.

The limitations lie in the compromises made as part of the rapid review approach, for example, our focus only on studies published in English, not searching grey literature, limited critical appraisal of the studies found.
‘Beyond Places of Safety’ – a qualitative study exploring the implementation of mental health crisis care innovations across England
Authors: Foye Una , Appleton Rebecca , Nyikavaranda Patrick , Lyons Natasha , Dare Ceri , Lynch Chris , Persaud Karen , Ahmed Nafiso , Stuart Ruth , Schlief Merle , Huong Xia , Sevdalis Nick , Sheridan-Rains Luke , Rojas-Garcia Antonio , Stefan Martin , Clark Jeremy , Simpson Alan , Johnson Sonia , Lloyd-Evans Brynmor
Published: January 2023

Background

Mental health acute and crisis care consumes a large share of mental health budgets internationally but is often experienced as unsatisfactory and difficult to access. As a result, there is an increasing move towards developing innovative community crisis services, to improve patient experience and relieve pressure on inpatient and emergency services. This study aims to understand what helps and hinders the implementation of innovative mental health crisis care projects in England.

Methods

Using a qualitative approach, 18 interviews were conducted with crisis care service managers exploring their experiences and views of the development and implementation of their service developed with support from an English national capital funding programme. A framework analysis was conducted informed by implementation science.

Results

Key facilitators to implementation of innovative crisis services included bottom-up development, service user involvement, strong collaborative working, and leadership and management buy-in. Key barriers that affected the projects implementation included the complexities of crisis care, workforce challenges and resourcing issues.

Conclusion

There is a recognised need to improve, update, and innovate current crisis care offers. Results from this study suggest that a range of models can help address the heterogenous needs of local populations and that such services can be successfully implemented where they utilise a whole-systems approach, involving service users and relevant professional stakeholders beyond mental health services in planning and developing the service.
Prior SARS-CoV-2 Infection and COVID-19 Vaccine Effectiveness against Outpatient Illness during Widespread Circulation of SARS-CoV-2 Omicron Variant, US Flu VE Network
Authors: Tartof Sara Y. , Xie Fagen , Yadav Ruchi , Wernli Karen J. , Martin Emily T. , Belongia Edward A. , Gaglani Manjusha , Zimmerman Richard K. , Talbot H. Keipp , Thornburg Natalie , Flannery Brendan , Chung Jessie R. ,   US Flu VE Network Investigators
Published: January 2023

Background

We estimated combined protection conferred by prior SARS-CoV-2 infection and COVID-19 vaccination against COVID-19-associated acute respiratory illness (ARI).

Methods

During SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variant circulation between October 2021 and April 2022, prospectively enrolled adult patients with outpatient ARI had respiratory and filter paper blood specimens collected for SARS-CoV-2 molecular testing and serology. Dried blood spots were tested for immunoglobulin-G antibodies against SARS-CoV-2 nucleocapsid (NP) and spike protein receptor binding domain antigen using a validated multiplex bead assay. Evidence of prior SARS-CoV-2 infection also included documented or self-reported laboratory-confirmed COVID-19. We used documented COVID-19 vaccination status to estimate vaccine effectiveness (VE) by multivariable logistic regression by prior infection status.

Results

455 (29%) of 1577 participants tested positive for SARS-CoV-2 infection at enrollment; 209 (46%) case-patients and 637 (57%) test-negative patients were NP seropositive, had documented previous laboratory-confirmed COVID-19, or self-reported prior infection. Among previously uninfected patients, three-dose VE was 97% (95% confidence interval [CI], 60%– 99%) against Delta, but not statistically significant against Omicron. Among previously infected patients, three-dose VE was 57% (CI, 20%–76%) against Omicron; VE against Delta could not be estimated.

Conclusions

Three mRNA COVID-19 vaccine doses provided additional protection against SARS-CoV-2 Omicron variant-associated illness among previously infected participants.
Pathogenic accumulation of T follicular helper cells in lupus disease depends on PD-L1 and IL-4 expressing basophils
Authors: Tchen John , Simon Quentin , Chapart Léa , Lamri Yasmine , Saidoune Fanny , Pacreau Emeline , Pellefigues Christophe , Bex-Coudrat Julie , Karasuyama Hajime , Miyake Kensuke , Hidalgo Juan , Fallon Padraic G. , Papo Thomas , Blank Ulrich , Benhamou Marc , Hanouna Guillaume , Sacre Karim , Daugas Eric , Charles Nicolas
Published: January 2023

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies raised against nuclear antigens and whose production is promoted by autoreactive T follicular helper (TFH) cells. Basophils, by accumulating in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms to be defined. Here, we demonstrate that a functional relationship between TFH cells and basophils occurs in SLO during lupus pathogenesis. On SLE patient blood basophils, PD-L1 expression was upregulated and associated with TFH and TFH2 cell expansions and with disease activity. In two distinct lupus-like mouse models, TFH cell pathogenic accumulation, maintenance and function, and disease activity were dependent on basophils and their expressions of PD-L1 and IL-4. Our study establishes a direct link between basophils and TFH cells in the SLE context that promotes autoreactive IgG production and lupus nephritis pathogenesis. Altering the basophil/TFH cell axis in the SLE context may represent a promising innovative intervention strategy in SLE.
ADAPTIVE TIME LOCATION SAMPLING FOR COMPASS, A SARS-COV-2 PREVALENCE STUDY IN FIFTEEN DIVERSE COMMUNITIES IN THE UNITED STATES
Authors: Zangeneh Sahar Z , Skalland Timothy , Yuhas Krista , Emel Lynda , De Dieu Tapsoba Jean , Reed Domonique , Amos Christopher I. , Donnell Deborah , Moore Ayana , Justman Jessica ,   the CoVPN 5002 Study Team
Published: January 2023

The COVPN 5002 (COMPASS) study aimed to estimate the prevalence of SARS-CoV-2 (active SARS-CoV-2 or prior SARS-CoV-2 infection) in children and adults attending public venues in 15 socio-demographically diverse communities in the United States. To protect against potential challenges in implementing traditional sampling strategies, time-location sampling (TLS) using complex sampling involving stratification, clustering of units, and unequal probabilities of selection was used to recruit individuals from neighborhoods in selected communities. The innovative design adapted to constraints such as closure of venues; changing infection hotspots; and uncertain policies. Recruitment of children and the elderly raised additional challenges in sample selection and implementation. To address these challenges, the TLS design adaptively updated both the sampling frame and the selection probabilities over time using information acquired from prior weeks. Although the study itself was specific to COVID-19, the strategies presented in this paper could serve as a case study that can be adapted for performing rigorous population-level inferences in similar settings and could help inform rapid and effective responses to future global public health challenges.
ODNA: Identification of Organellar DNA by Machine Learning
Authors: Martin Roman , Nguyen Minh Kien , Lowack Nick , Heider Dominik
Published: January 2023

Motivation

Identifying organellar DNA, such as mitochondrial or plastid sequences, inside a whole genome assembly, remains challenging and requires biological background knowledge. To address this, we developed ODNA based on genome annotation and machine learning to fulfill.

Results

ODNA is a software that performs organellar DNA sequence classification of a genome assembly by machine learning based on a pre-defined genome annotation workflow. We trained our model with 829,769 DNA sequences from 405 genome assemblies and achieved very high predictive performance (e.g., MCC of 0.61) on independent validation data, thus outperforming existing approaches significantly.

Availability

Our software ODNA is freely accessible as a web service athttps://odna.mathematik.uni-marburg.deand can also be run in a docker container. The source code can be found athttps://gitlab.com/mosga/odnaand the processed data at Zenodo (DOI: 10.5281/zenodo.7506483).
Smooth Muscle Cell Death Drives an Osteochondrogenic Phenotype and Severe Proximal Vascular Disease in Progeria
Authors: Murtada Sae-Il , Kawamura Yuki , Cavinato Cristina , Wang Mo , Ramachandra Abhay B. , Spronck Bart , Tellides George , Humphrey Jay D.
Published: January 2023

Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end of life. We associate progressive deterioration of arterial structure and function with single cell transcriptional changes, which reveals a rapid disease process in proximal elastic arteries that largely spares distal muscular arteries. These data suggest a novel sequence of progressive vascular disease in progeria: initial extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death in proximal arteries, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotypic modulation that results in an accumulation of proteoglycans that thickens the wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased pulse wave velocity drives left ventricular diastolic dysfunction, the primary diagnosis in progeria children. Mitigating smooth muscle cell loss / phenotypic modulation promises to have important cardiovascular implications in progeria patients.
Origin Matters: Using a Local Reference Genome Improves Measures in Population Genomics
Authors: Thorburn Doko-Miles J. , Sagonas Kostas , Binzer-Panchal Mahesh , Chain Frederic J.J. , Feulner Philine G.D. , Bornberg-Bauer Erich , Reusch Thorsten BH , Samonte-Padilla Irene E. , Milinski Manfred , Lenz Tobias L. , Eizaguirre Christophe
Published: January 2023

Genome-level sequencing enables us to ask fundamental questions about the genetic basis of adaptation, population structure, and epigenetic mechanisms, but usually requires a suitable reference genome for mapping population-level re-sequencing data. In some model systems, multiple reference genomes are available, giving researchers the challenging task of determining which reference genome best suits their data. Here we compare the use of two different reference genomes for the three-spined stickleback (Gasterosteus aculeatus), one novel genome derived from a European gynogenetic individual and the published reference genome of a North American individual. Specifically, we investigate the impact of using a local reference versus one generated from a distinct lineage on several common population genomics analyses. Through mapping genome resequencing data of 60 sticklebacks from across Europe and North America, we demonstrate that genetic distance among samples and the reference impacts downstream analyses. Using a local reference genome increased mapping efficiency and genotyping accuracy, effectively retaining more and better data. Despite comparable distributions of the metrics generated across the genome using SNP data (i.e., π, Tajima’sD, andFST), window-based statistics using different references resulted in different outlier genes and enriched gene functions. A marker-based analysis of DNA methylation distributions had a comparably high overlap in outlier genes and functions, yet with distinct differences depending on the reference genome. Overall, our results highlight how using a local reference genome decreases reference bias to increase confidence in downstream analyses of the data. Such results have significant implications in all reference-genome-based population genomic analyses.
The identification and analysis of meristematic mutations within the apple tree that developed theRubyMacsport mutation
Authors: Sun Hequan , Abeli Patrick , Campoy José Antonio , Rütjes Thea , Krause Kristin , Jiao Wen-Biao , Korff Maria von , Beaudry Randy , Schneeberger Korbinian
Published: January 2023

Understanding the molecular basis of sport mutations in fruit trees can accelerate breeding of novel cultivars. For this, we analyzed the DNA of the apple tree that evolved theRubyMacphenotype through a sport mutation that introduced changes in fruit coloration in upper branches of the tree. Unexpectedly, we not only found 46de novomutations, but also 54 somatic gene conversions (i.e., loss-of-heterozygosity mutations) distinguishing the mutant and wild-type branches of the tree. Approximately 30% of thede novomutations and 80% of the gene conversions were observed only in specific cells layers suggesting that they occurred in the corresponding meristematic layers. Interestingly, thede novomutations were enriched for GC=>AT transitions, while the gene conversions showed the opposite bias for AT=>GC transitions suggesting that GC-biased gene conversions have the potential to counteract the AT-bias ofde novomutations. By comparing the gene expression patterns in fruit skins from mutant and wild-type branches, we found 56 differentially expressed genes including 18 that were involved in anthocyanin biosynthesis. While none of the differently expressed genes harbored a mutation, we found that some of the mutations affected the integrity of candidate genes in regions of the genome that were recently associated with natural variation in fruit coloration.
CellCharter reveals spatial cell niches associated with tissue remodeling and cell plasticity
Authors: Varrone Marco , Tavernari Daniele , Santamaria-Martínez Albert , Walsh Logan A. , Ciriello Giovanni
Published: January 2023

Tissues are organized in cellular niches, the composition and interactions of which can be investigated using spatial omics technologies. However, systematic analyses of tissue composition are challenged by the scale and diversity of the data. Here we present CellCharter, an algorithmic framework to identify, characterize, and compare cellular niches in spatially resolved datasets. CellCharter outperformed existing approaches and effectively identified cellular niches across datasets generated using different technologies, and comprising hundreds of samples and millions of cells. In multiple human lung cancer cohorts, CellCharter uncovered a cellular niche composed of tumor-associated neutrophils and cancer cells expressing markers of hypoxia and cell migration. This cancer cell state was spatially segregated from more proliferative tumor cell clusters and was associated with tumor-associated neutrophil infiltration and poor prognosis in independent patient cohorts. Overall, CellCharter enables systematic analyses across data types and technologies to decode the link between spatial tissue architectures and cell plasticity.
Intrinsic microtubule destabilization of multiciliated choroid plexus epithelial cells during postnatal lifetime
Authors: Ho Kim Hoa , Scarpetta Valentina , Salio Chiara , D’Este Elisa , Meschkat Martin , Wurm Christian A. , Kneussel Matthias , Janke Carsten , Magiera Maria M. , Sassoè-Pognetto Marco , Brill Monika S. , Patrizi Annarita
Published: January 2023

Choroid plexus (ChP) epithelium is composed of specialized multiciliated cells. By using multiple microscopic techniques, biochemical approaches in various mutant mice and longitudinal analysis from mouse embryogenesis to aging, we show that ChP cilia are built on a gradient of events which are spatio-temporally regulated. We uncover that ChP cilia develop prenatally since early tissue morphogenesis, and proceeds as a multi-step process characterized by basal body multiplication and axoneme formation directly at the apical cellular compartment. Our data also show that choroid plexus cilia contain both primary and motile features. Remarkably, we demonstrate that ChP cilia undergo axoneme resorption, starting from early youth, through a tubulin destabilization process, which is primarily controlled by polyglutamylation levels and could be mitigated by the removal of the microtubule-severing enzyme spastin. Notably, we demonstrate that this phenotype is preserved in human samples.
A chromosome-scale assembly for tetraploid sour cherry (Prunus cerasusL.) ‘Montmorency’ identifies three distinct ancestralPrunusgenomes
Authors: Goeckeritz Charity Z. , Rhoades Kathleen E. , Childs Kevin L. , Iezzoni Amy F. , VanBuren Robert , Hollender Courtney A.
Published: January 2023

Background

Sour cherry (Prunus cerasusL.) is a valuable fruit crop in the Rosaceae family and a hybrid between progenitors most closely related to extantP. fruticosa(ground cherry) andP. avium(sweet cherry). Sour cherry is an allotetraploid with few genomic resources, so a genome sequence would greatly facilitate the improvement of this crop. InPrunus, two known classes of genes are of particular importance to breeding strategies: the self-incompatibility loci (S-alleles), which determine compatible crosses and are critically important for successful fertilization and fruit set, and the Dormancy Associated MADS-box genes (DAMs), which strongly affect dormancy transitions and flowering time.

Results

Here we report a chromosome-scale genome assembly for sour cherry cultivar ‘Montmorency’, the predominant sour cherry cultivar grown in the U.S. We also generated a draft assembly ofP. fruticosato use alongside a publishedP. aviumsequence for syntelog-based subgenome assignments for ‘Montmorency’. Using hierarchal k-mer clustering and phylogenomics, we provide compelling evidence this allotetraploid is trigenomic, containing two distinct subgenomes inherited from aP. fruticosa-likeancestor (A and A’) and two copies of the same subgenome inherited from aP. avium-likeancestor (BB). We therefore assigned the genome composition of ‘Montmorency’ to be AA’BB and show little to no recombination has occurred between progenitor subgenomes (A/A’ and B). TheS-alleles and DAMs in ‘Montmorency’ andP. fruticosawere manually annotated and demonstrated to support the three subgenome assignments. Lastly, the hybridization event that ‘Montmorency’ is descended from was estimated to have occurred less than 1.61 million years ago, making sour cherry a relatively recent allotetraploid.

Conclusions

The genome of sour cherry cultivar Montmorency highlights the evolutionary complexity of the genusPrunus. These genomic resources will inform future breeding strategies for sour cherry, comparative genomics in the Rosaceae, and questions regarding neopolyploidy.
Firing-rate-modulated spike detection and neural decoding co-design
Authors: Zhang Zheng , Constandinou Timothy G.
Published: January 2023

Objective

Translational efforts on spike-signal-based implantable brain-machine interfaces (BMIs) are increasingly aiming to minimise bandwidth while maintaining decoding performance. Developing these BMIs requires advances in neuroscience and electronic technology, as well as using low-complexity spike detection algorithms and high-performance machine learning models. While some state-of-the-art BMI systems jointly design spike detection algorithms and machine learning models, it remains unclear how the detection performance affects decoding.

Approach

We propose the co-design of the neural decoder with an ultra-low complexity spike detection algorithm. The detection algorithm is designed to attain a target firing rate, which the decoder uses to modulate the input features preserving statistical invariance.

Main results

We demonstrate a multiplication-free fixed-point spike detection algorithm with nearly perfect detection accuracy and the lowest complexity among studies we have seen. By co-designing the system to incorporate statistically invariant features, we observe significantly improved long-term stability, with decoding accuracy degrading by less than 10% after 80 days of operation. Our analysis also reveals a nonlinear relationship between spike detection and decoding performance. Increasing the detection sensitivity improves decoding accuracy and long-term stability, which means the activity of more neurons is beneficial despite the detection of more noise. Reducing the spike detection sensitivity still provides acceptable decoding accuracy whilst reducing the bandwidth by at least 30%.

Significance

Our findings regarding the relationship between spike detection and decoding performance can provide guidance on setting the threshold for spike detection rather than relying on training or trial-and-error. The trade-off between data bandwidth and decoding performance can be effectively managed using appropriate spike detection settings. We demonstrate improved decoding performance by maintaining statistical invariance of input features. We believe this approach can motivate further research focused on improving decoding performance through the manipulation of data itself (based on a hypothesis) rather than using more complex decoding models.
Retroviral infection and commensal bacteria dependently alter the metabolomic profile in a sterile organ
Authors: Spring Jessica , Beilinson Vera , DeFelice Brian C. , Sanchez Juan M. , Fischbach Michael , Chervonsky Alexander , Golovkina Tatyana
Published: January 2023

Both viruses and bacteria produce ‘pathogen associated molecular patterns’ that may affect microbial pathogenesis and anti-microbial responses. Additionally, bacteria produce metabolites while viruses could change metabolic profiles of the infected cells. Here, we used an unbiased metabolomics approach to profile metabolites in spleens and blood of Murine Leukemia Virus-infected mice monocolonized withLactobacillus murinusto show that viral infection significantly changes the metabolite profile of monocolonized mice. We hypothesize that these changes could contribute to viral pathogenesis or to the host response against the virus and thus, open a new avenue for future investigations.
Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the Glucocorticoid Receptor
Authors: Noddings Chari M. , Johnson Jill L. , Agard David A.
Published: January 2023

Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of ‘client’ proteins, including the glucocorticoid receptor (GR)1-3. Previously, we revealed that GR ligand binding activity is inhibited by Hsp70 and restored by Hsp90, aided by co-chaperones4. We then presented cryo-EM structures mechanistically detailing how Hsp70 and Hsp90 remodel the conformation of GR to regulate ligand binding5,6.In vivo, GR-chaperone complexes are found associated with numerous Hsp90 co-chaperones, but the most enigmatic have been the immunophilins FKBP51 and FKBP52, which further regulate the activity of GR and other steroid receptors7-9. A molecular understanding of how FKBP51 and FKBP52 integrate with the GR chaperone cycle to differentially regulate GR activationin vivois lacking due to difficulties reconstituting these interactions. Here, we present a 3.01 Å cryo-EM structure of the GR:Hsp90:FKBP52 complex, revealing, for the first time, that FKBP52 directly binds to the folded, ligand-bound GR using three novel interfaces, each of which we demonstrate are critical for FKBP52-dependent potentiation of GR activityin vivo. In addition, we present a 3.23 Å cryo-EM structure of the GR:Hsp90:FKBP51 complex, which, surprisingly, largely mimics the GR:Hsp90:FKBP52 structure. In both structures, FKBP51 and FKBP52 directly engage the folded GR and unexpectedly facilitate release of p23 through an allosteric mechanism. We also reveal that FKBP52, but not FKBP51, potentiates GR ligand bindingin vitro, in a manner dependent on FKBP52-specific interactions. Altogether, we reveal how FKBP51 and FKBP52 integrate into the GR chaperone cycle to advance GR to the next stage of maturation and how FKBP51 and FKBP52 compete for GR:Hsp90 binding, leading to functional antagonism.
Ethanolaminephosphate cytidyltransferase is essential for survival, lipid homeostasis and stress tolerance inLeishmania major
Authors: Basu Somrita , Pawlowic Mattie , Hsu Fong-Fu , Thomas Geoff , Zhang Kai
Published: January 2023

Glycerophospholipids including phosphatidylethanolamine (PE) and phosphatidylcholine (PC) are vital components of biological membranes. Trypanosomatid parasites of the genusLeishmaniacan acquire PE and PC viade novosynthesis and the uptake/remodeling of host lipids. In this study, we investigated the ethanolaminephosphate cytidyltransferase (EPCT) inLeishmania major, which is the causative agent for cutaneous leishmaniasis. EPCT is a key enzyme in the ethanolamine branch of the Kennedy pathway which is responsible for thede novosynthesis of PE. Our results demonstrate thatL. majorEPCT is a cytosolic protein capable of catalyzing the formation of CDP-ethanolamine from ethanolamine-phosphate and cytidine triphosphate. Genetic manipulation experiments indicate that EPCT is essential in both the promastigote and amastigote stages ofL. majoras the chromosomal null mutants cannot survive without the episomal expression of EPCT. This differs from our previous findings on the choline branch of the Kennedy pathway (responsible for PC synthesis) which is required only in promastigotes but not amastigotes. While episomal EPCT expression does not affect promastigote proliferation under normal conditions, it leads to reduced production of ethanolamine plasmalogen or plasmenylethanolamine, the dominant PE subtype inLeishmania. In addition, parasites with epsiomal EPCT exhibit heightened sensitivity to acidic pH and starvation stress, and significant reduction in virulence. In summary, our investigation demonstrates that proper regulation of EPCT expression is crucial for PE synthesis, stress response, and survival ofLeishmaniaparasites throughout their life cycle.

AUTHOR SUMMARY

In nature,Leishmaniaparasites alternate between fast replicating, extracellular promastigotes in sand fly gut and slow growing, intracellular amastigotes in macrophages. Previous studies suggest that promastigotes acquire most of their lipids viade novosynthesis whereas amastigotes rely on the uptake and remodeling of host lipids. Here we investigated the function of ethanolaminephosphate cytidyltransferase (EPCT) which catalyzes a key step in thede novosynthesis of phosphatidylethanolamine (PE) inLeishmania major. Results showed that EPCT is indispensable for both promastigotes and amastigotes, indicating thatde novoPE synthesis is still needed at certain capacity for the intracellular form ofLeishmaniaparasites. In addition, elevated EPCT expression alters overall PE synthesis and compromises parasite’s tolerance to adverse conditions and is deleterious to the growth of intracellular amastigotes. These findings provide new insight into howLeishmaniaacquire essential phospholipids and how disturbance of lipid metabolism can impact parasite fitness.
Gestational age-dependent decrease in fetal Hofbauer cells in placentas from pregnancies exposed to wildfire smoke in California
Authors: Basilio Emilia , Ozarslan Nida , Buarpung Sirirak , Benmarhnia Tarik , Padula Amy M. , Robinson Joshua F. , Gaw Stephanie L.
Published: January 2023

OBJECTIVE

Wildfires are more common over the last decade and the frequency of wildfire events has been accelerated by climate change. The existing body of literature suggests that exposure to wildfire smoke during pregnancy contributes to adverse perinatal outcomes such as preterm birth and fetal growth restriction. We hypothesize that exposures to wildfire smoke and its constituents triggers a fetal inflammatory response which contributes to pathological changes that underlie these adverse pregnancy outcomes. In this study, we quantified the presence of fetal macrophages (i.e., Hofbauer cells) in human placentas obtained between 2018 and 2020 to assess the relationship between fetal immune status and wildfire exposure.

STUDY DESIGN

We collected placentas from pregnancies from two hospitals in San Francisco over a two-year period that included two severe major wildfires. The average particulate matter < 2.5 μm (PM2.5) or wildfire specific PM2.5levels were estimated over the gestational duration of each sample. Immunostaining against CK7 and CD68 was performed to identify intravillous fetal Hofbauer cells. We assessed the gestational-age dependent relationship between placental CD68+ cell density and mean daily PM2.5or wildfire-specific PM2.5via linear regression and Welch’s t-test. Additionally, we compared placental CD68+ cell density with estimated peak wildfire exposures during the gestation to determine if timing of exposure during pregnancy may influence the occurrence of Hofbauer cells in the placenta.

RESULTS

The gestational ages ranged from 7-41 weeks (n = 67). The majority of samples were collected during one of two major wildfire events in Northern California (70%; n = 47). In general, we observed a significant inverse relationship between placental CD68 density and PM2.5 or wildfire specific PM2.5, however, these associations were only observed in first or second trimester samples, and not in term samples. For example, among first trimester samples (n=22), we observed lower mean CD68 density among samples likely to be exposed to wildfire events (mean= 1.42,SD= 0.8) as compared to those not exposed (mean= 3.73,SD= 1.983) (p= 0.0015). Based on our linear regression model results, we predicted that a one μg/m3increase in daily mean wildfire PM2.5was associated with a 0.457 decrease in CD68 density (ß =-0.457; 95% CI: -0.722, -0.193). This association was also significant for daily mean overall PM2.5, though smaller in magnitude (ß = -0.139; 95% CI: -0.218, -0.059).

CONCLUSIONS

Our results suggest that wildfire smoke exposures are associated with decreased presence of fetal Hofbauer cells in first and second trimester placentas, suggesting exposure may lead to impaired placental function via altered presence of fetal Hofbauer cells and changes in immune status.
Bacterial community modifies host genetics effect on early childhood caries
Authors: Blostein Freida , Zou Tianyu , Bhaumik Deesha , Salzman Elizabeth , Bakulski Kelly M. , Shaffer John R. , Marazita Mary L. , Foxman Betsy
Published: January 2023

Background

By age five approximately one-fifth of children have early childhood caries (ECC). Both the oral microbiome and host genetics are thought to influence susceptibility. Whether the oral microbiome modifies genetic susceptibility to ECC has not been tested. We test whether the salivary bacteriome modifies the association of a polygenic score (PGS, a score derived from genomic data that summarizes genetic susceptibility to disease) for primary tooth decay on ECC in the Center for Oral Health Research in Appalachia 2 longitudinal birth cohort.

Methods

Children were genotyped using the Illumina Multi-Ethnic Genotyping Array and underwent annual dental examinations. We constructed a PGS for primary tooth decay using weights from an independent, genome-wide association meta-analysis. Using Poisson regression, we tested for associations between the PGS (high versus low) and ECC incidence, adjusting for demographic characteristics (n=783). An incidence-density sampled subset of the cohort (n=138) had salivary bacteriome data at 24- months of age. We tested for effect modification of the PGS on ECC case status by salivary bacterial community state type (CST).

Results

By 60-months, 20.69% of children had ECC. High PGS was not associated with an increased rate of ECC (incidence-rate ratio:1.09 (95% confidence interval (CI): 0.83, 1.42)). However, having a cariogenic salivary bacterial CST at 24-months was associated with ECC (odds ratio (OR): 7.48 (95%CI: 3.06, 18.26)), which was robust to PGS adjustment. An interaction existed between the salivary bacterial CST and the PGS on the multiplicative scale (P= 0.04). The PGS was associated with ECC (OR: 4.83 (95% CI: 1.29, 18.17)) only among individuals with a noncariogenic salivary bacterial CST (n=70).

Conclusions

Genetic causes of caries may be harder to detect when not accounting for cariogenic oral microbiomes. As certain salivary bacterial CSTs increased ECC-risk across genetic-risk strata, preventing colonization of cariogenic microbiomes would be universally beneficial.
The correlation between small papillary thyroid cancers and gamma radionuclides Cs-137, Th-232, U-238 and K-40 using spatially-explicit, register-based methods
Authors: Bayadsi Haytham , Van Den Brink Paul , Erlandsson Mårten , Gudbjornsdottir Soffia , Sebraoui Samy , Koorem Sofi , Nordin Pär , Hennings Joakim , Englund Oskar
Published: January 2023

A steep increase of small papillary thyroid cancers (sPTCs) has been observed globally. A major risk factor for developing PTC is ionizing radiation. The aim of this study is to investigate whether geological differences in the prevalence of sPTCs in Sweden are correlated to the deposit of Caecium-137, Thorium-232 (Th-232), Uranium-238 (U-238) or Potassium-40 (K-40) using different Geographical Information System (GIS) methods. Datasets of 812 sPTC patients were combined with the datasets of the total population in Sweden and were layered with the gamma radionuclide deposits. The prevalence of metastatic sPTC was associated with significantly higher levels of Gamma radiation from Th-232, U-238 and K-40. The observed results clearly indicate that sPTC has causative factors that are neither evenly distributed among the population, nor geographically, calling for further studies with bigger cohorts where environmental factors are believed to play a major role in the pathogenesis of the disease.
Depression screening in chronic hemodialysis patients
Authors: Alicja Kubanek , Mateusz Przybylak , Przemysław Paul , Sylwia Kowalska Anna , Michał Błaszczyk , Aleksandra Macul-Sanewska , Kamila Czarnacka , Krzysztof Bednarski , Katarzyna Kanclerz , Aleksandra Szydłowska , Dariusz Świetlik , Przemysław Rutkowski , Leszek Bidzan , Marcin Renke , Jakub Grabowski
Published: January 2023

Purpose

Depressive disorder is common among hemodialysis (HD) patients and is associated with higher mortality rate. However, depression screening and treatment in dialysis population remains insufficient. The aim of the study was to show the prevalence of depression in patients on maintenance HD and to discuss the proper diagnostic approach, including dementia screening.

Patients and methods

We conducted a cross-sectional study that included 103 HD patients from one Dialysis Centre in Gdańsk (Poland). Cognitive functions were evaluated using Mini–Mental State Examination (MMSE). The screening for depression was assessed using Beck Depression Inventory (BDI-II). The diagnosis of depressive disorder was confirmed and its severity evaluated by psychiatrists based upon clinical assessment and scales. Sociodemographic, laboratory and dialysis data were also collected.

Results

According to BDI-II depressive symptoms were present in 43% of patients while the diagnosis of clinical Major Depressive Disorder (MDD) was confirmed by the psychiatrists in 13% of all subjects. In the depressive disorder group there was a prevalence of female and patients suffering from diabetes mellitus, levels of calcium phosphate index (CaxPi) were higher and Kt/V was lower. The optimal cut- off score for diagnosing major depressive disorder using BDI-II was ≥ 20 points. Cognitive impairment on the level of major neurocognitive disorder (dementia) was found in 18 % of the study group.

Conclusions

The prevalence of depression assessed using self- or clinician-administered questionnaires was higher than reported by clinical interview performed by the psychiatrist. Higher scores of CaxPi and lower Kt/V in depressive patients may suggest worse compliance in this group. The psychiatrist’s examination as a part of care at the Dialysis Centre could improve diagnosis of depression and its treatment with the goal to improve quality of life and lower the mortality rate in this population.
Prevalence of substance use and associated factors among patients with mental illness at Muhimbili National Hospital, Dar es Salaam, Tanzania
Authors: Karino Kilaye , Ambikile Joel S. , Iseselo Masunga K.
Published: January 2023

The burden of substance use among patients with mental illness is prevalent in developing countries including Tanzania with negative consequences on treatment outcomes. However, the current prevalence of substance use and its associated factors in this population remains unclear in Tanzania. This study aimed at determining the prevalence of substance use and associated factors among patients with mental illness at Muhimbili National Hospital, Dar es Salaam Tanzania.

We conducted a descriptive cross-sectional study between March and May 2022. Data were collected during a face-to-face interview with patients attending the outpatient clinic at the Psychiatric Unit at MNH. We used a structured social demographic questionnaire and WHO ASSIST V3.0 tool was used to collect the data. Bivariate and multivariate regression analyses were performed using SPSS version 26 to determine the association between patient characteristics and substance use. A p-value of less than 0.05 was considered statistically significant. A total of 364 patients were enrolled. Among these, 215 (59.1%) were males and the mean (SD) age was 35.57 (±9.01) years. We found the prevalence of substance use to be 32.7%, and the most commonly used substance was alcohol (21.7%), followed by tobacco (19.8%) and cannabis (12.7%). Being a male [Adjusted Odds Ratio (AOR): 2.133; 95% Confidence Interval (CI): 1.258-3.619; P=0.005], younger age [AOR:3.301; 95% CI: 1.152-9.453; P=0.026], positive family history of mental illness [AOR:2.423; 95% CI: 1.448-4.056; P=0.001], and having a family history of substance use [AOR:3.721; 95% CI: 2.215-6.252; P=0.001], were significantly associated with substances use.

In conclusion, substance use among patients with mental illness is prevalent. Establishing a routine screening program at the psychiatric clinics is essential in identifying substance use among these risk groups and providing appropriate treatment will improve treatment outcomes. Future research should explore help-seeking behaviors and the accessibility of substance use treatment in patients with mental illness.
Understanding the Biering-Sørensen test: contributors to extensor endurance in young adults with and without low back pain
Authors: Shaw Jonathan , Jacobs Jesse V. , Van Dillen Linda R. , Beneck George J. , Smith Jo Armour
Published: January 2023

Impaired paraspinal muscle endurance may contribute to persistent low back pain (LBP) and is frequently assessed using a single repetition of the Biering-Sørensen test. This study investigated how Sørensen test duration, muscle activation, and muscle fatigability are affected by multiple repetitions of the test, and determined predictors of Sørensen test duration in young, active adults with and without a history of LBP. Sixty-four individuals with and without persistent LBP performed 3 repetitions of the Sørensen test. Amplitude of activation and median frequency slope (fatigability) were calculated for the lumbar and thoracic paraspinals and the hamstrings. Duration of the test was significantly less for the 2ndand 3rdrepetitions in individuals with LBP. In individuals without LBP, fatigability of the lumbar paraspinals was the best predictor of test duration. In individuals with LBP, Sørensen test duration was predicted by fatigability of the hamstrings and amplitude of activation of the thoracic and lumbar paraspinals. Our findings demonstrate that it is necessary to amplify the difficulty of the Sørensen test to elucidate impairments in young, active adults with LBP. Training programs aiming to improve lumbar paraspinal performance in individuals with LBP should monitor performance of other synergist muscles during endurance exercise.