bluuebunny/crossref_metadata_2025 huggingface dataset:
The Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis cohort population structure and disease etiology
Authors: Pagalilauan Alison M. , Everest Elif , Rachimi Suzanna , Reich Daniel , Waldman Alex D. , Sadovnick A. Dessa , Vilariño-Guell Carles , Lenardo Michael J.
Published: April 2024

Background

Previous genetic and epidemiological studies have examined subpopulations from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) patient cohort, but an encompassing analysis of the study population has not yet been carried out.

Objective

This study examines patterns of multiple sclerosis (MS) prevalence in 13,663 cohort members, including 4,821 patients with MS or suspected MS and 8,842 family members.

Methods

We grouped participants into epidemiologic subgroups based on age of MS onset, clinical stage at diagnosis, symptom type at disease onset, sex, proband status, disability as measured by the EDSS, and ancestry based on reported ethnicity.

Results

We observed a 2.7:1 MS prevalence ratio of women to men, though disease severity was greater for male patients. Variation in the age of disease onset between patients was only slightly associated with sex and strongly associated with disease type. Specific types of clinical symptoms at disease onset were associated with the prognosis. Regional residence did not correlate with disease onset, type, or severity.

Conclusion

Population trends, as presented here, are not explained by environmental factors alone, highlighting the need for a comprehensive genetic analysis to understand disease variance across families.
Early Detection of Novel SARS-CoV-2 Variants from Urban and Rural Wastewater through Genome Sequencing and Machine Learning
Authors: Zhuang Xiaowei , Vo Van , Moshi Michael A. , Dhede Ketan , Ghani Nabih , Akbar Shahraiz , Chang Ching-Lan , Young Angelia K. , Buttery Erin , Bendik William , Zhang Hong , Afzal Salman , Moser Duane , Cordes Dietmar , Lockett Cassius , Gerrity Daniel , Kan Horng-Yuan , Oh Edwin C.
Published: April 2024

Genome sequencing from wastewater has emerged as an accurate and cost-effective tool for identifying SARS-CoV-2 variants. However, existing methods for analyzing wastewater sequencing data are not designed to detect novel variants that have not been characterized in humans. Here, we present an unsupervised learning approach that clusters co-varying and time-evolving mutation patterns leading to the identification of SARS-CoV-2 variants. To build our model, we sequenced 3,659 wastewater samples collected over a span of more than two years from urban and rural locations in Southern Nevada. We then developed a multivariate independent component analysis (ICA)-based pipeline to transform mutation frequencies into independent sources with co-varying and time-evolving patterns and compared variant predictions to >5,000 SARS-CoV-2 clinical genomes isolated from Nevadans. Using the source patterns as data-driven reference “barcodes”, we demonstrated the model’s accuracy by successfully detecting the Delta variant in late 2021, Omicron variants in 2022, and emerging recombinant XBB variants in 2023. Our approach revealed the spatial and temporal dynamics of variants in both urban and rural regions; achieved earlier detection of most variants compared to other computational tools; and uncovered unique co-varying mutation patterns not associated with any known variant. The multivariate nature of our pipeline boosts statistical power and can support accurate and early detection of SARS-CoV-2 variants. This feature offers a unique opportunity for novel variant and pathogen detection, even in the absence of clinical testing.
Asymptomatic seroconversion in healthy people against dengue and chikungunya in Kandy district of Sri Lanka
Authors: Edirisinghe L.E.A.D.A. , Mahakapuge T.A.N. , Kularatne S.A.M. , Kularatne S.A.M.D.A. , Rajapakse R.P.V.J.
Published: April 2024

Background

Both dengue and chikungunya are transmitted byAedes aegyptiand have many similarities in epidemiology and clinical manifestations. These two viruses are known to cause asymptomatic infection, however, studies to assess the seroprevalence in healthy individuals are limited. Our objective is to estimate the asymptomatic seroconversion status of both these infections Sri Lanka where dengue has been endemic and the last notable outbreak of chikungunya occurred in 2007.

Methods

The study was performed using venous blood samples of 454 healthy individuals (age range 11-78) in Kandy district, who had no known history of dengue or chikungunya infections in the past or present. Samples were tested for dengue NS1 antigen, dengue IgM, dengue IgG, Chikungunya IgM and Chikungunya IgG by using commercially available ELISA kits. Statistical data analysis was performed using SPSS software version 16.0 (SPSS, Inc., Chicago, IL, USA).Pvalue <0.05 was considered statistically significant.

Results

Of the 454 healthy individuals, 287 (63.2%) were positive for dengue IgG indicating a past infection and 18 (4%) were positive for dengue-specific IgM. Of the same total, 82 (18.1%) were positive chikungunya chikungunya-specific IgM and only 6 (1.3%) were positive for chikungunya-specific IgM. The number of individuals positive for both dengue IgG and Chikungunya IgG, indicating dual antibody prevalence or exposure to both diseases asymptomatically was 61(13.43%). For dengue specific IgG, the highest sero-conversion rate (80.4%) was observed in 51-60 year age group whilst the lowest (50%) in the age group 11-20. Out of the MOH areas, the highest prevalence (71.4%) of positives were observed in Bambaradeniya and the lowest prevalence (53.1%) in Yatinuwara suburbs in Kandy. The highest percentage of dengue IgM prevalence (6.3%) was observed in the age group 21-30 years and the lowest percentage (1.5%) was observed in the age group 11-20.

Conclusions

An asymptomatic seroconversion rate was observed in both dengue and Chikungunya infections. Dengue records a high rate due to its endemicity and periodic outbreaks. It is interesting to note the low-grade prevalence of Chikungunya infection contrary to the belief itsnon-existence in the island currently.
Whole-genome duplication in the Multicellularity Long Term Evolution Experiment
Authors: Tong Kai , Datta Sayantan , Cheng Vivian , Haas Daniella J. , Gourisetti Saranya , Yopp Harley L. , Day Thomas C. , Lac Dung T. , Conlin Peter L. , Bozdag G. Ozan , Ratcliff William C.
Published: April 2024

Whole-genome duplication (WGD) is widespread across eukaryotes and can promote adaptive evolution1–4. However, given the instability of newly-formed polyploid genomes5–7, understanding how WGDs arise in a population, persist, and underpin adaptations remains a challenge. Using our ongoing Multicellularity Long Term Evolution Experiment (MuLTEE)8, we show that diploid snowflake yeast (Saccharomyces cerevisiae) under selection for larger multicellular size rapidly undergo spontaneous WGD. From its origin within the first 50 days of the experiment, tetraploids persist for the next 950 days (nearly 5,000 generations, the current leading edge of our experiment) in ten replicate populations, despite being genomically unstable. Using synthetic reconstruction, biophysical modeling, and counter-selection experiments, we found that tetraploidy evolved because it confers immediate fitness benefits in this environment, by producing larger, longer cells that yield larger clusters. The same selective benefit also maintained tetraploidy over long evolutionary timescales, inhibiting the reversion to diploidy that is typically seen in laboratory evolution experiments. Once established, tetraploidy facilitated novel genetic routes for adaptation, playing a key role in the evolution of macroscopic multicellular size via the origin of evolutionarily conserved aneuploidy. These results provide unique empirical insights into the evolutionary dynamics and impacts of WGD, showing how it can initially arise due to its immediate adaptive benefits, be maintained by selection, and fuel long-term innovations by creating additional dimensions of heritable genetic variation.
Evaluating the Role of Endophyte-Rich Leaves in Protecting Tropical Trees Against a Generalist Herbivore and a Pathogen
Authors: Rolón Bolívar Aponte , Arnold A. Elizabeth , Juliá Mareli Sánchez , Van Bael Sunshine A.
Published: April 2024

1.

Plants use chemical compounds and physical barriers to defend themselves against natural enemies. For instance, tough leaves are considered to be better defended than soft leaves and we can measure this spectrum of defenses via leaf functional traits. Leaf traits such as leaf chemistry, lifespan, toughness, and leaf mass per area often are a plant’s first line of defense. Plants with longer lifespans that invest more in leaf tissue and higher leaf mass per area (LMA) typically feature robust constitutive defenses (e.g., leaf toughness, thickness, and dense cell walls) as well. In contrast, plants that invest more in leaf nutrients and have low LMA often invest more in induced defenses. Whether constitutive or induced, leaf traits represent an environmental filter for foliar endophytic fungi (FEF), which may play an additional role in plant defense. Our overarching assumption is that FEF alter leaf fate by interacting directly or indirectly with leaf traits, thus reshaping successive FEF colonization, development of leaf traits and response to plant enemies. To evaluate this hypothesis, we inoculated seedlings of seven tropical tree species that varied in leaf traits with natural and diverse endophyte communities. We confirmed the success of our inoculations of low FEF load (E-) and high FEF load (E+) treatment groups via culturing and culture-free amplicon sequencing. We then measured leaf removal by leaf-cutter ants and leaf necrosis due to a generalist fungal pathogen. Across the experiment, we observed greater herbivory in theE-treatment compared to theE+treatment, but no difference in pathogen damage. However, withinE-andE+treatment groups, leaves exposed to pathogen had greater leaf damage than non-exposed leaves. Dimensionality reduction of leaf functional traits (i.e., LMA, toughness, thickness, and anthocyanin levels) revealed relationships among traits and distinct host species characteristics. All leaf functional traits had significant correlations with FEF community composition. In turn, indicator species analyses reveal functional traits and taxonomic identities of FEF associated with high- and low leaf damage by natural enemies, suggesting new insights into cryptic roles of foliar symbionts in extending and modifying plant defenses in tropical forests.
Large-scale single-virus genomics uncovers hidden diversity of river water viruses and diversified gene profiles
Authors: Nishikawa Yohei , Wagatsuma Ryota , Tsukada Yuko , Chia-ling Lin , Chijiiwa Rieka , Hosokawa Masahito , Takeyama Haruko
Published: April 2024

Environmental viruses (primarily bacteriophages) are widely recognized as playing an important role in ecosystem homeostasis through the infection of host cells. However, the majority of environmental viruses are still unknown as their mosaic structure and frequent mutations in their sequences hinder genome construction in current metagenomics. To enable the large-scale acquisition of environmental viral genomes, we developed a new single-viral genome sequencing platform with microfluidic-generated gel beads. Amplification of individual DNA viral genomes in mass-produced gel beads allows high-throughput genome sequencing compared to conventional single-virus genomics. The sequencing analysis of river water samples yielded 1431 diverse viral single-amplified genomes, while viral metagenomics recovered 100 viral metagenome-assembled genomes at the comparable sequence depth. The 99.5% of viral single-amplified genomes were determined novel at the species level, most of which could not be recovered by a metagenomic assembly. The large-scale acquisition of diverse viral genomes identified protein clusters commonly detected in different viral strains, allowing the gene transfer to be tracked. Moreover, comparative genomics within the same viral species revealed that the profiles of various methyltransferase subtypes were diverse, suggesting an enhanced escape from host bacterial internal defense mechanisms. Our use of gel bead-based single-virus genomics will contribute to exploring the nature of viruses by accelerating the accumulation of draft genomes of environmental DNA viruses.
DNA virus infections shape transposable elements activity in vitro and in vivo
Authors: Tan Jiang , Franke Vedran , Neugebauer Eva , Lagisquet Justine , Kuderna Anna Katharina , Walter Stephanie , Landthaler Markus , Ensser Armin , Stamminger Thomas , Gramberg Thomas , Akalin Altuna , Wyler Emanuel , Full Florian
Published: April 2024

Transposable elements (TEs) are implicated in a variety of processes including placental and preimplantation development and a variety of human diseases. TEs are known to be activated in the context of viral infections, but the mechanisms and consequences are not understood. We show strong activation of TEs upon DNA virus infection, in particular the MLT- and THE1-class of LTR-containing retrotransposons as well as a subset of LINE-1-, Aluelements and HERVs. Mechanistically, two pathways induce TE upregulation: inhibition of the KAP1/TRIM28 repressive complex by phosphorylation, and expression of the pioneer factor double-homeobox 4 (DUX4), which is known to be crucial for TE induction during zygotic genome activation in embryonic development. In adults, DUX4 is usually silenced and we showed DUX4 expression upon infection with various DNA viruses. DUX4 binds to TEs upon infection and analysis of genes adjacent to TEs shows pathways that are important for DNA virus infections. Analysis of knockdown, knockout and overexpression data reveal that almost all TEs expressed upon herpesviral infection are regulated by KAP1/TRIM28 and DUX4. Interestingly, analysis of single cell sequencing data from patients with DNA virus-associated cancers showed that in vivo TE expression strongly correlates with virus infection, indicating a possible role in viral oncogenesis.
Computational stabilization of a non-heme iron enzyme enables efficient evolution of new function
Authors: King Brianne R. , Sumida Kiera H. , Caruso Jessica L. , Baker David , Zalatan Jesse G.
Published: April 2024

Directed evolution has emerged as a powerful tool for engineering new biocatalysts. However, introducing new catalytic residues can be destabilizing, and it is generally beneficial to start with a stable enzyme parent. Here we show that the deep learning-based tool ProteinMPNN can be used to redesign Fe(II)/αKG superfamily enzymes for greater stability, solubility, and expression while retaining both native activity and industrially-relevant non-native functions. For the Fe(II)/αKG enzyme tP4H, we performed site-saturation mutagenesis with both the wild-type and stabilized design variant and screened for activity increases in a non-native C-H hydroxylation reaction. We observed substantially larger increases in non-native activity for variants obtained from the stabilized scaffold compared to those from the wild-type enzyme. ProteinMPNN is user-friendly and widely-accessible, and straightforward structural criteria were sufficient to obtain stabilized, catalytically-functional variants of the Fe(II)/αKG enzymes tP4H and GriE. Our work suggests that stabilization by computational sequence redesign could be routinely implemented as a first step in directed evolution campaigns for novel biocatalysts.
Novel multiparametric bulk and single extracellular vesicle pipeline for adipose cell-specific biomarker discovery in paired human biospecimens
Authors: Hade Mangesh Dattu , Greenwald Jacelyn , Palacio Paola Loreto , Nguyen Kim Truc , Shantaram Dharti , Butsch Bradley L. , Kim Yongseok , Noria Sabrena , Brethauer Stacy A. , Needleman Bradley J. , Hsueh Willa , Wysocki Vicki H. , Reátegui Eduardo , Magaña Setty M.
Published: April 2024

Obesity remains a growing and global public health burden across a broad spectrum of metabolic, systemic, and neurodegenerative diseases. Previously considered merely a fat storage depot, adipose tissue is now recognized as an active endocrine organ crucial for metabolic and systemic regulation of local and distant organs. A burgeoning line of investigation centers on adipose-derived extracellular vesicles (ADEVs) and their pivotal role in obesity-associated pathobiology. However, robust methodologies are lacking for specifically isolating and characterizing human ADEVs. To bridge this gap, we have developed a robust multiparametric framework incorporating bulk and single EV characterization, proteomics, and mRNA phenotyping. EVs from matched human visceral adipose tissue, mature adipocyte-conditioned media, and plasma collected from the same individual bariatric surgical patients were analyzed and subjected to bottom-up proteomics analysis. This framework integrates bulk EV proteomics for cell-specific marker identification and subsequent single EV interrogation with single-particle interferometric reflectance imaging (SP-IRIS) and total internal reflection fluorescence (TIRF) microscopy. Our proteomics analysis revealed 76 unique proteins from adipose tissue-derived EVs (ATEVs), 512 unique proteins from adipocyte EVs (aEVs), and 1003 shared proteins. Prominent pathways enriched in ATEVs included lipid metabolism, extracellular matrix organization, and immune modulation, while aEVs exhibited enhanced roles in chromatin remodeling, oxidative stress responses, and metabolic regulation. Notably, adipose tissue-specific proteins such as adiponectin and perilipin were highly enriched in ADEVs and confirmed in circulating plasma EVs. Colocalization of key EV and adipocyte markers, including CD63 and PPARG, were validated in circulating plasma EVs. In summary, our study paves the way toward a tissue and cell-specific, multiparametric framework for an ‘adiposity EV signature’ in obesity-driven diseases.
The causal role of adiposity in mental illness: A systematic review and meta-analysis of Mendelian randomization studies
Authors: Gao Min , Doody Paul J , Koutoukidis Dimitrios A , Yu Yebo , Aveyard Paul , Stevens Richard , Dixon Padraig C
Published: April 2024

Importance

Excess adiposity is associated with mental illnesses, but the causality of these associations remains equivocal.

Objective

To examine the causal effect of adiposity on mental illnesses by summarizing and assessing evidence from Mendelian randomization (MR) studies.

Study Selection

Searches were conducted on Embase, Medline, and Web of Science from database inception to January 8th2024.

Data Extraction and Synthesis

Studies using MR study designs that estimated adiposity measures including body mass index, abdominal adiposity, peripheral adiposity, or body composition in relation to mental illnesses were included. Study quality was assessed with a scoring system reflecting MR study guidelines. Data were pooled in meta-analyses using random-effects models. Subgroup analyses were conducted by sex.

Main Outcomes and Measures

Outcomes were the presence or severity of depression, anxiety, eating disorders, bipolar disorder, obsessive compulsive disorder, post-traumatic stress disorder, schizophrenia, and related psychotic disorders.

Results

Forty-one studies with 184 MR estimates were included in the systematic review; and 16 studies with 30 MR estimates were included in meta-analysis. Pooled estimates suggested that general adiposity was causally associated with depression (OR: 1.05, 95% CI, 1.00-1.10, p<0.001; I2=82.8%), though the effect size was modest and there was high heterogeneity. Subgroup difference by sex in the causal relationship was notobserved(p=0.382). No evidence of causal associations was found between adiposity and other mental illnesses, though these analyses were characterized by high imprecision and heterogeneity.

Conclusion and Relevance

General adiposity appears to be causally associated with depression, suggesting psychological benefits of weight management. Evidence for causal associations between adiposity and other mental illnesses remains uncertain.

Key Points

Question

Is adiposity causally associated with mental illnesses?

Findings

In this systematic review of 41 Mendelian randomization studies, with 184 MR estimates, and meta-analysis of 30 MR estimates, general adiposity was causally associated with depression. There was no evidence of sex differences. Evidence of causal associations between adiposity and other mental illnesses was unclear.

Meaning

The findings suggest that higher adiposity can cause depression, which highlights the psychological importance of weight management.
Evaluation of a participatory approach to stratifying neighbourhoods across the Tanzanian city of Dar es Salaam in terms of income by comparing with latent profile analysis of deprivation based on national census data
Authors: Msuya Ibrahim , Boudou Martin , Levira Francis , Moshi Irene , O’Dwyer Jean , Killeen Gerard
Published: April 2024

Studying geographic heterogeneities in the characteristics of city neighbourhoods, such as population income and deprivation, has been a common practice in urban health studies for tailored and targeted interventions, especially in highly developed and diversified cities. While a range of different approaches has been applied to classify different parts of towns and cities, participatory stratification approaches (PSAs) have become popular despite their subjective basis because of their affordability, simplicity and practicality, all of which allow them to be frequently updated. While more objective statistical approaches, such as latent profile analysis (LPA), can also be used to stratify neighbourhoods using formal socio-economic and demographic data, these rely on the availability of rich datasets and advanced analytical capacities that are not always available in low and middle-income countries. This study assessed a PSA to stratify neighbourhoods across the Tanzania city of Dar es Salaam in terms of income, by comparing it with a complementary LPA using national census data from 2012 to stratify them in terms of deprivation. A consultative community-based workshop was used for the PSA, while 15 selected deprivation indicators from the census data were used to profile them using LPA. While the PSA allocated neighbourhoods to five income strata, six clear deprivation strata could be distinguished by LPA. A strong positive correlation was observed between the stratum identified by the LPA and that obtained through the PSA (ρ = 0.739, p < 0.0001). Furthermore, paired comparison of the two sets of correlation coefficients between each deprivation indicator and the stratum assigned by each stratification approach revealed no difference (V = 33, p-value = 0.1354), confirming that the two approaches yielded very similar patterns of stratification., Also, the two approaches yielded broadly comparable cartographic pictures of the city, depicting similar spatial distribution of wealth and poverty. Overall, this evidence indicates that subjective community knowledge and lived experience may be invaluable for understanding the built environment and for mapping out pockets of poverty and affluence at fine scales with minimum resources.
Analyzing Predictors and Geospatial Trends of the Number of Visits and Timing of Antenatal Care in Zambia: A Generalized Linear Mixed Model (GLMM) Investigation from 1992 to 2018
Authors: Shumba Samson , Fwemba Isaac , kaymba Violet
Published: April 2024

Antenatal care (ANC) plays a crucial role in preventing and detecting pregnancy risks, facilitating prompt treatment, and disseminating essential information to expectant mothers. This role is particularly vital in developing countries, where a 4.65% rise in maternal mortality rate was observed in 2022, with 800 maternal and 7,700 perinatal deaths reported. The study aims to analyse the predictors and geospatial trends of the number of visits and timing of antenatal care in Zambia from 1992 to 2018, utilizing a generalised linear mixed model approach. The analysis utilized the Zambia Demographic Health Survey (ZDHS) database. The relationship between dependent and independent variables was examined using the Rao-Scott Chi-square test. Predictors of inadequate utilisation of ANC were identified through the multilevel generalised linear model. Spatial effects were modeled using Quantum Geographic Information System (QGIS) version 3.34.1 to develop univariate choropleth maps. A total of 45, 140 (31, 482 women had less than 8 ANC visits and 2, 004 had 8 or more ANC visits) women with a prior childbirth were included in the study. The findings in the study revealed that among women aged 15 to 19 years in 1992, 1996 and 2013/14, the rates of inadequate antenatal care utilization (less than eight ANC visits) was 90.87%, 90.99%, and 99.63%, respectively. Lack of formal education was associated with inadequate ANC from 1992 to 2018, with percentages ranging from 91.12% to 99.64%. They were notable geospatial variations in the distribution of ANC underutilization across provinces with Luapula, Muchinga, Northwestern, Northern and Eastern recording higher proportions. Furthermore, the study showed that age (25 to 29 and 30 to 34) was associated with increased risk of inadequacy ANC utilization (AOR, 2.94; 95% CI, 1.20 – 7.19 and AOR, 2.65; 95% CI, 1.05 – 6.65 respectively). Higher education and wealth index correlated with reduced odds of inadequate ANC utilization. In conclusion, this study highlights worrisome trends in ANC utilization in Zambia, with a significant rise in inadequacy, especially in adhering to the WHO’s recommended eight ANC visits. Over the period from 1996 to 2018, there was a discernible decline in the prevalence of delayed initiation of ANC. The findings underscore a notable disparity between current ANC practices and established guidelines. Additionally, various factors predicting suboptimal ANC attendance have been identified. These insights call for targeted interventions to address the identified challenges and improve the overall quality and accessibility of ANC services in Zambia.
Systematic Review of Knowledge, Attitudes, and Practices of Dairy Farmers and Consumers Towards Bovine Tuberculosis in Low- and Middle-Income Countries
Authors: Van Der Zwan Abigail , Campbell Patricia T. , Shi Nancy , Bortoli Nikita De , Villanueva-Cabezas Juan Pablo
Published: April 2024

Background

Bovine Tuberculosis (bTB), caused byMycobacterium bovis, is a neglected zoonotic disease primarily associated with cattle. The incidence of bTB is highest in low-income settings with high cattle density and unpasteurised dairy consumption. Smallholder dairy farming has been steadily growing in low- and middle-income countries (LMICs) with limited professional support for adequate bTB surveillance and risk mitigation. Several studies have explored the knowledge, attitudes, and practices (KAP) of milk value chain’s stakeholders towards bTB in LMICs, but this evidence has not been collated and synthesised.

Methodology

We conducted a systematic review to determine what is known, believed, and done in relation to bTB among dairy producers and consumers in LMICs. We performed a systematic search of studies in OVID Medline, Scopus and CABI on 11 September 2023. KAP data were summarised using narrative synthesis and forest plots.

Results

We retrieved 2763 articles, retaining 51 for the review. Only studies from Africa (n=38) and Asia (n=13) met the eligibility criteria. Most populations reported awareness of human tuberculosis and knew it could be treated, but there was limited awareness of bTB and its zoonotic potential. Knowledge of bTB transmission routes and bTB mitigation varied and risky practices were also variable across populations. Inconsistencies in study design and survey tools suggest some results may have mid- to high risk of bias.

Conclusions

Awareness of bTB is surprisingly low among African and Asian populations with high bTB exposure risk, possibly due to the long-standing divide between animal and human health messages that has obscured the One Health implications of bTB. Addressing bTB in LMICs requires a structural One Health approach and standard KAP survey tools to adequately explore the socio-cultural, political, and economic processes and drivers favouring bTB spread and persistence.
Immunogenicity and safety of an Omicron XBB.1.16 adapted vaccine for COVID-19: Interim results from a randomized, controlled, non-inferiority clinical trial
Authors: López Fernandez María Jesús , Narejos Silvia , Castro Antoni , Echave-Sustaeta José María , Forner María José , Arana-Arri Eunate , Molto Josep , Bernad Laia , Pérez-Caballero Raúl , Prado Julia G , Raïch-Regué Dàlia , Boreika Rytis , Izquierdo-Useros Nuria , Blanco Julià , Puig-Barberà Joan , Natalini Martínez Silvina
Published: April 2024

Background

Global COVID-19 vaccination adapts to protect populations from emerging variants. This communication presents interim findings from the new Omicron XBB adapted PHH-1V81 vaccine compared to a XBB adapted mRNA vaccine against XBB and JN.1 SARS-CoV-2 strains.

Methods

In a Phase IIb/III pivotal trial, adults previously vaccinated with a primary scheme and at least one booster dose of an EU-approved mRNA vaccine randomly received either PHH-1V81 or BNT162b2 XBB.1.5 vaccine booster as a single dose. The primary efficacy endpoint assessed neutralisation titers against the Omicron XBB.1.16 variant at day 14. Secondary endpoints evaluated neutralization titers and cellular immunity against different variants. Safety endpoints comprised solicited reactions up to day 7 post-vaccination and serious adverse events until the cut-off date of the interim analysis. Changes in humoral responses were reported as GMT and GMFR assessed by PBNA or VNA.

Results

At the cut-off date, immunogenicity assessments included 599 participants. Both boosters elicited neutralizing antibodies against XBB.1.5, XBB.1.16 and JN.1 with PHH-1V81 inducing a higher response for all variants. PHH-1V8 booster triggers a superior neutralizing antibodies response against XBBs variants compared to the mRNA vaccine. Subgroup analysis consistently revealed higher neutralizing antibody responses with PHH-1V81 across age groups, number of prior vaccination shots, and SARS-CoV-2 infection history. Safety analysis involved 607 participants at the day 14 visit, revealing favourable safety profiles without any serious vaccine-related adverse events at cut-off date of the interim analysis (12thDecember 2023).

Conclusions

PHH-1V81 demonstrates superiority on humoral immunogenicity compared to mRNA vaccine agains XBB variants and non-inferiority against JN.1 with favourable safety profile and lower reactogenicity, confirming its potential as vaccine candidate.
Ochratoxin A status at birth is associated with reduced birthweight and ponderal index in rural Burkina Faso
Authors: Bastos-Moreira Yuri , Argaw Alemayehu , Di Palma Giulianmichela , Dailey-Chwalibóg Trenton , El-Hafi Jasmin , Ouédraogo Lionel Olivier , Toe Laeticia Celine , De Saeger Sarah , Lachat Carl , De Boevre Marthe
Published: April 2024

Background

Mycotoxin exposure during pregnancy has been associated with adverse birth outcomes and poor infant growth. We assessed multiple biomarkers and metabolites of exposure to mycotoxins at birth and their associations with birth outcomes and infant growth in 274 newborns in rural Burkina Faso.

Methods and findings

Whole blood microsamples were analyzed for mycotoxin concentrations in newborns in the Biospecimen sub-study nested in MISAME-III trial using ultra performance liquid chromatography coupled to tandem mass spectrometry. Unadjusted and adjusted associations between mycotoxin exposure, and birth outcomes and infant growth at 6 months were estimated using linear regression models for continuous outcomes and linear probability models with robust variance estimation for binary outcomes. Infant growth trajectories from birth to 6 months were compared by exposure status using mixed-effects models with random intercept for the individual infant and random slope for the infant’s age. Ochratoxin A (OTA) exposure was detected in 38.3% of newborns, with other mycotoxins being detected in the range of 0.36% and 4.01%. OTA exposure was significantly associated with adverse birth outcomes, such as lower birthweight (β (95% CI): −0.11 kg (−0.21, 0.00);p= 0.042) and ponderal index (β (95% CI): −0.62 gm/cm3(−1.19, −0.05);p= 0.034), and a marginally significant lower height growth trajectories during the first 6 months (β (95% CI): −0.08 cm/mo (−0.15, 0.0);p= 0.057).

Conclusions

OTA exposure was prevalent among newborns and also associated with lower growth at birth and during the first 6 months. The results emphasize the importance of nutrition-sensitive strategies to mitigate dietary OTA, as well as adopting food safety measures in Burkina Faso during the fetal period of development.
Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer’s disease (BenfoTeam)
Authors: Feldman Howard H. , Luchsinger José A. , Léger Gabriel C. , Taylor Curtis , Jacobs Diane M. , Salmon David P. , Edland Steven D. , Messer Karen , Revta Carolyn , Flowers Sarah A. , Jones Kerry S. , Koulman Albert , Yarasheski Kevin E. , Verghese Philip B. , Venkatesh Venky , Zetterberg Henrik , Durant January , Lupo Jody-Lynn , Gibson Gary E. ,   the ADCS BenfoTeam Study Group
Published: April 2024

Background

Benfotiamine provides an important novel therapeutic direction in Alzheimer’s disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches.

Objective

To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD.

Methods

This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA.

Conclusion

The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose.

Trial Registration

ClinicalTrials.gov identifier:NCT06223360, registered on January 25, 2024.
Health Perceptions of Adverse Weather in Older Adults in England: Analysis of 2019/20 Survey Data
Authors: Turner Grace , Moreira de Sousa Agostinho , O’Connell Emer , Kovats Sari , Brooks Katya , Landeg Owen , Ismail Sharif , Rajamani Anusha , Hajat Shakoor
Published: April 2024

Introduction

Health risks to vulnerable groups associated with hot and cold weather are well-documented. Older adults, aged 65 and above, are particularly vulnerable to higher and lower temperatures.

Aim

To explore older adult perception of health risks from high and low temperatures, what health-protective measures they have undertaken, and the factors associated with risks and responses.

Methods

Ipsos MORI conducted face-to-face surveys for the UK Health Security Agency with 461 participants in the cold weather survey and 452 in the hot weather survey. Participants reported temperature-related symptoms, risk perceptions for different groups, and behaviours during hot and cold weather. Data analysis involved using binomial logistic regression models to assess potential factors (demographics, vulnerability, behaviours, and responses) associated with older adults’ health risk perception in hot and cold weather.

Results

Less than half of older adults in both surveys agreed that hot or cold weather posed a risk to their health. Older adults with higher education, household income >£25,000 annually or home ownership were less likely to perceive their health at risk during cold weather. In both surveys, older adults who perceived people of the same age or people living alone as at an increased risk were more likely to perceive their own health as at risk. Furthermore, during cold weather, older adults were more likely to self-identify their health at risk when reporting other adults aged 65yrs+ to be at an increased risk, but not during hot weather. Various temperature-related protective behaviours were associated with older adults’ risk perception in hot and cold weather.

Conclusion

These findings highlight the need for effective risk communication strategies and targeted health messaging for older adults to support self-identification of risk. Future research should focus on barriers to risk perception and promoting health-protective behaviours in this population.
Atypical Audio-Visual Neural Synchrony and Speech Processing in children with Autism Spectrum Disorder
Authors: Wang Xiaoyue , Bouton Sophie , Kojovic Nada , Giraud Anne-Lise , Schaer Marie
Published: April 2024

Background: Children with Autism Spectrum Disorders (ASD) often exhibit communication difficulties that may stem from basic auditory temporal integration impairment but also be aggravated by an audio-visual integration deficit, resulting in a lack of interest in face-to-face communication. This study addresses whether speech processing anomalies in young (mean age 3.09-year-old) children with ASD are associated with alterations of audio-visual temporal integration. Methods: We used high-density electroencephalography (HD-EEG) and eye tracking to record brain activity and gaze patterns in 31 children (6 females) with ASD and 33 typically developing (TD) children (11 females), while they watched cartoon videos. Neural responses to temporal audio-visual stimuli were analyzed using Temporal Response Functions model and phase analyses for audiovisual temporal coordination. Results: The reconstructability of speech signals from auditory responses was reduced in children with ASD compared to controls, but despite more restricted gaze patterns in ASD it was similar for visual responses in both groups. Speech reception was most strongly affected when visual speech information was also present, an interference that was not seen in TD children. These differences were associated with a broader phase angle distribution (exceeding pi/2) in the EEG theta range in autistic children, signaling reduced reliability of audio-visual temporal alignment. Conclusion: These findings show that speech processing anomalies in ASD do not stand alone and that they are associated already at a very early development stage with audio-visual imbalance with lousier auditory response encoding and disrupted audio-visual temporal coordination.
Amyloid-beta increases MBP and MOBP translation in oligodendrocytes through dysregulation of hnRNP A2 dependent RNA dynamics
Authors: Gaminde-Blasco Adhara , Senovilla-Ganzo Rodrigo , Balantzategi Uxue , Garcia-Moreno Fernando , Matute Carlos , Baleriola Jimena , Alberdi Elena
Published: April 2024

Oligodendrocyte dysfunction, myelin degeneration, and white matter structural alterations are critical events in Alzheimer's disease (AD) that contribute to cognitive decline. A key hallmark of AD, Abeta oligomers, disrupt oligodendrocyte and myelin homeostasis, but a comprehensive global analysis of the mechanisms involved is lacking. Here, transcriptomic profiling of Abeta-exposed oligodendrocytes revealed widespread gene expression changes, particularly affecting pathways related to RNA localisation. Among the genes identified, we focused on Hnrnpa2/b1, the gene encoding the hnRNP A2 protein, which is essential for RNA transport and translation of myelin proteins. We confirmed aberrant upregulation of hnRNP A2 in hippocampal oligodendrocytes from post-mortem human brains of early-stage AD patients, Abeta-injected mouse hippocampi and Abeta-treated disrupting cells in vitro. RIP-seq analysis of the hnRNP A2 interactome revealed attenuated interactions with Hnrnpk and Hnrnpa2/b1, while interactions with Mbp and Mobp were enriched, suggesting changes in RNA metabolism of molecules associated with mRNA transport of myelin proteins. Abeta increased the total number and dynamics of mRNA-containing granules, facilitating local translation of the myelin proteins MBP and MOBP and attenuating Ca2+ signalling. These findings suggest that Abeta oligomers disrupt RNA metabolism mechanisms crucial for oligodendrocyte myelination through dysregulation of hnRNP A2 and myelin protein levels, potentially affecting oligodendroglia Ca2+ homeostasis.
Atomic insights into the signaling landscape ofE. coliPhoQ Histidine Kinase from Molecular Dynamics simulations
Authors: Lazaridi Symela , Yuan Jing , Lemmin Thomas
Published: April 2024

Bacteria rely on two-component systems to sense environmental cues and regulate gene expression for adaptation. The PhoQ/PhoP system exemplifies this crucial role, playing a key part in sensing magnesium (Mg2+) levels, antimicrobial peptides, mild acidic pH, osmotic upshift, and long-chain unsaturated fatty acids, promoting virulence in certain bacterial species. However, the precise details of PhoQ activation remain elusive. To elucidate PhoQ’s signaling mechanism at atomic resolution, we combined AlphaFold2 predictions with molecular modeling and carried out extensive Molecular Dynamics (MD) simulations. Our MD simulations revealed three distinct PhoQ conformations that were validated by experimental data. Notably, one conformation was characterized by Mg2+bridging the acidic patch in the sensor domain to the membrane, potentially representing a repressed state. Furthermore, the high hydration observed in a putative intermediate state lends support to the hypothesis of water-mediated conformational changes during PhoQ signaling. Our findings not only revealed specific conformations within the PhoQ signaling pathway, but also hold significant promise for understanding the broader histidine kinase family due to their shared structural features. Our approach paves the way for a more comprehensive understanding of histidine kinase signaling mechanisms across various bacterial species and opens the door for developing novel therapeutics that target PhoQ modulation.
Enabling preprint discovery, evaluation, and analysis with Europe PMC
Authors: Levchenko Mariia , Parkin Michael , McEntyre Johanna , Harrison Melissa
Published: April 2024

Preprints provide an indispensable tool for rapid and open communication of early research findings. Preprints can also be revised and improved based on scientific commentary uncoupled from journal-organised peer review. The uptake of preprints in the life sciences has increased significantly in recent years, especially during the COVID-19 pandemic, when immediate access to research findings became crucial to address the global health emergency.

With ongoing expansion of new preprint servers, improving discoverability of preprints is a necessary step to facilitate wider sharing of the science reported in preprints. To address the challenges of preprint visibility and reuse, Europe PMC, an open database of life science literature, began indexing preprint abstracts and metadata from several platforms in July 2018. Since then, Europe PMC has continued to increase coverage through addition of new servers, and expanded its preprint initiative to include the full text of preprints related to COVID-19 in July 2020 and then the full text of preprints supported by the Europe PMC funder consortium in April 2022. The preprint collection can be searched via the website and programmatically, with abstracts and the open access full text of COVID-19 and Europe PMC funder preprint subsets available for bulk download in a standard machine-readable JATS XML format. This enables automated information extraction for large-scale analyses of the preprint corpus, accelerating scientific research of the preprint literature itself.

This publication describes steps taken to build trust, improve discoverability, and support reuse of life science preprints in Europe PMC. Here we discuss the benefits of indexing preprints alongside peer-reviewed publications, and challenges associated with this process.
Flumequine, a fluoroquinolone in disguise
Authors: Swinkels Aram F. , Fischer Egil A.J. , korving Lisa , Christodoulou Rafaella , Wagenaar Jaap A. , Zomer Aldert L.
Published: April 2024

Fluoroquinolone resistance inE. coliisolates from livestock in Europe remains high even though the EMA restricted fluoroquinolone use in animals. However, flumequine, a quinolone similar to fluoroquinolones, is still used in livestock in the Netherland, Belgium, Greece or France. Therefore, we investigated whether flumequine selects for the same resistance mechanisms inE. coli.

To accomplish this, we investigated and enumerated resistant and non-resistantE. coliisolates obtained from caecal fermentation assays and from broilers exposed to different concentrations of flumequine and enrofloxacin.

Flumequine usage leads to approximately 3-fold increase of resistantE. coliin the caecal fermentation, comparable with enrofloxacin. Afterin vitroexposure to flumequine and enrofloxacin we detected the same SNPs (S83L, D87G) ingyrA. Furthermore, the same resistance-causing SNPs were found in phenotypic resistantE. coliisolates from broilers treated with enrofloxacin and flumequine.

Flumequine induces similar resistance mechanisms as enrofloxacin and restriction for use should be the same.