bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly Pathogenic Avian Influenza Vaccines: challenges for innovation, technological development and pandemic preparedness
Authors: Possas Cristina , Marques Ernesto TA , Oliveira Alessandra , Schumacher Suzanne , Mendes Flavia , Siqueira Marilda M , Antunes Adelaide , Homma Akira
Published: June 2023

Introduction

Highly Pathogenic Avian Influenza (HPAI) pandemic potential is a critical issue. Outbreaks of H5N1 Avian Flu, causing mass die-offs in poultry and other birds, are now affecting mammals from otters to dolphins worldwide. H5N1 and other HPAI viruses have so far caused rare human infections. However, if they evolve to spread between people, they could trigger major outbreaks. The main question is: how to overcome bottlenecks in HPAI vaccine development to accelerate scale-up and implement an effective global Vaccine Preparedness System?

Methods

From a patent landscape approach, we identified breakthroughs and gaps in HPAI vaccine development for the search period (2010-2021), discussing technological strategies in patent filings, including universal vaccine patent documents.

Results

Very few patent documents for human HPAI vaccines were retrieved: from 49 deposits in the search period, only 18 were in active status (37%), with few breakthroughs and in early stages of development. These results indicate a technological lag in HPAI vaccine development and highlight the constraints for scaling-up these vaccines when they will be needed. Current egg-based processes are laborious and too difficult to scale-up in the case of a pandemic. Concerning mRNA technology, there are still issues on the duration and level of protection mRNA vaccines might induce. Vaccinating farm animals is not sufficient to protect the population: if not properly executed, the virus could continue to circulate at a low level, increasing the chance of mutations and adaptation to humans. Universal Influenza vaccines would be key, but we identified only few (20 in the search period) patents for these vaccines, still in early stages of development. In addition, it is the impact immunological memory would have on the development of protective immunity to a broad-spectrum of viruses, due to original antigenic sin mechanism.

Discussion

This study identified critical barriers to overcome in HPAI vaccine development, improving efficacy and reducing costs. It highlights the urgent need for an effective global Vaccine Preparedness model, supported by Genomic, Antigenic and Epidemiological Surveillance, an Innovation Fund and Public-Private Partnerships. We strongly support WHO in coordinating a Global Initiative for Influenza Pandemic Preparedness.
Meta-Analysis of Breast Cancer Risk for Individuals with PALB2 Pathogenic Variants
Authors: Ruberu Thanthirige Lakshika M. , Braun Danielle , Parmigiani Giovanni , Biswas Swati
Published: June 2023

Background

Pathogenic variants in cancer susceptibility genes can now be tested efficiently and economically with the wide availability of multi-gene panel testing. This has resulted in an unprecedented rate of identifying individuals carrying pathogenic variants. These carriers need to be counselled about their future cancer risk conferred by the specific gene mutation. An important cancer susceptibility gene is PALB2. Several studies reported risk estimates for breast cancer (BC) associated with pathogenic variants in PALB2. Because of the variety of modalities (age specific risk, odds ratio, relative risk, and standardized incidence ratio) and effect sizes of these risk estimates, a meta-analysis of all of these estimates of BC risk is necessary to provide accurate counselling of patients with pathogenic variants in PALB2. The challenge, though, in combining these estimates is the heterogeneity of studies in terms of study design and risk measure.

Methods

We utilized a recently proposed novel Bayesian random-effects meta-analysis method that can synthesize and combine information from such heterogeneous studies. We applied this method to combine estimates from twelve different studies on BC risk for carriers of pathogenic PALB2 mutations, out of which two report age-specific penetrance, one reports relative risk, and nine report odds ratios.

Results

The estimated overall (meta-analysis based) risk of BC is 12.80% by age 50 (6.11% − 22.59%) and 48.47% by age 80 (36.05% − 61.74%).

Conclusion

Pathogenic mutations in PALB2 makes women more susceptible to BC. Our risk estimates can help clinically manage patients carrying pathogenic variants in PALB2.
Detection of circulating plasma tumour mutations in early stage triple negative breast cancer as an adjunct to pathological complete response assessment
Authors: Zaikova Elena , Cheng Brian Y.C , Cerda Viviana , Kong Esther , Lai Daniel , Lum Amy , Bates Cherie , Brok Wendie den , Kono Takako , Bourque Sylvie , Chan Angela , Feng Xioalan , Fenton David , Gurjal Anagha , Levasseur Nathalie , Lohrisch Caroline , Roberts Sarah , Shenkier Tamara , Simmons Christine , Taylor Sara , Villa Diego , Miller Ruth , Aguirre-Hernandez Rosalia , Aparicio Samuel , Gelmon Karen
Published: June 2023

Circulating tumour DNA (ctDNA) detection in liquid biopsy is an emerging alternative to tissue biopsy, but its utility in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) is not yet well understood. In this study, we determined the presence of ctDNA detectable actionable mutations with a clinically validated hotspot treatment indication panel in early stage TNBC patients, without local recurrence or metastatic disease at the time of evaluation. Sequencing of plasma DNA and validation of variants from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at much higher risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in NAT protocols may be identifiable by combining tissue response and sensitive ctDNA detection.
A quantitative evaluation of the impact of vaccine roll-out rate and coverage on reducing deaths from COVID-19: a counterfactual study on the impact of the delayed vaccination programme in Iran
Authors: Ghafari Mahan , Hosseinpour Sepanta , Rezaee-Zavareh Mohammad Saeid , Dascalu Stefan , Rostamian Somayeh , Aramesh Kiarash , Madani Kaveh , Kordasti Shahram
Published: June 2023

Vaccination has been a crucial factor in the fight against COVID-19 because of its effectiveness in suppressing virus circulation, lowering the risk of severe disease, and ultimately saving lives. Many countries with an early and rapid distribution of COVID-19 vaccines performed much better in reducing their total number of deaths than those with lower coverage and slower roll-out pace. However, we still do not know how many more deaths could have been averted if countries with slower vaccine roll-outs followed the same rate as countries with earlier and faster distribution of vaccines. Here, we investigated counterfactual scenarios for the number of avertable COVID-19 deaths in a given country based on other countries’ vaccine roll-out rates. As a case study, we compared Iran to eight model countries with similar income brackets and dominant COVID-19 vaccine types. Our analysis revealed that faster roll-outs were associated with higher numbers of averted deaths. While Iran’s percentage of fully vaccinated individuals would have been similar to Bangladesh, Nepal, Sri Lanka, and Turkey under counterfactual roll-out rates, adopting Turkey’s rates could have averted up to 50,000 more deaths, whereas following Bangladesh’s rates could have led to up to 52,800 additional losses of lives in Iran. Notably, a counterfactual scenario based on Argentina’s early but slow roll-out rate resulted in a smaller number of averted deaths in Iran, up to 12,600 more individuals. Following Montenegro’s or Bolivia’s model of faster per capita roll-out rates for Iran could have resulted in more averted deaths in older age groups, particularly during the Alpha and Delta waves, despite their lower overall coverage. Also, following Bahrain’s model as an upper bound benchmark, Iran could have averted 75,300 deaths throughout the pandemic, primarily in the >50 age groups. This study provides insights into future decisions on the management of infectious disease epidemics through vaccination strategies by comparing the relative performance of different countries in terms of their timing, pace, and coverage of vaccination in preventing COVID-19 deaths.
An ensemble ofGleditsia sinensis Lam. and gut microbiota against alcoholic liver disease
Authors: Oh Ki-Kwang , Yoon Sang-Jun , Lee Su-Been , Lee Sang Youn , Gupta Haripriya , Ganesan Raja , Sharma Satya Priya , Won Sung-Min , Jeong Jin-Ju , Kim Dong Joon , Suk Ki-Tae
Published: June 2023

Gleditsia sinensis Lam.(GSL) is a medicinal herb and a noticeable resource of possessing hepatic protective agents such as alcoholic liver disease (ALD). At present, it has been documented that gut microbiota (GM) is related directly to etiology of ALD. Nevertheless, the bioactive molecules in GSL, favorable GM, targets, and key mechanism(s) against ALD are yet to be revealed. Hence, we integrated the significant four components to clarify the nuanced pathogenesis with help of network pharmacology (NP) concept. We retrieved significant metabolites via gutMGene and constructed GSL or GM-Signaling pathways-Targets-Metabolites (GGSTM) networks. Finally, molecular docking test (MDT) was performed to verify the key findings. The gutMGene suggested that 16 GM and 6 metabolites were related to the two signaling pathways through GGSTM networks. Both MDT and frontier molecular orbitals (FMO) theory revealed the most stable conformers: equol fromLactobacillus paracasei JS1on IL6, Bauer-7-en-3-one, and Urs-12-en-3-one from GSL on PPARA, PPARD, and PPARG, respectively. In conclusion, this study sheds light on the combinatorial effects of GM, and GSL in treating ALD via systems biology concept.
Assessment of environmental impacts based on particulate matter, and chlorophyll content of urban trees
Authors: Abriha-Molnár Vanda Éva , Szabó Szilárd , Magura Tibor , Tóthmérész Béla , Abriha Dávid , Sipos Bianka , Simon Edina
Published: June 2023

Trees improve air quality, and they have irreplaceable aesthetic value in urban landscapes. The amount of dust deposited on tree leaves is a simple and cost-effective indicator of air quality. Our aim was to explore particle filtering capacity of roadside trees in an urbanized area. We also assessed the impact of meteorological conditions on the amount of deposited dust. We measured the leaf surface deposition, and chlorophyll content of leaves along a road section that started at an intersection and ended in a less disturbed suburban area in Debrecen city, Hungary. Samples were collected in July, and September fromCeltis occidentalis, a frequent species. We found a significant negative correlation between dust deposition on the leaves, and the distance from the intersection in July, meaning that the amount of dust on the leaves decreased as the distance from traffic increased. In September, dust deposition decreased considerably compared to July, caused by the rainfall before the second sampling. Chlorophyll content also had a significant negative correlation with the distance from the traffic intersection in July, as it decreased towards the less disturbed end of the transect. We also found a positive correlation between dust deposition and chlorophyll content in July. Surprisingly, the exposure to moderate amounts of pollutants in the air caused an increase in chlorophyll content. Our findings suggest that dust deposition on leaves serves as a reliable indicator of traffic intensity, because excess dust caused by the proximity of car traffic can be detected on the leaf surface. Although, certain weather conditions like rainfall and wind can disrupt the patterns in dust deposition that have developed over an extended period through wash-off and resuspension. Hence, it is advisable to consider these effects while selecting the sampling time and evaluating the results.

Highlights

Leaves of urban trees are used as bioindicators of deposited dust pollution.

Dust deposition, and chlorophyll content was measured along a roadside transect.

We found that dust and chlorophyll content decreased with distance from traffic emissions.

Moderate level of dust pollution resulted in an increase in chlorophyll content.
Germinal centers are permissive to subdominant antibody responses
Authors: Robert Philippe A. , Arulraj Theinmozhi , Meyer-Hermann Michael
Published: June 2023

A protective humoral response to pathogens requires the development of high affinity antibodies in germinal centers (GC). The combination of antigens available during immunization has a strong impact on the strength and breadth of the antibody response. Antigens can display various levels of immunogenicity, and a hierarchy of immunodominance arises when the GC response to an antigen dampens the response to other antigens. Immunodominance is a challenge for the development of vaccines to mutating viruses, and for the development of broadly neutralizing antibodies. The extent by which antigens with different levels of immunogenicity compete for the induction of high affinity antibodies and therefore contribute to immunodominance is not known. Here, we performin silicosimulations of the GC response, using a structural representation of antigens with complex surface amino acid composition and topology. We generate antigens with different levels of immunogenicity and perform simulations with combinations of these antigens. We found that GC dynamics were driven by the most immunogenic antigen and immunodominance arose as affinity maturation to less immunogenic antigens was inhibited. However, this inhibition was moderate since the less immunogenic antigen exhibited a weak GC response in the absence of other antigens. Less immunogenic antigens reduced the dominance of GC responses to more immunogenic antigens, albeit at a later time point. The simulations suggest that increased vaccine valence may decrease immunodominance of the GC response to strongly immunogenic antigens and therefore, act as a potential strategy for the natural induction of broadly neutralizing antibodies in GC reactions.
When is sympatric speciation a possible evolutionary outcome?
Authors: Venkataraman Pavithra , Saini Supreet
Published: June 2023

The process of speciation is the source of biodiversity. The most popularly accepted mode of speciation is allopatric speciation, where geography imposes the initial barrier to gene flow, and then biological barriers come up. On the other hand, sympatric speciation, which was not accepted as a possibility for long, requires that the process of speciation happen in the absence of a geographical barrier, in a well-mixed population. Several attempts have been made to theoretically identify the conditions in which speciation can occur in sympatry, but have several problems associated with them. We propose a model for sympatric speciation based on adaptation for resource utilization. We use this genetics- based model to investigate the relative roles of prezygotic and postzygotic barriers, from the context of ecological disruptive selection, sexual selection, and genetic architecture, in causing and maintaining sympatric speciation. We show that sexual selection that acts on secondary sexual traits does not play any role in the process of speciation in sympatry, and that assortative mating based on an ecologically relevant trait forces the population to show an adaptive response. We also demonstrate that understanding the genetic architecture of the trait under ecological selection is very important, and that it is not required for the strength of ecological disruptive selection to be very high in order for speciation to occur in sympatry. With this, we provide an insight into the kind of scenarios in which sympatric speciation can be demonstrated in lab.
Accelerometer-based predictions of behaviour elucidate factors affecting the daily activity patterns of spotted hyenas
Authors: Minasandra Pranav , Jensen Frants H. , Gersick Andrew S , Holekamp Kay E , Strauss Eli D , Strandburg-Peshkin Ariana
Published: June 2023

Animal activity patterns are highly variable and influenced by internal and external factors, including social processes. Quantifying activity patterns in natural settings can be challenging, as it is difficult to monitor animals over long time periods. Here, we developed and validated a machine-learning based classifier to identify behavioural states from accelerometer data of wild spotted hyenas(Crocuta crocuta), social carnivores that live in large fission-fusion societies. By combining this classifier with continuous collar-based accelerometer data from five hyenas, we generated a complete record of activity patterns over more than one month. We used these continuous behavioural sequences to investigate how past activity, individual idiosyncrasies, and social synchronisation influence hyena activity patterns. We found that hyenas exhibit characteristic crepuscular-nocturnal daily activity patterns. Time spent active was independent of activity level on previous days, suggesting that hyenas do not show activity compensation. We also found limited evidence for an effect of individual identity on activity, and showed that pairs of hyenas who spent more time together synchronised their activity patterns. This study sheds light on the patterns and drivers of activity in spotted hyena societies, and also provides a useful tool for quantifying behavioural sequences from accelerometer data.
Growth plate resting zone chondrocytes acquire transient clonal competency upon Hedgehog activation and efficiently transform into trabecular bone osteoblasts
Authors: Orikasa Shion , Matsushita Yuki , Fogge Michael , Mizuhashi Koji , Sakagami Naoko , Ono Wanida , Ono Noriaki
Published: June 2023

The resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP–indian hedgehog (Ihh) feedback regulation is essential for sustaining growth plate activities; however, molecular mechanisms regulating cell fates of PTHrP+resting chondrocytes and their eventual transformation into osteoblasts remain largely undefined. Here, in a mouse model, we utilized a tamoxifen-induciblePTHrP-creERline withPatched-1(Ptch1) floxed and tdTomato reporter alleles to specifically activate Hedgehog signaling in PTHrP+resting chondrocytes and trace the fate of their descendants. Hedgehog-activated PTHrP+chondrocytes formed large concentric clonally expanded cell populations within the resting zone (‘patched roses’) and generated significantly wider columns of chondrocytes, resulting in hyperplasia of the growth plate. Interestingly, Hedgehog-activated PTHrP+cell-descendants migrated away from the growth plate and eventually transformed into trabecular osteoblasts in the diaphyseal marrow space in the long term. Therefore, Hedgehog activation drives resting zone chondrocytes into transit-amplifying states as proliferating chondrocytes and eventually converts these cells into osteoblasts, unraveling a novel Hedgehog-mediated mechanism that facilitates osteogenic cell fates of PTHrP+skeletal stem cells.
Membrane-bound Interleukin-1α mediates leukocyte adhesion during atherogenesis
Authors: Mäder Christina , Speer Thimoteus , Wirth Angela , Boeckel Jes-Niels , Fatima Sameen , Shahzad Khurrum , Freichel Marc , Laufs Ulrich , Gaul Susanne
Published: June 2023

Background

The interleukin-1 (IL-1) family and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome contribute to atherogenesis but the underlying mechanism are incompletely understood. Unlike IL-1β, IL-1α is not dependent on the NLRP3 inflammasome to exert its pro-inflammatory effects. Here, a non-genetic model was applied to characterize the role of IL-1α, IL-1β and NLRP3 for the pathogenesis of atherosclerosis.

Methods

Atherogenesis was induced by gain-of-function PCSK9-AAV8 mutant viruses and feeding of a high-fat western diet (WTD) for 12 weeks in C57Bl6/J wildtype mice (control) and in Il1a-/-, Nlrp3-/-, and Il1b-/-mice.

Results

Il1a-/-mice showed reduced atherosclerotic plaque area in the aortic root with lower lipid accumulation, while no difference was observed between wildtype, Nlrp3-/-and Il1b-/-mice. Serum proteomic analysis showed a reduction of pro-inflammatory cytokines (e.g. IL-1β, IL-6) in Il1a-/-as well as in Nlrp3-/-and Il1b-/-mice. Bone marrow dendritic cells (BMDC) of WT, Nlrp3-/-and Il1b-/-mice and primary human monocytes showed translocation of IL-1α to the plasma membrane (csIL-1α) upon stimulation with LPS. The translocation of IL-1α to the cell surface was regulated by myristoylation and increased in mice with hypercholesterolemia. CsIL-1α and IL1R1 protein-protein interaction on endothelial cells induced VCAM1 expression and monocyte adhesion, which was abrogated by the administration of neutralizing antibodies against IL-1α and IL1R1.

Conclusions

Il1a-/-mice, but not Nlrp3-/-or Il1b-/-mice, are protected from atherosclerosis after induction of hypercholesterolemia independent of circulating cytokines. Myristoylation and translocation of IL-1α to the cell surface in myeloid cells facilitates leukocyte adhesion and contributes to the development of atherosclerosis.

Abstract Figure

Graphical abstract.

The role of cell-surface (cs) IL-1a in the initiation of atherosclerosis.
Coiled-coil domains are sufficient to drive liquid-liquid phase separation of proteins in molecular models
Authors: Ramirez Dominique A. , Hough Loren E. , Shirts Michael R.
Published: June 2023

Liquid-liquid phase separation (LLPS) is thought to be a main driving force in the formation of membraneless organelles. Examples of such organelles include the centrosome, central spindle, and stress granules. Recently, it has been shown that coiled-coil (CC) proteins, such as the centrosomal proteins pericentrin, spd-5, and centrosomin, might be capable of LLPS. CC domains have physical features that could make them the drivers of LLPS, but it is unknown if they play a direct role in the process. We developed a coarse-grained simulation framework for investigating the LLPS propensity of CC proteins, in which interactions which support LLPS arise solely from CC domains. We show, using this framework, that the physical features of CC domains are sufficient to drive LLPS of proteins. The framework is specifically designed to investigate how the number of CC domains, as well as multimerization state of CC domains, can affect LLPS. We show that small model proteins with as few as two CC domains can phase separate. Increasing the number of CC domains up to four per protein can somewhat increase LLPS propensity. We demonstrate that trimer-forming and tetramer-forming CC domains have a dramatically higher LLPS propensity than dimer-forming coils, which shows that multimerization state has a greater effect on LLPS than the number of CC domains per protein. These data support the hypothesis of CC domains as drivers of protein LLPS, and has implications in future studies to identify the LLPS-driving regions of centrosomal and central spindle proteins.

STATEMENT OF SIGNIFICANCE

The liquid-liquid phase separation of coiled-coil proteins has been implicated in the formation of membraneless organelles such as the centrosome and central spindle. Little is known about the features of these proteins that might drive their phase separation. We developed a modeling framework to investigate the potential role of coiled-coil domains in phase separation, and show that these domains are sufficient to drive the phenomenon in simulation. We additionally show the importance of multimerization state on the ability for such proteins to phase separate. This work suggests that coiled-coil domains should be considered for their contribution to protein phase separation.
Quantifying collective interactions in biomolecular phase separation
Authors: Ausserwöger Hannes , Qian Daoyuan , Krainer Georg , de Csilléry Ella , Welsh Timothy J. , Sneideris Tomas , Franzmann Titus M. , Qamar Seema , Erkamp Nadia A. , Nixon-Abell Jonathon , Kar Mrityunjoy , George-Hyslop Peter St , Hyman Anthony A. , Alberti Simon , Pappu Rohit V. , Knowles Tuomas P. J.
Published: June 2023

Biomolecular phase separation plays a pivotal role in governing critical biological functions and arises from the collective interactions of large numbers of molecules. Characterising the underlying collective interactions of phase separation, however, has proven to be challenging with currently available tools. Here, we propose a general and easily accessible strategy to quantify collective interactions in biomolecular phase separation with respect to composition and energetics. By measuring the dilute phase concentration of one species only, we determine tie line gradients and free energy dominance as dedicated descriptors of collective interactions. We apply this strategy to dissect the role of salts and small molecules on phase separation of the protein fused in sarcoma (FUS). We discover that monovalent salts can display both exclusion from or preferential partitioning into condensates to either counteract charge screening or enhance non-ionic interactions. Moreover, we show that the common hydrophobic interaction disruptor 1,6-hexanediol inhibits FUS phase separation by acting as a solvation agent capable of expanding the protein polypeptide chain. Taken together, our work presents a widely applicable strategy that enables quantification of collective interactions and provides unique insights into the underlying mechanisms of condensate formation and modulation.
ACCELEROMETER-BASED SEDENTARY BEHAVIOUR AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH THE GUT MICROBIOTA IN 8507 INDIVIDUALS FROM THE POPULATION-BASED SCAPIS
Authors: Baldanzi Gabriel , Sayols-Baixeras Sergi , Ekblom-Bak Elin , Ekblom Örjan , Dekkers Koen F. , Hammar Ulf , Nguyen Diem , Ahmad Shafqat , Ericson Ulrika , Arvidsson Daniel , Börjesson Mats , Johanson Peter J. , Smith J Gustav , Bergström Göran , Lind Lars , Engström Gunnar , Ärnlöv Johan , Kennedy Beatrice , Orho-Melander Marju , Fall Tove
Published: June 2023

Objective

Population-based studies investigating the relationship between physical activity and the gut microbiota composition have mainly relied on self-reported activity, potentially influenced by reporting bias. Here, we investigated associations of accelerometer-based sedentary behaviour and physical activity with the gut microbiota composition and functional profile in the large Swedish CArdioPulmonary bioImage Study.

Methods

In 8507 participants aged 50-65, the proportion of time in sedentary (SED), moderate-intensity (MPA), and vigorous-intensity (VPA) physical activity were estimated with hip-worn accelerometer. The gut microbiota was profiled using shotgun metagenomics of fecal samples. We fitted multivariable regression models, and adjusted for sociodemographic, lifestyle, and technical covariates while also accounting for multiple testing.

Results

Overall, SED and MPA were associated with microbiota species in opposite directions. For example, the strongest positive regression coefficient for MPA and the strongest negative for SED were withPrevotella copri, a plant-polysaccharide-degrading bacteria. Species associated with VPA aligned with the MPA associations, although with clear discrepancies. For instance,Phocaeicola vulgatuswas negatively associated with MPA, while the association with VPA was non-significant and in the positive direction. Additional adjustment for dietary variables or adiposity attenuated some of the associations. For the functional profile, MPA and VPA were generally associated with lower capacity for amino acid degradation.

Conclusion

Our findings suggest that sedentary behaviour and physical activity are associated with a similar set of gut microbiota species and functions, but in opposite directions. Furthermore, the intensity of physical activity may have specific effects on certain species of the gut microbiota.
On the Atrial Fibrillation Detection Performance of ECG-DualNet
Authors: Reich Christoph , Rohr Maurice , Kircher Tim , Antink Christoph Hoog
Published: June 2023

Atrial Fibrillation (AF) is a severe cardiac arrhythmia affecting a significant amount of the human population [1]. Quick diagnosis and treatment are critical in reducing the risk of severe sequelae such as stroke or heart failure. Rohret al. [2] recently proposed ECG-DualNet, a neural network for accurate AF detection in single-lead electrocardiogram (ECG) data. This short paper reports additional empirical results of ECG-DualNet to gain new insights on AF detection in single-lead ECG data with deep neural networks. We systematically analyze which ingredients of ECG-DualNet are crucial for achieving competitive AF detection results. We also scale the ECG-DualNet architecture to 130M parameters and perform large-scale supervised pre-training, providing additional empirical results. Finally, we provide recommendations for future research toward accurate and robust AF detection.
A multi-step analysis and co-produced principles to support Equitable Partnership with Liverpool School of Tropical Medicine, 125 years on
Authors: Karuga Robinson , Steege Rosie , Chowdhury Shahreen , Squire Bertie , Theobald Sally , Otiso Lilian
Published: June 2023

Transboundary health partnerships are shaped by global inequities. Voices from “global South” research partners are critical to understand and redress power asymmetries in research partnerships. We undertook research with Liverpool School of Tropical Medicine (LSTM) partners to inform LSTM’s equitable partnership strategy and co-develop principles for equitable partnerships.

We applied mixed methods and participatory approaches. An online survey (n=21) was conducted with transboundary partners on fairness of opportunity, fair process, and fair sharing of benefits in partnership with LSTM-Liverpool. We triangulated the survey with key informant interviews (n=12). Qualitative narratives were coded and analysed using the thematic framework approach. These findings were presented in a participatory workshop with transboundary partners to co-develop principles for equitable partnership, which were then refined and validated.

Transboundary partners identified being involved in agenda setting from the outset, shaping the design of research projects and theories of change as mechanisms to support fair opportunity however, funding mechanisms that shape power structures was reported as limiting fair opportunities. Fair process was supported by multi-directional, long-term collaborations with opportunities for capacity strengthening. Participants raised concerns about funder requirements and outdated language in contracting process that hindered equity. Fair benefit sharing was facilitated by early discussions on authorship to promote equity and policy influence. Funding also influenced the ability to travel and network, important for benefit sharing and fair opportunity. High paywalls limit sharing of research findings and access to research findings for many “global-South” partners.

The co-developed principles are part of ongoing reflections and dialogue to improve and undo harmful power structures that perpetuate coloniality within global health. While this process was conducted with LSTM-Liverpool partners, the principles to strengthen equity are applicable to other institutions engaged in transboundary research partnerships and relevant for funders.
The clinical, genomic, and microbiological profile of invasive multi-drug resistant Escherichia coli in a major teaching hospital in the United Kingdom
Authors: Hamilton William L. , Coscione Suny , Maes Mailis , Warne Ben , Pike Lindsay J. , Khokhar Fahad A. , Blane Beth , Brown Nicholas M. , Gouliouris Theodore , Dougan Gordon , Török M. Estée , Baker Stephen
Published: June 2023

Escherichia coliis a ubiquitous component of the human gut microbiome, but is also a common pathogen, causing around 40,000 bloodstream infections (BSI) in the UK annually. The number ofE. coliBSI has increased over the last decade in the UK, and emerging antimicrobial resistance (AMR) profiles threaten treatment options. Here, we combined clinical, epidemiological, and whole genome sequencing data with high content imaging to characterise over 300E. coliisolates associated with BSI in a large UK teaching hospital. Overall, only a limited number of sequence types (ST) were responsible for the majority of organisms causing invasive disease. The most abundant (20% of all isolates) was ST131, of which around 90% comprised the pandemic O25:H4 group. ST131-O25:H4 isolates were frequently multi-drug resistant (MDR), with a high prevalence of extended spectrum β-lactamases (ESBL) and fluoroquinolone resistance. There was no association between AMR phenotypes and the source ofE. colibacteraemia or whether the infection was healthcare-associated. Several clusters of ST131 were genetically similar, potentially suggesting a shared transmission network. However, there was no clear epidemiological associations between these cases, and they included organisms from both healthcare-associated and non-healthcare-associated origins. The majority of ST131 genetic clusters exhibited strong binding with an anti-O25b antibody, raising the possibility of developing rapid diagnostics targeting this pathogen. In summary, our data suggest that a restricted set of MDRE. colipopulations can be maintained and spread across both community and healthcare settings in this location, contributing disproportionately to invasive disease and AMR.

Impact statement

The pandemic ST131-O25:H4 lineage was a common cause ofE. colibloodstream infections in this location, and carried multiple AMR mechanisms including ESBL and fluoroquinolone resistance. The conserved antigenicity of ST131-O25:H4 raises the possibility of developing targeted immune therapeutics and rapid diagnostics for this common and frequently multi-drug resistant pathogen.
HIV prevalence and associated factors among married women, Mozambique, 2015
Authors: Nuvunga Samuel , Langa Denise Chitsondzo , Baltazar Cynthia Semá , Sacarlal Jahit , Rossetto Erika
Published: June 2023

Background

The 2021 human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) global report indicated that women and girls in sub-Saharan Africa remained the most affected groups, accounting for 62% of new infections in the region. In 2021 in Mozambique, the HIV prevalence rate among the adult population was 12.5%, with a rate of 15.4% among women of reproductive age. Our study assessed HIV prevalence and associated factors among married women in Mozambique.

Methodology

A cross-sectional epidemiological study was carried out using secondary data extracted from the 2015 Immunization, Malaria and HIV/AIDS (IMASIDA) survey in Mozambique. Married women (civil marriage and common law marriage) of reproductive age (15-49 years) were included. We applied sample weights for data analysis.

Results

Out of the 3,006 married women included in the study, 20.1% fell within the 20-24 age group (n=603), and the average age was 30 years (SD=8.9 years). HIV prevalence was 6.9%. Factors significantly associated with HIV infection were age group 35-49 years (aOR=2.5; CI[1.3-4.6]; p=0.005) compared to age group 15-24 years, lack of formal education and primary education compared to higher education (aOR 7.7; CI [1.1-52.9], p=0.038 and aOR=9.8; CI [1.6-60.1]; p=0.014 respectively), having an uncircumcised partner (aOR=1.9; CI [1.2-3.1]; p=0.008), and having three or more lifetime sex partners compared to one sex partner (aOR=3.6; CI [2.9-7.3]; p< 0.001). Women who were in one lifelong union had a lower risk of HIV positivity compared to women who hadmore than one union (aOR=0.5; CI[0.3-0.8] p=0.005).

Conclusion

The factors that contributed to a greater odds of HIV-positivity in this group of married Mozambican women were older age, low levels of education, having an uncircumcised partner and having more than one sexual partner throughout one’s lifetime. In order to have maximum effect, HIV prevention and control campaigns in Mozambique should be tailored tothese “higher-risk” populations.
Performance evaluation of artificial neural network and multiple linear regression in the prediction of body mass index in children
Authors: Asif Muhammad , Khosa Ghazi Khan , Alomair Abdullah Mohammad , Alomair Mohammad Ahmed , Aslam Muhammad , Arslan Muhammad , Sanaullah Muhammad , Wyszyńska Justyna
Published: June 2023

The body mass index (BMI) provides essential medical information related to body weight for the treatment and prognosis prediction of different diseases. The main goal of the present study was to evaluate the performance of artificial neural network (ANN) and multiple linear regression (MLR) model in the prediction of BMI in children. The data from a total of 5,964 children aged 5 to 12 years were included in study. Age, gender, neck circumference (NC), waist circumference (WC), hip circumference (HpC), and mid upper arm circumference (MUAC) measurements were used to estimate the BMI of children. The ANN and MLR were utilized to predict the BMI. The predictive performance of these methods was also evaluated. Gender-wise average comparison showed that median values of all the anthropometric measurements (except BMI) were significantly higher in boys as compared to girls. For the overall sample, the BMI prediction model was,― 0.147 X Age ― 0.367 X Gender + 0.176 X NC + 0.041 X WC + 0.060 X HpC + 0.404 X MUAC. A high R2value and lower RMSE, MAPE, and MAD indicated that the ANN is the best method for predicting BMI in children. Our results confirm that the BMI of children can be predicted by using ANN and MLR regression methods. However, the ANN method has a higher predictive performance than MLR.
In search of disentanglement in tandem mass spectrometry datasets
Authors: Abram Krzysztof Jan , McCloskey Douglas
Published: June 2023

Generative modeling and representation learning of tandem mass spectrometry data aim to learn an interpretable and instrument-agnostic digital representation of metabolites directly from MS/MS spectra. Interpretable and instrument-agnostic digital representations would facilitate comparisons of MS/MS spectra between instrument vendors and enable better and more accurate queries of large MS/MS spectra databases for metabolite identification. In this study, we apply generative modeling and representation learning using variational autoencoders to understand the extent to which tandem mass spectra can be disentangled into its factors of generation (e.g., collision energy, ionization mode, instrument type, etc.) with minimal prior knowledge of the factors. We find that variational autoencoders can disentangle tandem mass spectra data with the proper choice of hyperparameters into meaningful latent representations aligned with known factors of variation. We develop a two-step approach to facilitate the selection of models that are disentangled which could be applied to other complex and high-dimensional data sets.
Monitoring GPCR Conformation with GFP-Inspired Dyes
Authors: Belousov Anatoliy , Maslov Ivan , Orekhov Philipp , Khorn Polina , Kuzmichev Pavel , Baleeva Nadezhda , Motov Vladislav , Bogorodskiy Andrey , Krasnova Svetlana , Mineev Konstantin , Zinchenko Dmitry , Zernii Evgeni , Ivanovich Valentin , Permyakov Sergei , Hofkens Johan , Hendrix Jelle , Cherezov Vadim , Gensch Thomas , Mishin Alexander , Baranov Mikhail , Mishin Alexey , Borshchevskiy Valentin
Published: June 2023

Solvatochromic compounds have emerged as valuable environment-sensitive probes for biological research, with the chromophore of the green fluorescent protein (GFP) being a well-studied example. In this study, we demonstrate that synthetic analogues of the GFP chromophore can be used to investigate ligand-induced conformational changes in proteins. We synthesized thiol-reactive derivatives of four analogues of the GFP chromophore that exhibit notable solvatochromism. We used these derivatives to label two proteins: the soluble calcium sensor recoverin (Rec) and the transmembrane G protein-coupled A2Aadenosine receptor (A2AAR), via cysteines located or introduced in the regions that undergo structural changes upon ligand binding. Two of these dyes showed Ca2+-induced fluorescence changes when attached to Rec. Notably, our best-performing dye, DyeC, when attached to A2AAR, revealed agonist-induced changes in both fluorescence intensity and shape of the emission spectrum. Molecular dynamics (MD) simulations provided mechanistic insights into these changes showing the activation of A2AAR transfers DyeC to a more confined and more hydrophilic environment. Additionally, an allosteric modulator, HMA, induces changes in DyeC fluorescence spectra, indicating a distinct receptor conformation from apo, antagonist, or agonist-bound receptors. Our study demonstrates that GFP-inspired dyes are effective for detecting structural changes in GPCR (G protein-coupled receptors), with advantages such as the ability to perform both intensity-based and ratiometric tracking, red-shifted fluorescence spectra, high extinction coefficient, and sensitivity to allosteric modulation. These dyes expand the toolbox for tracking ligand-induced changes and facilitate new insights into conformational changes induced by allosteric modulators in GPCRs.
Novel histones and histone variant families in prokaryotes
Authors: Schwab Samuel , Hu Yimin , van Erp Bert , Cajili Marc K. M. , Hartmann Marcus D. , Alvarez Birte Hernandez , Alva Vikram , Boyle Aimee L. , Dame Remus T.
Published: June 2023

Histones are important chromatin-organizing proteins in eukaryotes and archaea. They form superhelical structures around which DNA is wrapped. Recent studies have shown that some archaea and bacteria contain alternative histones that exhibit different DNA binding properties, in addition to highly divergent sequences. However, the vast majority of these new histones are identified in metagenomes and thus are difficult to studyin vivo. The recent revolutionary breakthroughs in computational protein structure prediction by AlphaFold2 and RoseTTAfold allow for unprecedented insights into the potential function and structure of previously uncharacterized proteins. Here, we categorize the prokaryotic histone space into 17 distinct groups based on AlphaFold2 predictions. We identify a new superfamily of histones, termedα3 histones, which are common in archaea and present in several bacteria. Importantly, we establish the existence of a large family of histones throughout archaea and in some bacteriophages that, instead of wrapping DNA, bridge DNA, thereby diverging from conventional nucleosomal histones.
Construction and representation of human pangenome graphs
Authors: Andreace Francesco , Lechat Pierre , Dufresne Yoann , Chikhi Rayan
Published: June 2023

As a single reference genome cannot possibly represent all the variation present across human individuals, pangenome graphs have been introduced to incorporate population diversity within a wide range of genomic analyses. Several data structures have been proposed for representing collections of genomes as pangenomes, in particular graphs. In this work we collect all publicly available high-quality human haplotypes and constructed the largest human pangenome graphs to date, incorporating 52 individuals in addition to two synthetic references (CHM13 and GRCh38). We build variation graphs and de Bruijn graphs of this collection using five of the state-of-the-art tools:Bifrost,mdbg,Minigraph,Minigraph-Cactusandpggb. We examine differences in the way each of these tools represents variations between input sequences, both in terms of overall graph structure and representation of specific genetic loci. This work sheds light on key differences between pangenome graph representations, informing end-users on how to select the most appropriate graph type for their application.
Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy
Authors: Brindley Elizabeth , Heiland Mona , Mooney Catherine , Diviney Mairead , Mamad Omar , Hill Thomas D. M. , Yan Yan , Venø Morten T. , Reschke Cristina Ruedell , Batool Aasia , Langa Elena , Sanz-Rodriguez Amaya , Heller Janosch , Morris Gareth , Conboy Karen , Kjems Jørgen , Brennan Gary P. , Henshall David C.
Published: June 2023

The diagnosis of epilepsy is complex and challenging and would benefit from the availability of molecular biomarkers, ideally measurable in a biofluid such as blood. Experimental and human epilepsy are associated with altered brain and blood levels of various microRNAs (miRNAs). Evidence is lacking, however, as to whether any of the circulating pool of miRNAs originates from the brain. To explore the link between circulating miRNAs and the pathophysiology of epilepsy, we first sequenced argonaute 2 (Ago2)-bound miRNAs in plasma samples collected from mice subject to status epilepticus induced by intraamygdala microinjection of kainic acid. This identified time-dependent changes in plasma levels of miRNAs with known neuronal and microglial-cell origins. To explore whether the circulating miRNAs had originated from the brain, we generated mice expressing FLAG-Ago2 in neurons or microglia using tamoxifen-inducibleThy1orCx3cr1promoters, respectively. FLAG immunoprecipitates from the plasma of these mice after seizures contained miRNAs, including let-7i-5p and miR-19b-3p. Taken together, these studies confirm that a portion of the circulating pool of miRNAs in experimental epilepsy originates from the brain, increasing support for miRNAs as mechanistic biomarkers of epilepsy.
In Vivo Tissue Distribution of Microplastics and Systemic Metabolomic Alterations After Gastrointestinal Exposure
Authors: Garcia Marcus M. , Romero Aaron S. , Merkley Seth D. , Meyer-Hagen Jewel L. , Forbes Charles , Hayek Eliane El , Sciezka David P. , Templeton Rachel , Gonzalez-Estrella Jorge , Jin Yan , Gu Haiwei , Benavidez Angelica , Hunter Russell P. , Lucas Selita , Herbert Guy , Kim Kyle Joohyung , Cui Julia Yue , Gullapalli Rama , In Julie G. , Campen Matthew J. , Castillo Eliseo F.
Published: June 2023

Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on tissue function through metabolism remains largely unexplored. To investigate the impact of ingested MPs on target metabolomic pathways, mice were subjected to either polystyrene microspheres or a mixed plastics (5 µm) exposure consisting of polystyrene, polyethylene and the biodegradability and biocompatible plastic, poly-(lactic-co-glycolic acid). Exposures were performed twice a week for four weeks at a dose of either 0, 2, or 4 mg/week via oral gastric gavage. Our findings demonstrate that, in mice, ingested MPs can pass through the gut barrier, be translocated through the systemic circulation, and accumulate in distant tissues including the brain, liver, and kidney. Additionally, we report on the metabolomic changes that occur in the colon, liver and brain which show differential responses that are dependent on dose and type of MPs exposure. Lastly, our study provides proof of concept for identifying metabolomic alterations associated with MPs exposure and adds insight into the potential health risks that mixed MPs contamination may pose to humans.