bluuebunny/crossref_metadata_2025 huggingface dataset:
A deep learning transformer model predicts high rates of undiagnosed rare disease in large electronic health systems
Authors: Jordan Daniel M. , Vy Ha My T. , Do Ron
Published: December 2023

It is estimated that as many as 1 in 16 people worldwide suffer from rare diseases. Rare disease patients face difficulty finding diagnosis and treatment for their conditions, including long diagnostic odysseys, multiple incorrect diagnoses, and unavailable or prohibitively expensive treatments. As a result, it is likely that large electronic health record (EHR) systems include high numbers of participants suffering from undiagnosed rare disease. While this has been shown in detail for specific diseases, these studies are expensive and time consuming and have only been feasible to perform for a handful of the thousands of known rare diseases. The bulk of these undiagnosed cases are effectively hidden, with no straightforward way to differentiate them from healthy controls. The ability to access them at scale would enormously expand our capacity to study and develop drugs for rare diseases, adding to tools aimed at increasing availability of study cohorts for rare disease. In this study, we train a deep learning transformer algorithm, RarePT (Rare-Phenotype Prediction Transformer), to impute undiagnosed rare disease from EHR diagnosis codes in 436,407 participants in the UK Biobank and validated on an independent cohort from 3,333,560 individuals from the Mount Sinai Health System. We applied our model to 155 rare diagnosis codes with fewer than 250 cases each in the UK Biobank and predicted participants with elevated risk for each diagnosis, with the number of participants predicted to be at risk ranging from 85 to 22,000 for different diagnoses. These risk predictions are significantly associated with increased mortality for 65% of diagnoses, with disease burden expressed as disability-adjusted life years (DALY) for 73% of diagnoses, and with 72% of available disease-specific diagnostic tests. They are also highly enriched for known rare diagnoses in patients not included in the training set, with an odds ratio (OR) of 48.0 in cross-validation cohorts of the UK Biobank and an OR of 30.6 in the independent Mount Sinai Health System cohort. Most importantly, RarePT successfully screens for undiagnosed patients in 32 rare diseases with available diagnostic tests in the UK Biobank. Using the trained model to estimate the prevalence of undiagnosed disease in the UK Biobank for these 32 rare phenotypes, we find that at least 50% of patients remain undiagnosed for 20 of 32 diseases. These estimates provide empirical evidence of a high prevalence of undiagnosed rare disease, as well as demonstrating the enormous potential benefit of using RarePT to screen for undiagnosed rare disease patients in large electronic health systems.
Challenges faced by Human Resources for Health in Morocco: a scoping review
Authors: Al Hassani Wafaa , Achhab El Youness , Nejjari Chakib
Published: December 2023

Background

Human resources for health (HRH) play a pivotal role in effective health system operation, yet various impediments challenge sustainable development. This scoping review aimed to explore these challenges and potential solutions in aligning the health workforce to meet the evolving healthcare needs of the Moroccan population.

Methods

We conducted a scoping review searching PubMed, Science Direct, Cairn and Google Scholar for relevant articles published between 2014 and 2023. Additionally, non-peer-reviewed literature sourced from Ministry of Health consultations and allied websites was included.

Results

Among the nineteen studies meeting our inclusion criteria, the majority were cross-sectional and predominantly focused on challenges faced by nurses. While some papers delineated multiple HRH challenges (5/19), the rest addressed specific challenges. The identified challenges span organizational and personal levels. Organizationally, the focus was on training, lifelong learning, continuing education, health coverage and shortages, and job satisfaction. At a personal level, HRH in the public health sector encountered challenges such as burnout, stress, and broader occupational health concerns.

Conclusions

The reviewed publications underscored a spectrum of challenges necessitating robust policy interventions. Despite promising developments in the Moroccan healthcare system, addressing the unequal urban-rural HRH distribution, augmenting funding, and enhancing HRH quality of life stand as pivotal imperatives.
Transcriptomic Gene Network Profiling and Weak Signal Detection for Prediction of Ovarian Cancer Occurrence, Survival, and Severity by Integrating Bulk and Single-cell RNAseq Data
Authors: Li Yanming , Sardiu Mihaela , Koestler Devin C. , Yang Fengwei , Islam Md Tamzid , Komladzei Stephan , Akhter Murshalina
Published: December 2023

Background

Ovarian cancer (OC) is a significant gynecological malignancy characterized by its high mortality rate, poor long-term survival rate, and late-stage diagnosis. OC is the 5th leading cause of cancer death among woman and counts 2.1% of all cancer death. OC survival rates are much lower than other cancers that affect woman. Its 5-year survival rate is less than 50%. Only ∼17% of OC patients are diagnosed within the early stage. The majority are diagnosed at an advanced stage, making early detection and effective treatment critical challenges. Currently, the identified OC predictive genes are still very sparse, resulting in pool prognostic performance. There exists unmet needs to identify novel prognostic gene biomarkers for OC occurrence, survival, and clinical stages to promote the likelihood of survival and to perform optimal treatments or therapeutic strategies at the earliest stage possible.

Methods

Previous RNAseq analysis on OC focused on detecting differentially expressed (DE) genes only. Many genes, although having weak marginal differential effects, may still exude strong predictive effects on disease outcomes though regulating other DE genes. In this work, we employed a new machine learning method, netLDA, to detect such predictive coregulating genes with weak marginal DE effects for predicting OC occurrence, 5-year survival, and clinical stage. The netLDA detects predictive gene networks (PGN) containing strong DE genes as hub genes and detects coregulating weak genes within the PGNs. The network structures of the detected PGNs along with the strong and weak genes therein are then used in outcome prediction on test datasets.

Results

We identified different sets of signature genes for OC occurrence, survival, and clinical stage. Previously identified prognostic genes, such asEPCAM, UBE2C, CHD1L, TP53,CD24,WFDC2, andFANCI,were confirmed. We also identified novel predictive coregulating weak genes includingGIGYF2, GNPAT, RAD54L, andELL.Many of the detected predictive gene networks and coregulating weak genes therein overlapped with OC-related biological pathways such as KEGGtight junction, ribosome, andcell cyclepathways. The detection and incorporation of the gene networks and weak genes significantly improved the prediction performance. Cellular mapping of selected feature genes using single-cell RNAseq data further revealed the heterogeneous expression distributions of the signature genes on different cell types.

Conclusions

We established a transcriptomic gene network profile for OC prediction. The novel genes detected provide new targets for early diagnostics and new drug development for OC.
In-hospital Outcomes of Acute Ischemic Stroke in Atrial Fibrillation Patients on Anticoagulation: A Retrospective Analysis
Authors: Vasquez Moises A , Lambrakos Litsa K. , Velasquez Alex , Goldberger Jeffrey J. , Mitrani Raul D.
Published: December 2023

Background

Long-term anticoagulation (AC) therapy reduces the risk of stroke in patients with Atrial Fibrillation (AF). Data on the impact of AC on in-hospital stroke outcomes is lacking.

Methods

The National Inpatient Sample was used to identify adult inpatients with AF and a primary diagnosis of ischemic stroke between 2016 and 2020. Data was stratified between patients on AC users and nonusers. A multivariate regression model was used to describe the in-hospital outcomes, adjusting for significant comorbidities.

Results

A total of 655,540 patients with AF and a diagnosis of ischemic stroke were included, of which 194,560 (29.7%) were on long-term AC. Patients on AC tended to be younger (mean age, 77 vs 78), had a higher average CHA2DS2VASc score (4.48 vs 4.20), higher rates of hypertension (91% vs 88%), hyperlipidemia (64% vs 59%), and heart failure (34% vs 30%) compared to patients not on long-term AC. Use of AC was associated with decreased in-hospital mortality (aOR [95% CI]: 0.62 [0.60 - 0.63]), decreased stroke severity (mean NIHSS, 8 vs 10), decreased use of tPA (aOR 0.42 [0.41 - 0.43]), mechanical thrombectomy (aOR 0.85 [0.83 - 0.87]), hemorrhagic conversion (aOR 0.69 [0.67 - 0.70]), gastrointestinal bleeding (aOR 0.74 [0.70 - 0.77]), and discharge to skilled nursing facilities (aOR 0.90 [0.89 - 0.91]), compared to patients not on AC (P<0.001 for all comparisons).

Conclusion

Among patients with AF admitted with acute ischemic stroke, AC use prior to stroke was associated with decreased in-hospital mortality, decreased stroke severity, decreased discharge to SNF, and fewer stroke-related and bleeding complications.
Biomimetic Lipid-polymer composite membrane model to study Permeability through Cornea
Authors: Chakraborty Ruchira , Avinash Chavan Tejas , Misra Manju , Kumar Prasoon
Published: December 2023

The excised animal cornea is the gold standard for testing and evaluating drug permeability through a cornea. However, it has a concise shelf life and encounters ethical concerns. Also, ex-vivo models, which are incomplete replicas of the human cornea, may provide faulty results in the pre-clinical studies. To circumvent these problems, we have proposed an in-vitro biomimetic lipid-polymer composite membrane (BLCM) model as an artificial cornea to study drug permeability. We designed and fabricated a free-standing, electro-spun polystyrene (PS) nanofibrous membrane and impregnated its pores with phosphatidylcholine (PC). SEM, FTIR, and goniometer characterized the BLCM. Permeation data of the drug ganciclovir through the BLCM model in a Franz-diffusion cell corroborates with the excised goat corneal system. Also, owing to the simple and scalable fabrication method, BLCM can be used as an alternative to animal models for initial drug permeability screening and studies and accelerate drug development.
Growing out of the fins: implications of isometric and allometric scaling of morphology relative to increasing mass in blue sharks (Prionace glauca)
Authors: Seamone Scott G. , Sternes Phillip C. , McCaffrey Theresa M. , Tsao Natalie K. , Syme Douglas A.
Published: December 2023

Disproportional changes (i.e. allometry) in shark morphology have been attributed to shifts in function associated with niche shifts in life history, such as in habitat and diet. Photographs of blue sharks (Prionace glauca,26-145 kg) were used to analyze changes in parameters of body and fin morphology with increasing mass that are fundamental to swimming and feeding. We hypothesized that blue sharks would demonstrate proportional changes (i.e. isometry) in morphology with increasing mass because they do not undergo profound changes in prey and habitat type, but as a result, we predicted that blue sharks would grow into bodies with greater turning inertias and smaller frontal and surface areas, in addition to smaller spans and areas of the fins relative to mass. Many aspects of morphology increased with isometry. However, blue sharks demonstrated negative allometry in body density, whereas surface area, volume and roll inertia of the body, area, span and aspect ratio of both dorsal fins, span and aspect ratio of the ventral caudal fin, and span, length and area of the mouth increased with positive allometry. The dataset was divided in half based on mass to form two groups: smaller and larger sharks. Besides area of both dorsal fins, relative to mass, larger sharks had bodies with significantly greater turning inertia and smaller frontal and surface areas, in addition to fins with smaller spans and areas, compared to smaller sharks. Hence, isometric scaling does not necessarily imply functional similarity, and allometric scaling may sometimes be critical in maintaining, rather than shifting, function relative to mass. Both allometric and isometric changes in blue sharks are predicted to promote reduced costs of transport in migration, but conversely, decreased unsteady performance, such as in escape responses. These changes are likely beneficial for larger sharks that probably experience reductions in predation pressure.
Bio-contaminated Plastic Micropipette Tip Sterilization Stations: Environmentally, Economically, and Energetically Viable Solution
Authors: Veyssi Arian , Samineni Laxmicharan , Mohanty Rashmi P
Published: December 2023

Bioscientific research laboratories significantly contribute to global plastic waste production through their widespread use of plastic products, such as single-use micropipette tips. However, biologically contaminated pipette tips must undergo several washing and sterilization steps before being reused or recycled. Grenova Solutions provides such a decontamination station called TipNovus, which has been implemented by academic and government research labs to reuse pipette tips in sensitive biological assays. Despite this success, the high initial purchasing cost of these washing stations deter many laboratories from incorporating it into their workflow. Additionally, researchers are reluctant to reuse pipette tips due to concerns that the washing process may not thoroughly remove all contaminants. To mitigate these concerns, considering the University of Texas at Austin as an example, we performed a cost-benefit analysis of employing a university-wide washing station. We estimated that only single-time reuse of the pipette tips could result in a 100% return on investment from the equipment purchase cost within 3 months. Then, with our pilot experiments, we confirmed the TipNovus washing steps to be 100% efficient in sterilizing pipette tips contaminated with T7 bacteriophage, enabling their reuse in bacteriophage functionality assays. Finally, we proposed an alternative and more convenient autoclave-based sterilization method to decontaminate pipette tips.

Abstract Figure

SYNOPSIS

Single-use plastic micropipette tips discarded by bioresearch labs generate substantial waste. This study reports adopting standardized tip-washing and reuse systems in labs greatly reduces plastic waste and research expenditures.
Winners in good times and bad times: Aerobic anoxygenic phototrophic bacteria profit from photoheterotrophy under carbon-rich and poor conditions
Authors: Piwosz Kasia , Villena-Alemany Cristian , Całkiewicz Joanna , Mujakić Izabela , Náhlík Vít , Dean Jason , Koblížek Michal
Published: December 2023

Abstract Figure

Aerobic Anoxygenic Phototrophic (AAP) bacteria are an important component of freshwater bacterioplankton. They can support their heterotrophic metabolism with energy from light, and by that enhance their growth efficiency. Based on results from cultures, it was hypothesized that photoheterotrophy provides an advantage under carbon limitation and facilitates access to recalcitrant or low-energy carbon sources. However, verification of these hypotheses for natural AAP communities has been lacking. Here, we conducted whole community manipulation experiments and compared the growth of AAP bacteria under carbon limited and with recalcitrant or low-energy carbon sources under dark and light conditions to elucidate how they profit from photoheterotrophy. We found that it depends on the season. In spring, AAP bacteria induce photoheterotrophic metabolism under carbon limitation but they outperform heterotrophic bacteria when carbon is available. This effect seems to be driven by physiological responses rather than changes at the community level. In autumn photoheterotrophy is less beneficial. In both seasons, AAP bacteria responded negatively to recalcitrant or low-energy carbon sources in light. This unexpected observation may have ecosystem-level consequences as lake browning continues. In general, our findings contribute to the understanding of the dynamics of AAP bacteria observed in pelagic environments.
Modeling cellular self-organization in strain-stiffening hydrogels
Authors: Erhardt A.H. , Peschka D. , Dazzi C. , Schmeller L. , Petersen A. , Checa S. , Münch A. , Wagner B.
Published: December 2023

We develop a three-dimensional mathematical model framework for the collective evolution of cell populations by an agent-based model (ABM) that mechanically interacts with the surrounding extra-cellular matrix (ECM) modeled as a hydrogel. We derive effective two-dimensional models for the geometrical set-up of a thin hydrogel sheet to study cell-cell and cell-hydrogel mechanical interactions for a range of external conditions and intrinsic material properties. We show that without any stretching of the hydrogel sheets, cells show the well-known tendency to form long chains with varying orientations. Our results further show that external stretching of the sheet produces the expected nonlinear strain-softening or stiffening response, with, however, little qualitative variation of the over-all cell dynamics for all the materials considered. The behavior is remarkably different when solvent is entering or leaving from strain softening or stiffening hydrogels, respectively.
Chromosome fusion and programmed DNA elimination shape karyotypes of parasitic nematodes
Authors: Simmons James R. , Estrem Brandon , Zagoskin Maxim V. , Oldridge Ryan , Zadegan Sobhan Bahrami , Wang Jianbin
Published: December 2023

A growing list of metazoans undergo programmed DNA elimination (PDE), where a significant amount of DNA is selectively lost from the somatic genome during development. In some nematodes, PDE leads to the removal and remodeling of the ends of all germline chromosomes. In several species, PDE also generates internal breaks that lead to sequence loss and an increased number of somatic chromosomes. The biological significance of these karyotype changes associated with PDE and the origin and evolution of nematode PDE remain largely unknown. Here, we assembled the single germline chromosome of the horse parasiteParascaris univalensand compared the karyotypes, chromosomal gene organization, and PDE features among ascarid nematodes. We show that PDE inParascarisconverts an XX/XY sex-determination system in the germline into an XX/XO system in the somatic cells. Comparisons ofAscaris, Parascaris,andBaylisascarisascarid chromosomes suggest that PDE existed in the ancestor of these parasites, and their current distinct germline karyotypes were derived from fusion events of smaller ancestral chromosomes. The DNA breaks involved in PDE resolve these fused germline chromosomes into their pre-fusion karyotypes, leading to alterations in genome architecture and gene expression in the somatic cells. Cytological and genomic analyses further suggest that satellite DNA and the heterochromatic chromosome arms play a dynamic role in theParascarisgermline chromosome during meiosis. Overall, our results show that chromosome fusion and PDE have been harnessed in these ascarids to sculpt their karyotypes, altering the genome organization and serving specific functions in the germline and somatic cells.
Multi-omic analysis of guided and unguided forebrain organoids reveal differences in cellular composition and metabolic profiles
Authors: Øhlenschlæger Marie S. , Jensen Pia , Havelund Jesper F. , Sutcliffe Magdalena , Elmkvist Sofie B. , Criscuolo Lucrezia , Wingett Steven W. , Jakobsen Lene A. , Brewer Jonathan , Færgeman Nils J. , Lancaster Madeline A. , Larsen Martin R. , Bogetofte Helle
Published: December 2023

Neural organoids are invaluable model systems for studying neurodevelopment and neurological diseases. For this purpose, reproducible differentiation protocols are needed that minimize inter-organoid variability whilst generating neural organoids that physiologically resemble the brain area of interest. Currently, two main approaches are used: guided, where the differentiation towards neuroectoderm and subsequently specific CNS regions is driven by applying extrinsic signalling molecules, and unguided, where the intrinsic capability of pluripotent stem cells to generate neuroectoderm without external signalling is promoted. Despite the importance for the field, the resulting differences between these models have not been directly investigated.

To obtain an unbiased comparison, we performed a multi-omic analysis of forebrain organoids generated using a guided and unguided approach focusing on proteomic, lipidomic and metabolomic differences. Furthermore, we characterised differences in phosphorylation and sialylation states of proteins, two key post-translational modifications (PTMs) in neurodevelopment, and performed single cell transcriptomics (scRNAseq). The multi-omic analysis revealed considerable differences in neuronal-, synaptic and glial content, indicating that guided forebrain organoids contain a larger proportion of neurons, including GABAergic interneurons, and synapses whereas unguided organoids contain significantly more GFAP+cells and choroid plexus. Furthermore, substantial differences in mitochondrial- and metabolic profiles were identified, pointing to increased levels of oxidative phosphorylation and fatty acid β-oxidation in unguided forebrain organoids and a higher reliance on glycolysis in guided forebrain organoids.

Overall, our study comprises a thorough description of the multi-omic differences arising when generating guided and unguided forebrain organoids and provide an important resource for the organoid field studying neurodevelopment and -disease.
Genome evolution is surprisingly predictable after initial hybridization
Authors: Langdon Quinn K. , Groh Jeffrey S. , Aguillon Stepfanie M. , Powell Daniel L. , Gunn Theresa , Payne Cheyenne , Baczenas John J. , Donny Alex , Dodge Tristram O. , Du Kang , Schartl Manfred , Ríos-Cárdenas Oscar , Gutierrez-Rodríguez Carla , Morris Molly , Schumer Molly
Published: December 2023

Over the past two decades, evolutionary biologists have come to appreciate that hybridization, or genetic exchange between distinct lineages, is remarkably common – not just in particular lineages but in taxonomic groups across the tree of life. As a result, the genomes of many modern species harbor regions inherited from related species. This observation has raised fundamental questions about the degree to which the genomic outcomes of hybridization are repeatable and the degree to which natural selection drives such repeatability. However, a lack of appropriate systems to answer these questions has limited empirical progress in this area. Here, we leverage independently formed hybrid populations between the swordtail fishXiphophorus birchmanniandX. cortezito address this fundamental question. We find that local ancestry in one hybrid population is remarkably predictive of local ancestry in another, demographically independent hybrid population. Applying newly developed methods, we can attribute much of this repeatability to strong selection in the earliest generations after initial hybridization. We complement these analyses with time-series data that demonstrates that ancestry at regions under selection has remained stable over the past ∼40 generations of evolution. Finally, we compare our results to the well-studiedX. birchmanni×X. malinchehybrid populations and conclude that deeper evolutionary divergence has resulted in stronger selection and higher repeatability in patterns of local ancestry in hybrids betweenX. birchmanniandX. cortezi.
Development of novel high-resolution melting markers for the assessment of hybridization betweenMauremys sinensisandMauremys reevesiiin South Korea
Authors: Baek Hae-jun , Cheong Eujin , Kim Youngha , Koo Kyo Soung , Kim Su-Hwan , Park Chang-Deuk , Yoon Ju-Duk
Published: December 2023

The Chinese striped-necked turtleMauremys sinensiswas first reported in the wild in South Korea in 2012. Owing to its potential to hybridize with the native and endangeredMauremys reevesiiin South Korea, leading to ecosystem disturbance,M. sinensiswas designated as an ecosystem-disturbing species (EDS; hereafter) in 2020. Such hybridization betweenM. sinensisandM. reevesiihas previously been reported in Taiwan. To protect and conserve the native South KoreanM. reevesiipopulation, the extent of its hybridization needed to be examined. Therefore, we developed novel high-resolution melting markers to elucidate the status of hybridization betweenMauremys sinensisandMauremys reevesiiin South Korea. We identified the presence ofM. sinensis,M. reevesii, and their hybrid across 47 sites in South Korea. Among these sites, five locations were confirmed as areas of sympatry for bothM. sinensisandM. reevesii, with one hybrid individual identified at the Jeonju-si site. In total, hybrids were identified at four different sites. For more definitive species identification, blood samples were collected from the specimens and subjected to mitochondrial DNA (mtDNA) cytochrome c oxidase subunit I (COI) gene and nuclear DNA (nDNA)R35gene analysis, leading to the identification of two more hybrids from two other sites. To date, no hybrids ofM. sinensishave been confirmed to reproduce in the wild, yet this requires further research for validation. The high-resolution melting (HRM) marker in theR35gene developed in this study yielded three distinct curves that were designated asM. sinensis,M. reevesii, andM. sinensis×M. reevesii, aligning with those of theR35gene sequencing. The novel markers developed in this study serve as a valuable tool that can be used in future research on rapid detection of hybridization.
Gene expression signatures of salinity transitions inLimia perugiae(Poeciliidae), with comparisons to other teleosts
Authors: Wilson Elizabeth J. , Barts Nick , Coffin John , Johnson James B. , Rodríguez Peña Carlos M. , Kelley Joanna L. , Tobler Michael , Greenway Ryan
Published: December 2023

Salinity gradients act as strong environmental barriers that limit the distribution of aquatic organisms. Changes in gene expression associated with transitions between freshwater and saltwater environments can provide insight into organismal responses to variation in salinity. We used RNA-sequencing (RNA-seq) to investigate genome-wide variation in gene expression between a hypersaline population and a freshwater population of the livebearing fish speciesLimia perugiae(Poeciliidae). Our analyses of gill gene expression revealed potential molecular mechanisms underlying salinity tolerance in this species, including the enrichment of genes involved in ion transport, maintenance of chemical homeostasis, and cell signaling in the hypersaline population. We also found differences in gene expression patterns associated with cell cycle and protein folding processes between the hypersaline and freshwaterL. perugiae. Bidirectional freshwater-saltwater transitions have occurred repeatedly during the diversification of fishes, allowing for broad-scale examination of repeatable patterns in evolution. We compared transcriptomic variation inL. perugiaewith other teleosts that have made freshwater-saltwater transitions to test for convergence in gene expression. Among the four distantly related population pairs from high- and low-salinity environments that we included in our analysis, we found only ten shared differentially expressed genes, indicating little evidence for convergence. However, we found that differentially expressed genes shared among three or more lineages were functionally enriched for ion transport and immune functioning. Overall, our results—in conjunction with other recent studies— suggest that different genes are involved in salinity transitions across disparate lineages of teleost fishes.
Defining bottlenecks and opportunities for Lassa virus neutralization by structural profiling of vaccine-induced polyclonal antibody responses
Authors: Brouwer Philip J.M. , Perrett Hailee R. , Beaumont Tim , Nijhuis Haye , Kruijer Sabine , Burger Judith A. , Lee Wen-Hsin , Müller-Kraüter Helena , Sanders Rogier W. , Strecker Thomas , van Gils Marit J. , Ward Andrew B.
Published: December 2023

Lassa fever continues to be a major public health burden in endemic countries in West Africa, yet effective therapies or vaccines are lacking. The isolation of potent and protective neutralizing antibodies against the Lassa virus glycoprotein complex (GPC) justifies the development of vaccines that can elicit strong neutralizing antibody responses. However, Lassa vaccines candidates have generally been unsuccessful in doing so and the associated antibody responses to these vaccines remain poorly characterized. Here, we establish an electron-microscopy based epitope mapping pipeline that enables high-resolution structural characterization of polyclonal antibodies to GPC. By applying this method to rabbits vaccinated with a recombinant GPC vaccine and a GPC-derived virus-like particle, we reveal determinants of neutralization which involve epitopes of the GPC-C, GPC-A, and GP1-A competition clusters. Furthermore, by identifying previously undescribed immunogenic off-target epitopes, we expose challenges that recombinant GPC vaccines face. By enabling detailed polyclonal antibody characterization, our work ushers in a next generation of more rational Lassa vaccine design.
Progressive lifespan modifications in the corpus callosum following a single juvenile concussion in male mice monitored by diffusion MRI
Authors: Obenaus Andre , Noarbe Brenda P. , Lee Jeong Bin , Panchenko Polina E. , Noarbe Sean D. , Lee Yu Chiao , Badaut Jerome
Published: December 2023

Introduction

The sensitivity of white matter (WM) in acute and chronic moderate-severe traumatic brain injury (TBI) has been established. In concussion syndromes, particularly in preclinical rodent models, there is lacking a comprehensive longitudinal study spanning the lifespan of the mouse. We previously reported early modifications to WM using clinically relevant neuroimaging and histological measures in a model of juvenile concussion at one month post injury (mpi) who then exhibited cognitive deficits at 12mpi. For the first time, we assess corpus callosum (CC) integrity across the lifespan after a single juvenile concussion utilizing diffusion MRI (dMRI).

Methods

C57Bl/6 mice were exposed to sham or two severities of closed-head concussion (Grade 1, G1, speed 2 m/sec, depth 1mm; Grade 2, G2, 3m/sec, 3mm) using an electromagnetic impactor at postnatal day 17.In vivodiffusion tensor imaging was conducted at 1, 3, 6, 12 and 18 mpi (21 directions, b=2000 mm2/sec) and processed for dMRI parametric maps: fractional anisotropy (FA), axial (AxD), radial (RD) and mean diffusivity (MD). Whole CC and regional CC data were extracted. To identify the biological basis of altered dMRI metrics, astrocyte and microglia in the CC were characterized at 1 and 12 mpi by immunohistochemistry.

Results

Whole CC analysis revealed altered FA and RD trajectories following juvenile concussion. Shams exhibited a temporally linear increase in FA with age while G1/G2 mice had plateaued FA values. G2 concussed mice exhibited high variance of dMRI metrics at 12mpi, which was attributed to the heterogeneity of TBI on the anterior CC. Regional analysis of dMRI metrics at the impact site unveiled significant differences between G2 and sham mice. The dMRI findings appear to be driven, in part, by loss of astrocyte process lengths and increased circularity and decreased cell span ratios in microglia.

Conclusion

For the first time, we demonstrate progressive perturbations to WM of male mice after a single juvenile concussion across the mouse lifespan. The CC alterations were dependent on concussion severity with elevated sensitivity in the anterior CC that was related to astrocyte and microglial morphology. Our findings suggest that long-term monitoring of children with juvenile concussive episodes using dMRI is warranted, focusing on vulnerable WM tracts.
Prediction of Carbon Emissions in Guizhou Province-Based on Different Neural Network Models
Authors: Da Lian , ShiQiang Yang , Wu Yang , WenRui Ran , Min Zhang
Published: December 2023

Global warming caused by greenhouse gas emissions has become a major challenge facing people all over the world. The study of regional human activities and their impacts on carbon emissions is of great significance to achieve the ambitious goal of carbon neutrality and sustainable economic development. Guizhou Province is a typical karst area in China, and its energy consumption is mainly based on fossil fuels.Therefore, it is necessary to predict and analyze its carbon emissions. In this paper, BP neural network and extreme learning machine (ELM) model, which have the advantage of nonlinear processing, will be used to predict the carbon emissions of Guizhou Province from 2020 to 2040. Based on the energy consumption data of Guizhou Province, the carbon emissions of Guizhou Province are calculated by using the conversion method and the inventory compilation method. The data show that the carbon emissions of Guizhou Province show an “S” growth trend; In this paper, 12 influencing factors of carbon emissions are selected, and five influencing factors with larger correlation are screened out by using grey correlation analysis method, and the prediction model of carbon emissions in Guizhou Province is established and simulated, and the prediction performance of BP neural network, ELM and WOA-ELM are compared respectively. Compared with ELM model and BP neural network model, the prediction accuracy of WOA-ELM model is higher; Finally, three development scenarios of carbon emissions are set by scenario analysis, which are baseline scenario, high-speed scenario and low-carbon scenario. On this basis, the size and time of peak carbon emissions in Liaoning Province from 2020 to 2040 are predicted based on WOA-ELM model. The results show that the peak value of carbon dioxide in the low carbon scenario is up to 0.98 million tons 31294 in 2033, the peak value of carbon emissions in the high speed scenario is up to 0.37 million tons 30251 in 2036, and the peak value of carbon emissions in the baseline scenario is up to 0.61 million tons 26243 in 2038. Based on the peak time and prediction results of carbon emissions under the three scenarios, the main factors contributing to the reduction of carbon emissions in Guizhou Province are analyzed, and important data basis is provided for energy conservation and emission reduction in Guizhou Province.
Detection of pathogenic bacteria in ticks from Isiolo and Kwale counties of Kenya using metagenomics
Authors: Kimemia Bryson Brian , Musila Lillian , Lang’at Solomon , Odoyo Erick , Cinkovich Stephanie , Abuom David , Yalwala Santos , Khamadi Samoel , Johnson Jaree , Garges Eric , Ojwang Elly , Eyase Fredrick
Published: December 2023

Ticks are arachnid ectoparasites which rank second only to mosquitoes in the transmission of human diseases including bacteria responsible for anaplasmosis, ehrlichiosis, spotted fevers, and Lyme disease among other febrile illnesses. Due to paucity of data on bacteria transmitted by ticks in Kenya, this study undertook a bacterial metagenomic-based characterization of ticks collected from Isiolo, a semi-arid pastoralist County in Eastern Kenya, and Kwale, a coastal County with monsoon climate on the southern Kenyan border with Tanzania. A total of 2,918 ticks belonging to 3 genera and 10 species were pooled and screened in this study. Tick identification was confirmed through the sequencing of Cytochrome C Oxidase Subunit 1 (COI) gene. Bacterial 16S rRNA gene PCR amplicons obtained from the above samples were sequenced using the MinION (Oxford Nanopore Technologies) platform. The resulting reads were demultiplexed in Porechop, followed by trimming and filtering in Trimmomatic before clustering using Qiime2-VSearch. A SILVA database pretrained naïve Bayes classifier was used to taxonomically classify the Operational Taxonomic Units (OTUs). The bacteria of clinical interest detected in pooled tick assays were as follows:Rickettsia spp.59.43% of pools,Coxiella burnetii37.88%,Proteus mirabilis5.08%,Cutibacterium acnes6.08% andCorynebacterium ulcerans2.43%. These bacteria are responsible for spotted fevers, query fever (Q-fever), urinary tract infections, skin and soft tissue infections, eye infections and diphtheria-like infections in humans, respectively.P. mirabilis, C. acnesandC. ulceranswere detected only in Isiolo. Additionally, COI sequences allowed for the identification ofRickettsiaandCoxiellaspecies to strain level in some of the pools. Diversity analysis revealed that the tick genera had high levels of Alpha diversity but the differences between the microbiomes of the three tick genera studied were not significant. The detection ofCutibacterium acnes, commonly associated with human skin flora suggests that the ticks may have contact with humans potentially exposing them to bacterial infections. The findings in this study highlight the need for further investigation into the viability of these bacteria and the competency of ticks to transmit them. Clinicians in these high-risk areas also need to be appraised for them to include Rickettsial diseases and Q-fever as part of their differential diagnosis.
DNA-sequence and epigenomic determinants of local rates of transcription elongation
Authors: Liu Lingjie , Zhao Yixin , Siepel Adam
Published: December 2023

Across all branches of life, transcription elongation is a crucial, regulated phase in gene expression. Many recent studies in eukaryotes have focused on the regulation of promoter-proximal pausing of RNA Polymerase II (Pol II), but rates of productive elongation also vary substantially throughout the gene body, both within and across genes. Here, we introduce a probabilistic model for systematically evaluating potential determinants of the local elongation rate based on nascent RNA sequencing (NRS) data. Our model is derived from a unified model for both the kinetics of Pol II movement along the DNA template and the generation of NRS read counts at steady state. It allows for a continuously variable elongation rate along the gene body, with the rate at each nucleotide defined by a generalized linear relationship with nearby genomic and epigenomic features. High-dimensional feature vectors are accommodated through a sparse-regression extension. We show with simulations that the model allows accurate detection of associated features and accurate prediction of local elongation rates. In an analysis of public PRO-seq and epigenomic data, we identify several features that are strongly associated with reductions in the local elongation rate, including DNA methylation, splice sites, RNA stem-loops, CTCF binding sites, and several histone marks, including H3K36me3 and H4K20me1. By contrast, low-complexity sequences and H3K79me2 marks are associated with increases in elongation rate. In an analysis of DNAk-mers, we find that cytosine nucleotides are strongly associated with reductions in local elongation rate, particularly when preceded by guanines and followed by adenines or thymines. Increases in elongation rate are associated with thymines and A+T-richk-mers. These associations are generally shared across cell types, and by considering them our model is effective at predicting features of held-out PRO-seq data. Overall, our analysis is the first to permit genome-wide predictions of relative nucleotide-specific elongation rates based on complex sets of genomic and epigenomic covariates. We have made predictions available for the K562, CD14+, MCF-7, and HeLa-S3 cell types in a UCSC Genome Browser track.
High throughput screening of Leaf Economics traits in six wine grape varieties
Authors: Cui Boya , Mariani Rachel , Cathline Kimberley A. , Robertson Gavin , Martin Adam R.
Published: December 2023

Reflectance spectroscopy has become a powerful tool for non-destructive and high- throughput phenotyping in crops. Emerging evidence indicates that this technique allows for estimation of multiple leaf traits across large numbers of samples, while alleviating the constraints associated with traditional field- or lab-based approaches. While the ability of reflectance spectroscopy to predict leaf traits across species and ecosystems has received considerable attention, whether or not this technique can be applied to quantify within species trait variation have not been extensively explored. Employing reflectance spectroscopy to quantify intraspecific variation in functional traits is especially appealing in the field of agroecology, where it may present an approach for better understanding crop performance, fitness, and trait-based responses to managed and unmanaged environmental conditions. We tested if reflectance spectroscopy coupled with Partial Least Square Regression (PLSR) predicts rates of photosynthetic carbon assimilation (Amax), Rubisco carboxylation (Vcmax), electron transport (Jmax), leaf mass per area (LMA), and leaf nitrogen (N), across six wine grape (Vitis vinifera) varieties (Cabernet Franc, Cabernet Sauvignon, Merlot, Pinot Noir, Viognier, Sauvignon Blanc). Our PLSR models showed strong capability in predicting intraspecific trait variation, explaining 55%, 58%, 62%, and 64% of the variation in observedJmax,Vcmax, leaf N, and LMA values, respectively. However, predictions ofAmaxwere less strong, with reflectance spectra explaining only 29% of the variation in this trait. Our results indicate that trait variation within species and crops is less well-predicted by reflectance spectroscopy, than trait variation that exists among species. However, our results indicate that reflectance spectroscopy still presents a viable technique for quantifying trait variation and plant responses to environmental change in agroecosystems.
Genome-wide QTL mapping across three tissues highlights several Alzheimer’s and Parkinson’s disease loci potentially acting via DNA methylation
Authors: Ohlei Olena , Sommerer Yasmine , Dobricic Valerija , Homann Jan , Deecke Laura , Schilling Marcel , Bartrés-Faz David , Cattaneo Gabriele , Düzel Sandra , Fjell Anders M. , Lindenberger Ulman , Pascual-Leone Álvaro , Sabet Sanaz Sedghpour , Solé-Padullés Cristina , Tormos Josep M. , Vetter Valentin M. , Walhovd Kristine B. , Wesse Tanja , Wittig Michael , Franke Andre , Demuth Ilja , Lill Christina M. , Bertram Lars
Published: December 2023

DNA methylation (DNAm) is an epigenetic mark with essential roles in disease development and predisposition. Here, we created genome-wide maps of methylation quantitative trait loci (meQTL) in three peripheral tissues and used Mendelian randomization (MR) analyses to assess the potential causal relationships between DNAm and risk for two common neurodegenerative disorders, i.e. Alzheimer’s disease (AD) and Parkinson’s disease (PD). Genome-wide single nucleotide polymorphism (SNP; ∼5.5M sites) and DNAm (∼850K CpG sites) data were generated from whole blood (n=1,058), buccal (n=1,527) and saliva (n=837) specimens. We identified between 11 and 15 million genome-wide significant (p<10-14) SNP-CpG associations in each tissue. Combining these meQTL GWAS results with recent AD/PD GWAS summary statistics by MR strongly suggests that the previously described associations betweenPSMC3,PICALM, andTSPAN14and AD may be founded on differential DNAm in or near these genes. In addition, there is strong, albeit less unequivocal, support for causal links between DNAm atPRDM7in AD as well as atKANSL1/MAPTin AD and PD. Our study adds valuable insights on AD/PD pathogenesis by combining two high-resolution “omics” domains, and the meQTL data shared along with this publication will allow like-minded analyses in other diseases.
Individual effect of diet on postprandial glycemic response and its relationship with gut microbiome profile in healthy subjects: protocol for a series of randomized N-of-1 trials
Authors: Zamparette C.P. , Teixeira B.L. , Cruz G.N.F. , Filho V. B. , De Oliveira L.F.V.
Published: December 2023

Background

Type 2 diabetes causes over a million deaths annually, ranking in the top ten causes of death worldwide. Glycemic control through dietary adequacy is essential for treatment success and disease prevention. Recent evidence indicates that the glycemic response to various foods varies from individual to individual. The intestinal microbiome is seen as a potential key player, mediating the effect of foods on glycemic response. By design, however, most published studies cannot separate variation in the individual treatment effects (ITE) of different diets from within-individual variability of glycemic responses. In this context, the present study aims to assess the heterogeneity in the ITE of diet on glycemic response and investigate the relevance of the intestinal microbiome profile as a predictor of this heterogeneity.

Methods

This study is a series of N-of-1 randomized clinical trials. Each participant will undergo five treatment cycles of two prescribed diets (low-carb versus vegan) in one of two randomly chosen treatment sequences (ABBABAABBA or BAABABBAAB). The primary outcome is the positive incremental area-under-the-curve (iAUC) of the postprandial interstitial fluid glucose measured within 2 hours of meal consumption. The trial plans to recruit 80 healthy volunteers with ages between 18 and 60. Fecal samples will be collected at baseline for microbiome analysis by metagenomics shotgun technique. Random effects linear models will be used for the primary analysis.

Discussion

While significant variation of individual effects warrants personalized interventions, it is well-known that glycemic responses to the same food, in the same individual, vary from occasion to occasion. Yet, most clinical studies are based on designs that are incapable of separating ITE variation from within-individual variability. This is a major limitation since the personalization of dietary interventions is only justified by clinically relevant heterogeneity of individual-level effects. In this study, if significant ITE variation is indeed observed, then we will also be able to estimate the relationship between the intestinal microbiome and the expected diet effects. This is essential to identify predictive biomarkers, which can identify those who intrinsically benefit the most from which diet, going beyond pure associations with glycemic response. Conversely, observing negligible ITE variation in a large series of N-of-1 trials would cast major doubts on the relevance of personalizing dietary interventions for glycemic control. Therefore, the present study represents a major step toward understanding the clinical value of microbiome-driven precision nutrition.