bluuebunny/crossref_metadata_2025 huggingface dataset:
Care Bermuda, families of the patients with chronic mental disorders in Iran surrounded by psychosocial problems and needs: a qualitative study
Authors: Lohrasbi Fateme , Maghsoudi Jahangir , Alavi Mousa , Akbar Mohammad
Published: October 2023

Background:

A mental disorder is characterized by a clinically significant impairment of cognition, emotion regulation, or behavior. As a result of the shift in care from medical centers and hospitals to home care, we now see a change in the treatment of patients with chronic mental disorders. Consequently, families have become the main support system in the progressive care of these patients, leading to psychological and social problems. The current qualitative study investigated the social and psychological health needs and problems of family caregivers of patients with chronic mental disorders in Iran’s cultural and social context.

Methods:

This was a content analysis qualitative study. The study was conducted in three psychiatric hospitals in Farabi, Noor, Modares. Purposive sampling was done and continued until data saturation. Semi-structured, face-to-face, and individual interviews were conducted with 49 participants (15 family caregivers of patients with CMD and 34 members of the mental health care team). Data analysis was done using the conventional content analysis method.

Results:

Eight hundred seventy-five primary codes were obtained, which were classified into 10 subcategories and 3 main categories of ʻhealth challenges of caregiverʼ, ʻconfused concept of careʼ and “the need for a coherent support system.

Conclusion:

In Iranian society, after the patient is discharged from the hospital or care center, family members will change their role to the most important caregivers of these patients. The psychological and social health of these caregivers is destroyed because of the problems they have in providing care for their patients and their needs, which are not met.
Photon-Counting Detector CT for Femoral Stent Imaging in an Extracorporeally Perfused Human Cadaveric Model
Authors: Hartung Viktor , Gruschwitz Philipp , Huflage Henner , Augustin Anne Marie , Kleefeldt Florian , Peter Dominik , Lichthardt Sven , Ergün Süleyman , Bley Thorsten Alexander , Grunz Jan-Peter , Petritsch Bernhard
Published: October 2023

Background and Aims

This study aims to compare the performance of first-generation dual-source photon-counting detector computed tomography (PCD-CT) to third-generation dual-source energy-integrating detector (EID-CT) regarding stent imaging in the femoral arterial runoff.

Methods

Continuous extracorporeal perfusion was established in 1 human cadaver using an inguinal and infragenicular access and peristaltic pump. Seven peripheral stents were implanted into both superior femoral arteries by means of percutaneous angioplasty. Radiation dose-equivalent CT angiographies (high-/medium-/low-dose: 10/5/3 mGy) with constant tube voltage of 120 kVp, matching iterative reconstruction algorithm levels, and convolution kernels were used both with PCD-CT and EID-CT. In-stent lumen visibility, luminal and in-stent attenuation as well as contrast-to-noise ratio (CNR) were assessed via region of interest and diameter measurements. Results were compared using analyses of variance and regression analyses.

Results

Maximum in-stent lumen visibility achieved with PCD-CT was 94.48% ± 2.62%. The PCD-CT protocol with the lowest lumen visibility (BV40: 78.93% ± 4.67%) performed equal to the EID-CT protocol with the best lumen visibility (BV59: 79.49% ± 2.64%, P > 0.999). Photon-counting detector CT yielded superior CNR compared with EID-CT regardless of kernel and dose level (P < 0.001). Maximum CNR was 48.8 ± 17.4 in PCD-CT versus 31.28 ± 5.7 in EID-CT (both BV40, high-dose). The theoretical dose reduction potential of PCD-CT over EID-CT was established at 88% (BV40), 83% (BV48/49), and 73% (BV59/60), respectively. In-stent attenuation was not significantly different from luminal attenuation outside stents in any protocol.

Conclusions

With superior lumen visibility and CNR, PCD-CT allowed for noticeable dose reduction over EID-CT while maintaining image quality in a continuously perfused human cadaveric model.
Intraprocedural Versus Initial Follow-up Minimal Ablative Margin Assessment After Colorectal Liver Metastasis Thermal Ablation
Authors: Lin Yuan-Mao , Paolucci Iwan , Albuquerque Marques Silva Jessica , O'Connor Caleb S. , Fellman Bryan M. , Jones Aaron K. , Kuban Joshua D. , Huang Steven Y. , Metwalli Zeyad A. , Brock Kristy K. , Odisio Bruno C.
Published: October 2023

Objectives

The aim of this study was to investigate the prognostic value of 3-dimensional minimal ablative margin (MAM) quantified by intraprocedural versus initial follow-up computed tomography (CT) in predicting local tumor progression (LTP) after colorectal liver metastasis (CLM) thermal ablation.

Materials and Methods

This single-institution, patient-clustered, tumor-based retrospective study included patients undergoing microwave and radiofrequency ablation between 2016 and 2021. Patients without intraprocedural and initial follow-up contrast-enhanced CT, residual tumors, or with follow-up less than 1 year without LTP were excluded. Minimal ablative margin was quantified by a biomechanical deformable image registration method with segmentations of CLMs on intraprocedural preablation CT and ablation zones on intraprocedural postablation and initial follow-up CT. Prognostic value of MAM to predict LTP was tested using area under the curve and competing-risk regression model.

Results

A total of 68 patients (mean age ± standard deviation, 57 ± 12 years; 43 men) with 133 CLMs were included. During a median follow-up of 30.3 months, LTP rate was 17% (22/133). The median volume of ablation zone was 27 mL and 16 mL segmented on intraprocedural and initial follow-up CT, respectively (P < 0.001), with corresponding median MAM of 4.7 mm and 0 mm, respectively (P < 0.001). The area under the curve was higher for MAM quantified on intraprocedural CT (0.89; 95% confidence interval [CI], 0.83–0.94) compared with initial follow-up CT (0.66; 95% CI, 0.54–0.76) in predicting 1-year LTP (P < 0.001). An MAM of 0 mm on intraprocedural CT was an independent predictor of LTP with a subdistribution hazards ratio of 11.9 (95% CI, 4.9–28.9; P < 0.001), compared with 2.4 (95% CI, 0.9–6.0; P = 0.07) on initial follow-up CT.

Conclusions

Ablative margin quantified on intraprocedural CT significantly outperformed initial follow-up CT in predicting LTP and should be used for ablation endpoint assessment.
Adolescent environmental enrichment induces social resilience and alters neural gene expression in a selectively bred rodent model with anxious phenotype
Authors: O’Connor Angela M. , Hagenauer Megan H. , Thew Forrester Liam Cannon , Maras Pamela M. , Arakawa Keiko , Hebda-Bauer Elaine K. , Khalil Huzefa , Richardson Evelyn R. , Rob Farizah I. , Sannah Yusra , Watson Stanley J. , Akil Huda
Published: October 2023

Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are negatively affected in the future. Stress responses are established by an interplay between genetics, environment, and life experiences. Psychosocial stress is particularly impactful during adolescence, a critical period for the development of mood disorders. In this study we compared two established, selectively-bred Sprague Dawley rat lines, the “internalizing” bred Low Responder (bLR) line versus the “externalizing” bred High Responder (bHR) line, to investigate how genetic temperament and adolescent environment impact future responses to social interactions and psychosocial stress, and how these determinants of stress response interact. Male bLR and bHR rats were exposed to social and environmental enrichment in adolescence prior to experiencing social defeat and were then assessed for social interaction and anxiety-like behavior. Adolescent enrichment caused rats to display more social interaction, as well as nominally less social avoidance, less submission during defeat, and resilience to the effects of social stress on corticosterone, in a manner that seemed more notable in bLRs. For bHRs, enrichment also caused greater aggression during a neutral social encounter and nominally during defeat, and decreased anxiety-like behavior. To explore the neurobiology underlying the development of social resilience in the anxious phenotype bLRs, RNA-seq was conducted on the hippocampus and nucleus accumbens, two brain regions that mediate stress regulation and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory activity were enriched with differential expression in both regions, with a particularly large effect on gene sets that regulate social behaviors. Our findings provide further evidence that adolescent enrichment can serve as an inoculating experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipulating their environment has translational implications, as it underscores the feasibility of intervention strategies targeted at genetically vulnerable adolescent populations.
Four-dimensional quantitative analysis of cell plate development using lattice light sheet microscopy identifies robust transition points between growth phases
Authors: Sinclair Rosalie , Wang Minmin , Jawaid Zaki , Aaron Jesse , Rossetti Blair , Wait Eric , McDonald Kent , Cox Daniel , Heddleston John , Wilkop Thomas , Drakakaki Georgia
Published: October 2023

Cell plate formation during cytokinesis entails multiple stages occurring concurrently and requiring orchestrated vesicle delivery, membrane remodeling, and timely polysaccharide deposition, such as callose. Such a dynamic process requires dissection in time and space; hence this has been a major hurdle in studying cytokinesis. Using lattice light sheet microscopy (LLSM) we studied cell plate development in four dimensions, monitored by the behavior of the cytokinesis specific GTPase RABA2a.

We monitored the entire length of cell plate development, from its first emergence, with the aid of RABA2a, both in the presence and absence of cytokinetic callose. By developing a robust cytokinetic vesicle volume analysis, we identified distinct behavioral patterns allowing for the identification of three easily trackable, cell plate developmental phases. Notably, the phase transition between phase I and phase II is striking, indicating a switch from membrane accumulation to the recycling of excess membrane material.

We interrogated the role of callose using pharmacological inhibition with LLSM and electron microscopy. Loss of callose inhibited phase transition, establishing quantitatively the critical role and timing of the polysaccharide in cell plate expansion and maturation.

This study exemplifies the power of LLSM, combined with quantitative analysis to decode and untangle such a complex process.

Highlight

We employed lattice light sheet 4D microscopy in plants to dissect cytokinesis, a multistage process involving orchestrating delivery of membranes and timely polysaccharide deposition. Robust quantitative analysis revealed distinct phase shifts, while inhibition of callose deposition abolished the phase transition.
A lineage-specificSTAT5BN642Hmouse model to study NK-cell leukemia
Authors: Klein Klara , Kollmann Sebastian , List Julia , Hiesinger Angela , Kendler Jonatan , Rhandawa Mehak , Trifinopoulos Jana , Maurer Barbara , Grausenburger Reinhard , Moriggl Richard , Rülicke Thomas , Witalisz-Siepracka Agnieszka , Walter Wencke , Hoermann Gregor , Sexl Veronika , Gotthardt Dagmar
Published: October 2023

Patients with T- and NK-cell neoplasms frequently have somaticSTAT5Bgain-of-function mutations. The most frequentSTAT5Bmutation isSTAT5BN642H, which is known to drive murine T-cell leukemia although its role in NK-cell malignancies is unclear.

Introduction of theSTAT5BN642Hmutation into human NK-cell lines enhances their potential to induce leukemia in mice. We have generated a mouse model that enables tissue-specific expression ofSTAT5BN642Hand have selectively expressed the mutatedSTAT5Bin hematopoietic cells (N642Hvav/+) or exclusively in NK cells (N642HNK/NK). All N642Hvav/+mice rapidly develop an aggressive T-/NK T-cell leukemia, whereas N642HNK/NKmice display an indolent chronic lymphoproliferative disorder of NK cells (CLPD-NK) that progresses to an aggressive leukemia with age. Samples from NK-cell leukemia patients have a distinctive transcriptional signature driven by mutant STAT5B, which overlaps with that of murineSTAT5BN642H-expressing NK cells.

We have generated the first reliableSTAT5BN642H-driven pre-clinical mouse model that displays an indolent CLPD-NK progressing to aggressive NK-cell leukemia. This novelin vivotool will enable us to explore the transition from an indolent to an aggressive disease and will thus permit the study of prevention and treatment options for NK-cell malignancies.

Key points

Generation of a lineage-specificSTAT5BN642Htransgenic mouse model which develops NK-cell leukemia

Leukemic NK cells with a STAT5B gain of function mutation have a unique transcriptional profile in mice and human patients
Federated Learning for multi-omics: a performance evaluation in Parkinson’s disease
Authors: Danek Benjamin , Makarious Mary B. , Dadu Anant , Vitale Dan , Lee Paul Suhwan , Nalls Mike A , Sun Jimeng , Faghri Faraz
Published: October 2023

While machine learning (ML) research has recently grown more in popularity, its application in the omics domain is constrained by access to sufficiently large, high-quality datasets needed to train ML models. Federated Learning (FL) represents an opportunity to enable collaborative curation of such datasets among participating institutions. We compare the simulated performance of several models trained using FL against classically trained ML models on the task of multi-omics Parkinson’s Disease prediction. We find that FL model performance tracks centrally trained ML models, where the most performant FL model achieves an AUC-PR of 0.876 ± 0.009, 0.014 ± 0.003 less than its centrally trained variation. We also determine that the dispersion of samples within a federation plays a meaningful role in model performance. Our study implements several open source FL frameworks and aims to highlight some of the challenges and opportunities when applying these collaborative methods in multi-omics studies.

The Bigger Picture

The wide-scale application of artificial intelligence and computationally intensive analytical approaches in the biomedical and clinical domain is largely restricted by access to sufficient training data. This data scarcity exists due to the isolated nature of biomedical and clinical institutions, mandated by patient privacy policies in the health system or government legislation. Federated Learning (FL), a machine learning approach that facilitates collaborative model training is a promising strategy to address these restrictions. Therefore, understanding the limitations of cooperatively trained FL models, and their performance differences to similar, centrally trained models, is crucial to valuing their implementation in the broader biomedical research community.
VIBE: An R-package for advanced RNA-seq data exploration, disease stratification and therapeutic targeting
Authors: Khatri Indu , van Asten Saskia D , Moreno Leandro F. , Higgs Brandon W , Klijn Christiaan , Blokzijl Francis , Kolder Iris CRM
Published: October 2023

Background

Development of therapies e.g. antibody-based treatments, rely on several factors, including the specificity of target expression and characterization of downstream signaling pathways. While existing tools for analyzing and visualizing RNA-seq data offer evaluation of individual gene-level expression, they lack a comprehensive assessment of pathway-guided analysis, relevant for single- and dual-targeting therapeutics. Here, we introduce VIBE (VIsualization ofBulk RNAExpression data), an R package which provides a thorough exploration of both individual and combined gene expression, supplemented by pathway-guided analyses. VIBE’s versatility proves pivotal for disease stratification and therapeutic targeting in cancer, immune, metabolic, and other disorders.

Results

VIBE offers a wide array of functions that streamline the visualization and analysis of transcriptomics data for single- and dual-targeting therapies such as antibodies. Its intuitive interface allows users to evaluate the expression of target genes and their associated pathways across various indications, aiding in target and disease prioritization. Metadata, such as specific treatment or number of prior lines of therapy, can be easily incorporated to refine the identification of patient cohorts hypothesized to derive benefit from a given drug. Through real-world scenario representations using simulated data, we demonstrate how VIBE can be used to assist in indication selection for several user cases. VIBE integrates statistics in all graphics, enabling data-informed decision-making. Its enhanced user experience features include boxplot sorting and group genes either individually or averaged based on pathways, ensuring custom visuals for insightful decisions. For a deeper dive into its extensive functionalities, please review the vignettes on the GitHub repository (https://github.com/genmab/VIBE).

Conclusions

VIBE facilitates detailed visualization of individual and cohort-level summaries such as concordant or discordant expression of two genes or pathways. Such analyses can help to prioritize disease indications that are amenable to treatment strategies like bispecific antibody therapies or pathway-guided monoclonal antibody therapies. By using this tool, researchers can enhance the indication selection and potentially accelerate the development of novel targeted therapies with the end goal of precision, personalization, and ensuring treatments align perfectly with individual patient needs across a spectrum of medical domains.
Optimising analysis choices for multivariate decoding: creating pseudotrials using trial averaging and resampling
Authors: Scrivener C. L. , Grootswagers T. , Woolgar A.
Published: October 2023

Multivariate pattern analysis (MVPA) is a popular technique that can distinguish between condition-specific patterns of activation. Applied to neuroimaging data, MVPA decoding for inference uses above chance decoding to identify statistically reliable condition-specific information in neuroimaging data which may be missed by univariate methods. However, several analysis choices influence decoding success, and the combined effects of these choices have not been fully evaluated. We systematically assessed the influence of trial averaging and resampling on decoding accuracy and subsequent statistical outcome on simulated data. Although the optimal parameters varied with the classifier and cross-validation approach used, we found that modest trial averaging using roughly 5-10% of the total number of trials per condition improved accuracy and associated t-statistics. In addition, a resampling value of 2 could improve t-statistics and classification performance, but was not always necessary. We provide code to allow researchers to optimise analyses for the parameters of their data.
Sentinels for future coral reef conditions: assessment of environmental variability and water quality in semi-enclosed inland bays in the southern Caribbean
Authors: de Jong Chiara , van Os Iris , Sepúlveda-Rodríguez Guadalupe , de Baat Milo L. , Schoepf Verena
Published: October 2023

The mangrove-seagrass-coral reef continuum is of immense ecological and socio-economic importance, supporting biodiversity, carbon storage, coastal protection, fisheries, and tourism. The presence of extreme environmental conditions along this continuum could support adaptive refugia for climate-sensitive taxa such as reef-building corals but physicochemical conditions are rarely assessed at sufficient spatiotemporal resolution. Furthermore, coastal development and low water quality increasingly threaten these interconnected coastal ecosystems. Yet, time-integrated pollution monitoring is absent at most locations. Here, we used a multi-disciplinary approach to assess benthic cover, coral diversity, and >20 abiotic parameters characterizing two mangrove- and seagrass-dominated inland bays and two nearby coral reefs in Curaçao (southern Caribbean) during the cool, dry season and warm, wet season. This was combined with time-integrated pollution monitoring using bioindicators to assess nutrients and trace metal pollution (inland bays only), and passive samplers and bioassays to assess organic chemical pollution (all four sites) during the wet season. This approach revealed a previously undocumented extent of strong diel and seasonal environmental variability in the two inland bays, with temperature, pH and dissolved oxygen frequently reaching values predicted under moderate-to-severe future climate scenarios. In addition, the inland bays had greater nutrient concentrations (especially ammonium) and ecotoxicological risks than the nearby reefs during the wet season due to run-off, industrial- and wastewater effluents, ports and boating. Overall, our findings show that Curaçao’s inland bays have significant potential to serve as natural laboratories to study the effects of future ocean conditions on resident taxain situ. This however applies within the context of strong diel fluctuations and with the caveat of co-occurring stressors. Our work confirms the important role of mangrove and seagrass habitats as resilience hotspots for climate-sensitive taxa but also highlights the urgent need to improve monitoring, water quality and protection of these valuable habitats along the mangrove-seagrass-coral reef continuum.
Classification of bioactive peptides: a comparative analysis of models and encodings
Authors: Bizzotto Edoardo , Zampieri Guido , Treu Laura , Filannino Pasquale , Di Cagno Raffaella , Campanaro Stefano
Published: October 2023

Bioactive peptides are short amino acid chains possessing biological activity and exerting specific physiological effects relevant to human health, which are increasingly produced through fermentation due to their therapeutic roles. One of the main open problems related to biopeptides remains the determination of their functional potential, which still mainly relies on time-consuming in vivo tests. While bioinformatic tools for the identification of bioactive peptides are available, they are focused on specific functional classes and have not been systematically tested on realistic settings. To tackle this problem, bioactive peptide sequences and functions were collected from a variety of databases to generate a comprehensive collection of bioactive peptides from microbial fermentation. This collection was organized into nine functional classes including some previously studied and some newly defined such as immunomodulatory, opioid and cardiovascular peptides. Upon assessing their native sequence properties, four alternative encoding methods were tested in combination with a multitude of machine learning algorithms, from basic classifiers like logistic regression to advanced algorithms like BERT. By testing a total set of 171 models, it was found that, while some functions are intrinsically easier to detect, no single combination of classifiers and encoders worked universally well for all the classes. For this reason, we unified all the best individual models for each class and generated CICERON (Classification of bIoaCtive pEptides fRom micrObial fermeNtation), a classification tool for the functional classification of peptides. State-of-the-art classifiers were found to underperform on our benchmark dataset compared to the models included in CICERON. Altogether, our work provides a tool for real-world peptide classification and can serve as a benchmark for future model development.
A highly-contiguous genome assembly of the inbred Babraham pig (Sus scrofa) quantifies breed homozygosity and illuminates porcine immunogenetic variation
Authors: Schwartz John C. , Farrell Colin P. , Freimanis Graham , Sewell Andrew K. , Hammond John A. , Phillips John D.
Published: October 2023

The inbred Babraham pig serves as a valuable biomedical model for research due to its high level of homozygosity, including in the major histocompatibility complex (MHC) loci and likely other important immune-related gene complexes, which are generally highly diverse in outbred populations. As the ability to control for this diversity using inbred organisms is of great utility, we sought to improve this resource by generating a long-read whole genome assembly of a Babraham pig. The Babraham genome wasde novoassembled using PacBio long-reads and error-corrected using Illumina short-reads. The assembled contigs were then mapped to the current porcine reference assembly, Sscrofa11.1, to generate chromosome-level scaffolds. The resulting Babraham pig assembly is nearly as contiguous as Sscrofa11.1 with a contig N50 of 34.95 Mb and contig L50 of 23. The remaining sequence gaps are generally the result of poor assembly across large and highly repetitive regions such as the centromeres and tandemly duplicated gene families, including immune-related gene complexes, that often vary in gene content between haplotypes. We also further confirm homozygosity across the Babraham pig MHC and characterize the allele content across several immune-related gene complexes, including the contiguous assemblies of the antibody heavy chain locus and leukocyte receptor complex. The Babraham pig genome assembly provides an alternate highly contiguous porcine genome assembly as a resource for the livestock genomics community. The assembly will also aid biomedical and veterinary research that utilizes this animal model such as when controlling for genetic variation is critical.
Evaluating the definition and distribution of spring ephemeral wildflowers in eastern North America
Authors: Yancy Abby J. , Lee Benjamin R. , Kuebbing Sara E. , Neufeld Howard S. , Spicer Michelle Elise , Heberling J. Mason
Published: October 2023

The herbaceous layer accounts for the majority of plant biodiversity in eastern North American forests, encompassing substantial variation in life history strategy and function. One group of early season herbaceous understory species, colloquially referred to as “spring ephemeral wildflowers,” are of particular ecological and cultural importance. Despite this, little is known about the prevalence and biogeographic patterns of the spring ephemeral strategy. Here, we used georeferenced and dated observations from the Global Biodiversity Information Facility (GBIF) to define the phenological strategies of 559 herbaceous, vascular, understory plant species in eastern North America from a composite species list encompassing 16 site-level species lists ranging from Georgia to southern Canada. Specifically, we estimated activity periods from regional observations (primarily consisting of citizen scientist iNaturalist observations) and classified species as ephemeral if they completed all aboveground activity (including leafing, flowering, fruiting, and senescence) prior to an estimated date of canopy closure derived from remote-sensed data. We then evaluated the richness of these species at the landscape scale using estimates of biogeographic and environmental drivers aggregated for 100 km x 100 km grid cells. Importantly, our spatially-explicit approach defines each species’ spring ephemerality along a continuous scale (which we call the Ephemerality Index, EI) based on the proportion of its range in which it senesces before canopy closure (with EI = 0 indicating a species that is never ephemeral and EI = 1 indicating a species that is always ephemeral). We found that 18.4% (103 species) of understory wildflowers exhibited spring ephemerality in at least part of their range, with only 3.4% of all species exhibiting ephemeral behavior in all parts of their range. Ephemeral species had higher overall richness and composed a higher proportion of understory biodiversity in low-elevation areas with intermediate spring temperatures and elevated spring precipitation. Spring ephemerals peaked in both absolute species richness and relative proportion at mid latitudes. These biogeographic patterns deserve further study in other regions of the world and to uncover mechanisms behind these patterns. Using our new metric, our results demonstrate that the spring ephemeral strategy is not a discrete category, but rather a continuum that can vary across species’ ranges.
Ecological metabolomics of tropical tree communities across an elevational gradient: Implications for chemically-mediated biotic interactions and species diversity
Authors: Henderson David , Sedio Brian E. , Tello J. Sebastián , Cayola Leslie , Fuentes Alfredo F. , Alvestegui Belen , Muchhala Nathan , Myers Jonathan A.
Published: October 2023

Seminal hypotheses in ecology and evolution postulate that stronger and more specialized biotic interactions contribute to higher species diversity at lower elevations and latitudes. Plant-chemical defenses mediate biotic interactions between plants and their natural enemies and provide a highly dimensional trait space in which chemically mediated niches may facilitate plant species coexistence. However, the role of chemically mediated biotic interactions in shaping plant communities remains largely untested across large-scale ecological gradients. To test this hypothesis, we used ecological metabolomics to quantify the chemical dissimilarity of foliar metabolomes among 473 tree species (906 unique species-plot combinations) in 16 tropical tree communities along an elevational gradient in Madidi National Park, Bolivia. We predicted that chemical dissimilarity among co-occurring tree species would be greater, and chemical phylogenetic signal lower, in communities with greater tree species richness and warmer, wetter, and less-seasonal climates, as pressure from natural enemies is likely to be greater in these locales. Further, we predicted that these relationships should be especially pronounced for secondary metabolites derived from biosynthetic pathways known to include anti-herbivore and antimicrobial defenses than for primary metabolites. We found that median chemical dissimilarity among tree species with respect to all metabolites and secondary metabolites increased with tree species richness, decreased with elevation, and increased along a principal component of climatic variation that reflected increasing temperature and precipitation and decreasing seasonality. In contrast, median chemical dissimilarity among tree species with respect to primary metabolites was unrelated to tree species richness, elevation, or the principal component of climatic variation. Furthermore, phylogenetic signal of secondary and primary metabolites decreased with tree species richness. Among tree communities in moist forests, phylogenetic signal of secondary metabolites also increased with elevation and decreased with the temperature and precipitation. Our results support the hypothesis that chemically mediated biotic interactions shape elevational diversity gradients by imposing stronger selection for interspecific divergence in plant chemical defenses in warmer, wetter, and more stable climates. Our study also illustrates the promise of ecological metabolomics in the study of biogeography, community ecology, and complex species interactions in high-diversity ecosystems.
CASTER: Direct species tree inference from whole-genome alignments
Authors: Zhang Chao , Nielsen Rasmus , Mirarab Siavash
Published: October 2023

Genomes contain mosaics of discordant evolutionary histories, challenging the accurate inference of the tree of life. While genome-wide data are routinely used for discordance-aware phylogenomic analyses, due to modeling and scalability limitations, the current practice leaves out large chunks of the genomes. As more high-quality genomes become available, we urgently need discordance-aware methods to infer the tree directly from a multiple genome alignment. Here, we introduce CASTER, a site-based method that eliminates the need to predefine recombination-free loci. CASTER is statistically consistent under incomplete lineage sorting and is scalable to hundreds of mammalian whole genomes. We show both in simulations and on real data that CASTER is scalable and accurate and that its per-site scores can reveal interesting patterns of evolution across the genome.
Pharmacokinetics of Extended-release Buprenorphine (Ethiqa) in Female Yorkshire Swine (Sus scrofa domestica)
Authors: Stevey-Rindenow Lynlee M. , Saenz Marissa , La Vivian , Franklin Craig , Aycock-Williams Ari , Fueger Patrick T.
Published: October 2023

Despite the use of swine as a large animal translational surgical model, precise dosing regimens for commonly used analgesics such as buprenorphine, are currently lacking in this species. A newly available extended-release formulation of buprenorphine (XRB, Ethiqa) is FDA-indexed and approved for use in mice and rats; however, no studies have examined the efficacy and pharmacokinetic parameters of XRB in swine. The goal of this study was to determine the pharmacokinetics of the newly available XRB in swine. We hypothesized that after a single subcutaneous administration of XRB in adult swine, buprenorphine plasma concentrations would be at or above the therapeutic threshold of 0.1 ng/mL and that local injection side effects would be minimal. XRB was administered once, subcutaneously to two separate cohorts of adult female Yorkshire swine at low and high doses (0.2 and 0.4 mg/kg, respectively; n = 3 and 2). Blood was collected from an indwelling jugular catheter prior to and after XRB administration (13 total time points). Individual animal data indicated all animals reached therapeutic buprenorphine plasma concentrations by 8 h post administration. Average plasma buprenorphine levels for both the low- and high-dose cohorts reached therapeutic concentrations starting at 1.5 h after XRB administration and were maintained above therapeutic concentrations throughout the 96-h study period. In the low-dose cohort, the average half-life was 212.6 ± 107.1 h, whereas the half-lives in the high-dose cohort was 63.8 and 48.9 h. As expected, histology of XRB subcutaneous sites revealed mild injection site reactions characterized by granulomatous inflammation with intralesional cholesterol cleft formation. These results support our hypothesis and indicate that all animals maintained therapeutic plasma buprenorphine levels beginning at 8 h and maintaining past 96 h. Thus, XRB at either dose provide therapeutic levels of plasma buprenorphine and therefore its use should be further explored in swine.
Rewiring native post-transcriptional carbon regulators to build multi-layered genetic circuits and optimize engineered microbes for bioproduction
Authors: Simmons Trevor R. , Partipilo Gina , Stankes Anna C. , Srivastava Rashmi , Buchser Ryan , Chiu Darian , Keitz Benjamin K. , Contreras Lydia M.
Published: October 2023

As the bioprocessing and synthetic biology spaces rapidly expand, post-transcriptional regulation is emerging as driver for maximizing signal response rate and for minimizing cost per protein within cells. Designing robust post-transcriptional control systems that have precise tunability and can achieve diverse regulatory outcomes are paramount to advance the field. Herein, we develop a new approach for engineered post-transcriptional control in bacteria by rewiring a native regulatory system inEscherichia coli, the Carbon Storage Regulatory (Csr) Network, to create tunable, complex genetic circuits. First, by co-opting native components of the Csr Network to regulate translation of a target mRNA transcript, we establish a Csr-regulated Buffer Gate. Next, by rationally engineering the interactions between our synthetic construct and the native components of the Csr Network, we expand our original design into a genetic toolbox of 12 Buffer Gates that achieve precise tunability across a 10-fold range of target gene expression. Subsequently, to further regulatory capabilities using this approach, we develop a Csr-regulated NOT Gate through engineering a Csr-activated sequence into our synthetic constructs. We then build upon the Csr Buffer and Not Gates to create post-transcriptional dual input Boolean OR, NOR, AND and NAND Logic Gates, as well as a genetic pulse circuit. As a third step, we demonstrate portability of our Csr-regulated Buffer Gates into three industrially relevant bacteria by recapitulating Buffer Gate activity simply by leveraging the conserved homologous Csr Network in each species. Lastly, as a demonstration of downstream application, we apply our system to a proof-of-concept synthetic mevalonate pathway. Using our engineered constructs, we optimize mevalonate production inE.coli resulting in a three-fold increase in production relative to a transcriptionally controlled mevalonate pathway. As a whole, we establish a novel approach to rewire post-transcriptional regulatory networks for complex bacterial computation that can be utilized for efficient bioproduction in engineered microbes.
Non-linear phylogenetic regression using regularized kernels
Authors: Rosas-Puchuri Ulises , Santaquiteria Aintzane , Khanmohammadi Sina , Solís-Lemus Claudia , Betancur-R Ricardo
Published: October 2023

Phylogenetic regression is a type of Generalized Least Squares (GLS) method that incorporates a covariance matrix based on the evolutionary relationships between species (i.e., phylogenetic relationships). While this method has found widespread use in hypothesis testing via comparative phylogenetic methods, such as phylogenetic ANOVA, its ability to account for non-linear relationships has received little attention.

To address this issue, we utilized GLS in a high-dimensional feature space, employing linear combinations of transformed data to account for non-linearity, a common approach in kernel regression. We analyzed two biological datasets using both Radial Basis Function (RBF) and linear kernel transformations. The first dataset contained morphometric data, while the second dataset comprised discrete trait data and diversification rates as labels. Hyperparameter tuning of the model was achieved through cross-validation rounds in the training set.

In the tested biological datasets, regularized kernels reduced the error rate (as measured by RMSE) by around 20% compared to linear-based regression when data did not exhibit linear relationships. In simulated datasets, the error rate decreased almost exponentially with the level of non-linearity.

These results show that introducing kernels into phylogenetic regression analysis presents a novel and promising tool for complementing phylogenetic comparative methods. We have integrated this method into Python package named phyloKRR, which is freely available at:https://github.com/Ulises-Rosas/phylokrr.
Assessment of Deep Learning-Based Triage Application for Acute Ischemic Stroke on Brain MRI in the Emergency Room
Authors: Kim Jimin , Oh Se Won , Kim Jee Young , Meyer Heiko , Huwer Stefan , Zhao Gengyan , Han Dongyeob
Published: October 2023

Backgrounds

To improve the outcomes of acute ischemic stroke (AIS) patients, a well-organized triage system is essential in the emergency room (ER). This study aimed to assess the detection performance of a deep learning triage research application for AIS that was newly developed based on brain MRI in the ER.

Methods

This retrospective study consecutively enrolled 831 brain MRIs including mandatory diffusion-weighted image (DWI) performed in the ER of our institution from April to October 2021. MRIs were analyzed with this triage research application as the index test and results were compared with the gold standard of three neuroradiologists. We evaluated sensitivity, specificity, area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), and maximum F1 score for this application. We also compared changes in its detection performance with and without the addition of optional sequences, which were T1- and T2-weighted images.

Results

831 individuals (mean age, 64 years ± 16; 399 men, 432 women) were enrolled and 201 were positive for AIS. The application showed detection performance as follows; sensitivity, 90%; specificity, 89%; AUROC, 0.95 (95% confidence interval, 0.93-0.96); AUPRC, 0.91 (95% confidence interval, 0.86-0.94); and maximum F1 score, 0.86. The addition of optional sequences led to inferior performance compared to the mandatory sequence alone for detecting AIS.

Conclusions

The triage research application accurately detected AIS in a real-world ER with no additional benefits to its detection performance with optional sequences. Therefore, the triage research application can potentially help clinicians detect AIS in the ER sufficiently/adequately with only mandatory DWI.
Absence of Care Among Community-Living Older Persons with Dementia and Functional Limitations: A Cross-National Analysis of Population Survey from 22 Countries
Authors: Lin Zhuoer , Qian Yuting , Gill Thomas M. , Hou Xiaohui , Chen Shanquan , Chen Xi
Published: October 2023

Background

The provision of long-term care for persons living with dementia (PLWD) who have functional limitations is a significant global public health challenge. However, there is limited evidence on the patterns of care received by PLWD across countries and regions. This study aimed to examine the global trends in the absence of care for PLWD with functional limitations and identify potential sociodemographic disparities.

Methods

We used harmonized longitudinal survey data from four Health and Retirement Global Family of Studies that surveyed community-living persons aged 50 and older in the United States, England, 18 European countries and Israel, and China. The analysis focused on persons who reported functional limitations and developed dementia during the study periods (2012-2018). Functional limitations were assessed using activities of daily living (ADL) and instrumental activities of daily living (IADL). Absence of care was evaluated as the proportion of PLWD receiving no care for their ADL/IADL limitations.

Results

At least 20% of PLWD in both developed and developing countries received no care for their functional limitations, and this absence of care remained stable over time. The absence of care was notable for both ADL and IADL limitations, as well as for informal and formal care. Moreover, substantial disparities were observed, with less-educated individuals and those living alone experiencing greater absence of formal and informal care, respectively. These patterns and trends were consistent across all countries and regions studied.

Discussion and Implications

The findings underscore the pressing need to ensure basic care provision for persons with dementia and functional limitations, especially for those who are less educated or living alone. Policymakers should prioritize addressing these disparities and improving care provision for this population worldwide.
Predicting response and resistance to immune checkpoint blockade and surgery in melanoma patients
Authors: Mestrallet Guillaume
Published: October 2023

Melanoma remains a formidable clinical challenge, claiming the lives of 60,000 patients annually. Current therapeutic modalities encompass surgical intervention and immune checkpoint inhibitors (ICB). Nevertheless, the efficacy of ICB varies, necessitating the need to anticipate response and resistance outcomes, while also considering alternative approaches, such as surgical interventions coupled with autologous skin grafts. In pursuit of these objectives, we conducted a comprehensive analysis involving seven melanoma patient cohorts subjected to four distinct ICB treatments. Remarkably, our findings revealed varying response rates: 29% for Nivolumab, 43% for Pembrolizumab, 20% for Ipilimumab, and an encouraging 62.5% for the combination of Pembrolizumab and Ipilimumab. This underscores the superior clinical outcomes associated with anti-PD1+anti-CTLA4 therapy. Intriguingly, responders to Pembrolizumab and Ipilimumab exhibited distinct immunological characteristics, characterized by an augmentation in Th1 and M1 macrophages, alongside a reduction in CD4+ T cell infiltration. This phenomenon coincided with the upregulation of antigen presentation genes (HLA, CD80), heightened pro-inflammatory cytokine production (CCL5, CXCL9, CXCL10), and enhanced T cell responses. Furthermore, based on these response profiles, we have developed predictive software to forecast individual patient responses to available checkpoint inhibitor combinations. This innovative tool also facilitates precise calculations for the extent of melanoma resection required during surgery, graft sizing, and the determination of the necessary autologous skin cell resources. In conclusion, our approach advocates for tailored therapies, leveraging patient-specific attributes and computational predictions to enhance clinical outcomes following immunotherapy and surgical interventions. This strategy holds promise for advancing melanoma treatment paradigms.
Impact of cardiac rehabilitation and treatment compliance after ST-segment elevation myocardial infarction (STEMI) in France, the STOP SCA+ study
Authors: Laurent Emeline , Godillon Lucile , Tassi Marc-Florent , Marcollet Pierre , Chassaing Stéphan , Decomis Marie , Bezin Julien , Laure Christophe , Angoulvant Denis , Range Grégoire , Grammatico-Guillon Leslie
Published: October 2023

Introduction

Acute ST elevation myocardial infarction (STEMI) is one frequent and serious presentation of acute coronary syndrome. The STOP SCA+ study aimed to identify factors associated with negative outcomes one year after STEMI, particularly the impact of rehabilitation care and compliance.

Methods

Patients>18 years old hospitalized for STEMI management in five interventional cardiac centers in one French region (2.5 million inhabitants), between 2014 and 2018, were included. After a probabilistic matching with the National Health Insurance database (SNDS, 96% matching), compliance for cardiac tri-therapy was studied: aspirin, P2Y12 inhibitor statin. Factors associated with poor outcomes (ischemic complications, death) were analyzed using Cox modelling and those for the compliance by logistic regression.

Results

3,768 patients were included, with 84% of primary percutaneous coronary intervention. At one year, 3,362 were prescribed a tri-therapy (89.2%) among whom 53% were compliant; 2,478 patients went to cardiac rehabilitation (65.8%). Death occurred in 130 patients and/or ischemic complication in 194 (total poor outcome 8.0%). Compliance was not associated with complications over the year (HR 1.16 [0.86-1.57]), while the absence of cardiac rehabilitation was (2.31 [1.73-3.08]). Additionally, cardiac rehabilitation was associated with compliance (OR 1.55 [1.34-1.79]).

Discussion

STEMI clinical evolution at one year is mainly favorable. Pejorative outcomes were scarce, and appeared to be related to patients’ characteristics, initial STEMI presentation, and no access to rehabilitation. Compliance part in patient health outcome will need further modelling to accurately study its impact. Matching clinical and medico-administrative databases proved to be relevant for assessing outcomes at a large scale.

Key learning points

What is already known

Although the compliance with a cardiac treatment and cardiac rehabilitation immediately after a myocardial infarction are key factors for improving the prognosis, less is known about compliance maintenance at one year.

What this study adds

At one year, few poor outcomes occurred and were not associated with compliance to the cardiac tri-therapy, while they were associated with the absence of cardiac rehabilitation.

Matching two complementary clinical and medico-administrative databases proved to be reliable for assessing outcomes on a large scale (4,000 individuals over 5 years).