bluuebunny/crossref_metadata_2025 huggingface dataset:
Five-leaf generalizations of theD-statistic reveal the directionality of admixture
Authors: Leppälä Kalle , da Silva Coelho Flavio Augusto , Richter Michaela , Albert Victor A. , Lindqvist Charlotte
Published: February 2024

Over the past 15 years, theD-statistic, a four-taxon test for organismal admixture (hybridization, or introgression) which incorporates single nucleotide polymorphism data with allelic patterns ABBA and BABA, has seen considerable use. This statistic seeks to discern significant deviation from either a given species tree assumption, or from the balanced incomplete lineage sorting that could otherwise defy this species tree. However, while theD-statistic can successfully discriminate admixture from incomplete lineage sorting, it is not a simple matter to determine the directionality of admixture using only four-leaf tree models. As such, methods have been developed that use 5 leaves to evaluate admixture. Among these, theDFOILmethod, which tests allelic patterns on the “symmetric” treeS= (((1, 2), (3, 4)), 5), succeeds in finding admixture direction for many five-taxon examples. However,DFOILdoes not make full use of all symmetry, nor canDFOILfunction properly when ancient samples are included because of the reliance on singleton patterns (such as BAAAA and ABAAA). Here, we take inspiration fromDFOILto develop a new and completely general family of five-leaf admixture tests, dubbed Δ-statistics, that can either incorporate or exclude the singleton allelic patterns depending on individual taxon and age sampling choices. We describe two new shapes that are also fully testable, namely the “asymmetric” treeA= ((((1, 2), 3), 4), 5) and the “quasisymmetric” treeQ= (((1, 2), 3), (4, 5)), which can considerably supplement the “symmetric”S= (((1, 2), (3, 4)), 5) model used byDFOIL. We demonstrate the consistency of Δ-statistics under various simulated scenarios, and provide empirical examples using data from black, brown and polar bears, the latter also including two ancient polar bear samples from previous studies. RecentlyDFOILand one of these ancient samples was used to argue for a dominant polar bear → brown bear introgression direction. However, we find, using both this ancient polar bear and our own, that by far the strongest signal using bothDFOILand Δ-statistics on treeSis actually bidirectional gene flow of indistinguishable direction. Further experiments on treesAandQinstead highlight what were likely two phases of admixture: one with stronger brown bear → polar bear introgression in ancient times, and a more recent phase with predominant polar bear → brown bear directionality.

Code and documentation available athttps://github.com/KalleLeppala/Delta-statistics.
Heterologous Prime-Boost with Immunologically Orthogonal Protein Nanoparticles for Peptide Immunofocusing
Authors: Bhattacharya Sonia , Jenkins Matthew C. , Keshavarz-Joud Parisa , Bourque Alisyn Retos , White Keiyana , Alvarez Barkane Amina M. , Bryksin Anton V. , Hernandez Carolina , Kopylov Mykhailo , Finn M.G.
Published: February 2024

Protein nanoparticles are effective platforms for antigen presentation and targeting effector immune cells in vaccine development. Encapsulins are a class of protein-based microbial nanocompartments that self-assemble into icosahedral structures with external diameters ranging from 24 to 42 nm. Encapsulins fromMxyococcus xanthuswere designed to package bacterial RNA when produced inE. coliand were shown to have immunogenic and self-adjuvanting properties enhanced by this RNA. We genetically incorporated a 20-mer peptide derived from a mutant strain of the SARS-CoV-2 receptor binding domain (RBD) into the encapsulin protomeric coat protein for presentation on the exterior surface of the particle. This immunogen elicited conformationally-relevant humoral responses to the SARS-CoV-2 RBD. Immunological recognition was enhanced when the same peptide was presented in a heterologous prime/boost vaccination strategy using the engineered encapsulin and a previously reported variant of the PP7 virus-like particle, leading to the development of a selective antibody response against a SARS-CoV-2 RBD point mutant. While generating epitope-focused antibody responses is an interplay between inherent vaccine properties and B/T cells, here we demonstrate the use of orthogonal nanoparticles to fine-tune the control of epitope focusing.

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Development of rat organoids to study intestinal adaptations after Roux-en-Y Gastric Bypass
Authors: Benhaddou Soukaïna , Ribeiro-Parenti Lara , Vaugrente Amélie , Willemetz Alexandra , Gaudichon Claire , Douard Véronique , Le Gall Maude , Larraufie Pierre
Published: February 2024

Organoids from intestinal regions have proven to be useful tools to study intestinal epithelial responses to different conditions. Roux-en-Y gastric bypass (RYGB) has been associated with important intestinal adaptations, but the mechanisms underlying these changes are still poorly understood. Organoids could therefore be used to better decipher the intestinal adaptations associated with this surgery. Rat is a common model to assess RYGB responsesin vivo, but surprisingly, very few studies managed to develop organoids from rat small intestine. The primary objective of this study was to establish a protocol for cultivating organoids derived from the small intestine of healthy rats. The second objective of this study focuses on the development of organoids from the small intestine of rats subjected to RYGB to evaluate whether phenotypic or gene expression differences emerge.

We successfully devised a functional protocol for developing organoids from fresh or frozen rat small intestine tissues. The obtained organoids exhibit significant variability, making interpretation challenging. Variability is observed in size, shape, and the number of organoids developed from the same sample, but also gene expression, depending on samples prepared on different days or from fresh or frozen tissues. This protocol was then applied to the small intestine of RYGB or sham-operated rats. However, we did not detect any major difference in size between intestinal organoids derived from Sham rats and those from RYGB rats. The expression of several genes (peptide transporters, amino acid transporters, genes specific to certain types of intestinal cells, etc.) was also assessed, and inter-experiment variability was higher than any effect due to the operation on the rat the intestinal tissue was originating.

In conclusion, this study has established a functional protocol to grow small intestine organoids in rats. Initial results suggest that in our experimental conditions, organoids obtained from rats subjected to RYGB do not differ from those obtained from Sham rats. However, increasing the sample size and improving reproducibility between experiments will be essential to confirm these findings.
Pandemic Risk Assessment for a Swine Influenza A Virus in Comparative Human Substrates
Authors: Padykula Ian , Damodaran Lambodhar , Young Kelsey T. , Krunkosky Madelyn , Griffin Emily F. , North James F. , Neasham Peter J. , Pliasas Vasilis C. , Siepker Chris L. , Stanton James B. , Howerth Elizabeth W. , Bahl Justin , Kyriakis Constantinos S. , Tompkins S. Mark
Published: February 2024

Swine influenza A viruses pose a public health concern as novel and circulating strains occasionally spill over into human hosts, with the potential to cause disease. Crucial to preempting these events is the use of a threat assessment framework for human populations. However, established guidelines do not specify what animal models orin vitrosubstrates should be used. We completed an assessment of a contemporary swine influenza isolate, A/swine/GA/A27480/2019, using animal models and human cell substrates. Infection studiesin vivorevealed high replicative ability and a pathogenic phenotype in the swine host with replication corresponding to a complementary study performed in swine primary respiratory epithelial cells. However, replication was limited in human primary cell substrates. This contrasted with our findings in the Calu-3 cell line, which demonstrated a replication profile on par with the 2009 pandemic H1N1 virus. These data suggest selection of models is important for meaningful risk assessment.

Article Summary Line

A novel swine influenza A virus was rigorously assessed for pandemic potential in animal models and human surrogate culture models, illustrating a wide range in potential public health risk dependent on the model utilized.
Limited transmission of microbial species among coral reef fishes from the Great Barrier Reef, Australia
Authors: Costa Vincenzo A. , Bellwood David R. , Mifsud Jonathon C.O. , Geoghegan Jemma L. , Harvey Erin , Holmes Edward C.
Published: February 2024

Reef fishes account for one-third of all extant marine fishes and exhibit enormous biodiversity within a highly interactive ecosystem. Yet relatively little is known about the diversity and evolution of microbial species (bacteria, viruses, and eukaryotes) associated with reef fish, even though this may provide valuable insights into the factors that shape microbial communities within vertebrate hosts as well as the extent and pattern of cross-species transmission. Through metatranscriptomic sequencing we characterised the viruses, bacteria, and single-celled eukaryotes from 128 reef fish species inhabiting Lizard Island and Orpheus Island on the Great Barrier Reef, Australia. We assessed whether microbial communities differed between islands that are separated by approximately 450 kilometres, and to what extent viruses were able to emerge in new hosts. Notably, despite strong ecological interactions in the reef environment, and the presence of the same families and subfamilies of viruses and bacteria on both islands, there was minimal evidence for the cross-species transmission of individual microorganisms among fish species. An exception was the high prevalence of the bacterial pathogenPhotobacterium damselaeamong apparently healthy cardinalfishes from both islands, indicating that these fish species are natural reservoirs within the reef system. Overall, these data suggest that reef fishes have microbial-host associations that arose prior to the formation of the Great Barrier Reef, leading to strong host barriers to cross-species microbial transmission even within a highly interactive and species-rich environment.
High frequency post-pause word choices and task-dependent speech behavior characterize connected speech in individuals with mild cognitive impairment
Authors: Kleiman Michael J. , Galvin James E.
Published: February 2024

Background

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, including impairments in speech production and fluency. Mild cognitive impairment (MCI), a prodrome of AD, has also been linked with changes in speech behavior but to a more subtle degree.

Objective

This study aimed to investigate whether speech behavior immediately following both filled and unfilled pauses (post-pause speech behavior) differs between individuals with MCI and healthy controls (HCs), and how these differences are influenced by the cognitive demands of various speech tasks.

Methods

Transcribed speech samples were analyzed from both groups across different tasks, including immediate and delayed narrative recall, picture descriptions, and free responses. Key metrics including lexical and syntactic complexity, lexical frequency and diversity, and part of speech usage, both overall and post-pause, were examined.

Results

Significant differences in pause usage were observed between groups, with a higher incidence and longer latencies following these pauses in the MCI group. Lexical frequency following filled pauses was higher among MCI participants in the free response task but not in other tasks, potentially due to the relative cognitive load of the tasks. The immediate recall task was most useful at differentiating between groups. Predictive analyses utilizing random forest classifiers demonstrated high specificity in using speech behavior metrics to differentiate between MCI and HCs.

Conclusions

Speech behavior following pauses differs between MCI participants and healthy controls, with these differences being influenced by the cognitive demands of the speech tasks. These post-pause speech metrics can be easily integrated into existing speech analysis paradigms.
T cell and autoantibody profiling for primary immune regulatory disorders
Authors: Harris Emily M. , Chamseddine Sarah , Chu Anne , Senkpeil Leetah , Nikiciuk Matthew , Bourdine Aleksandra , Magin Logan , Al-Musa Amer , Woods Brian , Ozdogan Elif , Saker Sarife , van Konijnenburg David P. Hoytema , Yee Christina S.K. , Nelson Ryan W. , Lee Pui , Halyabar Olha , Hale Rebecca C. , Day-Lewis Megan , Henderson Lauren A. , Nguyen Alan A. , Elkins Megan , Ohsumi Toshiro K. , Gutierrez-Arcelus Maria , Peyper Janique M. , Platt Craig D. , Grace Rachael F. , LaBere Brenna , Chou Janet
Published: February 2024

Background

Limited clinical tools exist for characterizing primary immune regulatory disorders (PIRD), which are often diagnoses of exclusion. Increased CD4+CXCR5+PD1+circulating T follicular helper (cTfh) cell percentages have been identified as a marker of active disease in some, but not all, autoimmune disorders.

Objective

To develop a diagnostic approach that combines measurements of cellular and serologic autoimmunity.

Methods

We recruited 71 controls and 101 pediatric patients with PIRD with autoimmunity. Flow cytometry was used to measure CD4+CXCR5+T cells expressing the chemokine receptors CXCR3 and/or CCR6. IgG and IgA autoantibodies were quantified in 56 patients and 20 controls using a microarray featuring 1616 full-length, conformationally intact protein antigens. The 97.5thpercentile in the controls serves as the upper limit of normal for percentages of cTfh cells, CD4+CXCR5+T cells expressing CXCR3 and/or CCR6, and autoantibody intensity and number.

Results

We found that 27.7% of patients had increased percentages of CD4+CXCR5+PD1+cTfh cells and 42.5% had increased percentages of CD4+CXCR5+cells expressing CXCR3 and/or CCR6. Patients had significantly more diverse IgG and IgA autoantibodies than controls and 37.5% had increased numbers of high-titer autoantibodies. Integrating measurements of cTfh cells, CD4+CXCR5+T cells with CXCR3 and/or CCR6, and numbers of high-titer autoantibodies had 71.4% sensitivity (95% CI: 0.5852 – 0.8158) and 85% specificity (95% CI: 0.6396 – 0.9476) for patients with PIRD compared to controls.

Conclusion

By integrating CD4+T cell phenotyping and total burden of autoantibodies, this approach provides additional tools for the diagnosis of PIRD lacking clinical diagnostic criteria.

Highlights Box

Primary immune regulatory disorders (PIRD) are heterogenous and often diagnoses of exclusion if no genetic cause is identified. Current diagnostic tools do not combine cellular and serologic measures of autoimmunity.

Measuring activated CD4+T cells expressing the chemokine receptors CXCR3 and/or CCR6 and the total number of circulating autoantibodies can enhance detection of autoimmunity in PIRD beyond the capabilities of currently used tools.

This study identifies new indicators of autoimmunity that can be feasibly implemented and leveraged for improving the diagnosis of PIRD.
Modeling gene-environment interactions in Parkinson’s Disease:Helicobacter pyloriinfection ofPink1−/−mice induces CD8 T cell-dependent motor and cognitive dysfunction
Authors: Kazanova Alexandra , Sung Jacqueline , Oliveira Nathalia , Gavino Christina , Recinto Sherilyn , Bessaiah Hicham , Pei Jessica , Burns Lindsay , Miller Willemein , Brouillard-Galipeau Morgane , Zhu Lei , Guerra Lucia , Elemeery Moustafa Nouh , MacDonald Adam , Lanoix Joel , Thibault Pierre , McBride Heidi , Desjardins Michel , Stratton Jo Anne , Labrecque Nathalie , Gruenheid Samantha
Published: February 2024

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of motor function. Diagnosis occurs late: after motor symptom development downstream of the irreparable loss of a large proportion of the dopaminergic neurons in thesubstantia nigraof the brain. Understanding PD pathophysiology in its pre-motor prodromal phase is needed for earlier diagnosis and intervention. Genetic risk factors, environmental triggers, and dysregulated immunity have all been implicated in PD development. Here, we demonstrate in a mouse model deficient in the PD-associated genePink, that infection with the human PD-associated gastric bacteriumHelicobacter pylorileads to development of motor and cognitive signs resembling prodromal features of PD. This was also associated with proliferation and activation of primary mitochondria-reactive CD8 T cells and infiltration of CD8 T cells into the brain. Development of the motor and cognitive phenotypes in the infectedPink1−/−mice was abrogated when CD8 T cells were depleted prior to infection. We anticipate that this new model, which integrates genetic PD susceptibility, a PD-relevant environmental trigger, and specific immune changes that are required for symptom development, will be a valuable tool for increasing our understanding of this complex disease.
Complete chromosome 21 centromere sequences from a Down syndrome family reveal size asymmetry and differences in kinetochore attachment
Authors: Mastrorosa F. Kumara , Rozanski Allison N. , Harvey William T. , Knuth Jordan , Garcia Gage , Munson Katherine M. , Hoekzema Kendra , Logsdon Glennis A. , Eichler Evan E.
Published: February 2024

Down syndrome is the most common form of human intellectual disability caused by precocious segregation and nondisjunction of chromosome 21. Differences in centromere structure have been hypothesized to play a potential role in this process in addition to the well-established risk of advancing maternal age. Using long-read sequencing, we completely sequenced and assembled the centromeres from a parent-child trio where Trisomy 21 arose in the child as a result of a meiosis I error. The proband carries three distinct chromosome 21 centromere haplotypes that vary by 11-fold in length--both the largest (H1) and smallest (H2) originating from the mother. The longest H1 allele harbors a less clearly defined centromere dip region (CDR) as defined by CpG methylation and a significantly reduced signal by CENP-A chromatin immunoprecipitation sequencing when compared to H2 or paternal H3 centromeres. These epigenetic signatures suggest less competent kinetochore attachment for the maternally transmitted H1. Analysis of H1 in the mother indicates that the reduced CENP-A ChIP-seq signal, but not the CDR profile, pre-existed the meiotic nondisjunction event. A comparison of the three proband centromeres to a population sampling of 35 completely sequenced chromosome 21 centromeres shows that H2 is the smallest centromere sequenced to date and all three haplotypes (H1-H3) share a common origin of ~15 thousand years ago. These results suggest that recent asymmetry in size and epigenetic differences of chromosome 21 centromeres may contribute to nondisjunction risk.
Individual-specific associations between behavioral events and song notes shape budgerigar vocal sequences
Authors: Wewhare Nakul , Krishnan Anand
Published: February 2024

Complex behavioral sequences such as courtship displays are often multimodal, and coordination between modalities is critically important. However, in learned and variable behavioral sequences such as songs, individual variability may extend to multimodal coordination. However, individual variability in complex multimodal sequences and in coordination between distinct behaviors remains underexplored. Here, we report that budgerigars, which continuously learn and modify their complex warble songs, exhibit associations between behavioral events during courtship and song notes. Some associations are unique to individuals, and others are universal across individuals. Additionally, some individuals exhibit more unique associations than others. We also find that birds warbling without courtship emit all notes with broadly similar odds ratios. The presence of individual variability opens up the possibility that social learning may modify the associations between complex sequences of behaviors, and this results in both individual variability and hierarchical differences in the links between courtship or copulatory behaviors and song.
An arch worth revisiting:A study on the feline humeral supracondylar foramen and its evolutionary significance
Authors: Byrne Eimear , Johnston Robert D. , Kilroy David , Bhattacharjee Sourav
Published: February 2024

The supracondylar foramen with a seemingly osseous peripheral arch noticed on the medio-distal feline humeri had remained disputed among anatomists. Some scholars have argued in favor of homology between this foramen and the supracondyloid foramen formed in the presence of the ligament of Struthers in humans. Other theories include its presence as a retinaculum holding the median nerve and brachial artery to their anatomical position in a flexed elbow. Unfortunately, these theories lack investigative rigor. The emergence of non-invasive imaging modalities, such as micro-computed tomography, has enabled researchers to inspect the internal anatomy of bones without dismantling. Thus, a micro-computed tomographic investigation was conducted on three feline humeri specimens while the internal anatomy of the supracondylar foramina was examined. Unlike the humerus, the thin peripheral arch of the feline supracondylar foramen failed to elicit any osseous trabeculae or foci of calcification. While adhering to the humeral periosteum at its origin, the non-osseous arch, typical of a muscular tendon or a ligament, inserts into a bony spur attached to the medial humeral epicondyle suggestive of a ligament or aponeurotic extension of a (vestigial) brachial muscle, with the coracobrachialis longus emerging to be the most likely candidate.
A global-scale dataset of bat viral detection suggests that pregnancy reduces viral shedding
Authors: Eskew Evan A. , Olival Kevin J. , Mazet Jonna A. K. , Daszak Peter ,   PREDICT Consortium
Published: February 2024

Understanding viral infection dynamics in wildlife hosts can help forecast zoonotic pathogen spillover and human disease risk. Bats are particularly important reservoirs of zoonotic viruses, including some of major public health concern such as Nipah virus, Hendra virus, and SARS-related coronaviruses. Previous work has suggested that metapopulation dynamics, seasonal reproductive patterns, and other bat life history characteristics might explain temporal variation in spillover of bat-associated viruses into people. Here, we analyze viral dynamics in free-ranging bat hosts, leveraging a multi-year, global-scale viral detection dataset that spans eight viral families and 96 bat species from 14 countries. We fit hierarchical Bayesian models that explicitly control for important sources of variation, including geographic region, specimen type, and testing protocols, while estimating the influence of reproductive status on viral detection in female bats. Our models revealed that late pregnancy had a negative effect on viral shedding across multiple data subsets, while lactation had a weaker influence that was inconsistent across data subsets. These results are unusual for mammalian hosts, but given recent findings that bats may have high individual viral loads and population-level prevalence due to dampening of antiviral immunity, we propose that it would be evolutionarily advantageous for pregnancy to either not further reduce immunity or actually increase the immune response, reducing viral load, shedding, and risk of fetal infection. This novel hypothesis would be valuable to test given its potential to help monitor, predict, and manage viral spillover risk from bats.
The Role of Nde1 Phosphorylation in Interkinetic Nuclear Migration and Schizophrenia
Authors: Doobin David J , Helmer Paige , carabalona Aurelie , Bertipaglia Chiara , Vallee Richard B
Published: February 2024

Nde1 is a cytoplasmic dynein regulatory protein with important roles in vertebrate brain development. One noteworthy function is in the nuclear oscillatory behavior in neural progenitor cells, the control and mechanism of which remain poorly understood. Nde1 contains multiple phosphorylation sites for the cell cycle-dependent protein kinase CDK1, though the function of these sites is not well understood. To test their role in brain development we expressed phosphorylation-state mutant forms of Nde1 in embryonic rat brains usingin uteroelectroporation. We find that Nde1 T215 and T243 phosphomutants block apical interkinetic nuclear migration (INM) and, consequently, mitosis in radial glial progenitor cells. Another Nde1 phosphomutant at T246 also interfered with mitotic entry without affecting INM, suggesting a more direct role for Nde1 T246 in mitotic regulation. We also found that the Nde1 S214F mutation, which is associated with schizophrenia, inhibits CDK5 phosphorylation at an adjacent residue which causes alterations in neuronal lamination. These results together identify important new roles for Nde1 phosphorylation in neocortical development and disease and represent the first evidence for Nde1 phosphorylation roles in INM, neuronal lamination, and schizophrenia.

Significance Statement

The results presented in this study show the importance of Nde1 phosphoregulation during successive stages of neocortical development. Nde1 dysregulation may, in turn, have important consequences in human psychiatric disorders, such as schizophrenia, as well. We observed clear and potent effects of specific Nde1 phosphomutants in the control of INM and neural development. Our results provide strong support for new insight into the little-understood mechanism for triggering RGP mitotic entry. In the course of these studies, we obtained clear evidence for a novel post-mitotic role for Nde1 phosphorylation in schizophrenia.
Trends, District-Level Variations, and Socioeconomic Disparities in Cesarean Section Delivery and its Association with Neonatal Mortality in Bangladesh
Authors: Khan Md Nuruzzaman , Alam Md Badsha , Khanam Shimlin Jahan , Islam M Mofizul , Billah Md Arif
Published: February 2024

Background: Cesarean section (CS) rates have risen dramatically worldwide, with a majority of the countries exceeding the World Health Organization's (WHO) preferred rate of 10-15%. However, disparities exist, with evidence suggesting that socioeconomic disadvantage and geographic location play significant roles. Despite this, comprehensive estimates, especially in Bangladesh, remain scarce. This study aims to determine trends, district-level variations, and socioeconomic disparities in CS rates in Bangladesh. Methods: Data from six rounds of Bangladesh Demographic and Health Surveys were analyzed. The considered outcome variables were the occurrence of CS delivery in relation to the mode of delivery and delivery place. Neonatal mortality was also assessed as another outcome variable. Explanatory variables included districts, wealth quintiles, and socio-demographic characteristics. Descriptive statistics were used to provide an over-the-year trend and variation in CS delivery in Bangladesh. Multilevel mixed-effects binary logistic regressions were used to explore predictors of CS delivery and the association between CS and neonatal mortality. Results: Between 1999/2000 and 2017/18, hospital births in Bangladesh increased by 42%, primarily driven by a substantial rise in CS delivery, from 30% to 66%. Private healthcare facilities played a significant role, contributing 80% of the country's total CS delivery in 2017/18, a substantial increase from 45.5% in 1999/2000. In contrast, CS delivery rates in government healthcare facilities decreased from 49.7% to 15.5% during the same period. Deficient use of CS was reported by women in border and hilly districts, as well as those in the poorest wealth quintile. A clear link between a CS delivery and neonatal mortality was not found. Conclusion: The uneven distribution of CS delivery across districts and socioeconomic groups underscores the need for a more nuanced approach to childbirth. While government efforts to curb unnecessary use of CS have fallen short, this study suggests a one-size-fits-all strategy could worsen disparities. Instead, the focus should shift from mere accessibility to ensuring justified and appropriate utilization, with public healthcare facilities playing a key role in offering safe alternatives.
Evaluating Explanations from AI Algorithms for Clinical Decision-Making: A Social Science-based Approach
Authors: Ghanvatkar Suparna , Rajan Vaibhav
Published: February 2024

Explainable Artificial Intelligence (XAI) techniques generate explanations for predictions from AI models. These explanations can be evaluated for (i) faithfulness to the prediction, i.e., its correctness about the reasons for prediction, and (ii) usefulness to the user. While there are metrics to evaluate faithfulness, to our knowledge, there are no automated metrics to evaluate the usefulness of explanations in the clinical context. Our objective is to develop a new metric to evaluate usefulness of AI explanations to clinicians. Usefulness evaluation needs to consider both (a) how humans generally process explanations and (b) clinicians’ specific requirements from explanations presented by clinical decision support systems (CDSS). Our new scoring method can evaluate the usefulness of explanations generated by any XAI method that provides importance values for the input features of the prediction model. Our method draws on theories from social science to gauge usefulness, and uses literature-derived biomedical knowledge graphs to quantify support for the explanations from clinical literature. We evaluate our method in a case study on predicting onset of sepsis in intensive care units. Our analysis shows that the scores obtained using our method corroborate with independent evidence from clinical literature and have the required qualities expected from such a metric. Thus, our method can be used to evaluate and select useful explanations from a diverse set of XAI techniques in clinical contexts, making it a fundamental tool for future research in the design of AI-driven CDSS.
Digital Health Technologies for Metabolic Disorders in Older Adults: A Scoping Review Protocol
Authors: Huynh Panitda , Fleisch Elgar , Brändle Michael , Kowatsch Tobias , Jovanova Mia
Published: February 2024

Introduction

Metabolic disorders (type 2 diabetes, insulin resistance, hyperglycemia, obesity, hyperlipidemia, hypertension, nonalcoholic fatty liver disease, and metabolic syndrome) are leading causes of mortality and disability worldwide and disproportionately affect older adults relative to those younger. Digital health technologies (DHTs), such as patient monitoring, digital diagnostics, and digital therapeutics, emerge as promising tools for navigating health in day-to-day life. However, their role in targeting metabolic disorders, particularly among a key demographic of older adults, is not yet fully understood. Thus, this work aims to scope the use of DHTs in managing metabolic health disorders among older adults.

Methods and Analysis

We will conduct a scoping review following the recommended framework by Arksey and O’Malley (1). Our search will focus on three primary concepts: metabolic disorders, DHTs, and older adults. We plan to search five online databases—Cochrane, Embase, PubMed, Scopus, and Web of Science—to identify original research articles published between January 2014 and January 2024. Two reviewers will independently screen articles for inclusion based on predetermined criteria, and a separate reviewer will resolve conflicts. Data will be extracted using a standardized form, and the findings will be synthesized and reported qualitatively and quantitatively.

Ethics and dissemination

No ethics approval is required for this protocol and scoping review, as data will be used only from published studies with appropriate ethics approval. Results will be disseminated in a peer-reviewed publication.

This protocol has been preregistered on OSF Repository at:https://osf.io/9s8fm.

Strengths and limitations of this study

To our knowledge, this scoping review is the first to scope the landscape of DHTs for targeting metabolic disorders among older adults.

We apply the DHT Ecosystem Categorization for a more standardized overview of the peer-reviewed empirical literature across multiple databases and follow rigorous scoping review reporting guidelines.

Consistent with the nature of scoping reviews, our study does not include an assessment of the quality of the included studies, only involves studies in English, and does not include non-peer reviewed industry reports, which may also provide relevant information.

Since our pre-existing definition of metabolic disorders focuses on various pre-defined major conditions, there exists a possibility that we may not comprehensively capture all possible instances of metabolic disorders among older adults.
Multisectoral prioritization of zoonotic diseases in India: A One Health perspective
Authors: Tiwari Simmi , Roy Indranil , Daptardar Monal , Singh Ruchi , Mishra Anshuman , Kedia Richa , Manocha Harmesh , Diwedi Mayank , Dwivedi Amlesh , Shukla Gaurish , Shewale Ajit , Nale Tushar , Mishra Dipti , Sharma R.P. , Garcia Daniel , Gokhale Runa H. , Desai Meghna , Singh Sujeet
Published: February 2024

Introduction

To tackle the risk of emerging and re-emerging diseases, it is critical for countries with limited resources to prioritize endemic and emerging zoonotic diseases of greatest national concern. One Health is an integrated, unifying approach that aims to sustainably balance and optimize the health of people, animals, and ecosystems. In India, as a first step towards a multi-disciplinary, multi-sectoral, One Health approach to preventing and detecting zoonotic disease outbreaks, a national-level multi-stakeholder zoonotic disease prioritization workshop was organized to identify a list of zoonotic diseases of greatest national concern for India.

Methods

We followed the Good Reporting of a Mixed Methods Study (GRAMMS) guidelines to finalize a list of priority zoonotic diseases through a participatory action research approach involving 50 experts in zoonotic diseases. We used a prioritization process based on the U.S. Centers for Disease Control and Prevention’s semi-quantitative One Health Zoonotic Disease Prioritization (OHZDP) Process, with modifications per country need.

Results

We ranked forty zoonotic diseases based on five criteria: severity of illness in humans, the economic burden of the diseases, pandemic potential, capacity for prevention and control, and potential for introduction or increased transmission in India. The final list of zoonotic diseases ranked in the order of national significance includes the following top ten priority zoonotic diseases: Zoonotic Influenza (Zoonotic Influenza A viruses), Anthrax, Japanese Encephalitis, Leptospirosis, Brucellosis, Dengue, Rabies, Scrub typhus, Plague, and Crimean-Congo hemorrhagic fever. We conducted a sensitivity analysis to assess the impact of each criterion on the prioritized list; this analysis showed minimal changes in ranking for the top ten diseases.

Conclusion

For the successful adoption of One Health practices in India, multi-sectoral collaboration is critical at all levels – national, state, and provincial. This collaborative prioritization process conducted at the national level has the potential to catalyse such efforts and enhance zoonotic disease prevention and detection efforts at the state and local levels across India.
On the relationship between concentration buffering and noise reduction in phase separating systems
Authors: Zechner Christoph , Jülicher Frank
Published: February 2024

Biomolecular condensates have been proposed to buffer intracellular concentrations and reduce noise. Recent results demonstrate that concentrations need not be buffered in multicomponent systems, leading to a non-constant saturation concentration (csat) when individual components are varied. Simplified equilibrium considerations suggest that noise reduction might be closely related to concentration buffering and that a fixed saturation concentration is required for noise reduction to be effective. Here we present a theoretical analysis to demonstrate that these suggestions do not apply to mesoscopic fluctuating systems. We show that concentration buffering and noise reduction are distinct concepts, which cannot be used interchangeably. We further demonstrate that concentration buffering – and a constantcsat– are neither necessary nor sufficient for noise reduction to be effective. Clarity about these concepts is important for studying the role of condensates in controlling cellular noise and for the interpretation of concentration relationships in cells.
Friction-induced budding of a cancer cell monolayer
Authors: Dedenon Mathieu , Barbazán Jorge , Pérez-González Carlos , Vignjevic Danijela Matic , Sens Pierre
Published: February 2024

The environment surrounding a tumor plays a crucial role in cancer cell dissemination. Within this microenvironment, cancer-associated fibroblasts (CAFs) generate compressive forces and actively remodel tumors. Usingin vitrocircular clusters of cancer cell monolayers surrounded by CAFs, we generate structures that are reminiscent of multicellular buds observed in vivo for colo-rectal cancer. A supracellular contractile ring spontaneously assembles at the inner edge of the CAF monolayer and drives its closure on top of the cancer cells through a purse-string mechanism. The frictional shear stress exerted by CAFs triggers multilayering of cancer cells, followed by the emergence of a multicellular bud constricted by the CAF ring. To explain this observation, we developed a theoretical model based on continuum mechanics. This model outlines the early transformations in the shape of cancer cell monolayer and links the layering of cells to a general criterion involving height deformation. It identifies the specific physical conditions that favors budding, and reproduces the observed dependence of the budding probability and bud sizes with the diameter of the cancer cell cluster. Our findings highlight the importance of active mechanical interactions between the tumor and its micro-environment on aggressive modes of cancer invasion.
Decoupled degradation and translation enables noise-modulation by poly(A)-tails
Authors: Grandi Carmen , Emmaneel Martin , Nelissen Frank H. T. , Roosenboom Laura W. M. , Petrova Yoanna , Elzokla Omnia , Hansen Maike M. K.
Published: February 2024

Poly(A)-tails are crucial for mRNA translation and degradation, but the exact relationship between tail length and mRNA kinetics remains unclear. Here we employ a small library of identical mRNAs that differ only in their poly(A)-tail length to examine their behavior in human embryonic kidney cells. We find that tail length strongly correlates with mRNA degradation rates, but is decoupled from translation. Interestingly, an optimal tail length of ∼100 nucleotides displays the highest translation rate, which is identical to the average endogenous tail length measured by nanopore sequencing. Furthermore, poly(A)-tail length variability––a feature of endogenous mRNAs––impacts translation efficiency but not mRNA degradation rates. Stochastic modelling combined with single-cell tracking reveals that poly(A)-tails provide cells with an independent handle to tune gene expression fluctuations by decoupling mRNA degradation and translation. Together, this work contributes to the basic understanding of gene expression regulation and has potential applications in nucleic acid therapeutics.
Knockout mutations ofNicotiana benthamianadefenses reveal the relative importance of acylsugars, nicotine, and a serine protease inhibitor in a natural setting
Authors: Negin Boaz , Wang Fumin , Fischer Hillary D. , Jander Georg
Published: February 2024

Plants produce an immense diversity of defensive specialized metabolites. However, despite extensive functional characterization, the relative importance of different defensive compounds is rarely examined in natural settings. Here, we compare the efficacy of threeNicotiana benthamianadefensive compounds, nicotine, acylsugars, and a serine protease inhibitor, by growing plants with combinations of knockout mutations in a natural setting, quantifying invertebrate interactions, and comparing relative plant performance. Among the three tested compounds, acylsugars had the greatest defensive capacity, affecting aphids, leafhoppers, spiders, and flies. Nicotine mutants displayed increased leafhopper feeding and aphid colonization. Plants lacking both nicotine and acylsugars were more susceptible to flea beetles and thrips. By contrast, knockout of the serine protease inhibitor did not affect insect herbivory in the field. Complementary experiments under controlled laboratory conditions with caterpillars grasshoppers, and aphids confirmed results obtained in a natural setting. We conclude that the three metabolite groups collectively provide broad-spectrum protection toN. benthamiana. However, there is a gradient in their effects on the interacting invertebrates present in the field. Furthermore, we demonstrate that, even if individual metabolites do not have a measurable defensive benefit on their own, they can have an additive effect when combined with other defensive compounds.
Photoreceptor–induced sinapate synthesis contributes to photoprotection in Arabidopsis
Authors: Leonardelli Manuela , Tissot Nicolas , Podolec Roman , Ares-Orpel Florence , Glauser Gaétan , Ulm Roman , Demarsy Emilie
Published: February 2024

Plants must balance light capture for photosynthesis with protection from potentially harmful ultraviolet radiation (UV). Photoprotection is mediated by concerted action of photoreceptors, but the underlying molecular mechanisms are not fully understood. In this study, we provide evidence that UV RESISTANCE LOCUS 8 (UVR8) UV-B-, phytochrome red-, and cryptochrome blue-light photoreceptors converge on the induction ofFERULIC ACID 5-HYDROXYLASE 1(FAH1) that encodes a key enzyme in the phenylpropanoid biosynthesis pathway, leading to the accumulation of UV-absorbing sinapate esters.FAH1induction depends on the bZIP transcription factors ELONGATED HYPOCOTYL 5 (HY5) and HY5-HOMOLOG (HYH) that function downstream of all three photoreceptors. Noticeably, mutants with hyperactive UVR8 signalling rescuefah1UV sensitivity. Targeted metabolite profiling suggests that this phenotypic rescue is due to the accumulation of UV-absorbing metabolites derived from precursors of sinapate synthesis, namely coumaroyl-glucose and feruloyl-glucose. Our genetic dissection of the phenylpropanoid pathway combined with metabolomic and physiological analyses show that both sinapate esters and flavonoids contribute to photoprotection with sinapates playing a major role for UV screening. Our findings indicate that photoreceptor-mediated regulation ofFAH1and subsequent accumulation of sinapate “sunscreen” compounds is a key protective mechanism to mitigate damage, preserving photosynthetic performance, and ensuring plant survival under UV.
Dissecting the role of CAR signaling architectures on T cell activation and persistence using pooled screening and single-cell sequencing
Authors: Castellanos-Rueda Rocío , Wang Kai-Ling K. , Forster Juliette L. , Driessen Alice , Frank Jessica A. , Martínez María Rodríguez , Reddy Sai T.
Published: February 2024

Chimeric antigen receptor (CAR) T cells represent a promising approach for cancer treatment, yet challenges remain such as limited efficacy due to a lack of T cell persistence. Given its critical role in promoting and modulating T cell responses, it is crucial to understand how alterations in the CAR signaling architecture influence T cell function. Here, we designed a combinatorial CAR signaling domain library and performed repeated antigen stimulation assays, pooled screening and single-cell sequencing to investigate T-cell responses triggered by different CAR architectures. Parallel comparisons of CAR variants, at early, middle and late timepoints during chronic antigen stimulation systematically assessed the impact of modifying signaling domains on T cell activation and persistence. Our data reveal the predominant influence of membrane-proximal domains in driving T cell phenotype. Additionally, we highlight the critical role of CD40 costimulation in promoting potent and persistent T cell responses, followed by CTLA4, which induces a long-term cytotoxic phenotype. This work deepens the understanding of CAR T cell biology and may be used to guide the future engineering of CAR T cell therapies.
Long-term Culturing ofPseudomonas aeruginosain Static, Minimal Nutrient Medium Results in Increased Pyocyanin Production, Reduced Biofilm Production, and Loss of Motility
Authors: Cecil Rhiannon , Ornelas Elana , Phan Anh , Yoder-Himes Deborah
Published: February 2024

Pseudomonas aeruginosais a multidrug-resistant opportunistic human pathogen that can survive in many natural and anthropogenic environments. It is a leading cause of morbidity in individuals with cystic fibrosis and is one of the most prevalent pathogens associated with nosocomial infections in the United States. It has been shown that this organism can survive and persist in low nutrient environments such as sink drains and inside the respiratory system of human hosts. How adaptation to these types of environments influences phenotypic traits of this organism has not been well studied. Here we implemented an experimental evolution system designed to imitate these environmental niches and identified phenotypic changes that occurred as a result of adaptation to such environments in six strains ofP. aeruginosawith varying life history and colony phenotypes. We observed that adaptation to low nutrient environments resulted in decreased generation time, reduced cell size, reduced biofilm formation, increased pyocyanin production, and decreased motility. Our work is significant as it allows us to predict how this organism will evolve in hospital and domestic environments and can help us improve treatment options for patients.
Producing circular field harmonics inside elliptic magnet apertures with superconducting canted-cosine-theta coils
Authors: Brouwer L.
Published: February 2024

Superconducting magnets with noncircular aperture are desired for accelerators and many other high-field applications. This paper presents new methods for the analytic design of elliptic bore superconducting accelerator magnets. Part 1 of this work shares the derivation of current to field relations between a sheet current density on an elliptic cylinder and the magnetic field harmonics inside the aperture. This result is explored in the general context of elliptic bore magnet design with relevant scaling laws compared between elliptic and circular bore magnets. In part 2, this approach is applied to the specific geometry of canted-cosine-theta (CCT) accelerator magnets, enabling analytic winding design for single or mixed circular harmonics within elliptic aperture CCT magnets.

Published by the American Physical Society
2024