bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decoding Stability and Epistasis in Human Myoglobin by Deep Mutational Scanning and Codon-level Machine Learning
Authors: Küng Christoph , Protsenko Olena , Vanella Rosario , Nash Michael A. 
Published: February 2024

AbstractUnderstanding the linkage between protein sequence and phenotypic expression level is crucial in biotechnology. Machine learning algorithms trained with deep mutational scanning (DMS) data have significant potential to improve this understanding and accelerate protein engineering campaigns. However, most machine learning (ML) approaches in this domain do not directly address effects of synonymous codons or positional epistasis on predicted expression levels. Here we used yeast surface display, deep mutational scanning, and next-generation DNA sequencing to quantify the expression fitness landscape of human myoglobin and train ML models to predict epistasis of double codon mutants. When fed with near comprehensive single mutant DMS data, our algorithm computed expression fitness values for double codon mutants using ML-predicted epistasis as an intermediate parameter. We next deployed this predictive model to screen > 3·106unseen double codon mutantsin silicoand experimentally tested highly ranked candidate sequences, finding 14 of 16 with significantly enhanced expression levels. Our experimental DMS dataset combined with codon level epistasis-based ML constitutes an effective method for bootstrapping fitness predictions of high order mutational variants using experimental data from variants of lower order.
Rapid spread of a vertically transmitted symbiont induces drastic shifts in butterfly sex ratio
Authors: Miyata Mai , Nomura Masashi , Kageyama Daisuke 
Published: February 2024

BRIEF SUMMARYSex ratio dynamics constitutes a pivotal subject in evolutionary biology1. Under conditions of evolutionary equilibrium, the male-to-female ratio tends to be approximately 1:1; however, this equilibrium is susceptible to distortion by selfish genetic elements exemplified by driving sex chromosomes and cytoplasmic elements2,3. While previous studies have substantiated instances of these genetic elements distorting the sex ratio, studies specifically tracking the process with which these distorters spread within populations, leading to a transition from balanced parity to a skewed, female-biased state, are notably lacking. Herein, we present compelling substantiation regarding the rapid spread of the cytoplasmic endosymbiontWolbachiawithin a localized population of the pierid butterflyEurema hecabe(Figure 1A). This resulted in a shift in the sex ratio from near parity to an exceedingly skewed state overwhelmingly biased toward females, reaching 94.4% within a remarkably brief period of 4 years.
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

AbstractOver 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

AbstractProtein 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.Table of Contents graphic
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

AbstractOrganoids 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

AbstractSwine 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 LineA 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

AbstractReef 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

ABSTRACTBackgroundAlzheimer’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.ObjectiveThis 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.MethodsTranscribed 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.ResultsSignificant 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.ConclusionsSpeech 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

AbstractBackgroundLimited 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.ObjectiveTo develop a diagnostic approach that combines measurements of cellular and serologic autoimmunity.MethodsWe 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.ResultsWe 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.ConclusionBy 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 BoxPrimary 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

AbstractParkinson’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.
Individual-specific associations between behavioral events and song notes shape budgerigar vocal sequences
Authors: Wewhare Nakul , Krishnan Anand 
Published: February 2024

ABSTRACTComplex 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

AbstractThe 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.