bluuebunny/crossref_metadata_2025 huggingface dataset:
Inclusive pedagogy strategies to introduce high schoolers to systems biology
Authors: Watts Kelsey M , Richardson William
Published: March 2023

Women and non-white racial and ethnic groups remain underrepresented in science, technology, engineering, and math (STEM). To achieve a more diverse and equitable STEM workforce, the recruitment and retention of these historically marginalized communities in postsecondary education will also need to increase. Recently, the lens has turned to pedagogy and how creating a more inclusive classroom environment can foster STEM identity in previously marginalized communities. This work focuses on developing and piloting systems biology education modules designed to promote an inclusive learning environment in a summer outreach program for high school students by (1) utilizing a hybrid of unplugged activities with coded simulation and (2) a female-oriented problem statement. Based on initial findings in our pilot program, we anticipate that these techniques will enable students with limited prior computational experience to feel more comfortable and able to complete tasks, thereby increasing their self-efficacy and STEM identity. These modules could be a valuable tool for practitioners teaching high school or early college-level computational courses who instruct students with varied coding experience. Additionally, our analysis of the use of a female-oriented problem statement on female-identifying students’ self-efficacy provides potential evidence of the usefulness of representative problem statements in engaging underrepresented student populations. We believe these techniques could be adapted to address a variety of contexts across STEM disciplines and other fields to foster inclusive learning environments.
Human Cytomegalovirus Induces Significant Structural and Functional Changes in Terminally Differentiated Human Cortical Neurons
Authors: Adelman Jacob W. , Rosas-Rogers Suzette , Schumacher Megan L. , Mokry Rebekah L. , Terhune Scott S. , Ebert Allison D.
Published: March 2023

Human cytomegalovirus (HCMV) is a highly prevalent viral pathogen that typically presents asymptomatically in healthy individuals despite lifelong latency. However, in 10-15% of congenital cases, this beta-herpesvirus demonstrates direct effects on the central nervous system, including microcephaly, cognitive/learning delays, and hearing deficits. HCMV has been widely shown to infect neural progenitor cells, but the permissiveness of fully differentiated neurons to HCMV is controversial and chronically understudied, despite potential associations between HCMV infection with neurodegenerative conditions. Using a model system representative of the human forebrain, we demonstrate that induced pluripotent stem cell (iPSC)-derived, excitatory glutamatergic and inhibitory GABAergic neurons are fully permissive to HCMV, demonstrating complete viral replication, competent virion production, and spread within the culture. Interestingly, while cell proliferation was not induced in these post-mitotic neurons, HCMV did increase expression of proliferative markers Ki67 and PCNA suggesting alterations in cell cycle machinery. These finding are consistent with previous HCMV-mediated changes in various cell types and implicate the virus’ ability to alter proliferative pathways to promote virion production. HCMV also induces significant structural changes in forebrain neurons, such as the formation of syncytia and retraction of neurites. Finally, we demonstrate that HCMV disrupts calcium signaling and decreases neurotransmission, with action potential generation effectively silenced after 15 days post infection. Taken together, our data highlight the potential for forebrain neurons to be permissive to HCMV infection in the CNS, which could have significant implications on overall brain health and function.
Detection of Subclinical Pulmonary Edema After Acute ST-segment Elevation Myocardial Infarction Without Heart Failure by Chest Computed Tomography
Authors: Hua Minghui , Liang Rong , Gao Yufan , Cui Keyi , Liu Yanzhen , Liang Shuo , Li Ximing , Zhang Hong
Published: March 2023

BACKGROUND

Pulmonary edema is a severe complication in patients with acute myocardial infarction which indicates the development of heart failure (HF) and poor prognosis. However, subclinical pulmonary edema after acute ST-segment elevation myocardial infarction (STEMI) without HF has not received enough attention in clinical practice. We aimed to investigate the prognostic value and associated clinical characteristics of subclinical pulmonary edema after acute STEMI without HF detected by chest computed tomography (CT).

METHODS

A total of 276 patients with acute STEMI without HF who underwent chest CT were included in this study. K-means clustering analysis was performed to classify the patients into different subgroups based on the mean lung density. Clinical characteristics of the different subgroups were compared and used to establish a machine learning model for discriminating between them. Relative risk (RR) for major adverse cardiovascular events (MACEs) during hospitalization was compared between the subgroups.

RESULTS

The patients were classified into two subgroups. Subgroup 2 showed higher mean lung density than subgroup 1 (median [IQR], −727 [−747, −704] vs. −806 [−826, −785] HU, P < 0.001), with significantly higher levels of cardiac enzymes and numbers of inflammatory cells and significantly worse left ventricular function than subgroup 1. In the model analysis, the most important clinical characteristics were the levels of cardiac enzymes, numbers of inflammatory cells, and left ventricular function. The risk for MACEs was higher in subgroup 2 than in subgroup 1 (RR, 2.12; P = 0.002).

CONCLUSIONS

Subclinical pulmonary edema after acute STEMI without HF was mainly associated with elevated levels of cardiac enzymes, followed by increased numbers of inflammatory cells and worse left ventricular function. In addition, subclinical pulmonary edema provided crucial prognostic information for patients during hospitalization.
Cell-free quorum sensing to drive feedback and communication within populations of droplet interface bilayers
Authors: Gonzales David T. , Suraritdechachai Surased , Zechner Christoph , Tang T-Y Dora
Published: March 2023

Building synthetic multicellular systems using non-living molecular components is a grand challenge in the field of bottom-up synthetic biology. Towards this goal, a diverse range of chemistries have been developed to provide mechanisms of intercellular communication and methods to assemble multicellular compartments. However, building bottom-up synthetic multicellular systems is still challenging because it requires the integration of intercellular reaction networks with compatible cellular compartment properties. In this study, we encapsulated cell-free expression systems (CFES) expressing two quorum sensing genetic circuits into droplet interface bilayer (DIB) synthetic cells to demonstrate intercellular communication and feedback. We further develop a method of generating custom DIB multicellular structures by acoustic liquid handling to automatically dispense the CFES droplets and show the potential for multiplexing compartmentalized gene circuits for generating heterogeneous populations of cells. Our work provides a step towards building more complex multicellular systems with feedback mechanisms from the bottom-up to study and experimentally model biological multiscalar processes.
Bibliometric analysis on cannibalism/infanticide and maternal aggression towards pups in laboratory animals
Authors: Bravo José C. , Ugartemendia Lierni , Barman Arko , Rodríguez Ana B. , Pariente José A. , Bravo Rafael
Published: March 2023

Animal welfare has evolved during the past decades to improve not only the quality of life of laboratory animals but also the quality and reproducibility of scientific investigations. Bibliometric analysis has become an important tool to complete the current knowledge with academic databases. Our objective was to investigate whether scientific research on cannibalism/infanticide is connected with maternal aggression towards the offspring in laboratory animals. To carry out our research, we performed a specific search for published articles on each concept. Results were analyzed in the opensource environment RStudio with the package Bibliometrix. We obtained 228 and 134 articles for the first search (cannibalism/infanticide) and the second search (maternal aggression towards the pups) respectively. We observed that the interest in infanticide cannibalism started in the 1950s, while researchers started showing interest in maternal aggression towards the pups 30 years later. Our analyses indicated that maternal aggression had better citations in scientific literature. In addition, although our results showed some common features (e.g., oxytocin or medial preoptic area in the brain), we observed a gap between cannibalism/infanticide and maternal aggression towards the pups with only 18 published articles in common for both the searches. Therefore, we recommend researchers to combine both concepts in further investigations in the context of cannibalism for better dissemination and higher impact in laboratory animals’ welfare research.

Highlights

- Cannibalism/Infanticide and maternal aggression have been investigated separately.

- Maternal aggression has a higher impact on scientific literature.

- Combining both topics may increase cannibalism/infanticide impact.
Combining experiments and simulations to examine the temperature-dependent behaviour of a disordered protein
Authors: Pesce Francesco , Lindorff-Larsen Kresten
Published: March 2023

Intrinsically disordered proteins are a class of proteins that lack stable folded conformations and instead adopt a range of conformations that determine their biochemical functions. The temperature-dependent behaviour of such disordered proteins is complex and can vary depending on the specific protein and environment. Here, we have used molecular dynamics simulations and previously published experimental data to investigate the temperature-dependent behaviour of Histatin 5, a 24-residue-long polypeptide. We examined the hypothesis that Histatin 5 undergoes a loss of polyproline II structure with increasing temperature, leading to more compact conformations. We found that the conformational ensembles generated by the simulations generally agree with small-angle X-ray scattering data for Histatin 5, but show some discrepancies with the hydrodynamic radius as probed by pulsed-field gradient nuclear magnetic resonance spectroscopy, and with the secondary structure information derived from circular dichroism. We attempted to reconcile these differences by reweighting the conformational ensembles against the scattering and NMR data. By doing so, we were in part able to capture the temperature-dependent behaviour of Histatin 5 and to link the observed decrease in hydrodynamic radius with increasing temperature to a loss of polyproline II structure. We were, however, unable to achieve agreement with both the scattering and NMR data within experimental errors. We discuss different possibilities for this outcome including inaccuracies in the force field, differences in conditions of the NMR and scattering experiments, and issues related to the calculation of the hydrodynamic radius from conformational ensembles. Our study highlights the importance of integrating multiple types of experimental data when modelling conformational ensembles of disordered proteins and how environmental factors such as the temperature influence them.
Using double cutin vitroassembled CRISPR/Cas9 to modify the genome ofCoccidioides posadasii
Authors: Mead Heather L. , Kollath Daniel R. , Itogawa Ashley N. , Blackmon Austin V. , Morales Matthew M. , Bryant Mitchell L. , de Melo Teixeira Marcus , Barker Bridget M.
Published: March 2023

Although the genusCoccidioidesis divided into two closely related and putatively allopatric species, analysis shows that hybridization has occurred between species and at least oneC. posadasiiconserved fragment has introgressed into severalC. immitisgenomes in a population-specific manner. Transcript abundancein vitroandin vivofor ten ORFs in this introgressed region were measured for several isolates. We used signals of introgression and high mRNA transcript levels in the spherule as indicators of selection for genes related to critical biological processes involved inCoccidioidespathogenesis. The only transcript in the introgression region with significant expression was a gene that encodes for a betadefensin-like (DEFBL) peptide rich in serines and cysteines. Few virulence factors have been identified inCoccidioides, and we employed the CRISPR-Cas9 mediated gene deletion tool to delete this gene inCoccidioides.
Tbx5 overexpression in embryoid bodies increases TAK1 expression but does not enhance the differentiation of sinoatrial node cardiomyocytes
Authors: Dai Yunkai , Nasehi Fatemeh , Winchester Charles D. , Foley Ann C.
Published: March 2023

Genetic studies place Tbx5 at the apex of the sinoatrial node (SAN) transcriptional program. To understand its role in SAN differentiation, clonal embryonic stem (ES) cell lines were made that conditionally overexpress Tbx5, Tbx3, Tbx18, Shox2, Islet-1 and Map3k7/TAK1. and cardiac cells differentiated using embryoid bodies (EBs). EBs overexpressing Tbx5, Islet1, and TAK1 beat faster than cardiac cells differentiated from control ES cell lines suggesting possible roles in SAN differentiation. Tbx5 overexpressing EBs showed increased expression of TAK1, but cardiomyocytes did not differentiate as SAN cells. They showed no increase in the expression of Shox2, or Islet1 and decreased expression of HCN4. EBs constitutively overexpressing TAK1 direct cardiac differentiation to the SAN fate, but also have decreased phosphorylation of its targets, p38, and Jnk. This opens the possibility that blocking the phosphorylation of TAK1 targets may have the same impact as forced overexpression. To test this, we treated EBs with 5z-7-Oxozeanol (OXO), an inhibitor of TAK1 phosphorylation. Like TAK1 overexpressing cardiac cells, cardiomyocytes differentiated in the presence of OXO beat faster and showed increased expression of SAN genes (Shox2, HCN4, and Islet1). This suggests that activation of the SAN transcriptional network can be accomplished by blocking the phosphorylation of TAK1.
Tuning the stator subunit of the flagellar motor with coiled-coil engineering
Authors: Ridone Pietro , Winter Daniel L. , Baker Matthew A. B.
Published: March 2023

Many bacteria swim driven by an extracellular filament rotated by the bacterial flagellar motor. This motor is powered by the stator complex, MotA5MotB2, a heterodimeric complex which forms an ion channel which couples energy from the ion motive force to torque generation. Recent structural work revealed that stator complex consists of a ring of five MotA subunits which rotate around a central dimer of MotB subunits. Transmembrane (TM) domains TM3 and TM4 from MotA combine with the single TM domain from MotB to form two separate ion channels within this complex. Much is known about the ion binding site and ion specificity; however, to date, no modelling has been undertaken to explore the MotB-MotB dimer stability and the role of MotB conformational dynamics during rotation. Here, we modelled the central MotB dimer using coiled-coil engineering and modelling principles and calculated free energies to identify stable states in the operating cycle of the stator. We found 3 stable coiled-coil states with dimer interface angles of 28°, 56° and 64°. We tested the effect of strategic mutagenesis on the comparative energy of the states and correlated motility with a specific hierarchy of stability between the three states. In general, our results indicate agreement with existing models describing a 36° rotation step of the MotA pentameric ring during the power stroke and provide an energetic basis for the coordinated rotation of the central MotB dimer based on coiled-coil modelling.
Blood-based genome-wide DNA methylation correlations across body fat and adiposity-related biochemical traits
Authors: Hatton Alesha A , Hillary Robert F , Bernabeu Elena , McCartney Daniel L , Marioni Riccardo E , McRae Allan F
Published: March 2023

The recent increase in obesity levels across many countries is likely to be driven by nongenetic factors. The epigenetic modification DNA methylation (DNAm) may help to explore this as it is sensitive to both genetic and environmental exposures. While the relationship between DNAm and body fat traits has been extensively studied [1–9], there is limited literature on the shared associations of DNAm variation across such traits. Akin to genetic correlation estimates, which measure the degree of common genetic control between two traits, here we introduce an approach to evaluate the similarities in DNAm associations between traits, DNAm correlations. As DNAm can be both a cause and consequence of complex traits [5, 10, 11], DNAm correlations have the potential to provide novel insights into trait relationships above that currently obtained from genetic and phenotypic correlations. Utilising 7,519 unrelated individuals from Generation Scotland (GS), we calculated DNAm correlations using the bivariate OREML framework in the OSCA software [12] to investigate the shared associations of DNAm variation between traits. For each trait we also estimated the shared contribution of DNAm between sexes. We identified strong, positive DNAm correlations between each of the body fat traits (BMI, body fat % and waist to hip ratio; ranging from 0.96 to 1.00), finding larger associations than those identified by genetic and phenotypic correlations. We identified a significant deviation from 1 in the rDNAmfor BMI between males and females, with sex-specific DNAm changes associated with BMI identified at eight DNAm probes. Employing genome-wide DNAm correlations to evaluate the similarities in the associations of DNAm with complex traits has provided novel insight into obesity related traits beyond that provided by genetic correlations.
MoveFormer: a Transformer-based model for step-selection animal movement modelling
Authors: Cífka Ondřej , Chamaillé-Jammes Simon , Liutkus Antoine
Published: March 2023

The movement of animals is a central component of their behavioural strategies. Statistical tools for movement data analysis, however, have long been limited, and in particular, unable to account for past movement information except in a very simplified way. In this work, we propose MoveFormer, a new step-based model of movement capable of learning directly from full animal trajectories. While inspired by the classical step-selection framework and previous work on the quantification of uncertainty in movement predictions, MoveFormer also builds upon recent developments in deep learning, such as the Transformer architecture, allowing it to incorporate long temporal contexts. The model predicts an animal’s next movement step given its past movement history, including not only purely positional and temporal information, but also any available environmental covariates such as land cover or temperature. We apply our model to a diverse dataset made up of over 1550 trajectories from over 100 studies, and show how it can be used to gain insights about the importance of the provided context features, including the extent of past movement history. Our software, along with the trained model weights, is released as open source.
High performance imputation of structural and single nucleotide variants in Atlantic salmon using low-coverage whole genome sequencing
Authors: Gundappa Manu Kumar , Robledo Diego , Hamilton Alastair , Houston Ross D. , Prendergast James G. D. , Macqueen Daniel J.
Published: March 2023

Whole genome sequencing (WGS), despite its advantages, is yet to replace alternative methods for genotyping single nucleotide variants (SNVs). Structural variants (SVs) have larger effects on traits than SNVs, but are more challenging to accurately genotype. Using low-coverage WGS with genotype imputation offers a cost-effective strategy to achieve genome-wide variant coverage, but is yet to be tested for SVs. Here, we investigate combined SNV and SV imputation with low-coverage WGS data in Atlantic salmon (Salmo salar). As the reference panel, we used genotypes for high-confidence SVs and SNVs for n=445 wild individuals sampled from diverse populations. We also generated 15x WGS data (n=20 samples) for a commercial population out-with the reference panel, and called SVs and SNVs with gold-standard approaches. An imputation method (GLIMPSE) was tested at WGS depths of 1x, 2x, 3x and 4x for samples within and out-with the reference panel. SNVs were imputed with high accuracy and recall across all WGS depths, including for samples out-with the reference panel. For SVs, we compared imputation based purely on linkage disequilibrium (LD) with SNVs, to that supplemented with SV genotype likelihoods (GLs) from low-coverage WGS. Including SV GLs increased imputation accuracy, but as a trade-off with recall, requiring 3-4x coverage for best performance. Combining strategies allowed us to capture 84% of the reference panel deletions with 87% accuracy at 1x WGS. This study highlights the promise of reference panel imputation using low-coverage WGS, including novel opportunities to enhance the resolution of genome-wide association studies by capturing SVs.
Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts
Authors: Yabo Yahaya A. , Moreno-Sanchez Pilar M. , Pires-Afonso Yolanda , Kaoma Tony , Nosirov Bakhtiyor , Scafidi Andrea , Ermini Luca , Lipsa Anuja , Oudin Anaïs , Kyriakis Dimitrios , Grzyb Kamil , Poovathingal Suresh K. , Poli Aurélie , Muller Arnaud , Toth Reka , Klink Barbara , Berchem Guy , Berthold Christophe , Hertel Frank , Mittelbronn Michel , Heiland Dieter H. , Skupin Alexander , Nazarov Petr V. , Niclou Simone P. , Michelucci Alessandro , Golebiewska Anna
Published: March 2023

Background

A major contributing factor to glioblastoma (GBM) development and progression is its ability to evade the immune system by creating an immune-suppressive environment, where GBM-associated myeloid cells, including resident microglia and peripheral monocyte-derived macrophages, play critical pro-tumoral roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical in GBM patients and whether this heterogeneity is recapitulated in patient-derived orthotopic xenografts (PDOXs). A thorough understanding of the GBM ecosystem and its recapitulation in preclinical models is currently missing, leading to inaccurate results and failures of clinical trials.

Methods

Here, we report systematic characterization of the tumor microenvironment (TME) in GBM PDOXs and patient tumors at the single-cell and spatial levels. We applied single-cell RNA-sequencing, spatial transcriptomics, multicolor flow cytometry, immunohistochemistry and functional studies to examine the heterogeneous TME instructed by GBM cells. GBM PDOXs representing different tumor phenotypes were compared to glioma mouse GL261 syngeneic model and patient tumors.

Results

We show that GBM tumor cells reciprocally interact with host cells to create a GBM patient-specific TME in PDOXs. We detected the most prominent transcriptomic adaptations in myeloid cells, with brain-resident microglia representing the main population in the cellular tumor, while peripheral-derived myeloid cells infiltrated the brain at sites of blood-brain barrier disruption. More specifically, we show that GBM-educated microglia undergo transition to diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs. Additionally, we found novel microglial states expressing cell cycle programs, astrocytic or endothelial markers. Lastly, we show that temozolomide treatment leads to transcriptomic plasticity and altered crosstalk between GBM tumor cells and adjacent TME components.

Conclusion

Our data provide novel insights into the phenotypic adaptation of the heterogeneous TME instructed by GBM tumors. We show the key role of microglial phenotypic states in supporting GBM tumor growth and response to treatment. Our data place PDOXs as relevant models to assess the functionality of the TME and changes in the GBM ecosystem upon treatment.
Antibiotic Resistance Gene Variant Sequencing is Necessary to Reveal the Complex Dynamics of Immigration from Sewers to Activated Sludge
Authors: Gibson Claire , Kraemer Susanne A. , Klimova Natalia , Guo Bing , Frigon Dominic
Published: March 2023

Microbial community composition has increasingly emerged as a key determinant of antibiotic resistance gene (ARG) content. However, in activated sludge wastewater treatment plants (AS-WWTPs), a comprehensive understanding of the microbial community assembly process and its impact on the persistence of antimicrobial resistance (AMR) remains elusive. An important part of this process is the immigration dynamics (or community coalescence) between the influent and activated sludge. While the influent wastewater contains a plethora of ARGs, the persistence of a given ARG depends initially on the immigration success of the carrying population, and the possible horizontal transfer to indigenously resident populations of the WWTP.

The current study utilised controlled manipulative experiments that decoupled the influent wastewater composition from the influent microbial populations to reveal the fundamental mechanisms involved in ARG immigration between sewers and AS-WWTP. A novel multiplexed amplicon sequencing approach was used to track different ARG sequence variants across the immigration interface, and droplet digital PCR was used to quantify the impact of immigration on the abundance of the targeted ARGs. Immigration caused an increase in the abundance of over 70 % of the quantified ARGs. However, monitoring of ARG sequence variants at the immigration interface revealed various immigration patterns such as (i) suppression of the indigenous mixed liquor variant by the immigrant, or conversely (ii) complete immigration failure of the influent variant. These immigration profiles are reported for the first time here and highlight the crucial information that can be gained using our novel multiplex amplicon sequencing techniques. Future studies aiming to reduce AMR in WWTPs should consider the impact of influent immigration in process optimisation and design.
Development and applications of chimera platforms for tyrosine phosphorylation
Authors: Pergu Rajaiah , Shoba Veronika M. , Chaudhary Santosh K. , Munkanatta Godage Dhanushka N. P. , Deb Arghya , Singha Santanu , Dhawa Uttam , Anokhina Viktoriya , Singh Sameek , Siriwardena Sachini U. , Choudhary Amit
Published: March 2023

Chimeric small molecules that induce post-translational modification (PTM) on a target protein by bringing it in proximity to a PTM-inducing enzyme are furnishing novel modalities to perturb protein function. Despite recent advances, such molecules are unavailable for a critical PTM, tyrosine phosphorylation. Furthermore, the contemporary design paradigm of chimeric molecules, formed by joining a non-inhibitory binder of the PTM-inducing enzyme with the binder of the target protein, prohibits the recruitment of most PTM-inducing enzymes as their non-inhibitory binders are unavailable. Here, we report two platforms to generate phosphorylation-inducing chimeric small molecules (PHICS) for tyrosine phosphorylation. We generate PHICS from both non-inhibitory binders (scantily available, platform 1) and kinase inhibitors (abundantly available, platform 2) using cysteine-based group transfer chemistry. PHICS triggered phosphorylation on tyrosine residues in diverse sequence contexts and target proteins (e.g., membrane-associated, cytosolic) and displayed multiple bioactivities, including initiation of a growth receptor signaling cascade and death of drug-resistant cancer cells. These studies provide an approach to induce biologically relevant PTM and lay the foundation for pharmacologic PTM editing (i.e., induction or removal) on target proteins using abundantly available inhibitors of PTM-inducing or erasing enzymes.

TOC
The influence of early life exposures on the infant gut virome
Authors: Zhang Yichang , Castro-Mejía Josué L. , Deng Ling , Shah Shiraz A. , Thorsen Jonathan , Rodríguez Cristina Leal , Jessen Leon E. , Dion Moïra B. , Chawes Bo , Bønnelykke Klaus , Sørensen Søren J. , Bisgaard Hans , Moineau Sylvain , Petit Marie-Agnès , Stokholm Jakob , Nielsen Dennis S.
Published: March 2023

Large cohort studies have contributed significantly to our understanding of the factors that influence the development of the bacterial component of the gut microbiome (GM) during the first years of life. However, the factors that shape the colonization by other important GM members such as the viral fraction remain more elusive. Most gut viruses are bacteriophages (phages), i.e., viruses attacking bacteria in a host specific manner, and to a lesser extent, but also widely present, eukaryotic viruses, including viruses attacking human cells. Here, we utilize the deeply phenotyped COPSAC2010 birth cohort consisting of 700 infants to investigate how social, pre-, peri- and postnatal factors may influence the gut virome composition at one year of age, where fecal virome data was available from 645 infants.

Among the different exposures studied, having older siblings and living in an urban vs. rural area had the strongest impact on gut virome composition. Differential abundance analysis from a total of 16,118 viral operational taxonomic units (vOTUs) (mainly phages, but also 6.1% eukaryotic viruses) identified 2,105 vOTUs varying with environmental exposures, of which 5.9% were eukaryotic viruses and the rest was phages. Bacterial hosts for these phages were mainly predicted to be within theBacteroidaceae, Prevotellaceae, andRuminococcaceaefamilies, as determined by CRISPR spacer matches. Spearman correlation coefficients indicated strong co-abundance trends of vOTUs and their targeted bacterial host, which underlined the predicted phage-host connections. Further, our findings show that some gut viruses encode important metabolic functions and how the abundance of genes encoding these functions is influenced by environmental exposures. Genes that were significantly associated with early life exposures were found in a total of 42 vOTUs. 18 of these vOTUs had their life styles predicted, with 17 of them having a temperate lifestyle. These 42 vOTUs carried genes coding for enzymes involved in alanine, aspartate and glutamate metabolism, glycolysis-gluconeogenesis, as well as fatty acid biosynthesis. The latter implies that these phages could be involved in the utilization and degradation of major dietary components and affect infant health by influencing the metabolic capacity of their bacterial host.

Given the importance of the GM in early life for maturation of the immune system and maintenance of metabolic health, these findings provide a valuable source of information for understanding early life factors that predispose for autoimmune and metabolic disorders.
Distinct roles of the orbitofrontal cortex, ventral striatum, and dopamine neurons in counterfactual thinking of decision outcomes
Authors: Yun Mengxi , Nejime Masafumi , Kawai Takashi , Kunimatsu Jun , Yamada Hiroshi , Kim HyungGoo R. , Matsumoto Masayuki
Published: March 2023

Individuals often assess past decisions by comparing what was gained with what would have been gained had they acted differently. Thoughts of past alternatives that counter what actually happened are called “counterfactuals”. Recent theories emphasize the role of the prefrontal cortex in processing counterfactual outcomes in decision-making, although how subcortical regions contribute to this process remains to be elucidated. Here we report a clear distinction among the roles of the orbitofrontal cortex, ventral striatum and midbrain dopamine neurons in processing counterfactual outcomes in monkeys. Our findings suggest that actually-gained and counterfactual outcome signals are both processed in the cortico-subcortical network constituted by these regions but in distinct manners, and integrated only in the orbitofrontal cortex in a way to compare these outcomes. This study extends the prefrontal theory of counterfactual thinking and provides key insights regarding how the prefrontal cortex cooperates with subcortical regions to make decisions using counterfactual information.

Teaser

Cortical and subcortical systems both contribute to counterfactual thinking of decision outcomes but in distinct manners.
GATA6amplification is associated with improved survival ofTP53-mutated pancreatic cancer
Authors: Yang Jung-In , Habowski Amber , Deschênes Astrid , Belleau Pascal , Ha Taehoon , Zhou Edward , Tzanavaris Chris , Boyd Jeff , Hollweg Christopher , Zhu Xinhua , Tuveson David , King Daniel A.
Published: March 2023

Background

Molecular profiling of pancreatic adenocarcinoma (PDAC) demonstrates that genomic and transcriptomic features are associated with prognosis and chemosensitivity. We evaluated treatment outcomes by genetic alterations inTP53andGATA6to determine the prognostic and predictive impact of co-mutations, among patients with pancreatic cancer in New York’s largest healthcare system.

Methods

Retrospective analysis was performed of patients at Northwell Health diagnosed with PDAC between 2014 to 2022. Surgical status was used to segregate patients into two groups: resected and unresected.TP53genotype andGATA6amplification status were compared for overall survival (OS) as measured from time of diagnosis. Additionally, patient survival by chemotherapy regimen administered was evaluated. The Kaplan–Meier method was used to determine overall survival (OS) and the Wilcoxon test was used to compare survival curves. Previously established and published patient-derived organoids [1] were used to investigateGATA6expression, genetic status, and chemotherapy drug sensitivity.

Results

Tumor mutation status was available for 128 patients.TP53mutations were found in 104 patients (81.3%),GATA6amplifications were found in 18 patients (14.0%), and 16 (12.5%) patients had mutations in both genes. Patients withTP53mutations had worse OS compared to the wild-typeTP53population (n = 22) (median OS 22.4 months, 95% CI 12.5 to 41.1, vs. 44.3 months, 95% CI 24.0 to 82.0, HR 2.03, p = 0.038). Among patients with aTP53mutation, a survival advantage was observed in those who had aGATA6amplification (n=16) compared to those who did not (n=86) (median OS 25.5 months vs. 19.4 months, HR 1.82, p = 0.027). Among patients with unresected PDAC who wereTP53-mutant, the presence ofGATA6amplification (n=11) was associated with a substantial survival advantage compared toGATA6wildtype (n=52) (median OS 25.5 months, vs. 10.1 months, HR 0.35, p = 0.004). In theTP53mutation group, among 33 patients who received gemcitabine and nab-paclitaxel as the first-line palliative chemotherapy, patients withGATA6amplification (n = 8) had significantly improved survival compared to those withoutGATA6amplification (n = 25) (mean OS 23.1 months vs 9.4 months, HR 0.52, p = 0.017). However, pancreatic cancer organoids withTP53mutation (n=34) did not exhibit increased drug sensitivity to GnP withGATA6amplification.

Conclusions

Genetic mutations inTP53were associated with shorter OS than wild-typeTP53. We found thatGATA6amplification appeared to attenuate poor prognosis observed inTP53-mutant patients regardless of type of standard chemotherapy received.
Clinical Features of Genetic Resilience in Chronic Obstructive Pulmonary Disease
Authors: Ghosh Auyon J. , Moll Matthew , Hess Jonathan , Hobbs Brian D. , Love Angela , Coyne Liam , Cho Michael H. , Castaldi Peter , Middleton Frank A. , Perl Andras , Silverman Edwin K. , Hersh Craig P. , Glatt Stephen J.
Published: March 2023

Introduction

In the personalized risk quantification of chronic obstructive pulmonary disease (COPD), genome-wide association studies and polygenic risk scores (PRS) complement traditional risk factors, such as age and cigarette smoking. However, despite being at considerable levels of risk, some individuals do not develop COPD. Research on COPD resilience remains largely unexplored.

Methods

We applied the previously published COPD PRS to whole genome sequencing data from non-Hispanic white and African American individuals in the COPDGene study. We defined genetic resilience as individuals unaffected by COPD with a polygenic risk score above the 90thpercentile. We defined risk-matched case individuals as those with COPD (i.e., FEV1/FVC < 0.70) and a PRS above the 90thpercentile. We defined low risk individuals without COPD (i.e., FEV1/FVC > 0.70) as a polygenic risk score below the 10thpercentile. We compared genetically resilient individuals to risk-matched individuals with COPD and low risk individuals by demographics, lung function, respiratory symptoms, co-morbidities, and chest CT scan measurements. We also performed survival analyses, differential expression analysis, and matching for sensitivity analyses.

Results

We identified 211 resilient individuals without COPD, 605 genetic risk-matched individuals with COPD, and 527 low-risk individuals without COPD. Resilient individuals had higher FEV1% predicted and lower percent emphysema. In contrast, resilient individuals had higher airway wall thickness compared to low-risk unaffected individuals. While there was no difference in survival between low-risk and resilient individuals, resilient individuals had higher survival compared to risk matched cases. We also identified two genes that were differentially expressed between low-risk unaffected individuals and resilient individuals.

Conclusion

Genetically resilient individuals had a reduced burden of COPD disease-related measures compared to risk-matched cases but had subtly increased measures compared to low-risk unaffected individuals. Further genetic studies will be needed to illuminate the underlying pathobiology of our observations.
Evaluation of Atrial Fibrillation Detection in short-term Photoplethysmography (PPG) signals using artificial intelligence
Authors: Talukdar Debjyoti , de Deus Luis Felipe , Sehgal Nikhil
Published: March 2023

Atrial Fibrillation (AFIB) is a common atrial arrhythmia that affects millions of people worldwide. However, most of the time, AFIB is paroxysmal and can pass unnoticed in medical exams therefore regular screening is required. This paper proposes machine learning methods to detect AFIB from short-term ECG and PPG signals. Several experiments were conducted across five different databases with three of them containing ECG signals and the other two consisting of only PPG signals. A total of 269,842 signal segments were analyzed across all datasets (212,266 were of normal sinus rhythm (NSR) and 57,576 corresponded to AFIB segments). Experiments were conducted to investigate the hypothesis that a machine learning model trained to predict AFIB from ECG segments, could be used to predict AFIB from PPG segments. A random forest machine learning algorithm achieved the best accuracy and achieved a 90% accuracy rate on the UMMC dataset (216 samples) and a 97% accuracy rate on the MIMIC-III dataset (2,134 samples). The ability to detect AFIB with significant accuracy using machine learning algorithms from PPG signals, which can be acquired via non-invasive contact or contactless, is a promising step forward toward the goal of achieving large-scale screening for AFIB.
Dynamics of Eastern equine encephalitis virus during the 2019 outbreak in the Northeast United States
Authors: Hill Verity , Koch Robert T. , Bialosuknia Sean M. , Ngo Kiet , Zink Steven D. , Koetzner Cheri A. , Maffei Joseph G. , Dupuis Alan P. , Backenson P. Bryon , Oliver JoAnne , Bransfield Angela B. , Misencik Michael J. , Petruff Tanya A. , Shepard John J. , Warren Joshua L. , Gill Mandev S. , Baele Guy , Vogels Chantal B.F. , Gallagher Glen , Burns Paul , Hentoff Aaron , Smole Sandra , Brown Catherine , Osborne Matthew , Kramer Laura D. , Armstrong Philip M. , Ciota Alexander T. , Grubaugh Nathan D.
Published: March 2023

Eastern equine encephalitis virus (EEEV) causes a rare but severe disease in horses and humans, and is maintained in an enzootic transmission cycle between songbirds andCuliseta melanuramosquitoes. In 2019, the largest EEEV outbreak in the United States for more than 50 years occurred, centered in the Northeast. To explore the dynamics of the outbreak, we sequenced 80 isolates of EEEV and combined them with existing genomic data. We found that, like previous years, cases were driven by frequent short-lived virus introductions into the Northeast from Florida. Once in the Northeast, we found that Massachusetts was important for regional spread. We found no evidence of any changes in viral, human, or bird factors which would explain the increase in cases in 2019. By using detailed mosquito surveillance data collected by Massachusetts and Connecticut, however, we found that the abundance ofCs. melanurawas exceptionally high in 2019, as was the EEEV infection rate. We employed these mosquito data to build a negative binomial regression model and applied it to estimate early season risks of human or horse cases. We found that the month of first detection of EEEV in mosquito surveillance data and vector index (abundance multiplied by infection rate) were predictive of cases later in the season. We therefore highlight the importance of mosquito surveillance programs as an integral part of public health and disease control.
Computer Vision Analysis of Specimen Mammography to Predict Margin Status
Authors: Chen Kevin A , Kirchoff Kathryn E , Butler Logan R , Holloway Alexa D , Kapadia Muneera R , Gallagher Kristalyn K , Gomez Shawn M
Published: March 2023

Intra-operative specimen mammography is a valuable tool in breast cancer surgery, providing immediate assessment of margins for a resected tumor. However, the accuracy of specimen mammography in detecting microscopic margin positivity is low. We sought to develop a deep learning-based model to predict the pathologic margin status of resected breast tumors using specimen mammography. A dataset of specimen mammography images matched with pathology reports describing margin status was collected. Models pre-trained on radiologic images were developed and compared with models pre-trained on non-medical images. Model performance was assessed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). The dataset included 821 images and 53% had positive margins. For three out of four model architectures tested, models pre-trained on radiologic images outperformed domain-agnostic models. The highest performing model, InceptionV3, showed a sensitivity of 84%, a specificity of 42%, and AUROC of 0.71. These results compare favorably with the published literature on surgeon and radiologist interpretation of specimen mammography. With further development, these models could assist clinicians with identifying positive margins intra-operatively and decrease the rate of positive margins and re-operation in breast-conserving surgery.
Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder
Authors: Bigdeli Tim B. , Barr Peter B. , Rajeevan Nallakkandi , Graham David P. , Li Yuli , Meyers Jacquelyn L. , Gorman Bryan R. , Peterson Roseann E. , Sayward Frederick , Radhakrishnan Krishnan , Natarajan Sundar , Nielsen David A. , Wilkinson Anna V. , Malhotra Anil K. , Zhao Hongyu , Brophy Mary , Shi Yunling , O’Leary Timothy J. , Gleason Theresa , Przygodzki Ronald , Pyarajan Saiju , Muralidhar Sumitra , Gaziano J. Michael ,   Million Veteran Program (MVP),   Cooperative Studies Program (CSP) #572, Huang Grant D. , Concato John , Siever Larry J. , DeLisi Lynn E. , Kimbrel Nathan A. , Beckham Jean C. , Swann Alan C. , Kosten Thomas R. , Fanous Ayman H. , Aslan Mihaela , Harvey Philip D.
Published: March 2023

Objective

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed mental and physical health problems, prior pharmacological treatments, and aggregate genetic factors has potential to inform risk stratification and mitigation strategies.

Methods

In this study of 3,942 SCZ and 5,414 BPI patients receiving VA care, self-reported SB and ideation were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). These cross-sectional data were integrated with electronic health records (EHR), and compared by lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. Polygenic scores (PGS) for traits related to psychiatric disorders, substance use, and cognition were constructed using available genomic data, and exploratory genome-wide association studies were performed to identify and prioritize specific loci.

Results

Only 20% of veterans who self-reported SB had a corroborating ICD-9/10 code in their EHR; and among those who denied prior behaviors, more than 20% reported new-onset SB at follow-up. SB were associated with a range of psychiatric and non-psychiatric diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking, suicide attempt, and major depressive disorder were also associated with attempt and ideation.

Conclusions

Among individuals with a diagnosed mental illness, a GWAS for SB did not yield any significant loci. Self-reported SB were strongly associated with clinical variables across several EHR domains. Overall, clinical and polygenic analyses point to sequelae of substance-use related behaviors and other psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in clinical settings, underscoring the value of regular screening based on direct, in-person assessments, especially among high-risk individuals.
The MYO1B and MYO5B motor proteins and the SNX27 sorting nexin regulate membrane mucin MUC17 trafficking in enterocytes
Authors: Jäverfelt Sofia , Hellsén Gustaf , Kaji Izumi , Goldenring James R. , Pelaseyed Thaher
Published: March 2023

A dense glycocalyx, composed of the megaDalton-sized membrane mucin MUC17, coats the microvilli in the apical brush border of transporting intestinal epithelial cells, called enterocytes. The establishment of the MUC17-based glycocalyx in the mouse small intestine occurs at the critical suckling-weaning transition. The enterocytic glycocalyx extends 1 µm into the intestinal lumen and prevents the gut bacteria from directly attaching to the enterocytes. To date, the mechanism behind apical targeting of MUC17 to the brush border remains unknown. Here, we show that the actin-based motor proteins MYO1B and MYO5B, and the sorting nexin SNX27 regulate the intracellular trafficking of MUC17 in enterocytes. We demonstrate that MUC17 turnover at the brush border is slow and controlled by MYO1B and SNX27. Furthermore, we report that MYO1B regulates MUC17 protein levels in enterocytes, whereas MYO5B specifically governs MUC17 levels at the brush border. Together, our results extend our understanding of the intracellular trafficking of membrane mucins and provide mechanistic insights into how defective trafficking pathways render enterocytes sensitive to bacterial invasion.