bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved Spectral Inversion of Blood Oxygenation due to Reduced Tissue Scattering: Towards NIR-II Photoacoustic Imaging
Authors: Vincely Vinoin Devpaul , Bayer Carolyn L.
Published: August 2024

Significance

Conventional spectral photoacoustic imaging (sPAI) to assess tissue oxygenation (sO2) uses optical wavelengths in the first near infrared window (NIR-I). This limits the maximum imaging depth (∼1 cm) due to high spectral coloring of biological tissues.

Aim

Second near infrared or short-wave infrared (NIR-II or SWIR) wavelengths (950-1400 nm) show potential for deep tissue sPAI due to the exponentially reduced tissue scattering and higher maximum exposure threshold (MPE) in this wavelength range. However, to date, a systematic assessment of NIR-II wavelengths for sPAI of tissue sO2has yet to be performed.

Approach

The NIR-II PA spectra of oxygenated and deoxygenated hemoglobin was first characterized using a phantom. Optimal wavelengths to minimize spectral coloring were identified. The resulting NIR-II PA imaging methods were then validatedin vivoby measuring renal sO2in adult female rats.

Results

sPAI of whole blood under a phantom and of circulating renal blood in vivo, demonstrated PA spectra proportional to wavelength-dependent optical absorption. NIR-II wavelengths had a ∼50% decrease in error of spectrally unmixed blood sO2compared to conventional NIR-I wavelengths. In vivo measurements of renal sO2validated these findings and demonstrated a ∼30% decrease in error of estimated renal sO2when using NIR-II wavelengths for spectral unmixing in comparison to NIR-I wavelengths.

Conclusions

sPAI using NIR-II wavelengths improved the accuracy of tissue sO2measurements. This is likely due to the overall reduced spectral coloring in this wavelength range. Combined with the increased safe skin exposure fluence limits in this wavelength range, demonstrate the potential to use NIR-II wavelengths for quantitative sPAI of sO2from deep heterogeneous tissues.
An orphan gene is essential for efficient sperm entry into eggs inDrosophila melanogaster
Authors: Guay Sara Y. , Patel Prajal H. , Thomalla Jonathon M. , McDermott Kerry L. , O’Toole Jillian M. , Arnold Sarah E. , Obrycki Sarah J. , Wolfner Mariana F. , Findlay Geoffrey D.
Published: August 2024

While spermatogenesis has been extensively characterized in theDrosophila melanogastermodel system, very little is known about the genes required for fly sperm entry into eggs. We identified a lineage-specific gene, which we namedkatherine johnson(kj), that is required for efficient fertilization. Males that do not expresskjproduce and transfer sperm that are stored normally in females, but sperm from these males enter eggs with severely reduced efficiency. Using a tagged transgenic rescue construct, we observed that the KJ protein localizes around the edge of the nucleus at various stages of spermatogenesis but is undetectable in mature sperm. These data suggest thatkjexerts an effect on sperm development, the loss of which results in reduced fertilization ability. Interestingly, KJ protein lacks detectable sequence similarity to any other known protein, suggesting thatkjcould be a lineage-specific orphan gene. While previous bioinformatic analyses indicated thatkjwas restricted to themelanogastergroup ofDrosophila, we identified putative orthologs with conserved synteny, male-biased expression, and predicted protein features across the genus, as well as likely instances of gene loss in some lineages. Thus,kjwas likely present in theDrosophilacommon ancestor and subsequently evolved an essential role in fertility inD. melanogaster. Our results demonstrate a new aspect of male reproduction that has been shaped by a lineage-specific gene and provide a molecular foothold for further investigating the mechanism of sperm entry into eggs inDrosophila.

Article Summary

How fruit fly sperm enter eggs is poorly understood. Here, we identify a gene required for efficient fertilization. Sperm from males lacking this gene’s function cannot enter eggs. The gene appears to act during sperm production, rather than in mature sperm. Interestingly, the gene is undetectable outside of genusDrosophila, and its encoded protein shows no discernable similarity to other proteins. This study provides insights into sperm-egg interactions and illustrates how lineage-specific genes can impact important aspects of reproduction.
The repertoire of short tandem repeats across the tree of life
Authors: Chantzi Nikol , Georgakopoulos-Soares Ilias
Published: August 2024

Short tandem repeats (STRs) are widespread, dynamic repetitive elements with a number of biological functions and relevance to human diseases. However, their prevalence across taxa remains poorly characterized. Here we examined the impact of STRs in the genomes of 117,253 organisms spanning the tree of life. We find that there are large differences in the frequencies of STRs between organismal genomes and these differences are largely driven by the taxonomic group an organism belongs to. Using simulated genomes, we find that on average there is no enrichment of STRs in bacterial and archaeal genomes, suggesting that these genomes are not particularly repetitive. In contrast, we find that eukaryotic genomes are orders of magnitude more repetitive than expected. STRs are preferentially located at functional loci at specific taxa. Finally, we utilize the recently completed Telomere-to-Telomere genomes of human and other great apes, and find that STRs are highly abundant and variable between primate species, particularly in peri/centromeric regions. We conclude that STRs have expanded in eukaryotic and viral lineages and not in archaea or bacteria, resulting in large discrepancies in genomic composition.
Tritrichomonas murissensitizes the intestinal epithelium to doxorubicin-induced apoptosis
Authors: Janto Nicolas V. , Gleizes Antoine R. , Sun Siyang , Ari Gurel , Gracz Adam D.
Published: August 2024

Doxorubicin (DXR) is a widely used chemotherapy drug that can induce severe intestinal mucositis. While the influence of gut bacteria on DXR-induced damage has been documented, the role of eukaryotic commensals remains unexplored. We discoveredTritrichomonas muris(Tmu) in one of our mouse colonies exhibiting abnormal tuft cell hyperplasia, prompting an investigation into its impact on DXR-induced intestinal injury. Mice fromTmu-colonized andTmu-excluded facilities were injected with DXR, and tissue morphology and gene expression were evaluated at acute injury (6 h) and peak regeneration (120 h) phases. Contrary to previous reports, DXR did not significantly alter villus height, crypt depth, or crypt density in any mice. However, we did observe apoptosis, measured by cleaved caspase 3 (CC3) staining, in intestinal crypts at 6 h post-DXR that was significantly higher in mice colonized byTmu. Interestingly, while DXR did not alter the expression of active and facultative intestinal stem cell (ISC) marker genes in control mice, it significantly reduced their expression inTmu+mice.Tmu, but not DXR, is also associated with increased inflammation and expression of the type 2 cytokines IL-5 and IL-13. However, pre-treatment of intestinal organoids with these cytokines is not sufficient to drive elevated DXR-induced apoptosis. These findings highlight the significant influence of commensal microbiota, particularly eukaryotic organisms likeTmu, on intestinal biology and response to chemotherapy, underscoring the complexity of gut microbiota interactions in drug-induced mucositis.

NEW & NOTEWORTHY

Our study found that the eukaryotic commensalTritrichomonas muris(Tmu) significantly increases DXR-induced intestinal apoptosis in mice, despite no changes in tissue morphology.Tmualso reduces intestinal stem cell gene expression post-DXR injury, and elevates inflammation and type 2 cytokine expression in the absence of injury.In vitroorganoid assays suggest that type 2 cytokines alone are insufficient to promote increased DXR-associated apoptosis. These findings emphasize the complex role of gut microbiota in drug-induced intestinal damage.
A honey bee-associated virus remains infectious and quantifiable in postmortem hosts
Authors: Payne Alexandria N. , Prayugo Vincent , Dolezal Adam G.
Published: August 2024

Corpse-mediated transmission is a potentially viable route through which naïve hosts can become infected, but its likelihood for honey bee-associated viruses is largely unknown. While these viruses can be easily detected in deceased bees, it remains unclear if they stay infectious within postmortem hosts or if enough viral RNA degradation—and subsequently virus inactivation—occurs post-host death to render these viruses inviable. This knowledge gap has important implications for how researchers perform honey bee virus studies and for our general understanding of honey bee virus transmission. To better understand the resiliency of honey bee-associated viruses within deceased hosts, we first tested the hypothesis that postmortem specimens, stored in colony-normal temperature and humidity conditions, can be reliably used to quantify virus abundance. To determine this, we experimentally-infected adult honey bees with Israeli acute paralysis virus (IAPV) and then measured the virus levels of individuals sampled live or at different postmortem timepoints (4–, 12–, 24–, and 48–hours post-death) using RT-qPCR and a standard curve absolute quantification method. We found no significant differences based on when bees were sampled, indicating that postmortem honey bees are statistically comparable to using live-sampled bees and can be reliably used to quantify absolute IAPV abundance. We then performed a follow-up experiment that determined whether or not the IAPV detected in postmortem bees remained infectious over time. We found that IAPV extracted from postmortem bees remained highly infectious for at least 48–hours post-death, indicating that any viral RNA degradation that may have occurred during the postmortem interval did not adversely affect IAPV’s overall infectivity. The results from this study suggest that IAPV is more resilient to degradation than previously assumed, support the use of postmortem bees for downstream IAPV analyses, and indicate that postmortem hosts can act as sources of IAPV infection for susceptible individuals.
Multi-modal, Label-free, Optical Mapping of Cellular Metabolic Function and Oxidative Stress in 3D Engineered Brain Tissue Models
Authors: Zhang Yang , Savvidou Maria , Liaudanskaya Volha , Ramanathan Varshini , Bui Thi , Lindley Matthew , Sze Ash , Ugwu Ugochukwu O. , Fu Yuhang , Dilsizian Matthew E. , Chen Xinjie , Nasritdinova Sevara , Dey Aonkon , Miller Eric L. , Kaplan David L. , Georgakoudi Irene
Published: August 2024

Brain metabolism is essential for the function of organisms. While established imaging methods provide valuable insights into brain metabolic function, they lack the resolution to capture important metabolic interactions and heterogeneity at the cellular level. Label-free, two-photon excited fluorescence imaging addresses this issue by enabling dynamic metabolic assessments at the single-cell level without manipulations. In this study, we demonstrate the impact of spectral imaging on the development of rigorous intensity and lifetime label-free imaging protocols to assess dynamically metabolic functions over time in 3D engineered brain tissue models comprised of human induced neural stem cells, astrocytes, and microglia. Specifically, we rely on multi-wavelength spectral imaging to identify the excitation/emission profiles of key cellular fluorophores within human brain cells, including NAD(P)H, LipDH, FAD, and lipofuscin. These enable the development of methods to mitigate lipofuscin’s overlap with NAD(P)H and flavin autofluorescence to extract reliable optical metabolic function metrics from images acquired at two excitation wavelengths over two emission bands. We present fluorescence intensity and lifetime metrics reporting on redox state, mitochondrial fragmentation, and NAD(P)H binding status in neuronal monoculture and the triculture systems to highlight the functional impact of metabolic interactions between different cell types. Our findings reveal significant metabolic differences between neurons and glial cells, shedding light on metabolic pathway utilization, including the glutathione pathway, OXPHOS, glycolysis, and fatty acid oxidation. Collectively, our studies establish a label-free, non-destructive approach to assess the metabolic function and interactions among different brain cell types relying on endogenous fluorescence and illustrate the complementary nature of the information that is gained by combining intensity and lifetime-based images. Such methods can improve understanding of physiological brain function and dysfunction that occurs at the onset of cancers, traumatic injuries and neurodegenerative diseases.
Integrating gene expression and imaging data across Visium capture areas with visiumStitched
Authors: Eagles Nicholas J. , Bach Svitlana V. , Tippani Madhavi , Ravichandran Prashanthi , Du Yufeng , Miller Ryan A. , Hyde Thomas M. , Page Stephanie C. , Martinowich Keri , Collado-Torres Leonardo
Published: August 2024

Background

Visium is a widely-used spatially-resolved transcriptomics assay available from 10x Genomics. Standard Visium capture areas (6.5mm by 6.5mm) limit the survey of larger tissue structures, but combining overlapping images and associated gene expression data allow for more complex study designs. Current software can handle nested or partial image overlaps, but is designed for merging up to two capture areas, and cannot account for some technical scenarios related to capture area alignment.

Results

We generated Visium data from a postmortem human tissue sample such that two capture areas were partially overlapping and a third one was adjacent. We developed the R/Bioconductor packagevisiumStitched, which facilitates stitching the images together withFiji(ImageJ), and constructingSpatialExperimentR objects with the stitched images and gene expression data.visiumStitchedconstructs an artificial hexagonal array grid which allows seamless downstream analyses such as spatially-aware clustering without discarding data from overlapping spots. Data stitched withvisiumStitchedcan then be interactively visualized withspatialLIBD.

Conclusions

visiumStitchedprovides a simple, but flexible framework to handle various multi-capture area study design scenarios. Specifically, it resolves a data processing step without disrupting analysis workflows and without discarding data from overlapping spots.visiumStichedrelies on affine transformations byFiji, which have limitations and are less accurate when aligning against an atlas or other situations.visiumStichedprovides an easy-to-use solution which expands possibilities for designing multi-capture area study designs.
Overexpression of theApoegene in the frontal cortex of mice causes sex-dependent changes in learning, attention, and anxiety-like behavior
Authors: Ramos Lizbeth , Harr Abigail E. , Zakas Finian L. , Essig Samuel R. , Kempskie Griffen J. , Fadil Nelly A. , Schmid Makayla G. , Pompy Madison D. , Curley Michael C. , Gabel Lisa A. , Hallock Henry L.
Published: August 2024

Apolipoprotein E (ApoE) is a protein that is important for lipid storage, transport, and metabolism.APOEgene variants are associated with Alzheimer’s disease (AD), as well as attentional function in healthy humans. Previous research has shown thatApoetranscription is increased following stimulation of the pathway between the locus coeruleus (LC) and frontal cortex (FC) in mice. This result suggests thatApoemay affect attentional function by virtue of its expression in circuits that control attention. DoesApoecausally regulate attention, or is its expression simply a byproduct of neuronal activity in the LC and FC? To answer this question, we synthetically inducedApoetranscription in the FC of male and female mice, and subsequently tested their ability to learn a touchscreen-based rodent version of the continuous performance test of sustained attention (the rCPT). We found that increasedApoetranscription impaired performance when attentional demand was increased in male mice, while in female mice, increasedApoetranscription significantly accelerated rCPT learning. We further found that this increase inApoetranscription affected subsequent anxiety-like behavior and cellular activity in the FC in a sex-dependent manner. The results of this study provide insight into howApoecausally regulates translationally relevant behaviors in rodent models.
Geometric eigenmode brain fingerprinting and its longitudinal associations with adolescent mental health and wellbeing
Authors: Boyes Amanda , Schwenn Paul E. , Shan Zack Y. , Korgaonkar Mayuresh , Pang James , Prince Taliah , Mills Lia , Kennedy Michelle F. , Hermens Daniel F.
Published: August 2024

Background

‘Brain fingerprinting’ research posits that individual uniqueness can be identified by structural and functional features that may also be linked to mental health outcomes. Global structural features of the brain can be succinctly and directly captured from magnetic resonance imaging (MRI) via the eigenmodes of the cortical surface - known asgeometric eigenmodes. This research investigates how the uniqueness of geometric eigenmodes changes across adolescence and their longitudinal relation to mental health and wellbeing.

Methods

The current study utilised n=613 MRI, self-report and demographic datasets from N=116 community-recruited adolescents enrolled in the Longitudinal Adolescent Brain Study (LABS), between the ages of 12-17 years. MPRAGE scans at each participant’s visit were used to derive 225 left-hemisphere geometric eigenmodes. Eigenmodes were clustered into 14 eigengroups and developmental trajectories of their uniqueness and longitudinal associations with mental wellbeing and psychological distress were examined.

Results

All eigengroups become significantly more unique longitudinally, and higher mode (shorter wavelength) eigengroups were more unique than lower mode groups in adolescence. Less uniqueness in ‘eigengroup 6’ was significantly associated with higher psychological distress and lower mental wellbeing at concurrent and future timepoints.

Conclusion

Geometric eigengroup brain fingerprinting offers a novel way to examine neurodevelopment. This study provides evidence that eigengroups have distinct trajectories from adolescence to adulthood, consistent with other imaging studies demonstrating increasing uniqueness in this period. Importantly, they are associated with mental health state and thus may represent neurobiological markers for mental illness onset, building on previous LABS research demonstrating that the functional uniqueness of the ‘cognitive control network’ predicts psychological distress four months later.
noSpliceVelo infers gene expression dynamics without separating unspliced and spliced transcripts
Authors: Mahajan Tarun , Maslov Sergei
Published: August 2024

Modern single-cell transcriptomics has revolutionized biological research, but because of its destructive nature, it provides only static snapshots. Computational approaches that infer RNA velocity from the ratio of unspliced to spliced mRNA levels can be used to predict how gene expression changes over time. However, information about unspliced and spliced transcripts is not always available and may change on a timescale too short to accurately infer transitions between cellular states. Here we present noSpliceVelo, a novel technique for reconstructing RNA velocity without relying on unspliced and spliced transcripts. Instead, it exploits the temporal relationship between the variance and mean of bursty gene expression using a well-established biophysical model. When evaluated on datasets describing mouse pancreatic endocrinogenesis, mouse and human erythroid maturation, and neuronal stimulation in mouse embryonic cortex, noSpliceVelo performed comparably or better than scVelo, a splicing-based approach. In addition, noSpliceVelo inferred key biophysical parameters of gene regulation, specifically burst size and frequency, potentially distinguishing between transcriptional and epigenetic regulation.
Enhancing SARS-CoV-2 Lineage surveillance through the integration of a simple and direct qPCR-based protocol adaptation with established machine learning algorithms
Authors: Aksenen Cleber Furtado , Ferreira Débora Maria Almeida , Jeronimo Pedro Miguel Carneiro , Costa Thais de Oliveira , de Souza Ticiane Cavalcante , Lino Bruna Maria Nepomuceno Sousa , de Farias Allysson Allan , Miyajima Fabio
Published: August 2024

The emergence of the SARS-CoV-2 and continuous spread of its descendent lineages have posed unprecedented challenges to the global public healthcare system. Here we present an inclusive approach integrating genomic sequencing and qPCR-based protocols to increment monitoring of variant Omicron sublineages. Viral RNA samples were fast tracked for genomic surveillance following the detection of SARS-CoV-2 by diagnostic laboratories or public health network units in Ceara (Brazil) and analyzed using paired-end sequencing and integrative genomic analysis. Validation of a key structural variation was conducted with gel electrophoresis for the presence of a specific ORF7a deletion within the “BE.9” lineages. A simple intercalating dye-based qPCR assay protocol was tested and optimized through the repositioning primers from the ARTIC v.4.1 amplicon panel, which was able to distinguish between “BE.9” and “non-BE.9” lineages, particularly BQ.1. Three ML models were trained with the melting curve of the intercalating dye-based qPCR that enabled lineage assignment with elevated accuracy. Amongst them, the Support Vector Machine (SVM) model had the best performance and after fine-tuning showed ∼96.52% (333/345) accuracy in comparison to the test dataset. The integration of these methods may allow rapid assessment of emerging variants and increment molecular surveillance strategies, especially in resource-limited settings. Our approach not only provides a cost-effective alternative to complement traditional sequencing methods but also offers a scalable analytical solution for enhanced monitoring of SARS-CoV-2 variants for other laboratories through easy-to-train ML algorithms, thus contributing to global efforts in pandemic control.
Digital technology as a tool to provide social support to individuals with cancer in low- and middle-income countries: a scoping review
Authors: Dau Hallie , Kassam Fazila , Payne Beth A. , Miller Hana , Ogilvie Gina
Published: August 2024

BACKGROUND

Cancer is a rising cause of morbidity and mortality in low- and middle-income countries (LMICs). Individuals diagnosed with cancer in LMICs often have limited access to cancer prevention, diagnosis, and treatment services. Social support after a cancer diagnosis is associated with positive health outcomes in the long term. Digital technologies, such as the Internet and mobile phones, could be used to provide support to individuals with cancer in a more accessible way. This scoping review aims to understand how digital technology is currently being utilized by individuals with cancer for social support in LMICs.

METHODS

Four electronic databases were searched up to June 2024 to identify studies that reported on the use of digital technology for cancer social support in LMICs. Articles were included if they were published in English, included adults diagnosed with any type of cancer, and reported the use of digital technology for social support. Study characteristics, population demographics, and technological interventions reported were extracted.

RESULTS

In all, 15 articles from 12 studies were included in the scoping review. The results were centralized in four countries, and the most common cancer type reported was breast. Online health communities, Internet-based resources, mobile applications, and telecommunication were the four digital technologies reported. Overall, the articles demonstrated that the use of digital technology for social support can be beneficial for individuals diagnosed with cancer in LMICs.

CONCLUSION

There is a limited understanding of how digital technology can be used to support individuals with cancer in LMICs. Future research is needed to explore how digital technology can be utilized by underrepresented regions to offer avenues of support for regionally common cancer types such as cervical. Fundamentally, this scoping review highlights the need for additional research on the use of digital technology to support individuals with a cancer diagnosis in LMICs.
Efficacy, Safety and Cost-effectiveness of Atorvastatin 40mg versus 80 mg in South Asian Patients with acute coronary syndrome: A protocol for randomised clinical trial
Authors: Fernando Kavindya , Fernando Nilshan , Welhenge Chiranthi , Liyanage Shashima , Dayanath B.K.T.P. , De Silva Shamila , Mettananda Chamila
Published: August 2024

Introduction

Most guidelines recommend high-intensity statins for the secondary prevention of Acute Coronary Syndrome (ACS). However, it has been observed that South Asians are responsive to lower doses of statins to achieve the recommended target levels of low-density lipoprotein cholesterol (LDL-C). However, published data on this subject is limited. Therefore, we aim to compare the efficacy, safety and cost effectiveness of atorvastatin doses (80mg vs 40mg) in lowering the LDL-c levels to the less than 70 mg/dL within 12 weeks, among patients with incident ACS.

Methods and analysis

This single-centre, prospective, randomised, controlled, open-labelled clinical trial is being conducted among patients naïve for statins presenting with incident ACS to the Colombo North Teaching Hospital, Ragama, Sri Lanka. All participants are randomised to two groups, to receive oral atorvastatin 40 mg nocte, or 80 mg nocte. The percentage of patients achieving treatment goals, the percentage with statin induced adverse drug reactions and the mean cost to achieve treatment goals will be compared between the two groups in 6,12 and 24 weeks. Outcome will be analysed for the intention-to-treat population.

Ethics and dissemination

Ethical approval for this study has been obtained from the Ethics Review Committee of the Faculty of Medicine, University of Kelaniya (P/28/05/2022). This trial is registered in the Sri Lanka Clinical Trial Registry (SLCTR/2023/003). The results from this study will be disseminated as scientific publications in reputed journals.

Key points of this study

What is already known on this topic?

While the European guideline recommendation is to initiate atorvastatin at 80 mg dose for ACS, it has been observed that South Asians respond well to lower dose. Additionally, South Asians tend to experience more adverse effects with higher doses of statins. However, reports on differential action of atorvastatin in South Asians is limited.

What this study adds?

This study explores the efficacy, safety, and cost-effectiveness of a lower dose of atorvastatin (40 mg daily) compared to guideline recommended dose of 80mg in a South Asian cohort.

How might this study affect research, practice or policy?

The findings may influence statin dose recommendation for South Asians/Sri Lankans which will help to reduce unnecessary side effects and be cost saving as well in secondary prevention of ACS.
Using pet insurance claims to predict occurrence of vector-borne and zoonotic disease in humans
Authors: O’Brien Janice , McCullough Aliya , Debes Christian , Ruple Audrey
Published: August 2024

Taking a One Health approach to infectious diseases common to both dogs and people, pet insurance claims from 2008-2022 in the United States were compared to publicly available CDC-based data on human cases for Lyme disease, giardia, and Valley Fever (coccidioidomycosis). Despite having very different causative agents and etiologies, the disease trends for these three diseases were very similar between people and dogs both geographically and temporally. We furthermore demonstrated that adding dog data to the human data improves prediction models for those same diseases. With machine learning prediction tools for the pet insurance to increase prediction times and alert public health officials, pet insurance data could be a helpful tool to predict and detect diseases by estimating even earlier the effects of these common exposure diseases on human health. We also show the spatiotemporal distribution of intestinal worm diagnoses in dogs, and while it could not be directly compared to human data because the corresponding disease in humans (soil-transmitted helminths) has not been well monitored recently. However, these data can help inform researchers and public health workers.
Preliminary Development of a Multidomain Behavioral Intervention for Primary Prevention of Dementia in Midlife
Authors: Korthauer L.E. , Rosen R.K. , Arias I. , Tremont G. , Davis J.D.
Published: August 2024

Background

An estimated 40% of global cases of Alzheimer’s disease and related dementias (ADRD) may be prevented through modification of 12 risk factors. Midlife risk reduction is particularly important given the long prodromal period for ADRD. However, population adherence to these health behaviors is low, and large, multidomain behavioral interventions have suffered from poor adherence. The goal of this study was to use qualitative methods to develop a personalized health education intervention (TEACH: Tailored Education for Aging and Cognitive Health), which is grounded in the Health Belief Model.

Method

We conducted six focus groups in which we presented health information about a fictitious person, including images conveying ADRD risk and descriptions of personal health belief factors. Participants provided feedback about the images, their understanding of ADRD risk, and interpretation of the health belief concepts. Results were summarized using a framework matrix.

Results

Groups found the presented risk information to be understandable and relevant to health behaviors. They had strong reactions to presented images and descriptions, and they provided alternative language and suggestions to improve clarity. Participants noted some overlap between health belief constructs but were able to identify connections between health beliefs and personal behaviors.

Conclusions

Results guided the TEACH intervention development project, which includes creating an explanatory framework for disclosing individuals’ ADRD risk factors and health belief profile. The long-term goal is to develop a multi-domain intervention to promote sustained health behavior change for primary prevention of ADRD.
Spatial assessment of stromal B cell aggregates predicts response to checkpoint inhibitors in unresectable melanoma
Authors: Smithy James W. , Peng Xiyu , Ehrich Fiona D. , Moy Andrea P. , Yosofvand Mohammad , Maher Colleen , Aleynick Nathaniel , Vanguri Rami , Zhuang Mingqiang , Lee Jasme , Bleile MaryLena , Li Yanyun , Postow Michael A. , Panageas Katherine S. , Hollmann Travis J. , Callahan Margaret K. , Shen Ronglai
Published: August 2024

Quantitative assessment of multiplex immunofluorescence (mIF) data represents a powerful tool for immunotherapy biomarker discovery in melanoma and other solid tumors. In addition to providing detailed phenotypic information of immune cells of the tumor microenvironment, these datasets contain spatial information that can reveal biologically relevant interactions among cell types.

To assess quantitative mIF analysis as a platform for biomarker discovery, we used a 12-plex mIF panel to characterize tumor samples collected from 50 patients with melanoma prior to treatment with immune checkpoint inhibitors (ICI). Consistent with prior studies, we identified a strong association between stromal B cell percentage and response to ICI therapy. We then compared pathologist assessment of lymphoid aggregates with a density based clustering algorithm, DBSCAN, to both automatically detect B cell aggregates and quantify their size, morphology, and distance to tumor. Spatial neighborhood analysis identified TCF1+ and LAG3-T cell subpopulations enriched near stromal B cells. These analyses provide a roadmap for the further development and validation of spatial immunotherapy biomarkers in melanoma and other diseases.
Enhancing Stroke Awareness and Activation among High-Risk Populations: A Randomized Direct Mail Intervention in Diverse Healthcare Settings
Authors: Groves Christine C. , Damush Teresa M. , Myers Laura J. , Baye Fitsum , Daggy Joanne K. , Martin Holly , Mounsey Layne , Clark Daniel O. , Williams Linda S.
Published: August 2024

Background

Many patients are unaware of their stroke risk. The purpose of this research was to compare the effect of behaviorally tailored mailed messages on patient activation to reduce stroke risk.

Methods

We used electronic health records to construct Framingham Stroke Risk Scores (FSRS) in primary care patients from one Veterans Health Administration (VA) and one non-VA healthcare system, Eskenazi Health System (EHS). Four stroke risk messages were developed through patient interviews: standard, incentive ($5 gift card), salience, and incentive plus salience. Patients in the highest FSRS quintile were randomly assigned to receive one of the messages. All letters asked the patient to call a stroke prevention coordinator. Response to the messages was modeled separately in the two cohorts using logistic regression.

Results

From 6,695 eligible patients, 2,084 EHS patients (mean age 65.6, 36% male, 68% Black, mean FSRS 13.1) and 1,759 VA patients (mean age 75.6, 99% male, 86% White, mean FSRS 18.6) received a letter. Rates of calls to the coordinator were 13% among the EHS and 23% among the VA cohort. The EHS cohort was significantly more likely to respond to the incentive message compared to the standard message (OR = 1.97 [1.17, 3.09]), and the VA cohort was more likely to respond to the incentive plus salience message (OR = 1.50 [1.02, 2.22]). Older age (for VA) and Black race (for EHS) were also significantly associated with response. Among individuals calling the coordinator, 30% of the EHS cohort and 26% of the VA cohort were unaware they had stroke risk factors.

Conclusions

A mailed message including a $5 incentive was more effective than a standard message in engaging high-risk patients with their healthcare system; including a salience message may also be important in some patient populations. Many primary care patients are unaware of their stroke risk.
Evaluating the accuracy and reliability of large language models in assisting with pediatric differential diagnoses: A multicenter diagnostic study
Authors: Mansoor Masab A. , Ibrahim Andrew F. , Grindem David J. , Baig Asad
Published: August 2024

Importance

Large language models, such as GPT-3, have shown potential in assisting with clinical decision-making, but their accuracy and reliability in pediatric differential diagnosis in rural healthcare settings remain underexplored.

Objective

Evaluate the performance of a fine-tuned GPT-3 model in assisting with pediatric differential diagnosis in rural healthcare settings and compare its accuracy to human physicians.

Methods

Retrospective cohort study using data from a multicenter rural pediatric healthcare organization in Central Louisiana serving approximately 15,000 patients. Data from 500 pediatric patient encounters (age range: 0-18 years) between March 2023 and January 2024 were collected and split into training (70%, n=350) and testing (30%, n=150) sets.

Interventions

GPT-3 model (DaVinci version) fine-tuned using OpenAI API on training data for ten epochs.

Main Outcomes and Measures

Accuracy of fine-tuned GPT-3 model in generating differential diagnoses, evaluated using sensitivity, specificity, precision, F1 score, and overall accuracy. The model’s performance was compared to human physicians on the testing set.

Results

The fine-tuned GPT-3 model achieved an accuracy of 87% (131/150) on the testing set, with a sensitivity of 85%, specificity of 90%, precision of 88%, and F1 score of 0.87. The model’s performance was comparable to human physicians (accuracy 91%; P = .47).

Conclusions and Relevance

The fine-tuned GPT-3 model demonstrated high accuracy and reliability in assisting with pediatric differential diagnosis, with performance comparable to human physicians. Large language models could be valuable tools for supporting clinical decision-making in resource-constrained environments. Further research should explore implementation in various clinical workflows.
Universal dynamics of cohesin-mediated loop extrusion
Authors: Sabaté Thomas , Lelandais Benoît , Robert Marie-Cécile , Szalay Michael , Tinevez Jean-Yves , Bertrand Edouard , Zimmer Christophe
Published: August 2024

Most animal genomes are partitioned into Topologically Associating Domains (TADs), created by cohesin-mediated loop extrusion and defined by convergently oriented CTCF sites. The dynamics of loop extrusion and its regulation remains poorly characterizedin vivo. Here, we tracked TAD anchors in living human cells to visualize and quantify cohesin-dependent loop extrusion across multiple endogenous genomic regions. We show that TADs are dynamic structures whose anchors are brought in proximity about once per hour and for 6-19 min (∼16% of the time). TADs are continuously subjected to extrusion by multiple cohesin complexes, extruding loops at ∼0.1 kb/s. Remarkably, despite strong differences of Hi-C patterns between the chromatin regions, their dynamics is consistent with the same density, residence time and speed of cohesin. Our results suggest that TAD dynamics is governed primarily by CTCF site location and affinity, which allows genome-wide predictive models of cohesin-dependent interactions.
taxmyPHAGE: Automated taxonomy of dsDNA phage genomes at the genus and species level
Authors: Millard Andrew , Denise Remi , Lestido Maria , Thomas Moi , Turner Deven , Turner Dann , Sicheritz-Pontén Thomas
Published: August 2024

Background

Bacteriophages are now classified into genera and species based on genomic similarity. To identify new species and genera requires comparison against all phage genomes currently defined by the International Committee on the Taxonomy of Viruses. With increasing amounts of phage genomic data there is a clear need to fully automate the classification of phages into existing and new genera and species.

Materials and Methods

We created a MASH database for rapid searching of closely related phages, to then be compared with BLASTn to compute intergenomic similarity between bacteriophages (https://github.com/amillard/tax_myPHAGE/tree/main).

Results

Taxmyphage is provided as a conda repository and via a user-friendly website, that allows rapid classification of phages into existing taxa at the genus and species level.

Conclusions

Taxmyphage allows the rapid and accurate classification of phage genomes into existing genera and species, at a scale that is compatible with existing sequencing output.
4D bioprinting shape-morphing tissues in granular support hydrogels: Sculpting structure and guiding maturation
Authors: Pramanick Ankita , Hayes Thomas , McEvoy Eoin , Pandit Abhay , Daly Andrew C.
Published: August 2024

During embryogenesis, organs undergo dynamic shape transformations that sculpt their final shape, composition, and function. Despite this, current organ bioprinting approaches typically employ bioinks that restrict cell-generated morphogenetic behaviours resulting in structurally static tissues. Here, we introduce a novel platform that enables the bioprinting of tissues that undergo programmable and predictable 4D shape-morphing driven by cell-generated forces. Our method utilises embedded bioprinting to deposit collagen-hyaluronic acid bioinks within yield-stress granular support hydrogels that can accommodate and regulate 4D shape-morphing through their viscoelastic properties. Importantly, we demonstrate precise control over 4D shape-morphing by modulating factors such as the initial print geometry, cell phenotype, bioink composition, and support hydrogel viscoelasticity. Further, we observed that shape-morphing actively sculpts cell and extracellular matrix alignment along the principal tissue axis through a stress-avoidance mechanism. To enable predictive design of 4D shape-morphing patterns, we developed a finite element model that accurately captures shape evolution at both the cellular and tissue levels. Finally, we show that programmed 4D shape-morphing enhances the structural and functional properties of iPSC-derived heart tissues. This ability to design, predict, and program 4D shape-morphing holds great potential for engineering organ rudiments that recapitulate morphogenetic processes to sculpt their final shape, composition, and function.
Tracing Endometriosis: Coupling deeply phenotyped, single-cell based Endometrial Differences and AI for disease pathology and prediction
Authors: Duempelmann Lea , Sheppard Shaoline , Duo Angelo , Skrabalova Jitka , McKinnon Brett , Andrieu Thomas , Goehlsdorf Dennis , Muzumdar Sukalp , Donato Cinzia , Lusby Ryan , Solass Wiebke , Bösmüller Hans , Nestorov Peter , Mueller Michael D.
Published: August 2024

Endometriosis, affecting 1 in 9 women, presents treatment and diagnostic challenges. To address these issues, we generated the biggest single-cell atlas of endometrial tissue to date, comprising 466,371 cells from 35 endometriosis and 25 non-endometriosis patients without exogenous hormonal treatment. Detailed analysis reveals significant gene expression changes and altered receptor-ligand interactions present in the endometrium of endometriosis patients, including increased inflammation, adhesion, proliferation, cell survival, and angiogenesis in various cell types. These alterations may enhance endometriosis lesion formation and offer novel therapeutic targets. Using ScaiVision, we developed neural network models predicting endometriosis of varying disease severity (median AUC = 0.83), including an 11-gene signature-based model (median AUC = 0.83) for hypothesis-generation without external validation. In conclusion, our findings illuminate numerous pathway and ligand-receptor changes in the endometrium of endometriosis patients, offering insights into pathophysiology, targets for novel treatments, and diagnostic models for enhanced outcomes in endometriosis management.
Reverse development in the ctenophoreMnemiopsis leidyi
Authors: Soto-Angel Joan J. , Burkhardt Pawel
Published: August 2024

Reverse development, or the ability to rejuvenate by morphological reorganization into the preceding life cycle stage is thought to be restricted to a few species within Cnidaria. To date, the cnidarianTurritopsis dohrniiis the only known species capable of undergoing reverse development after the onset of sexual reproduction. Here, we demonstrate that the ctenophoreMnemiopsis leidyiis capable of reversal from mature lobate to early cydippid when fed following a period of stress. Our findings illuminate central aspects of ctenophore development, ecology, and evolution, and show the high potential ofM. leidyias a new model system to study reverse development and rejuvenation. Besides shedding light on the plasticity of developmental programs, our results raise fundamental questions about early animal development, body plans and life cycles.
Machine learning reveals signatures of promiscuous microbial amidases for micropollutant biotransformations
Authors: Marti Thierry D. , Schweizer Diana , Yu Yaochun , Schärer Milo R. , Probst Silke I. , Robinson Serina L.
Published: August 2024

Organic micropollutants - including pharmaceuticals, personal care products, pesticides and food additives - are prevalent in the environment and have unknown and potentially toxic effects. Humans are a direct source of micropollutants as the majority of pharmaceuticals are primarily excreted through urine. Urine contains its own microbiota with the potential to catalyze micropollutant biotransformations. Amidase signature (AS) enzymes are known for their promiscuous activity in micropollutant biotransformations, but the potential for AS enzymes from the urinary microbiota to transform micropollutants is not known. Moreover, characterization of AS enzymes to identify key chemical and enzymatic features predictive of biotransformation profiles is critical for developing benign-by-design chemicals and micropollutant removal strategies.

In this study, we biochemically characterized a new AS enzyme with arylamidase activity from a urine isolate,Lacticaseibacillus rhamnosus,and demonstrated its capability to hydrolyze pharmaceuticals and other micropollutants. To uncover the signatures of AS enzyme-substrate specificity, we then designed a targeted enzyme library consisting of 40 arylamidase homologs from diverse urine isolates and tested it against 17 structurally diverse compounds. We found that 16 out of the 40 enzymes showed activity on at least one substrate and exhibited diverse substrate specificities, with the most promiscuous enzymes active on nine different substrates.

Using an interpretable gradient boosting machine learning model, we identified chemical and amino acid features predictive of arylamidase biotransformations. Key chemical features from our substrates included the molecular weight of the amide carbonyl substituent and the number of charges in the molecule. Important amino acid features were found to be located on the protein surface and four predictive residues were located in close proximity of the substrate tunnel entrance.

Overall, this work highlights the understudied role of urine-derived microbial arylamidases and contributes to enzyme sequence-structure-substrate-based predictions of micropollutant biotransformations.
Genesis and regulation of C-terminal cyclic imides from protein damage
Authors: Xu Wenqing , Zhao Zhenguang , Su Matthew , Jain Atul , Lloyd Hannah C. , Feng Ethan Yang , Cox Nick , Woo Christina M.
Published: August 2024

C-Terminal cyclic imides are post-translational modifications (PTMs) that can arise from spontaneous intramolecular cleavage of asparagine or glutamine residues resulting in a form of irreversible protein damage. These protein damage events are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN), indicating that these aging-related modifications may require cellular quality control mechanisms to prevent deleterious effects. However, the factors that determine protein or peptide susceptibility to C-terminal cyclic imide formation or their effect on protein stability have not been explored in detail. Here, we characterize the primary and secondary structures of peptides and proteins that promote intrinsic formation of C-terminal cyclic imides in comparison to deamidation, a related form of protein damage. Extrinsic effects from solution properties and stressors on the cellular proteome additionally promote C-terminal cyclic imide formation on proteins like glutathione synthetase (GSS) that are susceptible to aggregation if the protein damage products are not removed by CRBN. This systematic investigation provides insight to the regions of the proteome that are prone to these unexpectedly frequent modifications, the effects of this form of protein damage on protein stability, and the biological role of CRBN.