bluuebunny/crossref_metadata_2025 huggingface dataset:
Hybracter: enabling scalable, automated, complete and accurate bacterial genome assemblies
Authors: Bouras George , Houtak Ghais , Wick Ryan R. , Mallawaarachchi Vijini , Roach Michael J. , Papudeshi Bhavya , Judd Lousie M. , Sheppard Anna E. , Edwards Robert A. , Vreugde Sarah
Published: May 2024

Improvements in the accuracy and availability of long-read sequencing mean that complete bacterial genomes are now routinely reconstructed using hybrid (i.e. short- and long-reads) assembly approaches. Complete genomes allow a deeper understanding of bacterial evolution and genomic variation beyond single nucleotide variants. They are also crucial for identifying plasmids, which often carry medically significant antimicrobial resistance genes. However, small plasmids are often missed or misassembled by long-read assembly algorithms. Here, we present Hybracter which allows for the fast, automatic and scalable recovery of near-perfect complete bacterial genomes using a long-read first assembly approach. Hybracter can be run either as a hybrid assembler or as a long-read only assembler. We compared Hybracter to existing automated hybrid and long-read only assembly tools using a diverse panel of samples of varying levels of long-read accuracy with manually curated ground truth reference genomes. We demonstrate that Hybracter as a hybrid assembler is more accurate and faster than the existing gold standard automated hybrid assembler Unicycler. We also show that Hybracter with long-reads only is the most accurate long-read only assembler and is comparable to hybrid methods in accurately recovering small plasmids.
Targeting Mycobacterium tuberculosis pH-driven adaptation
Authors: Dechow Shelby J. , Abramovitch Robert B.
Published: May 2024

Mycobacterium tuberculosis (Mtb) senses and adapts to host environmental cues as part of its pathogenesis. One important cue sensed by Mtb is the acidic pH of its host niche – the macrophage. Acidic pH induces widespread transcriptional and metabolic remodelling in Mtb. These adaptations to acidic pH can lead Mtb to slow its growth and promote pathogenesis and antibiotic tolerance. Mutants defective in pH-dependent adaptations exhibit reduced virulence in macrophages and animal infection models, suggesting that chemically targeting these pH-dependent pathways may have therapeutic potential. In this review, we discuss mechanisms by which Mtb regulates its growth and metabolism at acidic pH. Additionally, we consider the therapeutic potential of disrupting pH-driven adaptations in Mtb and review the growing class of compounds that exhibit pH-dependent activity or target pathways important for adaptation to acidic pH.
Design and Technical Feasibility Testing of a Medical Robot for Flexible Catheter Navigation Inside the Lung Airways
Authors: Gruionu Lucian Gheorghe , Langø Thomas , Leira Håkon Olav , Hofstad Erlend Fagertun , Udriştoiu Anca Loredana , Iacob Andreea Valentina , Constantinescu Cătălin , Chihaia Cristian , Gruionu Gabriel
Published: May 2024

The integration of medical robots is revolutionizing clinical medicine, especially in procedures requiring precision in instrument manipulation and navigation within the body using medical imaging techniques like fluoroscopy, CT, and MRI. This is particularly challenging in peripheral lung lesion examinations, where guiding long, flexible instruments through the lung airways to the target exposes medical professionals and patients to harmful X-ray radiation. Several robotic approaches exist but there are still shortcomings in terms of their large footprint in the operating room and complex and costly mechanical structure. The goal of our research was to develop and test the early feasibility of RoboCath, an innovative robotic platform designed for the adaptable navigation of long, flexible catheter-like medical instruments through the lung airways. RoboCath seamlessly integrates with existing medical devices, such as bronchoscopes, facilitating access to lower lung regions with precision. Its compact design is ideal for crowded operating rooms, ensures sterilization compatibility, and supports a broad range of procedures, including those requiring intricate instrument manipulation and medical imaging for navigation. This technology significantly reduces the reliance on X-ray, thereby minimizing radiation exposure to both healthcare providers and patients. The RoboCath system represents a significant advancement in the field of medical robotics, offering a novel solution to the challenges of lung lesion biopsy and diagnosis, with potential applications in various open orifice procedures.
Exposure to autoimmune disorders increases Alzheimer’s disease risk in a multi-site electronic health record analysis
Authors: Ramey Grace D. , Tang Alice , Phongpreecha Thanaphong , Yang Monica M. , Woldemariam Sarah R. , Oskotsky Tomiko T. , Montine Thomas J. , Allen Isabel , Miller Zachary A. , Aghaeepour Nima , Capra John A. , Sirota Marina
Published: May 2024

Molecular studies of Alzheimer’s disease (AD) implicate potential links between autoimmunity and AD, but the underlying clinical relationships between these conditions remain poorly understood. Electronic health records (EHRs) provide an opportunity to determine the clinical risk relationship between autoimmune disorders and AD and understand whether specific disorders and disorder subtypes affect AD risk at the phenotypic level in human populations. We evaluated relationships between 26 autoimmune disorders and AD across retrospective observational case-control and cohort study designs in the EHR systems at UCSF and Stanford. We quantified overall and sex-specific AD risk effects that these autoimmune disorders confer. We identified significantly increased AD risk in autoimmune disorder patients in both study designs at UCSF and at Stanford. This pattern was driven by specific autoimmunity subtypes including endocrine, gastrointestinal, dermatologic, and musculoskeletal disorders. We also observed increased AD risk from autoimmunity in both women and men, but women with autoimmune disorders continued to have a higher AD prevalence than men, indicating persistent sex-specificity. This study identifies autoimmune disorders as strong risk factors for AD that validate across several study designs and EHR databases. It sets the foundation for exploring how underlying autoimmune mechanisms increase AD risk and contribute to AD pathogenesis.
Colorectal ALOX15 as a host factor determinant of EPA and DHA effects on colorectal carcinogenesis
Authors: Zuo Xiangsheng , Kiyasu Yoshiyuki , Liu Yi , Deguchi Yasunori , Liu Fuyao , Moussalli Micheline , Tan Lin , Wei Bo , Wei Daoyan , Yang Peiying , Shureiqi Imad
Published: May 2024

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 polyunsaturated fatty acids (ω-3 PUFAs) derived from fish oil, are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. However, studies investigating the effects of EPA and DHA on colorectal carcinogenesis (CRC) have yielded conflicting results. The factors that determine these discrepant results remain unknown. Resolvins, oxidative metabolites of EPA and DHA, inhibit key pro-tumorigenic cytokine and chemokine signaling of colorectal cancer (e.g., IL-6, IL-1β, and CCL2). 15-lipoxygenase-1 (ALOX15), a critical enzyme for resolvin generation is commonly lost during human CRC. Whether ALOX15 expression, as a host factor, modulates the effects of EPA and DHA on CRC remains unknown. Therefore, we evaluated the effects of ALOX15 transgenic expression in colonic epithelial cells on resolvin generation by EPA and DHA and CRC in mouse models representative of human CRC. Our results revealed that 1) EPA and DHA effects on CRC were diverse, ranging from suppressive to promotive, and these effects were occasionally altered by the formulations of EPA and DHA (free fatty acid, ethyl ester, triglyceride); 2) EPA and DHA uniformly suppressed CRC in the presence of intestinal ALOX15 transgenic expression, which induced the production of resolvins, decreased colonic CCL3-5 and CXCL-5 expression and tumor associated macrophages while increasing CD8 T cell abundance in tumor microenvironment; and 3) RvD5, the predominant resolvin produced by ALOX15, inhibited macrophage generation of pro-tumorigenic cytokines. These findings demonstrate the significance of intestinal ALOX15 expression as a host factor in determining the effects of EPA and DHA on CRC.

Significance

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. Studies of EPA and DHA effects on colorectal carcinogenesis (CRC) have revealed inconsistencies; factors determining the direction of their impact on CRC have remained unidentified. Our data show that EPA and DHA effects on CRC were divergent and occasionally influenced by their formulations. More importantly, intestinal 15-lipoxgenase-1 (ALOX15) expression modulated EPA and DHA effects on CRC, leading to their consistent suppression of CRC. ALOX15 promoted EPA and DHA oxidative metabolism to generate resolvins, which inhibited key pro-tumorigenic inflammatory cytokines and chemokines, including IL-6. IL-1β, and CCL2. ALOX15 is therefore an important host factor in determining EPA and DHA effects on CRC.
SCORE: Serologic Evidence of COVID-19, Social, and Occupational Contacts in Healthcare Workers in a Sample of Long-Term Care and Acute Care Facilities in Southeastern Ontario (SCORE)
Authors: Martinez-Cajas Jorge L , Alvarado Beatriz , Jolly Ann , Gong Yanping , Stoner Bradley , Guan T. Hugh
Published: May 2024

Purpose

Healthcare workers (HCW) have been an essential societal resource to face the COVID-19 pandemic. Early in the pandemic, they were at increased risk of contracting SARS-CoV-2 infection. We established a longitudinal cohort of HCW in an acute care hospital and four long-term care facilities in Ontario, Canada to follow the incidence of SARS-CoV-2 infection, the immune response to infection and/or vaccination, and the occupational, household and community factors related to their risk of infection.

Participants

Two hundred participants were recruited between November 2020 and July 2021. They completed a baseline survey, monthly surveillance data for 9-12 months, a post-Omicron-wave survey, and provided blood samples for anti-SARS-CoV2 antibody measurements. We collected data on host-related factors (humoral response to vaccines and SARS-CoV-2 infection) and environmental factors (social contact history, occupational, household and community conditions) to establish the main determinants of risk of SARS-CoV-2 infection.

Findings

Here, we describe the cohort demographics, occupational characteristics, SARS-CoV-2 vaccination status and COVID-19 infection risk during the cohort follow-up.

Analyses

The data from this cohort of HCW allows analyses on 1) the risk factors for SARS-CoV-2 infection, 2) the impact of the Omicron variant on the risk of infection; 3) the relationship between humoral responses and SARS-CoV-2 infection/vaccination and, 4) their relationship of SARS-CoV-2 infection and the community, household and healthcare facility-related exposures.
Social inequalities in youth mental health in Canada, 2007-2022: a population-based repeated cross-sectional study
Authors: McKinnon Britt , Jahan Rabina , Mazza Julia
Published: May 2024

Background

Rising concern surrounds youth mental health in Canada, with growing disparities between females and males. However, less is known about recent trends by other sociodemographic factors, including sexual orientation, ethnocultural background, and socioeconomic status.

Methods

This study analyzed data from 96 683 youths aged 15-24 who participated in the nationally representative Canadian Community Health Survey (CCHS) between 2007 and 2022. Trends in absolute and relative inequalities in poor/fair self-rated mental health (SRMH) by sex, sexual orientation, racialized and Indigenous identity, and socioeconomic conditions were assessed.

Results

The percent of youths reporting poor/fair SRMH quadrupled from 4.3% in 2007-08 to 20.1% in 2021-22. During the same period, absolute inequalities in SRMH increased by 9.9 percentage points (95% CI: 6.6, 12.9) for females compared to males, 11.4 percentage points (95% CI: 4.6, 18.2) for Indigenous versus non-racialized youth, and 15.4 percentage points (95% CI: 5.7, 25.1) for youth (aged 18-24) identifying as lesbian, gay, or bisexual (LGB) compared to heterosexual.

Conclusion

The sustained deterioration in youth SRMH over the past decade and a half has been accompanied by widening inequalities across several dimensions important for health equity in Canada. Action is needed to identify and implement effective programs and policies to support youth mental health and address disparities.

What is already known on this topic

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Youth mental health has been declining in many countries, including Canada, especially among females

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Trends by other sociodemographic factors, including sexual orientation, ethnocultural background, and socioeconomic status, are less clear

What this study adds

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To our knowledge, this is the first study to examine long-term trends in youth mental health inequalities in Canada over a period marked by significant global events including the 2008 financial crisis and the COVID-19 pandemic.

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Findings show disproportionate declines in mental health among certain youth populations, including those from structurally marginalized backgrounds such as those identifying as lesbian, gay or bisexual (LGB) and Indigenous.

How this study might affect research, practice or policy

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These findings should encourage further research and action to identify and implement evidence-based programs and policies to support youth mental health and reduce disparities.
Radicle growth regulation of root parasitic plants by auxin-related compounds
Authors: Tsuzuki Kei , Suzuki Taiki , Kuruma Michio , Nishiyama Kotaro , Hayashi Ken-ichiro , Hagihara Shinya , Seto Yoshiya
Published: May 2024

Root parasitic plants in the Orobancheceae, such asStrigaandOrobanche, cause significant damage to crop production. The germination step of these root parasitic plants is induced by host-root-derived strigolactones (SLs). After germination, the radicles elongate toward the host and invade the host root. We have previously discovered that a simple amino acid, tryptophan (Trp), as well as its metabolite, the plant hormone indole-3-acetic acid (IAA), can inhibit radicle elongation ofOrobanche minor. These results suggest that auxin plays a crucial role in the radicle elongation step in root parasitic plants. In this report, we used various auxin chemical probes to dissect the auxin function in the radicle growth ofO. minorandStriga hermonthica. We found that synthetic auxins inhibited radicle elongation. In addition, auxin receptor antagonist, auxinole, rescued the inhibition of radicle growth by exogenous IAA. Moreover, a polar transport inhibitor of auxin,N-1-naphthylphthalamic acid (NPA), affected radicle tropism. We also proved that exogenously applied Trp is converted into IAA inO. minorseeds, and auxinole partly rescued this radicle elongation. Our data demonstrate a pivotal role of auxin in radicle growth. Thus, manipulation of auxin function in root parasitic plants should offer a useful approach to combat these parasites.
“Out of sight, out of mind”. The antagonistic role of the transcriptional memory associated with repeated acoustic stimuli on the priming of plant defense
Authors: Hadj-Amor Khaoula , Léger Ophélie , Raffaele Sylvain , Kovacic Magdalena , Duclos Aroune , Carvalho-Silva Pedro , Garcia Frédérick , Barbacci Adelin
Published: May 2024

Facilitating plant defense through priming holds significant promise for advancing sustainable crop health practices. The primed state of plants is correlated with a more rapid and efficient response, achievable by subjecting plants to recurrent stressors. Consequently, priming constitutes a dynamic transitional process between two distinct biological states, necessitating the establishment and maintenance of transcriptional memory mechanisms. Research on transcriptional memory has revealed molecular mechanisms including protein and transcription factor accumulation, as well as epigenetic modulations. Nonetheless, there remains a dearth of understanding regarding the interplay among the dynamics of transcriptional stress memory, its preservation, and the resultant emergent properties conferred upon the organism once primed. Here, we found that the robustness of transcriptional memory associated with repeated mechanical stimuli played an antagonistic role in the priming of plant defense. Incorporating experiments and computational modeling, we have analyzed the transcriptional stress memory ofArabidopsis thalianasubjected to daily acoustic stimulations. The observed enhanced resistance to the pathogenSclerotinia sclerotiorumfollowing three rounds of repeated acoustic stimulations is attributed to three primary mechanisms: the activation of a first line of defense in non-inoculated plants, an increase defense-associated gene diversification, and gene priming. These mechanisms are sustained by a transcriptional stress memory involving thousands of genes, likely regulated mostly by transcription factor cascades. Upon comparing the predictions of the transcriptional stress memory model with experimental outcomes, we propose that priming does not arise from the sequential activation of different pathways but rather from the simultaneous modulation of a broad spectrum of pathways. Pathway redundancy in the transcriptional memory topology imparts robustness to plant defense priming. Consequently, primed plants exhibit independence from limited genetic variations, preventing critical loss of resistance observed in naive plants. Pathway redundancies also imply strong limitations in increasing plant defense. Thus, plants remain unaffected by an increase in the daily rate of RAS and exhibited a stress memorization time limited to 1.5 days.
A continuous dynamic genome-scale model explains batch fermentations led by species of theSaccharomycesgenus
Authors: Moimenta Artai R. , Troitiño-Jordedo Diego , Henriques David , Contreras-Ruíz Alba , Minebois Romain , Morard Miguel , Barrio Eladio , Querol Amparo , Balsa–Canto Eva
Published: May 2024

Batch fermentation is a biotechnological dynamic process that produces various products by employing microorganisms that undergo different growth phases: lag, exponential, growth-non-growth, stationary, and decay. Genome-scale constrained-based models are commonly used to explore the phenotypic potential of these microorganisms.

Previous studies have primarily used dynamic Flux Balance Analysis (dFBA) to elucidate the metabolism during the exponential phase. However, this approach falls short in addressing the multi-phase nature of the process and secondary metabolism, posing significant challenges to our understanding of batch fermentation. A recent attempt at a solution was a discontinuous, multi-phase, multi-objective dFBA implementation.

However, this approximation lacks the mechanistic connection between phases, limiting its applicability in predicting intracellular fluxes during batch fermentation.

To overcome these limitations, we combined a novel continuous model with a genome-scale model to predict the distribution of intracellular fluxes throughout the batch fermentation process. The proposed model includes empirical descriptions of regulation that automatically identify the transition between phases. Its application to explain primary and secondary metabolism ofSaccharomycesspecies in batch fermentation results in biological insights that are in good agreement with the previous literature. The ability to account for all process phases and explain secondary metabolism makes this model a valuable and easy-to-use tool for exploring novel fermentation processes.

IMPORTANCE

This research proposes a novel dynamic genome-scale modelling approach for batch fermentation, a crucial process widely used to produce a diverse range of products such as biofuels, enzymes, pharmaceuticals, and food products or ingredients.

The proposed approach automatically accounts for the transitions between different phases of the fermentation process (lag, exponential, growth-no-growth, and stationary). This is a significant advancement over previous methods that required different model formulations for different phases.

We have successfully applied this modelling approach to explore the primary and secondary metabolism of three yeast species under batch fermentation conditions. The model accurately explained experimental data and provided biological insights consistent with previous research findings, instilling confidence in its reliability and accuracy.

The ability of this modelling approach to explain primary and secondary metabolism makes it a valuable tool for designing novel, more efficient, and effective fermentation processes, which could have far-reaching implications in industrial biotechnology.
Post-Transcriptional Modular Synthetic Receptors
Authors: Zhang Xiaowei , Mille-Fragoso Luis S. , Kaseniit K. Eerik , Lee Arden P. , Zhang Meng , Call Connor C. , Hu Yixin , Xie Yunxin , Gao Xiaojing J.
Published: May 2024

Inspired by the power of transcriptional synthetic receptors and hoping to complement them to expand the toolbox for cell engineering, we establish LIDAR (Ligand-Induced Dimerization Activating RNA editing), a modular post-transcriptional synthetic receptor platform that harnesses RNA editing by ADAR. LIDAR is compatible with various receptor architectures in different cellular contexts, and enables the sensing of diverse ligands and the production of functional outputs. Furthermore, LIDAR can sense orthogonal signals in the same cell and produce synthetic spatial patterns, potentially enabling the programming of complex multicellular behaviors. Finally, LIDAR is compatible with compact encoding and can be delivered as synthetic mRNA. Thus, LIDAR expands the family of synthetic receptors, holding the promise to empower basic research and therapeutic applications.
Transformation of an olfactory placode-derived cell into one with stem cell characteristics by disrupting epigenetic barriers
Authors: Abbas Ghazia , Vyas Rutesh , Noble Joyce C. , Lin Brian , Lane Robert P.
Published: May 2024

The mammalian olfactory neuronal lineage is regenerative, and accordingly, maintains a population of pluripotent cells that replenish olfactory sensory neurons and other olfactory cell types during the life of the animal. Moreover, in response to acute injury, the early transit amplifying cells along the olfactory sensory neuronal lineage are able to de-differentiate to shift resources in support of tissue restoration. In order to further explore plasticity of various cellular stages along the olfactory sensory neuronal lineage, we challenged the epigenetic stability of two olfactory placode-derived cell lines that model immature olfactory sensory neuronal stages. We found that perturbation of theEhmt2chromatin modifier transformed the growth properties, morphology, and gene expression profiles towards states with several stem cell characteristics. This transformation was dependent on continued expression of the large T-antigen, and was enhanced by Sox2 over-expression. These findings may provide momentum for exploring inherent cellular plasticity within early cell types of the olfactory lineage, as well as potentially add to our knowledge of cellular reprogramming.

SUMMARY STATEMENT

Discovering how epigenetic modifications influence olfactory neuronal lineage plasticity offers insights into regenerative potential and cellular reprogramming.
Mitochondria-derived Vesicles mediate Mito-nuclear Trafficking of Cargo
Authors: Rajeev Thejaswitha , Shil Dipak , Bhattacharjee Swagato , Ramesh Lariza , Samuel Victor , Nair Nidhi Y , Marib Areeba , Jayakumar Mrithulabhashini , Gayathri Sai , Surendran Arun , Johnson John B , Sundararaman Ananthalakshmy
Published: May 2024

Mito-nuclear communication is key to cellular homeostasis. Metabolites from TCA cycle, calcium, ROS and other small molecules are known to mediate retrograde signalling of mitochondria to the nucleus. Recently, the direct transfer of mitochondrial proteins to the nucleus has been described. However, the mechanism for direct transfer of mitochondrial protein complexes to the nucleus is not understood. In this study, we demonstrate the transit of mitochondrial proteins to the nucleus through mitochondria-derived vesicles (MDVs) which represents a novel intracellular trafficking route. Following an unbiased proteomic approach to detecting cargo proteins in cardiac MDVs, we screen for the presence of MDV cargo in the nucleus. Pyruvate dehydrogenase complex (PDH) and Cytochrome c oxidase subunit IV isoform 1 (COX4I1) are packaged into MDVs in cardiomyocytes but only PDH is targeted to the nucleus in this cell type demonstrating that a subset of cargo-selective MDVs fuse with the nucleus. Further, several mitochondrial stresses that are known to increase MDV generation triage these MDVs to other cellular destinations thereby reducing the nuclear pool of PDH. The transit of PDH through MDVs to the nucleus is a basal physiological process in cardiomyocytes. Mito-nuclear trafficking thus represents a physiological pathway in cardiac cells to enable cargo shuttle from mitochondria to the nucleus.
A metabolic atlas of mouse aging
Authors: Pilley Steven E , Awad Dominik , Latumalea Djakim , Esparza Edgar , Zhang Li , Shi Xuanyi , Unfried Maximilian , Wang Shuo , Mulondo Racheal , Kashyap Sriraksha Bharadwaj , Moaddeli Darius , Sajjakulnukit Peter , Sutton Damien , Wong Harrison , Coakley Aeowynn J. , Garcia Gilberto , Higuchi-Sanabria Ryo , Liu Sophia , Yu Bingfei , Tu William B , Kennedy Brian K. , Lyssiotis Costas A , Mullen Peter J
Published: May 2024

Humans are living longer, but this is accompanied by an increased incidence of age-related chronic diseases. Many of these diseases are influenced by age-associated metabolic dysregulation, but how metabolism changes in multiple organs during aging in males and females is not known. Answering this could reveal new mechanisms of aging and age-targeted therapeutics. In this study, we describe how metabolism changes in 12 organs in male and female mice at 5 different ages. Organs show distinct patterns of metabolic aging that are affected by sex differently. Hydroxyproline shows the most consistent change across the dataset, decreasing with age in 11 out of 12 organs investigated. We also developed a metabolic aging clock that predicts biological age and identified alpha-ketoglutarate, previously shown to extend lifespan in mice, as a key predictor of age. Our results reveal fundamental insights into the aging process and identify new therapeutic targets to maintain organ health.
Neuronal and oligodendroglial but not astroglial tau translates to in vivo tau-PET signals in primary tauopathies
Authors: Slemann Luna , Gnörich Johannes , Hummel Selina , Bartos Laura M. , Klaus Carolin , Kling Agnes , Kusche-Palenga Julia , Kunte Sebastian T. , Kunze Lea H. , Englert Amelie L. , Li Yunlei , Vogler Letizia , Katzdobler Sabrina , Palleis Carla , Bernhardt Alexander , Jäck Alexander , Zwergal Andreas , Hopfner Franziska , Römer Sebastian , Biechele Gloria , Stöcklein Sophia , Bischof Gerard , van Eimeren Thilo , Drzezga Alexander , Sabri Osama , Barthel Henryk , Respondek Gesine , Grimmer Timo , Levin Johannes , Herms Jochen , Paeger Lars , Willroider Marie , Beyer Leonie , Höglinger Günter U. , Roeber Sigrun , Franzmeier Nicolai , Brendel Matthias
Published: May 2024

Tau-PET receives growing interest as an imaging biomarker for the 4-repeat tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau-PET signals is still unclear. Therefore, we conducted a longitudinal [18F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and found elevated [18F]PI-2620 PET signal in the presence of high neuronal tau. Cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons compared to astrocytes of PS19 mice. Regional [18F]PI-2620 tau-PET signals during lifetime correlated with abundance of fibrillary tau in subsequent autopsy samples of PSP patients and disease controls. In autoradiography, tau-positive neurons and oligodendrocytes with high AT8 density but not tau-positive astrocytes were the driver of [18F]PI-2620 autoradiography signals in PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau-PET radiotracer binding in 4-repeat-tauopathies, yielding the capacity to translate to an in vivo signal.
Negative Selection Allows DNA Mismatch Repair-Deficient Mouse FibroblastsIn Vitroto Tolerate High Levels of Somatic Mutations
Authors: Zhang Lei , Lee Moonsook , Hao Xiaoxiao , Ehlert Joseph , Chi Zhongxuan , Jin Bo , Maslov Alexander Y. , Barabási Albert-László , Hoeijmakers Jan H. J. , Edelmann Winfried , Vijg Jan , Dong Xiao
Published: May 2024

Substantial numbers of somatic mutations have been found to accumulate with age in different human tissues. Clonal cellular amplification of some of these mutations can cause cancer and other diseases. However, it is as yet unclear if and to what extent an increased burden of random mutations can affect cellular function without clonal amplification. We tested this in cell culture, which avoids the limitation that an increased mutation burdenin vivotypically leads to cancer. We performed single-cell whole-genome sequencing of primary fibroblasts from DNA mismatch repair (MMR) deficientMsh2-/-mice and littermate control animals after long-term passaging. Apart from analyzing somatic mutation burden we analyzed clonality, mutational signatures, and hotspots in the genome, characterizing the complete landscape of somatic mutagenesis in normal and MMR-deficient mouse primary fibroblasts during passaging. While growth rate ofMsh2-/-fibroblasts was not significantly different from the controls, the number ofde novosingle-nucleotide variants (SNVs) increased linearly up until at least 30,000 SNVs per cell, with the frequency of small insertions and deletions (INDELs) plateauing in theMsh2-/-fibroblasts to about 10,000 INDELS per cell. We provide evidence for negative selection and large-scale mutation-driven population changes, including significant clonal expansion of preexisting mutations and widespread cell-strain-specific hotspots. Overall, our results provide evidence that increased somatic mutation burden drives significant cell evolutionary changes in a dynamic cell culture system without significant effects on growth. Since similar selection processes against mutations preventing organ and tissue dysfunction during aging are difficult to envision, these results suggest that increased somatic mutation burden can play a causal role in aging and diseases other than cancer.
Functional brain network dynamics of brooding in depression: insights from real-time fMRI neurofeedback
Authors: Ganesan Saampras , Misaki Masaya , Zalesky Andrew , Tsuchiyagaito Aki
Published: May 2024

Background

Brooding is a critical symptom and prognostic factor of major depressive disorder (MDD), which involves passively dwelling on self-referential dysphoria and related abstractions. The neurobiology of brooding remains under characterized. We aimed to elucidate neural dynamics underlying brooding, and explore their responses to neurofeedback intervention in MDD.

Methods

We investigated functional MRI (fMRI) dynamic functional network connectivity (dFNC) in 36 MDD subjects and 26 healthy controls (HCs) during rest and brooding. Rest was measured before and after fMRI neurofeedback (MDD-active/sham: n=18/18, HC-active/sham: n=13/13). Baseline brooding severity was recorded using Ruminative Response Scale - Brooding subscale (RRS-B).

Results

Four recurrent dFNC states were identified. Measures of time spent were not significantly different between MDD and HC for any of these states during brooding or rest. RRS-B scores in MDD showed significant negative correlation with measures of time spent in dFNC state 3 during brooding (r=-0.5, p= 1.7E-3, FDR-significant). This state comprises strong connections spanning several brain systems involved in sensory, attentional and cognitive processing. Time spent in this anti-brooding dFNC state significantly increased following neurofeedback only in the MDD active group (z=-2.09, p=0.037).

Limitations

The sample size was small and imbalanced between groups. Brooding condition was not examined post-neurofeedback.

Conclusion

We identified a densely connected anti-brooding dFNC brain state in MDD. MDD subjects spent significantly longer time in this state after active neurofeedback intervention, highlighting neurofeedback’s potential for modulating dysfunctional brain dynamics to treat MDD.
Stronger bat predation and weaker environmental constraints predict longer moth tails
Authors: Rubin Juliette J. , Campbell Caitlin J. , Carvalho Ana Paula S. , St. Laurent Ryan A. , Crespo Gina I. , Pierson Taylor L. , Guralnick Robert P. , Kawahara Akito Y.
Published: May 2024

Elaborate traits evolve via intense selective pressure, overpowering ecological constraints. Hindwing tails that thwart bat attack have repeatedly originated in moon moths (Saturniidae), with longer tails having greater anti-predator effect. Here, we take a macroevolutionary approach to evaluate the evolutionary balance between predation pressure and possible limiting environmental factors on tail elongation. To trace the evolution of tail length across time and space, we inferred a time-calibrated phylogeny of the entirely tailed moth group (Actias + Argema) and performed ancestral state reconstruction and biogeographical analyses. We generated metrics of predation via estimates of bat abundance from nearly 200 custom-built species distribution models and environmental metrics via estimates of bioclimatic variables associated with individual moth observations. To access community science data, we developed a novel method for measuring wing lengths from un-scaled photos. Integrating these data into phylogenetically-informed mixed models, we find a positive association between bat predation pressure and moth tail length and body size, and a negative association between environmental factors and these morphological traits. Regions with more insectivorous bats and more consistent temperatures tend to host longer-tailed moths. Our study provides insight into tradeoffs between biotic selective pressures and abiotic constraints that shape elaborate traits across the tree-of-life.
Spatiotemporal control of cell ablation using Ronidazole with Nitroreductase inDrosophila
Authors: Teeters Gary , Cucolo Christina E. , Kasar Sagar N. , Worley Melanie I. , Siegrist Sarah E.
Published: May 2024

The ability to induce cell death in a controlled stereotypic manner has led to the discovery of evolutionary conserved molecules and signaling pathways necessary for tissue growth, repair, and regeneration. Here we report the development of a new method to genetically induce cell death in a controlled stereotypic manner inDrosophila. This method has advantages over other current methods and relies on expression of theE. colienzyme Nitroreductase (NTR) with exogenous application of the nitroimidazole prodrug, Ronidazole. NTR expression is controlled spatially using the GAL4/UAS system while temporal control of cell death is achieved through timed feeding of Ronidazole supplied in the diet. In cells expressing NTR, Ronidazole is converted to a toxic substance inducing DNA damage and cell death. Caspase cell death is achieved in a range of NTR-expressing cell types with Ronidazole feeding, including epithelial, neurons, and glia. Removing Ronidazole from the diet restores cell death to normal unperturbed levels. Unlike other genetic ablation methods, temporal control is achieved through feeding not temperature, circumventing developmental complications associated with temperature changes. Ronidazole-NTR also requires only two transgenes, a GAL4 driver andUAS-NTR, which is generated as a GFP-NTR fusion allowing for easy setup of large-scale screening ofUAS-RNAilines. Altogether, Ronidazole-NTR provides a new streamlined method for inducing cell death inDrosophilawith temperature-independent ON/OFF control.
Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern
Authors: Rubio Adonis A. , Baharani Viren A. , Dadonaite Bernadeta , Parada Megan , Abernathy Morgan E. , Wang Zijun , Lee Yu E. , Eso Michael R. , Phung Jennie , Ramos Israel , Chen Teresia , Nesr Gina El , Bloom Jesse D. , Bieniasz Paul D. , Nussenzweig Michel C. , Barnes Christopher O.
Published: May 2024

The ongoing emergence of SARS-CoV-2 variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized N-terminal domain (NTD) and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from COVID-19 convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-EM structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596’s favorable binding profile, we designed a series of bispecific antibodies (bsAbs) termed CoV2-biRNs, that featured both NTD and RBD specificities. Notably, two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potentin vitroneutralization activity against all Omicron variants tested, including XBB.1.5, EG.5.1, and BA.2.86, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 significantly reduced the viral load within the lungs of K18-hACE2 mice following challenge with SARS-CoV-2 XBB.1.5. In conclusion, our NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.

One Sentence Summary

Bispecific antibodies with a highly cross-reactive NTD antibody demonstrate resilience to SARS-CoV-2 variants of concern.
Rapid radiation of a plant lineage sheds light on the assembly of dry valley biomes
Authors: Chen Ya-Ping , Sunojkumar Purayidathkandy , Spicer Robert A. , Hodel Richard G.J. , Soltis Douglas E. , Soltis Pamela S. , Paton Alan J. , Sun Miao , Drew Bryan T. , Xiang Chun-Lei
Published: May 2024

Southwest China is characterized by high plateaus, large mountain systems, and deeply incised dry valleys formed by major rivers and their tributaries. Despite the considerable attention given to alpine plant radiations in this region, the timing and mode of the diversification of the numerous plant lineages in the dry valley habitat remains unknown. To address this knowledge gap, we investigate the macroevolution ofIsodon(Lamiaceae), a lineage commonly distributed in the dry valleys in southwest China and wetter areas of Asia and Africa. We reconstructed a robust phylogeny encompassing nearly 90% of the approximately 140 extantIsodonspecies using transcriptome and genome-resequencing data. Our results suggest a rapid radiation ofIsodonduring the Pliocene that coincided with a habit shift from herbs to shrubs and a habitat shift from humid areas to dry valleys. The shrubby growth form likely acted as a preadaptation allowing for the movement ofIsodonspecies into these valleys. Ecological analysis highlighted aridity and precipitation as key factors influencing the niche preferences of different growth forms and species richness ofIsodon. Integrating our results with insights from tectonic movements in the Tibetan Plateau and adjacent regions, we infer that the interplay between topography and the evolution of the East Asian monsoon since the middle Miocene likely contributed to the formation of the dry valley biome in southwest China. This study enhances our understanding of evolutionary dynamics and ecological drivers shaping the distinctive flora of this region.
From hyperinsulinemia to cancer progression: how diminishing glucose storage capacity fuels insulin resistance
Authors: Kareva Irina
Published: May 2024

Type 2 diabetes (T2D) is a complex metabolic disorder characterized by insulin resistance, hyperglycemia and hyperinsulinemia, with a quarter to half of people with T2D unaware of their diagnosis until the disease has reached advanced stages. T2D is associated with increased risk and worse prognosis of cardiovascular disease, cognitive decline, and cancer. Here we propose an updated framework for describing emergence of insulin resistance that precedes development of T2D. We show that diminishing capacity to store excess glucose can qualitatively capture the transition from normal to diabetic phenotype as captured by responses to oral glucose tolerance tests (OGTTs). We then show that an emerging tumor can either progress or regress depending on the metabolic environment of the host, consistent with experimental results of Hopkins et al. (2018), who showed that drug-induced transient diabetic phenotype, and specifically hyperinsulinemia, resulted in loss of therapeutic efficacy, and its reversal restored drug sensitivity and response to therapy. Given the prevalence of hyperinsulinemia in individuals with normoglycemia, addressing this condition emerges as a promising avenue to augment cancer therapy outcomes.
Feasibility of time-restricted eating during pregnancy and effect on glycemic control in people with increased risk of gestational diabetes – a randomized controlled trial
Authors: Skarstad HS , Haganes KL , Sujan MAJ , Gellein TM , Johansen MK , Salvesen KÅ , Hawley JA , Moholdt T.
Published: May 2024

Time-restricted eating (TRE) is a nutritional intervention that confines the daily time-window for energy intake. TRE reduces fasting glucose concentrations in non-pregnant individuals, but whether this eating protocol is feasible and effective for glycemic control in pregnancy is unknown. The aim of this randomized controlled trial was to investigate the feasibility and effect of a 5-week TRE intervention among pregnant individuals at risk of gestational diabetes mellitus (GDM), compared with a usual-care control group. Participants underwent 2-h oral glucose tolerance tests and estimation of body composition, before and after the intervention. Interstitial glucose levels were continuously measured, and adherence rates and ratings of hunger were recorded daily. Thirty of 32 participants completed the trial. Participants allocated to TRE reduced their daily eating window from 12.3 (SD 1.3) to 9.9 (SD 1.0) h, but TRE did not affect glycemic measures, blood pressure, or body composition, compared with the control group. TRE increased hunger levels in the evening, but not in the morning, and induced only small changes in dietary intake. A 5-week TRE intervention was feasible for pregnant individuals with increased risk of GDM but had no effect on cardiometabolic outcomes.
The impact of behavioral interventions on respiratory viruses in a two-cohort study
Authors: Nikparvar Behnam , Exten Cara , Bharti Nita
Published: May 2024

Behavioral interventions are a critical tool for managing novel and emerging pathogens. However, the dynamics of behavioral interventions have been difficult to measure and are poorly understood. In this study, we investigate the uptake, persistence, and waning, of behavioral interventions among two cohorts in Centre County, PA, focusing on the three years following the emergence of SARS-CoV-2. We detected clusters of behaviors that followed similar patterns of engagement and variations over time and identified some novel COVID-19 behavioral interventions that may have severely disrupted non-COVID-19 respiratory disease incidence. Additionally, we detected links between changes in risk perception and changes in behaviors over time. These findings can inform recommendations around behavioral interventions during outbreak management, including information dissemination and behavioral guidelines.
Toward personalized skin cancer care: multiple skin cancer development in five cohorts
Authors: Wheless Lee , Liao Kai-Ping , Zheng Siwei , Li Yao , Yao Lydia , Xu Yaomin , Madden Christopher , Ike Jacqueline , Smith Isabelle T , Mosley Dominique , Grossarth Sarah , Hartman Rebecca I , Wilson Otis , Hung Adriana , Wehner Mackenzie R
Published: May 2024

Importance

Many patients will develop more than one skin cancer, however most research to date has examined only case status.

Objective

Describe the frequency and timing of the treatment of multiple skin cancers in individual patients over time

Design

Longitudinal claims and electronic health record-based cohort study

Setting

Vanderbilt University Medical Center database called the Synthetic Derivative, VA, Medicare, Optum Clinformatics® Data Mart Database, IBM Marketscan

Participants

All patients with a Current Procedural Terminology code for the surgical management of a skin cancer in each of five cohorts.

Exposures

None.

Main Outcomes and Measures

The number of CPT codes for skin cancer treatment in each individual occurring on the same day as an ICD code for skin cancer over time

Results

Our cohort included 5,508,374 patients and 13,102,123 total skin cancers treated.

Conclusions and Relevance

Nearly half of patients treated for skin cancer were treated for more than one skin cancer. Patients who have not developed a second skin cancer by 2 years after the first are unlikely to develop multiple skin cancers within the following 5 years. Better data formatting will allow for improved granularity in identifying individuals at high risk for multiple skin cancers and those unlikely to benefit from continued annual surveillance. Resource planning should take into account not just the number of skin cancer cases, but the individual burden of disease.

Key points

Question: How many skin cancer patients are treated for more than one skin cancer and how soon after the first skin cancer do they occur?

Findings: 43% of patients were treated for more than one skin cancer, the majority of which occurred within two years after the initial skin cancer. Just 3% of patients were treated for 10 or more skin cancers, but these patients accounted for 22% of all of the skin cancer treatments in the cohort Meaning: Nearly half of all skin cancer patients were treated for multiple skin cancers, while those without a second skin cancer after two years were less likely to be treated for a subsequent skin cancer within the next five years.