bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Hypertension in a STEMI-activated Subset of Patients from 2019 to 2021
Authors: Nguyen Trang , Lee Deborah , Lantz Rebekah , Hefner Dylan , Walk Casey T
Published: September 2023

Background

About 47% of United States adults have hypertension (HTN) per the 2017 Hypertension Clinical Practice Guidelines, where the blood pressure target is <130/90 mmHg. Prevalence is worse in certain distributions of the country with top quartile in the Southeastern pocket. In a subset of patients who present with ST-segment elevated myocardial infarction (STEMI), the prevalence is 30-40%. An interesting further subset of patients are those who presented as STEMI-alert during the COVID-19 pandemic. COVID-19 wreaked havoc on the world with its first confirmed case in 9 January 2020. International followed by national transport became limited, followed by announcement of a pandemic. Quarantines and lockdowns were set in place, especially in March 2020, to prevent epidemiologic spread.

Hypothesis

We were interested to observe if STEMI-alert patients during this period presented with worse background disease compared to years 2019 and 2021, years before and after COVID-lockdown and peak, including if the prevalence of background HTN increased in the population.

Methods

We evaluated 1001 adults who were STEMI-activated from 1 January 2019 to 31 December 2021 at five sites in Southwest Ohio. We obtained patient demographics and risk factors and performed multinomial logistic regression to compare years 2019 and 2021 to 2020. Statistical analysis was with SAS 9.4.

Results

For 1001 STEMI-alert patients, 244 patients (72.6%) had HTN in 2019, 250 (78.9%) in 2020 and 261 (75.0%) in 2021. Overall prevalence over the three years was 755 (75.4%). Compared to 2020, 2019 prevalence was not significant (p=0.12) (OR 0.72) (CI 0.47,1.09). Neither was 2021 (p=0.25) (OR 0.78) (CI 0.51,1.19).

Conclusion

STEMI-alert patients at our institution appeared to have higher overall prevalence of HTN than reported nationally by the Centers for Disease Control (CDC), 75.4% versus 47%. These may have self-selected for disease severity by STEMI-alert activation status. HTN may also be of higher prevalence in this region, be associated with poor disease detection or there may be patient compliance issues when antihypertensives are prescribed by a healthcare provider. HTN prevalence did not have statistical significance across the three observed years despite our hypothesis that patients would present with more background cardiac comorbidities such as HTN.
Testing the predictions of reinforcement: long-term empirical data from a damselfly mosaic hybrid zone
Authors: Arce-Valdés Luis Rodrigo , Ballén-Guapacha Andrea Viviana , Rivas-Torres Anais , Chávez-Ríos Jesús Ramsés , Wellenreuther Maren , Hansson Bengt , Guillén Rosa Ana Sánchez
Published: September 2023

Theoretical work suggests that reinforcement can cause the strengthening of prezygotic isolation in sympatry by mitigating the costs of maladaptive hybridization. However, only a handful of studies have tested all predictions of this theory in natural populations. We investigated reinforcement in a mosaic hybrid zone of the damselfliesIschnura elegansandI. graellsii.Firstly, we tested if the conditions of reinforcement were fulfilled by quantifying whether hybridization was costly, and prezygotic isolation was strengthening in sympatry compared with in allopatry. Secondly, we investigated three specific predictions of reinforcement: rarer female effect, presence of concordant prezygotic and postzygotic isolation asymmetries in sympatry, and greater premating asymmetries associated with weaker postzygotic isolation in sympatry. We found that reinforcement has strengthened mechanical isolation in one cross direction between species in sympatry. Our study details a case of reinforcement and heterospecific gene flow causing opposite effects between reciprocal heterospecific crosses and describes a natural model in which reproductive isolation is built by the simultaneous effects of reinforcement, the lock-and-key model, Bateson-Dobzhansky-Müller incompatibilities and Haldane’s rule.
A genome-scale Opisthokonta tree of life: toward phylogenomic resolution of ancient divergences
Authors: Liu Hongyue , Steenwyk Jacob L. , Zhou Xiaofan , Schultz Darrin T. , Kocot Kevin M. , Shen Xing-Xing , Rokas Antonis , Li Yuanning
Published: September 2023

Abstract

Ancient divergences within Opisthokonta—a major lineage that includes organisms in the kingdoms Animalia, Fungi, and their unicellular relatives— remain contentious, hindering investigations of the evolutionary processes that gave rise to two kingdoms and the repeated emergence of iconic phenotypes like multicellularity. Here, we use genome-scale amounts of data to reconstruct the most taxon-rich Opisthokonta tree of life to date (348 species) and place divergences in geologic time, suggesting a Mesoproterozoic origin (∼ 1.11 billion years ago). By dissecting multiple dimensions of phylogenomic error, such as the influence of taxon sampling and model complexity, we found that deep divergences within Holozoa remain unresolved and suggest Pluriformea is either sister to Ichthyosporea and Filozoa (Pluriformea-sister hypothesis) or is monophyletic to Ichthyosporea, forming the Teretosporea lineage (Teretosporea-sister hypothesis). A combination of information theory and sensitivity analyses revealed that the inferred unicellular Holozoa relationships are largely robust to common sources of analytical error, such as insufficient model complexity, and suggest that previous reports likely suffered from insufficient taxon sampling. Our study presents a robust Opisthokonta phylogenomic framework, highlights the challenges in resolving the relationships of unicellular Holozoa, and paves the way for illuminating ancient evolutionary episodes concerning the origin of two kingdoms.
Context-dependent hyperactivity insyngap1aandsyngap1bzebrafish autism models
Authors: Sumathipala Sureni H. , Khan Suha , Kozol Robert A. , Araki Yoichi , Syed Sheyum , Huganir Richard L. , Dallman Julia E.
Published: September 2023

Background and Aims

SYNGAP1 disorder is a prevalent genetic form of Autism Spectrum Disorder and Intellectual Disability (ASD/ID) and is caused byde novoor inherited mutations in one copy of theSYNGAP1gene. In addition to ASD/ID, SYNGAP1 disorder is associated with comorbid symptoms including treatment-resistant-epilepsy, sleep disturbances, and gastrointestinal distress. Mechanistic links between these diverse symptoms andSYNGAP1variants remain obscure, therefore, our goal was to generate a zebrafish model in which this range of symptoms can be studied.

Methods

We used CRISPR/Cas9 to introduce frameshift mutations in thesyngap1aandsyngap1bzebrafish duplicates (syngap1ab) and validated these stable models for Syngap1 loss-of-function. BecauseSYNGAP1is extensively spliced, we mapped splice variants to the two zebrafishsyngap1aandbgenes and identified mammalian-like isoforms. We then quantified locomotory behaviors in zebrafish syngap1ab larvae under three conditions that normally evoke different arousal states in wild type larvae: aversive, high-arousal acoustic, medium-arousal dark, and low-arousal light stimuli.

Results

We show that CRISPR/Cas9 indels in zebrafishsyngap1aandsyngap1bproduced loss-of-function alleles at RNA and protein levels. Our analyses of zebrafish Syngap1 isoforms showed that, as in mammals, zebrafish Syngap1 N- and C-termini are extensively spliced. We identified a zebrafishsyngap1α1-like variant that maps exclusively to thesyngap1bgene. Quantifying locomotor behaviors showed thatsyngap1ablarvae are hyperactive compared to wild type but to differing degrees depending on the stimulus. Hyperactivity was most pronounced in low arousal settings, with overall movement increasing with the number of mutantsyngap1alleles.

Conclusions

Our data support mutations in zebrafishsyngap1abas causal for hyperactivity associated with elevated arousal that is especially pronounced in low-arousal environments.
Estrogen-dependent development and transcriptome regulation of the lateral septal kisspeptin system
Authors: Szentkirályi-Tóth Soma , Göcz Balázs , Takács Szabolcs , Sárvári Miklós , Farkas Imre , Skrapits Katalin , Rumpler Éva , Póliska Szilárd , Wittmann Gábor , Fekete Csaba , Hrabovszky Erik
Published: September 2023

While hypothalamic kisspeptin (KP) neurons play well-established roles in puberty and reproduction, kisspeptin neurons in the lateral septum (KPLSneurons) and other extrahypothalamic sites have received less attention. We found that the onset of LS kisspeptin expression was linked to pubertal development and estrogen receptor signaling. Cell numbers were higher in femalesvs.males, continued to increase in adulthood and exogenous estrogen administered to adult mice was able to switch on theKiss1gene promoter in new sets of septal neurons. Using RNA-Seq studies of laser-microdissected neurons from ovariectomized mice treated with 17β-estradiol (E2)vs. vehicle, we found that KPLSneurons largely differ from hypothalamic KP neurons in their transcriptome profile which included 571 estrogen-dependent transcripts from which 80% were upregulated by a 4-day E2-treatment of ovariectomized mice. Notably,Kiss1expression in the LS was considerably lower than in hypothalamic KP neurons, being undetectable in ovariectomized mice and inducible by E2 supplementation. Finally, immunohistochemical detection of septal kisspeptin neurons and their fibers in the human brain suggested that the functions of this neuronal system are evolutionarily conserved. Ontogeny, sexual dimorphism and robust estrogenic regulation raise the intriguing possibility that the KPLSsystem is a new central player in the estrogen-dependent control of reproductive and/or non-reproductive functions in mice, with a possible human relevance supported by the immunohistochemical observations onpost mortemtissues.
IntegrativePTENEnhancer Discovery Reveals a New Model of Enhancer Organization
Authors: Cerda-Smith Christian G. , Hutchinson Haley M. , Liu Annie , Goel Viraat Y. , Sept Corriene , Kim Holly , Casaní-Galdón Salvador , Burkman Katherine G. , Bassil Christopher F. , Hansen Anders S. , Aryee Martin J. , Johnstone Sarah E. , Eyler Christine E. , Wood Kris C.
Published: September 2023

Enhancers possess both structural elements mediating promoter looping and functional elements mediating gene expression. Traditional models of enhancer-mediated gene regulation imply genomic overlap or immediate adjacency of these elements. We test this model by combining densely-tiled CRISPRa screening with nucleosome-resolution Region Capture Micro-C topology analysis. Using this integrated approach, we comprehensively define thecis-regulatory landscape for the tumor suppressorPTEN, identifying and validating 10 distinct enhancers and defining their 3D spatial organization. Unexpectedly, we identify several long-range functional enhancers whose promoter proximity is facilitated by chromatin loop anchors several kilobases away, and demonstrate that accounting for this spatial separation improves the computational prediction of validated enhancers. Thus, we propose a new model of enhancer organization incorporating spatial separation of essential functional and structural components.
A spatially mapped gene expression signature for intestinal stem-like cells identifies high-risk precursors of gastric cancer
Authors: Huang Robert J. , Wichmann Ignacio A. , Su Andrew , Sathe Anuja , Shum Miranda V. , Grimes Susan M. , Meka Rithika , Almeda Alison , Bai Xiangqi , Shen Jeanne , Nguyen Quan , Amieva Manuel R. , Hwang Joo Ha , Ji Hanlee P.
Published: September 2023

Objective

Gastric intestinal metaplasia (GIM) is a precancerous lesion that increases gastric cancer (GC) risk. The Operative Link on GIM (OLGIM) is a combined clinical-histopathologic system to risk-stratify patients with GIM. The identification of molecular biomarkers that are indicators for advanced OLGIM lesions may improve cancer prevention efforts.

Methods

This study was based on clinical and genomic data from four cohorts: 1) GAPS, a GIM cohort with detailed OLGIM severity scoring (N=303 samples); 2) the Cancer Genome Atlas (N=198); 3) a collation of in-house and publicly available scRNA-seq data (N=40), and 4) a spatial validation cohort (N=5) consisting of annotated histology slides of patients with either GC or advanced GIM. We used a multi-omics pipeline to identify, validate and sequentially parse a highly-refined signature of 26 genes which characterize high-risk GIM.

Results

Using standard RNA-seq, we analyzed two separate, non-overlapping discovery (N=88) and validation (N=215) sets of GIM. In the discovery phase, we identified 105 upregulated genes specific for high-risk GIM (defined as OLGIM III-IV), of which 100 genes were independently confirmed in the validation set. Spatial transcriptomic profiling revealed 36 of these 100 genes to be expressed in metaplastic foci in GIM. Comparison with bulk GC sequencing data revealed 26 of these genes to be expressed in intestinal-type GC. Single-cell profiling resolved the 26-gene signature to both mature intestinal lineages (goblet cells, enterocytes) and immature intestinal lineages (stem-like cells). A subset of these genes was further validated using single-molecule multiplex fluorescencein situhybridization. We found certain genes (TFF3andANPEP) to mark differentiated intestinal lineages, whereas others (OLFM4andCPS1) localized to immature cells in the isthmic/crypt region of metaplastic glands, consistent with the findings from scRNAseq analysis.

Conclusions

using an integrated multi-omics approach, we identified a novel 26-gene expression signature for high-OLGIM precursors at increased risk for GC. We found this signature localizes to aberrant intestinal stem-like cells within the metaplastic microenvironment. These findings hold important translational significance for future prevention and early detection efforts.
Inhibitory tagging both speeds and strengthens saccade target selection in the superior colliculus during visual search
Authors: Conroy Christopher , Nanjappa Rakesh , McPeek Robert M.
Published: September 2023

It has been suggested that, during difficult visual search tasks involving time pressure and multiple saccades, inhibitory tagging helps to facilitate efficient saccade target selection by reducing responses to objects in the scene once they have been searched and rejected. The superior colliculus (SC) is a midbrain structure involved in target selection, and recent findings suggest an influence of inhibitory tagging on SC activity. Precisely how, and by how much, inhibitory tagging influences target selection by SC neurons, however, is unclear. The purpose of this study, therefore, was to characterize and quantify the influence of inhibitory tagging on target selection in the SC. Rhesus monkeys performed a visual search task involving time pressure and multiple saccades. Early in the fixation period between saccades, a subset of SC neurons reliably discriminated the stimulus selected as the next saccade goal, consistent with a role in target selection. Discrimination occurred earlier and was more robust, however, when unselected stimuli in the search array had been previously fixated on the same trial. This indicates that inhibitory tagging both speeds and strengthens saccade target selection in the SC during multisaccade search. The results provide constraints on models of target selection based on SC activity.

NEW AND NOTEWORTHY

An important aspect of efficient behavior during difficult, time-limited visual search tasks is the efficient selection of sequential saccade targets. Inhibitory tagging, i.e., a reduction of neural activity associated with previously fixated objects, may help to facilitate such efficient selection by modulating the selection process in the superior colliculus (SC). In this study, we characterized and quantified this modulation and found that, indeed, inhibitory tagging both speeds and strengthens target selection in the SC.
Circulating Platelets Modulate Oligodendrocyte Progenitor Cell Differentiation During Remyelination
Authors: Philp Amber R. , Reyes Carolina R. , Mansilla Josselyne , Sharma Amar , Zhao Chao , Valenzuela-Krugmann Carlos , Rawji Khalil S. , Gonzalez Martinez Ginez A. , Dimas Penelope , Hinrichsen Bryan , Ulloa-Leal César , Waller Amie K. , Bessa de Sousa Diana M. , Castro Maite A. , Aigner Ludwig , Ehrenfeld Pamela , Silva Maria Elena , Kazanis Ilias , Ghevaert Cedric , Franklin Robin J.M. , Rivera Francisco J.
Published: September 2023

Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiationin vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (CALRHET), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.
Ageing-related defects in macrophage function are driven byMYCandUSF1transcriptional programmes
Authors: Moss Charlotte E. , Johnston Simon , Clements Martha , Codd Veryan , Hamby Stephen , Goodall Alison H. , Deshmukh Sumeet , Sudbery Ian , Coca Daniel , Wilson Heather L. , Kiss-Toth Endre
Published: September 2023

Macrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age-related immunity changes remain poorly understood, particularly in human macrophages. We report a substantial reduction in phagocytosis, migration and chemotaxis in human monocyte-derived macrophages (MDMs) from older (>50 years) compared with younger (18-30 years) donors, alongside downregulation of transcription factorsMYCandUSF1with age. In MDMs from young donors, knockdown ofMYCorUSF1decreased phagocytosis and chemotaxis and altered expression of genes associated with these functions, as well as adhesion and extracellular matrix remodelling. A concordant dysregulation ofMYCandUSF1target genes was also seen in MDMs from older donors. Furthermore, older age and loss of eitherMYCorUSF1in MDMs led to an increased cell size, altered morphology and reduced actin content. Together, these results defineMYCandUSF1as key drivers of MDM age-related functional decline and identify downstream targets to improve macrophage function in ageing.
Theta mediated dynamics of human hippocampal-neocortical learning systems in memory formation and retrieval
Authors: Gattas Sandra , Larson Myra Sarai , Mnatsakanyan Lilit , Sen-Gupta Indranil , Vadera Sumeet , Swindlehurst Lee , Rapp Paul E. , Lin Jack J. , Yassa Michael A.
Published: September 2023

Episodic memory arises as a function of dynamic interactions between the hippocampus and the neocortex, yet the mechanisms have remained elusive. Here, using human intracranial recordings during a mnemonic discrimination task, we report that 4-5 Hz (theta) power is differentially recruited during discrimination vs. overgeneralization, and its phase supports hippocampal-neocortical when memories are being formed and correctly retrieved. Interactions were largely bidirectional, with small but significant net directional biases; a hippocampus-to-neocortex bias during acquisition of new information that was subsequently correctly discriminated, and a neocortex-to-hippocampus bias during accurate discrimination of new stimuli from similar previously learned stimuli. The 4-5 Hz rhythm may facilitate the initial stages of information acquisition by neocortex during learning and the recall of stored information from cortex during retrieval. Future work should further probe these dynamics across different types of tasks and stimuli and computational models may need to be expanded accordingly to accommodate these findings.
Molecular and phylogenetic characterization of the monkeypox outbreak in the South of Spain
Authors: Casimiro-Soriguer Carlos S. , Perez-Florido Javier , Lara Maria , Camacho-Martinez Pedro , Merino-Diaz Laura , Pupo-Ledo Inmaculada , de Salazar Adolfo , Fuentes Ana , Viñuela Laura , Chueca Natalia , Martinez-Martinez Luis , Lorusso Nicola ,   The Andalusian genomic surveillance network, Lepe Jose A , Dopazo Joaquín , Garcia Federico
Published: September 2023

Until the May 2022 Monkeypox outbreak, which spread rapidly to many non-endemic countries, the virus was considered a viral zoonosis limited to some African countries. The Andalusian circuit of genomic surveillance was rapidly applied to characterize the Monkeypox outbreak in the South of Spain. Whole genome sequencing was used to obtain the genomic profiles of samples collected across the south of Spain, representative of all the provinces of Andalusia. Phylogenetic analysis was used to study the relationship of the isolates and the available sequences of the 2022 outbreak. Whole genome sequencing of a total of 160 monkeypox viruses from the different provinces that reported cases were obtained. Interestingly, we report the sequences of monkeypox viruses obtained from two patients who died. While one of the isolates bore no noteworthy mutations that explain a potential heightened virulence, in another patient the second consecutive genome sequence, performed after the administration of tecovirimat, uncovered a mutation within the A0A7H0DN30 gene, known to be a prime target for tecovirimat in its Vaccinia counterpart. In general, a low number of mutations were observed in the sequences reported, which were very similar to the reference of the 2022 outbreak (OX044336), as expected from a DNA virus. The samples likely correspond to several introductions of the circulating monkeypox viruses from the last outbreak. The virus sequenced from one of the two patients that died presented a mutation in a gene that bears potential connections to drug resistance. This mutation was absent in the initial sequencing prior to treatment.
DEAD box RNA helicase 5 is a new pro-viral host factor for Sindbis virus infection
Authors: Messmer Mélanie , Pierson Louison , Pasquier Charline , Djordjevic Nikola , Chicher Johana , Hammann Philippe , Pfeffer Sébastien , Girardi Erika
Published: September 2023

Background

RNA helicases are emerging as key factors regulating host-virus interactions. The DEAD-box ATP-dependent RNA helicase DDX5, which plays an important role in many aspects of cellular RNA biology, was also found to either promote or inhibit viral replication upon infection with several RNA viruses. Here, our aim is to examine the impact of DDX5 on Sindbis virus (SINV) infection.

Methods

We analysed the interaction between DDX5 and the viral RNA using imaging and RNA-immunoprecipitation approaches. The interactome of DDX5 in mock- and SINV-infected cells was determined by mass spectrometry. We validated the interaction with DDX17 and the viral capsid by co-immunoprecipitation in the presence or absence of an RNase treatment. We determined the subcellular localization of DDX5, its cofactor DDX17 and the viral capsid protein by co-immunofluorescence. Finally, we investigated the impact of DDX5 depletion and overexpression on SINV infection at the viral protein, RNA and infectious particle accumulation level. The contribution of DDX17 was also tested by knockdown experiments.

Results

In this study we demonstrate that DDX5 interacts with the SINV RNA during infection. Furthermore, the proteomic analysis of the DDX5 interactome in mock and SINV-infected HCT116 cells identified new cellular and viral partners and confirmed the interaction between DDX5 and DDX17. Both DDX5 and DDX17 re-localize from the nucleus to the cytoplasm upon SINV infection and interact with the viral capsid protein. We also show that DDX5 depletion negatively impacts the viral replication cycle, while its overexpression has a pro-viral effect. Finally, we observed that DDX17 depletion reduces SINV infection, an effect which is even more pronounced in a DDX5-depleted background, suggesting a synergistic pro-viral effect of the DDX5 and DDX17 proteins on SINV.

Conclusions

These results not only shed light on DDX5 as a novel and important host factor to the SINV life cycle, but also expand our understanding of the roles played by DDX5 and DDX17 as regulators of viral infections.
Multiple Intermediates in the Detergent-Induced Fusion of Lipid Vesicles
Authors: Dresser Lara G. , Kunstmann-Olsen Casper , Conteduca Donato , Hofmair Christopher M. , Smith Nathan , Clark Laura , Johnson Steven , Penedo J. Carlos , Leake Mark C. , Quinn Steven D.
Published: September 2023

Detergent-induced vesicle interactions, critical for applications including virus inactivation, varies according to the detergent type and membrane composition, but the underlying mechanistic details remain underexplored. Here, we use a lipid mixing assay based on Förster resonance energy transfer (FRET), and single-vesicle characterization approaches to identify that sub-micron sized vesicles are induced to fuse by the non-ionic detergent Triton-X 100. We demonstrate that the process is a multi-step mechanism, characterized by discrete values of FRET efficiency between membrane-embedded fluorophores, and involves permeabilization, vesicle docking, hemi-fusion and full lipid mixing at sub-solubilizing detergent concentrations. We also dissect the kinetics of vesicle fusion to surface-tethered vesicles using a label-free quartz-crystal microbalance with dissipation monitoring approach, opening a platform for biotechnology applications. The presented strategies provide mechanistic insight into the dynamics of vesicle fusion and have implications for applications including drug delivery and sensor development where transport and manipulation of encapsulated cargo is essential.
Phenformin’s impact on lifespan inC. elegansis resilient to environmental factors that inhibit metformin-induced longevity downstream ofskn-1/Nrf and AMP-activated protein kinase
Authors: Li Sainan , Ahsan Fasih , Zhou Yifei , Yerevanian Armen , Soukas Alexander A.
Published: September 2023

Despite being principally prescribed to treat type 2 diabetes, biguanides, especially metformin and phenformin, have been shown to extend lifespan and healthspan in preclinical models, and to reduce the impact of aging-associated diseases such as cancer. While there have been conflicting results in studies involving rodents and humans, consistent evidence from laboratories worldwide, including our own, indicates metformin and phenformin’s ability to significantly extend lifespan inC. elegans. However, the pro-longevity effect of metformin can vary depending on environmental conditions. Specifically, the choice of agar from different manufacturers or batches influences metformin’s ability to extend lifespan inC. elegans. We traced ability of certain agar batches to interfere with metformin-prompted lifespan extension to the presence of a factor that acts directly in the worm, independently of the bacterial food source, that prevents longevity promoting effects downstream of longevity effectorsskn-1and AMPK. In contrast, phenformin prompts robust lifespan extension in the face of environmental changes and exhibits broad positive effects in aging across genetically diverseCaenorhabditisspecies where the impact of metformin is highly variable. Thus metformin effects in aging are impacted by heretofore unappreciated environmental factors. Phenformin may represent a more robust agent with which to understand the longevity promoting mechanisms downstream of biguanides.
Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models
Authors: Dumont Beth L. , Gatti Daniel , Ballinger Mallory A. , Lin Dana , Phifer-Rixey Megan , Sheehan Michael J. , Suzuki Taichi A. , Wooldridge Lydia K. , Opoku Frempong Hilda , Churchill Gary , Lutz Cathleen , Rosenthal Nadia , White Jacqueline K. , Nachman Michael W.
Published: September 2023

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for a century. However, laboratory mice capture a narrow subset of the genetic variation found in wild mouse populations. This consideration inherently restricts the scope of potential discovery in laboratory models and narrows the pool of potentially identified phenotype-associated variants and pathways. Wild mouse populations are reservoirs of predicted functional and disease-associated alleles, but the sparsity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently imported, sequenced, and phenotyped a set of 11 wild-derived inbred strains developed from wild-caughtMus musculus domesticus. Each of these “Nachman strains” immortalizes a unique wild haplotype sampled from five environmentally diverse locations across North and South America: Saratoga Springs, New York, USA; Gainesville, Florida, USA; Manaus, Brazil; Tucson, Arizona, USA; and Edmonton, Alberta, Canada. Whole genome sequence analysis reveals that each strain carries between 4.73-6.54 million single nucleotide differences relative to the mouse reference assembly, with 42.5% of variants in the Nachman strain genomes absent from classical inbred mouse strains. We phenotyped the Nachman strains on a customized pipeline to assess the scope of disease-relevant neurobehavioral, biochemical, physiological, metabolic, and morphological trait variation. The Nachman strains exhibit significant inter-strain variation in >90% of 1119 surveyed traits and expand the range of phenotypic diversity captured in classical inbred strain panels alone. Taken together, our work introduces a novel wild-derived inbred mouse strain resource that will enable new discoveries in basic and preclinical research. These strains are currently available through The Jackson Laboratory Repository under laboratory codeNachJ.
Pateamine A mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs
Authors: Saito Hironori , Handa Yuma , Chen Mingming , Schneider-Poetsch Tilman , Shichino Yuichi , Takahashi Mari , Romo Daniel , Yoshida Minoru , Fürstner Alois , Ito Takuhiro , Fukuzawa Kaori , Iwasaki Shintaro
Published: September 2023

Small-molecule compounds that elicit mRNA-selective translation repression have attracted interest due to their potential for expansion of druggable space. However, only limited examples have been reported to date. Here, we show that pateamine A (PatA) represses translation in an mRNA-selective manner by clamping eIF4A, a DEAD-box RNA-binding protein, on GNG motifs. Through a systematic comparison of multiple eIF4A inhibitors by ribosome profiling, we found that PatA has unique mRNA selectivity in translation repression. Unbiased Bind-n-Seq revealed that PatA-targeted eIF4A exhibits a sequence preference for GNG motifs in an ATP-independent manner. This unusual RNA binding sterically hinders scanning by 40S ribosomes.In silicosimulation, combination of classical molecular dynamics simulation and quantum chemical calculation, and the subsequent development of an inactive PatA derivative revealed that the positive charge of the tertiary amine on the trienyl arm induces G selectivity. Moreover, we identified DDX3, another DEAD-box protein, as an alternative target of PatA, showing the same effect as on eIF4A. Our results provide an example of the sequence-selective anchoring of RNA-binding proteins and mRNA-selective inhibition of protein synthesis by small-molecule compounds.
Comparative transcriptomics of Venus flytrap (Dionaea muscipula) across stages of prey capture and digestion
Authors: Rentsch Jeremy D. , Blanco Summer Rose , Leebens-Mack James H.
Published: September 2023

The Venus flytrap,Dionaea muscipula, is perhaps the world’s best-known botanical carnivore. The act of prey capture and digestion along with its rapidly closing, charismatic traps make this species a compelling model for studying the evolution and fundamental biology of carnivorous plants. There is a growing body of research on the genome, transcriptome, and digestome ofDionaea muscipula, but surprisingly limited information on changes in trap transcript abundance over time since feeding. Here we present the results of a comparative transcriptomics project exploring the transcriptomic changes across seven timepoints in a 72-hour time series of prey digestion and three timepoints directly comparing triggered traps with and without prey items. We document a dynamic response to prey capture including changes in abundance of transcripts with Gene Ontology (GO) annotations related to digestion and nutrient uptake. Comparisons of traps with and without prey documented 174 significantly differentially expressed genes at 1 hour after triggering and 151 genes with significantly different abundances at 24 hours. Approximately 50% of annotated protein-coding genes in Venus flytrap genome exhibit change (10041 of 21135) in transcript abundance following prey capture. Whereas peak abundance for most of these genes was observed within 3 hours, an expression cluster of 3009 genes exhibited continuously increasing abundance over the 72-hour sampling period, and transcript for these genes with GO annotation terms including both catabolism and nutrient transport may continue to accumulate beyond 72 hours.
Spatiotemporal properties of common semantic categories for words and pictures
Authors: Bezsudnova Yulia , Quinn Andrew J. , Jensen Ole
Published: September 2023

The timing of semantic processing during object recognition in the brain is a topic of ongoing discussion. One way of addressing this question is by applying multivariate pattern analysis (MVPA) to human electrophysiological responses to object images of different semantic categories. However, while MVPA can reveal whether neuronal activity patterns are distinct for different stimulus categories, concerns remain on whether low-level visual features also contribute to the classification results. To circumvent this issue, we applied a cross-decoding approach to magnetoencephalography (MEG) data from stimuli from two different modalities: images and their corresponding written words. We employed items for three categories and presented them in a randomized order. We show that If the classifier is trained on words, pictures are classified between 150 - 430 ms from after stimulus onset, and when training on pictures, words are classified between 225 - 430 ms. The topographical map identified using a searchlight approach for cross-modal activation in both directions showed left lateralization confirming the involvement of linguistics representations. These results point to semantic activation of pictorial stimuli occurring at ≈150 ms whereas for words the semantic activation occurs at ≈230 ms.
Phage-induced efflux down-regulation boosts antibiotic efficacy
Authors: Kraus Samuel , Łapińska Urszula , Chawla Krina , Baker Evan , Attrill Erin L , O’Neill Paul , Farbos Audrey , Jeffries Aaron , Galyov Edouard E. , Korbsrisate Sunee , Barnes Kay B. , Harding Sarah V , Tsaneva-Atanasova Krasimira , Blaskovich Mark A T , Pagliara Stefano
Published: September 2023

The interactions between a virus and its host vary in space and time and are affected by the presence of molecules that alter the physiology of either the host or the virus. Determining the molecular mechanisms underpinning these interactions is paramount for predicting the fate of bacterial and phage populations and for designing rational phage-antibiotic therapies. We study the interactions between stationary phaseBurkholderia thailandensisand the phage ΦBp-AMP1. Although heterogeneous genetic resistance to phage rapidly emerges inB. thailandensis, the presence of phage enhances the efficacy of three major antibiotic classes, the quinolones, the beta-lactams and the tetracyclines, but antagonizes tetrahydrofolate synthesis inhibitors. We discovered that enhanced antibiotic efficacy is underpinned by reduced antibiotic efflux in the presence of phage. This new phage-antibiotic therapy allows for eradication of stationary phase bacteria, whilst requiring reduced antibiotic concentrations, which is crucial for treating infections in sites where it is difficult to achieve high antibiotic concentrations.
The gene expression signature of electrical stimulation in the human brain
Authors: Chatterjee Snehajyoti , Vanrobaeys Yann , Gleason Annie I , Park Brian J. , Heiney Shane A. , Rhone Ariane E. , Nourski Kirill V. , Langmack Lucy , Basu Budhaditya , Mukherjee Utsav , Kovach Christopher K. , Kocsis Zsuzsanna , Kikuchi Yukiko , Ayala Yaneri A. , Petkov Christopher I. , Hefti Marco M. , Bahl Ethan , Michaelson Jacob J , Kawasaki Hiroto , Oya Hiroyuki , Howard Matthew A. , Nickl-Jockschat Thomas , Lin Li-Chun , Abel Ted
Published: September 2023

Direct electrical stimulation has been used for decades as a gold standard clinical tool to map cognitive function in neurosurgery patients1–8. However, the molecular impact of electrical stimulation in the human brain is unknown. Here, using state-of-the-art transcriptomic and epigenomic sequencing techniques, we define the molecular changes in bulk tissue and at the single-cell level in the human cerebral cortex following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Direct electrical stimulation surprisingly had a robust and consistent impact on the expression of genes related to microglia-specific cytokine activity, an effect that was replicated in mice. Using a newly developed deep learning computational tool, we further demonstrate cell type-specific molecular activation, which underscores the effects of electrical stimulation on gene expression in microglia. Taken together, this work challenges the notion that the immediate impact of electrical stimulation commonly used in the clinic has a primary effect on neuronal gene expression and reveals that microglia robustly respond to electrical stimulation, thus enabling these non-neuronal cells to sculpt and shape the activity of neuronal circuits in the human brain.
MolPhase: An Advanced Phase Separation Predictor and an Investigation of Phytobacterial Effector in Plant
Authors: Liang Qiyu , Peng Nana , Xie Yi , Kumar Nivedita , Gao Weibo , Miao Yansong
Published: September 2023

We introduce MolPhase (http://molphase.sbs.ntu.edu.sg/), an advanced protein phase separation (PS) prediction algorithm that improves accuracy and reliability by utilizing diverse physicochemical features and extensive experimental datasets. MolPhase applies a user-friendly interface to compare distinct biophysical features side-by-side along protein sequences. By additional comparison with structural predictions, MolPhase enables efficient predictions of new phase-separating proteins and guides hypothesis generation and experimental design. Key contributing factors underlying MolPhase include pi-pi interaction, disorder, and prion-like domain. As an example, MolPhase finds that phytobacterial type III effectors (T3Es) are highly prone to homotypic PS, which was experimentally validatedin vitrobiochemically andin vivoin plants, mimicking their injection and accumulation in the host during microbial infection. In addition, the phase-separation of T3Es were evolved bothin vivoandin vitro, suggesting their determinative scaffolding function, though there is a difference in material properties, implying a difference in homotypic and heterotypic macromolecular condensation. Robust integration of MolPhase’s effective prediction and experimental validation exhibit the potential to evaluate and explore how biomolecule PS functions in biological systems.
Theoretical Considerations and Empirical Predictions of the Pharmaco- and Population Dynamics of Heteroresistance
Authors: Levin Bruce R. , Berryhill Brandon A. , Gil-Gil Teresa , Manuel Joshua A. , Smith Andrew P. , Choby Jacob E. , Andersson Dan I. , Weiss David S. , Baquero Fernando
Published: September 2023

Antibiotics are considered one of the most important contributions to clinical medicine in the last 100 years. Due to the use and overuse of these drugs, there have been increasing frequencies of infections with resistant pathogens. One form of resistance, heteroresistance, is particularly problematic; pathogens appear sensitive to a drug by common susceptibility tests. However, upon exposure to the antibiotic, resistance rapidly ascends, and treatment fails. To quantitatively explore the processes contributing to the emergence and ascent of resistance during treatment and the waning of resistance following cessation of treatment, we develop two distinct mathematical and computer-simulations models of heteroresistance. In our analysis of the properties of these models, we consider the factors that determine the response to antibiotic-mediated selection. In one model, heteroresistance is progressive, with each resistant state sequentially generating a higher resistance level. In the other model, heteroresistance is non-progressive, with a susceptible population directly generating populations with different resistance levels. The conditions where resistance will ascend in the progressive model are narrower than those of the non-progressive model. The rates of reversion from the resistant to the sensitive states are critically dependent on the transition rates and the fitness cost of resistance. Our results demonstrate that the standard test used to identify heteroresistance is insufficient. The predictions of our models are consistent with empirical results. Our results demand a reevaluation of the definition and criteria employed to identify heteroresistance. We recommend the definition of heteroresistance should include a consideration of the rate of return to susceptibility.

Significance Statement

This mathematical modeling and computer-simulation study quantitatively explores two broadly different, previously undescribed, classes of heteroresistance. In our analysis of the properties of these models, we consider the response of heteroresistant populations to antibiotic exposure, focusing on the conditions where heteroresistance could lead to clinical treatment failure. We also provide novel consideration to the rate of reversion from a resistant to sensitive state. Our analysis illustrates the need to include the reversion rate from resistant to sensitive in the definition of heteroresistance and questions the sufficiency of the method currently used to identify heteroresistance.
Functional copy number variation inSQUALENE EPOXIDASE-LIKEgenes affects photosystem II efficiency in Arabidopsis
Authors: van Bezouw Roel F.H.M. , Nguyen Thu-Phuong , Hoang Nam V. , Vincenzi Elena , van Velthoven Rosanne , Zhang Hui , Gao Yanrong , Zhang Wenyan , Jacobi Renze , de Snoo Bastiaan , Marquez Francisca Reyes , Catalá Livia Vazquez , Iqbal Muhammad , Jansen Stan , Mumm Roland , Harbinson Jeremy , Keurentjes Joost J.B. , Aarts Mark G.M.
Published: September 2023

In this study, we found a single quantitative trait locus for photosystem II efficiency (ΦPSII) in the Arabidopsis Ler-0 x Col-0 recombinant inbred line population. This locus on chromosome 5 is caused by genetic variation in a cluster of tandemly repeatedSQUALENE EPOXIDASE-LIKE(SQE-like) genes, with unknown function. We show the QTL is caused by variation in theSQE5,SQE6andSQE7genes affecting ΦPSIIin a dose-dependent manner, due to a combination of functional copies. Col-0 carries only one functional copy,SQE5, while Ler-0 carries functional copies ofSQE6and SQE7. Overexpression of a functional copy ofSQE6enhances ΦPSIIto exceed that of the Ler-0 parent in Arabidopsis, but does not affect ΦPSIIin tobacco. Phylogenetic analysis of theSQEandSQE-likesin 135 plant species revealed that theSQE-likes are evolutionary confined to two sister families, the Cleomaceae and Brassicaceae, and diversified independently. The tandem cluster of fourSQE-likegenes in Arabidopsis is likely the result of two recent gene duplication events, one generatingSQE5fromSQE4, the next one generatingSQE6andSQE7fromSQE5. The involvement ofSQE-likegenes in photosynthesis will open up new avenues to determine the function of these novel genes.
The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity
Authors: Mamar Hasan , Fajka-Boja Roberta , Mórocz Mónika , Jurado Eva Pinto , Zentout Siham , Mihuț Alexandra , Kopasz Anna Georgina , Mérey Mihály , Smith Rebecca , Haracska Lajos , Huet Sébastien , Timinszky Gyula
Published: September 2023

The clinical success of PARP1/2 inhibitors prompts the expansion of their applicability beyond homologous recombination deficiency. Here, we demonstrate that the loss of the accessory subunits of DNA polymerase epsilon, POLE3 and POLE4, sensitizes cells to PARP inhibitors. We show that the sensitivity of POLE4 knockouts is not due to a compromised response to DNA damage or homologous recombination deficiency. Instead, POLE4 deletion generates replication stress with the accumulation of single-stranded DNA gaps upon PARP inhibitor treatment. In POLE4 knockouts, replication stress leads to elevated DNA-PK signaling revealing a role of POLE4 in regulating DNA-PK activation. Moreover, POLE4 knockouts show synergistic sensitivity to the co-inhibition of ATR and PARP. Finally, POLE4 loss enhances the sensitivity of BRCA1-deficient cells to PARP inhibitors and counteracts acquired resistance consecutive to restoration of homologous recombination. Altogether, our findings establish POLE4 as a promising target to improve PARP inhibitor driven therapies and hamper acquired PARP inhibitor resistance.