bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bias assessment and correction for Levin’s population attributable fraction in the presence of confounding
Authors: Ferguson John , Alvarez Alberto , Mulligan Martin , Judge Conor , O’Donnell Martin 
Published: February 2023

AbstractIn 1953, Morton Levin introduced a simple approach to estimating population attributable fractions (PAF) depending only on risk factor prevalence and relative risk. This formula and its extensions are still in widespread use today, particularly to estimate PAF in populations where individual data is unavailable. Unfortunately, Levin’s approach is known to be asymptotically biased for the PAF when the risk factor-disease relationship is confounded even if relative risks that are correctly adjusted for confounding are used in the estimator.An alternative estimator, first introduced by Miettinen in 1972, is unbiased for the PAF provided the true relative risk is invariant across confounder strata. However, despite its statistical superiority, Miettinen’s estimator is seldom used in practice, as its direct application requires an estimate of risk factor prevalence within disease cases rather than an estimate of risk factor prevalence in the general population.Here we describe a simple re-expression of Miettinen’s estimand that depends on the causal relative risk, the unadjusted relative risk and the population risk factor prevalence. While this re-expression is not new, it has been underappreciated in the literature, and the associated estimator may be useful in estimating PAF in populations when individual data is unavailable provided estimated adjusted and unadjusted relative risks can be transported to the population of interest. Using the re-expressed estimand, we develop novel analytic formulae for the relative and absolute asymptotic bias in Levin’s formula, solidifying earlier work by Darrow and Steenland that used simulations to investigate this bias. We extend all results to settings with non-binary valued risk factors and continuous exposures and discuss the utility of these results in estimating PAF in practice.
Epoxyeicosatrienoic acids and sEH inhibition prevent cardiac dysfunction in CVB3-induced myocarditis by positively regulating type I interferon signaling
Authors: Zhou Zhou , Zhang Min , Zhao Chengcheng , Gao Xu , Wen Zheng , Wu Junfang , Chen Chen , Hu Jiong , Fleming Ingrid , Wang Dao Wen 
Published: February 2023

AbstractMyocarditis is a challenging inflammatory disease of the heart and better understanding of its etiology is needed to develop specific drug therapies. Epoxyeicosatrienoic acids (EETs), active molecules synthesized by cytochrome P450 enzymes from arachidonic acids and hydrolyzed to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), have been attributed anti-inflammatory activity. Here, we investigated whether EETs have immunomodulatory activity and exert protective effects on coxsackie B3 virus (CVB3)-induced myocarditis. Viral infection altered eicosanoid epoxide and diol levels in both patients with myocarditis and, in the murine heart, and correlated with the increased expression and activity of the sEH after CVB3 infection. Administration of a sEH inhibitor prevented CVB3-induced cardiac dysfunction and inflammatory infiltration. Importantly, EET/sEH inhibitor treatment attenuated vial infection/ improved viral resistance by activating type I interferon (IFN) signaling. At the molecular level, EETs enhanced the interaction between glycogen synthase kinase 3β (GSK3β) and TANK-binding kinase 1 (TBK1) to promote IFN-β production. Our findings revealed that EETs and sEH inhibitors prevent the progress of CVB3-induced myocarditis, particularly by promoting viral resistance by increasing IFN production.
Algorithmic Virtual Reality Reduces Parkinsonian Tremor
Authors: Cornacchioli John , Galambos Alec , Rentouli Stamatina , Canciello Robert , Marongiu Roberta , Cabrera Daniel , Njie eMalick G. 
Published: February 2023

AbstractParkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders, affecting approximately 6-7 million patients worldwide. Involuntary hand tremor (IHT), one of the cardinal motor symptoms of PD, is extremely debilitating to patients reducing their quality of life. In this study, we combined neuroscience together with the nascent field of medical virtual reality (VR). Our goals were to 1) generate technology to enable PD patients to leapfrog the real life difficulties of living with IHT by entering VR metaverse worlds in which they are tremor-free and can function at new heights, 2) to determine whether lack of tremors in VR modifies central biofeedback mechanisms to non-invasively reduce tremors in real life. We thus generated algorithms that adjusted the moving average centroid of digital hands to stabilize tremors in VR. We implemented these algorithms in the Oculus Rift VR system and enrolled nine subjects with PD in a trial that yielded several important observations. First, we established the Oculus Rift as a potent measurement device for IHT. Secondly, we determined parkinsonian tremors can be abolished in VR with algorithms that removed up to 99% of tremors from PD subjects’ digital hands (76% average reduction). These data suggest PD subjects can enter VR and be asymptomatic of PD IHT. To test whether our algorithms have measurable practical utility, we created a VR painting application, FingerPaint, and tested it against TiltBrush the leading VR painting application. We empirically demonstrate that complex freeform art created in FingerPaint had up to 51% reduction in tremor-associated parkinsonian drawing irregularities (24% average reduction). Lastly, we generated a technical framework wherein movements in the real-world can be measured side-by-side with those in VR. With this framework, we observed real life parkinsonian tremors were significantly reduced by up to 87% in real life when our algorithms abolished digital hand tremors in VR (35% average reduction). This reduction was observed in 78% of subjects and was progressive as subjects had increasingly reduced real life tremors the longer they were in VR.
Bioinformatic analysis of the spike protein cleavage sites of coronaviruses in the mammalian order Eulipotyphla
Authors: Guo Qinghua , Choi Annette , Millet Jean K. , Whittaker Gary R. 
Published: February 2023

AbstractThe mammalian order Eulipotyphla, including hedgehogs and shrews, represent a poorly understood reservoir of coronaviruses with zoonotic potential. Here, we carried out a bioinformatic analyses of these viruses based on the viral spike protein—to illustrate the complexity of coronavirus evolutionary history and the diversity of viruses from these host species, with a focus on the presence of possible furin cleavage sites within the spike protein. We found no evidence for cleavage by furin itself; however, certain strains of Wencheng Sm Shrew coronavirus were shown to have a predicted cleavage site for other member of the proprotein convertases, which are furin family members— suggesting their spillover potential. As the expanding urbanization and the trade of small mammals in the wet markets enhance the wildlife-human interactions, this may increase pathogen spillover risks. Therefore, we should implement broad wild animal surveillance and be vigilant of contact with these small wild mammals in light of one-health perspectives.
DLKcat cannot predict meaningfulkcatvalues for mutants and unfamiliar enzymes
Authors: Kroll Alexander , Lercher Martin J. 
Published: February 2023

AbstractThe recently published DLKcat model, a deep learning approach for predicting enzyme turnover numbers (kcat), claims to enable high-throughput kcat predictions for metabolic enzymes from any organism and to capturekcatchanges for mutated enzymes. Here, we critically evaluate these claims. We show that DLKcat predictions become positively misleading for enzymes with less than 60% sequence identity to the training data, performing worse than simply assuming a meankcatvalue for all reactions. Furthermore, DLKcat’s ability to predict mutation effects is much weaker than implied, capturing only 3% of the experimentally observed variation across mutants not included in the training data. These findings highlight significant limitations in DLKcat’s generalizability and its practical utility for predictingkcatvalues for novel enzyme families or mutants, which are crucial applications in fields such as metabolic modeling.
Body size-dependent effects on the distribution patterns of phoretic mites of the multi-symbiontRhynchophorus ferrugineus(Olivier, 1790) host
Authors: Matos Inês , Silva Diogo , Oliveira João , Gonçalves Claúdia , Alves Rita , Pereira Nuno , Catarino Francisco , Ameixa Olga M. C. C. , Sousa José Américo , Rangel Luis Filipe , Santos Maria João , Ayra-Pardo Camilo 
Published: February 2023

AbstractPhoretic mites have been found attached to different body parts of the red palm weevil (RPW),Rhynchophorus ferrugineus(Olivier, 1790), to disperse. However, the question of how the patterns of attachment sites are formed remains intriguing. Here, we conducted the first study of RPW-associated phoretic mites in Portugal, particularly in the districts of Viana do Castelo, Braga, Porto and Aveiro in Northern Portugal (macrohabitat), and investigated the patterns of mite distribution on six body parts of RPW (microhabitat). At the macrohabitat level, we detected seven phoretic mite taxa actively using the RPW host in each of the four studied districts, all documented for the first time in association with this invasive exotic species in Portugal. However, their relative abundance (species evenness) varied between districts, as did species diversity. All examined weevils carried mites, and the prevalence of the different taxa did not differ between districts or sex of weevils. Measured by mean abundance and degree of aggregation,Centrouropodasp. proved to be the common dominant taxon, whileAcarussp. AndC. rhynchoporuswere considered common subordinate taxa andUroovobellasp., Mesostigmata,N. extremicaandDendrolaelapssp. sparse taxa. At the microhabitat level, all taxa were present in all body parts of the RPW; the highest abundance was in a region encompassing the inner surface of the elytra and the membranous hind wings (subelytral space). Analysis of niche overlap revealed that the distribution patterns of phoretic mite taxa on the RPW were not randomly structured. In the subelytral space, interspecific coexistence of mites increased as a function of body size difference with the dominantCentrouropodasp. We conclude that the distribution patterns of RPW-associated phoretic mites show body size-dependent effects that resulted in the dominant taxon displacing similar size taxa and accepting taxa with which it has the greatest size difference as co-habitants.
Flexible visual learning and memory in nectar foraging hornets
Authors: Lacombrade Mathilde , Bajo Monica Doblas , Rocher Naïs , Navarro Emmanuel , Lubat Christian , Vogelweith Fanny , Thiéry Denis , Lihoreau Mathieu 
Published: February 2023

AbstractPollinators, such as bees, develop flexible memories of colours, patterns and shapes, for efficient flower recognition. Here we tested whether other insects facing the same foraging problem have evolved similar cognitive abilities for flexible learning. We trained wild hornets from two species commonly found in Europe (Vespa velutina nigrithoraxandVespa crabro) to associate sucrose solution rewards to colour stimuli in a Y maze. Hornets of both species succeeded in differential and reversal learning, and developed short and long-term memories of the learnt associations. Thus, just like bees, hornet foragers can learn various visual cue-reward associations and remember them over several hours or days for selecting flowers. Our study in non-model species illustrates how standard conditioning approaches can be used to explore and compare the cognitive abilities of animals with similar foraging ecology.
Comparative Transcriptomics and Genomics from Continuous Axenic Media Growth IdentifiesCoxiella burnetiiIntracellular Survival Strategies
Authors: Yadav Archana , Brewer Melissa N. , Elshahed Mostafa S. , Shaw Edward I. 
Published: February 2023

AbstractCoxiella burnetii(Cb) is an obligate intracellular pathogen in nature and the causative agent of acute Q fever as well as chronic diseases. In an effort to identify genes and proteins crucial to their normal intracellular growth lifestyle, we applied a “Reverse evolution” approach where the avirulent Nine Mile Phase II strain of Cb was grown for 67 passages in chemically defined ACCM-D media and gene expression patterns and genome integrity from various passages was compared to passage number one following intracellular growth. Transcriptomic analysis identified a marked downregulation of the structural components of the type 4B secretion system (T4BSS), the general secretory (sec) pathway, as well as 14 out of 118 previously identified genes encoding effector proteins. Additional downregulated pathogenicity determinants genes included several chaperones, LPS, and peptidoglycan biosynthesis. A general marked downregulation of central metabolic pathways was also observed, which was balanced by a marked upregulation of genes encoding transporters. This pattern reflected the richness of the media and diminishing anabolic and ATP-generation needs. Finally, genomic sequencing and comparative genomic analysis demonstrated an extremely low level of mutation across passages, despite the observed Cb gene expression changes following acclimation to axenic media.
H3K27me3 dictates atypical genome-nuclear lamina interactions and allelic asymmetry during early embryogenesis
Authors: Guerreiro Isabel , Rang Franka J. , Kawamura Yumiko K. , Groenveld Femke C. , Beek Ramada E. van , Lochs Silke J. A. , Boele Ellen , Peters Antoine H. M. F. , Kind Jop 
Published: February 2023

AbstractThe very first days of mammalian embryonic development are accompanied by epigenetic reprogramming and extensive changes in nuclear organization. In particular, genomic regions located at the periphery of the nucleus, termed lamina-associated domains (LADs), undergo major rearrangements after fertilization. However, the role of LADs in regulating gene expression as well as the interplay with various chromatin marks during preimplantation development remains elusive. In this study, we obtained single-cell LAD profiles coupled with the corresponding gene expression readout throughout the first days of mouse development. We detect extensive cell-cell LAD variability at the 2-cell stage, which surprisingly does not seem to functionally affect gene expression. This suggests an unusual uncoupling between 3D-nuclear genome organization and gene expression during totipotent developmental stages. By analyzing LAD dynamics and chromatin states across early developmental stages in an allelic-specific manner, we identify genomic regions that transiently detach from the nuclear lamina and are enriched by non-canonical H3K27me3. Upon maternal knock-out of a component of the Polycomb repressive complex 2 and concomitant loss of H3K27me3 during early embryogenesis, these regions relocate to the lamina at the 2-cell stage. Our results suggest that H3K27me3 is the prime determinant in establishing the atypical distribution of the genome at the nuclear periphery during the first days of embryonic development. This study provides insight into the molecular mechanisms regulating nuclear organization of parental genomes during very early mammalian development.
A deep-learning driven investigation of circuit basis for reflexive hypersensitivity to pain
Authors: Reddy Prannay , Vasudeva Jayesh , Shah Devanshi , Prajapati Jagat Narayan , Harikumar Nikhila , Barik Arnab 
Published: February 2023

AbstractObjectively measuring animal behavior is key to understanding the neural circuits underlying pain. Recent progress in machine vision has presented us with unprecedented scope in behavioral analysis. Here, we apply DeeplabCut (DLC) to dissect mouse behavior on the thermal-plate test — a commonly used paradigm to ascertain supraspinal contributions to noxious thermal sensation and pain hypersensitivity. We determine the signature characteristics of the pattern of mouse movement and posture in 3D in response to a range of temperatures from innocuous to noxious on the thermal-plate test. Next, we test how acute chemical and chronic inflammatory injuries sensitize mouse behaviors. Repeated exposure to noxious temperatures on the thermal-plate can induce learning, and in this study, we design a novel assay and formulate an analytical pipeline that will facilitate the dissection of plasticity mechanisms in pain circuits in the brain. Last, we record and test how activating Tacr1 expressing PBN neurons — a population responsive to sustained noxious stimuli-affects mouse behavior on the thermal plate test. Taken together, we demonstrate that by tracking a single body part of a mouse, we can reveal the behavioral signatures of mice exposed to noxious surface temperatures, report the alterations of the same when injured, and determine if a molecularly and anatomically defined pain responsive circuit plays a role in the reflexive hypersensitivity to thermal pain.
Cell-specific and shared enhancers control a high-density multi-gene locus active in mammary and salivary glands
Authors: Lee Hye Kyung , Willi Michaela , Liu Chengyu , Hennighausen Lothar 
Published: February 2023

AbstractRegulation of high-density loci harboring genes with different cell-specificities remains a puzzle. Here we investigate a locus that evolved through gene duplication1and contains eight genes and 20 candidate regulatory elements, including a super-enhancer. Five genes are expressed in mammary glands and account for 50% of all mRNAs during lactation, two are salivary-specific and one has dual specificity. We probed the function of eight candidate enhancers through experimental mouse genetics. Deletion of the super-enhancer led to a 98% reduced expression ofCsn3andFdcspin mammary and salivary glands, respectively, and Odam expression was abolished in both tissues. The other three casein genes were only marginally affected. Notably, super-enhancer activity requires the additional presence of a distalCsn3-specific enhancer. Our work identifies an evolutionary playground on which regulatory duality of a multigene locus was attained through an ancestral super-enhancer active in mammary and salivary tissue and gene-specific mammary enhancers.
A cytokine-responsive promoter is required for distal enhancer function mediating the hundreds-fold increase in milk protein gene expression during lactation
Authors: Lee Hye Kyung , Liu Chengyu , Hennighausen Lothar 
Published: February 2023

AbstractDuring lactation, specialized cells in the mammary gland produce milk to nourish the young. Milk protein genes are controlled by distal enhancers activating expression several hundred-fold during lactation. However, the role of promoter elements is not understood. We addressed this issue using theCsn2gene, which accounts for 10% of mRNA in mammary tissue. We identified STAT5 and other mammary transcription factors binding to three distal candidate enhancers and a cytokine-response promoter element. While deletion of the enhancers or the introduction of an inactivating mutation in a single promoter element had a marginable effect, their combined loss led to a 99.99% reduction ofCsn2expression. Our findings reveal the essential role of a promoter element in the exceptional activation of a milk protein gene and highlight the importance of analyzing regulatory elements in their native genomic context to fully understand the multifaceted functions of enhancer clusters and promoters.
Speeding up interval estimation forR2-based mediation effect of high-dimensional mediators via cross-fitting
Authors: Xu Zhichao , Li Chunlin , Chi Sunyi , Yang Tianzhong , Wei Peng 
Published: February 2023

AbstractMediation analysis is a useful tool in investigating how molecular phenotypes such as gene expression mediate the effect of exposure on health outcomes. However, commonly used mean-based total mediation effect measures may suffer from cancellation of component-wise mediation effects in opposite directions in the presence of high-dimensional omics mediators. To overcome this limitation, we recently proposed a variance-based R-squared total mediation effect measure that relies on the computationally intensive nonparametric bootstrap for confidence interval estimation. In the work described herein, we formulated a more efficient two-stage, cross-fitted estimation procedure for theR2measure. To avoid potential bias, we performed iterative Sure Independence Screening (iSIS) in two subsamples to exclude the non-mediators, followed by ordinary least squares regressions for the variance estimation. We then constructed confidence intervals based on the newly derived closed-form asymptotic distribution of theR2measure. Extensive simulation studies demonstrated that this proposed procedure is much more computationally efficient than the resampling-based method, with comparable coverage probability. Furthermore, when applied to the Framingham Heart Study, the proposed method replicated the established finding of gene expression mediating age-related variation in systolic blood pressure and identified the role of gene expression profiles in the relationship between sex and high-density lipoprotein cholesterol level. The proposed estimation procedure is implemented in R packageCFR2M.
Vaginal bacteria elicit acute inflammatory response in fallopian tube organoids: a model for pelvic inflammatory disease
Authors: Yu Bo , Nguyen Edward B. , McCartney Stephen , Strenk Susan , Valint Daniel , Liu Congzhou , Haggerty Catherine , Fredricks David N. 
Published: February 2023

ABSTRACTObjectiveTo facilitatein vitromechanistic studies in pelvic inflammatory disease (PID) and subsequent tubal factor infertility, as well as ovarian carcinogenesis, we sought to establish patient tissue derived fallopian tube (FT) organoids and to study their inflammatory response to acute vaginal bacterial infection.DesignExperimental study.SettingAcademic medical and research center.PatientsFT tissues were obtained from four patients after salpingectomy for benign gynecological diseases.InterventionsWe introduced acute infection in the FT organoid culture system by inoculating the organoid culture media with two common vaginal bacterial species,Lactobacillus crispatusandFannyhessea vaginae.Main Outcome MeasuresThe inflammatory response elicited in the organoids after acute bacterial infection was analyzed by the expression profile of 249 inflammatory genes.ResultsCompared to the negative controls that were not cultured with any bacteria, the organoids cultured with either bacterial species showed multiple differentially expressed inflammatory genes. Marked differences were noted between theLactobacillus crispatusinfected organoids and those infected byFannyhessea vaginae. Genes from the C-X-C motif chemokine ligand (CXCL) family were highly upregulated inF. vaginaeinfected organoids. Flow cytometry showed that immune cells quickly disappeared during the organoid culture, indicating the inflammatory response observed with bacterial culture was generated by the epithelial cells in the organoids.ConclusionPatient tissue derived FT organoids respond to acute bacterial infection with upregulation of inflammatory genes specific to different vaginal bacterial species. FT organoids is a useful model system to study the host-pathogen interaction during bacterial infection which may facilitate mechanistic investigations in PID and its contribution to tubal factor infertility and ovarian carcinogensis.