bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer cells communicate with macrophages to prevent T cell activation during development of cell cycle therapy resistance
Authors: Griffiths Jason I. , Cosgrove Patrick A. , Castaneda Eric Medina , Nath Aritro , Chen Jinfeng , Adler Frederick R. , Chang Jeffrey T. , Khan Qamar J. , Bild Andrea H.
Published: September 2022

Cancer cells evolve, acquire resistance to therapy and change their environment. One resistance mechanism involves altering communication with non-malignant cells in the tumor microenvironment (TME). By corrupting the signals for growth and survival, evolving cancer cells can engineer a pro-tumor TME. However, the specific interactions between malignant and non-malignant cells that predispose drug resistance and their changes during treatment remain widely unknown. Here we examine the composition, communication, and phenotypic diversity of tumor-associated cell populations in serial biopsies from early-stage ER+ breast cancers. These patients received either endocrine therapy (letrozole) alone or in combination with a CDK4/6 cell cycle inhibitor ribociclib, and were analyzed using single-cell RNA sequencing (scRNAseq). Our analyses reveal cancer cells from ribociclib resistant tumors stimulate macrophage differentiation towards an immune-suppressive phenotype through upregulation of a broad diversity of cytokines and growth factors. This shift in phenotype leads to reduced macrophage cell IL-15/-18 crosstalk with CD8+ T-cell via IL-2/15RA/18R receptors, resulting in diminished T-cell activation and recruitment. Thus, cancer communication promoting an immune-cold TME predispose tumors to develop CDK4/6 inhibitor resistance, and that the beneficial effects of cell cycle inhibitors through blocking cancer cell proliferation must be balanced against their known inhibitory effect on immune cell division and activation. An optimal treatment strategy will require coupling the prevention of cancer division with activation of an effective cytotoxic T-cell response.
When complex movement yields simple dispersal: behavioural heterogeneity, spatial spread and parasitism in groups of micro-wasps
Authors: Burte Victor , Cointe Melina , Perez Guy , Mailleret Ludovic , Calcagno Vincent
Published: September 2022

Understanding how behavioural dynamics, inter-individual variability and individual interactions scale-up to shape the spatial spread and dispersal of animal populations is a major challenge in ecology. For biocontrol agents, such as the microscopic Trichogramma parasitic wasps, an understanding of movement strategies is also critical to predict pest-suppression performance in the field.

We experimentally studied the spatial propagation of groups of parasitoids and their patterns of parasitism. We investigated whether population spread is density-dependent, how it is affected by the presence of hosts, and whether the spatial distribution of parasitism (dispersal kernel) can be predicted from the observed spread of individuals.

Using a novel experimental device and high-throughput imaging techniques, we continuously tracked the spatial spread of groups of parasitoids over large temporal and spatial scales (eight hours; and six metres, ca. 12,000 body lengths). We could thus study how population density, the presence of hosts and their spatial distribution impacted the rate of population spread, the spatial distribution of individuals during population expansion, the overall rate of parasitism and the dispersal kernel (position of parasitism events).

Higher population density accelerated population spread, but only transiently: the rate of spread reverted to low values after four hours, in a “tortoise-hare” effect. Interestingly, the presence of hosts suppressed this transiency and permitted a sustained high rate of population spread. Importantly, we found that population spread did not obey classical diffusion, but involved dynamical switches between resident and explorer movement modes. Population distribution was therefore not Gaussian, though surprisingly the distribution of parasitism (dispersal kernel) was.

Even homogenous asexual groups of animals were shown to develop behavioral heterogeneties over a few hours. Explorer individuals were responsible for most parasitism and dispersal, and determined spatial spread and density-dependent dispersal. We showed that simple Gaussian dispersal did not emerge from simple diffusion, but rather from the interplay of several non-linearities at individual level. This suggests expectations from classical diffusion theory may not hold generally to active dispersers. These results highlight the need to take into account behaviour and inter-individual heterogeneity to understand population spread in animals.
Dual-Coil Transcranial Magnetic Stimulation Reveals Temporal Dynamics of Bilateral Corticomotor Excitability During Response Inhibition
Authors: Ratcliffe Chantelle E. , McAllister Craig J. , MacDonald Hayley J.
Published: September 2022

A changing environment may suddenly require some parts of a multi-component response to be cancelled, while others continue. Such partial cancellation consistently produces a behavioural delay in the remaining component. This delay may reflect a three-step process of non-selective neural inhibition of all response components, functional uncoupling of components, and selective initiation of the remaining response. However, most neurophysiological evidence supporting this hypothesis has been recorded from muscles of a single hand, without direct comparison between response components. We aimed to simultaneously record - and therefore directly compare - corticomotor excitability (CME) in the cancelled and responding hands using a dual-coil technique not yet applied in this context. Human participants received transcranial magnetic stimulation to both primary motor cortices 1ms apart while performing a bimanual response inhibition task. Motor evoked potentials (MEPs) were recorded from both first dorsal interosseous (FDI) muscles as a measure of CME during partial cancellation. An equivalent reduction in CME was evident for both the responding and cancelled FDI muscles 175 ms after the stop cue during successful partial cancellation. The responding FDI subsequently exhibited an increase in CME above levels in the cancelled hand, leading to the unimanual response. This study reveals, for the first time, the temporal dynamics of CME for both response components simultaneously during a bimanual response inhibition task. Our results provide strong evidence that neural modulation during sudden partial cancellation can be viewed in light of the stop-change framework as a sequential non-selective stop, uncouple and switch, then selectively go process.
Differences in self-reported benefits for student-artist versus faculty experiences in a virtual artist-in-residence program
Authors: Cuevas Skylar , Liu Qi (Kathy) , Qian Helen , Joffe Max E. , Calvitti Karisa , Schladt Megan , Skaar Eric P. , Oliver Kendra H.
Published: September 2022

The value of science communication in engaging the public has been well established. While many new programs bridge the arts and sciences, conducting comprehensive examination of exiting art-science programs can produce more efficient training and program development guidance for improving visual communications in the sciences. Here, we recruited a variety of scientists and artists to collaborate in creating visual science communication products over three summers. Using survey data, we performed qualitative and quantitative analyses to define sources for negative and positive experiences and outcomes from the Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4) Artist-in-Residence (AiR) program. Further, we analyze responses from participants, student-artists and faculty, to specify areas for improvement and areas successful in producing a positive experience and outcome in an AiR program. We found that time and virtual delivery of the program could be modified to improve the experience. Additionally, we found that student participants had more positive responses about “learning something new” from the program than faculty members. However, the most surprising aspect of our analysis suggests that for both “way of thinking” and “science communication to the public or general audience,” there may be more significant beneficial gains for faculty compared to students. We conclude this analysis with suggestions to enhance the benefits and outcomes of an AiR program and ways to minimize the difficulties, such as communication and collaboration, faced by participants and program designers.
Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome
Authors: Minteer Christopher J. , Thrush Kyra , Niimi Peter , Rozowsky Joel , Liu Jason , Frank Mor , McCabe Thomas , Hofstatter Erin , Rozenblit Mariya , Pusztai Lajos , Beckman Kenneth , Gerstein Mark , Levine Morgan E.
Published: September 2022

Aging is the leading risk factor for cancer. While it’s been proposed that the age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. Here, we show that both aging and cancer share a common epigenetic replication signature, which we modeled from DNA methylation data in extensively passaged immortalized human cellsin vitroand tested on clinical tissues. This epigenetic signature of replication – termed CellDRIFT – increased with age across multiple tissues, distinguished tumor from normal tissue, and was escalated in normal breast tissue from cancer patients. Additionally, within-person tissue differences were correlated with both predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Overall, our findings suggest that age-related replication drives epigenetic changes in cells, pushing them towards a more tumorigenic state.

One sentence summary

Cellular replication leaves an epigenetic fingerprint that may partially underly the age-associated increase in cancer risk.
Age-related complexity of the resting state MEG signals: a multiscale entropy analysis
Authors: Makani Armin , Akhavan Amir , Shahbazi Farhad , Noruzi Mohammad , Zare Marzieh
Published: September 2022

The effects of aging on the brain can be studied by examining the changes in complexity of brain signals and fluid cognitive abilities. This paper is a relatively large-scale study in which the complexity of the resting-state MEG (rsMEG) signal was investigated in 602 healthy participants (298 females and 304 males) aged 18 to 87. In order to quantify the brain signals’ complexity, the multiscale entropy is applied. This study investigates the relationship between age and fluid intelligence with brain complexity and the variations of the complexity asymmetry between the left-right brain hemispheres across the life span. In the analysis of the brain signals, the gender difference was considered. The results showed that the complexity of rsMEG decreases across the lifespan. However, the complexity difference between the left-right brain hemispheres positively correlates with age. Furthermore, the results demonstrated that fluid intelligence and age have a positive correlation. Finally, the frequency analysis revealed a significant increase in the relative power of low and high gamma rhythms in females compared to males in all age groups.
Optogenetic Instruction of Cell Fate by Temporal Patterning of Mechanobiological Signals
Authors: Sampayo Rocío G. , Sakamoto Mason , Kumar Sanjay , Schaffer David V.
Published: September 2022

During the intricate process by which cells give rise to tissues, embryonic and adult stem cells are exposed to diverse mechanical signals from the extracellular matrix (ECM) that influence their fate. Cells can sense these cues in part through dynamic generation of protrusions, modulated and controlled by cyclic activation of Rho GTPases. However, it remains unclear how extracellular mechanical signals regulate Rho GTPase activation dynamics and how such rapid, transient activation dynamics are integrated to yield long-term, irreversible cell fate decisions. Here, we report that ECM stiffness cues alter not only the magnitude but also the temporal frequency of RhoA and Cdc42 activation in adult neural stem cells (NSCs). Using optogenetics to control the frequency of RhoA and Cdc42 activation, we further demonstrate that these dynamics are functionally significant, where high- or low-frequency activation of RhoA and Cdc42 drives astrocytic or neuronal differentiation, respectively. In addition, high-frequency Rho GTPase activation induces sustained phosphorylation of the TGFβ pathway effector SMAD1, which in turn promotes astrocytic differentiation. By contrast, under low-frequency Rho GTPase stimulation, cells fail to accumulate SMAD1 phosphorylation and undergo neurogenesis. Our findings reveal the temporal patterning of Rho GTPase signaling and the resulting accumulation of a SMAD1 signal as a critical mechanism through which ECM stiffness cues regulate NSC fate.
Advanced Feedback Enhances Sensorimotor Adaptation
Authors: Wang Tianhe , Avraham Guy , Tsay Jonathan S. , Thummala Tanvi , Ivry Richard B.
Published: September 2022

It is widely recognized that sensorimotor learning is enhanced when the feedback is provided throughout the movement compared to when it is provided at the end of the movement. However, the source of this advantage is unclear: Continuous feedback is more ecological, dynamic, and available earlier than endpoint feedback. Here we assess the relative merits of these factors using a method that allows us to manipulate feedback timing independent of actual hand position. By manipulating the onset time of ‘endpoint’ feedback, we found that adaptation was modulated in a non-monotonic manner, with the peak of the function occurring in advance of the hand reaching the target. Moreover, at this optimal time, learning was of similar magnitude as that observed with continuous feedback. By varying movement duration, we demonstrate that this optimal time occurs at a relatively fixed time after movement onset, an interval we hypothesize corresponds to when the comparison of the sensory prediction and feedback generates the strongest error signal.
Differential modularity of the mammalian Engrailed 1 enhancer network directs eccrine sweat gland development
Authors: Aldea Daniel , Kokalari Blerina , Atsuta Yuji , Dingwall Heather L. , Zheng Ying , Nace Arben , Cotsarelis George , Kamberov Yana G.
Published: September 2022

Enhancers are context-specific regulators of expression that drive biological complexity and variation through the redeployment of conserved genes. An example of this is the enhancer-mediated control of the transcription of Engrailed 1 (EN1), a pleiotropic gene whose expression is required for the specification of eccrine sweat glands in mammals. We have previously identified an enhancer, ECE18 that has been highly and repeatedly derived on the human lineage to potentiate ectodermal EN1 and induce our species’ uniquely high eccrine gland density. Intriguingly, ECE18 quantitative activity is negligible outside of primates and ECE18 is not required for En1 regulation and eccrine gland specification in mice, raising the possibility that distinct enhancers have evolved to modulate the same trait. Here we report the identification of the ECE20 enhancer and show it has conserved functionality in mouse and human developing skin ectoderm. Unlike ECE18, knock-out of ECE20 in mice reduces ectodermal En1 and eccrine gland number. Notably, we find ECE20, but not ECE18, is also required for En1 expression in the embryonic mouse brain, demonstrating that ECE20 is a pleiotropic En1 enhancer. Finally, that ECE18 deletion does not potentiate the eccrine phenotype of ECE20 knockout mice supports the secondary incorporation of ECE18 into the regulation of this trait in primates. Our findings reveal that the mammalian En1 regulatory machinery diversified to incorporate both shared and lineage-restricted enhancers to regulate the same phenotype, and also have implications for understanding the forces that shape the robustness and evolvability of developmental traits.
Dictys: dynamic gene regulatory network dissects developmental continuum with single-cell multi-omics
Authors: Wang Lingfei , Trasanidis Nikolaos , Wu Ting , Dong Guanlan , Hu Michael , Bauer Daniel E. , Pinello Luca
Published: September 2022

Gene regulatory networks (GRNs) are key determinants of cell function and identity and are dynamically rewired during development and disease. Despite decades of advancement, challenges remain in GRN inference: dynamic rewiring, causal inference, feedback-loop modeling, and context specificity. To address them, we develop Dictys, a dynamic GRN inference and analysis method which leverages multi-omic single-cell assays of chromatin accessibility and gene expression, context specific transcription factor (TF) footprinting, stochastic process network, and efficient probabilistic modeling of scRNA-seq read counts. Dictys improves GRN reconstruction accuracy and reproducibility and enables the inference and comparative analysis of context specific and dynamic GRNs across developmental contexts. Dictys’ network analyses recover unique insights in human blood and mouse skin development with cell-type specific and dynamic GRNs. Its dynamic network visualizations enable time-resolved discovery and investigation of developmental driver TFs and their regulated targets. Dictys is available as a free, open source, and user-friendly Python package.
Genomic architecture of migration timing in a long-distance migratory songbird
Authors: de Greef Evelien , Suh Alexander , Thorstensen Matt J. , Delmore Kira E. , Fraser Kevin C.
Published: September 2022

The impact of climate change on spring phenology poses risks to migratory birds, as migration timing is controlled predominantly by endogenous mechanisms. Despite numerous studies on internal cues controlling migration, the underlying genetic basis of migration timing remains largely unknown. We investigated the genetic architecture of migration timing in a long-distance migratory songbird (purple martin, Progne subis subis) by integrating genomic data with an extensive dataset of direct migratory tracks. Our findings show migration has a predictable genetic basis in martins and maps to a region on chromosome 1. This region contains genes that could facilitate nocturnal flights and act as epigenetic modifiers. Additionally, we found that genomic variance explained a higher proportion of historic than recent environmental spring phenology data, which may suggest a reduction in the adaptive potential of migratory behavior in contemporary populations. Overall, these results advance our understanding of the genomic underpinnings of migration timing and could provide context for conservation action.
Genetic loss of norepinephrine does not alter adult hippocampal neurogenesis in dopamine β-hydroxylase deficient mice
Authors: Kapri Darshana , Vadodaria Krishna C. , Rommelfanger Karen S. , Ogbonmwan Yvonne E. , Liles L. Cameron , Fernandes-Thomas Kimberly A. , Salvi Sonali S. , Husain Basma F.A. , Weinshenker David , Vaidya Vidita A.
Published: September 2022

Norepinephrine (NE), and specific adrenoceptors, have been reported to influence distinct aspects of adult hippocampal neurogenesis, including latent stem cell activation, progenitor proliferation, and differentiation. These findings are predominantly based on the use of pharmacological approaches in both in vitro and in vivo systems. Here, we sought to assess the consequences of genetic ablation of NE on adult hippocampal neurogenesis, by examining dopamine β hydroxylase knockout (Dbh-/-) mice, which lack NE from birth. We find that Dbh-/- mice exhibit no difference in adult hippocampal progenitor proliferation and survival. Further, the number of immature newborn neurons, labeled using stage-specific developmental markers within the hippocampal neurogenic niche, was also unaltered in Dbh -/- mice. In contrast, the noradrenergic neurotoxin DSP-4, which had previously been shown to reduce adult hippocampal neurogenesis in rats, also resulted in a decline in hippocampal progenitor proliferation in C57/Bl6N mice. These findings indicate that pharmacological lesioning of noradrenergic afferents in adulthood, but not the complete genetic loss of NE from birth, impairs adult hippocampal neurogenesis in mice.
The triplet codons across the watershed between the non-living and living matters
Authors: Li Dirson Jian
Published: September 2022

Three nucleotides per codon had been determined before deciphering the genetic code. However, it is still a mystery why there are three nucleotides per codon. This is a deceptively simple problem, which need first to clarify the prebiotic picture that has been in debate for decades. The triplet nature of life has been observed not only in the triplet codons but also in the universal 3-base periodicity in genome sequences. Here, a statistical picture on the prebiotic sequence evolution has been proposed by ascertaining the profound relationship between the evolution of the genetic code and the diversification of life. There are indications that the triplet nature of the genetic code is due to a mixture of the periods in the superhelical structures of bent DNAs.
Hippocampal damage causes retrograde amnesia for objects’ visual, but not odour, properties in male rats
Authors: Lacoursiere Sean G. , McAllister Brendan B. , Hadikin Crystal , Tschetter Wayne W. , Lehmann Hugo , Sutherland Robert J.
Published: September 2022

Damage to the hippocampus produces profound retrograde amnesia, but odour and object discrimination memories can be spared in the retrograde direction. Prior lesion studies testing retrograde amnesia for object/odour discriminations are problematic due to sparing of large parts of the hippocampus, which may support memory recall, and/or the presence of uncontrolled, distinctive odours that may support object discrimination. To address these issues, we used a simple object discrimination test to assess memory in male rats. Two visually distinct objects, paired with distinct odour cues, were presented. One object was associated with a reward. Following training, neurotoxic hippocampal lesions were made usingN-methyl-D-aspartate(NMDA). The rats were then tested on the preoperatively learned object discrimination problem, with and without the availability of odour or visual cues during testing. The rats were also postoperatively trained on a new object discrimination problem. Lesion sizes ranged from 67-97% of the hippocampus (average of 87%). On the preoperatively learned discrimination problem, the rats with hippocampal lesions showed preserved object discrimination memory when tested in the dark (i.e., without visual cues) but not when the explicit odour cues were removed from the objects. Hippocampal lesions increased the number of trials required to reach criterion but did not prevent rats from solving the postoperatively learned discrimination problem. Our results support the idea that long-term memories for odours, unlike recall of visual properties of objects, does not depend on the hippocampus in rats, consistent with previous observations that hippocampal damage does not cause retrograde amnesia for odour memories.
Poly-omic risk scores predict inflammatory bowel disease diagnosis
Authors: Arehart Christopher H. , Sterrett John D. , Garris Rosanna L. , Quispe-Pilco Ruth E. , Gignoux Christopher R. , Evans Luke M. , Stanislawski Maggie A.
Published: September 2022

Inflammatory Bowel Disease (IBD) is characterized by complex etiology and a disrupted colonic ecosystem. We provide a framework for the analysis of multi-omic data, which we apply to study the gut ecosystem in IBD. Specifically, we train and validate models using data on the metagenome metatranscriptome, virome, and metabolome from the Human Microbiome Project 2 IBD Multi-omics Database, with 1,785 repeated samples from 131 individuals (103 cases, 27 controls). After splitting the participants into training and testing groups, we used mixed effects least absolute shrinkage and selection operator (LASSO) regression to select features for each -omic. These features, with demographic covariates, were used to generate separate single-omic prediction scores. All four single-omic scores were then combined into a final regression to assess the relative importance of the individual -omics and the predictive benefits when considered together. We identified several species, pathways, and metabolites known to be associated with IBD risk, and we explored the connections between datasets. Individually, metabolomics and viromics scores were more predictive than metagenomics or metatranscriptomics, and when all four scores were combined, we predicted disease diagnosis with a Nagelkerke’s R2of 0.46 and an AUC of 0.80 [95% CI: 0.63, 0.98]. Our work suggests that some single-omic models for complex traits are more predictive than others, that incorporating multiple -omics datasets may improve prediction, and that each -omic data type provides a combination of unique and redundant information. This modeling framework can be extended to other complex traits and multi-omic datasets.

Importance

Complex traits are characterized by many biological and environmental factors, such that multi-omics datasets are well-positioned to help us understand their underlying etiologies. We applied a prediction framework across multiple -omics (metagenomics, metatranscriptomics, metabolomics, and viromics) from the gut ecosystem to predict inflammatory bowel disease (IBD) diagnosis. The predicted scores from our models highlighted key features and allowed us to compare the relative utility of each -omic dataset in single-omic versus multi-omics models. Our results emphasized the importance of metabolomics and viromics over metagenomics and metatranscriptomics for predicting IBD status. The greater predictive capability of metabolomics and viromics is likely because these -omics serve as markers of lifestyle factors such as diet. This study provides a modeling framework for multi-omic data, and our results show the utility of combining multiple -omic data types to disentangle complex disease etiologies and biological signatures.
A Structural Heart-Brain Axis Mediates the Association Between Cardiovascular Risk and Cognitive Function
Authors: Jaggi Akshay , Conole Eleanor L.S. , Raisi-Estabragh Zahra , Gkontra Polyxeni , McCracken Celeste , Neubauer Stefan , Petersen Steffen E. , Cox Simon , Lekadir Karim
Published: September 2022

Elevated vascular disease risk associates with poorer cognitive function, but the mechanism for this link is poorly understood. A leading theory, the structural-functional model argues that vascular risk may drive adverse cardiac remodelling, which in turn leads to chronic cerebral hypoperfusion and subsequent brain structural damage. This model predicts that variation in heart and brain structure should associate with both greater vascular risk and lower cognitive function. This study tests that prediction in a large sample of the UK Biobank (N=11,962). We assemble and summarise vascular risk factors, cardiac magnetic resonance radiomics, brain structural and diffusion MRI indices, and cognitive assessment. We also extract ‘heart-brain axes’ capturing the covariation in heart and brain structure. Many heart and brain measures partially explain the vascular risk – cognitive function association, like left ventricular end-diastolic volume and grey matter volume. Notably, a heart-brain axis, capturing correlation between lower myocardial intensity, lower grey matter volume, and poorer thalamic white matter integrity, completely mediates the association, supporting the structural-functional model. Our findings also complicate this theory by finding that brain structural variation cannot completely explain the heart structure – cognitive function association. Our results broadly offer evidence for the structural functional hypothesis, identify imaging biomarkers for this association by considering covariation in heart and brain structure, and generate novel hypotheses about how cardiovascular risk may link to cognitive function.
Tailored Magnetic Resonance Fingerprinting
Authors: Poojar Pavan , Qian Enlin , Fung Maggie , Quarterman Patrick , Jambawalikar Sachin R. , Lignelli Angela , Geethanath Sairam
Published: September 2022

Neuroimaging of certain pathologies requires both multi-parametric qualitative and quantitative imaging. The role of the quantitative MRI (qMRI) is well accepted but suffers from long acquisition times leading to patient discomfort, especially in geriatric and pediatric patients. Previous studies show that synthetic MRI can be used in order to reduce the scan time and provide qMRI as well as multi-contrast data. However, this approach suffers from artifacts such as partial volume and flow. In order to increase the scan efficiency (the number of contrasts and quantitative maps acquired per unit time), we designed, simulated, and demonstrated rapid, simultaneous, multi-contrast qualitative (T1 weighted, T1 fluid attenuated inversion recovery (FLAIR), T2 weighted, water, and fat), and quantitative imaging (T1 and T2 maps) through the approach of tailored MR fingerprinting (TMRF) to cover whole-brain in approximately four minutes.

We performed TMRF on in vivo four healthy human brains and in vitro ISMRM/NIST phantom and compared with vendor supplied gold standard (GS) and MRF sequences. All scans were performed on a 3T GE Premier system and images were reconstructed offline using MATLAB. The reconstructed qualitative images were then subjected to custom DL denoising and gradient anisotropic diffusion denoising. The quantitative tissue parametric maps were reconstructed using a dense neural network to gain computational speed compared to dictionary matching. The grey matter and white matter tissues in qualitative and quantitative data for the in vivo datasets were segmented semi-automatically. The SNR and mean contrasts were plotted and compared across all three methods. The GS images show better SNR in all four subjects compared to MRF and TMRF (GS>TMRF>MRF). The T1 and T2 values of MRF are relatively overestimated as compared to GS and TMRF. The scan efficiency for TMRF is 1.72 min-1 which is higher compared to GS (0.32 min-1) and MRF (0.90 min-1).
Differential contagiousness of respiratory disease across the United States
Authors: Mallela Abhishek , Lin Yen Ting , Hlavacek William S.
Published: September 2022

The initial contagiousness of a communicable disease within a given population is quantified by the basic reproduction number, denoted R0. The value of R0 gives the expected number of new cases generated by an infectious person in a wholly susceptible population and depends on both pathogen and population properties. On the basis of compartmental models that reproduce Coronavirus Disease 2019 (COVID-19) surveillance data, we estimated region-specific R0 values for 280 of 384 metropolitan statistical areas (MSAs) in the United States (US), which account for 95% of the US population living in urban areas and 82% of the total population. Our estimates range from 1.9 to 7.7 and quantify the relative susceptibilities of regional populations to spread of respiratory diseases.

One-Sentence Summary

Initial contagiousness of Coronavirus Disease 2019 varied over a 4-fold range across urban areas of the United States.

LA-UR-22-29514
Long-term air pollution, cardiometabolic multimorbidity, and genetic susceptibility: a multi-state modeling study of 415,855 participants
Authors: Gao Xu , Jiang Meijie , Huang Ninghao , Guo Xinbiao , Baccarelli Andrea A. , Huang Tao
Published: September 2022

Background

Cardiometabolic multimorbidity (CMM) with at least two cardiometabolic diseases (CMDs) including type II diabetes (T2D), ischemic heart disease (IHD), and stroke, is a global health problem with multiplicative mortality risk and deserves to be investigated as a top priority. Although air pollution is a leading modifiable environmental risk for individual CMD, its impacts on CMM progression were poorly understood.

Objective

To elucidate the impact of air pollution on CMM progression, individually and in the context of genetic preposition.

Design

Multi-state modeling cohort study.

Setting

Data were extracted from the UK Biobank.

Participants

415,855 eligible UK Biobank adults that were free of CMDs at baseline.

Measurements

Annual concentrations of particulate matter (PM) with a diameter of ≤2.5 μm (PM2.5), 2.5-10 μm (PM2.5-10), and ≤10 μm (PM10), and nitrogen oxides (NOx and NO2) were estimated using Land Use Regression model.

Results

During a median follow-up of 8.93 years, 33,375 participants had a first CMD (FCMD), and 3,257 subsequently developed CMM. PM2.5, PM10, NO2, and NOx levels, as well as their combined exposure were associated with increased FCMD risks and even higher risks of CMM. Particularly, per a 5-μg/m3 increase in PM2.5, risks for FCMD and CMM increased by 27% (95% confidence interval: 20%-34%) and 41% (18%-68%), respectively. By FCMD types, participants with IHD had a higher risk of CMM than those with T2D or stroke. Eighty-five CMD-related genetic variants were associated with CMM trajectories in our study and associations of air pollution with FCMD and CMM risks could be aggravated progressively with increasing genetic risks.

Limitations

Other major air pollutants including ozone and SO2 were not considered due to the data availability.

Conclusions

Air pollution has profound adverse health impacts on the progression of CMM through multi-stage dynamics, especially for individuals with IHD and high genetic risk.
Germ cell-specific proteins ACRV1 and AKAP4 facilitate identification of rare spermatozoa in semen of non-obstructive azoospermia patients
Authors: Zhang Junyan , Kanoatov Mirzo , Jarvi Keith , Gauthier-Fisher Andrée , Moskovtsev Sergey I. , Librach Clifford , Drabovich Andrei P.
Published: September 2022

Non-obstructive azoospermia (NOA), the most severe form of male infertility due to testicular failure, could be treated with intra-cytoplasmic sperm injection (ICSI), providing spermatozoa were retrieved with the microdissection testicular sperm extraction (mTESE). Here, we hypothesized that some testis- and germ cell-specific proteins would facilitate flow cytometry-assisted identification of rare spermatozoa in semen cell pellets of NOA patients, thus enabling non-invasive diagnostics prior to mTESE. Data mining and extensive verification by targeted proteomic assays and immunofluorescent microscopy revealed a panel of testis-specific proteins expressed at the continuum of germ cell differentiation, including the late germ cell-specific proteins AKAP4_HUMAN and ASPX_HUMAN (ACRV1 gene) with the exclusive expression in spermatozoa tails and acrosomes, respectively. A multiplex imaging flow cytometry assay revealed low numbers of the morphologically intact AKAP4+/ASPX+/Hoechst+ spermatozoa in semen pellet of NOA patients. While the previously suggested soluble markers for spermatozoa retrieval suffered from low diagnostic specificity, our multi-step gating strategy and visualization of AKAP4+/ASPX+/Hoechst+ cells bearing elongated tails and acrosome-capped nuclei facilitated fast and unambiguous identification of the mature intact spermatozoa. Pending further validation, our assay may emerge as a non-invasive test to predict the retrieval of morphologically intact spermatozoa by mTESE, thus improving diagnostics and treatment of the severe forms of male infertility.
Viable Monkeypox virus in the environment of a patient room
Authors: Marimuthu Kalisvar , Ching Wong Judith Chui , Lim Poh Lian , Octavia Sophie , Huan Xiaowei , Ng Yi Kai , Yang Jun Jing , Sutjipto Stephanie , Linn Kyaw Zaw , Setoh Yin Xiang , Ong Chong Hui Clara , Griffiths Jane , Farhanah Sharifah , Cheok Thai Shawn , Binti Sulaiman Nur Ashikin , Congcong Sipaco Barbara , Neves Erica Sena , Loo Liang Hui , Hakim Luqman , Sim Shuzhen , Lim Merrill , Nazeem Mohammad , Vasoo Shawn , Tham Kwok Wai , Ng Oon Tek , Ng Lee Ching
Published: September 2022

We conducted a prospective environmental surveillance study to investigate the air, surface, dust and water contamination of a room occupied by a patient infected with Monkeypox virus (MPXV) at various stages of his illness. The patient tested positive for MPXV from a throat swab and skin lesions. Environmental sampling was conducted in a negative pressure room with 12 unidirectional HEPA air changes per hour and daily cleaning of the surfaces. A total of 179 environmental samples were collected on days 7, 8, 13, and 21 of his illness. Air, surface, and dust contamination was highest during the first eight days of the illness, with a gradual decline to the lowest contamination level by day 21. Viable MPXV was isolated from surfaces and dust samples and no viable virus was isolated from the air and water samples.

Synopsis

Inadequate research prevail on the mode of transmission for monkeypox virus. This study reports the findings of viable monkeypox virus from the patient environment, highlighting its implications for human health and impact on infection and prevention control measures.
Neural Correlates of Impulsive Compulsive Behaviors in Parkinson’s Disease: A Japanese Retrospective Study
Authors: Kimura Ikko , Revankar Gajanan S. , Ogawa Kotaro , Amano Kaoru , Kajiyama Yuta , Mochizuki Hideki
Published: September 2022

Background

Impulsive compulsive behavior (ICB) often disturb patients with Parkinson’s Disease (PD), of which impulse control disorder (ICD) and dopamine dysregulation syndrome (DDS) are two major subsets. Although the nucleus accumbens (NAcc) is involved in ICB, it remains unclear how the NAcc affects cortical function and defines the different behavioral characteristics of ICD and DDS.

Objectives

To identify the most involved cortico-striatal network in ICB and the differences in these networks between patients with ICD and those with DDS using structural and resting-state functional magnetic resonance imaging.

Methods

Patients with PD were recruited using the data from a previous cohort study and were divided into patients with ICB (ICB group) and those without ICB (non-ICB group) using the Japanese version of the Questionnaire for Impulsive Compulsive Disorders in Parkinson’s Disease (J-QUIP). From these two groups, we extracted 37 pairs matched for age, sex, disease duration, and levodopa equivalent daily dose of dopamine agonists. Patients with ICB were further classified as either having ICD or DDS based on the J-QUIP subscore. General linear models were used to compare the gray matter volume and functional connectivity (FC) of the NAcc, caudate, and putamen between the ICB and non-ICB groups and between patients with ICD and those with DDS.

Results

We found no significant differences in gray matter volume between the ICB and non-ICB groups or between patients with ICD and those with DDS. Compared with the non-ICB group, the FC of the right NAcc in the ICB group was lower in the bilateral ventromedial prefrontal cortex and higher in the left middle occipital gyrus. Patients with DDS showed higher FC between the right putamen and left superior temporal gyrus and higher FC between the left caudate and bilateral middle occipital gyrus than patients with ICD. In contrast, patients with ICD exhibited higher FC between the left NAcc and the right posterior cingulate cortex than patients with DSS.

Conclusions

The functionally altered network between the right NAcc and ventromedial prefrontal cortex was associated with the presence of ICB in PD, and the surrounding cortico-striatal networks may differentiate between the behavioral characteristics of patients with ICD and those with DDS.
The rapid radiation of Bomarea (Alstroemeriaceae: Liliales), driven by the rise of the Andes
Authors: Tribble Carrie M. , Alzate-Guarín Fernando , Gándara Etelvina , Vartoumian Araz , Burleigh J. Gordon , Zenil-Ferguson Rosana , Specht Chelsea D. , Rothfels Carl J.
Published: September 2022

Complex geological events such as mountain uplift affect how, when, and where species originate and go extinct, but measuring those effects is a longstanding challenge. The Andes arose through a series of complex geological processes over the past c. 100 million years, impacting the evolution of regional biota by creating barriers to gene flow, opening up new habitats, and changing local climate patterns. Bomarea are tropical geophytes with ranges extending from central Mexico to central Chile. Of the roughly 120 species of Bomarea, most are found in the Andes, and previous work has suggested that Bomarea diversified rapidly and recently, corresponding with the uplift of the Andes. While many Bomarea species occur over small, isolated ranges, Bomarea edulis occurs significantly beyond the ranges of any other Bomarea species (from central Mexico to northern Argentina) and is thought to have potentially humanmediated dispersal, due to its status as a pre-Columbian food plant. To untangle the potential drivers of diversification and biogeographic history in Bomarea, we used a target-capture approach to sequence nuclear loci of 174 accessions of 124 species, including 16 outgroup species from across the family (Alstroemeriaceae). We included 43 individuals of B. edulis from across its range to assess species monophyly and identify infraspecific phylogeographic patterns. We model biogeographic range evolution in Bomarea and test if Andean orogeny has impacted its diversification. We find that Bomarea originated in the central Andes during the mid-Miocene, then spread north, following the trajectory of major mountain uplift events. Most observed speciation events occurred during the Pleistocene, while global climate cooled and oscillated and the northern Andes achieved their current form. Furthermore, we find that Andean lineages diversified faster than their non-Andean relatives. These results demonstrate a clear macroevolutionary signal of Andean orogeny on this neotropical radiation.
Contextual influences of visual perceptual inferences
Authors: A-Izzeddin Emily J , Mattingley Jason B , Harrison William J
Published: September 2022

Humans have well-documented priors for many features present in nature that guide visual perception. Despite being putatively grounded in the statistical regularities of the environment, scene priors are frequently violated due to the inherent variability of visual features from one scene to the next. However, these repeated violations do not appreciably challenge visuo-cognitive function, necessitating the broad use of priors in conjunction with context-specific information. We investigated the trade-off between participants’ internal expectations formed from both longer-term priors and those formed from immediate contextual information using a perceptual inference task and naturalistic stimuli. Notably, our task required participants to make perceptual inferences about naturalistic images using their own internal criteria, rather than making comparative judgements. Nonetheless, we show that observers’ performance is well approximated by a model that makes inferences using a prior for low-level image statistics, aggregated over many images. We further show that the dependence on this prior is rapidly re-weighted against contextual information, whether relevant or irrelevant. Our results therefore provide insight into how apparent high-level interpretations of scene appearances follow from the most basic of perceptual processes, which are grounded in the statistics of natural images.
Acute hyper- and hypoglycemia uncouples the metabolic cooperation between glucose and lactate to disrupt sleep
Authors: Carroll Caitlin M. , Stanley Molly , Raut Ryan V. , Constantino Nicholas J. , Irmen Riley E. , Mitra Anish , Snipes J. Andy , Raichle Marcus E. , Holtzman David M. , Gould Robert W. , Kishida Kenneth T. , Macauley Shannon L.
Published: September 2022

The sleep-wake cycle is a master regulator of metabolic and neuronal activity and when altered, can have profound effects on metabolic health and disease. Although consideration is given to how fluctuations in blood glucose affect peripheral physiology and metabolism, less is known about how glucose dysregulation impacts the intrinsic cooperation between brain metabolism and neuronal activity to regulate sleep. To understand the effect of peripheral hyper- and hypoglycemia on these relationships, we paired biosensors measuring hippocampal interstitial fluid (ISF) levels of glucose and lactate with cortical EEG/EMG recordings to produce simultaneous subsecond recordings of ISF glucose, lactate, and sleep-wake states. First, we describe a conserved temporal relationships between ISF glucose and lactate based on their intrinsic oscillations, diurnal rhythms, and sleep/wake cycles. ISF glucose and lactate oscillations are largely anti-correlated but the frequency of their oscillations dictate their power, coherence, and phase. While ISF glucose and lactate both have diurnal fluctuations, only ISF lactate is consistently elevated during wake. During wake, fluctuations in ISF lactate are associated with changes in the EEG power spectrum, suggesting wake-related activity is more closely associated with ISF lactate. Modulation of glucose availability via both hyper- or hypoglycemia disrupts the relationship between peripheral metabolism, brain metabolism, and sleep. Hyper- and hypo-glycemia increase ISF lactate, decrease NREM, and alter EEG spectral activity, again demonstrating ISF lactate drives wake-associated behaviors and disrupts sleep. Taken together, these studies demonstrate that peripheral glucose homeostasis is necessary for maintaining the relationships between brain metabolism, neuronal activity, and sleep-wake patterns and deviations in blood glucose levels are sufficient to disrupt the metabolic signature of sleep-wake states, putting the brain at risk in diseases like type-2-diabetes and Alzheimer’s disease.

Graphical Abstract. Peripheral glucose homeostasis directly modifies sleep/wake patterns
Development of Machine Learning Model for Pan-cancer Subgroup Identification using Multi-omics Data
Authors: Khadirnaikar Seema R , Shukla Sudhanshu , Prasanna S R Mahadeva
Published: September 2022

Cancer is a heterogeneous disease and patients with tumors from different organs can share similar epigenetic and genetic alterations. Therefore, it is crucial to identify the novel subgroup of patients with similar molecular characteristics. It is possible to propose a better treatment strategy when the heterogeneity of the patient is accounted for during subgroup identification irrespective of the tissue of origin. In this work, mRNA, miRNA, DNA methylation, and protein expression features from pan-cancer samples were concatenated and non-linearly projected to lower dimension using machine learning (ML) algorithm. This data was then clustered to identify multi-omics based novel subgroups. The clinical characterization of these ML subgroups indicated significant differences in overall survival (OS) and disease free survival (DFS) (p-value < 0.0001). The subgroups formed by the patients from different tumors shared similar molecular alterations in terms of immune microenvironment, mutation profile, and enriched pathways. Further, decision-level and feature-level fused classification models were built to identify the novel subgroups for unseen samples. Additionally, the classification models were used to obtain the class labels for the validation samples and the molecular characteristics were verified. To summarize, this work identified novel ML subgroups using multi-omics data and showed that patients with different tumor types can be similar molecularly. We also proposed and validated the classification models for subgroup identification. The proposed classification models can be used to identify the novel multi-omics subgroups and the molecular characteristics of each subgroup can be used to design appropriate treatment regimen.