bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of Episode of Hemodynamic Instability Using an Electrocardiogram Based Analytic: A Retrospective Cohort Study
Authors: Benson Bryce , Belle Ashwin , Lee Sooin , Bassin Benjamin S. , Medlin Richard P. , Sjoding Michael W. , Ward Kevin R.
Published: June 2023

Background

Predicting the onset of hemodynamic instability before it occurs remains a sought-after goal in acute and critical care medicine. Technologies that allow for this may assist clinicians in preventing episodes of hemodynamic instability (EHI). We tested a novel noninvasive technology, the Analytic for Hemodynamic Instability-Predictive Indicator (AHI-PI), which analyzes a single lead of electrocardiogram (ECG) and extracts heart rate variability and morphologic waveform features to predict an EHI prior to its occurrence.

Methods

Retrospective cohort study at a quaternary care academic health system using data from hospitalized adult patients between August 2019 and April 2020 undergoing continuous ECG monitoring with intermittent noninvasive blood pressure (NIBP) or with continuous intra-arterial pressure (IAP) monitoring.

Results

AHI-PI’s low and high-risk indications were compared with the presence of EHI in the future as indicated by vital signs (heart rate > 100 beats/min with a systolic blood pressure < 90 mmHg or a mean arterial blood pressure of < 70 mmHg). 4,633 patients were analyzed (3,961 undergoing NIBP monitoring, 672 with continuous IAP monitoring). 692 patients had an EHI (380 undergoing NIBP, 312 undergoing IAP). For IAP patients, the sensitivity and specificity of AHI-PI to predict EHI was 89.7% and 78.3% with a positive and negative predictive value of 33.7% and 98.4% respectively. For NIBP patients, AHI-PI had a sensitivity and specificity of 86.3% and 80.5% with a positive and negative predictive value of 11.7% and 99.5% respectively. Both groups performed with an AUC of 0.87. AHI-PI predicted EHI in both groups with a median lead time of 1.1 hours (average lead time of 3.7 hours for IAP group, 2.9 hours for NIBP group).

Conclusions

AHI-PI predicted EHIs with high sensitivity and specificity and within clinically significant time windows that may allow for intervention. Performance was similar in patients undergoing NIBP and IAP monitoring.
Phase locking of auditory steady state responses is modulated by a predictive sensory context and linked to degree of myelination in the cerebellum
Authors: Larsen Kit Melissa , Thapaliya Kiran , Barth Markus , Siebner Hartwig R. , Garrido Marta I.
Published: June 2023

Background

40 Hz auditory steady state responses (ASSR) can be evoked by brief auditory clicks delivered at 40 Hz. While the neuropharmacology behind the generation of ASSR is well examined, the link between ASSR and microstructural properties of the brain is unclear. Further, whether the 40 Hz ASSR can be manipulated through processes involving top-down control, such as prediction, is currently unknown.

Methods

We recorded EEG in 50 neurotypical participants while they engaged in a 40 Hz Auditory steady state paradigm. We manipulated the predictability of tones to test the modulatory effect of prediction on 40 Hz steady state responses. Further, we acquired T1w and T2w structural MRI and used the T1/T2 ratio as a proxy to determine myelination in grey matter.

Results

The phase locking of the 40 Hz ASSR was indeed modulated by prediction and this modulation extended to all frequency bands, suggesting prediction violation as a phase resetting mechanism. Interestingly, we found that the prediction violation of the phase locking at 40 Hz (gamma) was associated with the degree of grey matter myelination in the right cerebellum.

Discussion

We demonstrate that prediction violations evoke resetting of oscillatory activity and suggest that the efficiency of this process is promoted by greater cerebellar myelin. Our findings provide a structural-functional relationship for myelin and phase locking of auditory oscillatory activity. These results introduce a setting for looking at the interaction of predictive processes and ASSR in disorders where these processes are impaired such as in psychosis.
Feasibility of a social protection linkage program for individuals at-risk for tuberculosis in Uganda
Authors: Nanyunja Grace , Kadota Jillian L. , Namale Catherine , Hudson Mollie , Nalugwa Talemwa , Turyahabwe Stavia , Cattamanchi Adithya , Katamba Achilles , Muhumuza Prosper , Shete Priya B.
Published: June 2023

Introduction

Social protection interventions have the potential to accelerate progress towards global tuberculosis (TB) targets. We piloted a screening and linkage program at four community health centers (HC) to enroll adults seeking TB diagnostic evaluation services into existing government-supported social protection programs in Uganda.

Methods

From May-December 2021, health center staff were asked to screen adults being evaluated for TB for eligibility for government-supported social protection programs, and to refer eligible people to a sub-county community development office (CDO) responsible for enrolling community members into government-supported social protection programs. Linkage was facilitated with a transportation reimbursement via mobile money and referral documentation confirming program eligibility. We assessed feasibility using programmatic data and conducted post-intervention surveys to understand experiences with the linkage program.

Results

Of 855 people undergoing TB evaluation, 655 (76%) adults met criteria for at least one government-supported social protection program. 25 (4%) of those were not interested in referral; the rest were referred to their local CDO. While 386 (61%) of the 630 participants reported to the CDO seeking social protection enrolment, only 122 (32%) of those were ultimately enrolled into a social protection scheme, representing only 19% (n=655) of those eligible. In participant surveys, among those seeking enrolment at the CDO (n=60; 65% of those surveyed), 46 (77%) were not enrolled into a social protection program. Reasons for non-enrollment were either unknown to the participant (n=25, 54%) or due to operational challenges at the CDO including a lack of human resources or available groups join in the social protection program (n=20, 43%). 61 (63%) survey participants indicated that they would not have sought social protection enrollment without the referral program.

Conclusion

Most adults seeking TB diagnostic evaluation are eligible for and interested in obtaining government-supported social protection. We found facilitated linkage from HCs to CDOs offering social protection services to be feasible, however ultimate enrollment into programs was limited. Additional research is needed to identify strategies to improve access to existing social protection programs for eligible TB-affected individuals.
Expansion-assisted selective plane illumination microscopy for nanoscale imaging of centimeter-scale tissues
Authors: Glaser Adam , Chandrashekar Jayaram , Vasquez Sonya , Arshadi Cameron , Ouellette Naveen , Jiang Xiaoyun , Baka Judith , Kovacs Gabor , Woodard Micah , Seshamani Sharmishtaa , Cao Kevin , Clack Nathan , Recknagel Andrew , Grim Anna , Balaram Pooja , Turschak Emily , Hooper Marcus , Liddell Alan , Rohde John , Hellevik Ayana , Takasaki Kevin , Erion Barner Lindsey , Logsdon Molly , Chronopoulos Chris , de Vries Saskia , Ting Jonathan , Perlmutter Steve , Kalmbach Brian , Dembrow Nikolai , Tasic Bosiljka , Reid R. Clay , Feng David , Svoboda Karel
Published: June 2023

Recent advances in tissue processing, labeling, and fluorescence microscopy are providing unprecedented views of the structure of cells and tissues at sub-diffraction resolutions and near single molecule sensitivity, driving discoveries in diverse fields of biology, including neuroscience. Biological tissue is organized over scales of nanometers to centimeters. Harnessing molecular imaging across intact, three-dimensional samples on this scale requires new types of microscopes with larger fields of view and working distance, as well as higher throughput. We present a new expansion-assisted selective plane illumination microscope (ExA-SPIM) with aberration-free 1×1×3 μm optical resolution over a large field of view (10.6×8.0 mm2) and working distance (35 mm) at speeds up to 946 megavoxels/sec. Combined with new tissue clearing and expansion methods, the microscope allows imaging centimeter-scale samples with 250×250×750 nm optical resolution (4× expansion), including entire mouse brains, with high contrast and without sectioning. We illustrate ExA-SPIM by reconstructing individual neurons across the mouse brain, imaging cortico-spinal neurons in the macaque motor cortex, and visualizing axons in human white matter.
Risk of Coronavirus Disease 2019 (COVID-19) among Those Up-to-Date and Not Up-to-Date on COVID-19 Vaccination by US CDC Criteria
Authors: Shrestha Nabin K. , Burke Patrick C. , Nowacki Amy S. , Gordon Steven M.
Published: June 2023

Background

The CDC recently defined being “up-to-date” on COVID-19 vaccination as having received at least one dose of a COVID-19 bivalent vaccine. The purpose of this study was to compare the risk of COVID-19 among those “up-to-date” and “not up-to-date”.

Methods

Employees of Cleveland Clinic in Ohio, USA, in employment when the COVID-19 bivalent vaccine first became available, and still employed when the XBB lineages became dominant, were included. Cumulative incidence of COVID-19 since the XBB lineages became dominant was compared across the ”up-to-date” and “not up-to-date” states, by treating COVID-19 bivalent vaccination as a time- dependent covariate whose value changed on receipt of the vaccine. Risk of COVID-19 by vaccination status was also evaluated using multivariable Cox proportional hazards regression adjusting for propensity to get tested for COVID-19, age, sex, most recent prior SARS-CoV-2 infection, and number of prior vaccine doses.

Results

COVID-19 occurred in 1475 (3%) of 48 344 employees during the 100-day study period. The cumulative incidence of COVID-19 was lower in the “not up-to-date” than the “up-to-date” state. On multivariable analysis, being “up-to-date” was not associated with lower risk of COVID-19 (HR, 1.05; 95% C.I., 0.88-1.25;P-value, 0.58). Results were very similar when those 65 years and older were only considered “up-to-date” after 2 doses of the bivalent vaccine.

Conclusions

Since the XBB lineages became dominant, adults “up-to-date” on COVID-19 vaccination by the CDC definition do not have a lower risk of COVID-19 than those “not up-to-date”, bringing into question the value of this risk classification definition.

Among 48 344 working-aged Cleveland Clinic employees, those “up-to-date” on COVID-19 vaccination did not have a lower risk of COVID-19 than those not “up-to-date”. The current CDC definition provides a meaningless classification of risk of COVID-19 in the adult population.
Evaluating the effects of supervised consumption sites on housing prices in Montreal, Canada using controlled interrupted time series and hedonic price models
Authors: Schaefer Maximilian , Panagiotoglou Dimitra
Published: June 2023

Background

In 2017, three brick and mortar supervised consumption sites (SCS) began operating in Montreal, Canada. Opponents argued the sites would attract people who use drugs to the respective neighbourhoods, contributing to reductions in residential real estate values.

Methods

We used controlled interrupted time series and hedonic price models to evaluate the effects of Montreal’s SCSs on residential real estate. We linked the Quebec Professional Association of Real Estate Brokers’ housing sales data provided by Centris Inc. with Statistics Canada’s census tract data, neighbourhood proximity measures, and Canadian Urban Environmental Health Research Consortium’s gentrification measures. We restricted analysis to sales between 1 January 2014 and 31 December 2021, and within 1,000m of a SCS (treated) or a men’s homeless shelter (control). We controlled for internal (e.g., number of bed/bathrooms, unit size) and external attributes (e.g., neighbourhood demographics; proximity to amenities), and included a spatio-temporal lag to account for correlation between sales.

Results

When controlling for census tract data and gentrification measures, the price of homes sold immediately after SCSs were implemented was 5.2% lower (95% CI: -1.4%, -8.8%) compared with control sales (level effect). However, the monthly value increased 0.6% faster (95% CI: 0.4%, 0.7%) in treated neighbourhoods (trend effect). Compared with the counterfactual (i.e., SCS never implemented), sales in treated neighbourhoods observed an absolute increase of $37,931.86 (95% CI: $12,223.35, $138,088.50) by December 2021. When we also controlled for proximity scores, the immediate level effect post-implementation disappeared (−3.3%, 95% CI: -0.7%, 1.1%), but monthly trend gains persisted (0.9%, 95% CI: 0.7%, 1.0%).

Conclusion

We observed a modest negative effect on prices immediately following SCS implementation. However, controlling for proximity to neighbourhood amenities eliminated the level effect. Positive month-on-month price gains were consistently observed, suggesting community wide benefits of SCS implementation.
Metabolomic and genomic prediction of common diseases in 477,706 participants in three national biobanks
Authors:   Nightingale Health Biobank Collaborative Group, Barrett Jeffrey C. , Esko Tõnu , Fischer Krista , Jostins-Dean Luke , Jousilahti Pekka , Julkunen Heli , Jääskeläinen Tuija , Kerimov Nurlan , Kerminen Sini , Kolde Anastassia , Koskela Harri , Kronberg Jaanika , Lundgren Sara N. , Lundqvist Annamari , Mäkelä Valtteri , Nybo Kristian , Perola Markus , Salomaa Veikko , Schut Kirsten , Soikkeli Maiju , Soininen Pasi , Tiainen Mika , Tillmann Taavi , Würtz Peter ,   the Estonian Biobank Research Team
Published: June 2023

Identifying individuals at high risk of chronic diseases via easily measured biomarkers could improve public health efforts to prevent avoidable illness and death. Here we present nuclear magnetic resonance blood metabolomics from half a million samples from three national biobanks. We built metabolomic risk scores that identify a high-risk group for each of 12 diseases that cause the most morbidity in high-income countries and show consistent cross-biobank replication of the relative risk of disease for these groups. We show that these metabolomic risk scores are more strongly associated with future disease onset than polygenic scores for most of these diseases. In a subset of 18,000 individuals with metabolomic biomarkers measured at two time points we show that people whose scores change have dramatically different future risk of disease, suggesting that repeat measurements capture the benefits of lifestyle change. We show cross-biobank calibration of our scores. Since metabolomics can be measured from a standard blood sample, we propose such tests can be feasibly implemented today in preventative health programs.

One-Sentence Summary

Biomarkers from half a million blood samples identifies people at increased risk of chronic diseases and can be used for early detection today.
Harmonization of Later-Life Cognitive Function Across National Contexts: Results from the Harmonized Cognitive Assessment Protocols (HCAPs)
Authors: Gross Alden L. , Li Chihua , Briceno Emily M. , Rentería Miguel Arce , Jones Richard N. , Langa Kenneth M. , Manly Jennifer J. , Nichols Emma L. , Weir David , Wong Rebeca , Berkman Lisa , Lee Jinkook , Kobayashi Lindsay C.
Published: June 2023

Background

The Harmonized Cognitive Assessment Protocol (HCAP) is an innovative instrument for cross-national comparisons of later-life cognitive function, yet its suitability across diverse populations is unknown. We aimed to harmonize general and domain-specific cognitive scores from HCAPs across six countries, and evaluate precision and criterion validity of the resulting harmonized scores.

Methods

We statistically harmonized general and domain-specific cognitive function across the six publicly available HCAP partner studies in the United States, England, India, Mexico, China, and South Africa (N=21,141). We used an item banking approach that leveraged common cognitive test items across studies and tests that were unique to studies, as identified by a multidisciplinary expert panel. We generated harmonized factor scores for general and domain- specific cognitive function using serially estimated graded-response item response theory (IRT) models. We evaluated precision of the factor scores using test information plots and criterion validity using age, gender, and educational attainment.

Findings

IRT models of cognitive function in each country fit well. We compared measurement reliability of the harmonized general cognitive function factor across each cohort using test information plots; marginal reliability was high (r> 0·90) for 93% of respondents across six countries. In each country, general cognitive function scores were lower with older ages and higher with greater levels of educational attainment.

Interpretation

We statistically harmonized cognitive function measures across six large, population-based studies of cognitive aging in the US, England, India, Mexico, China, and South Africa. Precision of the estimated scores was excellent. This work provides a foundation for international networks of researchers to make stronger inferences and direct comparisons of cross-national associations of risk factors for cognitive outcomes.

Funding

National Institute on Aging (R01 AG070953, R01 AG030153, R01 AG051125, U01 AG058499; U24 AG065182; R01AG051158)
A frameshift variant in the melanophilin gene is associated with loss of pigment from shed skin in ball pythons (Python regius)
Authors: Lederer Izabella , Shahid Basmah , Dao Uyen M. , Brogdon Alex , Byrtus Hannah , Delva Marcelin , Deva Orson , Hatfield Paige , Hertz Mikayla , Justice Jenna , Mavor Sarah , Pilbeam Erin , Rice Zoe , Simpson Abbey , Temar Hallie , Wynn Richard , Xhangolli Joana , Graves Chiron W. , Seidel Hannah S.
Published: June 2023

Melanophilin is a myosin adaptor required for transporting the pigment melanin within cells. Loss of melanophilin in fish, birds, and mammals causes pigmentation defects, but little is known about the role of melanophilin in non-avian reptiles. Here we show that a frameshift in the melanophilin gene in ball python (P. regius) is associated with loss of pigment from shed skin. This variant is predicted to remove the myosin-binding domain of melanophilin and thereby impair transport of melanin-containing organelles. Our study represents the first description of a melanophilin variant in a non-avian reptile and confirms the role of melanophilin across vertebrates.
Nuclear aging in polyglutamine-induced neurodegeneration
Authors: Pereira Dina , Cunha-Santos Janete , Vasconcelos-Ferreira Ana , Duarte-Neves Joana , Onofre Isabel , Carmona Vítor , Aveleira Célia A , Lopes Sara M , Lobo Diana D , Martins Inês M , Gonçalves Nélio , Cavadas Cláudia , Pereira de Almeida Luís
Published: June 2023

Machado-Joseph disease (MJD) is an autosomal dominantly-inherited neurodegenerative disorder characterized by an over-repetition of the CAG trinucleotide of theATXN3gene, conferring a toxic gain-of-function to the resulting ataxin-3 protein. Despite the significant advances produced over the last years, the molecular mechanisms involved in MJD are still unclear and no treatment able to modify the disease progression is available. Aging is the major risk factor for neurodegenerative disorders, being associated with the occurrence and progression of several diseases, such as Alzheimer’s, Huntington’s, among others. The nuclear membrane proteins - lamins - and lamin-processing related proteins, such as ZMPSTE24, have been shown to be altered, not only during normal aging, but also in neurodegenerative disorders, such as Alzheimer’s disease.

Taking this into account, we aimed at investigating the role of aging in MJD by evaluating the presence of age-related markers in human and animal MJD models. Decreased levels of lamins B and C, together with decreased ZMPSTE24 levels were identified in the different MJD models. Accordingly, abnormalities in nuclear circularity, a hallmark of aging, were also observed in a N2a MJD cellular model, supporting an age-related phenotype. Furthermore, overexpressing progerin, the abnormal lamin A, generated in Hutchinson Guilford Progeria Syndrome patients that present premature and accelerated aging, in a relevant brain area of a lentiviral MJD mouse model, induced an aggravation of MJD-associated neuropathology.

Our results suggest that aging is a key player in the context of MJD pathogenesis, unveiling new pathways for the development of future therapies for the disease.
Increased dispersal explains increasing local diversity with global biodiversity declines
Authors: Fagan Brennen , Pitchford Jon W. , Stepney Susan , Thomas Chris D
Published: June 2023

The narrative of biodiversity decline in response to human impacts is overly simplistic because different biodiversity metrics show different trajectories at different spatial scales. It is also debated whether human-caused biodiversity changes lead to subsequent, accelerating change (cascades) in ecological communities, or alternatively build increasingly robust community networks with decreasing extinction rates and reduced invasibility. Mechanistic approaches are needed that simultaneously reconcile different metrics of biodiversity change, and explore the robustness of communities to further change. We develop a trophically-structured, mainland-archipelago metacommunity model of community assembly. Varying the parameters across model simulations shows that local alpha diversity (the number of species per island) and regional gamma diversity (the total number of species in the archipelago) depend on both the rate of extirpation per island and on the rate of dispersal between islands within the archipelago. In particular, local diversity increases with increased dispersal and heterogeneity between islands, but regional diversity declines because the islands become biotically similar and local one-island and few-island species are excluded (homogenisation, or reduced beta diversity). This mirrors changes observed empirically: real islands have gained species (increased local and island-scale community diversity) with increased human-assisted transfers of species, but global diversity has declined with the loss of endemic species. However, biological invasions may be self-limiting. High-dispersal, high local-diversity model communities become resistant to subsequent invasions, generating robust species-community networks unless dispersal is extremely high. A mixed-up world is likely to lose many species, but the resulting ecological communities may nonetheless be relatively robust.

Significance Statement

Biodiversity is commonly regarded as threatened due to human impacts, but biodiversity metrics at different scales produce contradictory results. A framework is needed that can reproduce and connect these results across scales and address whether biodiversity change will inexorably accelerate following perturbation or become self-limiting as new ecological communities form. We address this challenge by constructing size-structured model communities using a mainland/island paradigm and tracking diversity at different scales. Our simulations reproduce the literature’s discrepancy across scales and provide new insight. Ecological communities (islands) gain species with increasing (human-assisted) dispersal, but global diversity declines with the consequent loss of endemic species. Communities also become less invasible as dispersal increases, suggesting that human-mediated dispersal favours robust communities that resist subsequent change.
Ketogenic diet as a metabolic vehicle for enhancing the therapeutic efficacy of mebendazole and devimistat in preclinical pediatric glioma
Authors: Mukherjee Purna , Greenwood Bennett , Henao Juan , Kiebish Michael A. , Seyfried Thomas N.
Published: June 2023

Invasion of high-grade glioma (HGG) cells through the brain and spinal cord is a leading cause of cancer death in children. Despite advances in treatment, survivors often suffer from life-long adverse effects of the toxic therapies. This study investigated the influence of nutritional ketosis on the therapeutic action of mebendazole (MBZ) and devimistat (CPI-613) against the highly invasive VM-M3 glioblastoma cells in juvenile syngeneic p20-p25 mice; a preclinical model of pediatric HGG. Cerebral implantation of the VM-M3 glioblastoma cells invaded throughout the brain and the spinal column similar to that seen commonly in children with malignant glioma. The maximum therapeutic benefit of MBZ and CPI-613 on tumour invasion and mouse survival occurred only when the drugs were administered together with a ketogenic diet (KD). MBZ reduced VM-M3 tumour cell growth and invasion when evaluated underin-vitroandin-vivoconditions through inhibition of both the glutaminolysis and the glycolysis pathways.

Moreover, administration of the drugs with the KD allowed a low dosing for the juvenile mice, which minimized toxicity while improving overall survival. This preclinical study in juvenile mice highlights the potential importance of a diet/drug therapeutic strategy for managing childhood brain cancer.
Gauge equivariant convolutional neural networks for diffusion mri
Authors: Hussain Uzair , Khan Ali R.
Published: June 2023

Diffusion MRI (dMRI) is an imaging technique widely used in neuroimaging research, where the signal carries directional information of underlying neuronal fibres based on the diffusivity of water molecules. One of the shortcomings of dMRI is that numerous images, sampled at gradient directions on a sphere, must be acquired to achieve a reliable angular resolution for model-fitting, which translates to longer scan times, higher costs, and barriers to clinical adoption. In this work we introduce gauge equivariant convolutional neural network (gCNN) layers for dMRI that overcome the challenges associated with the signal being acquired on a sphere with antipodal points identified. This is done by noting that the domain is equivalent to the real projective plane, ℝP2, which is a non-euclidean and a non-orientable manifold. This is in stark contrast to a rectangular grid which typical convolutional neural networks (CNNs) are designed for. We apply our method to upsample angular resolution for predicting diffusion tensor imaging (DTI) parameters from just six diffusion gradient directions. The symmetries introduced allow gCNNs the ability to train with fewer subjects as compared to a baseline model that involves only 3D convolutions.
Parthenogenesis, sexual conflict, and selection on fertilization rates in switching environments
Authors: Liu Xiaoyuan , Pitchford Jon W. , Constable George W.A.
Published: June 2023

In the face of varying environments, organisms exhibit a variety of reproductive modes, from asexuality to obligate sexuality. Should reproduction be sexual, the morphology of the sex cells (gametes) produced by these organisms has important evolutionary implications; these cells can be the same size (isogamy), one larger and one smaller (anisogamy), and finally the larger cell can lose its capacity for motility (oogamy, the familiar sperm-egg system). Understanding the origin of the sexes, which lies in the types of gametes they produce, thus amounts to explaining these evolutionary transitions. Here we extend classic results in this area by exploring these transitions in a model in which organisms can reproduce both sexually and asexually (a reproductive mode present in many algae). In particular, we investigate the co-evolution of gamete cell size with fertilization rate, which is a proxy for motility and pheromone production but usually held constant in such models. Using adaptive dynamics generalized to the case of switching environments, we find that isogamy can evolve to anisogamy through evolutionary branching, and that anisogamy can evolve to oogamy or suppressed pheromone production through a further branching driven by sexual conflict. We also derive analytic conditions on the model parameters required to arrest evolution on this isogamy-oogamy trajectory, with low fertilization rates and stochastically switching environments stabilizing isogamy under a bet-hedging strategy, and low fertilization costs stabilizing anisogamy and pheromone production.
Targeting CD301+ macrophage inhibits endometrial fibrosis and improves pregnancy outcome
Authors: Lv Haining , Sun Haixiang , Wang Limin , Yao Simin , Liu Dan , Zhang Xiwen , Pei Zhongrui , Zhou Jianjun , Wang Huiyan , Dai Jianwu , Yan Guijun , Ding Lijun , Wang Zhiyin , Cao Chenrui , Zhao Guangfeng , Hu Yali
Published: June 2023

Macrophages are a key and heterogeneous cell population involved in endometrial repair and regeneration during the menstrual cycle, but their role in the development of intrauterine adhesion (IUA) and sequential endometrial fibrosis remains unclear. Here, we reported that CD301+ macrophages were significantly increased and showed their most active interaction with profibrotic cells in the endometria of IUA patients compared with the normal endometria by single-cell RNA sequencing, bulk RNA sequencing and experimental verification. Increasing CD301+ macrophages promoted the differentiation of endometrial stromal cells into myofibroblasts and resulted in extracellular matrix accumulation, which destroyed the physiological architecture of endometrial tissue, drove endometrial fibrosis and ultimately led to female infertility or adverse pregnancy outcomes. Mechanistically, CD301+ macrophages secreted GAS6 to activate the AXL/NF-κB pathway, up-regulating the profibrotic protein synthesis. Targeted deletion of CD301+ macrophages or inhibition of AXL by Bemcentinib blunted the pathology and improved the outcomes of pregnancy in mice, supporting the therapeutic potential of targeting CD301+ macrophages for treating endometrial fibrosis.
Monocytes use protrusive forces to generate migration paths in viscoelastic collagen-based extracellular matrices
Authors: Adebowale Kolade , Allan Cole , Ha Byunghang , Saraswathibhatla Aashrith , Zhu Junqin , Indana Dhiraj , Popescu Medeea C. , Demirdjian Sally , Martinez Hunter A. , Esclamado Alex , Yang Jin , Bassik Michael C. , Franck Christian , Bollyky Paul L. , Chaudhuri Ovijit
Published: June 2023

Circulating monocytes are recruited to the tumor microenvironment, where they can differentiate into macrophages that mediate tumor progression. To reach the tumor microenvironment, monocytes must first extravasate and migrate through the type-1 collagen rich stromal matrix. The viscoelastic stromal matrix around tumors not only stiffens relative to normal stromal matrix, but often exhibits enhanced viscous characteristics, as indicated by a higher loss tangent or faster stress relaxation rate. Here, we studied how changes in matrix stiffness and viscoelasticity, impact the three-dimensional migration of monocytes through stromal-like matrices. Interpenetrating networks of type-1 collagen and alginate, which enable independent tunability of stiffness and stress relaxation over physiologically relevant ranges, were used as confining matrices for three-dimensional culture of monocytes. Increased stiffness and faster stress relaxation independently enhanced the 3D migration of monocytes. Migrating monocytes have an ellipsoidal or rounded wedge-like morphology, reminiscent of amoeboid migration, with accumulation of actin at the trailing edge. Matrix adhesions were dispensable for monocyte migration in 3D, but migration did require actin polymerization and myosin contractility. Mechanistic studies indicate that actin polymerization at the leading edge generates protrusive forces that open a path for the monocytes to migrate through in the confining viscoelastic matrices. Taken together, our findings implicate matrix stiffness and stress relaxation as key mediators of monocyte migration and reveal how monocytes use pushing forces at the leading edge mediated by actin polymerization to generate migration paths in confining viscoelastic matrices.

Significance Statement

Cell migration is essential for numerous biological processes in health and disease, including for immune cell trafficking. Monocyte immune cells migrate through extracellular matrix to the tumor microenvironment where they can play a role in regulating cancer progression. Increased extracellular matrix (ECM) stiffness and viscoelasticity have been implicated in cancer progression, but the impact of these changes in the ECM on monocyte migration remains unknown. Here, we find that increased ECM stiffness and viscoelasticity promote monocyte migration. Interestingly, we reveal a previously undescribed adhesion-independent mode of migration whereby monocytes generate a path to migrate through pushing forces at the leading edge. These findings help elucidate how changes in the tumor microenvironment impact monocyte trafficking and thereby disease progression.
BIFROST: a method for registering diverse imaging datasets of theDrosophilabrain
Authors: Brezovec Bella E. , Berger Andrew B. , Hao Yukun A. , Lin Albert , Ahmed Osama M. , Pacheco Diego A. , Thiberge Stephan Y. , Murthy Mala , Clandinin Thomas R.
Published: June 2023

The heterogeneity of brain imaging methods in neuroscience provides rich data that cannot be captured by a single technique, and our interpretations benefit from approaches that enable easy comparison both within and across different data types. For example, comparing brain-wide neural dynamics across experiments and aligning such data to anatomical resources, such as gene expression patterns or connectomes, requires precise alignment to a common set of anatomical coordinates. However, this is challenging because registeringin vivofunctional imaging data toex vivoreference atlases requires accommodating differences in imaging modality, microscope specification, and sample preparation. We overcome these challenges inDrosophilaby building anin vivoreference atlas from multiphoton-imaged brains, called the Functional Drosophila Atlas (FDA). We then develop a two-step pipeline, BrIdge For Registering Over Statistical Templates (BIFROST), for transforming neural imaging data into this common space and for importingex vivoresources such as connectomes. Using genetically labeled cell types as ground truth, we demonstrate registration with a precision of less than 10 microns. Overall, BIFROST provides a pipeline for registering functional imaging datasets in the fly, both within and across experiments.

Significance

Large-scale functional imaging experiments inDrosophilahave given us new insights into neural activity in various sensory and behavioral contexts. However, precisely registering volumetric images from different studies has proven challenging, limiting quantitative comparisons of data across experiments. Here, we address this limitation by developing BIFROST, a registration pipeline robust to differences across experimental setups and datasets. We benchmark this pipeline by genetically labeling cell types in the fly brain and demonstrate sub-10 micron registration precision, both across specimens and across laboratories. We further demonstrate accurate registration betweenin-vivobrain volumes and ultrastructural connectomes, enabling direct structure-function comparisons in future experiments.
HIV self-testing positivity rate and linkage to confirmatory testing and care: a telephone survey in Côte d’Ivoire, Mali, and Senegal
Authors: Kra Arsène Kouassi , Fotso Arlette Simo , Rouveau Nicolas , Maheu-Giroux Mathieu , Boily Marie-Claude , Silhol Romain , d’Elbée Marc , Vautier Anthony , Larmarange Joseph
Published: June 2023

Abstract

HIV self-testing (HIVST) empowers individuals to decide when and where to test and with whom to share their results. From 2019 to 2022, the ATLAS program distributed ∼ 400 000 HIVST kits in Côte d’Ivoire, Mali, and Senegal. It prioritised key populations, including female sex workers and men who have sex with men, and encouraged secondary distribution of HIVST to their partners, peers and clients.

To preserve the confidential nature of HIVST, use of kits and their results were not systematically tracked. Instead, an anonymous phone survey was carried out in two phases during 2021 to estimate HIVST positivity rates (phase 1) and linkage to confirmatory testing (phase 2). Initially, participants were recruited via leaflets from March to June and completed a sociobehavioural questionnaire. In the second phase (September-October), participants who had reported two lines or who reported a reactive result were recontacted to complete another questionnaire. Of the 2 615 initial participants, 89.7% reported a consistent response between the number of lines on the HIVST and their interpretation of the result (i.e., ‘non-reactive’ for 1 line, ‘reactive’ for 2 lines).

Overall positivity rate based on self-interpreted HIVST results was 2.5% considering complete responses, and could have ranged from 2.4% to 9.1% depending on the interpretation of incomplete responses. Using the reported number of lines, this rate was estimated at 4.5% (ranging from 4.4% to 7.2%). Positivity rates were significantly lower only among respondents with higher education. No significant difference was observed by age, key population profile, country or history of HIV testing.

The second phase saw 78 out of 126 eligible participants complete the questionnaire. Of the 27 who reported a consistent reactive response in the first phase, 15 (56%, 95%CI: 36 to 74%) underwent confirmatory HIV testing, with 12 (80%) confirmed as HIV-positive, all of whom began antiretroviral treatment.

The confirmation rate of HIVST results was fast, with 53% doing so within a week and 91% within three months of self-testing. Two-thirds (65%) went to a general public facility, and one-third to a facility dedicated to key populations.

The ATLAS HIVST distribution strategy reached people living with HIV in West Africa. Linkage to confirmatory testing following a reactive HIVST remained relatively low in these first years of HIVST implementation. However, if confirmed HIV-positive, almost all initiated treatment. HIVST constitutes a relevant complementary tool to existing screening services.
Computational prediction of gamma-oryzanol as potential agonist of human peroxisome proliferator-activated receptor gamma (ppar-γ)
Authors: Biswal Prasanta Kumar , Behera Swagatika , Mohapatra Snehamayee , Kar Durga Madhab , Samanta Luna , Behera Pabitra Mohan , Kar Rajat Kumar
Published: June 2023

Diabetes mellitus is one of the complex metabolic disorders associated with individuals leading sedentary lifestyles. It leads to several complications rendering the normal function of vital organs like heart, liver, kidney, eye and brain. Scientists and doctors across the globe are involved in research for understanding the complex genetics of this disorder and formulating newer therapeutics accordingly. The finding of potential chemical entities and their underlying agonists or antagonist activities significantly controls the disorder but with some consequences. Thus there is demand for natural compounds and indigenous treatment methods for controlling the disorder with least or no adverse consequences. In the current work we present computational prediction of gamma-oryzanol as potential agonist of human peroxisome proliferator-activated receptor gamma (PPAR-γ). A group of four gamma-oryzanol compound structures reported in PubChem database were downloaded and docked in the ligand binding site of five different human PPAR-γ structures reported in PDB database. It was observed that most of the gamma-oryzanol compounds occupied themselves in the ligand binding P1, P2, P3, P4 sites with similar orientations as that of co-crystal agonists. Their binding conformations were assisted by some reasonable docking scores (−7 to -11 kcal/mol) and hydrogen bond interactions with some important conserved amino acid residues lining the ligand binding site. Additionally we have done a comparative molecular dynamics studies to reveal the flexibility of gamma-oryzanol in the ligand binding site in comparison to the co-crystal agonist and a scaffold analysis using the structure of six agonists and gamma-oryzanol for fetching potential scaffolds which may helpful in designing of new chemical entities.
AraENCODE: a comprehensive epigenomic database ofArabidopsis Thaliana
Authors: Wang Zhenji , Liu Minghao , Lai Fuming , Fu Qiangqiang , Xie Liang , Fang Yaping , Zhou Qiangwei , Li Guoliang
Published: June 2023

Arabidopsis (Arabidopsis thaliana) is a vital model organism in plant biology and genetics. In the last two decades, researchers have made significant progresses in characterizing the chromatin conformation and epigenomic information within the Arabidopsis genome. This information includes but is not limited to the higher structure of chromosomes, histone modification, DNA methylation, and chromatin accessibility. The results of these studies have provided an additional layer of information that complements the DNA sequence data. However, utilizing such knowledge poses a challenge for certain groups that lack bioinformatics analysts or adequate computing resources. A user-friendly and reproducible platform for accessing this information is urgently needed. In this study, we have developed a comprehensive epigenomic database for Arabidopsis (AraENCODEhttp://glab.hzau.edu.cn/AraENCODE), which comprises a total of 4,511 data libraries, including published chromatin conformation capture datasets (Hi-C, HiChIP), epigenomic datasets (ChIP-Seq, ATAC-Seq, FAIRE-Seq, MNase-Seq, DNase-Seq, BS-seq), and transcriptome data (RNA-Seq, miRNA-Seq). Furthermore, we have incorporated various existing resources, such as single nucleotide polymorphisms (SNPs), cis-regulatory modules, and multi-omics associations. We aim to provide a novel platform for investigating the regulation of epigenetic and chromatin interactions in Arabidopsis in relation to biological processes.
Deep learning-based survival prediction using DNA methylation-derived 3D genomic information
Authors: Yang Jeewon , Lee Dohoon , Koo Bonil , Kim Sun
Published: June 2023

Three-dimensional (3D) genome states are closely related to cancer development. Nonetheless, the 3D genome information has not been clinically utilized to the best of our knowledge, due to the costly production of Hi-C data which is a manifest source of 3D genome information. Therefore, there is a need for a novel metric computable from a 3D genome-related data which is more easily accessible for the clinical utilization of 3D genome information. We here propose a method to extract 3D genome-aware epigenetic features from DNA methylation data and use these features for a deep learning-based survival prediction. These features are derived from the 3D genome structures which are rebuilt from the DNA methylation data in an individual level. The results showed that usage of 3D genome-aware features contributed to more accurate risk prediction across seven cancer types, suggesting the effectiveness of the knowledge about 3D genome structure embedded in these features. The deeper biological investigation revealed that altered DNA methylation level in risk-high group could be related to the anomalously activated genes involved in cancer-related pathways. Altogether, the risks predicted from 3D genome-aware epigenetic features showed its significance as a survival predictor in seven cancer types, along with its biological importance.
In Vitro Reduction of Device Thrombosis Using a Combined Nitrite and Red Light Treatment
Authors: Alipour Elmira , Jordan James E. , Poudel Laxman , Files D. Clark , Kim-Shapiro Daniel B.
Published: June 2023

Device thrombosis occurs in otherwise life-saving procedures involving blood-contacting medical devices. Despite the use of systemic blood thinners, anticoagulants, and antiplatelet agents, device thrombosis can lead to substantial neurological damage, limb loss, death, and prolonged illness. Systemic treatments can also lead to bleeding. New methods to locally reduce thrombosis are urgently needed. Earlier work has shown that nitrite is a unique nitric oxide (NO) donor that is well-suited to use in blood and that its ability to inhibit platelet activation is potentiated by far-red light. In this study, we have applied our combined nitrite/light treatment in a prototypical technique used to prevent device thrombosis in extracorporeal circulation. We show that circuit pressure and survival are improved by an average of 213 percent with our treatment compared to the control. In addition, the dual therapy preserved platelet numbers at the end of the circulation time (%17 difference in platelet loss), and it reduced circuit hemolysis 2.3 fold. Thus, the combination of nitrite and red-light illumination has potential to prevent device thrombosis and to lead new clinical applications and practices.
Genomics resolves historical uncertainties on phylogenetics and accommodates the systematics of marmosets and Goeldi’s monkey (Primates: Platyrrhini)
Authors: Costa-Araújo Rodrigo , Roos Christian , Röhe Fabio , de Sousa e Silva José , de Freitas Patricia Domingues , Pissinatti Alcides , Boubli Jean P. , Farias Izeni P. , Hrbek Tomas
Published: June 2023

Marmosets, with a total of 24 species classified into four genera (Callithrix,Cebuella,MicoandCallibella), are the smallest of the anthropoids and one of the most diverse and widespread groups of primates in South America. In contrast, the Goeldi’s monkey (Callimico goeldii) is represented by a single species of black, small, fungi-eating primates, endemic to west Amazonia. The phylogenetic relationships of marmoset genera and the phylogenetic position of Goeldi’s monkey, and consequently their systematics, remain uncertain and subject to debate because earlier studies revealed incongruent conclusions. Here we tackle this issue by first reviewing the systematics and the history of phylogenetic studies of marmosets and Goeldi’s monkey. We then explore their phylogenetic relationships by reconstructing a time-calibrated phylogeny using a genome-wide sampling of all lineages of marmosets, tamarins, Goeldi’s monkey, lion tamarins, capuchins, and squirrel monkeys. Our results clearly demonstrate that historical disagreements on phylogenetics and systematics of marmosets are due to incomplete lineage sorting, low phylogenetic signal of morphological and ecological characters, and low sampling at the DNA level. We show that Goeldi’s monkey is a sister lineage to marmosets and suggest that past incongruencies between studies on its phylogenetics and systematics are due to homoplasy of morphological characters traditionally used to infer primate relationships. Accordingly, we accommodate a genus-level classification for marmosets based on a fully-resolved phylogeny and multiple biological traits, redefine the genusMico, update the definitions ofCallibella,Callithrix, andCebuella, and sediment the family-level classification of Goeldi’s monkey.