Mapping the transcriptome: Realizing the full potential of spatial data analysis.

RNA sequencing in situ allows for whole-transcriptome characterization at high resolution, while retaining spatial information. These data present an analytical challenge for bioinformatics-how to leverage spatial information effectively? Properties of data with a spatial dimension require special handling, which necessitate a different set of statistical and inferential considerations when compared to non-spatial data. The geographical sciences primarily use spatial data and have developed methods to analye them. Here we discuss the challenges associated with spatial analysis and examine how we can take advantage of practice from the geographical sciences to realize the full potential of spatial information in transcriptomic datasets.

STW-MD: a novel spatio-temporal weighting and multi-step decision tree method for considering spatial heterogeneity in brain gene expression data.

Gene expression during brain development or abnormal development is a biological process that is highly dynamic in spatio and temporal. Previous studies have mainly focused on individual brain regions or a certain developmental stage. Our motivation is to address this gap by incorporating spatio-temporal information to gain a more complete understanding of brain development or abnormal brain development, such as Alzheimer's disease (AD), and to identify potential determinants of response. In this study, we propose a novel two-step framework based on spatial-temporal information weighting and multi-step decision trees. This framework can effectively exploit the spatial similarity and temporal dependence between different stages and different brain regions, and facilitate differential gene analysis in brain regions with high heterogeneity. We focus on two datasets: the AD dataset, which includes gene expression data from early, middle and late stages, and the brain development dataset, spanning fetal development to adulthood. Our findings highlight the advantages of the proposed framework in discovering gene classes and elucidating their impact on brain development and AD progression across diverse brain regions and stages. These findings align with existing studies and provide insights into the processes of normal and abnormal brain development.

Hourglass, a compass navigating global and regional heterogeneity of pancreatic cancer†.

Advances in the digital pathology field have facilitated the characterization of histology samples for both clinical and preclinical research. However, uncovering subtle correlations between bioimaging, clinical and molecular parameters requires extensive statistical analysis. As a user-friendly software, Hourglass, simplifies multiparametric dataset analysis through intuitive data visualization and statistical tools. Systemic analysis of interleukin-6 (IL-6)/pStat3 signaling pathway through Hourglass revealed differences in regional immune cell composition within tumors. Moreover, these regional disparities were partially mediated by sex. Overall, Hourglass simplifies information extraction from complex datasets, resolving overlooked regional and global spatial tumor differences. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Geographical patterns of social cohesion drive disparities in early COVID infection hazard.

The uneven spread of COVID-19 has resulted in disparate experiences for marginalized populations in urban centers. Using computational models, we examine the effects of local cohesion on COVID-19 spread in social contact networks for the city of San Francisco, finding that more early COVID-19 infections occur in areas with strong local cohesion. This spatially correlated process tends to affect Black and Hispanic communities more than their non-Hispanic White counterparts. Local social cohesion thus acts as a potential source of hidden risk for COVID-19 infection.

Evaluating the immunologically "cold" tumor microenvironment after treatment with immune checkpoint inhibitors utilizing PET imaging of CD4 + and CD8 + T cells in breast cancer mouse models.

BACKGROUND: Immune-positron emission tomography (PET) imaging with tracers that target CD8 and granzyme B has shown promise in predicting the therapeutic response following immune checkpoint blockade (ICB) in immunologically "hot" tumors. However, immune dynamics in the low T-cell infiltrating "cold" tumor immune microenvironment during ICB remain poorly understood. This study uses molecular imaging to evaluate changes in CD4 + T cells and CD8 + T cells during ICB in breast cancer models and examines biomarkers of response. METHODS: [89Zr]Zr-DFO-CD4 and [89Zr]Zr-DFO-CD8 radiotracers were used to quantify changes in intratumoral and splenic CD4 T cells and CD8 T cells in response to ICB treatment in 4T1 and MMTV-HER2 mouse models, which represent immunologically "cold" tumors. A correlation between PET quantification metrics and long-term anti-tumor response was observed. Further biological validation was obtained by autoradiography and immunofluorescence. RESULTS: Following ICB treatment, an increase in the CD8-specific PET signal was observed within 6 days, and an increase in the CD4-specific PET signal was observed within 2 days in tumors that eventually responded to immunotherapy, while no significant differences in CD4 or CD8 were found at the baseline of treatment that differentiated responders from nonresponders. Furthermore, mice whose tumors responded to ICB had a lower CD8 PET signal in the spleen and a higher CD4 PET signal in the spleen compared to non-responders. Intratumoral spatial heterogeneity of the CD8 and CD4-specific PET signals was lower in responders compared to non-responders. Finally, PET imaging, autoradiography, and immunofluorescence signals were correlated when comparing in vivo imaging to ex vivo validations. CONCLUSIONS: CD4- and CD8-specific immuno-PET imaging can be used to characterize the in vivo distribution of CD4 + and CD8 + T cells in response to immune checkpoint blockade. Imaging metrics that describe the overall levels and distribution of CD8 + T cells and CD4 + T cells can provide insight into immunological alterations, predict biomarkers of response to immunotherapy, and guide clinical decision-making in those tumors where the kinetics of the response differ.

Spatial Analysis of Drug-Susceptible and Multidrug-Resistant Cases of Tuberculosis, Ho Chi Minh City, Vietnam, 2020-2023.

We characterized the spatial distribution of drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) cases in Ho Chi Minh City, Vietnam, a major metropolis in southeastern Asia, and explored demographic and socioeconomic factors associated with local TB burden. Hot spots of DS and MDR TB incidence were observed in the central parts of Ho Chi Minh City, and substantial heterogeneity was observed across wards. Positive spatial autocorrelation was observed for both DS TB and MDR TB. Ward-level TB incidence was associated with HIV prevalence and the male proportion of the population. No ward-level demographic and socioeconomic indicators were associated with MDR TB case count relative to total TB case count. Our findings might inform spatially targeted TB control strategies and provide insights for generating hypotheses about the nature of the relationship between DS and MDR TB in Ho Chi Minh City and the wider southeastern region of Asia.

The root microlandscape of arbuscular mycorrhizal fungi.

Understanding the drivers of assemblages of arbuscular mycorrhizal fungi (AMF) is essential to leverage the benefits of AMF for plant growth and health. Arbuscular mycorrhizal fungi are heterogeneously distributed in space even at small scale. We review the role of plant distribution in driving AMF assemblages (the passenger hypothesis), using a transposition of the conceptual framework of landscape ecology. Because rooting systems correspond to habitat patches with limited carrying capacity that differ in quality due to host-preference effects, we suggest considering plant communities as mosaics of AMF microhabitats. We review how predictions from landscape ecology apply to plant community effects on AMF, and the existing evidence that tests these predictions. Although many studies have been conducted on the effect of plant compositional heterogeneity on AMF assemblages, they mostly focused on the effect of plant richness, while only a few investigated the effect of configurational heterogeneity, plant connectivity or plant community temporal dynamics. We propose key predictions and future prospects to fill these gaps. Considering plant communities as landscapes extends the passenger hypothesis by including a spatially explicit dimension and its associated ecological processes and may help understand and manipulate AMF assemblages at small spatial scales.

Resolving spatial response heterogeneity in glioblastoma.

PURPOSE: Spatial intratumoral heterogeneity poses a significant challenge for accurate response assessment in glioblastoma. Multimodal imaging coupled with advanced image analysis has the potential to unravel this response heterogeneity. METHODS: Based on automated tumor segmentation and longitudinal registration with follow-up imaging, we categorized contrast-enhancing voxels of 61 patients with suspected recurrence of glioblastoma into either true tumor progression (TP) or pseudoprogression (PsP). To allow the unbiased analysis of semantically related image regions, adjacent voxels with similar values of cerebral blood volume (CBV), FET-PET, and contrast-enhanced T1w were automatically grouped into supervoxels. We then extracted first-order statistics as well as texture features from each supervoxel. With these features, a Random Forest classifier was trained and validated employing a 10-fold cross-validation scheme. For model evaluation, the area under the receiver operating curve, as well as classification performance metrics were calculated. RESULTS: Our image analysis pipeline enabled reliable spatial assessment of tumor response. The predictive model reached an accuracy of 80.0% and a macro-weighted AUC of 0.875, which takes class imbalance into account, in the hold-out samples from cross-validation on supervoxel level. Analysis of feature importances confirmed the significant role of FET-PET-derived features. Accordingly, TP- and PsP-labeled supervoxels differed significantly in their 10th and 90th percentile, as well as the median of tumor-to-background normalized FET-PET. However, CBV- and T1c-related features also relevantly contributed to the model's performance. CONCLUSION: Disentangling the intratumoral heterogeneity in glioblastoma holds immense promise for advancing precise local response evaluation and thereby also informing more personalized and localized treatment strategies in the future.

Effect of unequal vaccination coverage and migration on long-term pathogen evolution in a metapopulation.

Worldwide inequalities in vaccine availability are expected to affect the spread and spatial distribution of infectious diseases. It is unclear, however, how spatial variation in vaccination coverage can affect the long-term evolution of pathogens. Here we use an analytical model and numerical simulations to analyse the influence of different imperfect vaccines on the potential evolution of pathogen virulence in a two-population model where vaccination coverage varies between populations. We focus on four vaccines, with different modes of action on the life cycle of a pathogen infecting two host populations coupled by migration. We show that, for vaccines that reduce infection risk or transmissibility, spatial heterogeneity has little effect on pathogen prevalence and host mortality, and no effect on the evolution of pathogen virulence. In contrast, vaccines that reduce pathogen virulence can select for more virulent pathogens and may lead to the coexistence of different pathogen strains, depending on the degree of spatial heterogeneity in the metapopulation. This heterogeneity is driven by two parameters: pathogen migration and the difference in the vaccination rate between the two populations. We show that vaccines that only reduce pathogen virulence select mainly for a single pathogen strategy in the long term, while vaccines that reduce both transmission and virulence can favor the coexistence of two pathogen genotypes. We discuss the implications and potential extensions of our analysis.

Spatial analyses of immune cell infiltration in cancer: current methods and future directions: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.

Shining a Light on How Soil Organic Carbon Behaves at Fine Scales under Long-Term Elevated CO2: An 8 Year Free-Air Carbon Dioxide Enrichment Study.

Building and protecting soil organic carbon (SOC) are critical to agricultural productivity, soil health, and climate change mitigation. We aim to understand how mechanisms at the organo-mineral interfaces influence SOC persistence in three contrasting soils (Luvisol, Vertisol, and Calcisol) under long-term free air CO2 enrichment conditions. A continuous wheat-field pea-canola rotation was maintained. For the first time, we provided evidence to a novel notion that persistent SOC is molecularly simple even under elevated CO2 conditions. We found that the elevated CO2 condition did not change the total SOC content or C forms compared with the soils under ambient CO2 as identified by synchrotron-based soft X-ray analyses. Furthermore, synchrotron-based infrared microspectroscopy confirmed a two-dimensional microscale distribution of similar and less diverse C forms in intact microaggregates under long-term elevated CO2 conditions. Strong correlations between the distribution of C forms and O-H groups of clays can explain the steady state of the total SOC content. However, the correlations between C forms and clay minerals were weakened in the coarse-textured Calcisol under long-term elevated CO2. Our findings suggested that we should emphasize identifying management practices that increase the physical protection of SOC instead of increasing complexity of C. Such information is valuable in developing more accurate C prediction models under elevated CO2 conditions and shift our thinking in developing management practices for maintaining and building SOC for better soil fertility and future environmental sustainability.

The influence of scale-dependent geodiversity on species distribution models in a biodiversity hotspot.

Improving models of species' distributions is essential for conservation, especially in light of global change. Species distribution models (SDMs) often rely on mean environmental conditions, yet species distributions are also a function of environmental heterogeneity and filtering acting at multiple spatial scales. Geodiversity, which we define as the variation of abiotic features and processes of Earth's entire geosphere (inclusive of climate), has potential to improve SDMs and conservation assessments, as they capture multiple abiotic dimensions of species niches, however they have not been sufficiently tested in SDMs. We tested a range of geodiversity variables computed at varying scales using climate and elevation data. We compared predictive performance of MaxEnt SDMs generated using CHELSA bioclimatic variables to those also including geodiversity variables for 31 mammalian species in Colombia. Results show the spatial grain of geodiversity variables affects SDM performance. Some variables consistently exhibited an increasing or decreasing trend in variable importance with spatial grain, showing slight scale-dependence and indicating that some geodiversity variables are more relevant at particular scales for some species. Incorporating geodiversity variables into SDMs, and doing so at the appropriate spatial scales, enhances the ability to model species-environment relationships, thereby contributing to the conservation and management of biodiversity. This article is part of the Theo Murphy meeting issue 'Geodiversity for science and society'.

Activation of PKC affects the ventricular restitution properties and arrhythmogenesis through L-type Ca+ current.

OBJECTIVE: To investigate the role of protein kinase C (PKC) in action potential duration (APD) restitution and ventricular tachyarrhythmias (VAs). METHODS AND RESULTS: Rabbits hearts were isolated and prepared for Langendorff perfusion technique. The stimuli-extra-stimulus (S1-S2) method and dynamic S1 pacing protocol were performed to construct APD restitution and to induce APD alternans or VA, respectively, at 10 sites throughout the ventricular chamber. Administration of phorbol-12-myristate-13-acetate (PMA) (100 nM) (n = 15) greatly steepened the restitution curves (Smax > 1) (p < .01) at each site compared to the control group (n = 15). Furthermore, treatment with PMA also induced larger spatial dispersions of Smax (p < .05) and decreased the thresholds of the VA and APD alternans (p < .01). However, perfused with the PKC inhibitor, bisindolylmaleimide (BIM) (500 nM) (n = 10), reversibly flattened the APD restitution curves at each site (Smax < 1), decreased the spatial dispersions of Smax, and increased the thresholds of APD alternans and VA. According to the results of patch-clamp, peak amplitude of L-type Ca2+ current was significantly increased by addition of PMA compared with control (CTL) group (p < .05). Antagonize this current with verapamil (n = 10) can fully inhibited the PMA induced increasing of Smax and inducibility of VA and alternans. CONCLUSION: PKC activation increased the dispersion of APD restitution and thus led to occurrence of VA, which possibly related to the increased Ca2+ influx.

Source apportionment of soil PTE in a northern industrial county using PMF model: Partitioning strategies and uncertainty analysis.

Positive matrix factorization (PMF) has commonly been applied for source apportionment of potentially toxic elements (PTE) in agricultural soil, however, spatial heterogeneity of PTE significantly undermines the accuracy and reliability of PMF results. In this study, a representative industrial-agricultural hub in North China (Xuanhua district, Zhangjiakou City) was selected as the research subject, multiple partition processing (PP) strategies and uncertainty analyses were integrated to advance the PMF modeling and associated algorithm mechanisms were comparatively discussed. Specifically, we adopted three methods to split the research area into several subzones according to industrial density (PP-1), population density (PP-2), and the ecological risk index (PP-3) respectively, to rectify the spatial bias phenomenon of PTE concentrations and to achieve a more interpretable result. Our results indicated that the obvious enrichment of Cd, Pb, and Zn was found in the agricultural soil, with Hg and Cd accounted for 83.49% of the overall potential ecological risk. Combining proper PP with PMF can significantly improve the modelling accuracy. Uncertainty analysis showed that interval ratios of tracer species (Cd, Pb, Hg, and Zn) calculated by PP-3 were consistently lower than that of PP-1 and PP-2, indicating that PP-3 coupled PMF can afford the optimal modeling results. It suggested that natural sources, fertilizers and pesticides, atmosphere deposition, mining, and smelting were recognized as the major contributor for the soil PTE contamination. The contribution of anthropogenic activities, specifically fertilizers and pesticides, and atmosphere deposition, increased by 1.64% and 5.91% compared to PMF results. These findings demonstrate that integration of proper partitioning processing into PMF can effectively improve the accuracy of the model even at the case of soil PTE contamination with high heterogeneity, offering support to subsequently implement directional control strategies.

Threshold dynamics of a reaction-advection-diffusion schistosomiasis epidemic model with seasonality and spatial heterogeneity.

Most water-borne disease models ignore the advection of water flows in order to simplify the mathematical analysis and numerical computation. However, advection can play an important role in determining the disease transmission dynamics. In this paper, we investigate the long-term dynamics of a periodic reaction-advection-diffusion schistosomiasis model and explore the joint impact of advection, seasonality and spatial heterogeneity on the transmission of the disease. We derive the basic reproduction number R 0 and show that the disease-free periodic solution is globally attractive when R 0 < 1 whereas there is a positive endemic periodic solution and the system is uniformly persistent in a special case when R 0 > 1 . Moreover, we find that R 0 is a decreasing function of the advection coefficients which offers insights into why schistosomiasis is more serious in regions with slow water flows.

Measuring spatial inequalities in maternal and child mortalities in Pakistan: evidence from geographically weighted regression.

BACKGROUND: In developing countries, the death probability of a child and mother is more significant than in developed countries; these inequalities in health outcomes are unfair. The present study encompasses a spatial analysis of maternal and child mortalities in Pakistan. The study aims to estimate the District Mortality Index (DMI), measure the inequality ratio and slope, and ascertain the spatial impact of numerous factors on DMI scores across Pakistani districts. METHOD: This study used micro-level household datasets from multiple indicator cluster surveys (MICS) to estimate the DMI. To find out how different the DMI scores were, the inequality ratio and slope were used. This study further utilized spatial autocorrelation tests to determine the magnitude and location of the spatial dependence of the clusters with high and low mortality rates. The Geographically Weighted Regression (GWR) model was also applied to examine the spatial impact of socioeconomic, environmental, health, and housing attributes on DMI. RESULTS: The inequality ratio for DMI showed that the upper decile districts are 16 times more prone to mortalities than districts in the lower decile, and the districts of Baluchistan depicted extreme spatial heterogeneity in terms of DMI. The findings of the Local Indicator of Spatial Association (LISA) and Moran's test confirmed spatial homogeneity in all mortalities among the districts in Pakistan. The H-H clusters of maternal mortality and DMI were in Baluchistan, and the H-H clusters of child mortality were seen in Punjab. The results of GWR showed that the wealth index quintile has a significant spatial impact on DMI; however, improved sanitation, handwashing practices, and antenatal care adversely influenced DMI scores. CONCLUSION: The findings reveal a significant disparity in DMI and spatial relationships among all mortalities in Pakistan's districts. Additionally, socioeconomic, environmental, health, and housing variables have an impact on DMI. Notably, spatial proximity among individuals who are at risk of death occurs in areas with elevated mortality rates. Policymakers may mitigate these mortalities by focusing on vulnerable zones and implementing measures such as raising public awareness, enhancing healthcare services, and improving access to clean drinking water and sanitation facilities.

Unveiling spatial disparities in basic medical and health services: insights from China's provincial analysis.

Based on the panel data of 31 provinces (municipalities and autonomous regions) in China from 2012 to 2019, this paper constructs the evaluation index system of basic medical and health services in China from seven dimensions: medical and health facilities, health expenditure, medical services, traditional Chinese medicine hospital services, maternal and child health care, people's health and medical security, disease control and public health. The entropy method was used to measure the level of basic medical and health services in China, and its spatial differences and convergence characteristics were further investigated. In this study, we employ the entropy weight method, σ convergence, and ß convergence as our primary methodologies. The entropy weight method is used to evaluate the variability of each indicator, determine the weights of indicators, and quantify the information content of the data. σ convergence illustrates the process by which the variance of a sample decreases over time. ß convergence refers to the gradual approach of variables within an economic system towards their long-term equilibrium level over time. The results show that: (1) The scores of basic medical and health services in China's four major regions (including Northeast, East, Central and West) remain in a relatively stable state, with small fluctuations and great room for improvement; (2) There are significant regional differences in the level of basic medical and health services in China, and the intra-regional differences are much greater than the inter-regional differences; (3) There is no significant σ convergence observed in China and its four major regions; however, there is a notable presence of ß convergence.

Replication across space and time must be weak in the social and environmental sciences.

Replicability takes on special meaning when researching phenomena that are embedded in space and time, including phenomena distributed on the surface and near surface of the Earth. Two principles, spatial dependence and spatial heterogeneity, are generally characteristic of such phenomena. Various practices have evolved in dealing with spatial heterogeneity, including the use of place-based models. We review the rapidly emerging applications of artificial intelligence to phenomena distributed in space and time and speculate on how the principle of spatial heterogeneity might be addressed. We introduce a concept of weak replicability and discuss possible approaches to its measurement.

Undernutrition among children and its determinants across the parliamentary constituencies of India: a geospatial analysis.

In India, undernutrition among children has been extremely critical for the last few decades. Most analyses of undernutrition among Indian children have used the administrative boundaries of a state or a district level as a unit of analysis. This paper departs from such a practice and focuses instead on the political boundaries of a parliamentary constituency (PC) as the unit of analysis. The PC is a critical geopolitical unit where political parties and party candidates make election promises and implement programmes to improve the socio-economic condition of their electorate. A focus on child undernutrition at this level has the potential for greater policy and political traction and could lead to a paradigm shift in the strategy to tackle the problem by creating a demand for political accountability. Different dimensions and new approaches are also required to evaluate the socio-economic status and generate concrete evidence to find solutions to the problem. Given the significance of advanced analytical methods and models embedded into geographic information system (GIS), the current study, for the first time, uses GIS tools and techniques at the PC level, conducting in-depth analysis of undernutrition and its predictors. Hence, this paper examines the spatial heterogeneity in undernutrition across PCs by using geospatial techniques such as univariate and bivariate local indicator of spatial association and spatial regression models. The analysis highlights the high-low burden areas in terms of local hotspots and identifies the potential spatial risk factors of undernutrition across the constituencies. Striking variations in the prevalence of undernutrition across the constituencies were observed. Most of these constituencies that performed poorly both in terms of child nutrition and socio-economic indicators were located in the northern, western, and eastern parts of India. A statistically significant association of biological, socio-economic, and environmental factors such as women's body mass index, anaemia in children, poverty, household sanitation facilities, and institutional births was established. The results highlight the need to bring in a mechanism of political accountability that directly connects elected representatives to maternal and child health outcomes. The spatial variability and pattern of undernutrition indicators and their correlates indicate that priority setting in research may also be greatly influenced by the neighbourhood association.

Mapping of spastic muscle activity after stroke: difference between passive stretch and active contraction.

BACKGROUND: Investigating the spatial distribution of muscle activity would facilitate understanding the underlying mechanism of spasticity. The purpose of this study is to investigate the characteristics of spastic muscles during passive stretch and active contraction by high-density surface electromyography (HD-sEMG). METHODS: Fourteen spastic hemiparetic subjects and ten healthy subjects were recruited. The biceps brachii (BB) muscle activity of each subject was recorded by HD-sEMG during passive stretch at four stretch velocities (10, 60, 120, 180˚/s) and active contraction at three submaximal contraction levels (20, 50, 80%MVC). The intensity and spatial distribution of the BB activity were compared by the means of two-way analysis of variance, independent sample t-test, and paired sample t-test. RESULTS: Compared with healthy subjects, spastic hemiparetic subjects showed significantly higher intensity with velocity-dependent heterogeneous activation during passive stretch and more lateral and proximal activation distribution during active contraction. In addition, spastic hemiparetic subjects displayed almost non-overlapping activation areas during passive stretch and active contraction. The activation distribution of passive stretch was more distal when compared with the active contraction. CONCLUSIONS: These alterations of the BB activity could be the consequence of deficits in the descending central control after stroke. The complementary spatial distribution of spastic BB activity reflected their opposite motor units (MUs) recruitment patterns between passive stretch and active contraction. This HD-sEMG study provides new neurophysiological evidence for the spatial relationship of spastic BB activity between passive stretch and active contraction, advancing our knowledge on the mechanism of spasticity. TRIAL REGISTRATION: ChiCTR2000032245.