bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping lineage-resolved scRNA-seq data with spatial transcriptomics using TemSOMap
Authors: Pan Xinhai , Danies-Lopez Alejandro , Zhang Xiuwei
Published: November 2024

Spatial transcriptomics (ST) has become a powerful technique that advances the study of cell spatial organization and cell-cell interactions. While ST can preserve location information of cells or spots, limitations of such technologies include lower number of genes, and lower resolution compared to scRNA-seq datasets. These limitations can be alleviated by integrating scRNA-seq data with the ST data. By mapping the single cells onto the spatial data, we can infer the spatial coordinates of the cells from the scRNA-seq dataset. We consider leveraging temporal information in this challenging task of spatial location inference. During tissue formation, cells divided from the same ancestor are likely to be located close to each other in the tissue, thus the cell clonal or lineage information can improve cell location inference. CRISPR/Cas9-based lineage tracing technologies have enabled paired sequencing of cells’ gene expression and lineage barcodes. The lineage barcodes can be used to reconstruct the cell lineage tree, which represents cells’ clonal relationships. In order to incorporate this information, we developed TemSOMap (Temporal dynamics guidedSpatialOmicsMapping), which infers the spatial coordinates of cells by mapping a paired gene expression and lineage barcode dataset onto a spatial transcriptomics dataset. TemSOMap utilizes a machine learning framework to infer a cell-to-spot mapping matrix by minimizing a loss function based on expression and lineage. We show that TemSOMap more accurately infers the spatial location of single cells compared to state-of-the-art baseline methods under various scenarios, using both simulated and real datasets. The resulting lineage-resolved ST data can help us better understand the spatio-temporal dynamics of cells in a tissue. TemSOMap is publicly available athttps://github.com/ZhangLabGT/TemSOMap.
Phytoassisted synthesis of biogenic silver nanoparticles usingVernonia amygdalinaleaf extract: characterization, antibacterial, anti-inflammatory, and acute toxicity profile
Authors: Gildas Fonye Nyuyfoni , Parfait Nkana Blondeau , Deli Vandi , Kedi Philippe Belle Ebanda , Antoinette Ntoumba Agnes , Christian Nanga Chick , Geordamie Chimi Tchatchouang , Guilaine Djuidje Annie , Alex Kevin Tako Djimefo , Ines Danielle Evouna Madeleine , Fanny-Aimee Essombe Malolo , Costly Kang Eha-Kang , Leonard Kwati , Ndzeidze Gilbert Njowir , Awawou Paboudam Gbambie , Francois Eya’ane Meva
Published: November 2024

The increasing rate of antimicrobial resistance and pathological consequences associated with long-term use of available anti-inflammatory drugs justifies the urgent need to discover and rationally design new effective antimicrobial and anti-inflammatory drugs. This study reports the antibacterial, anti-inflammatory, and acute toxicity profile ofVernonia amygdalinaleaf extract-mediated silver nanoparticles (VA-AgNPs).The VA-AgNPs were synthesized by mixing Ag+ions with aqueous leaf extract fromVernonia amygdalinaand then characterized using UV-visible spectrophotometry (UV-Vis), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). An antibacterial study onEscherichia colistrains, carrageenan-induced rat paw edema, and oral acute toxicity assays were performed. The change in color from light brown to dark brown showed the formation of VA-AgNPs which was further confirmed by the surface plasmon resonance picked between 400 and 450 nm on the UV-Vis spectrum. Synthetic stability studies revealed an increase in VA-AgNPs formation at basic pH and with increasing reactant quantities. The X-ray pattern showed nanocrystalline particles of Ag and AgCl of 13, and 18 nm mean sizes, respectively. SEM images depicted aggregates of spherical shape. The synthesized VA-AgNPs inhibitedEscherichia coligrowth with a minimum inhibition concentration of 0.125 mg/mL and rat paw edema with a maximum inhibition percentage of 96% at a dose of 0.4 mg/kg body weight. The oral administration of VA-AgNPs was associated with no toxicity sign, supporting their use for the development of new effective antibacterial and anti-inflammatory drugs.
Association between loneliness and hippocampal responses to dynamic social stimuli in psychotic disorders
Authors: McKenna Faye , Vinke Louis N. , Avanaki Mona , Holt Daphne J.
Published: November 2024

Background

The incidence of loneliness has increased over the past several decades worldwide and is particularly common among people with serious mental illnesses. However, this public health problem has been difficult to address, in part because the neurocognitive mechanisms underlying loneliness are poorly understood.

Methods

To investigate these mechanisms, a functional magnetic resonance imaging (fMRI) study was conducted which accounted for known cognitive biases associated with loneliness. Participants with (n = 40) and without (n = 60) psychotic disorders (PD) viewed images of faces that appeared to approach or withdraw from the participants, while fMRI data were collected. Following the scanning, participants rated the trustworthiness of the faces, and these ratings were included as weights in the fMRI analyses. Neural responses to approaching versus withdrawing faces were measured, and whole brain regression analyses, with loneliness as the regressor, were performed.

Results

In the PD and full samples, a higher level of loneliness was significantly associated with greater responses of the hippocampus and areas of the basal ganglia to withdrawing (versus approaching) face stimuli. Moreover, the effects in the hippocampus, but not the basal ganglia, remained significant after controlling for potential confounds such as social activity levels, depression and social anhedonia. Lastly, in a subset of the sample (n = 66), greater hippocampal responses to withdrawing faces predicted greater loneliness one year later.

Conclusions

Heightened responses of the hippocampus to withdrawing faces may represent a candidate objective marker of loneliness that could be modified by interventions targeting loneliness.
Methanol Crude Extract ofLitsea MonopetalaLeaves combats oxidative stress, clot formation, inflammation and stool frequency in Animal Model
Authors: Labu Zubair Khalid , Karim Samira , Arifuzzaman Sarder
Published: November 2024

Litsea monopetala(LM) leaves are used in traditional medicine systems in the South Asian region for treating ailments such as digestive issues, respiratory problems, and skin disorders. In this study, we first investigated the possible antioxidant, thrombolytic characteristics, analgesic, and antidiarrheal activity of the methanolic crude extract of LM leaves. To assess the antioxidant, thrombolytic, analgesic, and antidiarrheal activity of the crude extract we used DPPH free radical scavenging, clot lysis, acetic acid, and castor oil-induced animal model, respectively. Before applying the extract to the animal model, phytochemical screening was performed to estimate the bioactive compounds (e.g.- phenol, flavonoid, alkaloids, tannins, and others) present. The extract exhibited DPPH free radical scavenging features with an IC50of 8.99 µg/mL compared to ascorbic acid, an IC50of 13.38 µg/ml. At 500 mg/kg dose, the extract produced a significant decrease (67.05%) in the frequency of writhings while diclofenac sodium decreased by 74.15%. The extract also significantly (P<0.01) decreased the frequency of diarrhea when compared to the standard drug of loperamide (3mg/kg). Finally, we assessed the clot lysis function as representative of the thrombolytic activity of extracts in comparison to streptokinase and demonstrated clot lysis action (74.15% decrease). From a therapeutic implication, we suggest that crude extract of LM’s leaves may contribute to the alternative or additive strategy to modulate conditions such as oxidative stress, clot formation, inflammation and diarrhea.
Loss of KDM6A-mediated genomic instability and metabolic reprogramming differentially regulates responses to immune checkpoint therapy and chemotherapy in bladder cancer
Authors: Singh Pratishtha , Raychaudhuri Deblina , Chakraborty Bidisha , Meher Swadhin , Tannir Aminah J. , Majumdar Anurag , Hawkins Jessalyn , Xiong Yun , Lorenzi Philip , Sharma Padmanee , Pilié Patrick , Goswami Sangeeta
Published: November 2024

Mutations in genes encoding critical epigenetic regulators are frequently noted in bladder cancer, however, the impact of these mutations on therapeutic efficacy is unclear. One of the most common driver mutations in bladder cancer occurs in theKDM6Agene, which encodes a histone demethylase that promotes gene transcription. Retrospective analyses of patients with bladder cancer demonstrated thatKDM6Amutations correlate with improved overall survival (OS) with immune checkpoint therapy (ICT), while they are associated with lower OS in patients undergoing cisplatin-based chemotherapy. Mechanistic studies utilizing CRISPR-Cas9 mediated deletion ofKdm6ashowed reduced expression of DNA mismatch repair (MMR) and DNA double-stranded base repair (DSBR) genes in tumor cells with improved response to anti-PD-1 therapy and attenuated sensitivity to cisplatin-based chemotherapy in preclinical models of bladder cancer. Additionally, the loss ofKdm6a-mediated reduction in glycolysis and intratumoral lactate accumulation impaired histone 3 lysine 9 lactylation (H3K9la) and histone 3 lysine 18 lactylation (H3K18la) in Tregs with concurrent decrease in the expression of key genes includingFoxp3, TgfbandPdcd1and their immune-suppressive function. Further, reduced expansion of PD-1hiTregs improved the ratio of cytotoxic T cells to Tregs and response to anti-PD-1 therapy inKdm6adeficient tumor-bearing mice. Collectively, this study provided key insights into the role of KDM6A-mediated epigenetic regulation of DNA repair and metabolic reprogramming which potentially govern response to chemotherapy and ICT thus highlighting the utility ofKDM6Amutation status for patient stratification and development of personalized treatment algorithms.
Species Diversity and Mitochondrial DNA Analysis of Sponges (Porifera, Demospongiae) in an Anchialine Cave on the Yucatan Peninsula
Authors: Suárez-Moo Pablo , Rivera-Domínguez Adán J. , Márquez-Velázquez Norma A. , Prieto-Davó Alejandra
Published: November 2024

The anchialine ecosystem in the southeastern Gulf of Mexico has an unexplored fauna, among the most understudied groups is Porifera, molecular approaches to investigate their biology and evolution remain largely short. To broaden these studies, sponge individuals collected in the anchialine cave “Xcalac” in the Mexican state of Quintana-Roo were analyzed using 18S rRNA sequences from sponge metagenomes. The three individuals studied belong to theCinachyrella, Xestospongia, and Suberitesgenera. The mitochondrial (mt) genomes ofCinachyrellasp. n. andXestospongiasp. n. were 18,493 bp to 19,604 bp in length, containing 14 protein-coding genes, 2 rRNA genes (rrnS and rrnL), and 23–25 tRNA genes, respectively. The phylogenomic analysis showed thatCinachyrellasp. n. had the same gene arrangement as the members of its subclade, including sponge species of theCinachyrellaandGeodiagenera. The mt genome ofXestospongiasp. n. contained the same gene arrangement as found in other sponges of the same genus and differed from other genera such asPetrosiaandHaliclonaby an tRNA (tyrosine, Y1). Variation in mitochondrial genomes (size, gene content, and gene order) was observed when comparing sampled sponge species from the class Demospongiae to the class Homoscleromorpha. This is the first record ofCinachyrellasp. n andSuberites sp. n.in an anchialine cave on the southeastern Yucatan peninsula, and the first report of the mitochondrial genome analysis ofCinachyrellasp. n. andXestospongiasp. n., contributing to a better understanding of the diversity and phylogeny of sponges in this ecosystem.
StableLift: Optimized Germline and Somatic Variant Detection Across Genome Builds
Authors: Wang Nicholas K. , Wiltsie Nicholas , Winata Helena K. , Fitz-Gibbon Sorel , Gonzalez Alfredo E. , Zeltser Nicole , Agrawal Raag , Oh Jieun , Arbet Jaron , Patel Yash , Yamaguchi Takafumi N. , Boutros Paul C.
Published: November 2024

Reference genomes are foundational to modern genomics. Our growing understanding of genome structure leads to continual improvements in reference genomes and new genome “builds” with incompatible coordinate systems. We quantified the impact of genome build on germline and somatic variant calling by analyzing tumour-normal whole-genome pairs against the two most widely used human genome builds. The average individual had a build-discordance of 3.8% for germline SNPs, 8.6% for germline SVs, 25.9% for somatic SNVs and 49.6% for somatic SVs. Build-discordant variants are not simply false-positives: 47% were verified by targeted resequencing. Build-discordant variants were associated with specific genomic and technical features in variant- and algorithm-specific patterns. We leveraged these patterns to create StableLift, an algorithm that predicts cross-build stability with AUROCs of 0.934 ± 0.029. These results call for significant caution in cross-build analyses and for use of StableLift as a computationally efficient solution to mitigate inter-build artifacts.
SpaMTP: Integrative Statistical Analysis and Visualisation of Spatial Metabolomics and Transcriptomics data
Authors: Causer Andrew , Lu Tianyao , Fitzgerald Christopher , Newman Andrew , Vu Hani , Tan Xiao , Vo Tuan , Cui Cedric , Narayana Vinod K. , Whittle James R. , Best Sarah A. , Freytag Saskia , Nguyen Quan
Published: November 2024

The ability to spatially measure multi-modal data provides an unprecedented opportunity to comprehensively explore molecular regulation at transcriptional, translational and metabolic levels to acquire insights on cellular activities underpinning health and disease. However, there is currently a lack of analytical tools to integrate complementary information across different spatial-omics data modalities, particularly with respect to spatial metabolomics data, which is becoming increasingly invaluable. We introduceSpaMTP, a versatile software that implements an end-to-end integrative analysis of spatial metabolomics and transcriptomics data. Based inR, SpaMTPbridges processing functionalities for metabolomics data fromCardinalwith user-friendly cell-centric analyses implemented in Seurat. Furthermore,SpaMTP’scomprehensive analysis pipeline covers (1) automated mass-to-charge ratio (m/z) metabolite annotation; (2) a wide range of metabolite-gene based downstream statistical analyses including differential expression, pathway analysis, and correlation analysis; (3) integrative spatial-omics analysis; and (4) a suite of visualisation functions. For flexibility and interoperability,SpaMTPincludes various functions for data import/export and object conversion, enabling seamless integration with otherRandPythonpackages. We demonstrated the utility ofSpaMTPto draw new biological understandings through analysing two biological system. We believe this software and implemented methods will be broadly utilised in spatial multi-omics and spatial metabolomics analyses.
Discovery of a Novel Missense Mutation in the RIMS1 Gene Potentially Enhances the Severity of Retinitis Pigmentosa (RP) Caused by RP1 Mutation in Humans
Authors: Lazaro-Guevara José M. , Garrido-Lopez Karen M. , Soberanis Laura Sofía Reyna , Sandoval-Vargas Maria A. , Flores-Robles Bryan-Josué , Téllez-Arreola José Luis
Published: November 2024

Retinitis pigmentosa (RP) is a genetically diverse disorder characterized by the progressive degeneration of photoreceptors, ultimately leading to vision impairment and potential blindness. Understanding the disease progression and developing effective therapies is challenging due to its complex genetic landscape. This study unveils a di-genic complexity in RP involving a novel missense mutation in the RIMS1 and RP1 genes, traditionally associated with Cone-Rod Dystrophy. This mutation potentially enhances the RP phenotype, particularly in cases caused by RP1 mutations. We conducted a comprehensive genetic analysis on a family with a severe form of RP, focusing on the combined effects of RIMS1 and RP1. Using a targeted gene panel of 322 inherited retinal dystrophy (IRD) genes, we discovered a significant interaction between the RIMS1 variant and RP1 mutation within the cohort. Interestingly, patients with identical mutations exhibited substantial disease severity and progression differences. This discrepancy was particularly apparent in Patient E_1, who experienced rapid vision decline, emphasizing the impact of the mutation when combined with RP1. Biological network analysis shed light on the intricate genetic interplay, indicating a complex mechanism of disease modulation. Our findings contribute to a more nuanced understanding of RP’s genetic heterogeneity. The RIMS1 variant may serve as a modifier of the disease phenotype. This discovery expands our comprehension of the genetic factors influencing RP and underscores the importance of considering digenic interactions in future research and therapy development for retinal dystrophies.
In Holistic Admissions, a Combination of Non-Academic Explanatory Variables Has Significant Predictive Value for Applicant Ranking
Authors: Bergemann Andrew D. , Smith Stephen R. , Daboub Joel A.
Published: November 2024

A medical school with a focus on community engagement has innovated its admissions process to include three different interview formats and one novel task format. Each component is designed to assess specific attributes of applicants, including teamwork skills, cultural competence, and service orientation. Correlations between these components are low, consistent with the original purpose that each should assess different attributes. To understand the use of the data by the members of the committee that ranks applicants, the authors created a model of seven explanatory variables, comprised of the three interview ratings and one task rating, a review of the written applications, and two measures of past academic performance. With regression analysis, the model significantly predicted applicant rankings, with most of the predictive capacity retained after omission of academic metrics. The results display that the school has developed innovations that allow for a reduced dependence upon academic history, and instead uses a truly holistic approach that is tailored to its mission. Most importantly, the work establishes that the admissions committee uses all the diverse forms of data provided to make decisions, which until this point has been an open question in holistic admissions.
Alzheimer’s-associated inflammatory alterations mediate tau-associated neurodegeneration in limbic and temporal regions across clinical variants of Alzheimer’s disease
Authors: Lao Patrick , Lee Seonjoo , Talmasov Daniel , Dass Dina , Chikwem Nbdusi , Johnson Aubrey , Smith Anna , Guzman Diana , Okafor Amarachukwu , Houlihan Hannah , Heuer Lauren , Sanchez Thairi , Rossano Samantha , Kreisl William , Noble James , Qureshi Yasir , Small Scott
Published: November 2024

Objectives

Microglia monitor and respond to the brain’s microenvironment to maintain homeostasis. However, in Alzheimer’s disease and related dementias (ADRD), microglia may contribute to pathology. We hypothesized that AD-related inflammatory changes, measured with TSPO PET, would be locally associated with amyloid, tau, and neurodegeneration, and influence key pathways among them.

Methods

Participants (21 controls, 25 with ADRD) from the Longitudinal Imaging of Microglial Activation in Different Clinical Variants of Alzheimer’s Disease study underwent baseline amyloid PET (Florbetaben SUVR), tau PET (MK6240 SUVR), TSPO PET (ER176 SUVR), and structural MRI (gray matter volume). Cognitive assessments and consensus diagnoses (e.g., MCI, AD, PCA, FTD, LATE) were performed at the CUIMC ADRC with biomarker information when available. We evaluated regional colocalization of biomarker elevation in ADRD compared to controls, TSPO associations with ATN biomarkers, and TSPO mediations along key ATN pathways. Sensitivity analyses were stratified by amyloid positivity.

Results

Elevated TSPO was spatially colocalized with elevated tau (8 regions), amyloid (7 regions), and neurodegeneration (4 regions). Higher TSPO in limbic, temporal, and parietal regions was associated with higher tau (0.8 to 2.3, p<0.03), which remained significant after adjusting for amyloid and neurodegeneration in the inferior parietal cortex. TSPO mediated the association between tau and neurodegeneration in limbic and temporal regions (−0.27 to -0.39,p<0.02; 43%to89%of the total effect), while tau did not mediate the association between TSPO and neurodegeneration. TSPO also mediated the association between amyloid and tau, as well as tau across progressive Braak stages, but only in amyloid-positive ADRD.

Conclusion

Across ADRD diagnoses with different underlying brain microenvironments (e.g., pathology/copathology) to which microglia are sensitive, higher microglia density was associated with greater tau burden and mediated tau-associated neurodegeneration. Glia may represent a promising target for intervention strategies in ADRD-associated tau and neurodegeneration.
Using Genetics, Genomics, and Transcriptomics to Identify Therapeutic Targets in Juvenile Idiopathic Arthritis
Authors: Tarbell Evan , Jarvis James N.
Published: November 2024

Despite progress in improving outcomes for oligoarticular and polyarticular juvenile idiopathic arthritis (JIA), the field still faces considerable challenges. More than half of adults who had JIA continue to have active disease and have developed functional limitations. Medication side-effects are common and intrusive. Thus, the field continues to search for therapeutic agents that target specific aspects of disease pathobiology and will be accompanied by fewer and less intrusive side effects. We identified 28 candidate target genes that were associated with JIA according to Open Targets Genetics and were also differentially expressed in the CD4+ T cells of children with active JIA patients (when compared to healthy controls). Of the 28 candidates, the strongest new target to emerge was homeodomain interacting kinase (HIPK1), which suppresses T cell activation and is within thePTPN22locus tagged by rs6679677. This locus includes an enhancer element that contacts the HIPK1 promoter, and HIPK1 shows decreased expression in JIA CD4+ T cells when compared to controls. Gene Ontology terms associated with HIPK1 were overrepresented among the differentially expressed genes between JIA and controls and PML, a known co-regulator of HIPK1, showed a similar suppressed gene expression profile. Two downstream transcription factors of HIPK1, TP53 and GATA4, showed enriched binding patterns near the promoters of JIA up-regulated genes. Taken together, these data suggest a pathogenic role for HIPK1 in JIA and make it a prime candidate for therapeutic modulation.
Association of Hippocampus volume with normal serum Natrium levels and predictive analyses of cognitive adversities in non-demented middle-aged and older adults
Authors: Hallab Asma ,   Alzheimer’s Disease Neuroimaging Initiative
Published: November 2024

Introduction

Serum Natrium abnormalities are largely observed in older adults and are associated with higher risks. Less is known about the association between serum Natrium variations and medial temporal brain structures, mainly involved in cognition and memory. The study’s objective was to explore the association between serum Natrium and Hippocampus volume and to assess associated cognitive risks.

Methods

Non-demented ADNI3 participants (healthy controls (HC) and with mild cognitive impairment (MCI)) with complete serum Natrium, ADAS13score, and Hippocampus volume at baseline were included. Linear and non-linear associations were evaluated. To assess the odds of MCI, logistic regression adjusted was performed. Holm method was used to adjust for Family-wise error rate in the main analysis and reported as aq-value.

Results

A total of 469 cases with a median age of 70 years (IQR: 66, 76) were included. The median serum Natrium level was 141 (IQR: 139, 142). Serum Natrium levels showed a significant association with Hippocampus volume in the total study population and MCI subgroup (Adj.ßMCI=-95 (−162, −28),p=0.006,q=0.036). Serum Natrium levels did not show a significant association neither with the ADAS13 total score (Adj.ßTotal=-0.04(−0.28, 0.21),p=0.8) nor with the odds of being diagnosed with MCI at baseline (ORMCI= 1.00(0.88, 1.13),p= 0.935).

Conclusions

Normal Serum Natrium variations were significantly associated with Hippocampus volumes depending on the underlying neurodegenerative pathology, thus, without predicting clinically relevant cognitive adversity. Further studies are needed to better understand the mechanisms and assess protective factors.

Key findings

Serum Natrium levels within normal ranges were significantly associated with Hippocampus volume.

The association between Serum Natrium levels and Hippocampus volume was particularly significant in participants with mild cognitive impairment.

There was no significant association between serum Natrium and ADAS13total score.

Serum Natrium levels within normal ranges did not predict concomitant risk of mild cognitive impairment.
Assisted Reproductive Technology Dataset of Embryo Time-lapse Images and Clinical Data
Authors: Zhylko Dmytro , Del Gallego Raquel , Pardo Sarah , Mahmood Rameen , Hsieh Ya Tung , Selim Salma , Nogueira Daniela , El-Khatib Ibrahim , Lawrenz Barbara , Fatemi Human M. , Shamout Farah E.
Published: November 2024

In this report, we present Version 1.0 of the Assisted Reproductive Technology (ART) Dataset, a multi-modal fertility dataset from treatments performed at the ART Fertility Clinic in Abu Dhabi, United Arab Emirates, between 2015 and 2022. The data consists of Electronic Health Records (EHR) and embryo development image sequences captured with the Vitrolife EmbryoScope time-lapse system, providing detailed treatment, morphology, and pregnancy outcome information. The final processed dataset consists of a total of 14,776 embryos from 1,810 patients across 2,500 treatments. This dataset will be used in the development of machine learning models for automated analysis of embryo development and viability, to assist clinical decision-making. This report provides a summary of the statistics of the dataset, as well as the extraction and pre-processing pipelines of the time-lapse images and EHR data. The dataset is private, so we publish this report for transparency on data pre-processing pipelines to share the methodology with similar studies that may arise.
Personalized Single-cell Transcriptomics Reveals Molecular Diversity in Alzheimer’s Disease
Authors: Chandrashekar Pramod Bharadwaj , Alatkar Sayali Anil , Kalafut Noah Cohen , Jin Ting , Gupta Chirag , Burzak Ryan , Huang Xiang , Liu Shuang , Li Athan Z. ,   PsychAD Consortium, Girdhar Kiran , Voloudakis Georgios , Hoffman Gabriel E. , Bendl Jaroslav , Fullard John F. , Lee Donghoon , Roussos Panos , Wang Daifeng
Published: November 2024

Precision medicine for brain diseases faces many challenges, including understanding the heterogeneity of disease phenotypes. Such heterogeneity can be attributed to the variations in cellular and molecular mechanisms across individuals. However, personalized mechanisms remain elusive, especially at the single-cell level. To address this, the PsychAD project generated population-level single-nucleus RNA-seq data for 1,494 human brains with over 6.3 million nuclei covering diverse clinical phenotypes and neuropsychiatric symptoms (NPSs) in Alzheimer’s disease (AD). Leveraging this data, we analyzed personalized single-cell functional genomics involving cell type interactions and gene regulatory networks. In particular, we developed a knowledge-guided graph neural network model to learn latent representations of functional genomics (embeddings) and quantify importance scores of cell types, genes, and their interactions for each individual. Our embeddings improved phenotype classifications and revealed potentially novel subtypes and population trajectories for AD progression, cognitive impairment, and NPSs. Our importance scores prioritized personalized functional genomic information and showed significant differences in regulatory mechanisms at cell type level across various phenotypes. Such information also allowed us to further identify subpopulation-level biological pathways, including ancestry for AD. Finally, we associated genetic variants with cell type-gene regulatory network changes across individuals, i.e., gene regulatory QTLs (grQTLs), providing novel functional genomic insights compared to existing QTLs. We further validated our results using external cohorts. Our analyses are available through iBrainMap, an open-source computational framework, and as a personalized functional genomic atlas for Alzheimer’s Disease.
Visualizing Geospatial and Temporal Phenotype Prevalences
Authors: Murray Michael , Ho Yuk-Lam , Panickan Vidul A. , Heise David , Connatser Keith , Muralidhar Sumitra , Honerlaw Jacqueline , Cho Kelly
Published: November 2024

High-throughput phenotyping strategies are capable of classifying large volumes of patients. However, translating this data to real world applications is challenging. We have developed GeoPheno, a tool which displays the geospatial prevalences of EHR-based phenotypes in the Veteran population over time. Our flexible tool can display data from a wide array of phenotypes and is integrated with the CIPHER phenotype library, allowing users to view the definitions of the conditions being visualized.
Non-invasive imaging of cell-based therapies using acoustic reporter genes
Authors: Shivaei Shirin , Liu Ann , Abedi Mohamad H. , Revilla Julio , Hurvitz Isabella U. , Swift Margaret B. , Shapiro Mikhail G.
Published: November 2024

Cell-based therapies are a major emerging category of medicine. The ability of engineered cells to traffic to and function at specific anatomical locations is a major aspect of their performance. However, there is a lack of non-invasive, non-ionizing, cost-accessible methods to track these therapies inside the body and ensure proper function. Here, we establish a platform forin vivoimaging of primary cell therapies using ultrasound – a ubiquitously accessible technology for high-resolution non-invasive imaging. We introduce and optimize a lentiviral delivery system to express acoustic reporter genes based on gas vesicles in primary mammalian cells such as T cells, showing that this results in robust ultrasound contrast. Additionally, we develop genetic circuits making it possible to monitor T cell activation via activity-dependent promoters. We apply this technology to primary human T cells, using it to non-invasively track their accumulation and proliferation as a targeted therapy in a mouse tumor xenograft model and compare it to invasive, terminal measures such as immunohistology. By making it possible to visualize cell-based therapies and their function inside opaque living organs with unprecedented resolution and accessibility, this technology has the potential to significantly accelerate their development and effective use.
Transcriptome Analysis of Archived Tumor Tissues by Visium, GeoMx DSP, and Chromium Methods Reveals Inter- and Intra-Patient Heterogeneity
Authors: Dong Yixing , Saglietti Chiara , Bayard Quentin , Perez Almudena Espin , Carpentier Sabrina , Buszta Daria , Tissot Stephanie , Dubois Rémy , Kamburov Atanas , Kang Senbai , Haignere Carla , Sarkis Rita , Andre Sylvie , Gaveta Marina Alexandre , Lastra Silvia Lopez , Piazzon Nathalie , Santos Rita , Von Loga Katharina , Hoffmann Caroline , Coukos George , Peters Solange , Soumelis Vassili , Durand Eric Y. , De Leval Laurence , Gottardo Raphael , Homicsko Krisztian , Madissoon Elo
Published: November 2024

Recent advancements in probe-based, full-transcriptome, high-resolution technologies for Formalin-Fixed Paraffin-Embedded (FFPE) tissues, such as Visium CytAssist, Chromium Flex (10X Genomics), and GeoMx DSP (Nanostring), have opened new opportunities for studying decades-old archival samples in biobanks, facilitating the generation of data from extensive cohorts. However, the experimental protocols can be labor-intensive and costly; therefore, it is thus essential for researchers to carefully evaluate the strengths and limitations of each technology in relation to their specific research objectives.

Here, we report the results of a comparative analysis of the three methods mentioned above on FFPE archival tumor samples from four non-small cell lung cancer, four breast cancer and six diffuse large B-cell lymphoma. We highlight some relative advantages and disadvantages of each method in the context of operational challenges, bioinformatic analysis and biological discovery. Our results show that: 1) all three methods yielded good-quality, highly reproducible transcriptomic data from serial sections of the same FFPE block; 2) GeoMx data contained mixtures of cell types, even when pre-selecting areas with cell type-specific markers; 3) high-throughput spot-level (Visium) or cell-level (Chromium) data enabled the identification of tumor heterogeneity within and between patients, which could be used to identify targeted therapies.

Our data support the use of Visium and Chromium for high-throughput and discovery-driven projects, while the GeoMx platform could be suited for addressing specialized questions on targeted regions. All data generated from this study, including GeoMx, Visium, Chromium, H&E, and expert annotations are publicly available.
C1q in non-immune human serum has a non-redundant complement function towards clinical Mycobacterium tuberculosis complex strains
Authors: Duque Mario Alejandro , Götz Maximilian Peter , Rousseau Emilie , Homolka Susanne , Niemann Stefan , Garred Peter , Hölscher Christoph , Walter Kerstin , Rosbjerg Anne
Published: November 2024

TheMycobacterium tuberculosiscomplex (MTBC) includes three human-adapted species:Mycobacterium tuberculosis,Mycobacterium africanum, andMycobacterium canettii. With their genetic diversity and inherent virulence, these bacteria interact with host factors to influence tuberculosis (TB) transmission and pathogenesis. A critical yet poorly understood aspect of the immune response in TB involves the role of the complement system. Our study aimed to assess the general interaction between the complement system and key clinical MTBC strains representing the principal lineages known to vary in virulence. We found that not only mannose binding lectin (MBL) from the lectin pathway, but also C1q from the classical pathway directly recognize mycobacteria. While MBL generally showed a higher level of binding than C1q, the binding interactions varied across different MTBC strains. We further observed that complement activation products C4b, C3b and the terminal complement complex (TCC) were deposited on the surface of MTBC strains. Inhibition of MBL alone did not substantially alter complement activation, whereas C1q inhibition ceased activation for most strains investigated. Exposure to human serum did not impact the viability or growth of the MTBC strains. In conclusion, both the classical and lectin pathways of complement via C1q and MBL are activated by a broad range of lineages of the MTBC. The classical pathway is the main complement activator in non-immune serum across diverse MTBC lineages, with C1q playing a potentially novel role in the immune response in TB.
Specificity in transcription factor clustering is encoded in the genome
Authors: Dongre Shivali , Vastenhouw Nadine
Published: November 2024

Transcription factors (TFs) often form clusters in the nucleus. Clusters can facilitate transcription, but it remains unclear how they form. It has been suggested that clusters are seeded by the sequence-specific binding of TFs to DNA, and grow by IDR-IDR interactions that bring in more TFs. This model, however, does not explain how TFs can cluster in specific combinations. Here, we study TF clustering by quantitative imaging of Nanog, Pou5f3, and Sox19b in zebrafish embryos. Using mutant and chimaeric TFs, we show that the formation of a TF cluster requires the DBD as well as at least one of its IDRs. In contrast with the existing model, however, IDRs are not sufficient to join a pre-existing cluster. Instead, both IDR and DBD are needed. Thus, for any TF to join a cluster, motif recognition is required, which explains the specificity in cluster formation. Finally, we show that while IDRs are required to join a cluster, their amino acid sequence is interchangeable, and the DBD can confer specificity to any IDR. Taken together, our work changes the model of cluster formation and explains how specificity is achieved in the organization of transcriptional machinery in the nucleus.
A novelPbunavirusphage from the Ganges River in biocontrol of multidrug-resistantPseudomonas aeruginosain wastewater by downregulation oflas/rhlsystems and reduction of KPC carbapenemases
Authors: Samson Rachel , Joshi Sai , Pramanik Rinka , Khairnar Krishna , Dharne Mahesh
Published: November 2024

Wastewater systems are reservoirs of multidrug-resistant (MDR) pathogens, includingPseudomonas aeruginosa, mirroring those found in the hospital effluents. Effective treatment of raw sewage for MDRP. aeruginosaabatement is critical for safe effluent disposal. This study reports the isolation of a novel phage (ɸPRS-1) within thePbunavirusgenus from a pristine stretch of the Ganges River, targeting the MDR strain ofP. aeruginosa. Antibacterial and antibiofilm assays of ɸPRS-1 againstP. aeruginosaPAO1 demonstrated robust efficacy, achieving log10reductions of 8.14 in planktonic cells, 9.83 in biofilm inhibition, and 7.01 in biofilm disruption after 24 hours. Additionally, ɸPRS-1 effectively disrupted the preformed biofilm of various other MDRP. aeruginosastrains with >5 log10reductions. Mechanistically, ɸPRS-1 downregulated quorum-sensing genes and reduced the carbapenemase resistance KPC cluster, validated through qRT-PCR analysis. Evaluation of ɸPRS-1 in raw sewage revealed a 4.2 log10CFU/mL reduction in theP. aeruginosacounts, highlighting its efficacy in complex environmental matrices.In vitro,cytotoxicity assays confirmed the phage’s safety. The use of ɸPRS-1 for tackling MDRP. aeruginosain the wastewater offers a sustainable alternative, potentially reducing reliance on other treatment methods. The findings have attempted to deliver SDGs 3, 6, 11, 14, and 15.

Highlights

A novel phage (ɸPRS-1) from an untapped location of the Ganges River

ɸPRS-1 reduces planktonic cells of MDRP. aeruginosaby 8.14 log10in 24 hours

Antibiofilm potentials: 9.83 log10reduction (inhibition) >5 log10reduction (disruption)

Downregulates quorum-sensing genes and reduces KPC resistance in MDRP. aeruginosa

ɸPRS-1 shows 4.2 log10CFU/mL reduction of MDRP. aeruginosain raw sewage

Graphical Abstract
Proton selective conductance and gating of lysosomal cation channel TMEM175
Authors: Schulze Tobias , Sprave Timon , Groebe Carolin , Krumbach Jan , Behringer Magnus , Hamacher Kay , Thiel Gerhard , Grimm Christian , Rauh Oliver
Published: November 2024

The lysosomal cation channel TMEM175 is crucial for maintaining lysosomal function and pH homeostasis, and its aberrant function is linked to Parkinson’s disease (PD). While TMEM175 activity was first interpreted in the context of its potassium (K+) selective conductance, subsequent studies revealed also a substantial permeability to protons (H+). Here we dissect the complex changes in TMEM175 conductance and current reversal voltages in response to pH jumps on the luminal side of the channel protein. In whole-cell patch clamp experiments with plasma membrane redistributed TMEM175 we show that a pH jump from symmetrical pH 7.4 to pH 4.7 on the luminal side triggers a continuous rise in inward and outward current, concomitant with a transient positive excursion of the reversal voltage (Erev). The peak Erevshift remains almost 100 mV below the estimated equilibrium voltage for protons and shows little sensitivity to the K+gradient. The data are consistent with a scenario in which a TMEM175 mediated proton flux elicits a fast collapse of the pH gradient. In MD simulations we identify the luminal H57 as titratable partner for the formation of intra- and inter-subunit salt bridges with D279 and E282 for stabilizing the channel open state. This presumed gating function is confirmed by mutational studies and lysosomal patch-clamp experiments in which a H57Y mutant exhibits a reduced pH dependency of activation. Our findings contribute to a better comprehension of TMEM175’s complex electrophysiological properties and foster understanding of TMEM175 as a pharmacological target for neurodegenerative disease therapy.
Kudoagenomes from contaminated hosts reveal extensive gene order conservation and rapid sequence evolution
Authors: Weber Claudia C , Paulini Michael ,   Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team,   Wellcome Sanger Institute Tree of Life Core Informatics team, Blaxter Mark L
Published: November 2024

Myxozoans are obligate endoparasites that belong to the phylumCnidaria. Compared to their closest free-living relatives, they have evolved highly simplified body plans and reduced genomes.Kudoa iwatai, for example, has lost upwards of two thirds of genes thought to have been present in its ancestors. However, little is known about myxozoan genome architecture because of a lack of sufficiently contiguous genome assemblies.

This work presents two new, near-chromosomalKudoagenomes, built entirely from low-coverage long reads from infected fish samples. The results illustrate the potential of using unsupervised learning methods to disentangle sequences from different sources, and facilitate producing genomes from undersampled taxa. Extracting distinct components of chromatin interaction networks allows scaffolds from mixed samples to be assigned to their source genomes. Meanwhile, low-dimensional embeddings of read composition permit targeted assembly of potential parasite reads.

Despite drastic changes in genome architecture in the lineage leading toKudoaand considerable sequence divergence between the two genomes, gene order is highly conserved. Although parasitic cnidarians show rapid protein evolution compared to their free-living relatives, there is limited evidence of less efficient selection. While deleterious substitutions may become fixed at a higher rate, large evolutionary distances between species make robustly analysing patterns of molecular evolution challenging. These observations highlight the importance of filling in taxonomic gaps, to allow a comprehensive assessment of the impacts of parasitism on genome evolution.
Leukemia confers a durable imprint on healthy hematopoietic stem and progenitor cells
Authors: Chen Ding-Wen , Schrey Julie M. , Fan Jian-Meng , Adams Sarah E. , Taylor Deanne M. , Wafula Eric K. , Kurre Peter
Published: November 2024

Recent models of infection and experimental inflammation reveal that hematopoietic stem and progenitor cells (HSPCs) can generate a memory of the exposure that heightens the response to subsequent stimulation, a process termed central trained immunity. Inflammation is also a constitutive feature of cancer, including hematologic malignancies. Here, we adapt a translationally relevant model of acute myeloid leukemia (AML) to determine if inflammation in the bone marrow (BM) niche durably reprograms resident healthy HSPCs. To simulate the onset of malignancy along with the associated inflammatory surge as well as the subsequent remission, we generated hematopoietic chimera with healthy HSPCs and HSPCs bearing a doxycycline-responsive oncogene (hMLL-AF9) expression cassette, a validated model of AML. Results show that the exposure to AML blasts in the BM leaves healthy HSPCs during experimental remission with broad transcriptomic, epigenetic changes and enhanced reliance on glycolysis. A heterologous secondary challenge of AML-experienced animals resulted in pronounced gene expression changes in inflammatory and metabolic pathways. These augmented responses coincided with altered chromatin accessibility in AML-experienced HSPCs. Motif analysis of the epigenome in AML trained HSPC points to the involvement of core hematopoietic transcription factors. Altogether, these observations provide first evidence for the durable inflammatory reprogramming of healthy HSPCs in the cancer microenvironment.
Tumoral hypoxic extracellular vesicles create a protective microenvironment for triple-negative breast cancer
Authors: Pachane Bianca C. , Bottaro Pedro H. T. , Machado Aline M. , de Castro Cynthia A. , Guerra Gabriela , Gozzer Larissa T. , Grigoli Marina M. , Zutião Artur D. , Fuzer Angelina M. , Cominetti Marcia R. , Altei Wanessa F. , Selistre-de-Araujo Heloisa S.
Published: November 2024

Background

The highly metastatic triple-negative breast cancer (TNBC) relies on its tumor microenvironment (TME) to maintain phenotypic heterogeneity and progression. Extracellular vesicles from hypoxic TNBC were previously shown to aid tumoral invasion but their function in the tumor microenvironment is still unclear.

Methods

We used a novel method to investigate the TMEin vitrocalled multicellular circulating co-culture, to characterize how TNBC-derived hypoxic EVs (EVh) interfere with tumoral and endothelial cells, fibroblasts, monocytes and macrophages.

Results

EVh promoted monocyte differentiation to M2-like macrophages and inhibited macrophage-derived phagocytosis in endothelial and tumoral cells. The protection of endothelial, tumoral and stromal cellular integrity by EVh increased pro-tumoral and pro-angiogenic signaling, collagen matrix synthesis and a potential differentiation to cancer-associated fibroblasts.

Conclusion

Our findings highlighted the critical role of EVh in protecting tumor cells, indicating its cooperation towards a protective TME, which was demonstrated by the multicellular circulating co-culture and conventional co-culture protocols, leading to an adequate system with potential for investigating other tumor-related processes, including circulating tumor cells and metastasis.Graphical Abstract
FIBOS: R and Python packages for analyzing protein packing and structure
Authors: Soares Herson H. M. , Romanelli João P. R. , Fleming Patrick J. , Silveira Carlos H. da
Published: November 2024

Advances in prediction of the 3D structures of most known proteins through machine learning methods have achieved unprecedented accuracies. However, although these computed structure models (CSMs) are overall remarkably good, they still challenge accuracy at the atomic level, especially in refinement of interatomic packing. The Occluded Surface (OS) algorithm is widely used for atomic packing analysis. But it lacks implementations in high-level languages like R and Python, limiting its accessibility. We introduce FIBOS, an R and Python package incorporating the OS methodology with enhancements. It embeds efficient Fortran code from the original OS. It also improves the original algorithm by using Fibonacci spirals to distribute surface dots, reducing anisotropy and ensuring a more even point distribution. As a case study using FIBOS, we compared packing densities between experimental protein structures and AlphaFold predictions. While average packing densities are similar, AlphaFold models exhibit comparatively greater variability and less homogeneity, potentially reflecting local inaccuracies. The FIBOS package provides an accessible tool for protein packing density analysis in R and Python, facilitating structural assessment in the era of extensive computational protein models.

Availability and implementation

The R and Python packages code are available athttps://github.com/insilico-unifei/fibos-Randhttps://github.com/insilico-unifei/fibos-py.