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Garza, A.

Publications and source records attributed to Garza, A..

10 recordsLinked to original sources

Gravitropism Shapes the Pareto Front of Root System Architecture

The root systems of wild tomatoes (S. Pimpinellifolium) can be understood as biological networks in which the lateral roots branch from a single main root and together balance two competing objectives: minimizing the material cost of building the network (wiring cost) and minimizing the transport time from the root tips to the shoot (conduction delay). Our prior work showed that S. Pimpinellifolium root architectures cluster near the Pareto-optimal front defined by these two objectives, with morphological diversity resolving into four qualitative topologies ((Chandrasekhar and Julkowska, 2022)). That framework assumed lateral roots grow as straight lines - ignoring gradual onset of lateral root gravitropism, the tendency of roots to curve toward the gravity vector. Because curved trajectories are longer than straight lines, gravitropism directly increases both wiring cost and conduction delay, constraining which architectures are physically realizable and thereby reshaping the Pareto front itself. Here we extend the model to explicitly incorporate lateral root gravitropism, producing predicted architectures that align much more closely with observed S. Pimpinellifolium root systems. We present a computational method to infer gravitropic sensitivity directly from anatomical tracing data - without reorientation assays - and apply it to 2423 arbors across different root topologies, growth conditions, and hormone treatments. Incorporating gravitropism reveals variation invisible to the straight-line model:notably, lateral roots show reduced gravitropic sensitivity under salt stress, mirroring a phenomenon previously described only for main roots and overlooked in lateral roots until now.

plant biology↗

Metastatic Osteosarcoma is Characterized by Loss of Osteoblastic Lineage Fidelity

Osteosarcoma (OS) is a rare and aggressive bone cancer with limited therapeutic progress in several decades. To characterize the transcriptional diversity of malignant cell states in OS, we analyzed single-nucleus RNA sequencing data from 24 tumors, including both primary and metastatic lesions. We identified a canonical osteoblastic cell state that predominated in primary tumor cells, but was dampened in metastases. Integrating tumor data with data from embryonic skeletal development and an experimental osteoblast differentiation model revealed that metastatic OS cells resemble poorly specified mesenchyme enriched for non-osseous programs. Clonal populations in metastatic samples acquired mesenchymal cell states distinct from paired primary tumors. Similar cell state shifts were evident in post-treatment primary tumors relative to paired pre-treatment samples. Our results suggest that localized post-treatment and metastatic OS malignant cells lose osteoblastic lineage fidelity, which may represent a unifying axis of disease evolution and reveal new therapeutic vulnerabilities.

Cancer Biology↗

Conserved Neuronal-like and Secretory Programs Define the Spatial Architecture of Gastroenteropancreatic Neuroendocrine Tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic (snRNA-seq and snATAC-seq) and spatial transcriptomic profiling across 38 well-differentiated pancreatic (pNET) and small-intestinal (siNET) tumors to define conserved malignant programs, their regulatory circuits, and spatial niches. We observed two conserved malignant cell programs spanning a continuous transcriptional spectrum: a neuronal-like program (si-cNMF1/p-cNMF1), and a secretory neuroendocrine program (si-cNMF2/p-cNMF2). Matched chromatin accessibility profiles uncovered distinct, tissue-specific regulatory networks, including MAX::MYC and MITF transcription factor binding motifs in siNETs versus ISL1 and TFAP4 in pNETs, indicating organ-specific epigenetic control. Spatial transcriptomic analyses revealed that si/p-cNMF1-high regions localized to high cell density, immune-rich tumor areas, whereas si/p-cNMF2-high regions occupied stromal and vascularized niches and co-occured with fibroblast and endothelial compartments enriched for TGFB1-ITGB1, VEGFA-FLT1, and LAMA2-ITGA1 signaling. Across both tumor types, the cNMF2 program was enriched in metastatic lesions and was enrichedfor pro-fibrotic and pro-angiogenic gene signatures. Thus, GEP-NETs are organized along a conserved neuronal-to-secretory axis defined by distinct epigenetic programs and spatially coupled to specific microenvironmental niches. This framework unifies NET heterogeneity across organ sites and identifies pathway-specific, microenvironment-linked vulnerabilities for therapeutic targeting.

cancer biology↗

Tumor-myeloid crosstalk drives therapy resistance in localized bladder cancer

Neoadjuvant cisplatin-based chemotherapy results in pathologic complete response for only a minority of patients with muscle-invasive bladder cancer (MIBC), and mechanisms of resistance and the effects of chemotherapy on the MIBC microenvironment remain incompletely understood. Here, we defined the single-cell and spatial transcriptomes of cancer and immune cells from MIBC patients with resistance to cisplatin-based chemotherapy. Tumors with persistent MIBC after chemotherapy harbored cancer cells expressing epithelial-to-mesenchymal programs that were associated with worse overall survival in independent cisplatin-treated bladder cancer cohorts. These cisplatin-resistant tumor cells were infiltrated by macrophages that upregulated tumor permissive programs defined by increased PARP14 expression in spatially resolved multicellular niches. Macrophage reprogramming through PARP14 inhibition sensitized tumors to cisplatin via downregulation of tumor cell pathways implicated in resistance. Our results demonstrate that cancer cells and macrophages cooperate to promote cisplatin resistance and identify macrophage-directed PARP14 inhibition as a novel therapeutic strategy to sensitize MIBC to cisplatin.

cancer biology↗

Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We identified tumor microenvironmental features previously described to associate with therapy response. We identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.

cancer biology↗

Rare germline structural variants increase risk for pediatric solid tumors

AO_SCPLOWBSTRACTC_SCPLOWPediatric solid tumors are rare malignancies that represent a leading cause of death by disease among children in developed countries. The early age-of-onset of these tumors suggests that germline genetic factors are involved, yet conventional germline testing for short coding variants in established predisposition genes only identifies pathogenic events in 10-15% of patients. Here, we examined the role of germline structural variants (SVs)--an underexplored form of germline variation--in pediatric extracranial solid tumors using germline genome sequencing of 1,766 affected children, their 943 unaffected relatives, and 6,665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and a four-fold increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we revealed burdens of ultra-rare SVs that cause loss-of-function of highly expressed, mutationally intolerant, neurodevelopmental genes, as well as noncoding SVs predicted to disrupt three-dimensional chromatin domains in neural crest-derived tissues. Collectively, our results implicate rare germline SVs as a predisposing factor to pediatric solid tumors that may guide future studies and clinical practice.

genomics↗

Integrin-like adhesin CglD confers traction and stabilizes bacterial focal adhesions involved in myxobacterial gliding motility

AO_SCPLOWBSTRACTC_SCPLOWIntegrins are crucial for eukaryotic cell attachment and motility within the extracellular matrix (ECM) via focal-adhesion formation, with their evolutionary emergence important for the development of multicellularity. Intriguingly, single gliding cells of the predatory deltaproteobacterium Myxococcus xanthus form bacterial focal-adhesion (bFA) sites; therein, helically-trafficked motors become immobilized at anchored locations through Glt apparatus association with cell-surface integrin I-domain-like adhesin CglB. Using traction-force, bead-force, and total internal reflection-fluorescence microscopies combined with biochemical approaches, we herein identify the von Willebrand A domain-containing cell-surface lipoprotein CglD to be a {beta}-integrin-like outer-membrane lipoprotein that functionally associates with and anchors the trans-envelope Glt-CglB gliding apparatus, stabilizing and efficiently anchoring this assembly at bFAs. Calcium dependence governs CglD importance, consistent with its integrated ECM eukaryotic cartilage oligomeric matrix protein domains. CglD thus confers mechanosensory and mechanotransductory capabilities to the gliding apparatus, helping explain bFA-mediated trans-envelope force transduction, from inner-membrane-embedded motors to the cell surface.

microbiology↗

A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions.

To eliminate vertical HIV transmission and achieve therapy-free viral suppression among children living with HIV, novel strategies beyond antiretroviral therapy (ART) are necessary. Our group previously identified a triple bNAb combination comprising of 3BNC117, PGDM1400 and PGT151 that mediates robust in vitro neutralization and non-neutralizing effector functions against a cross-clade panel of simian human immunodeficiency viruses (SHIVs). In this study, we evaluated the safety, pharmacokinetics, and antiviral potency of this bNAb combination in infant rhesus macaques (RMs). We demonstrate that subcutaneous infusion of the triple bNAb regimen was well tolerated in pediatric monkeys and resulted in durable systemic and mucosal distribution. Plasma obtained from passively-immunized RMs demonstrated potent HIV-neutralizing and Fc-mediated antiviral effector functions. Finally, using the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker, which was recently identified as a surrogate endpoint for evaluation of the preventative efficacy (PE) of bNAbs against mucosal viral acquisition in human clinical trials, we demonstrated that our regimen has a predicted PE[≥]90% against a large panel of plasma and breast milk-derived HIV strains and cross-clade SHIV variants. This data will guide the development of combination bNAbs for eliminating vertical HIV transmission and for achieving ART-free viral suppression among children living with HIV.

immunology↗

Unraveling a Bacterial Starvation Response Through the Direct Targets of a Starvation-Induced Transcriptional Activator

Organisms frequently encounter environments with nutrient shortages and their survival depends on changes in physiology and the ability to conserve resources. In bacteria, many physiological changes associated with starvation have been identified, but the underlying genetic components and regulatory networks that direct these physiological changes are often poorly defined. Here, we aimed to better define the gene regulatory networks that mediate the starvation response in Myxococcus xanthus, a bacterium that copes with starvation by producing fruiting bodies filled with dormant and stress-resistant spores. We focused on the direct promoter/gene targets of Nla28, a transcriptional activator/enhancer binding protein (EBP) that is important for early rounds of gene expression following starvation. Using expression profiling to identify genes that are downregulated in nla28 mutant cells and bioinformatics to identify the putative promoters of these genes, 12 potential promoter targets (37 genes) of Nla28 were identified. The results of in vitro promoter binding assays, coupled with in vitro and in vivo mutational analyses, suggested that the 12 promoters are in vivo targets of Nla28 and that Nla28 dimers use tandem, imperfect repeats of an 8-bp sequence for binding. Interestingly, nine of the Nla28 target promoters are intragenic, located in the protein coding sequence of an upstream gene or in the protein coding sequence of one gene within an operon (internal promoters). Based on mutational analyses, we concluded that the 12 Nla28 target loci contain at least one gene important for production of stress-resistant spores following starvation. Most of these loci contain genes predicted to be involved in regulatory or defense-related functions. Using the consensus Nla28 binding sequence, followed by bioinformatics and expression profiling, 58 additional promoters and 102 genes were tagged as potential Nla28 targets. Among these putative Nla28 targets, functions such as regulatory, metabolic and cell envelope biogenesis were commonly assigned to genes.

microbiology↗

Soft Windowing Application to Improve Analysis of High-throughput Phenotyping Data

MotivationHigh-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximises analytic power while minimising noise from unspecified environmental factors.\n\nResultsHere we introduce \"soft windowing\", a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant p-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft windowed and non-windowed approaches, respectively, from a set of 2,082 mutant mouse lines. Our method is generalisable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources.\n\nAvailability and ImplementationThe method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin.

bioinformatics↗