Biology subjects

Wolff, A.

Publications and source records attributed to Wolff, A..

10 recordsLinked to original sources

bioRxiv2026

A blastema in sea star larvae integrates wound signaling to drive regeneration-specific and developmental gene expression patterns.

Whether regeneration depends on the reactivation of developmental programs, regeneration-specific regulatory mechanisms, or both remains a central question in regeneration biology. Here, we investigate these processes in regenerating larvae of the sea star Patiria miniata, a deuterostome with robust regenerative capacity. By integrating single-nucleus transcriptomics with chromatin accessibility profiling across development and regeneration, we identify a regeneration-induced blastema cell state that is molecularly distinct from pre-existing larval populations and serves as the source of regenerated tissues. We show that regeneration is associated with distinct classes of regeneration-responsive enhancers, including regeneration-specific elements and enhancers reused from development, which link wounding signals to gene regulatory network (GRN) activation. These enhancer classes converge on regulatory programs associated with the transcription factor Runx, positioning Runx as a central node within the inferred regeneration GRN. Notably, we identify a Runx-associated regulatory framework that provides a mechanistic explanation for the de novo emergence of sox4 cells during regeneration through novel deployment of developmentally shared enhancers. Together, our results provide a framework for how wound-induced signals specify regenerative cell states and how regeneration-specific and developmental gene regulatory networks may be coordinated to rebuild lost tissues.

developmental biology↗

bioRxiv2026

Community-Based Surveillance for Highly Pathogenic Avian Influenza Viruses among Deceased Birds

Highly pathogenic avian influenza (HPAI) viruses of H5N1 clade 2.3.4.4b, are spreading worldwide, posing a threat to wildlife, domestic animals, and humans. In 2025, a multidisciplinary collaboration for HPAI H5N1 surveillance among birds within Galveston County, Texas, was initiated. Between November and December 2025, oropharyngeal and cloacal swabs were collected from wild and domestic birds reported as dead or dying by Galveston County residents. Specimens were studied with molecular assays, Sanger sequencing, virus isolation, and next-generation sequencing. Molecular evidence of HPAI H5N1 was detected in 7 of 10 (70%) birds, and the virus was successfully cultured in MDCK cells. Next-generation sequencing analysis of eight influenza A genome segments demonstrated a 4:4 gene segment reassortant constellation within clade 2.3.4.4b, consistent with genotype D1.1. Community members exposed to HPAI were offered antiviral prophylaxis. No human infections were identified. This surveillance demonstrates that community involvement combined with cross-sectoral collaboration can ensure rapid detection and characterization of circulating avian influenza viruses. Sustained local surveillance is essential for early warning, risk assessment, and prevention of virus spread to poultry, mammals, and humans.

molecular biology↗

bioRxiv2025

Differential functional connectivity between hippocampus and prefrontal cortex is associated with heterogeneity in open field exploration

A common paradigm in behavioral neuroscience involves recording neural activity from freely moving rodents as they forage in an open field. This procedure is often used in studies investigating spatial navigation, where recording is conducted in regions such as the hippocampus and entorhinal cortex. It is usually assumed that there is no systematic variation in behavior in this paradigm, thereby allowing spatial representations to be examined without the confounding effects of behavior change. Here we show that the behavior of rats in this paradigm can be algorithmically divided into at least two distinct modes, and that the transitions between these modes is marked by distinct differences in theta and gamma band power in the hippocampus, as well as transition-associated communication between hippocampus and prefrontal cortex, with information strongly flowing from hippocampus to prefrontal cortex during the transition period. Moreover, we show that following a maternal immune activation intervention, intra-regional changes in power are preserved, but communication between hippocampus and prefrontal cortex is impaired. These findings demonstrate that animals in the open field perform distinct behaviors that are accompanied by marked changes in brain activity and regional communication.

neuroscience↗

bioRxiv2025

BTRR complex deficiency is a driver for genomic instability in Bloom syndrome

Biallelic loss-of-function (LoF) variants in the BTRR complex members BLM, TOP3A, RMI1, and RMI2 cause Bloom syndrome (BSyn). The BTRR complex mainly acts on DNA replication and DNA repair processes, and dysfunction of this complex underlies the increased genomic instability and cancer predisposition associated with the BSyn phenotype. Here, we report CRISPR/Cas9-based genome-edited isogenic induced pluripotent stem cell (iPSC) models with compound heterozygous LoF variants in BLM, TOP3A, and RMI1. The cellular phenotype of all three BTRR-deficient iPSC lines included chromosome segregation defects, increased sister chromatid exchange rates, and impaired DNA single-strand template repair. Using single-cell whole genome sequencing, we showed that BTRR complex deficiency causes increased genome copy number alterations (CNAs) and, therefore, is a driver for genomic instability. CNA load was further induced by applying replication stress, and we observed that BTRRKO iPSCs acquired fewer de novo CNA events compared to wild-type cells, suggesting a possible selection loss against cells with high levels of DNA damage. Importantly, stress-induced and non-stress-induced CNAs in single-cell genomes were not stochastically distributed throughout the genome, but instead enriched at fragile sites. This finding might offer an opportunity for the development of novel NGS-based approaches to measure rates of genomic instability in disease conditions.

genetics↗

bioRxiv2022

Hierarchical cue control of drug seeking in the face of cost

Addiction is characterized by intermittent drug seeking despite rising costs. This behavior is heavily influenced by environmental stimuli that signal drug availability and reinforce seeking. We aimed to establish the relationship between three key aspects of human drug use in rats: the intermittent, binge nature of drug intake, the motivational conflict of drug seeking in the face of escalating negative costs, and the ability of different drug cues to interact to modulate relapse. Rats were trained to self administer cocaine on an intermittent access schedule, where brief drug availability states were signaled by a shift in the ambient lighting of the environment and cocaine delivery was signaled by a separate proximal cue. Rats then went through a conflict procedure, where foot shock intensity associated with cocaine seeking was escalated until intake was suppressed. We completed relapse tests where the drug delivery cue was non contingently presented alone, or in the context of dynamic drug availability state transitions. Intermittent access spurred psychomotor sensitization and binge-like cocaine intake. The intensity of binge-like drug taking during training was predictive of later drug seeking despite escalating costs. In relapse tests, the ability of a proximal drug cue to trigger relapse was gated by the presence of a global cue signaling drug-availability state transitions. Our results suggest that the pattern of drug intake plays a role in many features of addiction, including modifying an individuals willingness to endure high costs associated with drug seeking. Further, our results indicate that drug-related sensory information can be hierarchically organized to exert a dynamic modulating influence on drug-seeking motivation.

neuroscience↗

bioRxiv2021

Single-cell transcription profiles in Bloom syndrome patients link BLM deficiency with altered condensin complex expression signatures

Bloom syndrome (BS) is an autosomal recessive disease clinically characterized by primary microcephaly, growth deficiency, immunodeficiency, and predisposition to cancer. It is mainly caused by biallelic loss-of-function mutations in the BLM gene, which encodes the BLM helicase, acting in DNA replication and repair processes. Here, we describe the gene expression profiles of three BS fibroblast cell lines harboring causative, biallelic truncating mutations obtained by single-cell (sc) transcriptome analysis. We compared the scRNA transcription profiles from three BS patient cell lines to two age-matched wild-type controls and observed specific deregulation of gene sets related to the molecular processes characteristically affected in BS, such as mitosis, chromosome segregation, cell cycle regulation, and genomic instability. We also found specific upregulation of genes of the Fanconi anemia pathway, in particular FANCM, FANCD2, and FANCI, which encode known interaction partners of BLM. The significant deregulation of genes associated with inherited forms of primary microcephaly observed in our study might explain in part the molecular pathogenesis of microcephaly in BS, one of the main clinical characteristics in patients. Finally, our data provide first evidence of a novel link between BLM dysfunction and transcriptional changes in condensin complex I and II genes. Overall, our study provides novel insights into gene expression profiles in BS on a single-cell level, linking specific genes and pathways to BLM dysfunction.

genetics↗

bioRxiv2020

The hybrid nature of task-evoked activity: Inside-out neural dynamics in intracranial EEG and Deep Learning

A.The standard approach in neuroscience research infers from the external stimulus (outside) to the brain (inside) through stimulus-evoked activity. Recently challenged by Buzsaki, he advocates the reverse; an inside-out approach inferring from the brains activity to the neural effects of the stimulus. If so, stimulus-evoked activity should be a hybrid of internal and external components. Providing direct evidence for this hybrid nature, we measured human intracranial stereo-electroencephalography (sEEG) to investigate how prestimulus variability, i.e., standard deviation, shapes poststimulus activity through trial-to-trial variability. We first observed greater poststimulus variability quenching in trials exhibiting high prestimulus variability. Next, we found that the relative effect of the stimulus was higher in the later (300-600ms) than the earlier (0-300ms) poststimulus period. These results were extended by our Deep Learning LSTM network models at the single trial level. The accuracy to classify single trials (prestimulus low/high) increased greatly when the models were trained and tested with real trials compared to trials that exclude the effects of the prestimulus-related ongoing dynamics (corrected trials). Lastly, we replicated our findings showing that trials with high prestimulus variability in theta and alpha bands exhibits faster reaction times. Together, our results support the inside-out approach by demonstrating that stimulus-related activity is a hybrid of two factors: 1) the effects of the external stimulus itself, and 2) the effects of the ongoing dynamics spilling over from the prestimulus period, with the second, i.e., the inside, dwarfing the influence of the first, i.e., the outside. B. Significance StatementOur findings signify a significant conceptual advance in the relationship between pre- and poststimulus dynamics in humans. These findings are important as they show that we miss an essential component - the impact of the ongoing dynamics - when restricting our analyses to the effects of the external stimulus alone. Consequently, these findings may be crucial to fully understand higher cognitive functions and their impairments, as can be seen in psychiatric illnesses. In addition, our Deep Learning LSTM models show a second conceptual advance: high classification accuracy of a single trial to its prestimulus state. Finally, our replicated results in an independent dataset and task showed that this relationship between pre- and poststimulus dynamics exists across tasks and is behaviorally relevant.

neuroscience↗

bioRxiv2020

Bridging the gap - Spontaneous fluctuations shape stimulus-evoked spectral power

Spontaneous fluctuations of neural activity have been shown to influence trial-by-trial variation in perceptual, cognitive, and behavioural outcomes. This implies that these fluctuations affect stimulus-related neural processes, and hence should affect stimulus-evoked neural activity. However, the mechanisms by which spontaneous neural activity shapes stimulus-evoked neural activity have rarely been examined. Employing a large-scale magnetoencephalographic dataset, as well as an electroencephalographic replication dataset, we observed that for high-frequency power, high pre-stimulus activity leads to greater evoked desynchronization (negative interaction); in contrast, for low-frequency power, high pre-stimulus activity induces greater event-related synchronization (positive interaction). We show that both positive and negative interactions are manifest primarily in cortical oscillations, rather than scale-free activity, and can also be observed in the time domain. In summary, we demonstrate positive and negative spontaneous-evoked interaction in multiple electrophysiological processes; these mechanisms "bridge the gap" between spontaneous and evoked activity and provide novel insights into how spontaneous activity influences behaviour and cognition.

neuroscience↗

bioRxiv2018

A non-catalytic function of carbonic anhydrase IX contributes to the glycolytic phenotype and pH regulation in human breast cancer cells

The most aggressive and invasive tumor cells often reside in hypoxic microenvironments and rely heavily on rapid anaerobic glycolysis for energy production. This switch from oxidative phosphorylation to glycolysis, along with up-regulation of the glucose transport system, significantly increases the release of lactic acid from cells into the tumor microenvironment. Excess lactate and proton excretion exacerbate extracellular acidification to which cancer cells, but not normal cells, adapt. We have hypothesized that carbonic anhydrases (CAs) play a role in stabilizing both intracellular and extracellular pH to favor cancer progression and metastasis. Here we show that proton efflux (acidification) using the glycolytic rate assay is dependent on both extracellular pH (pHe) and CA IX expression. Yet, isoform selective sulfonamide-based inhibitors of CA IX did not alter proton flux, which suggests that the catalytic activity of CA IX is not necessary for this regulation. Other investigators have suggested the CA IX cooperates with the MCT transport family to excrete protons. To test this possibility, we examined the expression patterns of selected ion transporters and show that members of this family are differentially expressed within the molecular subtypes of breast cancer. The most aggressive form of breast cancer, triple negative breast cancer (TNBC), appears to coordinately express the monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CA IX). This supports a possible mechanism that utilizes the intramolecular H+ shuttle system in CA IX to facilitate proton efflux through MCT4.

cancer biology↗

bioRxiv2018

Selective inhibition of CA IX over CA XII using benzene sulfonamides: Disconnect between CA activity and growth inhibition in breast cancer cells

Carbonic anhydrases (CAs) have been linked to tumor progression, particularly membrane-bound CA isoform IX (CA IX). The role of CA IX in the context of breast cancer is to regulate the pH of the tumor microenvironment. In contrast to CA IX, expression of CA XII, specifically in breast cancer, is associated with better outcome despite performing the same catalytic function. In this study, we have structurally modeled the orientation of bound ureido-substituted benzene sulfonamides (USBs) within the active site of CA XII, in comparison to CA IX and cytosolic off-target CA II, to understand isoform specific inhibition. This has identified specific residues within the CA active site, which differ between isoforms that are important for inhibitor binding and isoform specificity. The ability of these sulfonamides to block CA IX activity in breast cancer cells is less effective than their ability to block activity of the recombinant protein (by one to two orders of magnitude depending on the inhibitor). The same is true for CA XII activity but now they are two to three orders of magnitude less effective. Thus, there is significantly greater specificity for CA IX activity over CA XII. While the inhibitors block cell growth, without inducing cell death, this again occurs at two orders of magnitude above the Ki values for inhibition of CA IX and CA XII activity in their respective cell types. Surprisingly, the USBs inhibited cell growth even in cells where CA IX and CA XII expression was ablated. Despite the potential for these sulfonamides as chemotherapeutic agents, these data suggest that we reconsider the role of CA activity on growth potentiation.

cancer biology↗