Biology subjects

Adam, I.

Publications and source records attributed to Adam, I..

17 recordsLinked to original sources

bioRxiv2026

Restoration of deficient IL-15 signaling enhances innate lymphoid cell immunity in brain metastasis

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s), collectively known as group 1 innate lymphoid cells (ILCs), are critical mediators of anti-tumor immunity, yet their role in brain metastasis remains poorly defined. Using single-cell RNA sequencing and functional depletion models, we show that group 1 ILCs fail to provide adequate tumor control in breast cancer brain metastasis (BCBM). In contrast to the liver, where diverse, functionally competent group 1 ILC populations facilitate excellent metastatic control, group 1 ILCs in BCBM show limited diversity and profound tissue-specific dysfunction such that their depletion had no effect on tumor burden despite modest parenchymal infiltration. We attribute this group 1 ILC dysfunction to severely restricted IL-15 availability, with IL-15R protein detected at 500-fold lower concentration in the brain than in the liver. Local IL-15 complex administration restored group 1 ILC accumulation, cytotoxicity, and tissue residency, significantly reducing brain metastatic burden independent of T cells. Intracranial delivery of IL-15-secreting induced pluripotent stem-cell-derived (iPSC)-NK cells, already in clinical testing for non-small cell lung cancer, significantly reduced tumor burden. Collectively, these findings reveal how tissue-specific differences in cytokine availability shape group 1 ILC population diversity and disease response, establishing localized IL-15 signaling as a compelling strategy to unlock innate immunity against intracranial malignancies.

immunology↗

bioRxiv2026

Cell-of-origin shapes tumor subtype in BRCA1-associated triple-negative breast cancer

Pathogenic germline BRCA1 variants greatly increase lifetime breast cancer risk, with no targeted prevention. Accrual of mutations following DNA repair errors in luminal progenitors is considered the chief mechanism of triple-negative breast cancer (TNBC) initiation, which cannot explain the organ specificity nor the phenotypic spectrum of the disease. Here we show that TNBC also originates in basal-myoepithelial cells, and that the cell of origin shapes TNBC subtype through aberrant epithelial differentiation, likely due to pleiotropic role of BRCA1 in regulating hormone signaling. Single-cell RNA sequencing of 67,001 cells from Wap-Cre Brca1/p53 mice and reanalysis of published Blg-Cre data show that aberrant basal-myoepithelial differentiation (Wap-Cre) generates the mesenchymal subtype (TNBC-M) and aberrant luminal differentiation (Blg-Cre) the basal-like subtype (TNBC-BL1). We also show that both subtypes occur at comparable frequency in BRCA1 carriers. Aberrant basal-myoepithelial differentiation precedes tumor formation, and only tumors derived from transplanted basal cells reproduce the basal-containing phenotype of spontaneous tumors. Comparison with a developmental atlas identifies de-differentiation of myoepithelial cells into basal cells lacking myoepithelial markers, a fetal state, whereas experimental metastases shift toward luminal states while retaining a TNBC-M-like transcriptional program. These findings support the inclusion of basal-myoepithelial and luminal cells in targeted prevention strategies for BRCA1 carriers, and adoption of TNBC subtyping for patient stratification and improving outcomes.

cancer biology↗

bioRxiv2026

Single-cell profiling of synchronous multi-organ metastasis reveals a systemic CD74+ lipid-associated macrophage niche driving polymetastatic breast cancer

Systemic, multi-organ metastasis is the primary cause of breast cancer mortality, yet the biological mechanisms that allow disseminated tumor cells to simultaneously colonize physiologically diverse tissues remain poorly understood. Current paradigms focus on organ-specific tropism, largely overlooking the potential for systemic, conserved and synchronized programs that facilitate widespread colonization. Here, we present a high-resolution, multi-organ atlas of metastatic ecosystems and their niches using a synchronous model of brain, lung, liver, and bone metastasis combined with in vivo proximal niche labeling and single-cell RNA sequencing. We identify a remarkably conserved proximal niche program defined by the accumulation of CD74+ lipid-associated, metastasis-associated macrophages (LA-MAMs) across all metastatic sites. CD74+ LA-MAMs are characterized by a unique metabolic-immune signature and drive T cell suppression. We show that the cytokine Macrophage Migration Inhibitory Factor (MIF), secreted by metastatic cells, acts as the universal paracrine mediator that instructs the LA-MAM phenotype via the CD74 receptor. Interference of the MIF-CD74 axis effectively disrupts the LA-MAM niche, mitigates T cell exhaustion, and reduces metastatic burden across all organs. Analysis of a 100-patient cohort of metastasis samples from different sites confirms that the MIF-CD74 axis is a hallmark of human multi-organ colonization and independently predicts poor post-metastasis survival. Our findings define a synchronized and systemic metastatic niche that can be targeted, providing a mechanistic rationale for neutralizing the MIF-CD74 axis to treat polymetastatic breast cancer.

cancer biology↗

bioRxiv2025

PHLDA2 promotes breast cancer metastasis by co-opting a developmental program for placental vascular remodeling

Identifying drivers of metastasis is essential for developing new treatments for patients with advanced disease. Here, we identify PHLDA2 as a robust driver of breast cancer metastasis. Previous work established PHLDA2 as an imprinted gene expressed by trophoblasts which are critical for vascular remodeling during placental development. We find that hypomethylation of PHLDA2 in breast tumors correlates with increased gene expression, which is associated with metastasis and poor survival in breast cancer patients. RNA-sequencing showed that PHLDA2 overexpression results in upregulation of genes that control invasion, extracellular matrix assembly, and vascular remodeling, consistent with trophoblast functions in placental development. Using an in vitro vascularized microtumor (VMT) system, we find that PHLDA2 functions through SPARC, which promotes metastasis by inducing vascular permeability and enhancing tumor dissemination. These data suggest that increased expression of PHLDA2 through hypomethylation promotes metastasis by ectopic expression of a developmental program for vascular remodeling.

cancer biology↗

bioRxiv2025

JiSuJi, a virtual muscle for small animal simulations, accurately predicts force from naturalistic spike trains

Physics-based simulators for neuromechanical control of virtual animals have the potential to significantly enhance our understanding of intricate structure-function relationships in neuromuscular systems, their neural activity and motor control. However, a key challenge is the accurate prediction of the forces that muscle fibers produce based on their complex patterns of electrical activity ("spike trains") while preserving model simplicity for broader applicability. In this study, we present a chemomechanical, three-dimensional finite-element muscle model - JiSuJi (pronounced ji su j[i], meaning "ultrafast muscle" in Chinese) - that efficiently and accurately predicts muscle forces from naturalistic spike trains. The models performance is validated against songbird vocal muscles, a particularly fast and therefore challenging muscle type. Our results demonstrate that JiSuJi accurately predicts both isometric and non-isometric muscle forces across a variety of naturalistic neural activity patterns. JiSuJi furthermore outperforms state-of-the-art muscle simulators for accuracy, while maintaining computational efficiency. Simulating muscle behavior offers a promising approach for investigating the underlying mechanisms of neuro-muscular interactions and precise motor control, especially in the fast-contracting muscles of animal model systems.

neuroscience↗

bioRxiv2024

Data-driven insights into the association between oxidative stress and calcium-regulating proteins in cardiovascular disease.

A growing body of biomedical literature suggests a bidirectional regulatory relationship between cardiac calcium (Ca2+)-regulating proteins and reactive oxygen species (ROS), which is integral to the pathogenesis of various cardiac disorders via oxidative stress signaling. To address the challenge of finding hidden connections within the growing volume of biomedical research, we developed a data science pipeline for efficient data extraction, transformation, and loading. Employing the CaseOLAP (Context-Aware Semantic Analytic Processing) algorithm, our pipeline quantifies interactions between 128 human cardiomyocyte Ca2+-regulating proteins and eight cardiovascular disease (CVD) categories. Our machine learning analysis of CaseOLAP scores reveals that the molecular interfaces of Ca2+-regulating proteins uniquely associate with cardiac arrhythmias and diseases of the cardiac conduction system, distinguishing them from other CVDs. Additionally, a knowledge graph analysis identified 59 of the 128 Ca2+-regulating proteins as involved in OS-related cardiac diseases, with cardiomyopathy emerging as the predominant category. By leveraging a link prediction algorithm, our research illuminates interactions between Ca2+-regulating proteins, OS, and CVDs. The insights gained from our study provide a deeper understanding of the molecular interplay between cardiac ROS and Ca2+-regulating proteins in the context of CVDs. Such understanding is essential for the innovation and development of targeted therapeutic strategies.

bioinformatics↗

bioRxiv2024

Familiarity of an environment prevents song suppression in isolated zebra finches

Despite the wide use of zebra finches as an animal model to study vocal learning and production, little is known about impacts on their welfare caused by routine experimental manipulations such as changing their social context. Here we conduct a post-hoc analysis of singing rate, an indicator of positive welfare, to gain insights into stress caused by social isolation, a common experimental manipulation. We find that isolation in an unfamiliar environment reduces singing rate for several days, indicating the presence of an acute stressor. However, we find no such decrease when social isolation is caused by either removal of a social companion or by transfer to a familiar environment. Furthermore, during repeated brief periods of isolation, singing rate remains high when isolation is induced by removal of social companions, but it fails to recover from a suppressed state when isolation is induced by recurrent transfer to an unknown environment. These findings suggest that stress from social isolation is negligible compared to stress caused by environmental changes and that frequent short visits of an unfamiliar environment are detrimental rather than beneficial. Together, these insights can serve to refine experimental studies and design paradigms maximizing the birds wellbeing and vocal output.

zoology↗

bioRxiv2024

A complex Plasmodium falciparum cryptotype circulating at low frequency across the African continent

The population structure of the malaria parasite Plasmodium falciparum can reveal underlying demographic and adaptive evolutionary processes. Here, we analyse population structure in 4,376 P. falciparum genomes from 21 countries across Africa. We identified a strongly differentiated cluster of parasites, comprising [~]1.2% of samples analysed, geographically distributed over 13 countries across the continent. Members of this cluster, named AF1, carry a genetic background consisting of a large number of highly differentiated variants, rarely observed outside this cluster, at a multitude of genomic loci distributed across most chromosomes. At these loci, the AF1 haplotypes appear to have common ancestry, irrespective of the sampling location; outside the shared loci, however, AF1 members are genetically similar to their sympatric parasites. AF1 parasites sharing up to 23 genomic co-inherited regions were found in all major regions of Africa, at locations over 7,000 km apart. We coined the term cryptotype to describe a complex common background which is geographically widespread, but concealed by genomic regions of local origin. Most AF1 differentiated variants are functionally related, comprising structural variations and single nucleotide polymorphisms in components of the MSP1 complex and several other genes involved in interactions with red blood cells, including invasion and erythrocyte antigen export. We propose that AF1 parasites have adapted to some as yet unidentified evolutionary niche, by acquiring a complex compendium of interacting variants that rarely circulate separately in Africa. As the cryptotype spread across the continent, it appears to have been maintained mostly intact in spite of recombination events, suggesting a selective advantage. It is possible that other cryptotypes circulate in Africa, and new analysis methods may be needed to identify them.

genomics↗

bioRxiv2024

Reannotation of the zebra finch genome reveals undiscovered transcriptional complexity

The zebra finch has become a paradigmatic model system to mechanistically investigate vocal communication from genes to behavior. Here, we report 1) a comprehensive map of the polyadenylated fraction of the transcriptome of the male zebra finch telencephalon at two ages, during the song learning phase at 50 days and when fully adult at 2 years as well as 2) as an expanded and refined annotation of the zebra finch genome based on our transcriptome data. Using high-throughput next generation sequencing of paired-end strand- specific cDNA fragments, we detected over 50% of the annotated protein coding transcripts (ENSEMBL v.55) in the telencephalon at both stages. We exploited the information gained from the paired-end sequence reads and from reads falling onto splice junctions to update the existing annotation (ENS55) with new transcript structures and alternative splicing events. The dataset allowed to refine 2822 of the available gene models by extending them in the 3-UTR and to detect 11391 undiscovered transcriptional units in non-coding regions. Our results illustrate the value of continuously incorporating new transcriptional evidence into existing annotations.

molecular biology↗

bioRxiv2023

Peak performance singing requires daily vocal exercise in songbirds

Vocal signals mediate much of human and non-human communication. Key performance traits - such as repertoire size, speed and accuracy of delivery - affect communication efficacy in fitness-decisive contexts such as mate choice and resource competition1. Specialized fast vocal muscles2,3 are central to accurate sound production4, but it is unknown whether vocal, like limb muscles5,6, need exercise to gain and maintain peak performance7,8. Here, we show that for song development in juvenile songbirds, the closest analogue to human speech acquisition9, regular vocal muscle exercise is crucial to achieve adult peak muscle performance. Furthermore, adult vocal muscle performance reduces within two days of abolishing exercise, leading to downregulation of critical proteins transforming fast to slower muscle fibre types. Daily vocal exercise is thus required to both gain and maintain peak vocal muscle performance, and if absent changes vocal output. We show that conspecifics can detect these acoustic changes and females prefer the song of exercised males. Song thus contains information on recent exercise status of the sender. Daily investment in vocal exercise to maintain peak performance is an unrecognized cost of singing and could explain why many birds sing daily even under adverse conditions10. Because neural regulation of syringeal and laryngeal muscle plasticity is equivalent, vocal output may reflect recent exercise status in all vocalizing vertebrates.

neuroscience↗

bioRxiv2021

Driving singing behaviour in songbirds using multi-modal, multi-agent virtual reality

Interactive biorobotics provides unique experimental potential to study the mechanisms underlying social communication but is limited by our ability to build expressive robots that exhibit the complex behaviours of birds and small mammals. An alternative to physical robots is to use virtual reality (VR). Here, we designed and built a modular, audio-visual virtual reality environment that allows online, multi-modal, multi-agent interaction for social communication. We tested this system in songbirds, which provide an exceptionally powerful and tractable model system to study social communication. We show that zebra finches (Taeniopygia guttata) communicating through the VR environment exhibit normal call timing behaviour, males sing female directed song and both males and females display high-intensity courtship behaviours to their mates. These results suggest that the VR system provides a sufficiently natural environment to elicit normal social communication behaviour. Furthermore, we developed a fully unsupervised online song motif detector and used it to manipulate the virtual social environment of male zebra finches based on the number of motifs sung. Our VR setup represents a first step in taking automatic behaviour annotation into the online domain and allows for animal-computer interaction using higher level behaviours such as song. Our unsupervised acoustic analysis eliminates the need for annotated training data thus reducing labour investment and experimenter bias.

animal behavior and cognition↗

bioRxiv2020

Syringeal vocal folds do not have a voice in zebra finch vocal development

Vocal behaviour can be dramatically changed by both neural circuit development and postnatal maturation of the body. During song learning in songbirds, both the song system and syringeal muscles are functionally changing, but it is unknown if maturation of sound generators within the syrinx contributes to vocal development. Here we densely sample the respiratory pressure control space of the zebra finch syrinx in vitro. We show that the syrinx produces sound very efficiently and that key acoustic parameters, minimal fundamental frequency, entropy and source level, do not change over development in both sexes. Thus, our data suggests that the observed acoustic changes in vocal development must be attributed to changes in the motor control pathway, from song system circuitry to muscle force, and not by material property changes in the avian analog of the vocal folds. We propose that in songbirds, muscle use and training driven by the sexually dimorphic song system are the crucial drivers that lead to sexual dimorphism of the syringeal skeleton and musculature. The size and properties of the instrument are thus not changing, while its player is.

neuroscience↗

bioRxiv2020

Units of motor production: Bengalese finches interrupt song within syllables

Birdsong consists of syllables that are separated by silent intervals. Previous work in zebra finches showed that syllables correspond to the smallest motor production units (Cynx, 1990; Franz and Goller, 2002) by inducing song stops using strobe light. In this study, we interrupted the song of six Bengalese finches experimentally with the birds own song as auditory stimulus using an interactive playback approach. Five of the tested males interrupted their ongoing vocalizations within syllables (16 instances of induced interrupted syllables) in response to the playback. Additionally, we observed 9 spontaneous interruptions in our control recordings. This study establishes that birds can interrupt ongoing syllables within extremely short latencies in response to an auditory stimulus, and that auditory stimuli interrupt syllables more effectively than visual stimuli. Even if syllables are the functionally stable production units, the ability to disrupt those units differs between species and individuals, indicating various degrees of vocal control.

animal behavior and cognition↗

bioRxiv2020

Increasing muscle speed drives changes in the neuromuscular transform of motor commands during postnatal development in songbirds

Progressive changes in vocal behavior over the course of vocal imitation leaning are often attributed exclusively to developing neural circuits, but the effects of postnatal body changes remain unknown. In songbirds, the syrinx transforms song system motor commands into sound, and exhibits changes during song learning. Here we test the hypothesis that the transformation from motor commands to force trajectories by syringeal muscles functionally changes over vocal development in zebra finches. Our data collected in both sexes show that only in males, muscle speed significantly increases and that supralinear summation occurs and increases with muscle contraction speed. Furthermore, we show that previously reported sub-millisecond spike timing in the avian cortex can be resolved by superfast syringeal muscles and that the sensitivity to spike timing increases with speed. Because motor neuron and muscle properties are tightly linked, we make predictions on the boundaries of the yet unknown motor code that correspond well with cortical activity. Taken together, we show that syringeal muscles undergo essential transformations during song learning that drastically change how neural commands are translated into force profiles and thereby acoustic features. We propose that the song system motor code must compensate for these changes to achieve its acoustic targets. Our data thus supports the hypothesis that the neuromuscular transformation changes over vocal development and emphasizes the need for an embodied view of song motor learning. Significance statementFine motor skill learning typically occurs in a postnatal period when the brain is learning to control a body that is changing dramatically due to growth and development. How the developing body influences motor code formation and vice versa remains largely unknown. Here we show that vocal muscles in songbirds undergo critical transformations during song learning that drastically change how neural commands are translated into force profiles and thereby acoustic features. We propose that the motor code must compensate for these changes to achieve its acoustic targets. Our data thus support the hypothesis that the neuromuscular transformation changes over vocal development and emphasizes the need for an embodied view of song motor learning.

neuroscience↗

bioRxiv2020

One-to-one innervation of vocal muscles allows precise control of birdsong

The motor control resolution of any animal behavior is limited to the minimal force step available when activating muscles, which is set by the number and size distribution of motor units (MUs) and muscle specific force [1, 2]. Birdsong is an excellent model system for understanding sequence learning of complex fine motor skills [3], but we know surprisingly little how the motor pool controlling the syrinx is organized [4] and how MU recruitment drives changes in vocal output [5]. Here we combine measurements of syringeal muscle innervation ratios with muscle stress and an in vitro syrinx preparation to estimate MU size distribution and the control resolution of fundamental frequency (fo), a key vocal parameter, in zebra finches. We show that syringeal muscles have extremely small MUs, with 50% innervating [≤] 3, and 13 - 17% innervating a single muscle fiber. Combined with the lowest specific stress (5 mN/mm2) known to skeletal vertebrate muscle, small force steps by the major fo controlling muscle provide control of 50 mHz to 4.2 Hz steps per MU. We show that the song system has the highest motor control resolution possible in the vertebrate nervous system and suggest this evolved due to strong selection on fine gradation of vocal output. Furthermore, we propose that high-resolution motor control was a key feature contributing to the radiation of songbirds that allowed diversification of song and speciation by vocal space expansion.

neuroscience↗

bioRxiv2019

A molecular barcode and online tool to identify and map imported infection with Plasmodium vivax

Imported cases present a considerable challenge to the elimination of malaria. Traditionally, patient travel history has been used to identify imported cases, but the long-latency liver stages confound this approach in Plasmodium vivax. Molecular tools to identify and map imported cases offer a more robust approach, that can be combined with drug resistance and other surveillance markers in high-throughput, population-based genotyping frameworks. Using a machine learning approach incorporating hierarchical FST (HFST) and decision tree (DT) analysis applied to 831 P. vivax genomes from 20 countries, we identified a 28-Single Nucleotide Polymorphism (SNP) barcode with high capacity to predict the country of origin. The Matthews correlation coefficient (MCC), which provides a measure of the quality of the classifications, ranging from -1 (total disagreement) to 1 (perfect prediction), exceeded 0.9 in 15 countries in cross-validation evaluations. When combined with an existing 37-SNP P. vivax barcode, the 65-SNP panel exhibits MCC scores exceeding 0.9 in 17 countries with up to 30% missing data. As a secondary objective, several genes were identified with moderate MCC scores (median MCC range from 0.54-0.68), amenable as markers for rapid testing using low-throughput genotyping approaches. A likelihood-based classifier framework was established, that supports analysis of missing data and polyclonal infections. To facilitate investigator-lead analyses, the likelihood framework is provided as a web-based, open-access platform (vivaxGEN-geo) to support the analysis and interpretation of data produced either at the 28-SNP core or full 65-SNP barcode. These tools can be used by malaria control programs to identify the main reservoirs of infection so that resources can be focused to where they are needed most.

molecular biology↗

bioRxiv2017

Fundamental Constraints In Synchronous Muscle Limit Superfast Motor Control In Vertebrates

Superfast muscles (SFM) are extremely fast synchronous muscles capable of contraction rates up to 250 Hz, enabling precise motor execution at the millisecond time scale. To allow such speed, the archetypal SFM, found in the toadfish swimbladder, has hallmark structural and kinetic adaptations at each step of the conserved excitation-contraction coupling (ECC) pathway. More recently SFM phenotypes have been discovered in most major vertebrate lineages, but it remains unknown whether all SFM share ECC adaptations for speed, and if SFM arose once, or from independent evolutionary events. Here we use genomic analysis to identify the myosin heavy chain genes expressed in bat and songbird SFM to achieve rapid actomyosin crossbridge kinetics and demonstrate that these are evolutionarily and ontologically distinct. Furthermore, by quantifying cellular morphometry and calcium signal transduction combined with force measurements we show that all known SFM share multiple functional adaptations that minimize ECC transduction times. Our results suggest that SFM evolved independently in sound producing organs in ray-finned fish, birds, and mammals, and that SFM phenotypes operate at a maximum operational speed set by fundamental constraints in synchronous muscle. Consequentially, these constraints set a fundamental limit to the maximum speed of fine motor control.

physiology↗