Biology subjects

Rosen, J.

Publications and source records attributed to Rosen, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Early dynamics of a neutrophil interferon program drive immunotherapy resistance and limit durable anti-tumor immunity

Despite the remarkable success of immune checkpoint blockade (ICB), durable clinical benefit remains limited to a subset of patients, highlighting the need for predictive biomarkers and new therapeutic targets. Here, we investigated the early immune dynamics associated with anti-PD1 responsiveness using longitudinal single-cell transcriptomics, spatial transcriptomics, and neutrophil-specific genetic perturbations in preclinical models of triple-negative breast cancer. We identified a conserved neutrophil interferon-stimulated gene (ISG) program that emerges before overt tumor divergence and predicts resistance to anti-PD1 therapy. Successful treatment was associated with an early reduction of IFN-responsive neutrophils in both blood and tumor tissues, whereas persistent neutrophil IFN signaling correlated with therapeutic resistance. Mechanistically, genetic disruption of either type I or type II interferon signaling in neutrophils enhanced anti-PD1 efficacy and promoted durable anti-tumor immune memory. Spatial analyses further revealed an inverse association between IFN-responsive neutrophils and tertiary lymphoid structure-enriched regions during effective therapy. Together, these findings identify IFN-responsive neutrophils as early determinants of immunotherapy outcome and establish dynamic neutrophil interferon programs as candidate blood-based biomarkers and therapeutic targets for cancer immunotherapy.

cancer biology↗

bioRxiv2025

Genetic Influences on Neural Responses in Placebo Analgesia Circuitry

Placebo analgesia is a well-established medical phenomenon with overlapping neural representations between humans and rodents, but the genetic contribution to this conserved neural circuitry remains unknown. Using functional brain imaging in 305 monozygotic and dizygotic twins, we quantified the heritability of neural activation in placebo analgesia brain circuity during evoked pain, including the rostral anterior cingulate cortex, brainstem and cerebellum, using the ACE model. Neural responses showed significant heritability, with additive genetics accounting for 21 to 49% of the variance (A = 0.21-0.49), indicating that genetics have a moderate effect on pain-evoked brain activity within the placebo analgesia circuitry. For the first time, our findings reveal a heritable component of the neural network supporting placebo analgesia. By linking genetic variations to neural responses in placebo analgesia circuitry, this study bridges human and preclinical research and opens new ways for improving clinical trial methodology and tailoring pain therapies to individual genetic profiles.

neuroscience↗

bioRxiv2025

Anti-CSF-1R therapy with combined immuno- chemotherapy coordinate an adaptive immune response to eliminate macrophage enriched Triple Negative Breast Cancers

Patients diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory metronomic Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic syngeneic Trp53 null TNBC genetically engineered mouse models (GEMMs) that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along with CTX disrupted the M-CSF/CSF-1R axis which upregulated IL-17, IL-15 and type II interferon resulting in elevated B- and T cell infiltration. Addition of an anti-PD-1 maintenance dose helped overcome de novo PD-L1 intra-tumoral heterogeneity (ITH) associated recurrence in lung and liver mTNBC.

cancer biology↗

bioRxiv2024

Master regulators governing protein abundance across ten human cancer types

Protein abundance correlates only moderately with mRNA levels, and are modulated post-transcriptionally by a network of regulators including ribosomes, RNA-binding proteins (RBPs), and the proteasome. Here, we identified Master Protein abundance Regulators (MaPRs) across ten cancer types by devising a new computational pipeline that jointly analyzed transcriptomes and proteomes from 1,305 tumor samples. We identified 232 to 1,394 MaPRs per cancer type, mediating up to 79% of post- transcriptional regulatory networks. MaPRs exhibit high network connectivity, strong genetic dependency in cancer cells, and significant enrichment for RBPs. Combining tumor up-regulation, druggability, and target network analyses identified cancer-specific vulnerabilities. MaPRs predict tumor proteomic subtypes more accurately than other proteins. Finally, significant portions of RBP MaPR-target relationships were validated by experimental evidence from eCLIP binding and knockdown assays. Our findings uncover central MaPRs that govern post-transcriptional networks, highlighting diverse processes underlying human proteome regulation and identifying key regulators in cancer biology.

systems biology↗

bioRxiv2024

Something to sink your teeth into: the mechanics of tooth indentation in frugivorous fishes

Frugivorous vertebrates engage in a mutualism with fruiting plants: the former receive a nutrient subsidy and the latter benefit by having their seeds distributed far from parent plants. Vertebrate frugivores like primates and bats have particular morphologies, like wide jaws and blunt teeth, which are thought to aid in dismantling fruit and obtaining trapped sugars. However, variation among frugivores and fruits has made the identification of common frugivore phenotypes difficult. We measured the performance of frugivorous fish dentitions whether this performance was comparable to fruit-eating bats and primates. We also explored how fruit characteristics affect puncture performance, and how indentation of fruit differs mechanically from harder foods like nuts. Finally, we used photoelasticity and videography to visualize how serrasalmid dentitions propagate stresses in simple gel models. We expected that frugivore dentitions would exhibit low force and then high work when engaging fruit tissues. Aligning with our expectation, the most frugivorous serrasalmid we tested, Colossoma, had dental performance that matched the low force, high work model. Indentation behavior differed between food types, both between fruits and nuts, and among different fruits. We also documented considerable differences in the indentation performances of different serrasalmid dentitions, among frugivores, omnivores, and carnivores. We propose that some differences in the morphology of frugivore dentitions make them better for granivory (eating seeds) than the softer fruit tissues. Fishes exhibit convergent mechanical and morphological strategies with other vertebrates for obtaining nutrition from fruits and seeds.

evolutionary biology↗

bioRxiv2024

Cortical Representation of the Glottal Events during Speech Production

To learn complex motor skills, an organism must be able to assign sensory feedback events to the actions that caused them. This matching problem would be simple if motor neuron output led sensory feedback with a fixed, predictable lag. However, nonlinear dynamics in the brain and the bodys periphery can decouple the timing of critical events from that of the motor output which caused them. During human speech production, for example, phonation from the glottis (a sound source for speech) begins suddenly when subglottal pressure and laryngeal tension cross a sharp threshold (i.e. a bifurcation). Only if the brain can predict the timing of these discrete peripheral events resulting from motor output, then, would it be possible to match sensory feedback to movements based on temporal coherence. We show that event onsets in the human glottal waveform, as measured using electroglottography, are reflected in the human electroencephalogram during speech production, leading up to the time of the event itself. Conversely, glottal event times can be decoded from the electroencephalogram. After prolonged exposure to delayed auditory feedback, subjects recalibrate their behavioral threshold for detecting temporal auditory-motor mismatches, and decoded event times decouple from actual movements. This suggests decoding performance is driven by plastic predictions of peripheral timing, providing a missing component for hindsight credit assignment in motor control, in which specific feedback events are associated with the neural activity that gave rise to movements. We discuss parallel findings from the birdsong system suggesting that results may generalize across vocal learning species. Significance StatementTo learn complex motor skills such as speech, the brain must pair actions with sensory feedback. However, feedback is delayed in time relative to actual movement, rendering this "hindsight credit assignment" problem a nontrivial task. We present evidence that events in the glottis, the articulatory organ that generates sound for human speech, are predictively encoded in the human brain during speech production. Given that corresponding events in auditory feedback are known to be prominently encoded in cortex, this highlights a common temporal marker by which articulatory gestures and sensory feedback could be aligned. Findings suggest activity in the human vocomotor system is shaped by biophysical dynamics in the vocal periphery, aligning with corresponding results in the birdsong system.

neuroscience↗

bioRxiv2023

A deep-learning-based screening platform in aging-relevant human motor neurons to identify therapeutic compounds for amyotrophic lateral sclerosis

Age is the primary risk factor for most neurodegenerative diseases including amyo-trophic lateral sclerosis (ALS). Despite the clear importance of age on the development and progression of ALS, age is rarely considered a factor in cellular or animal models of ALS. The recent advent of direct reprogramming methodologies, whereby somatic cells such as fibroblasts can be converted into neurons while retaining the age signature of the host, has facilitated the study of age-relevant human cells in vitro for the first time. Despite the promise of this technology, age is a complex, multidimensional, and dy-namic phenotype that makes the interpretation of the interplay between age and dis-ease a great challenge. To circumvent these challenges, we developed a screening platform for directly reprogrammed neurons in an age-relevant human cellular model to better model and identify disease-modifying targets and pathways for ALS. This plat-form uses deep learning image analysis to screen compounds for efficacy against ALS-associated cellular phenotypes and efficiently classifies ALS-like phenotypic signatures as well as predicts the age of the original fibroblast donor. Notably, our work identified NCB-0846, a TNIK/MAP4K7 inhibitor, as a novel compound with the ability to revert ALS-like phenotypes. Moreover, we show that chronic dosing of NCB-0846 in the SOD1G93A mouse model of ALS significantly reduced serum neurofilament-L levels. Our findings establish the power of a platform that combines direct reprogramming of human cells and deep learning as a powerful tool for combatting aging and age-related diseases.

neuroscience↗

bioRxiv2023

Targeting EIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A by Zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages towards an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that Zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon response uniformly across models. The induction of an interferon response is partially due to the inhibition of Sox4 translation by Zotatifin. A similar induction of interferon-stimulated genes was observed in breast cancer patient biopsies following Zotatifin treatment. Surprisingly, Zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened interferon response resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for Zotatifin, and provide a rationale for new combination regimens comprising Zotatifin and chemotherapy or immunotherapy as treatments for TNBC. One Sentence SummaryTargeting EIF4A sensitizes TNBC to immune therapy and chemotherapy by suppressing Sox4, inducing an interferon response, and reprograming the tumor immune microenvironment.

cancer biology↗

bioRxiv2023

Chiropterans are a hotspot for horizontal transfer of DNA transposons in Mammalia

Horizontal transfer of transposable elements is an important mechanism contributing to genetic diversity and innovation. Bats (order Chiroptera) have repeatedly been shown to experience horizontal transfer of transposable elements at what appears to be a high rate compared to other mammals. We investigated the occurrence of horizontally transferred DNA transposons involving bats. We found over 200 putative horizontally transferred elements within bats; sixteen transposons were shared across distantly related mammalian clades and two other elements were shared with a fish and two lizard species. Our results indicate that bats are a hotspot for horizontal transfer of DNA transposons. These events broadly coincide with the diversification of several bat clades, supporting the hypothesis that DNA transposon invasions have contributed to genetic diversification of bats.

molecular biology↗

bioRxiv2022

Insights into mammalian TE diversity via the curation of 248 mammalian genome assemblies

We examined transposable element (TE) content of 248 placental mammal genome assemblies, the largest de novo TE curation effort in eukaryotes to date. We find that while mammals resemble one another in total TE content and diversity, they show substantial differences with regard to recent TE accumulation. This includes multiple recent expansion and quiescence events across the mammalian tree. Young TEs, particularly LINEs, drive increases in genome size while DNA transposons are associated with smaller genomes. Mammals tend to accumulate only a few types of TE at any given time, with one TE type dominating. We also found association between dietary habit and the presence of DNA transposon invasions. These detailed annotations will serve as a benchmark for future comparative TE analyses among placental mammals. One-Sentence SummaryA de novo assessment of TE content in 248 mammals finds informative trends in mammalian genome evolution.

genomics↗

bioRxiv2021

Gray Matter Differentiation Between Two Subordinate Personality Traits of Extraversion: Enthusiasm and Assertiveness

Enthusiasm and assertiveness are two subordinate personality traits of extraversion. These traits reflect different aspects of extroversion and have distinct implications on mental health. Whereas enthusiasm predicts satisfaction in life and positive relationships, assertiveness predicts psychological distress and reduced social support. The neural basis of these subordinate traits is not well understood. To investigate brain regions where enthusiasm and assertiveness have diverging relationship with morphology, enthusiasm and assertiveness were regressed to gray matter volume (GMV) across the whole brain in a sample of 301 healthy individuals. A significant interaction was found between enthusiasm and assertiveness in the left angular gyrus (t(296) = 4.18, family wise error corrected, FWE p = .001 (cluster-level); Cluster size = 880 voxels). Larger GMV in this area was associated with more enthusiasm and less assertiveness. Our study emphasizes the value of separating extraversion into its subordinate traits when investigating associations to neuroanatomy.

neuroscience↗

bioRxiv2021

From telomere to telomere: the transcriptional and epigenetic state of human repeat elements

Mobile elements and highly repetitive genomic regions are potent sources of lineage-specific genomic innovation and fingerprint individual genomes. Comprehensive analyses of large, composite or arrayed repeat elements and those found in more complex regions of the genome require a complete, linear genome assembly. Here we present the first de novo repeat discovery and annotation of a complete human reference genome, T2T-CHM13v1.0. We identified novel satellite arrays, expanded the catalog of variants and families for known repeats and mobile elements, characterized new classes of complex, composite repeats, and provided comprehensive annotations of retroelement transduction events. Utilizing PRO-seq to detect nascent transcription and nanopore sequencing to delineate CpG methylation profiles, we defined the structure of transcriptionally active retroelements in humans, including for the first time those found in centromeres. Together, these data provide expanded insight into the diversity, distribution and evolution of repetitive regions that have shaped the human genome.

genomics↗

bioRxiv2021

Whole Brain Correlates of Individual Differences in Skin Conductance Responses during Human Fear Conditioning

Understanding the neural basis for individual differences in the conditioned skin conductance response (SCR) may inform on autonomic regulation in fear-related psychopathology. Previous region-of-interest (ROI) analyses have implicated the amygdala in regulating conditioned SCR, but whole brain analyses are lacking. This study examined correlations between individual differences in conditioned SCR and neural activity throughout the whole brain by using data from a large functional magnetic resonance imaging study (N = 285). Results show that conditioned SCR correlates with activity in the dorsal anterior cingulate cortex/anterior midcingulate cortex, anterior insula, bilateral temporoparietal junction, right frontal operculum, bilateral dorsal premotor cortex, right superior parietal lobe and midbrain. A ROI analysis replicated a correlation between amygdala activity and conditioned SCR, but amygdala contribution to SCR was modest compared with other regions. We suggest that implicated neural regions belong to a large-scale midcingulo-insular network related to salience detection and autonomic-interoceptive processing. Altered activity within this network may underlie individual differences in conditioned SCR and autonomic aspects of psychopathology.

neuroscience↗

bioRxiv2021

The genome sequence of the cereal pest Sitophilus oryzae: an unprecedented transposable element content

BackgroundThe rice weevil Sitophilus oryzae is one of the most important agricultural pests, causing extensive damage to cereal in fields and to stored grains. S. oryzae has an intracellular symbiotic relationship (endosymbiosis) with the Gram-negative bacterium Sodalis pierantonius and is a valuable model to decipher host-symbiont molecular interactions. ResultsWe sequenced the Sitophilus oryzae genome using a combination of short and long reads to produce the best assembly for a Curculionidae species to date. We show that S. oryzae has undergone successive bursts of transposable element (TE) amplification, representing 72% of the genome. In addition, we show that many TE families are transcriptionally active, and changes in their expression are associated with insect endosymbiotic state. S. oryzae has undergone a high gene expansion rate, when compared to other beetles. Reconstruction of host-symbiont metabolic networks revealed that, despite its recent association with cereal weevils (30 Kyear), S. pierantonius relies on the host for several amino acids and nucleotides to survive and to produce vitamins and essential amino-acids required for insect development and cuticle biosynthesis. ConclusionsHere we present the genome of an agricultural pest beetle, which may act as a foundation for pest control. In addition, S. oryzae may be a useful model for endosymbiosis, and studying TE evolution and regulation, along with the impact of TEs on eukaryotic genomes.

genomics↗

bioRxiv2021

PolyA: a tool for adjudicating competing annotations of biological sequences

Annotation of a biological sequence is usually performed by aligning that sequence to a database of known sequence elements. When that database contains elements that are highly similar to each other, the proper annotation may be ambiguous, because several entries in the database produce high-scoring alignments. Typical annotation methods work by assigning a label based on the candidate annotation with the highest alignment score; this can overstate annotation certainty, mislabel boundaries, and fails to identify large scale rearrangements or insertions within the annotated sequence. Here, we present a new software tool, PolyA, that adjudicates between competing alignment-based annotations by computing estimates of annotation confidence, identifying a trace with maximal confidence, and recursively splicing/stitching inserted elements. PolyA communicates annotation certainty, identifies large scale rearrangements, and detects boundaries between neighboring elements.

bioinformatics↗

bioRxiv2021

Acyloxyacyl Hydrolase is a Host Determinant of Gut Microbiome-Mediated Pelvic Pain

Dysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS or "IC") is a debilitating condition of chronic pelvic pain often with co-morbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in IC/BPS patients. We previously identified the locus encoding acyloxyacyl hydrolase, Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of GI microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and reduced trans-epithelial electrical resistance consistent with a "leaky gut" phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S rRNA sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Co-housing AOAH-deficient mice with wild type mice resulted in converged microbiota and altered predicted metagenomes. Co-housing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and the dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.

systems biology↗

bioRxiv2021

Genetic influences on brain activation and large-scale functional connectivity during nociceptive processing: a twin study

Nociceptive processing in the human brain is a signal that enables harm avoidance, with large interindividual variance. The relative contributions of genes and environment to the neural structures that support nociception have not been studied in twins previously. Here, we employed a classic twin-design to determine brain structures influenced by additive genetics. We found genetic influences on nociceptive processing in the midcingulate cortex, bilateral posterior insulae and thalamus. In addition to brain activations, we found genetic contributions to large-scale functional connectivity during nociceptive processing. We conclude that additive genetics influence specific aspects of nociceptive processing, which improves our understanding of human nociceptive processing.

neuroscience↗

bioRxiv2020

3D Epigenomic Characterization Reveals Insights Into Gene Regulation and Lineage Specification During Corticogenesis

Lineage-specific epigenomic changes during human corticogenesis have previously remained elusive due to challenges with tissue heterogeneity and sample availability. Here, we analyze cis-regulatory chromatin interactions, open chromatin regions, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational human brain samples. We show that chromatin looping underlies transcriptional regulation for lineage-specific genes, with transcription factor motifs, families of transposable elements, and disease-associated variants enriched at distal interacting regions in a cell type-specific manner. A subset of promoters exhibit unusually high degrees of chromatin interactivity, which we term super interactive promoters. Super interactive promoters are enriched for critical lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of cell type-specific transcription. Finally, we present CRISPRview, a novel approach for validating distal interacting regions in primary cells. Our study presents the first characterization of cell type-specific 3D epigenomic landscapes during human corticogenesis, advancing our understanding of gene regulation and lineage specification during human brain development.

genomics↗