Biology subjects

Lee, S. E.

Publications and source records attributed to Lee, S. E..

At least 19 recordsLinked to original sources

bioRxiv2026

A rationally designed neuraminidase immunogen elicits humoral responses to a conserved viral site

Efforts to develop a universal influenza vaccine have primarily focused on the surface-exposed viral hemagglutinin (HA), but neuraminidase (NA) is an additional target for cross-reactive, protective responses. Here, we used hyperglycosylation as an immunogen design approach to reshape anti-NA humoral immunity toward conserved antigenic regions. Iterative design produced a hyperglycosylated NA immunogen that retained enzymatic activity and reactivity to a conformation-specific antibody recognizing the conserved catalytic site. In mice, the hyperglycosylated immunogen elicited serum antibody responses of comparable magnitude to those elicited by the wild-type NA immunogen. However, serum antibodies elicited by the hyperglycosylated immunogen had increased breadth, recognizing N2 NAs from H2N2 and H3N2 viruses spanning nearly 65 years of antigenic drift, as well as a heterosubtypic N9 NA. Single B cell analyses identified a monoclonal antibody that competed with a component of the serum antibody response elicited by the hyperglycosylated immunogen, and structural characterization showed that it recognizes a previously undefined, conserved epitope at the NA tetramer interface. Passive transfer of this interface-directed antibody partially protected mice against lethal heterologous influenza challenge. Collectively, these data show that glycan shielding can reshape and enrich humoral responses toward a conserved antigenic region on NA. The immunogen and hyperglycosylation design strategy described here provide a template for developing next- generation NA-based influenza vaccines. ONE SENTENCE SUMMARYA hyperglycosylated influenza neuraminidase immunogen reshapes humoral immunity and elicits antibodies targeting a conserved tetramer-interface epitope.

immunology↗

bioRxiv2025

Dengue Virus NS1 Binds Ephrin B1 to Trigger Endothelial Dysfunction

Dengue virus (DENV), a member of the Flaviviridae family, is the most prevalent and medically important mosquito-borne viral pathogen. Infected cells secrete the viral non-structural protein 1 (NS1) into the bloodstream, where it can interact with endothelial cells to induce vascular leak. Host factors involved in NS1-mediated endothelial dysfunction are incompletely understood, leading us to investigate the host interactome of DENV NS1 in endothelial cells via a comparative mass spectrometry approach. We identified ephrin B1 (EFNB1) as a critical host factor in NS1-mediated endothelial barrier dysfunction and show that phosphorylation of EFNB1 is necessary for induction of barrier dysfunction. Further, we map the interface of the EFNB1-NS1 complex through biochemical and computational approaches, and we show that EFNB1-Fc-fusion proteins can act as decoys to block NS1-induced barrier dysfunction in vitro and in vivo. This study provides insights into the mechanism of flavivirus NS1-mediated endothelial barrier dysfunction and new avenues to target vascular leak.

microbiology↗

bioRxiv2025

DLK inhibition has sex-specific effects on neuroprotection and locomotor recovery after spinal cord injury

Spinal cord injury (SCI) causes devastating functional deficits, in part due to neuroinflammation, oxidative stress, and excitotoxicity that drive death of lesion-adjacent viable neurons. Dual leucine zipper kinase (DLK) is a neuron-enriched kinase that responds to cellular stress by activating the c-Jun N-terminal kinase (JNK) pathway, driving both stress-responsive gene expression and neuronal apoptosis. We hypothesized that SCI would robustly activate DLK signaling and that acute pharmacological inhibition of DLK would suppress JNK pathway activation, thereby enhancing neuroprotection and locomotor recovery in our mouse model of moderate contusion SCI. Using western blotting, we observed that SCI induced strong and sustained activation of the JNK pathway in the injured spinal cord starting at 4 hours post-injury through 7 days. Complementary analysis of single-nucleus RNA-seq revealed that DLK expression is highly enriched in neurons across all injury phases. Following SCI, neurons exhibited robust, time-dependent upregulation of multiple DLK-responsive transcripts, consistent with sustained pathway activation during the acute and subacute periods. Systemic treatment with the selective DLK inhibitor IACS-52825 effectively suppressed intraspinal JUN activation in a dose-dependent manner. However, unexpectedly, treatment delayed functional recovery and expanded lesion volume by 71% in male mice with no significant effect in females. These findings highlight the complex roles of DLK signaling after SCI, revealing a need to understand the sex-specific molecular mechanisms that modulate injury outcomes. Future studies should further optimize timing, location, and cellular targeting of DLK therapeutic strategies to improve neuroprotection and neurologic recovery after SCI.

neuroscience↗

bioRxiv2025

Respiratory viral infection is associated with increased Pseudomonas abundance in cystic fibrosis airways

Acute respiratory viral infections are an important driver of morbidity and mortality in people with chronic lung disease and are frequently associated with pulmonary exacerbations and a transition from intermittent to chronic bacterial infection of the airways. Chronic Pseudomonas aeruginosa infections are associated with worsened lung function, poor outcomes, and increased hospital visits. We sought to improve understanding of the effects of respiratory viral infections and host immune response on the resident bacterial community of the airways, using cystic fibrosis as a model. We performed an observational longitudinal study of 38 adults with CF and collected sinus and sputum samples at 6-month intervals from 2017 - 2021. We performed 16S rRNA amplicon sequencing to characterize the airway microbiota, real-time RT-PCR for viral infection detection, and cytokine quantification. We observed viral positivity rates of 19% and 14% in sinus and sputum samples, respectively. Human rhinovirus was the most frequently observed viral pathogen in both sinus and sputum samples. We measured a significant perturbance of the bacterial community during viral infection that did not return to baseline following resolution of the viral infection. This perturbation was driven by a significant increase in Pseudomonas relative abundance during viral infection. Furthermore, we found significant associations with increased Pseudomonas relative abundance for several pro-inflammatory and antiviral cytokines, including interleukin (IL)-2, IL-8, and interferon (IFN)-{lambda}1. These findings indicate an important role for respiratory viral infections and the host immune response in the development and maintenance of chronic Pseudomonas infections in the context of CF airway disease and broadly expand our understanding of viral-bacterial coinfection of the airways. IMPORTANCERespiratory infections are a leading cause of morbidity and mortality worldwide, and co-infections are associated with worsened disease outcomes. In viral-bacterial co-infection, clinical and mechanistic studies show that a preceding acute respiratory viral infection promotes the establishment and exacerbation of bacterial infections, leading to increased morbidity. Although people with cystic fibrosis do not experience more frequent acute respiratory viral infections, their outcomes are worse, with prolonged symptoms and hospitalizations. When examining how acute viral infections shape the microbiota in the respiratory tract of pwCF, we observe a disturbance of the microbial community composition during viral infections that does not return to baseline after the acute viral infection resolves. Moreover, we show that Pseudomonas relative abundance is significantly increased in the airways of pwCF during viral infection and that increased concentrations of antiviral cytokines - such as interferon (IFN)-{lambda}1 - are associated with increased Pseudomonas abundance. These findings offer evidence that the progression of chronic Pseudomonas infections in pwCF are influenced by acute respiratory viral infections and the subsequent antiviral response in the airways. This study furthers our understanding of viral-bacterial coinfection in the context of CF.

microbiology↗

bioRxiv2025

Differential DNA damage response to WRN inhibition identifies a targetable vulnerability in ARID1A-mutated cancers

ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancers. However, effective clinical treatments for patients with this mutation are limited, highlighting a demand for new therapeutic strategies. Here, we establish Werner syndrome ATP-dependent helicase (WRN) as a critical vulnerability target in ARID1A-mutated cancers. Upon genetic and pharmacological inhibition of WRN, ARID1A-mutated cells had defective Chk1-mediated DNA damage signaling, resulting in compensatory Chk2 activation, leading to G1-phase arrest and apoptosis, whereas ARID1A-proficient cells underwent Chk1-dependent G2/M arrest. Additional p21 inhibition, combined with WRN suppression, drove G1-arrested cells to re-enter the cell cycle, triggering mitotic catastrophe. The anti-tumor efficacy of WRN inhibition was validated using in vivo cell lines and patient-derived xenograft mouse models. Our findings define WRN as a selective therapeutic target in ARID1A-mutated cancers and suggest a combinatorial strategy of WRN and p21 inhibition as a therapeutic approach.

cancer biology↗

bioRxiv2025

Astrocytic MAOB-GABA axis as a molecular brake on repair following spinal cord injury

Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system (CNS) injury. The glial scar has been proposed as a major contributor to this failure in the regenerative process. However, its underlying molecular and cellular mechanisms remain unclear. Here, we report that monoamine oxidase B (MAOB)-dependent excessive GABA release from reactive astrocytes suppresses CNS repair system by reducing BDNF and TrkB expression in severe spinal cord injury (SCI) animal models. Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery. Notably, the selective MAOB inhibitor, KDS2010, facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model. Its dose-dependent effects were further validated in a monkey SCI model. Moreover, KDS2010 demonstrates a tolerable safety profile and dose-proportional pharmacokinetics in healthy humans during a phase 1 clinical trial. Our findings identify the astrocytic MAOB-GABA axis as a crucial molecular and cellular brake on CNS repair system following SCI and highlight translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.

neuroscience↗

bioRxiv2025

Yeast DNA Polymerase δ Proofreading Nuclease Suppresses Translesion Synthesis and Facilitates Recombination in DNA Lesion Bypass.

Translesion synthesis (TLS) employs specialized polymerases to incorporate nucleotides opposite DNA lesions, allowing replication to continue temporarily without repairing the lesions, while sacrificing replication fidelity (1). TLS depends on a ubiquitin molecule attached to the clamp PCNA at residue Lys164 (2, 3); the precise biochemical and molecular basis how PCNA modification stimulates TLS is still elusive (4-10). In this study, we discovered that DNA polymerase {delta} (Pol {delta}) 3 to 5 "proofreading" exonuclease degrades nascent TLS synthesis opposite pyrimidine dimers and inhibits TLS on both leading and lagging strands. Rad18 E3 ligase and PCNA ubiquitylation become dispensable for TLS when Pol {delta} exonuclease is inactive. Biochemical reconstitution showed that the major UV lesion bypass polymerase Rad30 is intrinsically inefficient at bypassing thymidine dimers and requires multiple turnovers. Pol {delta} exonuclease impedes Rad30 activity both catalytically and non-catalytically during and post-lesion bypass. Importantly, PCNA and PCNA ubiquitylation enhance processivity of Rad30 after thymidine dimer bypass, a critical step for further DNA synthesis extension and overcoming Pol {delta} inhibition. Our study reveals a new paradigm how PCNA ubiquitylation facilitates TLS and the new role of Pol {delta} nuclease in lesion bypass pathway choice and replication fidelity at fork-blocking DNA lesions.

genetics↗

bioRxiv2025

Distinct modes of dopamine modulation on striatopallidal synaptic transmission

Dopamine (DA) affects voluntary movement by modulating basal ganglia function. In the classical model, DA depletion leads to overactivity of the indirect pathway and excessively inhibits the thalamus, resulting in hypokinesia. The contribution of DA on striatopallidal synapses, an initial hub in the indirect pathway connecting the striatum to the external globus pallidus (GPe), remains poorly understood because of the sparse DA innervation. Here, we combine optogenetic projection targeting, whole cell patch clamp recordings in acute brain slices from mice, and computational modeling to overcome this limitation. We show that DA activates D2R receptors (D2Rs) and D4 receptors (D4Rs) differentially in distinct GPe subregions. In a pinwheel-like fashion, dorsolateral and ventromedial GPe expresses high levels of D2Rs, which exert presynaptic inhibition, while in dorsomedial and ventrolateral GPe D4Rs cause postsynaptic inhibition. DA depletion by 6-OHDA (6-hydroxydopamine) reverses the region- specific effect of DA, shifting it in the opposite direction and contributing to hypokinesia. These findings reveal the mechanism by which the different modality information conveyed spatially through the indirect pathway is differentially modulated by DA at striatopallidal synapses.

neuroscience↗

bioRxiv2025

Antarctic photosynthesis: energy transfer and charge separation in the diatom Chaetoceros Simplex

The polar oceanic environment poses extreme challenges to photosynthetic organisms, which have evolved atypical strategies to maintain efficient photosynthesis in cold temperatures. Here, the psychrophilic diatom Chaetoceros simplex (C. simplex) is studied in vivo in the dark-adapted state using steady-state and time-resolved fluorescence methods. Our results show that all fucoxanthin chlorophyll a/c protein (FCP) antenna transfer energy to photosystem I (PSI) or photosystem II (PSII), with no detached FCPs. PSI exhibits no fluorescence of red forms of chlorophyll (chl) beyond 700 nm in both 279 K and 77 K conditions. Despite this, it apparently has a long decay time of [~]85 ps indicating the presence of a large core-antenna supercomplex. PSII has an average lifetime of [~]500ps in open state (QA oxidized) and [~]1220 ps in closed state (QA reduced). PSII of C. simplex has kinetics that are slightly slower than temperate diatoms, suggesting slightly larger antenna. In addition, fucoxanthin (fx) molecules of FCP that absorb in the 500 - 550 nm range (fx-red) transfer more energy to PSII than fx that absorb in the blue range (fx-blue, 462 nm max absorption). A subpopulation of red-shifted, aggregated FCPs are detected at 77 K, that are active in energy transfer uphill at 279 K. Overall, our results indicate relatively larger antenna of PSI and PSII and an absence of red chls in PSI of cold-adapted species, compared to temperate species.

biophysics↗

bioRxiv2024

Chemical perturbations impacting histone acetylation governcolorectal cancer differentiation

Dysregulated epigenetic programs that restrict differentiation, reactivate fetal genes, and confer phenotypic plasticity are critical to colorectal cancer (CRC) development. By screening a small molecule library targeting epigenetic regulators using our dual reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 promotes CRC differentiation and anti-tumor activity. Comprehensive biochemical, chemical, and genetic experiments revealed that on-target blockade of the HDAC1/2 catalytic domain mediated the differentiated phenotype. Unbiased profiling of histone posttranslational modifications induced by HDAC1/2 inhibition nominated acetylation of specific histone lysine residues as potential regulators of differentiation. Genome-wide assessment of implicated marks indicated that H3K27ac gains at HDAC1/2-bound regions associated with open chromatin and upregulation of differentiation genes upon HDAC1/2 inhibition. Disrupting H3K27ac by degrading acetyltransferase EP300 rescued HDAC1/2 inhibitor-mediated differentiation of a patient-derived CRC model using single cell RNA-sequencing. Genetic screens revealed that DAPK3 contributes to CRC differentiation induced by HDAC1/2 inhibition. These results highlight the importance of specific chemically targetable histone modifications in governing cancer cell states and epigenetic reprogramming as a therapeutic strategy in CRC. BRIEF SUMMARYHDAC1/2 inhibition promotes colorectal cancer differentiation via gains in H3K27ac, which can be reversed by blocking its acetyltransferase EP300.

cancer biology↗

bioRxiv2024

Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread

Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen transmitted by tick bites, with no vaccines or specific therapeutics approved to date. Severe disease manifestations include hemorrhage, endothelial dysfunction, and multiorgan failure. Infected cells secrete the viral glycoprotein GP38, whose extracellular function is presently unknown. GP38 is considered an important target for vaccine and therapeutic design as GP38-specific antibodies can protect against severe disease in animal models, albeit through a currently unknown mechanism of action. Here, we show that GP38 induces endothelial barrier dysfunction in vitro, and that CCHFV infection, and GP38 alone, can trigger vascular leak in a mouse model. Protective antibodies that recognize specific antigenic sites on GP38, but not a protective neutralizing antibody binding the structural protein Gc, potently inhibit endothelial hyperpermeability in vitro and vascular leak in vivo during CCHFV infection. This work uncovers a function of the secreted viral protein GP38 as a viral toxin in CCHFV pathogenesis and elucidates the mode of action of non-neutralizing GP38-specific antibodies.

microbiology↗

bioRxiv2024

Adaptive thermogenesis is mediated by GDF15 via the GFRAL neuronal axis in mice

Adaptive thermogenesis is a key homeostatic mechanism that primarily occurs in brown adipocytes and enables the maintenance of body temperature. Although this process involves coordinated responses in multiple tissues, including the browning of white adipocytes, the precise inter-organ crosstalk underlying adaptive thermogenesis is unclear. Here, we investigate the pivotal role of the GDNF family receptor alpha-like (GFRAL) neuronal axis in modulating compensatory thermogenic responses in brown and white adipose depots under stress conditions, specifically the mitochondrial unfolded protein response resulting from genetic modification and cold exposure. We employed a mouse model with targeted deletion of Crif1 in the mitoribosomes of brown adipocytes, and cold-exposed mice and immortalized adipocytes, to uncover the mechanism by which mitochondrial stress-induced growth differentiation factor 15 (GDF15) expression affects metabolism and facilitates adaptive thermogenesis. We found that Crif1 deletion resulted in browning of inguinal white adipose depots, increased energy expenditure, reduced food intake, and resistance to weight gain. Retrograde neuronal tracing established that GFRAL-positive neurons in the hindbrain and sympathetic preganglionic neurons in the spinal cord mediated the GDF15-associated browning of inguinal white adipose tissue. Intervention studies using antisense oligonucleotides to inhibit Gfral expression blunted the effect of Crif1 deletion on energy expenditure and food intake, further confirming the essential role the GFRAL axis plays in GDF15-driven thermogenic adaptation in white adipose tissue. Our findings suggest that the GFRAL neuronal axis is key in coordinating the adaptive thermogenic response across multiple tissues and adipose depots, thereby ensuring metabolic homeostasis during mitochondrial stress.

molecular biology↗

bioRxiv2023

Atrophy-driven functional network collapse in neurodegenerative disease

Cognitive and behavioral deficits in Alzheimers disease (AD) and frontotemporal dementia (FTD) result from brain atrophy and altered functional connectivity. However, it is unclear how atrophy relates to functional connectivity disruptions across dementia subtypes and stages. We addressed this question using structural and functional MRI from 221 patients with AD (n=82), behavioral variant FTD (n=41), corticobasal syndrome (n=27), nonfluent (n=34) and semantic (n=37) variant primary progressive aphasia, and 100 cognitively normal individuals. Using partial least squares regression, we identified three principal structure-function components. The first component showed overall atrophy correlating with primary cortical hypo-connectivity and subcortical/association cortical hyper-connectivity. Components two and three linked focal syndrome-specific atrophy to peri-lesional hypo-connectivity and distal hyper-connectivity. Structural and functional component scores predicted global and domain-specific cognitive deficits. Anatomically, functional connectivity changes reflected alterations in specific brain activity gradients. Eigenmode analysis identified temporal phase and amplitude collapse as an explanation for atrophy-driven functional connectivity changes.

neuroscience↗

bioRxiv2023

Effects of circadian disruption via dim light at night in C57BL6/J mice on recoveryafter spinal cord injury

Spinal cord injury (SCI) can cause long-lasting locomotor deficits, pain, and mood disorders. Anatomical and functional outcomes are exacerbated by inflammation after SCI, which causes secondary damage. One promising target after SCI is manipulating the circadian system, which optimizes biology and behavior for time of day - including neuroimmune responses and mood- related behaviors. Circadian disruption after SCI is likely worsened by a disruptive hospital environment, which typically includes dim light-at-night (dLAN). Here, we hypothesized that mice subjected to SCI, then placed in dLAN, would exhibit worsened locomotor deficits, pain- like behavior, and anxiety-depressive-like symptoms compared to mice maintained in light days with dark nights (LD). C57BL/6J mice received sham surgery or moderate T9 contusion SCI, then were placed permanently in LD or dLAN. dLAN after SCI did not worsen locomotor deficits; rather, SCI-dLAN mice showed slight improvement in open-field locomotion at the final timepoint. Although dLAN did not alter SCI-induced heat hyperalgesia, SCI-dLAN mice exhibited an increase in mechanical allodynia at 13 days post-SCI compared to SCI-LD mice. SCI-LD and SCI-dLAN mice had similar outcomes using sucrose preference (depressive-like) and open-field (anxiety-like) tests. At 21 dpo, SCI-dLAN mice had reduced preference for a novel juvenile compared to SCI-LD, implying that dLAN combined with SCI may worsen this mood-related behavior. Finally, lesion size was similar between SCI-LD and SCI-dLAN mice. Therefore, newly placing C57BL/6J mice in dLAN after SCI had modest effects on locomotor, pain-like, and mood-related behaviors. Future studies should consider whether clinically-relevant circadian disruptors, alone or in combination, could be ameliorated to enhance outcomes after SCI.

neuroscience↗

bioRxiv2023

C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types

IntroductionA hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. MethodsWe leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, cerebellum) with average gene expression values for 15,633 protein-coding genes, including 50 genes known to be associated with ALS, FTD, or ALS-FTD. We then evaluated whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significant C9orf72 radiogenomic correlations (i.e., C9orf72 gene network) were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. ResultsA total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 gene network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic motor neurons in the spinal cord, and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with multiple neurotransmitter systems, protein ubiquitination, autophagy, and MAPK signaling, among others. ConclusionsConsidered together, we identified a network of C9orf72-associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

neuroscience↗

bioRxiv2023

Discrete projections from MCH neurons mediate anti-parkinsonian effects of acupuncture

Parkinsons disease (PD) presents with typical motor dysfunction and non-motor symptoms, including memory loss. Although acupuncture is suggested as an alternative therapy for PD, its neuroanatomical mechanisms remain unclear. We demonstrate that acupuncture ameliorates both motor and memory deficits in PD mice through activation of melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus and zona incerta (LH/ZI)--MCHLH/ZI-- via nerve conduction. We identify two distinct subpopulations of MCHLH/ZI projecting to the substantia nigra and hippocampus, each of which is responsible for controlling motor and memory function. This effect can be attributed to MCH-mediated recovery from dopaminergic neurodegeneration, reactive gliosis, and impaired hippocampal synaptic plasticity. Collectively, MCHLH/ZI constitutes not only the neuroanatomical basis of acupuncture but also a potential cellular target for treating both motor and non-motor PD symptoms. One-Sentence SummaryAcupuncture alleviates both motor and non-motor symptoms in Parkinsons disease by activating two distinct MCH projections.

neuroscience↗

bioRxiv2023

Beclin1-Deficient Adipocytes Promote Tumor Progression by YAP/TAZ-dependent Adipocyte Transformation

Adipocytes are crucial components of the tumor microenvironment (TME) that play a prominent role in supporting tumor growth. However, the characteristics of cancer-associated adipocytes (CAAs) that contribute to the pro-tumorigenic niche remain to be fully established. Here, we used adipocyte-specific Beclin1 KO (BaKO) mice to investigate the role of maladaptive adipocytes in promoting tumor progression. BECN1-deficient adipocytes exhibited downregulation of adipogenic markers and activation of YAP/TAZ signaling, similar to the traits observed in CAAs. Thus, we generated adipocyte-specific Becn1/Yap1/Taz KO mice, which exhibit markedly restored phenotypes in adipose tissue, resulting in tumor regression compared to that in BaKO. Further, we observed dysregulation of the BECN1-YAP/TAZ axis in the adipose tissue of mice fed a high-fat diet (HFD). Treatment with the YAP/TAZ inhibitor, verteporfin, suppressed tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Our findings provide insights into CAA formation and its significance in determining malignant TME, thereby suggesting a potential dual therapeutic strategy simultaneously targeting adipocyte homeostasis and cancer growth.

biochemistry↗

bioRxiv2023

Spinal cord injury in mice amplifies anxiety: a novel light-heat conflict test exposes increased salience of anxiety over heat

Spinal cord injury (SCI) predisposes individuals to anxiety and chronic pain. Anxiety- and pain-like behavior after SCI can be tested in rodents, yet commonly used tests assess one variable and may not replicate effects of SCI or sex differences seen in humans. Thus, novel preclinical tests should be optimized to better evaluate behaviors relating to anxiety and pain. Here, we use our newly developed conflict test - the Thermal Increments Dark-Light (TIDAL) test - to explore how SCI affects anxiety- vs. pain-like behavior, and whether sex affects post-SCI behavior. The TIDAL conflict test consists of two plates connected by a walkway; one plate remains illuminated and at an isothermic temperature, whereas the other plate is dark but is heated incrementally to aversive temperatures. Control mice are tested with both plates illuminated (thermal place preference). Female and male mice received moderate T9 contusion SCI or remained uninjured. At 7 days post-operative (dpo), mice with SCI increased dark plate preference throughout the TIDAL conflict test compared to uninjured mice. SCI increased dark plate preference for both sexes, although female (vs. male) mice remained on the heated-dark plate to higher temperatures. Mice with SCI that repeated TIDAL at 7 and 21 dpo showed reduced preference for the dark-heated plate at 21 dpo. Overall, in female and male mice, SCI enhances the salience of anxiety (vs. heat sensitivity). The TIDAL conflict test meets a need for preclinical anxiety- and pain-related tests that recapitulate the human condition; thus, future rodent behavioral studies should incorporate TIDAL or other conflict tests to help understand and treat neurologic disorders.

animal behavior and cognition↗