Biology subjects

Hashimoto, C.

Publications and source records attributed to Hashimoto, C..

8 recordsLinked to original sources

bioRxiv2025

Rictor CRISPR Gene Editing by Lipid Nanoparticle Delivery Stimulates Anti-Tumor Immunity in Breast Cancer Liver Metastasis Model

Triple-negative breast cancer (TNBC) is a highly aggressive subtype, accounting for 10-15% of breast cancer cases in the United States. Liver metastases, common in advanced TNBC, are linked to especially poor outcomes, with a 5-year survival rate of just 11%. Although immune checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 show promise, durable responses in TNBC remain uncommon. This is largely due to a profoundly immunosuppressive tumor microenvironment (TME), driven by tumor-associated myeloid cells. Tumor-associated macrophages (TAMs) and neutrophils (TANs) polarize into immunosuppressive M2 and N2 phenotypes, respectively, suppressing T cell activity through cytokines, ROS, and checkpoint ligands such as VISTA. Myeloid-derived suppressor cells (MDSCs) further inhibit immunity by depleting nutrients and inducing regulatory T cells. As a result, despite its immunogenic features, TNBC remains resistant to immunotherapy due to persistent myeloid-mediated suppression. Here, we developed ionizable lipid nanoparticles (iLNPs) engineered to deliver the CRISPR-Cas12a ribonuclease complex targeting Rictor, a critical component of mTORC2, for in vivo reprograming of myeloid cells. The intravenous (IV) injection of CRISPR Rictor-targeting iLNP (CR-Ric-LNP) showed efficient uptake by circulating myeloid cells and accumulation into the breast cancer liver metastases. Notably, Rictor gene editing triggered pro-inflammatory activation of myeloid cells in the TME, enhancing antitumor responses. Single-cell RNA sequencing revealed that Rictor silencing treated samples showed induced rapid remodeling of the TME, with a significant reduction in immunosuppressive macrophages within 24 hours of treatment. Concurrently, cytotoxic T-cell populations exhibited increased interferon-gamma (Ifng) production, driving the emergence of specific myeloid clusters that were responsive to Interferon signaling, particularly in macrophages and neutrophils. A shift from an immunosuppressive to an inflammatory TME was further evidenced by an elevated Cxcl10/Spp1 ratio in myeloid cells. CR-Ric-LNP treatment also enhanced T-cell activation, reducing exhausted T cells and regulatory T cells (Tregs) while expanding natural killer (NK) cells, naive CD4+, and CD8+ T cells. These changes correlated with a decreased proportion of tumor cells and proliferating cells, ultimately leading to a significant survival benefit in a 4T1 breast cancer liver metastasis model. Our findings demonstrate that myeloid-targeted Rictor silencing reprograms the TME, promoting antitumor immunity and improving therapeutic outcomes. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/661471v1_ufig1.gif" ALT="Figure 1"> View larger version (109K): org.highwire.dtl.DTLVardef@10a5e7aorg.highwire.dtl.DTLVardef@1c0c005org.highwire.dtl.DTLVardef@17ec6b5org.highwire.dtl.DTLVardef@27c507_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Carbon and nitrogen stable isotopic profiling of chimpanzees and other primate hairs in Kalinzu Forest Reserve, Uganda

Stable isotope analysis is a widely used tool in primate ecology for investigating diet and environment, with numerous studies focusing on chimpanzees. However, few studies have explored the dietary niche of chimpanzees in comparison to other primates or examined intra-individual dietary variability. This limitation hinders the understanding of the comparability of isotopic data with the wealth of behavioral observational data in primate ecology. In this study, we report the carbon and nitrogen stable isotope ratios of hairs from wild chimpanzees and four other primate species in the Kalinzu Forest Reserve, Uganda. Bulk analysis revealed that both plant foods and chimpanzees in Kalinzu exhibited lower carbon isotope ratios than expected for the regions rainfall. Additionally, preliminary compound-specific nitrogen isotope analysis of amino acids was conducted, revealing that chimpanzees in Kalinzu have a lower degree of faunivory than the sympatric Cercopithecus primates. Furthermore, ultra-fine sectioning of a hair sample was conducted to investigate dietary variation over daily to weekly timescales. In one adult male chimpanzee, carbon and nitrogen isotope ratios fluctuated by more than 1{per thousand} within approximately 10 days. These findings highlight the importance of recognizing uncontrolled ecological variability and hidden intra-individual dietary changes when interpreting stable isotope data in relation to behavior and environmental traits.

ecology↗

bioRxiv2024

Predictability of next elements in chimpanzee gesture sequences

Recent research has produced evidence for basic combinatorial abilities in the vocal systems of different animal species. Here, we investigate the structure of gesture sequences in Eastern chimpanzees (Pan troglodytes schweinfurthii) to detect whether gestural communication shows non-random combinations and how combinatorial rules influence predictability. Gesture, as compared to vocalization, offers greater flexibility in how signals are combined--for example overlapping in time -- and as the parsing of signals into sequences is dependent on researcher decisions, we employ a multiverse approach, considering four different definitions of what constitutes a sequence based on varying time thresholds. Our results indicate that sequences tend to be short (even with the most liberal time-window) and that transitions between some gesture types occur more frequently than expected by chance, with some transitions showing significant association across all time-windows. These transitions often involve repetition, suggesting persistence as a key aspect of chimpanzee gestural sequences. Information about previous gestures reduced uncertainty in predicting subsequent gestures. The order of gestures within sequences appears to be less critical than their cooccurrence, challenging assumptions based on the linear patterning derived from vocal communication. Our findings highlight the importance of methodological choices in sequence definition and suggest that chimpanzee gestural communication is characterised by a mix of predictability and flexibility, with implications for understanding the evolution of complex communication systems.

animal behavior and cognition↗

bioRxiv2023

Many morphs: parsing gesture signals from the noise

Parsing signals from noise is a general problem for signallers and recipients, as well as for researchers studying communicative systems. Substantial research efforts have been invested in comparing how other species encode information and meaning in their signals, and how signalling is structured. However, our ability to do so depends on identifying and discriminating signals that represent meaningful units of analysis. Early approaches to defining signal repertoires applied top- down approaches, classifying cases into predefined signal types. Recently, more labour-intensive methods have taken a bottom-up approach describing the features of each signal in detail and clustering cases into types based on patterns of similarity between them in multi-dimensional feature-space that were previously undetectable. Nevertheless, it remains essential to assess whether the resulting repertoires are composed of relevant units from the perspective of the species using them, and redefining repertoires when additional data makes more detailed analyses feasible. In this paper we provide a framework that takes data from the largest set of wild chimpanzee (Pan troglodytes) gestures currently available, splitting gesture types at a fine scale based on modifying features of gesture expression and then determining whether this splitting process increases the information content of the communication system. Our method allows different features of interest to be incorporated into the splitting process, providing substantial future flexibility across - for example - species, populations, and levels of signal granularity. In doing so we provide a powerful tool allowing researchers interested in gestural communication to establish repertoires of relevant units for subsequent analyses within and between systems of communication.

animal behavior and cognition↗

bioRxiv2022

Do males know? Evidence-driven rainmaking of male bonobos to meet fertile phase of females

In most mammals, female sexual receptivity (estrus) closely coincides with ovulation, providing males with precise fertility signals. However, in some anthropoid primates living in multi-male societies, females display extended receptivity along with exaggerated sexual swellings that probabilistically indicate ovulation. This raises the question about how males successfully time mating, particularly when ovulation is difficult to predict from such cues as seen in bonobos. To address this question, we combined daily variation in swelling size, hormonal profiles, and male mating behaviors. By estimating day-specific ovulation probabilities relative to the onset of the maximal swelling phase and detumescence, we also examined how male efforts correlate with female fertility. Our results revealed that while ovulation probability was widely distributed and difficult to predict when aligned with the onset of the swelling phase, male behavior was closely aligned with the conception probability. Males concentrated mating efforts late in the phase and stopped after detumescence. High-ranking males intervened in copulations involving females with higher conception probabilities, specifically those with maximal swelling and older infants. When multiple females exhibited maximal swelling, males preferentially followed females whose maximal swelling started earlier and who had older infants. Male-male aggression increased when there were more females with maximal swelling. However, this tendency was reversed when male party size exceeded the average. Importantly, our results revealed that the low predictability of ovulation is best explained by inter- and intra-individual variation in the length of maximal swelling phase, rather than ovulation occurring randomly within that phase in bonobos. Males effectively manage such a noisy signal by prioritizing late-phase ovulatory cues and integrating reproductive history, thereby extracting usable timing information. This behavioral mechanism helps explain the persistence of conspicuous yet noisy ovulatory signals in bonobos. Since males are capable of inferring ovulation timing even under noisy conditions, selection may not favor highly precise female signals. Instead, it shifts more of the time and energy costs onto males, allowing conspicuous female traits to be maintained.

animal behavior and cognition↗

bioRxiv2021

What is unique about the human eye? Comparative image analysis on the external eye morphology of human and nonhuman great apes

The gaze-signaling hypothesis and the related cooperative-eye hypothesis posit that humans have evolved special external eye morphology, including exposed white sclera (the white of the eye), to enhance the visibility of eye-gaze direction and thereby facilitate conspecific communication through joint-attentional interaction and ostensive communication. However, recent quantitative studies questioned these hypotheses based on new findings that humans are not necessarily unique in certain eye features compared to other great ape species. Therefore, there is currently a heated debate on whether external eye features of humans are distinguished from those of other apes and how such distinguished features contribute to the visibility of eye-gaze direction. This study leveraged updated image analysis techniques to test the uniqueness of human eye features in facial images of great apes. Although many eye features were similar between humans and other species, a key difference was that humans have uniformly white sclera which creates clear visibility of both eye outline and iris -the two essential features contributing to the visibility of eye-gaze direction. We then tested the robustness of the visibility of these features against visual noises such as darkening and distancing and found that both eye features remain detectable in the human eye, while eye outline becomes barely detectable in other species under these visually challenging conditions. Overall, we identified that humans have distinguished external eye morphology among other great apes, which ensures robustness of eye-gaze signal against various visual conditions. Our results support and also critically update the central premises of the gaze-signaling hypothesis.

animal behavior and cognition↗

bioRxiv2021

Proliferation maintains the undifferentiated status of stem cells: the role of the planarian cell cycle regulator Cdh1

The coincidence of cell cycle arrest and differentiation has been described in a wide variety of stem cells and organisms for decades, but the causal relationship is still unclear due to the complicated regulation of the cell cycle. Here, we used the planarian Dugesia japonica since it possesses a quite simple cell cycle regulation in which cdh1 is the only factor that arrests the cell cycle. When cdh1 was functionally inhibited, the planarians could not maintain their tissue homeostasis and could not regenerate their missing body parts. While the ablation of cdh1 caused pronounced propagation of the stem cells, the progenitor and differentiated cells were decreased. Further analysis indicated that the stem cells without cdh1 expression did not undergo differentiation even though they received ERK signaling activation as an induction signal. These results suggested that stem cells could not acquire differentiation competence without cell cycle arrest. Thus, we propose that cell cycle regulation determines the differentiation competence and that cell cycle exit to G0 enables stem cells to undergo differentiation. Summary statementBy using planarians, which have quite simple cell cycle regulation, we revealed that stem cells with cell cycle progression could not undergo differentiation even though an induction signal was activated.

developmental biology↗

bioRxiv2019

The diet and feeding behaviour of the black-and-white colobus (Colobus guereza) in the Kalinzu Forest, Uganda

One of the goals for primate feeding ecology is to understand the factors that affect inter- and intra-specific variations. Therefore, a detailed description of basic feeding ecology in as many populations and sites as possible is necessary and warrants further understanding. The black-and-white colobus (Colobus guereza) or guereza is widely distributed in Africa and is one of the well-studied colobines in terms of their feeding; they demonstrate considerable variation in their diets in response to local conditions. We studied the diet of a group of guerezas in the Kalinzu Forest, Uganda, for over 30 consecutive months using behavioural observation (4,308 h total), phenology, and vegetation surveys. A total of 31 plant species were consumed by the study group. This study group was predominantly folivorous; the majority of their feeding time was involved in feeding on young leaves (87%). However, during certain times of the year, fruits and seeds accounted for 45% of monthly feeding time. Young leaves of Celtis durandii were by far the most important food, which constituted 58% of the total feeding records. There was a significant increase in the consumption of fruits and flowers once young leaf availability was low, but their consumption of fruits did not significantly increase even when fruit availability was high. Their monthly dietary diversity increased as the number of available plants with young leaves declined, suggesting that much of the dietary diversity in the study group may be attributable to the young leaf portion of their diet. Our findings may help contribute to a better understanding of the dietary adaptations and feeding ecology of guerezas in response to local environmental conditions.

ecology↗