Biology subjects

Sela, Y.

Publications and source records attributed to Sela, Y..

10 recordsLinked to original sources

bioRxiv2025

Circadian rhythms in sexual behavior and their influence on reproductive outcomes in mice

Circadian clocks coordinate mammalian reproductive physiology, and circadian misalignment (resulting from shift work, jet lag, etc.) is known to impair fertility. Despite the well-established links between clock function and reproductive success, it remains unclear whether male and female mice maintained under standard ad libitum feeding conditions exhibit circadian rhythms in the propensity for sexual behavior, and to what degree such timing influences reproductive outcomes. Using standardized mating paradigms in C57BL/6J mice, we identified a circadian rhythm in sexual behavior in both sexes, with peak sexual activity most often occurring at circadian time (CT) 13-16 and a trough at CT4-7. To test the functional significance of these rhythms, we conducted 1-hour mating trials across four cohorts of C57BL/6J mice with pairs of mice having either aligned (e.g. male CT16 peak and female CT16 peak) or misaligned (e.g. male CT16 peak and female CT4 nadir) sexual behavior phases and monitored mating outcomes via ultrasound. While pregnancies were almost as frequent across all four cohorts, the numbers of live offspring were significantly more frequent when both the male and female mated at their peak phases than when both mice mated at their troughs. Notably, mating specifically during the males behavioral peak increased the likelihood of successful delivery of pups, suggesting that male circadian phase is a key determinant of miscarriage vs successful birth. These findings establish a circadian rhythm in the propensity for sexual behavior under standard feeding and housing conditions and indicate that mating time--particularly relative to the males circadian peak--can influence reproductive success. This insight provides a foundation for translational studies that explore whether intercourse timed to the circadian rhythms of the couple might help to increase fertility chances.

physiology↗

bioRxiv2024

Whole-Plant Physiological Identification and Quantification of Disease Progression

Visual estimates of plant symptoms are traditionally used to quantify disease severity. Yet, the methodologies used to assess these phenotypes are often subjective and do not allow tracking of disease progression from very early stages. Here, we hypothesized that quantitative analysis of whole-plant physiological vital functions can be used to objectively determine plant health, providing a more sensitive way to detect disease. We studied the tomato wilt that is caused by Fusarium oxysporum f. sp. lycopersici. Physiological performance of infected and non-infected tomato plants was compared using a whole-plant pot-based lysimeter functional-phenotyping system in a semi-environmentally controlled greenhouse. Water-balance traits of the plants were measured continuously and simultaneously in a quantitative manner. Infected plants exhibited early reductions in transpiration and biomass gain, which preceded visual disease symptoms. These changes in transpiration proved to be effective quantitative indicators for assessing both plant susceptibility to infection and virulence of the fungus. Physiological changes linked to fungal outgrowth and toxin release contributed to reduced hydraulic conductance during initial infection stages. The functional-phenotyping method objectively captures early-stage disease progression, advancing plant disease research and management. This approach emphasizes the potential of quantitative whole-plant physiological analysis over traditional visual estimates for understanding and detecting plant diseases.

plant biology↗

bioRxiv2023

Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells

Crosstalk between cellular metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to degenerative disease, including cancer. Here, we investigated whether maintenance of circadian rhythms depends upon specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to overall levels of a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function in an in vitro mouse model of pancreatic adenocarcinoma. Metabolic profiling of a library of congenic tumor cell clones revealed significant differences in levels of lactate, pyruvate, ATP, and other crucial metabolites that we used to identify candidate clones with which to generate circadian reporter lines. Despite the shared genetic background of the clones, we observed diverse circadian profiles among these lines that varied with their metabolic phenotype: the most hypometabolic line had the strongest circadian rhythms while the most hypermetabolic line had the weakest rhythms. Treatment of these tumor cell lines with bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist shown to increase OxPhos, decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, treatment with the Complex I antagonist rotenone enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function, and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

cancer biology↗

bioRxiv2021

MYC hyperactivates WNT signaling in APC/CTNNB1-mutated colorectal cancer cells through miR-92a-dependent repression of DKK3

Activation of Wnt signaling is among the earliest events of colon cancer development. It is achieved either via activating mutations in the CTNNB1 gene encoding {beta}-catenin, the key transcription factor in the Wnt pathway, or most commonly by inactivating mutations in APC, a major {beta}-catenin binding partner and negative regulator. However, our analysis of recent Pan Cancer Atlas data revealed that CTNNB1 mutations significantly co-occur with those affecting Wnt receptor complex components (e.g., Frizzled and LRP6), underscoring the importance of additional regulatory events even in the presence of common APC/CTNNB1 mutations. In our effort to identify non-mutational hyperactivating events, we determined that KRAS-transformed murine colonocytes overexpressing direct {beta}-catenin target MYC show significant upregulation of the Wnt signaling pathway and reduced expression of Dickkopf 3 (DKK3), a reported ligand for Wnt co-receptors. We demonstrate that Myc suppresses Dkk3 transcription through one of mir-17-92 cluster microRNAs, miR-92a. We further examined the role of DKK3 by overexpression and knockdown and discovered that DKK3 suppresses Wnt signaling in APC-null murine colonic organoids and human colon cancer cells despite the presence of downstream activating mutations in the Wnt pathway. Conversely, MYC overexpression in the same cell lines resulted in hyperactive Wnt signaling, acquisition of epithelial-to-mesenchymal transition markers, and enhanced migration and invasion and metastasis in syngeneic orthotopic mouse colon cancer model. Our results suggest that the MYC->miR-92a-|DKK3 axis hyperactivates Wnt signaling, forming a feedforward oncogenic loop. SIGNIFICANCECommon APC and CTNNB1 mutations activate Wnt signaling in colorectal cancers. Here we demonstrate that further potentiation of this pathway involves microRNA-dependent repression of the DKK3 gene by the Myc oncoprotein.

cancer biology↗

bioRxiv2021

Impaired top-down auditory processing despite extensive single-neuron responses during human sleep

Sleep in all species is universally defined as a reversible, homeostatically-regulated state of a reduced behavioral responsiveness, with a high arousal threshold in response to external sensory stimulation1. However, it remains unclear whether sleep mainly gates motor output or affects responses along sensory pathways, and whether sleep primarily modulates specific aspects of the sensory response such as feedforward vs. feedback signaling2-7. Here, we simultaneously recorded polysomnography, iEEG, microwire LFPs, and neuronal spiking activity during wakefulness and sleep in 13 epilepsy patients implanted with clinical depth electrodes, while presenting auditory stimuli (e.g. click-trains, words, music). The results revealed robust spiking and induced LFP high-gamma (80-200Hz) power responses during both NREM and REM sleep across the lateral temporal lobe. The magnitude of the responses was only moderately attenuated in sleep, most notably for late responses beyond the early auditory cortex. Nonetheless, sleep responses maintained their tight locking with soundwave envelopes and their information content was only minimally affected. In contrast, a decrease in LFP alpha-beta (10-30Hz) power responses was prevalent in wakefulness but significantly disrupted in sleep. Entrainment to 40 Hz click-trains was comparable across REM sleep and wakefulness, but reduced in NREM sleep. In conclusion, our results establish the presence of extensive and robust auditory responses during sleep while LFP alpha-beta power decrease, likely reflecting top-down processes8-10, is deficient. More broadly, our findings suggest that feedback signalling is key to conscious sensory processing11-13.

neuroscience↗

bioRxiv2020

Anesthetic Drug Concentration Rather Than Abrupt Behavioral Unresponsiveness Linearly Degrades Responses in the Rat Primary Auditory Cortex

Despite extensive knowledge of its molecular and cellular effects, how anesthesia affects sensory processing remains poorly understood. In particular, it remains unclear whether anesthesia modestly or robustly degrades activity in primary sensory regions, and whether such changes are linked to anesthesia drug concentration vs. behavioral unresponsiveness, since these are typically confounded. Here, we employed slow gradual intravenous propofol anesthesia induction together with auditory stimulation and intermittent assessment of behavioral responsiveness while recording epidural EEG, and neuronal spiking activity in the primary auditory cortex (PAC) of eight rats. We found that all main components of neuronal activity including spontaneous firing rates, onset response magnitudes, onset response latencies, post-onset neuronal silence duration, and late-locking to 40Hz click-trains, gradually deteriorated in a dose- dependent manner with increasing anesthesia levels without showing abrupt changes around loss of righting reflex or other time-points. Thus, the dominant factor affecting PAC responses is the anesthesia drug concentration rather than any sudden, dichotomous behavioral state changes. Our findings explain a wide array of seemingly conflicting results in the literature that, depending on the precise definition of wakefulness (vigilant vs. drowsy) and anesthesia (light vs. deep/surgical), report a spectrum of effects in primary regions ranging from minimal to dramatic differences.

neuroscience↗

bioRxiv2020

Dissecting phenotypic transitions in metastatic disease via photoconversion-based isolation

Cancer patients presenting with surgically resectable disease often harbor occult metastases, a potential source of relapse that is targetable only through systemic therapy. Studies of this occult fraction have been limited by a lack of tools with which to isolate discrete cells based on spatial grounds. We developed PIC-IT, photoconversion-based isolation technique allowing efficient recovery of cell clusters of any size including solitary disseminated tumor cells (DTCs), which are largely inaccessible otherwise. In a murine pancreatic cancer model, transcriptional profiling of spontaneously arising DTCs revealed phenotypic heterogeneity, functionally reduced propensity to proliferate and enrichment for inflammatory-response phenotype associated with NF-{kappa}B /AP-1 signaling. Pharmacological inhibition of NF-{kappa}B depleted DTCs but had no effect on macrometastases, suggesting DTCs are particularly dependent on this pathway. PIC-IT enables systematic investigation of the earliest stages of metastatic colonization. Moreover, this new technique can be applied to other biological systems in which isolation and characterization of spatially distinct cell populations is not currently feasible.

cancer biology↗

bioRxiv2020

A Sub-Minute Resolution Prediction of Brain Temperature Based on Sleep-Wake State in the Mouse

While brain temperature is of neurobiological and clinical importance, it is still unclear which factors contribute to its daily dynamics and to what degree. We recorded cortical temperature in mice alongside sleep-wake state during 4 days including a 6h sleep deprivation, and developed a mathematical tool to simulate temperature based on the sleep-wake sequence. The model estimated temperature with remarkable precision accounting for 91% of its variance based on three main factors with the sleep-wake sequence accounting for most of the variance (74%) and time-of-day ( circadian) the least (9%). As third factor, prior wake prevalence, was discovered to up-regulate temperature, explaining 43% of the variance. With similar accuracy the model predicted cortical temperature in a second, independent cohort using the parameters optimized for the first. Our model corroborates the profound influence of sleep-wake state on brain temperature, and can help differentiate thermoregulatory from sleep-wake driven effects in experiments affecting both.

neuroscience↗

bioRxiv2019

Sleep differentially affects early and late neuronal responses to sounds in auditory and perirhinal cortices

A fundamental feature of sleep is reduced behavioral responsiveness to external events, but the extent of processing along sensory pathways remains poorly understood. While responses are comparable across wakefulness and sleep in auditory cortex (AC), neuronal activity in downstream regions remains unknown. Here we recorded spiking activity in 435 neuronal clusters evoked by acoustic stimuli in the perirhinal cortex (PRC) and in AC of freely behaving male rats across wakefulness and sleep. Neuronal responses in AC showed modest (around 10%) differences in response gain across vigilance states, replicating previous studies. By contrast, PRC neuronal responses were robustly attenuated by 47% and 36% during NREM sleep and REM sleep, respectively. Beyond the separation according to cortical region, response latency in each neuronal cluster was correlated with the degree of NREM sleep attenuation, such that late (>40ms) responses in all monitored regions diminished during NREM sleep. The robust attenuation of late responses prevalent in PRC represents a novel neural correlate of sensory disconnection during sleep, opening new avenues for investigating the mediating mechanisms.\n\nSignificance StatementReduced behavioral responsiveness to sensory stimulation is at the core of sleeps definition, but it is still unclear how the sleeping brain responds differently to sensory stimuli. In the current study we recorded neuronal spiking responses to sounds along the cortical processing hierarchy of rats during wakefulness and natural sleep. Responses in auditory cortex only showed modest changes during sleep, whereas sleep robustly attenuated the responses of neurons in high-level perirhinal cortex. We also found that during NREM sleep, the response latency predicts the degree of sleep attenuation in individual neurons above and beyond their anatomical location. These results provide anatomical and temporal signatures of sensory disconnection during sleep and pave the way to understanding the underlying mechanisms.

neuroscience↗

bioRxiv2019

Oncogenic Notch promotes long-range regulatory interactions within hyperconnected 3D cliques

Chromatin loops enable transcription factor-bound distal enhancers to interact with their target promoters to regulate transcriptional programs. Although developmental transcription factors, such as active forms of Notch, can directly stimulate transcription by activating enhancers, the effect of their oncogenic subversion on the 3-dimensional (3D) organization of the cancer genome is largely undetermined. By mapping chromatin looping genome-wide in Notch-dependent triple-negative breast cancer and B-cell lymphoma, we show that far beyond the well-characterized role of Notch as an activator of distal enhancers, Notch regulates its direct target genes through establishing new long-range regulatory interactions. Moreover, a large fraction of Notch-promoted regulatory loops forms highly interacting enhancer and promoter spatial clusters, termed "3D cliques". Loss-and gain-of-function experiments show that Notch preferentially targets hyperconnected 3D cliques that regulate the expression of crucial proto-oncogenes. Our observations suggest that oncogenic hijacking of developmental transcription factors can dysregulate transcription through widespread effects on the spatial organization of cancer genomes.

cancer biology↗