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Investigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models. Currently technologies for monitoring and controlling neural activities in 3D models are lacking. Here the authors report a 3D high-density multielectrode array, with optical stimulation and drug delivery, to investigate neural circuit dynamics in engineered 3D neural tissues.

Preclinical uterine cancer models using the rabbit VX2 system have been described in previous studies; however, they often involve complex procedures such as cell culture, uterine suturing, or imaging validation. This study aimed to establish a technically simple and reproducible rabbit model of uterine cancer using VX2 tumor fragments. We established a rabbit uterine cancer model by injecting minced VX2 tumor tissue into the endometrium of New Zealand White rabbits. We first generated VX2 tumors in donor rabbits via subcutaneous thigh injection and harvested them after three weeks. Recipient rabbits were assigned to two cohorts with scheduled assessments at 14 days or 4 weeks post-implantation. Tumor formation was assessed at each time point by intraoperative inspection and histopathological analysis. In the initial 14-day cohort (n = 8), all rabbits developed well-defined uterine tumors without perioperative complications. Histological analysis confirmed viable tumor growth. No lymph node metastasis or distant spread was observed at the 14-day endpoint. In a separate, extended 4-week cohort (n = 8), all rabbits also developed uterine tumors. This cohort demonstrated tumor progression, with 75% exhibiting retroperitoneal lymph node metastasis, and 37.5% showing peritoneal metastasis. This study demonstrates the feasibility and reproducibility of a simplified VX2 uterine cancer model using tumor fragments. Furthermore, the model replicates metastatic progression, including retroperitoneal lymph node and peritoneal metastasis, by 4 weeks. The model may serve as a reliable platform for future preclinical studies involving uterine tumor biology and metastatic progression.

In native tissues, cellular and acellular components are anisotropically organized and often aligned in specific directions, providing structural and mechanical properties for actuating biological functions. Thus, engineering alignment not only allows for emulation of native tissue structures but might also enable implementation of specific functionalities. However, achieving desired alignment is challenging, especially in three-dimensional constructs. By exploiting the elastomeric property of polydimethylsiloxane and fibrillogenesis kinetics of collagen, here we introduce a simple yet effective method to assemble and align fibrous structures in a multi-modular three-dimensional conglomerate. Applying this method, we have reconstructed the CA3–CA1 hippocampal neural circuit three-dimensionally in a monolithic gel, in which CA3 neurons extend parallel axons to and synapse with CA1 neurons. Furthermore, we show that alignment of the fibrous scaffold facilitates the establishment of functional connectivity. This method can be applied for reconstructing other neural circuits or tissue units where anisotropic organization in a multi-modular structure is desired. Alignment or anisotropic organisation within and between cells enables biological function but is challenging to engineer. Here, the authors align collagen fibres in a pre-strained polydimethylsiloxane mould to generate a 3D scaffold that guides hippocampal neuron axon growth to form CA3–CA1 neural circuits.

Introduction/BackgroundThis study aimed to determine the safety and efficacy of the RKP00156 vaginal tablet, a CDK9 inhibitor, in healthy women and patients with cervical intraepithelial neoplasia grade 2 (CIN2).MethodologyWe conducted a phase 1/2a clinical trial of RKP00156. In step 1, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered transvaginally to 24 healthy women. In step 2, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered once daily for 4 weeks in 62 patients with CIN2. The primary endpoints of this trial were the safety of RKP00156 and the change in the human papillomavirus (HPV) viral load.ResultsA total of 86 patients were enrolled and randomized. RKP00156 administration did not cause serious drug-associated adverse events (AEs). Although no significant difference in the HPV viral load was found between the experimental and placebo groups, a reduction in the HPV viral load was observed in the 25 mg-dose group (-98.61%; 95% confidence interval, -99.83% to 4.52%; p = 0.046) after treatment completion in patients with a high HPV viral load, despite a lack of statistical power. No differences in histologic regression and HPV clearance were observed.ConclusionThe tolerability and safety of RKP00156 was proved with no serious AEs. Although the study did not show any significance in histologic regression and HPV clearance, our findings indicate that RKP00156 may have a possibility of short-term inhibitory effect on HPV replication in patients with higher viral loads.DisclosuresI have no disclosure to declare.Abstract 116 Figure 1

BackgroundPreclinical uterine cancer models using the rabbit VX2 system have been described in previous studies; however, they often involve complex procedures such as cell culture, uterine suturing, or imaging validation. This study aimed to establish a technically simple and reproducible rabbit model of uterine cancer using VX2 tumor fragments.MethodsWe established a rabbit uterine cancer model by injecting minced VX2 tumor tissue into the endometrium of New Zealand White rabbits. We first generated VX2 tumors in donor rabbits via subcutaneous thigh injection and harvested them after three weeks. Recipient rabbits were assigned to two cohorts with scheduled assessments at 14 days or 4 weeks post-implantation. Tumor formation was assessed at each time point by intraoperative inspection and histopathological analysis.ResultsIn the initial 14-day cohort (n = 8), all rabbits developed well-defined uterine tumors without perioperative complications. Histological analysis confirmed viable tumor growth. No lymph node metastasis or distant spread was observed at the 14-day endpoint. In a separate, extended 4-week cohort (n = 8), all rabbits also developed uterine tumors. This cohort demonstrated tumor progression, with 75% exhibiting retroperitoneal lymph node metastasis, and 37.5% showing peritoneal metastasis.ConclusionThis study demonstrates the feasibility and reproducibility of a simplified VX2 uterine cancer model using tumor fragments. Furthermore, the model replicates metastatic progression, including retroperitoneal lymph node and peritoneal metastasis, by 4 weeks. The model may serve as a reliable platform for future preclinical studies involving uterine tumor biology and metastatic progression.

The burning of a sheet of cellulose-based material, such as paper or cloth, involves uneven shrinkage which causes wrinkling. We simulate this geometrically complicated phenomenon by modeling the effects of heat transfer, shrinkage and partial ablation on a thin shell. A strain-limitation technique is applied to a two-layer structure of springs arranged as a body-centered square. Although this structure is over-constrained, convergence can be achieved using a new successive fast projection method. We also remesh the shells dynamically to deal with the topological changes that occur as regions burn away.

In response to phasic and tonic release, dopamine neurotransmission is regulated by its receptor subtypes, mainly dopamine receptor type 1 and 2 (DRD1 and DRD2). These dopamine receptors are known to form a heterodimer, however the receptor crosstalk between DRD1 and DRD2 was only suspected by measuring their downstream signaling products, due to the lack of methodology for selectively detecting individual activity of different dopamine receptors. Here, we develop red DRD1 sensor (R-DRD1) and green DRD2 sensor (G-DRD2) which can specifically monitor the real-time activity of DRD1 and DRD2, and apply these multicolor sensors to directly measure the receptor crosstalk in the DRD1-DRD2 heterodimer. Surprisingly, we discover that DRD1 activation in the heterodimer is inhibited only at micromolar phasic concentration of dopamine, while DRD2 activation is selectively inhibited at nanomolar tonic dopamine level. Differential receptor crosstalk in the DRD1-DRD2 heterodimer further modulates their downstream cAMP level. These data imply a novel function of the DRD1-DRD2 heterodimer at physiological dopamine levels of phasic and tonic release. Our approach utilizing multicolor receptor sensors will be useful to discover novel function of GPCR heterodimers.

Research on cultured meat has primarily focused on the mass proliferation or differentiation of muscle cells; thus, the food characteristics of cultured meat remain relatively underexplored. As the quality of meat is determined by its organoleptic properties, cultured meat with similar sensory characteristics to animal-derived meat is highly desirable. In this study, we control the organoleptic and nutritional properties of cultured meat by tailoring the 2D differentiation of primary bovine myoblasts and primary bovine adipose-derived mesenchymal stem cells on gelatin/alginate scaffolds with varying stiffness. We assess the effect of muscle and adipose differentiation quality on the sensory properties of cultured meat. Thereafter, we fabricate cultured meat with similar sensory profiles to that of conventional beef by assembling the muscle and adipose constructs composed of highly differentiated cells. We introduce a strategy to produce cultured meat with enriched food characteristics by regulating cell differentiation with scaffold engineering. Achieving organoleptic properties of conventional meat is important for cultured meat production. Here, the authors demonstrate that the texture, flavor, and nutritional content of cultured meat can be significantly enhanced by regulating cell differentiation inside hydrogel scaffolds.

Individual lifestyle risk factors have been associated with an increased risk of mortality. However, limited evidence is available on the combined association of lifestyle risk factors with mortality in non-Western populations. The analysis included 37,472 participants (aged ≥19 years) in the Korea National Health and Nutrition Examination Surveys (2007–2014) for whom the data were linked to death certificates/medical records through December 2016. A lifestyle risk score was created using five unhealthy behaviors: current smoking, high-risk alcohol drinking, unhealthy weight, physical inactivity, and insufficient/prolonged sleep. Cox proportional hazards models were used to estimate hazard ratio (HR) and 95% confidence interval (CI). During up to 9 years of follow-up, we documented 1,057 total deaths. Compared to individuals with zero lifestyle risk factor, those with 4–5 lifestyle risk factors had 2.01 times (HR = 2.01, 95% CI = 1.43–2.82) and 2.59 times (HR = 2.59, 95% CI = 1.24–5.40) higher risk of all-cause and cardiovascular mortality, respectively. However, higher lifestyle risk score was not significantly associated with cancer mortality (p-trend >0.05). In stratified analyses, the positive associations tended to be stronger in adults aged <65 years, unemployed, and those with lower levels of education. In conclusion, combined unhealthy lifestyle behaviors were associated with substantially increased risk of total and cardiovascular mortality in Korean adults.