Crosstalk Model Research Articles

Thermal Crosstalk Modelling and Compensation Methods for Programmable Photonic Integrated Circuits

Thermal Crosstalk Modelling and Compensation Methods for Programmable Photonic Integrated Circuits

Inter-Mode Crosstalk Estimation between Cores for LPmn Modes in Weakly Coupled Few-Mode Multicore Fiber with Perturbations.

A novel inter-mode crosstalk (IMXT) model of LPmn mode for weakly coupled few-mode multicore fiber is proposed based on the coupled mode theory (CMT) with bending and twisting perturbations. A universal expression of the mode coupling coefficient (MCC) between LPmn modes is derived. By employing this MCC, the universal semi-analytical model (USAM) of inter-core crosstalk (ICXT) can be applied to calculate the IMXT. Simulation results show that our model is generally consistent with previous theories when stochastic perturbations are absent. Moreover, our model can work effectively when stochastic perturbations are present, where former theories are not able to work properly. It has been theoretically found that the MCC has an intimate relationship with core pitch. Our model, based on the CMT, can provide physical characteristics in detail, which has not been reported clearly by former theories. In addition, our model is applicable to phase-matching and non-phase-matching regions of both real homogeneous and heterogeneous few-mode multicore fibers (FM-MCFs) with a wider range of applications.

Differential regulation of heparan sulfate biosynthesis in fibroblasts cocultured with normal vs. cancerous prostate cells.

Heparan sulfate proteoglycans (HSPGs) regulate a wide range of biological activities in both physiological and pathological conditions. Altered expression or deregulated function of HSPGs and their heparan sulfate (HS) chains significantly contribute to carcinogenesis as well and crucially depends on the functioning of the complex system of HS biosynthetic/modifying enzymes termed as "GAGosome". Here, we aimed at investigating the expression profile of the system in a cell culture model of stroma-epithelial crosstalk and searching for transcription factors potentially related to the regulation of expression of the genes involved. Coculture of BjTERT-fibroblasts with normal PNT2 human prostate epithelial cells resulted in significant downregulation (2-4-fold) of transcriptional activity of HS metabolism-involved genes (EXT1/2, NDST1/2, GLCE, HS2ST1, HS3ST1/2, HS6ST1/2, SULF1/2, HPSE) in both cell types, whereas coculture with prostate cancer cells (LNCaP, PC3, DU145) demonstrated no significant interchanges. Human Transcription Factor RT2 Profiler PCR array and manual RT-PCR verification supposed FOS, MYC, E2F, SRF, NR3C1 as potential candidates for regulation and/or coordination of HS biosynthesis. Taken together, transcriptional activity of HS biosynthetic system in normal fibroblasts and prostate epithelial cells during their coculture might be controlled by their intercellular communication, reflecting of adaptation of these cells to each other. The regulation is attenuated or abrogated if normal fibroblasts interact with prostate cancer cells making the cancer cells independent of the limiting effects of fibroblasts, thus contributing to possibility of unlimited growth and progression. Overall, these data demonstrate an ability of cell-cell interactions to affect transcriptional activity of HS biosynthesis-involved genes.

8K Real-Time Video-Transmission Using PDM and FDM in 220-GHz Band Based on Polarization Crosstalk Model and Optimization Strategy

8K Real-Time Video-Transmission Using PDM and FDM in 220-GHz Band Based on Polarization Crosstalk Model and Optimization Strategy

Modeling and analysis of crosstalk induced effects in graphene-carbon nanotube composite interconnects

This paper proposes an equivalent circuit model for two-line coupled multilayer graphene nanoribbon - single-wall carbon nanotube (MLGNR-SWCNT) composite interconnects (MSCs), incorporating the effects of coupling capacitance and mutual inductance. We also examine the temperature-dependent crosstalk effect on the victim line of MSCs in the time domain using decoupling techniques and the ABCD parameter matrix approach. This analysis is conducted at the global level of 7 nm, 14 nm, and 22 nm technology nodes, comparing the performance of MSCs with MLGNR, SWCNT, and copper (Cu) interconnects, validated through HSPICE simulations. Our results reveal that the crosstalk delay of all interconnects induced by dynamic crosstalk exhibits superior performance in the in-phase crosstalk mode compared to the out-of-phase mode at room temperature. In particular, MSCs demonstrate less crosstalk delay in both crosstalk modes compared to SWCNT and Cu interconnects. In addition, we analyze the crosstalk delay of the victim line for two-line coupled MSCs at varying temperatures in out-of-phase crosstalk mode, comparing them with MLGNR, SWCNT, and Cu interconnects. Simulation results indicate that the crosstalk delay is temperature-dependent, increasing with rising temperatures, and the crosstalk delay of MSCs is the least of all interconnects. Furthermore, we investigate the crosstalk noise of MSCs induced by functional crosstalk at different temperatures, comparing it with MLGNR, SWCNT, and Cu interconnects. It is observed that the crosstalk noise peak remains constant with temperature changes across all interconnects; however, the holding time and width of crosstalk noise increases with rising temperatures and MSCs have the least crosstalk noise peak and crosstalk noise width of all interconnects. Also, numerical results exhibit that reducing interconnect temperature, SWCNT diameter, and edge roughness of MLGNR are effective strategies to diminish the crosstalk delay of MSCs. In addition, increasing line spacing is identified as an effective method to reduce crosstalk noise peak of MSCs of different lengths. The proposed model results show excellent agreement with HSPICE simulation data. Therefore, our analysis of crosstalk effect manifests that MLGNR-SWCNT composite can be a promising material to replace SWCNT and copper as an ideal material for global interconnect applications in thermally variable environments.

Cross Talking Calcium, IP3 and Buffer Dynamics Alters ATP and NADH Level in Obese and Normal Hepatocyte Cell.

The cross talk between calcium (Ca2+), IP3 and buffer dynamics regulate various mechanisms in hepatocyte cells. The study of independent systems of calcium, IP3, and buffer signaling provides limited information about cell dynamics. In the current study, coupled reaction-diffusion equations are used to design a cross-talk model for IP3, buffer, and calcium dynamics in a hepatocyte cell. The one-way feedback of calcium, buffer, and IP3 in ATP production, ATP degradation, and NADH production rate is incorporated into the model. Numerical simulation has been done using the Finite Element Method (FEM) along the spatial direction and the Crank-Nicolson (C-N) method along the temporal direction. The numerical results are analysed to determine the effects of alterations in processes of cross-talking dynamics of IP3, buffer, and calcium on ATP and NADH production and degradation rate of ATP in a hepatocyte cell under normal and obesity conditions. The comparative analysis of these findings unveils notable distinctions induced by obesity in calcium dynamics, ATP and NADH synthesis, and ATP degradation kinetics.

Studying Adipose Endothelial Cell/Adipocyte Cross-Talk in Human Subcutaneous Adipose Tissue.

Microvascular endothelial cells (MVECs) have many critical roles, including control of vascular tone, regulation of thrombosis, and angiogenesis. Significant heterogeneity in endothelial cell (EC) genotype and phenotype depends on their vascular bed and host disease state. The ability to isolate MVECs from tissue-specific vascular beds and individual patient groups offers the opportunity to directly compare MVEC function in different disease states. Here, using subcutaneous adipose tissue (SAT) taken at the time of insertion of cardiac implantable electronic devices (CIED), we describe a method for the isolation of a pure population of functional human subcutaneous adipose tissue MVEC (hSATMVEC) and an experimental model of hSATMVEC-adipocyte cross-talk. hSATMVEC were isolated following enzymatic digestion of SAT by incubation with anti-CD31 antibody-coated magnetic beads and passage through magnetic columns. hSATMVEC were grown and passaged on gelatin-coated plates. Experiments used cells at passages 2-4. Cells maintained classic features of EC morphology until at least passage 5. Flow cytometric assessment showed 99.5% purity of isolated hSATMVEC, defined as CD31+/CD144+/CD45-. Isolated hSATMVEC from controls had a population doubling time of approximately 57 h, and active proliferation was confirmed using a cell proliferation imaging kit. Isolated hSATMVEC function was assessed using their response to insulin stimulation and angiogenic tube-forming potential. We then established an hSATMVEC-subcutaneous adipocyte co-culture model to study cellular cross-talk and demonstrated a downstream effect of hSATMVEC on adipocyte function. hSATMVEC can be isolated from SAT taken at the time of CIED insertion and are of sufficient purity to both experimentally phenotype and study hSATMVEC-adipocyte cross-talk.

Abstract 4214: Tissue-engineered 3D model for elucidating the role of the bone niche in osteosarcoma therapy response

Abstract Introduction. Osteosarcoma (OS) is an aggressive pediatric bone cancer whose 5-year survival rate has remained stagnant for nearly 40 years, and often exhibits high therapy resistance. Experimental models that can elucidate how the OS bone niche modulates OS signaling and drug response could accelerate discovery of new targeted therapies. Our group has recently reported a biomaterials-based 3D in vitro model of OS with bone matrix mimicking cues: a gelatin microribbon scaffold coated with hydroxyapatite particles (GelHA µRBs). We demonstrated this 3D OS model can better mimic in vivo signaling and drug responses than standard 2D culture. However, the potential of this 3D model for probing OS-bone niche crosstalk has not yet been investigated. We hypothesize that OS-bone crosstalk will modulate OS drug response and signaling. To test this hypothesis, here we aim to establish a 3D model to assess the effect of tissue engineered (TE) bone on OS drug response and signaling. Methods. Gel µRBs were fabricated by wet spinning as previously described. To generate tissue engineered bone, human mesenchymal stem cells (hMSCs) were encapsulated (15 M/mL) in GelHA µRBs and cultured in osteogenic medium for 28 days. A PDX-derived OS line (OS052) was used. Three groups were studied: OS monoculture, separate coculture (paracrine only), and OS cells seeded directly on TE bone (paracrine plus direct contact). For all groups, 96K OS cells were seeded per sample. OS cells were labeled with firefly luciferase to allow tracking of OS cell viability and proliferation using bioluminescence. Gemcitabine, a standard chemotherapy drug for OS, was used as the model drug (0.001 to 1 uM). Outcome analyses include cell viability, proliferation, gene expression, and immunostaining. Results. TE bone enhances OS resistance to gemcitabine in both separate coculture and direct seeding on bone, as shown by bioluminescence. At 1 uM, OS cell death in monoculture, separate coculture, and seeding on bone was on average 98.19%, 82.05%, and 64.44%. These results indicate that both paracrine signaling from osteoblasts and direct contact with bone ECM contribute to OS drug resistance. TE bone did not significantly impact OS proliferation over 7 days as shown by bioluminescence. Ongoing studies will assess the effect of TE bone on OS expression of key proteins in the bone niche (RANK/RANKL/OPG) and OS response to cabozantinib, a cMET inhibitor whose antiproliferative effect may be osteoblast-mediated. Conclusions. Here we report a tissue engineered 3D model to study the crosstalk between OS cells and bone niche. The results support our hypothesis that bone niche contributes to OS drug resistance, which is mediated through both paracrine signals and ECM. This model can be used to further elucidate the mechanisms through which the bone niche influences OS progression and drug resistance, and for screening potential drug candidates that target such crosstalk. Citation Format: Abena Darkwah Peasah, Callan Monette, Jeehee Lee, Michelle Tai, E. Alejandro Sweet-Cordero, Fan Yang. Tissue-engineered 3D model for elucidating the role of the bone niche in osteosarcoma therapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4214.

Abstract 6647: Established 3D tumor-spheroid co-culture models demonstrate macrophage plasticity and unveil potential supportive roles of macrophages in the T cell-tumor-macrophage crosstalk post radiation therapy

Abstract Ionizing radiation therapy (RT) has been characterized as an immunogenic event that in some tumors results in cell-death mediated activation of innate inflammatory and immunostimulatory mediators. These inflammatory mediators in turn modulate lymphocyte effector function in the tumor environment that can contribute to radiation-mediated control of tumors. We aim to model these interactions ex vivo, to identify the critical signals regulating immune function. We demonstrate that it is necessary to establish a three-dimensional model for crosstalk between tumor cells and immune cells to recapitulate myeloid and T cell responses to radiation. We have established 3D tumor spheroid co-culture models using murine MC38 colon carcinoma and Panc02-SIY pancreatic carcinoma cell lines with bone-marrow derived macrophages (BMDM). The spheroid cultures were exposed to 12 Gy RT and maintained in culture over a period of 5 days. Analyses were done using live-cell imaging and flow cytometry. Our findings demonstrate a decrease in hypoxia post RT, and exposure to RT increased the phagocytosis of dying cancer cells by macrophages. This was followed by a significant increase in CD80 and CD86 expression on the surface of macrophages in co-cultures on day 3 and day 4 post RT. These data matched our analyses of tumors treated in vivo with radiation and analyzed on day 4 post RT. In addition to RT-mediated upregulation of costimulatory molecules on macrophages, we also observed an increase in PD-L1 expression that may also impact T cell responses. To test T cell function in the 3D model, antigen-specific T cells were added to the Panc-02-SIY and BMDM spheroid co-cultures, which resulted in enhanced T cell proliferation in RT-treated groups. To assess the mechanism of macrophage activation in co-cultures, we evaluated HMGB1 as an innate adjuvant that may cause TLR4-mediated macrophage activation; however, the pattern of activation did not match that of RT. The involvement of the nucleic acid sensing cGAS-STING pathway was assessed by using BMDM from STING knockout (KO) mice in the 3D co-cultures. Similar upregulation of CD80 and CD86 were observed on STING KO macrophages in 3D co-cultures on day 4 post RT, indicating the observed phenomena to be independent of STING signaling. Ongoing studies aim to decrypt the innate downstream signaling pathways involved in RT-mediated polarization of macrophages so as to identify potential targeted therapies for tumor-associated macrophages, and also translate this to patient tumors. Citation Format: Aanchal Preet Kaur, Alejandro F. Alice, Megan R. Potuznik, Gwen Kramer, Jason Baird, David J. Friedman, Marka R. Crittenden, Michael J. Gough. Established 3D tumor-spheroid co-culture models demonstrate macrophage plasticity and unveil potential supportive roles of macrophages in the T cell-tumor-macrophage crosstalk post radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6647.

SMYD4 monomethylates PRMT5 and forms a positive feedback loop to promote hepatocellular carcinoma progression.

Both lysine and arginine methyltransferases are thought to be promising therapeutic targets for malignant tumors, yet how these methyltransferases function in malignant tumors, especially hepatocellular carcinoma (HCC), has not been fully elucidated. Here, we reported that SMYD4, a lysine methyltransferase, acts as an oncogene in HCC. SMYD4 was highly upregulated in HCC and promoted HCC cell proliferation and metastasis. Mechanistically, PRMT5, a well-known arginine methyltransferase, was identified as a SMYD4-binding protein. SMYD4 monomethylated PRMT5 and enhanced the interaction between PRMT5 and MEP50, thereby promoting the symmetrical dimethylation of H3R2 and H4R3 on the PRMT5 target gene promoter and subsequently activating DVL3 expression and inhibiting expression of E-cadherin, RBL2, and miR-29b-1-5p. Moreover, miR-29b-1-5p was found to inversely regulate SMYD4 expression in HCC cells, thus forming a positive feedback loop. Furthermore, we found that the oncogenic effect of SMYD4 could be effectively suppressed by PRMT5 inhibitor invitro and invivo. Clinically, high coexpression of SMYD4 and PRMT5 was associated with poor prognosis of HCC patients. In summary, our study provides a model of crosstalk between lysine and arginine methyltransferases in HCC and highlights the SMYD4-PRMT5 axis as a potential therapeutic target for the treatment of HCC.

Regulation of calcium entry by cyclic GMP signaling in Toxoplasma gondii

Ca2+ signaling impacts almost every aspect of cellular life. Ca2+ signals are generated through the opening of ion channels that permit the flow of Ca2+ down an electrochemical gradient. Cytosolic Ca2+ fluctuations can be generated through Ca2+ entry from the extracellular milieu or release from intracellular stores. In Toxoplasma gondii, Ca2+ ions play critical roles in several essential functions for the parasite, like invasion of host cells, motility, and egress. Plasma membrane Ca2+ entry in T.gondii was previously shown to be activated by cytosolic calcium and inhibited by the voltage-operated Ca2+ channel blocker nifedipine. However, Ca2+ entry in T.gondii did not show the classical characteristics of store regulation. In this work, we characterized the mechanism by which cytosolic Ca2+ regulates plasma membrane Ca2+ entry in extracellular T.gondii tachyzoites loaded with the Ca2+ indicator Fura-2. We compared the inhibition by nifedipine with the effect of the broad spectrum TRP channel inhibitor, anthranilic acid or ACA, and we find that both inhibitors act on different Ca2+ entry activities. We demonstrate, using pharmacological and genetic tools, that an intracellular signaling pathway engaging cyclic GMP, protein kinase G, Ca2+, and the phosphatidyl inositol phospholipase C affects Ca2+ entry and we present a model for crosstalk between cyclic GMP and cytosolic Ca2+ for the activation of T.gondii's lytic cycle traits.

MiR-124-3p negatively impacts embryo implantation via suppressing uterine receptivity formation and embryo development

During embryo implantation, blastocyst interacts with the receptivity endometrium and the endometrial epithelium secretes nurturing fluid to support embryonic development. Interferon-λ (IFN-λ) is a novel, non-redundant regulator that participates in the fetal–maternal interaction; however, the precise molecular mechanism underlying its impact on uterine receptivity remains elusive. Here, microarray profiling revealed that 149 specific miRNAs were differentially expressed in the human endometrial cells following IFN-λ treatment. In particular, miR-124-3p expression was significantly reduced after IFN-λ treatment (p < 0.05). An in vivo mouse pregnancy model showed that miR-124-3p overexpression notably decreased embryo implantation rate and led to an aberrant epithelial phenotype. Furthermore, miR-124-3p negatively impacted the migration and proliferation of endometrial cells, and hindered embryonic developmental competence in terms of blastocyst formation and global DNA re-methylation. Downstream analysis showed that LIF, MUC1 and BCL2 are potential target genes for miR-124-3p, which was confirmed using western blotting and immunofluorescence assays. In conclusion, IFN-λ-driven downregulation of miR-124-3p during embryo implantation modulates uterine receptivity. The dual functional role of miR-124-3p suggests a cross-talk model wherein, maternal endometrial miRNA acts as a transcriptomic modifier of the peri-implantation endometrium and embryo development.

Integrative modeling and analysis of signaling crosstalk reveal molecular switches coordinating Yes-associated protein transcriptional activities

The transcriptional co-activator YAP forms complexes with distinct transcription factors, controlling cell fate decisions, such as proliferation and apoptosis. However, the mechanisms underlying its context-dependent function are poorly defined. This study explores the interplay between the TGF-β and Hippo pathways and their influence on YAP's association with specific transcription factors. By integrating iterative mathematical modeling with experimental validation, we uncover molecular switches, predominantly controlled by RASSF1A and ITCH, which dictate the formation of YAP-SMAD (proliferative) and YAP-p73 (apoptotic) complexes. Our results show that RASSF1A enhances the formation of apoptotic complexes, whereas ITCH promotes the formation of proliferative complexes. Notably, higher levels of ITCH transform YAP-SMAD activity from a transient to a sustained state, impacting cellular behaviors. Extending these findings to various breast cancer cell lines highlights the role of cellular context in YAP regulation. Our study provides new insights into the mechanisms of YAP transcriptional activities and their therapeutic implications.

Network dynamics investigation of omics-data-driven circadian-hypoxia crosstalk logical model in gallbladder cancer reveals key therapeutic target combinations.

Recent findings in cancer research have pointed towards the bidirectional interaction between circadian and hypoxia pathways. However, little is known about their crosstalk mechanism. In this work, we aimed to investigate this crosstalk at a network level utilizing the omics information of gallbladder cancer. Differential gene expression and pathway enrichment analysis were used for selecting the crucial genes from both the pathways, followed by the construction of a logical crosstalk model using GINsim. Functional circuit identification and node perturbations were then performed. Significant node combinations were used to investigate the temporal behavior of the network through MaBoSS. Lastly, the model was validated using published in vitro experimentations. Four new positive circuits and a new axis viz. BMAL1/ HIF1αβ/ NANOG, responsible for stemness were identified. Through triple node perturbations viz.a. BMAL:CLOCK (KO or E1) + P53 (E1) + HIF1α (KO); b. P53 (E1) + HIF1α (KO) + MYC (E1); and c. HIF1α (KO) + MYC (E1) + EGFR (KO), the model was able to inhibit cancer growth and maintain a homeostatic condition. This work provides an architecture for drug simulation analysis to entrainment circadian rhythm and in vitro experiments for chronotherapy-related studies. Insight Box. Circadian rhythm and hypoxia are the key dysregulated processes which fuels-up the cancer growth. In the present work we have developed a gallbladder cancer (GBC) specific Boolean model, utilizing the RNASeq data from GBC dataset and tissue specific interactions. This work adequately models the bidirectional nature of interactions previously illustrated in experimental papers showing the effect of hypoxia on dysregulation of circadian rhythm and the influence of this disruption on progression towards metastasis. Through the dynamical study of the model and its response to different perturbations, we report novel triple node combinations that can be targeted to efficiently reduce GBC growth. This network can be used as a generalized framework to investigate different crosstalk pathways linked with cancer progression.

Generation of porcine endometrial organoids and their use as a model for enhancing embryonic attachment and elongation.

Porcine endometrial organoids (EOs) were isolated and characterized, revealing distinctive features such as unique extracellular matrix formation, fusion into uterine bud-like structures, and facilitation of embryo elongation. The yield of EOs was significantly enhanced by cryopreservation medium supplemented with the rock inhibitor (Y-27632), resulting in reduced expression of apoptotic mRNAs and microRNAs. Endometrial organoids (EOs) are acceptable models for understanding maternal-embryonic cross talk. This study was conducted to generate EOs and optimize their cryopreservation and provide coculture modeling with embryos. The endometrial tissues were used for culturing the organoids inside domes of Matrigel®. To improve the long-term storage of EOs, 10 µM ROCK inhibitor (RI) was added to the cryopreservation medium. Day 7 parthenogenetically activated embryos were cocultured with EOs or EO outgrowths, and embryonic cell numbers and embryo attachment were monitored. Spherical EOs 100-300 µm in size can be retrieved on day 7 of culture, and larger EOs, approximately 1.5 mm in diameter, can be maintained in the Matrigel® dome for 21 days. The nuclear expression of Ki67 indicates that more than 80% of EOs nuclei were proliferative. EOs exhibit unique novel characters such as formation of extracellular matrix and ability for fusion. RI increased the yield and quality of organoids after freezing or thawing. The cell number of cocultured embryos increased five-fold, and the proportion of trophoblast outgrowths increased seven-fold compared with those of control embryos. The embryos cultured with EO-conditioned medium showed a better attachment rate than the other models, and - for the first time - we report embryonic elongation. Immunofluorescence staining of the attached embryos showed CDX2 in the periphery of EOs outgrowths. The 3D assembly and cryopreservation of EOs was optimized, and EO coculture supported embryo attachment, trophoblast outgrowth, and elongation, which would provide a valuable tool for studying the intricate processes involved in porcine embryo implantation.

Deciphering the Immune Microenvironment in Waldenstrom's Macroglobulinemia

Recent studies have demonstrated the occurrence of somatic mutations of MYD88 and CXCR4 as key players in Waldenstrom's Macroglobulinemia (WM) pathogenesis and disease progression. Despite the significant improvement in the knowledge of the molecular mechanisms supporting WM biology whether immunosuppressive mechanisms could contribute to WM pathogenesis remains unexplored. We interrogated the transcriptome signatures of the bone marrow (BM) microenvironment of WM patients (n:22) as compared to healthy individuals (n:10), we found a significant enrichment for a Treg-signature, and for CD40/CD40L signaling-related genes (FDR &amp;lt;0.001; P &amp;lt;0.01). These findings were confirmed using a transgenic murine lymphoplasmacytic/WM model, where the BM immune microenvironment showed an increased number of infiltrating CD4+ T lymphocytes over CD8+ T cells. Further characterization of the T-cell compartment revealed the presence of abundant CD4+CD25+FoxP3+ Treg cells, with respect to control mice. Murine WM cells recruited a significantly higher number of more abundant Ki67+Treg cells, as compared to B lymphocytes from healthy mice. Collectively, these results suggest that immunosuppressive Treg cells may play in supporting WM disease biology. These findings prompted us to focus on Tregs and their role in supporting WM pathogenesis. We performed bulk RNA sequencing of Tregs isolated from both WM patients (n:14) and healthy donors/HD (n:8); showing a peculiar transcriptome signature characterizing WM-derived Tregs as compared to their normal cellular counterpart. WM patient-derived Tregs presented with transcriptome profiling enriched for FOXP3-target genes and to Treg induction, as compared to healthy donor-derived Tregs; with WM-Tregs showing a significant enrichment for genes related to interferon- and TNFα-related genes via NF-kB. The functional impact of Treg in WM biology was next studied. We observed a significantly higher ability of WM cells to favor both induction and expansion of CD4+CD25+FoxP3+ Tregs, as compared to HD-derived CD19+ B-cells; paralleled by a significantly higher increase of Ki67-positive Treg induced by WM cells as compared to HD-derived CD19+ B-cells. Same results were obtained using WM primary cells. Data were further corroborated by demonstrating significant enrichment of several pro-proliferative- and pro-survival pathways in WM-Tregs, versus HD-counterpart, including MAPK- and PI3K/AKT-related genes. To gain insight into the potential molecular mechanisms responsible for the observed Treg induction in WM, we performed scRNAseq using the whole cell population harvested at the end of the induction assay. We evaluated the B-T-cell interactions at single cell level, adopting a B-&amp;gt;T cross-talk model; and identified a set of four high-priority genes (CD40, TNF, TNFSF14, ICAM2): although all of them were expressed in B cells, only the expression of CD40 was maximal and virtually restricted to the B clusters, with the other three genes showing a more diffuse pattern. Importantly, CD40-ligand was shown to be the interactor expressed within the Treg cell compartment. Given the identified CD40/CD40L axis as a potential regulator of the WM cell/Treg cross-talk, we used the CD40/CD40L inhibitor DRI-C21045; and found a significant decrease in Treg induction and Treg proliferation. Halting CD40/CD40L interaction inhibited Treg induction and growth, also within the context of CXCR4-mutated WM, supported by inhibition of p-AKT and p-ERK in Treg cells. CD40/CD40L blockade led to inhibition of WM cell growth. Overall our studies have demonstrated the existence of a Treg-mediated immunosuppressive phenotype in WM, which can be therapeutically reversed by blocking the CD40L/CD40 axis to inhibit WM cell growth.

Effects of positive end-expiratory pressure on intracranial pressure, cerebral perfusion pressure, and brain oxygenation in acute brain injury: Friend or foe? A scoping review

BackgroundPatients with acute brain injury (ABI) are a peculiar population because ABI does not only affect the brain but also other organs such as the lungs, as theorized in brain–lung crosstalk models. ABI patients often require mechanical ventilation (MV) to avoid the complications of impaired respiratory function that can follow ABI; MV should be settled with meticulousness owing to its effects on the intracranial compartment, especially regarding positive end-expiratory pressure (PEEP). This scoping review aimed to (1) describe the physiological basis and mechanisms related to the effects of PEEP in ABI; (2) examine how clinical research is conducted on this topic; (3) identify methods for setting PEEP in ABI; and (4) investigate the impact of the application of PEEP in ABI on the outcome. MethodsThe five-stage paradigm devised by Peters et al. and expanded by Arksey and O'Malley, Levac et al., and the Joanna Briggs Institute was used for methodology. We also adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension criteria. Inclusion criteria: we compiled all scientific data from peer-reviewed journals and studies that discussed the application of PEEP and its impact on intracranial pressure, cerebral perfusion pressure, and brain oxygenation in adult patients with ABI. Exclusion criteria: studies that only examined a pediatric patient group (those under the age of 18), experiments conducted solely on animals; studies without intracranial pressure and/or cerebral perfusion pressure determinations, and studies with incomplete information. Two authors searched and screened for inclusion in papers published up to July 2023 using the PubMed-indexed online database. Data were presented in narrative and tubular form. ResultsThe initial search yielded 330 references on the application of PEEP in ABI, of which 36 met our inclusion criteria. PEEP has recognized beneficial effects on gas exchange, but it produces hemodynamic changes that should be predicted to avoid undesired consequences on cerebral blood flow and intracranial pressure. Moreover, the elastic properties of the lungs influence the transmission of the forces applied by MV over the brain so they should be taken into consideration. Currently, there are no specific tools that can predict the effect of PEEP on the brain, but there is an established need for a comprehensive monitoring approach for these patients, acknowledging the etiology of ABI and the measurable variables to personalize MV. ConclusionPEEP can be safely used in patients with ABI to improve gas exchange keeping in mind its potentially harmful effects, which can be predicted with adequate monitoring supported by bedside non-invasive neuromonitoring tools.

Effect of dual-task interaction combining postural and visual perturbations on cortical activity and postural control ability

Previous studies have suggested cortical involvement in postural control in humans by measuring cortical activities and conducting dual-task paradigms. In dual-task paradigms, task performance deteriorates and can be facilitated in specific dual-task settings. Theoretical frameworks explaining these dual-task interactions have been proposed and debated for decades. Therefore, we investigated postural control performance under different visual conditions using a virtual reality system, simultaneously measuring cortical activities with a functional near-infrared spectroscopy system. Twenty-four healthy participants were included in this study. Postural stability and cortical activities after perturbations were measured under several conditions consisting of postural and visual perturbations. The results showed that concurrent visual and postural perturbations could facilitate cortical activities in the supplementary motor area and superior parietal lobe. Additionally, visual distractors deteriorated postural control ability and cortical activation of the supplementary motor area. These findings supported the theoretical framework of the “Cross talk model”, in which concurrent tasks using similar neural domains can facilitate these task performances. Furthermore, it indicated that the cortical resource capacity and domains activated for information processing should be considered in experiments involving dual-task paradigms and training.

Performance analysis of Cu-MWCNT bundled HCTSVs using ternary logic

This paper presents an investigation of crosstalk issues for coupled heterogeneous coaxial through silicon vias (HCTSVs) in ternary logic. Crosstalk issues are investigated for coupled HCTSVs using Cu-MWCNT as a conductive filler and polymer liners such as polyimide, polypropylene carbonate (PPC), and benzocyclobutene (BCB) as insulating materials. The electrical equivalent circuit model is utilized to investigate the crosstalk induced by the ternary inverter in coupled HCTSVs. The effects of crosstalk such as functional and dynamic crosstalk for proposed HCTSVs are compared with Multi-walled CNT (MWCNT) TSVs using Hewlett simulation program with integrated circuit emphasis (HSPICE) simulations. Other performance parameters are also investigated, including power dissipation, power delay product (PDP), and energy delay product (EDP). The proposed model's crosstalk effects are also investigated for various TSV heights. The BCB-based coupled Cu-MWCNT HCTSVs provide a significant improvement in crosstalk at reduced TSV height. The proposed HCTSVs also improved overall performance by 32.12% when compared to the MWCNT based TSVs. As a result, Cu-MWCNT based HCTSVs with BCB liner are better than conventional TSVs for ternary logic integrated circuits (ICs).

Design of crosstalk aware energy harvesting system-on-chip

A crosstalk noise aware design methodology is developed, suitable for advanced energy harvesting systems-on-chip (SoCs). The proposed methodology enables accurate substrate crosstalk modeling via process characterization, Python based layout extraction and RC modeling, providing a reliable design flow for robust integrated circuits (IC) implementation. The SoC’s noise coupling performance degradation is accurately estimated, co-calculating the impact of the package and printed-circuit-board (PCB) design. The proposed design flow is seamlessly integrated into the standard design suite. An energy harvesting SoC is used as a product level vehicle. The system is developed in a 0.18 μm CMOS process. The noise aggressor is a digital Maximum Power Point Tracking (MPPT) block, while the noise victim is a DC-DC boost converter and the input voltage sensor. The proposed crosstalk design flow effectively captures the hardware efficiency values, with 14.6% maximum deviation from experimental results, while the standard methodology presents high deviation up to 51.08%.