Analog Functions Research Articles

Histone Methylation-Mediated Reproductive Toxicity to Consumer Product Chemicals in Caenorhabditis elegans: An Epigenetic Adverse Outcome Pathway (AOP).

The significance of histone methylation in epigenetic inheritance underscores its relevance to disease and the chronic effects of environmental chemicals. However, limited evidence of the causal relationships between chemically induced epigenetic changes and organismal-level effects hinders the application of epigenetic markers in ecotoxicological assessments. This study explored the contribution of repressive histone marks to reproductive toxicity induced by chemicals in consumer products in Caenorhabditis elegans, applying the adverse outcome pathway (AOP) framework. Triclosan (TCS) and tetrabromobisphenol A (TBBPA) exposures caused reproductive toxicity and altered histone methyltransferase (HMT) and histone demethylase (HDM) activities, increasing the level of trimethylation of H3K9 and H3K27. Notably, treatment with an H3K27-specific HMT inhibitor alleviated reproductive defects and the transcriptional response of genes related to vitellogenin, xenobiotic metabolism, and oxidative stress. Comparison of points of departure (PODs) based on calculated benchmark concentrations (BMCs) revealed the sensitivity of histone-modifying enzyme activities to these chemicals. Our findings suggest that the 'disturbance of HMT and HDM' can serve as the molecular initiating event (MIE) leading to reproductive toxicity in the epigenetic AOP for TCS and TBBPA. The study extended the biological applicability of these enzymes by identifying model species with analogous protein sequences and functions. This combined approach enhances the essentiality, empirical support, and taxonomic domain of applicability (tDOA), which are crucial considerations for ecotoxicological AOPs. Given the widespread use and environmental distribution of chemicals in consumer products, this study proposes histone-modifying enzyme activity as an effective screening tool for reproductive toxicants and emphasizes the integration of epigenetic mechanisms into a prospective ERA.

Theoretical study of ultrafast spin dynamics in a Co-Fe molecular Prussian blue analog and spin logic functionality design

Theoretical study of ultrafast spin dynamics in a Co-Fe molecular Prussian blue analog and spin logic functionality design

A DUF21 domain-containing protein regulates plant dwarfing in watermelon.

Dwarf or semi-dwarf plant structures are well-suited for intensive farming, maximizing yield, and minimizing labor costs. Watermelon (Citrullus lanatus) is classified as an annual vine plant with elongated internodes, yet the mechanism governing watermelon dwarfing remains unclear. In this study, a compact watermelon mutant dwarf, induced by the insertion of T-DNA, was discovered. Through re-sequencing, a gene named domain of unknown function 21 (ClDUF21), located downstream of the T-DNA insertion site, was identified as the candidate gene for the dwarf mutant, and its functionality was subsequently confirmed. Watermelon mutants generated through CRISPR/Cas9-mediated knockout of ClDUF21 revealed that homozygous mutants displayed a pronounced dwarfing phenotype, and protein-protein interaction analysis confirmed the direct interaction between ClDUF21 and ClDWF1. Subsequently, we employed CRISPR/Cas9 technology to precisely modify the homologous gene CsDUF21 in cucumber (Cucumis sativus) and performed protein interaction validation between CsDUF21 and CsDWF1, thereby demonstrating that the CsDUF21 gene also exhibits analogous functionality in plant dwarfing. These findings demonstrate that ClDUF21 governs plant dwarfism by modulating the brassinosteroid synthesis pathway via ClDWF1.

Statistical physical view of statistical inference in Bayesian linear regression model.

This paper considers similarities between statistical physics and Bayes inference through the Bayesian linear regression model. Some similarities have been discussed previously, such as the analogy between the marginal likelihood in Bayes inference and the partition function in statistical mechanics. In particular, this paper considers the proposal to associate discrete sample size with inverse temperature [C. H. LaMont and P. A. Wiggins, Phys. Rev. E 99, 052140 (2019)2470-004510.1103/PhysRevE.99.052140]. The previous study suggested that incorporating this similarity motivates the derivation of analogs of thermodynamic functions such as energy and entropy. The study also anticipated that those analogous functions have potential to describe Bayes estimation from physical points of view and to provide physical insights into mechanisms of estimation. This paper incorporates a macroscopic perspective as an asymptotics similar to the thermodynamic limit into the previous suggestion. Its motivation stems from the statistical mechanical concept of deriving thermodynamic functions that characterize macroscopic properties of macroscopic systems. This incorporation not only allows analogs of macroscopic thermodynamic functions to be considered but also suggests a candidate for an analog of inverse temperature with continuity, which is partly consistent with the previous proposal to associate the discrete sample size with inverse temperature. On the basis of this suggestion, we analyze analogs of macroscopic thermodynamic functions for a Bayesian linear regression model which is the basis of various machine learning models. We further investigate, through the behavior of these functions, how Bayes estimation is described from the perspective of physics and what kind of physical insight is obtained. As a result, the estimation of regression coefficients, which is the primary task of regression, appears to be described by the physical picture of balance between decreasing energy and increasing entropy as in equilibrium states of thermodynamic systems. More specifically we observe the physical view of Bayes inference as follows: the estimation succeeds where the effect of decreasing energy is dominant at low temperature. On the other hand, the estimation fails where the effect of increasing entropy is dominant at high temperature.

Human neural stem cell-derived extracellular vesicles protect against ischemic stroke by activating the PI3K/AKT/mTOR pathway.

Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells, and can thus be used as substitutes for stem cells in stem cell therapy, thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments. This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke. However, the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear, presenting challenges for clinical translation. To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside, we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke. We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis. The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase, mammalian target of rapamycin, and protein kinase B, and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor. These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Finally, we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile. Therefore, human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.

Vangl2 regulates intercellular junctions by remodeling actin-based cytoskeleton through the Rock signaling pathway during spermatogenesis in Eriocheir sinensis

As a key planar cell polarity protein, Van Gogh-like 2 (Vangl2) is essential for mammalian spermatogenesis. As a decapod crustacean, Eriocheir sinensis exhibits distinct spermatogenic processes due to its unique seminiferous tubule morphology and hemolymph-testis barrier (HTB). To determine whether Vangl2 performs analogous functions in E. sinensis, we identified the Es-Vangl2. Es-Vangl2 exhibited high expression and wide distribution in the testes, indicating its crucial involvement in spermatogenesis. Following targeted knockdown of Es-Vangl2in vivo, the structure of seminiferous tubules was disrupted, characterized by vacuolization of the germinal zone and obstruction of spermatozoon release. Concurrently, the integrity of the HTB was compromised, accompanied by reduced expression and aberrant localization of junction proteins. More importantly, the regulatory influence of Es-Vangl2 was manifested through modulating the organization of microfilaments, a process mediated by epidermal growth factor receptor pathway substrate 8 (Eps8). Further studies demonstrated that these phenotypes resulting from Es-Vangl2 knockdown were attributed to the inhibition of Rock signaling pathway activity, which was verified by the Es-Rock interference and Y27632 inhibition assays. In summary, the findings highlight the pivotal role of Es-Vangl2 in stabilizing HTB integrity by regulating Eps8-mediated actin remodeling through the Rock signaling pathway in the spermatogenesis of E. sinensis.

Prominin 1 and Tweety Homology 1 both induce extracellular vesicle formation.

Prominin-1 (Prom1) is a five-transmembrane-pass integral membrane protein that associates with curved regions of the plasma membrane. Prom1 interacts with membrane cholesterol and actively remodels the plasma membrane. Membrane bending activity is particularly evident in photoreceptors, where Prom1 loss-of-function mutations cause failure of outer segment homeostasis, leading to cone-rod retinal dystrophy (CRRD). The Tweety Homology (Ttyh) protein family has been proposed to be homologous to Prominin, but it is not known whether Ttyh proteins have an analogous membrane-bending function. Here, we characterize the membrane-bending activity of human Prom1 and Ttyh1 in native bilayer membranes. We find that Prom1 and Ttyh1 both induce formation of extracellular vesicles (EVs) in cultured mammalian cells and that the EVs produced are physically similar. Ttyh1 is more abundant in EV membranes than Prom1 and produces EVs with membranes that are more tubulated than Prom1 EVs. We further show that Prom1 interacts more stably with membrane cholesterol than Ttyh1 and that this may contribute to membrane bending inhibition in Prom1 EVs. Intriguingly, a loss-of-function mutation in Prom1 associated with CRRD induces particularly stable cholesterol binding. These experiments provide mechanistic insight into Prominin function in CRRD and suggest that Prom and Ttyh belong to a single family of functionally related membrane-bending, EV-generating proteins.

An Ultra-Low-Voltage Approach to Accurately Set the Quiescent Current of Digital Standard Cells Used for Analog Design and Its Application on an Inverter-Based Operational Transconductance Amplifier

An approach to design analog building blocks based on digital standard cells is presented in this work. By ensuring that every CMOS inverter from a standard-cell library operates with a well-defined quiescent current and output voltage, the suggested method makes it possible to construct analog circuits that are resistant against PVT variations. The method uses the local supply voltages connected to the source terminals of the p-channel and n-channel MOS transistors of the standard-cell inverters as control inputs. It is based on adaptive supply voltage generator (ASVG) reusable blocks, which are comparable to those used in digital applications to handle process variations. All of the standard-cell inverters used for analog functions receive the local supply voltages produced by the ASVGs, which enable setting each cell’s quiescent current to a multiple of a reference current and each cell’s static output voltage to an appropriate reference voltage. Both the complete custom design of the ASVG blocks and a theoretical study of the feedback loop of the ASVG are presented. An application example through the design of a fully synthesizable two-stage operational transconductance amplifier (OTA) is also provided. The TSMC 180 nm CMOS technology has been used to implement both the OTA and the ASV generators. Simulation results have demonstrated that the proposed approach allows to accurately set the quiescent current of standard-cell inverters, dramatically reducing the effect of PVT variations on the pmain performance parameters of the standard-cell-based two-stage OTA.

Evolutionary plasticity and functional repurposing of the essential metabolic enzyme MoeA.

MoeA, or gephyrin in higher eukaryotes, is crucial for molybdenum cofactor biosynthesis required in redox reactions. Gephyrin is a moonlighting protein also involved in postsynaptic receptor clustering, a feature thought to be a recent evolutionary trait. We showed previously that a repurposed copy of MoeA (Glp) is involved in bacterial cell division. To investigate how MoeA acquired multifunctionality, we used phylogenetic inference and protein structure analyses to understand the diversity and evolutionary history of MoeA. Glp-expressing Bacteria have at least two copies of the gene, and our analysis suggests that Glp has lost its enzymatic role. In Archaea we identified an ancestral duplication where one of the paralogs might bind tungsten instead of molybdenum. In eukaryotes, the acquisition of the moonlighting activity of gephyrin comprised three major events: first, MoeA was obtained from Bacteria by early eukaryotes, second, MogA was fused to the N-terminus of MoeA in the ancestor of opisthokonts, and finally, it acquired the function of anchoring GlyR receptors in neurons. Our results support the functional versatility and adaptive nature of the MoeA scaffold, which has been repurposed independently both in eukaryotes and bacteria to carry out analogous functions in network organization at the cell membrane.

Closed-loop identification of stabilized models using dual input–output parameterization

This paper introduces a dual input–output parameterization (dual IOP) for the identification of linear time-invariant systems from closed-loop data. It draws inspiration from the recent input–output parameterization developed to synthesize a stabilizing controller. The controller is parameterized in terms of closed-loop transfer functions, from the external disturbances to the input and output of the system, constrained to lie in a given subspace. Analogously, the dual IOP method parameterizes the unknown plant with analogous closed-loop transfer functions, also referred to as dual parameters. In this case, these closed-loop transfer functions are constrained to lie in an affine subspace guaranteeing that the identified plant is stabilized by the known controller. Compared with existing closed-loop identification techniques guaranteeing closed-loop stability, such as the dual Youla parameterization, the dual IOP requires neither a doubly-coprime factorization of the controller nor a nominal plant that is stabilized by the controller. The dual IOP does not depend on the order and the state-space realization of the controller either, as in the dual system-level parameterization. Simulation shows that the dual IOP outperforms the existing benchmark methods.

The relationship between single leg balance and proprioception of the knee joint in individuals with non-specific chronic back pain

BackgroundProprioceptive information from the hips, knees, and ankles as well as joint coordination are important for maintaining and controlling balance. Regional receptors in the muscles, joints, skin, and tendons as well as proprioception in the knee joint provide the necessary joint activity and stability. Pain may occur with a decreased sense of balance and proprioception. ObjectiveTo investigate the relationship between single-leg balance and proprioception of the knee joint in individuals with non-specific chronic low back pain. DesignFifty-two individuals with non-specific chronic low back pain, 30 females and 22 males, were included in our study, with a range of 18–50 years (mean age:25.15 ± 8.2 years). MethodPain intensity at rest and activity was assessed using Visual Analogue Scale (VAS), and disability and function were assessed using Oswestry Disability Index (ODI). Single-leg balance measurements were performed using Prokin TecnoBody kinematic balance device. A goniometer was used to evaluate the proprioception of the knee joint. ResultsThere were low-level negative correlations between VAS resting pain intensity and medium-lateral standard deviation value (p = 0.018; r = −0.327) and ellipse area measure (p = 0.039; r = −0.287) from static balance assessments. There were low-level negative correlations between VAS activity pain intensity and medium-lateral standard deviation value (p = 0.039; r = −0.288), ellipse area (p = 0.044; r = −0.281), and perimeter measure (p = 0.043; r = −0.282) from static balance assessments. No correlation was seen between ODI and clinical balance and proprioception assessments (p > 0.05). There was no correlation between clinical balance and proprioception evaluations (p > 0.05). ConclusionAs a result of the study, it was decided that there is a minimal relationship between single-leg balance and knee joint proprioception in people with nonspecific low back pain.

Antibacterial, anti-invasive, and anti-inflammatory activity of bovine lactoferrin extracted from milk or colostrum versus whole colostrum.

Lactoferrin (Lf), a multifunctional cationic glycoprotein extracted from milk or colostrum, is able to chelate two ferric ions per molecule, inhibit the formation of reactive oxygen species, interact with the anionic components of bacteria or host cells, and enter inside host cell nucleus, thereby exerting antibacterial, anti-invasive, and anti-inflammatory activities. By virtue of Lf presence, bovine colostrum is expected to perform analogous functions to pure Lf, along with additional activities attributable to other bioactive constituents. The present research aims to compare the antibacterial, anti-invasive, and anti-inflammatory activities of bovine Lf purified from milk (mbLf) and colostrum (cbLf) in comparison to those exhibited by whole bovine colostrum (wbc). The results demonstrated a major efficacy of mbLf in inhibiting pathogenic bacteria and in exerting anti-invasive and anti-survival activities with respect to cbLf and wbc. Furthermore, mbLf lowered IL-6 levels to those of uninfected cells, while a less evident decrease was observed upon cbLf treatment. Conversely, wbc managed to slightly lower IL-6 levels compared to those synthesized by infected cells. These data demonstrate that, to obtain maximum effectiveness in such activities, Lf should be formulated/used without addition of other substances and should be sourced from bovine milk rather than colostrum.

Prominin 1 and Tweety Homology 1 both induce extracellular vesicle formation.

Prominin-1 (Prom1) is a five-transmembrane-pass integral membrane protein that associates with curved regions of the plasma membrane. Prom1 interacts with membrane cholesterol and actively remodels the plasma membrane. Membrane bending activity is particularly evident in photoreceptors, where Prom1 loss-of-function mutations cause failure of outer segment homeostasis, leading to cone-rod retinal dystrophy (CRRD). The Tweety Homology (Ttyh) protein family has been proposed to be homologous to Prominin, but it is not known whether Ttyh proteins have an analogous membrane-bending function. Here, we characterize the membrane-bending activity of human Prom1 and Ttyh1 in native bilayer membranes. We find that Prom1 and Ttyh1 both induce formation of extracellular vesicles (EVs) in cultured mammalian cells and that the EVs produced are physically similar. Ttyh1 is more abundant in EV membranes than Prom1 and produces EVs with membranes that are more tubulated than Prom1 EVs. We further show that Prom1 interacts more stably with membrane cholesterol than Ttyh1 and that this may contribute to membrane bending inhibition in Prom1 EVs. Intriguingly, a loss-of-function mutation in Prom1 associated with CRRD induces particularly stable cholesterol binding. These experiments provide mechanistic insight into Prominin function in CRRD and suggest that Prom and Ttyh belong to a single family of functionally related membrane-bending, EV-generating proteins.

Abstract 3147: DXC025, a novel anti-MUC1/EGFR bispecific antibody-tubulysin conjugate with a function linker, exhibits potent anti-tumor efficacy

Abstract Antibody-drug conjugates (ADCs) have become a promised drug class in cancer therapy. Armed with three main components-an antibody, a linker molecule, and a cytotoxic agent (“payload”), plus sites of the antibody conjugation and the distribution of tumor-associate antigens, nowadays ADCs have proved the unique ability of the precision of targeted therapy, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. Both epidermal growth factor receptor (EGFR) and mucin 1 (MUC1) are tumor-associated antigens (TAA) that are co-expressed in many solid tumors, such as, colon cancer, non-small cell lung cancer (NSCLC), esophageal cancer, epidermal cancer, and pancreatic cancer. In particular, MUC1, a glycoprotein essential for the formation of the epithelial mucous barrier, is hypoglycosylated and dimerizes with EGFR, a potent oncoprotein, in transformed cells. For our anti-Muc1 ADC clinical program, for treatment of colon and pancreatic cancers, it was found out that the highly glycosylated transmembrane Muc1 had much more turning over rates on the luminal surface of epithelial cells. Here, we first designed and generated bispecific Fab/scFv antibodies targeting both MUC1 and EGFR, using the knob-into-hole technology. The addition of the affinity- and internalization-optimized anti-EGFR arm to the other single Muc1 arm was aimed to broaden tumor selectivity and to reduce on-target toxicity, for the treatment of gastrointestinal tumors in comparison to individual full IgG1-ADC, either EGFR or Muc1-ADC. Indeed, many of generated anti- MUC1/EGFR bispecific antibodies (BsAbs) showed strong binding affinity in MUC1modetateEGFRmodetate cells, in addition to both MUC1 and EGFR highly expressed cells. Internalization assays demonstrated that the BsAbs were endocytosed in tumor cells co-expressing EGFR and MUC1 more efficiently than monoclonal antibodies targeting MUC1. The selected BsAbs were subsequently conjugated with tubulysin B analogs with varieties of Tubulysin B analog payloads and function peptidyl spacer/linkers to generate bispecific ADC (DXC025) candidates. DXC025 candidates exhibited very potent cytotoxicity in vitro against epidermal cancer, lung adenocarcinoma, and pancreatic cancer cell lines with IC50 of single or tens digital pM. In in vivo cell-derived xenograft (CDX) models, DXC025 candidates demonstrated much superior efficacies of tumor growth inhibition in comparison with parental (monoclonal), either Muc1- or EGFR- ADC for the treatment of gastrointestinal tumors. These results indicated that the MUC1/EGFR-ADC (DXC025) would be a promising ADC candidate for targeted treatment of either Muc1- or EGFR-expressing gastrointestinal tumors. Citation Format: Xingyan Jiang, Junxiang Jia, Huihui Guo, Xiangfei Kong, Yongfang Xu, Sishi Ye, Yong Du, Zhicang Ye, Qikuang Cen, Lingli Zhang, Yongxiang Chen, Gaituo Chen, Lu Bai, Yunxia Zheng, Wei Zheng, Jun Zheng, Juan Wang, Wenjun Li, Yuanyuan Huang, Linyao Zhao, Yifang Xu, Mengmeng Liu, Binbin Chen, Meng Dai, Miaomiao Chen, Zhixiang Guo, Qingliang Yang, Robert Y. Zhao. DXC025, a novel anti-MUC1/EGFR bispecific antibody-tubulysin conjugate with a function linker, exhibits potent anti-tumor efficacy [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 3147.

Combining GWAS and comparative genomics to fine map candidate genes for days to flowering in mung bean

BackgroundMung bean (Vigna radiata (L.) Wilczek), is an important pulse crop in the global south. Early flowering and maturation are advantageous traits for adaptation to northern and southern latitudes. This study investigates the genetic basis of the Days-to-Flowering trait (DTF) in mung bean, combining genome-wide association studies (GWAS) in mung bean and comparisons with orthologous genes involved with control of DTF responses in soybean (Glycine max (L) Merr) and Arabidopsis (Arabidopsis thaliana).ResultsThe most significant associations for DTF were on mung bean chromosomes 1, 2, and 4. Only the SNPs on chromosomes 1 and 4 were heavily investigated using downstream analysis. The chromosome 1 DTF association is tightly linked with a cluster of locally duplicated FERONIA (FER) receptor-like protein kinase genes, and the SNP occurs within one of the FERONIA genes. In Arabidopsis, an orthologous FERONIA gene (AT3G51550), has been reported to regulate the expression of the FLOWERING LOCUS C (FLC). For the chromosome 4 DTF locus, the strongest candidates are Vradi04g00002773 and Vradi04g00002778, orthologous to the Arabidopsis PhyA and PIF3 genes, encoding phytochrome A (a photoreceptor protein sensitive to red to far-red light) and phytochrome-interacting factor 3, respectively. The soybean PhyA orthologs include the classical loci E3 and E4 (genes GmPhyA3, Glyma.19G224200, and GmPhyA2, Glyma.20G090000). The mung bean PhyA ortholog has been previously reported as a candidate for DTF in studies conducted in South Korea.ConclusionThe top two identified SNPs accounted for a significant proportion (~ 65%) of the phenotypic variability in mung bean DTF by the six significant SNPs (39.61%), with a broad-sense heritability of 0.93. The strong associations of DTF with genes that have orthologs with analogous functions in soybean and Arabidopsis provide strong circumstantial evidence that these genes are causal for this trait. The three reported loci and candidate genes provide useful targets for marker-assisted breeding in mung beans.

Abstract B016: Novel curcumin analogues as therapies for endometrial cancer with TP53 mutations

Abstract The protein p53 is designated as the guardian of the genome because it is the principal tumor suppressor and functions to surveil the genome, enforce cell cycle checkpoints, and trigger apoptosis when genomic instability is beyond repair. Mutations in TP53 are found in >50% of human tumors and in 25% of the deadliest endometrial malignancies. Yet, few studies have targeted the mutant protein to restore its wild type (WT) tumor suppressor functions. Curcumin, a turmeric derivative, has been shown to help return WT function to mutant p53. However, curcumin is not bioavailable to most of the body because of its water insolubility, hydrophobic nature and rapid metabolization. Our laboratory is testing novel, more bioavailable analogs of curcumin including HO-3867 and AKT-100. In these studies, we tested these agents in preclinical models of serous endometrial cancer to assess their effects on cell growth and p53-dependent signaling. We used CyQUANT cell proliferation assay to identify IC50 values for HO-3867 and AKT-100 in ECC-1 and KLE endometrial cancer cell lines. We performed RNA sequencing to elucidate mechanisms of action and verified p53 expression changes via Western blotting. IC50 values ranged from 100 nanomolar (AKT-100) to low micromolar (HO-3867). RNA sequencing data revealed the re-enforcement of cell cycle checkpoints including the upregulation of CDKN1A (p21) and GADD45 (Gadd45). Proliferative signaling downstream of ATM, an important protein kinase stimulating cell growth, was downregulated by both agents. Western blotting confirmed the classic negative feedback loop of p53, where total p53 levels decreased after drug treatment. Taken together, our findings show that AKT-100 and HO-3867 are able to restore WT tumor suppressor function in otherwise oncogenic mutant p53 by reducing cell replication and promoting apoptosis. Thus, curcumin analogues such as AKT-100 and HO-3867 show promise in the treatment of a subset of endometrial tumors expressing mutant p53 by returning WT p53 functionality, and future studies will move to in vivo analyses of curcumin analogue function. Citation Format: Kimberly K. Leslie, Alex Goss, Jamie Padilla, Lane E. Smith. Novel curcumin analogues as therapies for endometrial cancer with TP53 mutations [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B016.

Ammonia stress-induced heat shock factor 1 enhances white spot syndrome virus infection by targeting the interferon-like system in shrimp.

Ammonia is the end product of protein catabolism and is derived from feces and unconsumed foods. It threatens the health and growth of aquatic animals. In this study, we demonstrated that ammonia stress suppresses shrimp antiviral immunity by targeting the shrimp interferon-like system and that heat shock factor 1 (Hsf1) is a central regulator of this process. When shrimp are stressed by ammonia, they activate Hsf1 for stress relief and well-being. Hsf1 upregulates the expression of negative regulators that inhibit the production and function of interferon analogs in shrimp, thereby enhancing white spot syndrome viral infection. Therefore, this study, from a molecular perspective, explains the problem in the aquaculture industry that animals living in stressed environments are more susceptible to pathogens than those living in unstressed conditions. Moreover, this study provides new insights into the side effects of heat shock responses and highlights the complexity of achieving cellular homeostasis under stressful conditions.

Bitter taste receptors in the reproductive system: Function and therapeutic implications.

Type 2 taste receptors (TAS2Rs), traditionally known for their role in bitter taste perception, are present in diverse reproductive tissues of both sexes. This review explores our current understanding of TAS2R functions with a particular focus on reproductive health. In males, TAS2Rs are believed to play potential roles in processes such as sperm chemotaxis and male fertility. Genetic insights from mouse models and human polymorphism studies provide some evidence for their contribution to male infertility. In female reproduction, it is speculated that TAS2Rs influence the ovarian milieu, shaping the functions of granulosa and cumulus cells and their interactions with oocytes. In the uterus, TAS2Rs contribute to uterine relaxation and hold potential as therapeutic targets for preventing preterm birth. In the placenta, they are proposed to function as vigilant sentinels, responding to infection and potentially modulating mechanisms of fetal protection. In the cervix and vagina, their analogous functions to those in other extraoral tissues suggest a potential role in infection defense. In addition, TAS2Rs exhibit altered expression patterns that profoundly affect cancer cell proliferation and apoptosis in reproductive cancers. Notably, TAS2R agonists show promise in inducing apoptosis and overcoming chemoresistance in these malignancies. Despite these advances, challenges remain, including a lack of genetic and functional studies. The application of techniques such as single-cell RNA sequencing and clustered regularly interspaced palindromic repeats(CRISPR)/CRISPR-associated endonuclease 9 gene editing could provide deeper insights into TAS2Rs in reproduction, paving the way for novel therapeutic strategies for reproductive disorders.

Open-source design of integrated circuits

This paper presents the design of a self-clocked 12-bit non-binary fully differential SAR-ADC using the SKY130 open-source PDK. The entire mixed-signal circuit design and layout were created with free and open-source software. The ADC reaches a sample rate of up to 1.44 MS/s at 1.8 V supply while consuming 703 μ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\upmu$$\\end{document}W of power on a small 0.175 mm2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{2}$$\\end{document} area. A configurable decimation filter can increase the ADC resolution up to 16 bits while using an oversampling factor of 256. A 9‑bit thermometer-coded and 3‑bit binary-coded DAC matrix using a 448 aF waffle-capacitor results in a total capacitance of 1.83 pF per input. Realizations of configurable analog functions using the form factor of SKY130 high-density standard cells allow the parametrization of an analog circuit in a hardware description language and hardening of the macro in an intentionally digital workflow.

Low-complexity hybrid precoding for sub-connected millimeter wave massive MIMO systems

Hybrid analog-digital precoding architectures facilitate practical implementation of millimeter wave (mmW) massive multiple-input multiple-output (mmW-mMIMO) systems by reducing the number of radio frequency chains required. The spectral efficiency (SE) and energy efficiency (EE) optimization problems of these systems are typically non-convex and NP-hard, as the joint optimization that involves the analog and digital precoding functions along with the constant modulus constraints required by analog phase shifters, results in highly non-linear problems. To address such problems, we propose a decoupled two-stage design. More specifically, in the first stage, a closed-form approximation of the effective channel is proposed, and thus the SE maximization problem can be transformed to an effective channel gain maximization problem. Then, the analog precoding matrices can be generated to facilitate the second stage, where the digital precoding matrix is devised for maximizing the system’s EE. In addition, the circuit power consumption statistics of the system modules are exploited and a sub-connected mmW-mMIMO architecture is adopted during EE optimization. Finally, simulation results are provided to validate the effectiveness of our proposed mmW-mMIMO scheme with hybrid precoding.