ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer.

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity.

Genome-wide analysis of FRF gene family and functional identification of HvFRF9 under drought stress in barley.

FHY3 and its homologous protein FAR1 are the founding members of FRS family. They exhibited diverse and powerful physiological functions during evolution, and participated in the response to multiple abiotic stresses. FRF genes are considered to be truncated FRS family proteins. They competed with FRS for DNA binding sites to regulate gene expression. However, only few studies are available on FRF genes in plants participating in the regulation of abiotic stress. With wide adaptability and high stress-resistance, barley is an excellent candidate for the identification of stress-resistance-related genes. In this study, 22 HvFRFs were detected in barley using bioinformatic analysis from whole genome. According to evolution and conserved motif analysis, the 22 HvFRFs could be divided into subfamilies I and II. Most promoters of subfamily I members contained abscisic acid and methyl jasmonate response elements; however, a large number promoters of subfamily II contained gibberellin and salicylic acid response elements. HvFRF9, one of the members of subfamily II, exhibited a expression advantage in different tissues, and it was most significantly upregulated under drought stress. In-situ PCR revealed that HvFRF9 is mainly expressed in the root epidermal cells, as well as xylem and phloem of roots and leaves, indicating that HvFRF9 may be related to absorption and transportation of water and nutrients. The results of subcellular localization indicated that HvFRF9 was mainly expressed in the nuclei of tobacco epidermal cells and protoplast of arabidopsis. Further, transgenic arabidopsis plants with HvFRF9 overexpression were generated to verify the role of HvFRF9 in drought resistance. Under drought stress, leaf chlorosis and wilting, MDA and O2 - contents were significantly lower, meanwhile, fresh weight, root length, PRO content, and SOD, CAT and POD activities were significantly higher in HvFRF9-overexpressing arabidopsis plants than in wild-type plants. Therefore, overexpression of HvFRF9 could significantly enhance the drought resistance in arabidopsis. These results suggested that HvFRF9 may play a key role in drought resistance in barley by increasing the absorption and transportation of water and the activity of antioxidant enzymes. This study provided a theoretical basis for drought resistance in barley and provided new genes for drought resistance breeding.

Computation-aided Design of Rod-Shaped Janus Base Nanopieces for Improved Tissue Penetration and Therapeutics Delivery.

Despite the development of various drug delivery technologies, there remains a significant need for vehicles that can improve targeting and biodistribution in "hard-to-penetrate" tissues. Some solid tumors, for example, are particularly challenging to penetrate due to their dense extracellular matrix (ECM). In this study, we have formulated a new family of rod-shaped delivery vehicles named Janus base nanopieces (Rod JBNps), which are more slender than conventional spherical nanoparticles, such as lipid nanoparticles (LNPs). These JBNp nanorods are formed by bundles of DNA-inspired Janus base nanotubes (JBNts) with intercalated delivery cargoes. To develop this novel family of delivery vehicles, we employed a computation-aided design (CAD) methodology that includes molecular dynamics and response surface methodology. This approach precisely and efficiently guides experimental designs. Using an ovarian cancer model, we demonstrated that JBNps markedly improve penetration into the dense ECM of solid tumors, leading to better treatment outcomes compared to FDA-approved spherical LNP delivery. This study not only successfully developed a rod-shaped delivery vehicle for improved tissue penetration but also established a CAD methodology to effectively guide material design.

Antivesiculation and Complete Unbinding of Tail-Tethered Lipids.

We report the effect of tail-tethering on vesiculation and complete unbinding of bilayered membranes. Amphiphilic molecules of a bolalipid, resembling the tail-tethered molecular structure of archaeal lipids, with two identical zwitterionic phosphatidylcholine headgroups self-assemble into a large flat lamellar membrane, in contrast to the multilamellar vesicles (MLVs) observed in its counterpart, monopolar nontethered zwitterionic lipids. The antivesiculation is confirmed by small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cyro-TEM). With the net charge of zero and higher bending rigidity of the membrane (confirmed by neutron spin echo (NSE) spectroscopy), the current membrane theory would predict that membranes should stack with each other (aka "bind") due to dominant van der Waals attraction, while the outcome of the nonstacking ("unbinding") membrane suggests that the theory needs to include entropic contribution for the nonvesicular structures. This report pioneers an understanding of how the tail-tethering of amphiphiles affects the structure, enabling better control over the final nanoscale morphology.

Block Sequence Effects on the Self-Assembly Behaviors of Polypeptide-Based Penta-Block Copolymer Hydrogels.

Peptide-based hydrogels have great potential for applications in tissue engineering, drug delivery, and so on. We systematically synthesize, characterize, and investigate the self-assembly behaviors of a series of polypeptide-based penta-block copolymers by varying block sequences and lengths. The copolymers contain hydrophobic blocks of poly(γ-benzyl-l-glutamate) (PBG, Bx) and two kinds of hydrophilic blocks, poly(l-lysine) (PLL, Ky) and poly(ethylene glycol) (PEG, EG34), where x and y are the number of repeating units of each block, where PBG and PLL blocks have unique functions for nerve regeneration and cell adhesion. It shows that a sufficient length of the middle hydrophilic segment capped with hydrophobic end PBG blocks is required. They first self-assemble into flower-like micelles and sequentially form transparent hydrogels (as low as 2.3 wt %) with increased polymer concentration. The hydrogels contain a microscale porous structure, a desired property for tissue engineering to facilitate the access of nutrient flow for cell growth and drug delivery systems with high efficiency of drug storage. We hypothesize that the structure of Bx-Ky-EG34-Ky-Bx agglomerates is beyond micron size (transparent), while that of Ky-Bx-EG34-Bx-Ky is on the submicron scale (opaque). We establish a working strategy to synthesize a polypeptide-based block copolymer with a wide window of sol-gel transition. The study offers insight into rational polypeptide hydrogel design with specific morphology, exploring the novel materials as potential candidates for neural tissue engineering.

Strongly coupled plasmonic metal nanoparticles with reversible pH-responsiveness and highly reproducible SERS in solution.

We report a facile method to prepare polymer-grafted plasmonic metal nanoparticles (NPs) that exhibit pH-responsive surface-enhanced Raman scattering (SERS). The concept is based on the use of pH-responsive polymers, such as poly(acrylic acid) (PAA) and poly(allylamine hydrochloride) (PAH), as multidentate ligands to wrap around the surface of NPs instead of forming polymer brushes. Upon changing the solvent quality, the grafted pH-responsive polymers would drive reversible aggregation of NPs, leading to a decreased interparticle distance. This creates numerous hot spots, resulting in a secondary enhancement of SERS as compared to the SERS from discrete NPs. For negatively charged PAA-grafted NPs, the SERS response at pH 2.5 showed a secondary enhancement of up to 104-fold as compared to the response for discrete NPs at pH 12. Similarly, positively charged PAH-grafted AuNPs showed an opposite response to pH. We demonstrated that enhanced SERS with thiol-containing and charged molecular probes was indeed from the pH-driven solubility change of polymer ligands. Our method is different from the conventional SERS sensors in the solid state. With pH-responsive polymer-grafted NPs, SERS can be performed in solution with high reproducibility and sensitivity but without the need for sample pre-concentration. These findings could pave the way for innovative designs of polymer ligands for metal NPs where polymer ligands do not compromise interparticle plasmon coupling.

Mapping Cellular Interactions from Spatially Resolved Transcriptomics Data.

Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently, through the introduction of spatially resolved transcriptomics technologies (SRTs), especially those that achieve single cell resolution. However, significant challenges remain to analyze such highly complex data properly. Here, we introduce a Bayesian multi-instance learning framework, spacia, to detect CCCs from data generated by SRTs, by uniquely exploiting their spatial modality. We highlight spacia's power to overcome fundamental limitations of popular analytical tools for inference of CCCs, including losing single-cell resolution, limited to ligand-receptor relationships and prior interaction databases, high false positive rates, and most importantly the lack of consideration of the multiple-sender-to-one-receiver paradigm. We evaluated the fitness of spacia for all three commercialized single cell resolution ST technologies: MERSCOPE/Vizgen, CosMx/Nanostring, and Xenium/10X. Spacia unveiled how endothelial cells, fibroblasts and B cells in the tumor microenvironment contribute to Epithelial-Mesenchymal Transition and lineage plasticity in prostate cancer cells. We deployed spacia in a set of pan-cancer datasets and showed that B cells also participate in PDL1/PD1 signaling in tumors. We demonstrated that a CD8+ T cell/PDL1 effectiveness signature derived from spacia analyses is associated with patient survival and response to immune checkpoint inhibitor treatments in 3,354 patients. We revealed differential spatial interaction patterns between γδ T cells and liver hepatocytes in healthy and cancerous contexts. Overall, spacia represents a notable step in advancing quantitative theories of cellular communications.

UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance.

Prostate cancer (PCa) is primarily driven by aberrant Androgen Receptor (AR) signaling. Although there has been substantial advancement in antiandrogen therapies, resistance to these treatments remains a significant obstacle, often marked by continuous or enhanced AR signaling in resistant tumors. While the dysregulation of the ubiquitination-based protein degradation process is instrumental in the accumulation of oncogenic proteins, including AR, the molecular mechanism of ubiquitination-driven AR degradation remains largely undefined. We identified UBE2J1 as the critical E2 ubiquitin-conjugating enzyme responsible for guiding AR ubiquitination and eventual degradation. The absence of UBE2J1, found in 5-15% of PCa patients, results in disrupted AR ubiquitination and degradation. This disruption leads to an accumulation of AR proteins, promoting resistance to antiandrogen treatments. By employing a ubiquitination-based AR degrader to adeptly restore AR ubiquitination, we reestablished AR degradation and inhibited the proliferation of antiandrogen-resistant PCa tumors. These findings underscore the fundamental role of UBE2J1 in AR degradation and illuminate an uncharted mechanism through which PCa maintains heightened AR protein levels, fostering resistance to antiandrogen therapies.

Correlating structural changes in thermoresponsive hydrogels to the optical response of embedded plasmonic nanoparticles.

Stimuli-responsive microgels, composed of small beads with soft, deformable polymer networks swollen through a combination of synthetic control over the polymer and its interaction with water, form a versatile platform for development of multifunctional and biocompatible sensors. The interfacial structural variation of such materials at a nanometer length scale is essential to their function, but not yet fully comprehended. Here, we take advantage of the plasmonic response of a gold nanorod embedded in a thermoresponsive microgel (AuNR@PNIPMAm) to monitor structural changes in the hydrogel directly near the nanorod surface. By direct comparison of the plasmon response against measurements of the hydrogel structure from dynamic light scattering and nuclear magnetic resonance, we find that the microgel shell of batch-polymerized AuNR@PNIPMAm exhibits a heterogeneous volume phase transition reflected by different onset temperatures for changes in the hydrodyanmic radius (RH) and plasmon resonance, respectively. The new approach of contrasting plasmonic response (a measure of local surface hydrogel structure) with RH and relaxation times paves a new path to gain valuable insight for the design of plasmonic sensors based on stimuli-responsive hydrogels.

ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers.

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide co-activator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate and breast cancers acquire lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Statement of Significance: This study reveals a novel epigenetic mechanism regulating tumor lineage plasticity and therapy response, enhances understanding of drug resistance and unveils a new therapeutic strategy for prostate cancer and other malignancies. Our findings also illuminate TET2's oncogenic role and mechanistically connect TET2-driven epigenetic rewiring to lineage plasticity and therapy resistance.

Effects of miR-204-5p and Target Gene EphB2 on Cognitive Impairment Induced by Aluminum Exposure in Rats.

Aluminum is a common environmental neurotoxin. Aluminum ions can cross the blood-brain barrier and accumulate in different brain regions, damage brain tissue, and cause cognitive impairment, but the molecular mechanism of aluminum neurotoxicity is not precise. This study investigated the effects of miR-204-5p, target gene EphB2, and downstream signaling pathway NMDAR-ERK-CREB-Arc on cognitive dysfunction induced by aluminum exposure. The results showed that the learning and memory of the rats were impaired in behavior. The accumulation of aluminum in the hippocampus resulted in the damage of nerve cell morphology in the CA1 region of the hippocampus. The expression level of miR-204-5p was increased, and the mRNA and protein expressions of EphB2, NMDAR2B, ERK1/2, CREB, and Arc were decreased. The results indicated that the mechanism of impaired learning and memory induced by aluminum exposure might promote the expression of miR-204-5P and further inhibit the expression of the target gene EphB2 and its downstream signaling pathway NMDAR-ERK-CREB-Arc.

Morphological control and modern applications of bicelles.

Bicellar systems have become popularized as their rich morphology can be applied in biochemistry, physical chemistry, and drug delivery technology. To the biochemical field, bicelles are powerful model membranes for the study of transmembrane protein behavior, membrane transport, and environmental interactions with the cell. Their morphological responses to environmental changes reveal a profound fundamental understanding of physical chemistry related to the principle of self-assembly. Recently, they have also drawn significant attention as theranostic nanocarriers in biopharmaceutical and diagnostic research due to their superior cellular uptake compared to liposomes. It is evident that applications are becoming broader, demanding to understand how the bicelle will form and behave in various environments. To consolidate current works on the bicelle's modern applications, this review will discuss various effects of composition and environmental conditions on the morphology, phase behavior, and stability. Furthermore, various applications such as payload entrapment and polymerization templating are presented to demonstrate their versatility and chemical nature.

Anti-melanoma differentiation-associated gene 5 and anti-Ro52 antibody-dual positive dermatomyositis accompanied by rapidly lung disease: Three case reports.

BACKGROUND: Clinically amyopathic deramatomyositis was manifested as the various cutaneous dermatomyositis (DM) manifestations without muscle weakness. Anti-melanoma differentiation-associated gene 5 (anti-MDA5) and anti-Ro52 antibody-dual positive clinically amyopathic DM patients are at a high risk of developing rapidly progressive interstitial lung disease, and they exhibit an immensely high half-year mortality. CASE SUMMARY: We presented three patients with anti-MDA5 and anti-Ro52 antibody-dual positive DM patients and we reviewed the previous studies on the link between anti-MDA5 and anti-Ro52 antibody-dual positive DM. Although we aggressively treated these patients similarly, but they all exhibited different prognoses. We reviewed the importance of clinical cutaneous rashes as well as the pathogenesis and treatment in the dual positive anti-MDA5 and anti-Ro52 associated DM. CONCLUSION: Patients with anti-MDA5 anti-Ro52 antibody-dual positive DM should be accurately diagnosed at an early stage and should be treated aggressively, thus, the patient's prognosis can be significantly modified.

Synthesis of Polymer Nanoweb via a Lipid Template.

We report a generalized platform for synthesizing a polymer nanoweb with a high specific surface area via a bicellar template, composed of 1,2-dipalmitoyl phosphocholine (DPPC), 1,2-dihexanoyl phosphocholine (DHPC), and 1,2-dipalmitoyl phosphoglycerol (DPPG). The pristine bicelle (in the absence of monomer or polymer) yields a variety of well-defined structures, including disc, vesicle, and perforated lamella. The addition of styrene monomers in the mixture causes bicelles to transform into lamellae. Monomers are miscible with DPPC and DPPG initially, while polymerization drives polymers to the DHPC-rich domain, resulting in a polymer nanoweb supported by the outcomes of small angle neutron scattering, differential scanning calorimetry, and transmission electron microscopy.

The Critical Interplay of CAF Plasticity and Resistance in Prostate Cancer.

Prostate cancer is a common malignancy driven by the androgen receptor (AR) pathway, with androgen deprivation therapy (ADT) being a standard treatment. However, the development of castration-resistant prostate cancer (CRPC) poses a significant challenge. CRPC is characterized by significantly increased tumor heterogeneity and lineage plasticity. Current research has primarily emphasized intrinsic tumor mechanisms, paying less attention to the role of the tumor microenvironment in cancer recurrence and drug resistance. In their recent study published in Cancer Cell, Wang and colleagues used single-cell RNA sequencing in genetically engineered mouse models with prostate tumors at different stages. They revealed that SPP1+ myofibroblastic cancer-associated fibroblasts (myCAF), induced by ADT, play an instrumental role in CRPC development. Their work also underscores the association between therapy-induced phenotypic alterations of CAFs and disease progression. This discovery highlights the potential for stromal compartment targeting as a means to mitigate CRPC development and overcome treatment resistance.

Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer.

Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, EP300. Functional screening identifies eight crucial drivers for androgen receptor (AR)-targeted therapy resistance in PCa that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. These results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring AR-targeted therapy resistance in PCa.

Site-Specific Chemistry on Gold Nanorods: Curvature-Guided Surface Dewetting and Supracolloidal Polymerization.

Control of interparticle interactions in terms of their direction and strength highly relies on the use of anisotropic ligand grafting on nanoparticle (NP) building blocks. We report a ligand deficiency exchange strategy to achieve site-specific polymer grafting of gold nanorods (AuNRs). Patchy AuNRs with controllable surface coverage can be obtained during ligand exchange with a hydrophobic polystyrene ligand and an amphiphilic surfactant while adjusting the ligand concentration (CPS) and solvent condition (Cwater in dimethylformamide). At a low grafting density of ≤0.08 chains/nm2, dumbbell-like AuNRs with two polymer domains capped at the two ends can be synthesized through surface dewetting with a high purity of >94%. These site-specifically-modified AuNRs exhibit great colloidal stability in aqueous solution. Dumbbell-like AuNRs can further undergo supracolloidal polymerization upon thermal annealing to form one-dimensional plasmon chains of AuNRs. Such supracolloidal polymerization follows the temperature-solvent superposition principle as revealed by kinetic studies. Using the copolymerization of two AuNRs with different aspect ratios, we demonstrate the design of chain architectures by varying the reactivity of nanorod building blocks. Our results provide insights into the postsynthetic design of anisotropic NPs that potentially serve as units for polymer-guided supracolloidal self-assembly.

Next-generation poly-L-histidine formulations for miRNA mimic delivery.

Many diseases, especially cancer, are caused by the abnormal expression of non-coding microRNAs (miRNAs), which regulate gene expression, leading to the development of miRNA-based therapeutics. Synthetic miRNA inhibitors have shown promising efficacy in blocking the activity of aberrant miRNAs that are upregulated in disease-specific pathologies. On the other hand, miRNAs that aid in preventing certain diseases and are reduced in expression in the disease state need different strategies. To tackle this, miRNA mimics, which mimic the activity of endogenous miRNAs, can be delivered for those miRNAs downregulated in different disease states. However, the delivery of miRNA mimics remains a challenge. Here, we report a cationic polylactic-co-glycolic acid (PLGA)-poly-L-histidine delivery system to deliver miRNA mimics. We chose miR-34a mimics as a proof of concept for miRNA delivery. miR-34a-loaded PLGA-poly-L-histidine nanoparticles (NPs) were formulated and biophysically characterized to analyze the structural properties of miRNA mimic-loaded NPs. In vitro efficacy was determined by investigating miR-34a and downstream target levels and performing cell viability and apoptosis assays. We confirmed in vivo efficacy through prolonged survival of miR-34a NP-treated A549-derived xenograft mice treated intratumorally. The results of these studies establish PLGA-poly-L-histidine NPs as an effective delivery system for miRNA mimics for treating diseases characterized by downregulated miRNAs.

Stable Discoidal Bicelles: Formulation, Characterization, and Functions.

Bicellar mixtures have been used as alignable membrane substrates under a magnetic field applicable for the structural characterization of membrane-associated proteins. Recently, it has shown that bicelles can serve as nanocarriers to effectively deliver hydrophobic therapeutic molecules to cancer cells with a three- to ten-fold enhancement compared to that of liposomes of a chemically identical composition. In this chapter, detailed preparation protocol, common structural characterization methods, the structural stability, the cellular uptake and a few unique functions of bicellar nanodiscs are discussed.