Polarity Signaling Research Articles

Administration of Liposomal-Based Pde3b Gene Therapy Protects Mice Against Collagen-Induced Rheumatoid Arthritis via Modulating Macrophage Polarization.

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by synovial inflammation and joint destruction. Despite progress in RA therapy, it remains difficult to achieve long-term remission in RA patients. Phosphodiesterase 3B (Pde3b) is a member of the phosphohydrolyase family that are involved in many signal transduction pathways. However, its role in RA is yet to be fully addressed. Studies were conducted in arthritic DBA/1 mice, a suitable mouse strain for collagen-induced rheumatoid arthritis (CIA), to dissect the role of Pde3b in RA pathogenesis. Next, RNAi-based therapy with Pde3b siRNA-loaded liposomes was assessed in a CIA model. To study the mechanism involved, we investigated the effect of Pde3b knockdown on macrophage polarization and related signaling pathway. We demonstrated that mice with CIA exhibited upregulated Pde3b expression in macrophages. Notably, intravenous administration of liposomes loaded with Pde3b siRNA promoted the macrophage anti-inflammatory program and alleviated CIA in mice, as indicated by the reduced inflammatory response, synoviocyte infiltration, and bone and cartilage erosion. Mechanistic study revealed that depletion of Pde3b increased cAMP levels, by which it enhanced PKA-CREB-C/EBPβ pathway to transcribe the expression of anti-inflammatory program-related genes. Our results support that Pde3b is involved in the pathogenesis of RA, and Pde3b siRNA-loaded liposomes might serve as a promising therapeutic approach against RA.

PDZome-wide and structural characterization of the PDZ-binding motif of VANGL2

VANGL2 is a core component of the non-canonical Wnt/Planar Cell Polarity signaling pathway that uses its highly conserved carboxy-terminal type 1 PDZ-binding motif (PBM) to bind a variety of PDZ proteins. In this study, we characterize and quantitatively assess the largest VANGL2 PDZome-binding profile documented so far, using orthogonal methods. The results of our holdup approach support VANGL2 interactions with a large panel of both long-recognized and unprecedented PDZ domains. Truncation and point mutation analyses of the VANGL2 PBM establish that, beyond the strict requirement of the P-0 / V521 and P-2 / T519 amino acids, upstream residues, including E518, Q516 and R514 at, respectively, P-3, P-5 and P-7 further contribute to the robustness of VANGL2 interactions with two distinct PDZ domains, SNX27 and SCRIBBLE-PDZ3. In agreement with these data, incremental amino-terminal deletions of the VANGL2 PBM causes its overall affinity to progressively decline. Moreover, the holdup data establish that the PDZome binding repertoire of VANGL2 starts to diverge significantly with the truncation of E518. A structural analysis of the SYNJ2BP-PDZ/VANGL2 interaction with truncated PBMs identifies a major conformational change in the binding direction of the PBM peptide after the P-2 position. Finally, we report that the PDZome binding profile of VANGL2 is dramatically rearranged upon phosphorylation of S517, T519 and S520. Our crystallographic approach illustrates how SYNJ2BP accommodates a S520-phosphorylated PBM peptide through the ideal positioning of two basic residues, K48 and R86. Altogether our data provides a comprehensive view of the VANGL2 PDZ network and how this network specifically responds to the post-translation modification of distinct PBM residues. These findings should prove useful in guiding future functional and molecular studies of the key PCP component VANGL2.

Cytoneme-mediated transport of active Wnt5b-Ror2 complexes in zebrafish.

Chemical signalling is the primary means by which cells communicate in the embryo. The underlying principle refers to a group of ligand-producing cells and a group of cells that respond to this signal because they express the appropriate receptors1,2. In the zebrafish embryo, Wnt5b binds to the receptor Ror2 to trigger the Wnt-planar cell polarity (PCP) signalling pathway to regulate tissue polarity and cell migration3,4. However, it remains unclear how this lipophilic ligand is transported from the source cells through the aqueous extracellular space to the target tissue. In this study, we provide evidence that Wnt5b, together with Ror2, is loaded on long protrusions called cytonemes. Our data further suggest that the active Wnt5b-Ror2 complexes form in the producing cell and are handed over from these cytonemes to the receiving cell. Then, the receiving cell has the capacity to initiate Wnt-PCP signalling, irrespective of its functional Ror2 receptor status. On the tissue level, we further show that cytoneme-dependent spreading of active Wnt5b-Ror2 affects convergence and extension in the zebrafish gastrula. We suggest that cytoneme-mediated transfer of ligand-receptor complexes is a vital mechanism for paracrine signalling. This may prompt a reevaluation of the conventional concept of characterizing responsive and non-responsive tissues solely on the basis of the expression of receptors.

Mechanical control of neural plate folding by apical domain alteration

Vertebrate neural tube closure is associated with complex changes in cell shape and behavior, however, the relative contribution of these processes to tissue folding is not well understood. At the onset of Xenopus neural tube folding, we observed alternation of apically constricted and apically expanded cells. This apical domain heterogeneity was accompanied by biased cell orientation along the anteroposterior axis, especially at neural plate hinges, and required planar cell polarity signaling. Vertex models suggested that dispersed isotropically constricting cells can cause the elongation of adjacent cells. Consistently, in ectoderm, cell-autonomous apical constriction was accompanied by neighbor expansion. Thus, a subset of isotropically constricting cells may initiate neural plate bending, whereas a ‘tug-of-war’ contest between the force-generating and responding cells reduces its shrinking along the body axis. This mechanism is an alternative to anisotropic shrinking of cell junctions that are perpendicular to the body axis. We propose that apical domain changes reflect planar polarity-dependent mechanical forces operating during neural folding.

Protein phosphatase 1 regulates core PCP signaling.

Planar cell polarity (PCP) signaling polarizes epithelial cells within the plane of an epithelium. Core PCP signaling components adopt asymmetric subcellular localizations within cells to both polarize and coordinate polarity between cells. Achieving subcellular asymmetry requires additional effectors, including some mediating post-translational modifications of core components. Identification of such proteins is challenging due to pleiotropy. We used mass spectrometry-based proximity labeling proteomics to identify such regulators in the Drosophila wing. We identified the catalytic subunit of protein phosphatase1, Pp1-87B, and show that it regulates core protein polarization. Pp1-87B interacts with the core protein Van Gogh and at least one serine/threonine kinase, Dco/CKIε, that is known to regulate PCP. Pp1-87B modulates Van Gogh subcellular localization and directs its dephosphorylation in vivo. PNUTS, a Pp1 regulatory subunit, also modulates PCP. While the direct substrate(s) of Pp1-87B in control of PCP is not known, our data support the model that cycling between phosphorylated and unphosphorylated forms of one or more core PCP components may regulate acquisition of asymmetry. Finally, our screen serves as a resource for identifying additional regulators of PCP signaling.

Comprehensive immunoprofiling of neurodevelopmental disorders suggests three distinct classes based on increased neurogenesis, Th-1 polarization or IL-1 signaling

Neurodevelopmental disorders (NDDs) are a spectrum of conditions with commonalities as well as differences in terms of phenome, symptomatome, neuropathology, risk factors and underlying mechanisms. Immune dysregulation has surfaced as a major pathway in NDDs. However, it is not known if neurodevelopmental disorders share a common immunopathogenetic mechanism. In this study, we explored the possibility of a shared immune etiology in three early-onset NDDs, namely Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD) and Intellectual Disability Disorder (IDD).A panel of 48 immune pathway-related markers was assayed in 135 children with NDDs, represented by 45 children with ASD, ADHD and IDD in each group, along with 35 typically developing children. The plasma levels of 48 immune markers were analyzed on the Multiplex Suspension Assay platform using Pro Human cytokine 48-plex kits. Based on the cytokine/chemokine/growth factor levels, different immune profiles were computed.The primary characteristics of NDDs are depletion of the compensatory immune-regulatory system (CIRS) (z composite of IL-4, IL-10, sIL-1RA, and sIL-2R), increased interleukin (IL)-1 signaling associated with elevated IL-1α and decreased IL-1-receptor antagonist levels, increased neurogenesis, M1/M2 macrophage polarization and increased IL-4 as well as C-C Motif Chemokine Ligand 2 (CCL2) levels. With a cross-validated sensitivity of 81.8% and specificity of 94.4%, these aberrations seem specific for NDDs. Many immunological abnormalities are shared by ASD, ADHD and IDD, which are distinguished by minor differences in IL-9, IL-17 and CCL12. In contrast, machine learning reveals that NDD group consists of three immunologically distinct clusters, with enhanced neurogenesis, Th-1 polarization, or IL-1 signaling as the defining features.NDD is characterized by immune abnormalities that have functional implications for neurogenesis, neurotoxicity, and neurodevelopment. Using machine learning, NDD patients could be classified into subgroups with qualitatively distinct immune disorders that may serve as novel drug targets for the treatment of NDDs.

Early enterovirus translation deficits extend viral RNA replication and elicit sustained MDA5-directed innate signaling.

Multiple pattern recognition receptors sense vRNAs and initiate downstream innate signaling: endosomal Toll-like receptors (TLRs) 3, 7, and 8 and cytoplasmic RIG-I-like receptors (RLRs) RIG-I, and MDA5. They engage distinct signaling scaffolds: mitochondrial antiviral signaling protein (RLR), MyD88, and TLR-adaptor interacting with SLC15A4 on the lysosome (TLR7 and TLR8) and toll/IL-1R domain-containing adaptor inducing IFN (TLR3). By virtue of their unusual vRNA structure and direct host cell entry path, the innate response to EVs uniquely is orchestrated by MDA5. We reported that PVSRIPO's profound attenuation and loss of cytopathogenicity triggers MDA5-directed polar TBK1-IRF3 signaling that generates priming of polyfunctional antitumor CD8+ T-cell responses and durable antitumor surveillance in vivo. Here we unraveled EV-host relations that control suppression of host type-I IFN responses and show that PVSRIPO's deficient immediate host eIF4G cleavage generates unopposed MDA5-directed downstream signaling cascades resulting in sustained type-I IFN release.

Decadal Change in the Linkage between QBO and the Leading Mode of Southeast China Winter Precipitation

Abstract In this study, observational and model datasets are used to analyze winter precipitation and its leading empirical orthogonal function (EOF1) mode over Southeast China. EOF1 displays a dominant monosign pattern during the last 60 years; however, its major impacting factors have a decadal transition near the mid-1990s. The first principal component (PC1) is related to El Niño–Southern Oscillation (ENSO) after the mid-1990s and to the quasi-biennial oscillation (QBO) before the mid-1990s. An enhanced ENSO–precipitation relationship is associated with stronger ENSO-induced tropical zonal circulation and the westward shift of ENSO-induced SST over the tropical Pacific after the mid-1990s compared to before the mid-1990s. Negative correlation coefficients between QBO and precipitation are evident before the mid-1990s but are no longer statistically significant after the mid-1990s. This change originates from the interaction between QBO’s subtropical influences and the Holton–Tan effect. The QBO’s subtropical influence and the Holton–Tan effect lead to a zonal pressure gradient and meridional wind anomalies over East Asia before the mid-1990s, which further influence the meridional transport of water vapor and precipitation over Southeast China. However, the Holton–Tan effect is enhanced after the mid-1990s. Downward stratospheric polar vortex signals and the QBO’s subtropical influence cause a meridional pressure gradient over East Asia, and thus the relevant moisture flux divergence lacks statistical significance. The above results indicate that the subtropical response to QBO and the Holton–Tan effect should be considered together when using the QBO signal to improve forecasts of winter precipitation over East Asia. Significance Statement Southeast China winter precipitation (SCWP) is often attributed to variation in lower-atmospheric dynamics and sea surface temperature, such as El Niño–Southern Oscillation (ENSO). Few studies focus on the role of the mid- to upper atmosphere. In this study, we diagnose the influence of the stratospheric quasi-biennial oscillation (QBO) on SCWP. Both observational and modeling analyses indicate a strong decadal change in the QBO–SCWP relationship, which limits the use of the QBO in seasonal forecasts of SCWP. This decadal change originates from the strength of the QBO’s modulation of the stratospheric polar vortex. Our results provide a new perspective on the use of the mid- to upper atmosphere in seasonal forecasts of SCWP.

Increased Persistence in Winter-to-Spring Precipitation Anomalies over South China since the Late 1990s and the Possible Mechanisms

Abstract This study reveals that South China precipitation (SCP) anomalies tend to persist well from winter to the following spring after the late 1990s, favoring long-lasting drought or flood events over South China. Mechanism analysis indicates that the interdecadal changes in El Niño–Southern Oscillation (ENSO) and the preceding November central Asian snow cover could contribute to the increased persistence of winter-to-spring SCP anomalies. ENSO has a stable impact on winter SCP, whereas its impact on spring SCP is significantly enhanced after the late 1990s. With a weakened intensity and faster decay rate in the recent two decades, the ENSO-related spring SST anomalies over the tropical Pacific are relatively weaker, inducing a weakened and more southward-located western North Pacific anticyclone. This further leads to an interdecadal migration of the spring rainfall belt anomaly, consequently favoring the persistence of winter-to-spring SCP anomalies after the late 1990s. Additionally, the impacts of November central Asian snow cover on winter and spring SCP are both strengthened after the late 1990s. In the most recent two decades, the snow-cover-related cooling effect has become stronger, which induces winter cyclonic anomalies over Lake Baikal, favoring increased winter SCP. In addition, increased snow cover excites upward-propagating waves from the troposphere to the stratosphere, consequently weakening the stratospheric polar vortex. In spring, the stratospheric polar vortex signals propagate downward and result in a negative Arctic Oscillation in the troposphere, favoring more spring SCP. Therefore, central Asian snow cover is also conductive to the persistence of winter-to-spring SCP anomalies after the late 1990s.

Xiaoshuan Tongluo recipe alleviated acute hyperglycemia-enhanced hemorrhagic transformation by regulating microglia polarization in thromboembolic stroke rats

BackgroundsHemorrhagic transformation (HT) is a complication after stroke and is associated with increased mortality and disability. Hyperglycemia is a risk factor for HT incidence and seriously affects the treatment of stroke. There are no effective drugs to cure HT in the clinic. The Xiaoshuan Tongluo effective component group (XECG) is a Chinese medicine formula reconstituted by active ingredients, which is clinically used for the treatment of stroke. However, the roles of XECG in hyperglycemia-enhanced HT are not clear. This study aims to evaluate the effects of XECG on hyperglycemia-enhanced HT and explore the potential mechanisms. MethodsIn this study, a hyperglycemia-induced HT model was used. XECG (100, 200, 400 mg·kg−1) was orally administered for 5 days before the operation, and the incidence of HT was evaluated. Microglia polarization and related signaling pathways were measured to clarify the mechanisms of XECG on hyperglycemia-induced HT. ResultsOur results revealed that pretreatment with XECG alleviated neurological deficits and BBB disruption and improved the incidence and severity of HT enhanced by hyperglycemia. Further studies confirmed that XECG regulated microglial polarization by inhibiting the M1 phenotype and promoting the M2 phenotype and inhibited the activation of the HMGB1-RAGE-NF-κB signaling pathway. ConclusionsThese results suggested that pretreatment with XECG alleviated hyperglycemia-enhanced HT. XECG may be a potential drug for the treatment of HT.

3D Chiral Self-Assembling Matrixes for Regulating Polarization of Macrophages and Enhance Repair of Myocardial Infarction.

The regulation of inflammatory response at the site of injury and macrophage immunotherapy is critical for tissue repair. Chiral self-assemblies are one of the most ubiquitous life cues, which is closely related to biological functions, life processes, and even the pathogenesis of diseases. However, the role of supramolecular chiral self-assemblies in the regulation of immune functions in the internal environment of tissues has not been fully explored yet. Herein, 3D supramolecular chiral self-assembling matrixes are prepared to regulate the polarization of macrophages and further enhance the repair of myocardial infarction (MI). Experiments studies show that M-type (left-handed) self-assembling matrixes significantly inhibit inflammation and promote damaged myocardium repair by upregulating M2 macrophage polarization and downstream immune signaling compared with P-type (right-handed), and R-type (non-chirality) self-assembling matrixes. Classical molecular dynamics (MD) simulation demonstrates that M-type self-assembling matrixes display higher stereo-affinity to cellular binding, which enhances the clustering of mechanosensitive integrin β1 (Itgβ1) and activates focal adhesion kinase (FAK) and Rho-associated protein kinase (ROCK), as well as downstream PI3K/Akt1/mTOR signaling axes to promote M2 polarization. This study of designing a 3D chiral self-assembling matrixes microenvironment suitable for regulating the polarization of macrophages will provide devise basis for immunotherapy with biomimetic materials.

Synthetic Par polarity induces cytoskeleton asymmetry in unpolarized mammalian cells

Polarized cells rely on a polarized cytoskeleton to function. Yet, how cortical polarity cues induce cytoskeleton polarization remains elusive. Here, we capitalized on recently established designed 2D protein arrays to ectopically engineer cortical polarity of virtually any protein of interest during mitosis in various cell types. This enables direct manipulation of polarity signaling and the identification of the cortical cues sufficient for cytoskeleton polarization. Using this assay, we dissected the logic of the Par complex pathway, a key regulator of cytoskeleton polarity during asymmetric cell division. We show that cortical clustering of any Par complex subunit is sufficient to trigger complex assembly and that the primary kinetic barrier to complex assembly is the relief of Par6 autoinhibition. Further, we found that inducing cortical Par complex polarity induces two hallmarks of asymmetric cell division in unpolarized mammalian cells: spindle orientation, occurring via Par3, and central spindle asymmetry, depending on aPKC activity.

Regulation of Cell Adhesion and Migration via Microtubule Cytoskeleton Organization, Cell Polarity, and Phosphoinositide Signaling.

The capacity for cancer cells to metastasize to distant organs depends on their ability to execute the carefully choreographed processes of cell adhesion and migration. As most human cancers are of epithelial origin (carcinoma), the transcriptional downregulation of adherent/tight junction proteins (e.g., E-cadherin, Claudin and Occludin) with the concomitant gain of adhesive and migratory phenotypes has been extensively studied. Most research and reviews on cell adhesion and migration focus on the actin cytoskeleton and its reorganization. However, metastasizing cancer cells undergo the extensive reorganization of their cytoskeletal system, specifically in originating/nucleation sites of microtubules and their orientation (e.g., from non-centrosomal to centrosomal microtubule organizing centers). The precise mechanisms by which the spatial and temporal reorganization of microtubules are linked functionally with the acquisition of an adhesive and migratory phenotype as epithelial cells reversibly transition into mesenchymal cells during metastasis remains poorly understood. In this Special Issue of "Molecular Mechanisms Underlying Cell Adhesion and Migration", we highlight cell adhesion and migration from the perspectives of microtubule cytoskeletal reorganization, cell polarity and phosphoinositide signaling.

Cancer-associated fibroblasts influence Wnt/PCP signaling in gastric cancer cells by cytoneme-based dissemination of ROR2

Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment influencing cancer progression. Besides shaping the extracellular matrix, these fibroblasts provide signaling factors to facilitate tumor survival and alter tumor behavior. In gastric cancer, one crucial signaling pathway influencing invasion and metastasis is the Wnt/Planar Cell Polarity (PCP) signaling. The crucial PCP ligand in this context is WNT5A, which is produced by the CAFs, and gastric cancer cells react upon this signal by enhanced polarized migration. Why gastric cancer cells respond to this signal is still unclear, as their expression level for the central WNT5A receptor, ROR2, is very low. Here, we show that CAFs display long and branched filopodia that form an extensive, complex network engulfing gastric cancer cells, such as the gastric cancer cell line AGS. CAFs have a significantly higher expression level of ROR2 than normal gastric fibroblasts and AGS cells. By high-resolution imaging, we observe a direct transfer of fluorescently tagged ROR2 from CAF to AGS cells by signaling filopodia, known as cytonemes. Surprisingly, we find that the transferred ROR2 complexes can activate Wnt/JNK signaling in AGS cells. Consistently, blockage of ROR2 function in the CAFs leads to reduced paracrine Wnt/JNK signaling, cell polarization, and migration of the receiving AGS cells. Complementary, enhanced migration via paracrine ROR2 transfer was observed in a zebrafish in vivo model. These findings demonstrate a fresh role for cytoneme-mediated signaling in the tumor microenvironment. Cytonemes convey Wnt receptors from CAFs to gastric cancer cells, allowing them to respond to Wnt/PCP signals.

Evaluation of the Field-Test Results of Advanced ISDB-T System With Low-Rate LDPC Codes

This article analyses low-density parity-check (LDPC) codes for forward error correction (FEC) in the next generation of digital terrestrial broadcasting systems for transmitting high-volume content services, such as ultra high definition television (UHDTV). We assess the performance of the LDPC codes used by the Advanced ISDB-T system with 2x2 MIMO transmission using experimental data obtained in field measurements in Brazil. Channel power, carrier-to-noise threshold, and receiving threshold were measured for four different low-rates LDPC codes, two modulation types, and three receiving antenna heights at outdoor sites in urban areas. The coverage analysis shows that the channel power presents a similar distribution for horizontal and vertical polarized signals. C/N threshold analysis shows that in sites with high vehicular traffic, the C/N threshold and reception threshold values were much higher than in other sites with less heavy vehicular traffic. Among the five coding-modulation combinations used in the field tests, the transmission configuration with LDPC code rate 2/16 and QPSK modulation was the one that presented the best results partially meeting the requirement of C/N <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\leq $</tex-math> </inline-formula> 0dB. The transmission configuration with LDPC code rate 3/16 and QPSK modulation showed C/N results just above 0dB, but offering 50% higher data transmission rate.

No Late Cretaceous true polar wander oscillation and implications for stability of Earth relative to the rotation axis

Knowledge of Earth's stability with respect to the spin axis sets boundary conditions for understanding the deep mantle and interpreting records of past climate. Recently it has been argued that the solid Earth rotated by 12∘, and then rotated back, 86 to 78 million years ago. Herein we reanalyze the paleomagnetic data and report new rock magnetic analyses, from the Scaglia Rossa limestone of Italy on which this true polar wander (TPW) was based. We find that these data record an unrecognized secondary magnetization carried by authigenic hematite. This overprint has a differential angular effect on the normal and reversed polarity primary magnetizations, creating biased directions. This bias, together with probable tectonic and sedimentary slide rotations, creates false polar wander signals. The recognition of these artifacts serves as a cautionary tale and indicates that the null hypothesis of no large TPW since the Late Cretaceous cannot be rejected. This stability is fundamentally different from that of other planetary bodies which have undergone large polar wander, and provides the framework for Earth's climate history. Because of uncertainties in paleolongitude and geomagnetic field morphology, the unambiguous definition of terrestrial TPW deeper in time remains elusive.

A WNT4- and DKK3-driven canonical to noncanonical Wnt signaling switch controls multiciliogenesis.

Multiciliated cells contain hundreds of cilia whose directional movement powers the mucociliary clearance of the airways, a vital host defense mechanism. Multiciliated cell specification requires canonical Wnt signaling, which then must be turned off. Next, ciliogenesis and polarized ciliary orientation are regulated by noncanonical Wnt/planar cell polarity (Wnt/PCP) signaling. The mechanistic relationship between the Wnt pathways is unknown. We show that DKK3, a secreted canonical Wnt regulator and WNT4, a noncanonical Wnt ligand act together to facilitate a canonical to noncanonical Wnt signaling switch during multiciliated cell formation. In primary human airway epithelial cells, DKK3 and WNT4 CRISPR knockout blocks, whereas ectopic expression promotes, multiciliated cell formation by inhibiting canonical Wnt signaling. Wnt4 and Dkk3 single-knockout mice also display defective ciliated cells. DKK3 and WNT4 are co-secreted from basal stem cells and act directly on multiciliated cells via KREMEN1 and FZD6, respectively. We provide a novel mechanism that links specification to cilium biogenesis and polarization for proper multiciliated cell formation.

Anti-phagocytosis-blocking repolarization-resistant membrane-fusogenic liposome (ARMFUL) for adoptive cell immunotherapy.

Equipping multiple functionalities on adoptive effector cells is essential to overcome the complex immunological barriers in solid tumors for superior antitumor efficacy. However, current cell engineering technologies cannot endow these functionalities to cells within a single step because of the different spatial distributions of targets in one cell. Here, we present a core-shell anti-phagocytosis-blocking repolarization-resistant membrane-fusogenic liposome (ARMFUL) to achieve one-step multiplexing cell engineering for multifunctional cell construction. Through fusing with the M1 macrophage membrane, ARMFUL inserts an anti-CD47 (aCD47)-modified lipid shell onto the surface and simultaneously delivers colony-stimulating factor 1 receptor inhibitor BLZ945-loaded core into the cytoplasm. The surface-presenting aCD47 boosts macrophage's phagocytosis against the tumor by blocking CD47. The cytoplasm-located BLZ945 prompts its polarization resistance to M2 phenotype in the immunosuppressive microenvironment via inactivating the intracellular M2 polarization signaling pathway. This ARMFUL provides a versatile cell engineering platform to customize multimodal cellular functions for enhanced adoptive cell therapy.

Chemical Nuclear Polarization during the Photoreduction of Anthraquinones

The mechanism and products of the photoreaction of 2-isopropyl-9,10-anthraquinone (1) with ethanol have been established. An analysis of the signals of chemical nuclear polarization (CNP) showed that during the formation of CNP, only the mechanism of singlet-triplet transitions in radical pairs takes place without the participation of a triplet mechanism. In the study of the phase of multiplet and integral effects, the elementary acts of photoreaction were determined, and the structure of the anthrasemiquinone radical participating in the reaction was established.

Ubiquitin-mediated degradation at the Golgi apparatus.

The Golgi apparatus is an essential organelle of the secretory pathway in eukaryotic cells. It processes secretory and transmembrane proteins and orchestrates their transport to other endomembrane compartments or the plasma membrane. The Golgi apparatus thereby shapes the cell surface, controlling cell polarity, cell-cell communication, and immune signaling. The cytosolic face of the Golgi hosts and regulates signaling cascades, impacting most notably the DNA damage response and mitosis. These essential functions strongly depend on Golgi protein homeostasis and Golgi integrity. Golgi fragmentation and consequent malfunction is associated with neurodegenerative diseases and certain cancer types. Recent studies provide first insight into the critical role of ubiquitin signaling in maintaining Golgi integrity and in Golgi protein quality control. Similar to well described pathways at the endoplasmic reticulum, ubiquitin-dependent degradation of non-native proteins prevents the accumulation of toxic protein aggregates at the Golgi. Moreover, ubiquitination regulates Golgi structural rearrangements in response to cellular stress. Advances in elucidating ubiquitination and degradation events at the Golgi are starting to paint a picture of the molecular machinery underlying Golgi (protein) homeostasis.