Simultaneous Enhancement of Thermal Insulation and Impact Resistance in Transparent Bulk Composites.

Transparent bulk glass is highly demanded in devices and components of daily life to transmit light and protect against external temperature and mechanical hazards. However, the application of glass is impeded by its poor functional performance, especially in terms of thermal isolation and impact resistance. Here, a glass composite integrating the nacre-inspired structure and shear stiffening gel (SSG) material is proposed. Benefiting from the combination of these two elements, this nacre-inspired SSG/glass composite (NSG) exhibits superior thermal insulation and impact resistance while maintaining transparency simultaneously. Specifically, the low thermal conductivity of the SSG combined with the anisotropic heat transfer capability of the nacre-inspired structure enhances the out-of-plane thermal insulation of NSG. The deformations over large volumes in nacre-inspired facesheets promote the deformation region of the SSG core, synergistic effect of tablet sliding mechanism in nacre-inspired structure and strain-rate enhancement in SSG material cause the superior impact resistance of overall panels in a wide range of impact velocities. NSG demonstrates outstanding properties such as transparency, light weight, impact resistance, and thermal insulation, which are major concerns for the application in engineering fields. In conclusion, this bioinspired SSG/glass composite opens new avenues to achieve comprehensive performance improvements for transparent structural materials.

Comprehensive Single-Cell Immune Profiling Defines the Patient Multiple Myeloma Microenvironment Following Oncolytic Virus Therapy in a Phase Ib Trial.

PURPOSE: Our preclinical studies showed that the oncolytic reovirus formulation pelareorep (PELA) has significant immunomodulatory anti-myeloma activity. We conducted an investigator-initiated clinical trial to evaluate PELA in combination with dexamethasone (Dex) and bortezomib (BZ) and define the tumor immune microenvironment (TiME) in patients with multiple myeloma treated with this regimen. PATIENTS AND METHODS: Patients with relapsed/refractory multiple myeloma (n = 14) were enrolled in a phase Ib clinical trial (ClinicalTrials.gov: NCT02514382) of three escalating PELA doses administered on Days 1, 2, 8, 9, 15, and 16. Patients received 40 mg Dex and 1.5 mg/m2 BZ on Days 1, 8, and 15. Cycles were repeated every 28 days. Pre- and posttreatment bone marrow specimens (IHC, n = 9; imaging mass cytometry, n = 6) and peripheral blood samples were collected for analysis (flow cytometry, n = 5; T-cell receptor clonality, n = 7; cytokine assay, n = 7). RESULTS: PELA/BZ/Dex was well-tolerated in all patients. Treatment-emergent toxicities were transient, and no dose-limiting toxicities occurred. Six (55%) of 11 response-evaluable patients showed decreased paraprotein. Treatment increased T and natural killer cell activation, inflammatory cytokine release, and programmed death-ligand 1 expression in bone marrow. Compared with nonresponders, responders had higher reovirus protein levels, increased cytotoxic T-cell infiltration posttreatment, cytotoxic T cells in significantly closer proximity to multiple myeloma cells, and larger populations of a novel immune-primed multiple myeloma phenotype (CD138+ IDO1+HLA-ABCHigh), indicating immunomodulation. CONCLUSIONS: PELA/BZ/Dex is well-tolerated and associated with anti-multiple myeloma activity in a subset of responding patients, characterized by immune reprogramming and TiME changes, warranting further investigation of PELA as an immunomodulator.

Layered Inorganic Silicate Aerogel Pillared by Nanoclusters for High Temperature Thermal Insulation.

Layered inorganic material, with large-area interlayer surface and interface, provides an essential material platform for constructing new configuration of functional materials. Herein, a layered material pillared with nanoclusters realizing high temperature thermal insulation performance is demonstrated for the first time. Specifically, systematic synchrotron radiation spectroscopy and finite element calculation analysis show that ZrOx nanoclusters served as "pillars" to effectively produce porous structures with enough boundary defect while maintaining the layered structure, thereby significantly reducing solid state thermal conductivity (≈0.32 W m-1  K-1 , 298-573 K). Moreover, the layered inorganic silicate material assembled aerogel also exhibits superior thermal insulation performance from room temperature (0.034 W m-1  K-1 , 298 K, air conditions) to high temperature (0.187 W m-1  K-1 , 1073 K, air conditions) and largely enhanced compressive strength (42 kPa at 80% compression), which is the best layered material-based aerogel that has achieved synergistic improvement in thermal and mechanical performance so far. Layered inorganic silicate aerogel pillared by nanoclusters will pave a new avenue for the design of advanced thermal insulation materials under extreme conditions.

Anomalous inapplicability of nacre-like architectures as impact-resistant templates in a wide range of impact velocities.

Nacre is generally regarded as tough body armor, but it was often smashed by predators with a certain striking speed. Nacre-like architectures have been demonstrated to dissipate abundant energy by tablets sliding at static or specific low-speed loads, but whether they're still impact-resistant templates in a wide range of impact velocities remains unclear. Here, we find an anomalous phenomenon that nacre-like structures show superior energy-dissipation ability only in a narrow range of low impact velocities, while they exhibit lower impact resistance than laminated structures when impact velocity exceeds a critical value. This is because the tablets sliding in nacre-like structure occurs earlier and wider at low impact velocities, while it becomes localized at excessive impact velocities. Such anomalous phenomenon remains under different structural sizes and boundary conditions. It further inspires us to propose a hybrid architecture design strategy that achieves optimal impact resistance in a wide range of impact velocities.

A Prestressing Strategy Enabled Synergistic Energy-Dissipation in Impact-Resistant Nacre-Like Structures.

The application of prestresses is a valuable strategy for enhancing the overall mechanical performances of structural materials. Residual stresses, acting as prestresses, exist naturally in biological structural materials, such as the nacre with the 3D "brick-and-mortar" arrangement. Although regulation of the tablets sliding has recently been demonstrated to be vital to improve toughness in synthetic nacre-like structures, the effects of prestresses on the tablets-sliding mechanism in these nacre-like structures remain unclear. Here, by a combination of simulation, additive manufacturing, and drop tower testing the authors reveal that, at a critical prestress, synergistic effects between the prestress-enhanced tablets sliding and prestress-weakened structural integrality result in optimized impact resistance of nacre-like structures. Furthermore, the prestressing strategy is easily implemented to a designed nacre-inspired separator to enhance the impact resistance of lithium batteries. The findings demonstrate that the prestressing strategy combined with bioinspired architectures can be exploited for enhancing the impact resistance of engineering structural materials and energy storage devices.

Nacreous aramid-mica bulk materials with excellent mechanical properties and environmental stability.

Low density, high strength and toughness, together with good environmental stability are always desirable but hardly to achieve simultaneously for man-made structural materials. Replicating the design motifs of natural nacre clearly provides one promising route to obtain such kind of materials, but fundamental challenges remain. Herein, by choosing aramid nanofibers and mica microplatelets as building blocks, we produce a nacreous aramid-mica bulk material with a favorable combination of low density (∼1.7 g cm-3), high strength (∼387 MPa) and toughness (∼14.3 MPa m1/2), and impressive mechanical stability in some harsh environments, including acid/alkali solutions, strong ultraviolet radiation, boiling water, and liquid nitrogen, standing out from previously reported biomimetic bulk composites. Moreover, the obtained material outperforms other bulk nacre-mimetics and most engineering structural materials in terms of its specific strength (227 MPa/[Mg m-3]) and specific toughness (8.4 MPa m1/2/[Mg m-3]), making it a new promising engineering structural material for different technical fields.

Integrated contact lens sensor system based on multifunctional ultrathin MoS2 transistors.

Smart contact lenses attract extensive interests due to their capability of directly monitoring physiological and ambient information. However, previous demonstrations usually lacked efficient sensor modalities, facile fabrication process, mechanical stability, or biocompatibility. Here, we demonstrate a flexible approach for fabrication of multifunctional smart contact lenses with an ultrathin MoS2 transistors-based serpentine mesh sensor system. The integrated sensor systems contain a photodetector for receiving optical information, a glucose sensor for monitoring glucose level directly from tear fluid, and a temperature sensor for diagnosing potential corneal disease. Unlike traditional sensors and circuit chips sandwiched in the lens substrate, this serpentine mesh sensor system can be directly mounted onto the lenses and maintain direct contact with tears, delivering high detection sensitivity, while being mechanically robust and not interfering with either blinking or vision. Furthermore, the in vitro cytotoxicity tests reveal good biocompatibility, thus holding promise as next-generation soft electronics for healthcare and medical applications.

Discontinuous fibrous Bouligand architecture enabling formidable fracture resistance with crack orientation insensitivity.

Bioinspired architectural design for composites with much higher fracture resistance than that of individual constituent remains a major challenge for engineers and scientists. Inspired by the survival war between the mantis shrimps and abalones, we design a discontinuous fibrous Bouligand (DFB) architecture, a combination of Bouligand and nacreous staggered structures. Systematic bending experiments for 3D-printed single-edge notched specimens with such architecture indicate that total energy dissipations are insensitive to initial crack orientations and show optimized values at critical pitch angles. Fracture mechanics analyses demonstrate that the hybrid toughening mechanisms of crack twisting and crack bridging mode arising from DFB architecture enable excellent fracture resistance with crack orientation insensitivity. The compromise in competition of energy dissipations between crack twisting and crack bridging is identified as the origin of maximum fracture energy at a critical pitch angle. We further illustrate that the optimized fracture energy can be achieved by tuning fracture energy of crack bridging, pitch angles, fiber lengths, and twist angles distribution in DFB composites.

A Nacre-Inspired Separator Coating for Impact-Tolerant Lithium Batteries.

The commercial ceramic nanoparticle coated microporous polyolefin separators used in lithium batteries are still vulnerable under external impact, which may cause short circuits and consequently severe safety threats, because the protective ceramic nanoparticle coating layers on the separators are intrinsically brittle. Here, a nacre-inspired coating on the separator to improve the impact tolerance of lithium batteries is reported. Instead of a random structured ceramic nanoparticle layer, ion-conductive porous multilayers consisting of highly oriented aragonite platelets are coated on the separator. The nacre-inspired coating can sustain external impact by turning the violent localized stress into lower and more uniform stress due to the platelet sliding. A lithium-metal pouch cell using the aragonite platelet coated separator exhibits good cycling stability under external shock, which is in sharp contrast to the fast short circuit of a lithium-metal pouch cell using a commercial ceramic nanoparticle coated separator.

GRP78 regulates CD44v membrane homeostasis and cell spreading in tamoxifen-resistant breast cancer.

GRP78 conducts protein folding and quality control in the ER and shows elevated expression and cell surface translocation in advanced tumors. However, the underlying mechanisms enabling GRP78 to exert novel signaling functions at cell surface are just emerging. CD44 is a transmembrane protein and an important regulator of cancer metastasis, and isoform switch of CD44 through incorporating additional variable exons to the extracellular juxtamembrane region is frequently observed during cancer progression. Using super-resolution dual-color single-particle tracking, we report that GRP78 interacts with CD44v in plasma membrane nanodomains of breast cancer cells. We further show that targeting cell surface GRP78 by the antibodies can effectively reduce cell surface expression of CD44v and cell spreading of tamoxifen-resistant breast cancer cells. Our results uncover new functions of GRP78 as an interacting partner of CD44v and as a regulator of CD44v membrane homeostasis and cell spreading. This study also provides new insights into anti-CD44 therapy in tamoxifen-resistant breast cancer.

Nuclear receptor/Wnt beta-catenin interactions are regulated via differential CBP/p300 coactivator usage.

Over 400 million years ago, the evolution of vertebrates gave rise to a life cycle in which the organism began to live longer particularly as an adult. To accommodate such a longer lifespan, the organism underwent adaptation, developing a mechanism for long-lived cellular homeostasis. This adaptation required a population of long-lived relatively quiescent somatic stem cells (SSCs) along with a more proliferative differentiated daughter cell population, and was necessary to safeguard the genetic attributes with which SSCs were endowed. Intriguingly, cAMP response element binding protein (CREB)-binding protein (CBP) and E1A-binding protein, 300 kDa (p300), the highly homologous Kat3 coactivators had diverged, through duplication of ancestral Kat3, immediately preceding the evolution of vertebrates, given that both CBP and p300 have been detected in nearly all vertebrates versus non-vertebrates. We now demonstrate that a relatively small, highly evolutionarily conserved, amino terminal 9 amino acid deletion in CBP versus p300, plays a critical role in allowing for both robust maintenance of genomic integrity in stem cells and the initiation of a feed-forward differentiation mechanism by tightly controlling the interaction of the nuclear receptor family with the Wnt signaling cascade in either an antagonistic or synergistic manner.

Endoplasmic reticulum stress activates SRC, relocating chaperones to the cell surface where GRP78/CD109 blocks TGF-ß signaling.

The discovery that endoplasmic reticulum (ER) luminal chaperones such as GRP78/BiP can escape to the cell surface upon ER stress where they regulate cell signaling, proliferation, apoptosis, and immunity represents a paradigm shift. Toward deciphering the mechanisms, we report here that, upon ER stress, IRE1α binds to and triggers tyrosine kinase SRC activation, leading to ASAP1 phosphorylation and Golgi accumulation of ASAP1 and Arf1-GTP, resulting in KDEL receptor dispersion from the Golgi and suppression of retrograde transport. At the cell surface, GRP78 binds to and acts in concert with a glycosylphosphatidylinositol-anchored protein, CD109, in blocking TGF-ß signaling by promoting the routing of the TGF-ß receptor to the caveolae, thereby disrupting its binding to and activation of Smad2. Collectively, we uncover a SRC-mediated signaling cascade that leads to the relocalization of ER chaperones to the cell surface and a mechanism whereby GRP78 counteracts the tumor-suppressor effect of TGF-ß.

Differentiation Therapy Targeting the ß-Catenin/CBP Interaction in Pancreatic Cancer.

BACKGROUND: Although canonical Wnt signaling is known to promote tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), a cancer driven principally by mutant K-Ras, the detailed molecular mechanisms by which the Wnt effector ß-catenin regulates such tumorigenesis are largely unknown. We have previously demonstrated that ß-catenin's differential usage of the Kat3 transcriptional coactivator cyclic AMP-response element binding protein-binding protein (CBP) over its highly homologous coactivator p300 increases self-renewal and suppresses differentiation in other types of cancer. AIM/METHODS: To investigate Wnt-mediated carcinogenesis in PDAC, we have used the specific small molecule CBP/ß-catenin antagonist, ICG-001, which our lab identified and has extensively characterized, to examine its effects in human pancreatic cancer cells and in both an orthotopic mouse model and a human patient-derived xenograft (PDX) model of PDAC. RESULTS/CONCLUSION: We report for the first time that K-Ras activation increases the CBP/ß-catenin interaction in pancreatic cancer; and that ICG-001 specific antagonism of the CBP/ß-catenin interaction sensitizes pancreatic cancer cells and tumors to gemcitabine treatment. These effects were associated with increases in the expression of let-7a microRNA; suppression of K-Ras and survivin; and the elimination of drug-resistant cancer stem/tumor-initiating cells.

Characterization of Imatinib Resistant CML Leukemic Stem/Initiating Cells and Their Sensitivity to CBP/Catenin Antagonists.

BACKGROUND AND OBJECTIVE: The development of the tyrosine kinase inhibitor Imatinib (IM) represents a milestone in CML (Chronic Myeloid Leukemia) treatment. However, it is not curative and patients develop IM resistance. IM resistance has been previously correlated with the emergence of drug-resistant LIC/LSC (Leukemia Initiating Cell/Leukemia Stem Cell) and increased nuclear catenin levels and enhanced Wnt signaling. It has been demonstrated previously that drug resistant CML LIC/LSC can be safely eliminated both in vitro and in vivo via disruption of the CBP/catenin interaction, utilizing the highly biochemically selective small molecule CBP/catenin antagonist ICG- 001. METHODS: Here, we utilized an in vitro IM selection of primary CML patients' samples to identify drug-resistant LIC/LSC populations. In this report, we characterized the drug-resistant CML LIC/LSC population using FACS, Smartchip qPCR and colony assays to analyze cell surface markers, transcriptomics and function. RESULTS: As opposed to previous characterization of the CML leukemic stem cell population as being either CD34+CD38- or CD34+CD38+, the in vitro selected Imatinib resistant (IM-R) CML LSC population was consistently CD34-CD38-. In Long-Term Culture Initiating Cell assay (LTC-IC, a surrogate assay for long term repopulating stem cells), our results suggest that the CBP/catenin antagonist ICG- 001 sensitizes LIC/LSC to IM treatment by forced differentiative elimination of the CML LIC/LSC population. CONCLUSION: In vitro selected IM resistant cells are negative for both CD34 and CD38 by FACS analysis. These cells acquire CD34/CD38 expression after co-culture with stromal cells. CBP/catenin antagonist ICG-001 facilitates IM function in eliminating these cells.

Analysis of optimal crosslink density and platelet size insensitivity in graphene-based artificial nacres.

Exploration of graphene-based artificial nacres with excellent mechanical properties demonstrates the potential to surpass natural nacre. Recent experimental studies report that optimal crosslink density defined as concentration of the surface functional groups is usually observed in these artificial nacres towards superb mechanical performance. A hybrid model integrating a nonlinear shear-lag model and atomistic simulations reveals the emergence of an optimal crosslink density at which the maximum strength and toughness are achieved. The origin is due to the balance among the reduction of in-plane tensile properties of the graphene sheets, the enhancement of the shear strength of the interlayer and the reduction of interface plasticity. In addition, our results also reveal that the size insensitivity of the graphene sheet appears when the shear stress of the interlayer is highly localized, the increase of the crosslink density intensifies the nonuniformity of the shear stress and the optimal mechanical properties of the artificial nacre cannot be further enhanced by tuning the size of the graphene sheets. Three kinds of interface molecular interactions with their optimal crosslink densities are also proposed to simultaneously maximize the strength and toughness of graphene-based artificial nacres.

Small molecule p300/catenin antagonist enhances hematopoietic recovery after radiation.

There is currently no FDA approved therapeutic agent for ARS mitigation post radiation exposure. Here we report that the small molecule YH250, which specifically antagonizes p300/catenin interaction, stimulates hematopoiesis in lethally or sublethally irradiated mice. A single administration of YH250 24 hours post irradiation can significantly stimulate HSC proliferation, improve survival and accelerate peripheral blood count recovery. Our studies suggest that promotion of the expansion of the remaining HSC population via stimulation of symmetric non-differentiative proliferation is at least part of the mechanism of action.

Genetic mutations associated with metastatic clear cell renal cell carcinoma.

Metastasis is the major cause of death among cancer patients, yet early detection and intervention of metastasis could significantly improve their clinical outcomes. We have sequenced and analyzed RNA (Expression) and DNA (Mutations) from the primary tumor (PT), tumor extension (TE) and lymphatic metastatic (LM) sites of patients with clear cell renal cell carcinoma (CCRCC) before treatment. Here, we report a three-nucleotide deletion near the C-region of Plk5 that is specifically associated with the lymphatic metastasis. This mutation is un-detectable in the PT, becomes detectable in the TE and dominates the LM tissue. So while only a few primary cancer cells carry this mutation, the majority of metastatic cells have this mutation. The increasing frequency of this mutation in metastatic tissue suggests that this Plk5 deletion could be used as an early indicator of CCRCC metastasis, and be identified by low cost PCR assay. A large scale clinical trial could reveal whether a simple PCR assay for this mutation at the time of nephrectomy could identify and stratify high-risk CCRCC patients for treatments.

The effects of apolipoprotein F deficiency on high density lipoprotein cholesterol metabolism in mice.

Apolipoprotein F (apoF) is 29 kilodalton secreted sialoglycoprotein that resides on the HDL and LDL fractions of human plasma. Human ApoF is also known as Lipid Transfer Inhibitor protein (LTIP) based on its ability to inhibit cholesteryl ester transfer protein (CETP)-mediated transfer events between lipoproteins. In contrast to other apolipoproteins, ApoF is predicted to lack strong amphipathic alpha helices and its true physiological function remains unknown. We previously showed that overexpression of Apolipoprotein F in mice reduced HDL cholesterol levels by 20-25% by accelerating clearance from the circulation. In order to investigate the effect of physiological levels of ApoF expression on HDL cholesterol metabolism, we generated ApoF deficient mice. Unexpectedly, deletion of ApoF had no substantial impact on plasma lipid concentrations, HDL size, lipid or protein composition. Sex-specific differences were observed in hepatic cholesterol content as well as serum cholesterol efflux capacity. Female ApoF KO mice had increased liver cholesteryl ester content relative to wild type controls on a chow diet (KO: 3.4+/-0.9 mg/dl vs. WT: 1.2+/-0.3 mg/dl, p<0.05). No differences were observed in ABCG1-mediated cholesterol efflux capacity in either sex. Interestingly, ApoB-depleted serum from male KO mice was less effective at promoting ABCA1-mediated cholesterol efflux from J774 macrophages relative to WT controls.

Increased expression of cathepsins and obesity-induced proinflammatory cytokines in lacrimal glands of male NOD mouse.

PURPOSE: Lacrimal glands (LGs) of male NOD mice, a model of Sjögren's syndrome (SjS), exhibit immune cell infiltration and lipid deposition. The mechanism of SjS was further investigated by characterizing gene expression profiles of NOD mouse LGs in comparison with those of healthy control mice. Differentially expressed genes were further investigated at the protein level to correlate changes in location and abundance with development of disease. METHODS: Microarray followed by real-time RT-PCR was conducted to compare the gene expression in 12-week-old male NOD mouse LG relative to that in matched BALB/c mouse LG. Immunofluorescence and Western blot analyses were used to localize and quantify proteins of interest. Enzymatic assays measured catalytic activity of cathepsins. RESULTS: Cathepsin H (Ctsh), S (Ctss), and Z (Ctsz) and proinflammatory factors, including tumor necrosis factor (Tnf), interleukin 6 (Il6), and interleukin 1 beta (Il1b), were upregulated at the mRNA level. Increased cathepsin S immunofluorescence was detected in lysosomes and secretory vesicle-like organelles in LG acinar cells and CD68-positive infiltrating macrophages in NOD mouse LG. Cathepsin S (CATS) and cathepsin H (CATH) activities were significantly higher in NOD mouse LG lysate than in control lysates, and CATS was also significantly elevated in NOD mouse tears. CONCLUSIONS: Expression of CATS and CATH increases in parallel with proinflammatory cytokines during the development of autoimmune inflammatory disease in the NOD mouse disease model. Tear CATS may represent a biomarker for diagnosis of dacryoadenitis in SjS.

Duct system of the rabbit lacrimal gland: structural characteristics and role in lacrimal secretion.

PURPOSE: To develop a nomenclature for the lacrimal duct system in the rabbit, based on the anatomic and structural characteristics of each duct segment, and to provide RT-PCR and immunofluorescence data to support the notion that the duct system plays important roles in lacrimal function. METHODS: Paraffin-embedded lacrimal glands (LGs) were stained with hematoxylin and eosin (H&E) and evaluated with a stereomicroscope. Cryosections of LG were stained with cresyl violet, and acinar cells and ductal epithelial cells were isolated from each duct segment by laser capture microdissection (LCM). mRNA levels from these cells were analyzed by real-time RT-PCR. Standard protocol was followed for immunofluorescence detection of ionic transporters. RESULTS: The lacrimal duct system was divided into six segments on the basis of morphologic characteristics: the intercalated, intralobular, interlobular, intralobar, interlobar, and main excretory ducts. Although the morphologic features change incrementally along the entire duct system, the gene expression of ionic transporters and aquaporins, including AE3, AQP4, AQP5, CFTR, ClC2gamma, KCC1, NHE1, NKAalpha1, NKAbeta1, NKAbeta2, NKAbeta3, and NKCC1 varied greatly among duct segments. Immunofluorescence results were generally in accordance with the abundance of mRNAs along the acinus-duct axis. CONCLUSIONS: Most LG research has focused on the acinar cells, with relatively little attention being paid to the lacrimal ducts. The lack of knowledge regarding the lacrimal ducts was so profound that a precise nomenclature had not been established for the duct system. The present data establish a nomenclature for each segment of the lacrimal duct system and provide evidence that ducts play critical roles in lacrimal secretion.