Negative Linear Compressibility and Interlayer Gap Closure in Layered Rare-Earth Hydroxyhalide (YCl(OH)2) under High Pressure.

Layered materials have attracted extensive attention due to their exceptional physical and chemical properties. Understanding the structural evolution of such materials under high pressure is crucial for the development of new functional materials. In this study, the structure evolution of the synthesized layered rare-earth hydroxyhalide YCl(OH)2 under high pressures up to approximately 9.4 GPa was explored by using a diamond anvil cell combined with synchrotron single-crystal X-ray diffraction. Simultaneously, high-pressure Raman spectroscopy experiment was conducted to 10.3 GPa. Our findings indicate that YCl(OH)2 maintains its symmetry within the experimental pressure range. The pressure-volume data of YCl(OH)2 were fitted to the third-order Birch-Murnaghan equation of state (EoS) to derive its EoS parameters including zero-pressure unit-cell volume (VT0), isothermal bulk modulus (KT0), and its pressure derivative (K'T0): VT0 = 142.47 (1) Å3, KT0 = 38.2 (18) GPa, and K'T0 = 9.8 (1). However, the unit-cell parameters a, b, and c exhibit a distinct compressional behavior, with the a-axis being the most compressible and the b-axis being the least. Particularly noteworthy is the observation that YCl(OH)2 displays a negative linear compressibility along the b-axis within the pressure range of 0.4-5.3 GPa. Further detailed structure refinement and Raman spectroscopy analyses indicate that the anomalous behavior of the b-axis could be attributed to the formation of the O-H···O hydrogen bonding chains along the b direction. Moreover, the coordination number of Y3+ increased from 8 to 9 as the pressure reached 5.3 GPa due to the reduction of the interlayer spacing upon compression, ultimately leading to the closure of the interlayer gap.

Cyclometalated Platinum(II) Metallomesogens Based on Half-Disc-Shaped ß-Diketonate Ligands with Hexacatenar: Crystal Structures, Mesophase Properties, and Semiconductor Devices.

A series of new half-disc-shaped platinum(II) complexes [Pt(ppy)(ALn-6OCnH2n+1)] (Pt-An), [Pt(ppyF)(ALn-6OCnH2n+1)] (Pt-Bn), and [Pt(ppyCF3)(ALn-6OCnH2n+1)] (Pt-Cn) (ALn-6OCnH2n+1 = 1,3-bis(3,4,5-trialkoxyphenyl)propane-1,3-dionato; n = 1, 6, 12) with concise structures have been designed and synthesized, in which 2-phenylpyridine (ppy) derivatives were used as cyclometalated ligands and hexacatenar ß-diketonate derivatives ALn-6OCnH2n+1 as auxiliary ligands. The single-crystal data of the methoxy diketonate analogues Pt-A1, Pt-B1, and Pt-C1 indicate that they all display excellent square planarity. These platinum(II) complexes show a certain emission tunability (ranging from λ = 506-535 nm) by the introduction of fluorine or trifluoromethyl into ppy. Thermal studies reveal that the fluorine-substituted complexes are liquid crystals but the trifluoromethyl-substituted complexes are not. The platinum(II) complexes Pt-A12, Pt-B6, and Pt-B12 can form a hexagonal columnar mesophase via intermolecular π-π interactions. In addition, compared to the reported platinum(II) metallomesogens, Pt-A12 and Pt-B12 exhibit improved ambipolar carrier mobility behaviors in semiconductor devices at the liquid crystal states.

Leveraging genetic diversity in mice to inform individual differences in brain microstructure and memory.

In human Alzheimer's disease (AD) patients and AD mouse models, both differential pre-disease brain features and differential disease-associated memory decline are observed, suggesting that certain neurological features may protect against AD-related cognitive decline. The combination of these features is known as brain reserve, and understanding the genetic underpinnings of brain reserve may advance AD treatment in genetically diverse human populations. One potential source of brain reserve is brain microstructure, which is genetically influenced and can be measured with diffusion MRI (dMRI). To investigate variation of dMRI metrics in pre-disease-onset, genetically diverse AD mouse models, we utilized a population of genetically distinct AD mice produced by crossing the 5XFAD transgenic mouse model of AD to 3 inbred strains (C57BL/6J, DBA/2J, FVB/NJ) and two wild-derived strains (CAST/EiJ, WSB/EiJ). At 3 months of age, these mice underwent diffusion magnetic resonance imaging (dMRI) to probe neural microanatomy in 83 regions of interest (ROIs). At 5 months of age, these mice underwent contextual fear conditioning (CFC). Strain had a significant effect on dMRI measures in most ROIs tested, while far fewer effects of sex, sex*strain interactions, or strain*sex*5XFAD genotype interactions were observed. A main effect of 5XFAD genotype was observed in only 1 ROI, suggesting that the 5XFAD transgene does not strongly disrupt neural development or microstructure of mice in early adulthood. Strain also explained the most variance in mouse baseline motor activity and long-term fear memory. Additionally, significant effects of sex and strain*sex interaction were observed on baseline motor activity, and significant strain*sex and sex*5XFAD genotype interactions were observed on long-term memory. We are the first to study the genetic influences of brain microanatomy in genetically diverse AD mice. Thus, we demonstrated that strain is the primary factor influencing brain microstructure in young adult AD mice and that neural development and early adult microstructure are not strongly altered by the 5XFAD transgene. We also demonstrated that strain, sex, and 5XFAD genotype interact to influence memory in genetically diverse adult mice. Our results support the usefulness of the 5XFAD mouse model and convey strong relationships between natural genetic variation, brain microstructure, and memory.

Delayed diapedesis of CD8 T cells contributes to long-term pathology after ischemic stroke in male mice.

OBJECTIVE: Stroke is a debilitating disorder with significant annual mortality and morbidity rates worldwide. Immune cells are recruited to the injured brain within hours after stroke onset and can exhibit either protective or detrimental effects on recovery. However, immune cells, including CD8 T cells, persist in the injured brain for weeks, suggesting a longer-term role for the adaptive immune system during functional recovery. The aim of this study was to determine if the delayed secondary diapedesis of CD8 T cells into the ischemic brain negatively impacts functional recovery after transient ischemic stroke in male mice. RESULTS: Mice exhibited an increased number of leukocytes in the ipsilesional hemispheres at 14 days (3-fold; p < 0.001) and 30 days (2.2-fold; p = 0.02) after transient middle cerebral artery occlusion (tMCAo) compared to 8 days post-tMCAo, at which time acute neuroinflammation predominantly resolves. Moreover, mice with higher ipsilesional CD8 T cells at 30 days (R2 = 0.52, p < 0.01) exhibited worse functional recovery. To confirm a detrimental role of chronic CD8 T cell diapedesis on recovery, peripheral CD8 T cells were depleted beginning 10 days post-tMCAo. Delayed CD8 T cell depletion improved motor recovery on the rotarod (F(1,28) = 4.264; p = 0.048) compared to isotype control-treated mice. CD8 T cell-depleted mice also exhibited 2-fold (p < 0.001) reduced leukocyte infiltration at 30 days post-tMCAo. Specifically, macrophage, neutrophil, and CD4 T cell numbers were reduced in the ipsilesional hemisphere of the CD8 T cell-depleted mice independent of inflammatory status of the post-stroke CNS (e.g. microglial phenotype and cytokine production). RNAseq identified a unique profile for brain infiltrating CD8 T cells at 30 days post-tMCAo, with 46 genes differentially expressed relative to CD8 T cells at 3 days post-tMCAo. CONCLUSION: Our data reveal a role for CD8 T cells in the chronic phase post-stroke that can be therapeutically targeted. We demonstrate long-term CD8 T cell recruitment into the ipsilesional hemisphere that affects both immune cell numbers present in the injured brain and functional recovery through one month after stroke onset.

EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer.

EGFR inhibition is an effective treatment in the minority of non-small cell lung cancer (NSCLC) cases harboring EGFR-activating mutations, but not in EGFR wild type (EGFRwt) tumors. Here, we demonstrate that EGFR inhibition triggers an antiviral defense pathway in NSCLC. Inhibiting mutant EGFR triggers Type I IFN-I upregulation via a RIG-I-TBK1-IRF3 pathway. The ubiquitin ligase TRIM32 associates with TBK1 upon EGFR inhibition, and is required for K63-linked ubiquitination and TBK1 activation. Inhibiting EGFRwt upregulates interferons via an NF-κB-dependent pathway. Inhibition of IFN signaling enhances EGFR-TKI sensitivity in EGFR mutant NSCLC and renders EGFRwt/KRAS mutant NSCLC sensitive to EGFR inhibition in xenograft and immunocompetent mouse models. Furthermore, NSCLC tumors with decreased IFN-I expression are more responsive to EGFR TKI treatment. We propose that IFN-I signaling is a major determinant of EGFR-TKI sensitivity in NSCLC and that a combination of EGFR TKI plus IFN-neutralizing antibody could be useful in most NSCLC patients.

Phosphoprotein-based biomarkers as predictors for cancer therapy.

Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.

A Frequency-Selective pH-Responsive paraCEST Agent.

Paramagnetic chemical exchange saturation transfer (paraCEST) agents are well-suited for imaging tissue pH because the basis of CEST, chemical exchange, is inherently sensitive to pH. Several previous pH-sensitive paraCEST agents were based on an exchanging Ln3+ -bound water molecule as the CEST antenna but this design often added additional line-broadening to the bulk water signal due to T2 exchange. We report herein a pH-sensitive paraCEST agent that lacks an inner-sphere water molecule but contains one Ln-bound -OH group for CEST activation. The Yb3+ complex, Yb(1), displayed a single, highly shifted CEST peak originating from the exchangeable Yb-OH proton, the frequency of which changed over the biologically relevant pH range. CEST images of phantoms ranging in pH from 6 to 8 demonstrate the potential of this agent for imaging pH. Initial rodent imaging studies showed that Gd(1) remains in the vascular system much longer than anticipated but is cleared slowly via renal filtration.

A PoleP286R mouse model of endometrial cancer recapitulates high mutational burden and immunotherapy response.

Cancer is instigated by mutator phenotypes, including deficient mismatch repair and p53-associated chromosomal instability. More recently, a distinct class of cancers was identified with unusually high mutational loads due to heterozygous amino acid substitutions (most commonly P286R) in the proofreading domain of DNA polymerase ε, the leading strand replicase encoded by POLE. Immunotherapy has revolutionized cancer treatment, but new model systems are needed to recapitulate high mutational burdens characterizing human cancers and permit study of mechanisms underlying clinical responses. Here, we show that activation of a conditional LSL-PoleP286R allele in endometrium is sufficient to elicit in all animals endometrial cancers closely resembling their human counterparts, including very high mutational burden. Diverse investigations uncovered potentially novel aspects of Pole-driven tumorigenesis, including secondary p53 mutations associated with tetraploidy, and cooperation with defective mismatch repair through inactivation of Msh2. Most significantly, there were robust antitumor immune responses with increased T cell infiltrates, accelerated tumor growth following T cell depletion, and unfailing clinical regression following immune checkpoint therapy. This model predicts that human POLE-driven cancers will prove consistently responsive to immune checkpoint blockade. Furthermore, this is a robust and efficient approach to recapitulate in mice the high mutational burdens and immune responses characterizing human cancers.

In vivo MRS measurement of 2-hydroxyglutarate in patient-derived IDH-mutant xenograft mouse models versus glioma patients.

PURPOSE: To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS: Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS: The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION: The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.

Imaging Insulin Secretion from Mouse Pancreas by MRI Is Improved by Use of a Zinc-Responsive MRI Sensor with Lower Affinity for Zn2+ Ions.

It has been demonstrated that divalent zinc ions packaged with insulin in ß-cell granules can be detected by MRI during glucose-stimulated insulin secretion using a gadolinium-based Zn2+-sensitive agent. This study was designed to evaluate whether a simpler agent design having single Zn2+-sensing moieties but with variable Zn2+ binding affinities might also detect insulin secretion from the pancreas. Using an implanted MR-compatible window designed to hold the pancreas in a fixed position for imaging, we now demonstrate that focally intense "hot spots" can be detected in the tail of the pancreas using these agents after administration of glucose to stimulate insulin secretion. Histological staining of the same tissue verified that the hot spots identified by imaging correspond to clusters of islets, perhaps reflecting first-responder islets that are most responsive to a sudden increase in glucose. A comparison of images obtained when using a high-affinity Zn2+ sensor versus a lower-affinity sensor showed that the lower-affinity sensors produced the best image contrast. An equilibrium model that considers all possible complexes formed between Zn2+, the GdL sensor, and HSA predicts that a GdL sensor with lower affinity for Zn2+ generates a lower background signal from endogenous Zn2+ prior to glucose-stimulated insulin secretion (GSIS) and that the weaker binding affinity agent is more responsive to a further increase in Zn2+ concentration near ß-cells after GSIS. These model predictions are consistent with the in vivo imaging observations.

Selective Nonnuclear Estrogen Receptor Activation Decreases Stroke Severity and Promotes Functional Recovery in Female Mice.

Estrogens provide neuroprotection in animal models of stroke, but uterotrophic effects and cancer risk limit translation. Classic estrogen receptors (ERs) serve as transcription factors, whereas nonnuclear ERs govern numerous cell processes and exert beneficial cardiometabolic effects without uterine or breast cancer growth in mice. Here, we determined how nonnuclear ER stimulation with pathway-preferential estrogen (PaPE)-1 affects stroke outcome in mice. Ovariectomized female mice received vehicle, estradiol (E2), or PaPE-1 before and after transient middle cerebral artery occlusion (tMCAo). Lesion severity was assessed with MRI, and poststroke motor function was evaluated through 2 weeks after tMCAo. Circulating, spleen, and brain leukocyte subpopulations were quantified 3 days after tMCAo by flow cytometry, and neurogenesis and angiogenesis were evaluated histologically 2 weeks after tMCAo. Compared with vehicle, E2 and PaPE-1 reduced infarct volumes at 3 days after tMCAo, though only PaPE-1 reduced leukocyte infiltration into the ischemic brain. Unlike E2, PaPE-1 had no uterotrophic effect. Both interventions had negligible effect on long-term poststroke neuronal or vascular plasticity. All mice displayed a decline in motor performance at 2 days after tMCAo, and vehicle-treated mice did not improve thereafter. In contrast, E2 and PaPE-1 treatment afforded functional recovery at 6 days after tMCAo and beyond. Thus, the selective activation of nonnuclear ER by PaPE-1 decreased stroke severity and improved functional recovery in mice without undesirable uterotrophic effects. The beneficial effects of PaPE-1 are also associated with attenuated neuroinflammation in the brain. PaPE-1 and similar molecules may warrant consideration as efficacious ER modulators providing neuroprotection without detrimental effects on the uterus or cancer risk.

Metabolic and cardiovascular effects of chronic mild hyperuricemia in rodents.

Mildly elevated serum uric acid levels are common in people with metabolic syndrome and type 2 diabetes mellitus (T2DM), but whether elevated uric acid has a causal role in the pathogenesis of diabetes remains uncertain. We tested whether chronic mild hyperuricemia in rodents under controlled laboratory conditions can cause glucose intolerance in otherwise healthy animals, or whether it can worsen glucometabolic control in animals that are genetically predisposed to T2DM. We used an established model of experimental hyperuricemia in rodents with potassium oxonate dietary supplementation, which led to sustained, approximately two-fold elevation of uric acid compared with control animals. We also reversed the hyperuricemic effect of oxonate in some animals by treatment with a xanthine oxidase inhibitor. Manipulation of serum uric acid levels in Sprague-Dawley rats for up to 18 weeks did not affect fasting glucose and glucose tolerance. Blood pressure was also not affected by hyperuricemia in rats fed a Western-type diet. We next sought to determine whether uric acid may aggravate or accelerate the onset of glucometabolic abnormalities in rats already predisposed to T2DM. Chronic oxonate treatment in Zucker diabetic fatty (ZDF) and lean control rats for up to 6 weeks did not affect fasting glucose, insulin, and glucose tolerance in ZDF rats. Taken together, these findings indicate that elevated uric acid does not directly contribute to the pathogenesis of glucose intolerance and T2DM in rodents.

Presaturation Power Adjusted Pulsed CEST: A Method to Increase Independence of Target CEST Signals.

Chemical exchange saturation transfer (CEST) imaging has been demonstrated to discuss the concentration changes of amide proton, glutamate, creatine, or glucose measured at 3.5, 3.0, 2.0, and 1.0-1.2 ppm. However, these peaks in z-spectra are quite broad and overlap with each other, and thus, the independence of a CEST signal on any specific metabolite is still open to question. Here, we described whether there was interference among the CEST signals and how these CEST signals behave when the power of the presaturation pulse was changed. Based on these results, further experiments were designed to investigate a method to increase the independence of the CEST signal in both phantoms and animals. The result illustrates a clear interference among CEST signals. A presaturation power adjusted pulsed- (PPAP-) CEST method which was designed based on the exchange rates of the metabolites can be used to remove contributions from other exchanging species in the same sample. Further, the method was shown to improve the independence of the glutamate signal in vivo in the renal medulla in mice. The PPAP-CEST method has the potential to increase the independence of any target CEST signals in vivo by choosing the appropriate combination of pulse amplitudes and durations.

TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer.

Although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is effective only in a subset of non-small cell lung cancer (NSCLC) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. TNF is a major mediator of inflammation-induced cancer. We find that a rapid increase in TNF level is a universal adaptive response to EGFR inhibition in NSCLC, regardless of EGFR status. EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21, resulting in decreased TNF mRNA stability. Conversely, EGFR inhibition results in loss of miR-21 and increased TNF mRNA stability. In addition, TNF-induced NF-κB activation leads to increased TNF transcription in a feed-forward loop. Inhibition of TNF signaling renders EGFRwt-expressing NSCLC cell lines and an EGFRwt patient-derived xenograft (PDX) model highly sensitive to EGFR inhibition. In EGFR-mutant oncogene-addicted cells, blocking TNF enhances the effectiveness of EGFR inhibition. EGFR plus TNF inhibition is also effective in NSCLC with acquired resistance to EGFR inhibition. We suggest concomitant EGFR and TNF inhibition as a potentially new treatment approach that could be beneficial for a majority of lung cancer patients.

Biomimetic nanoparticles with enhanced affinity towards activated endothelium as versatile tools for theranostic drug delivery.

Activation of the vascular endothelium is characterized by increased expression of vascular adhesion molecules and chemokines. This activation occurs early in the progression of several diseases and triggers the recruitment of leukocytes. Inspired by the tropism of leukocytes, we investigated leukocyte-based biomimetic nanoparticles (i.e., leukosomes) as a novel theranostic platform for inflammatory diseases. Methods: Leukosomes were assembled by combining phospholipids and membrane proteins from leukocytes. For imaging applications, phospholipids modified with rhodamine and gadolinium were used. Leukosomes incubated with antibodies blocking lymphocyte function-associated antigen 1 (LFA-1) and CD45 were administered to explore their roles in targeting inflammation. In addition, relaxometric assessment of NPs was evaluated. Results: Liposomes and leukosomes were both spherical in shape with sizes ranging from 140-170 nm. Both NPs successfully integrated 8 and 13 µg of rhodamine and gadolinium, respectively, and demonstrated less than 4% variation in physicochemical features. Leukosomes demonstrated a 16-fold increase in breast tumor accumulation relative to liposomes. Furthermore, quantification of leukosomes in tumor vessels demonstrated a 4.5-fold increase in vessel lumens and a 14-fold increase in vessel walls. Investigating the targeting mechanism of action revealed that blockage of LFA-1 on leukosomes resulted in a 95% decrease in tumor accumulation. Whereas blockage of CD45 yielded a 60% decrease in targeting and significant increases in liver and spleen accumulation. In addition, when administered in mice with atherosclerotic plaques, leukosomes exhibited a 4-fold increase in the targeting of inflammatory vascular lesions. Lastly, relaxometric assessment of NPs demonstrated that the incorporation of membrane proteins into leukosomes did not impact the r1 and r2 relaxivities of the NPs, demonstrating 6 and 30 mM-1s-1, respectively. Conclusion: Our study demonstrates the ability of leukosomes to target activated vasculature and exhibit superior accumulation in tumors and vascular lesions. The versatility of the phospholipid backbone within leukosomes permits the incorporation of various contrast agents. Furthermore, leukosomes can potentially be loaded with therapeutics possessing diverse physical properties and thus warrant further investigation toward the development of powerful theranostic agents.

Dual-Drug Containing Core-Shell Nanoparticles for Lung Cancer Therapy.

Late-stage diagnosis of lung cancer occurs ~95% of the time due to late manifestation of its symptoms, necessitating rigorous treatment following diagnosis. Existing treatment methods are limited by lack of specificity, systemic toxicity, temporary remission, and radio-resistance in lung cancer cells. In this research, we have developed a folate receptor-targeting multifunctional dual drug-loaded nanoparticle (MDNP) containing a poly(N-isopropylacrylamide)-carboxymethyl chitosan shell and poly lactic-co-glycolic acid (PLGA) core for enhancing localized chemo-radiotherapy to effectively treat lung cancers. The formulation provided controlled releases of the encapsulated therapeutic compounds, NU7441 - a potent radiosensitizer, and gemcitabine - an FDA approved chemotherapeutic drug for lung cancer chemo-radiotherapy. The MDNPs showed biphasic NU7441 release and pH-dependent release of gemcitabine. These nanoparticles also demonstrated good stability, excellent hemocompatibility, outstanding in vitro cytocompatibility with alveolar Type I cells, and dose-dependent caveolae-mediated in vitro uptake by lung cancer cells. In addition, they could be encapsulated with superparamagnetic iron oxide (SPIO) nanoparticles and visualized by MRI in vivo. Preliminary in vivo results demonstrated the low toxicity of these particles and their use in chemo-radiotherapy to effectively reduce lung tumors. These results indicate that MDNPs can potentially be used as nano-vehicles to provide simultaneous chemotherapy and radiation sensitization for lung cancer treatment.

Calcium-Induced Morphological Transitions in Peptide Amphiphiles Detected by 19F-Magnetic Resonance Imaging.

Misregulation of extracellular Ca2+ can indicate bone-related pathologies. New, noninvasive tools are required to image Ca2+ fluxes and fluorine magnetic resonance imaging (19F-MRI) is uniquely suited to this challenge. Here, we present three, highly fluorinated peptide amphiphiles that self-assemble into nanoribbons in buffered saline and demonstrate these nanostructures can be programmed to change 19F-NMR signal intensity as a function of Ca2+ concentration. We determined these nanostructures show significant reduction in 19F-NMR signal as nanoribbon width increases in response to Ca2+, corresponding to 19F-MR image intensity reduction. Thus, these peptide amphiphiles can be used to quantitatively image biologically relevant Ca2+ concentrations.

Laquinimod has no effects on brain volume or cellular CNS composition in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease.

BACKGROUND: Laquinimod is an anti-inflammatory agent with good central nervous system (CNS) bioavailability, and neuroprotective and myelorestorative properties. A clinical trial in patients with multiple sclerosis demonstrated that laquinimod significantly reduced loss of brain volume. The cellular substrate or molecular events underlying that treatment effect are unknown. In this study, we aimed to explore laquinimod's potential effects on brain volume, animal behavior, cellular numbers and composition of CNS-intrinsic cells and mononuclear cells within the CNS, amyloid beta (Aß) accumulation and tau phosphorylation in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. METHODS: Utilizing a dose response study design, four months old F1 3xTg-AD/C3H mice were treated for 10months between ages 4 and 14months with laquinimod (5, 10, or 25mg/kg), or PBS administered by oral gavage. Brain volumes were measured in a 7 Tesla magnetic resonance imager (MRI) at ages 4 and 14months. Behavioral testing included locomotor and rearing activity and the Morris water maze task. Cell numbers and immunophenotypes were assessed by multiparameter flow cytometry. Aß deposition and tau phosphorylation were determined by immunohistochemistry. RESULTS: In the F1 3xTg-AD/C3H animal model of AD, there was no detectable reduction of brain volume over a period of 10months of treatment, as there was not brain atrophy in any of the placebo or treatment groups. Laquinimod had no detectable effects on most neurobehavioral outcomes. The number or composition of CNS intrinsic cells and mononuclear subsets isolated from the CNS were not altered by laquinimod. CONCLUSION: This is the first demonstration that there are no age-associated brain volume changes in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Consequently, laquinimod had no effect on that outcome of this study. Most secondary outcomes on the effects of laquinimod on behavior and the number and composition of CNS-intrinsic cells and mononuclear cells within the CNS were also negative.

Interactions of Renal-Clearable Gold Nanoparticles with Tumor Microenvironments: Vasculature and Acidity Effects.

The success of nanomedicines in the clinic depends on our comprehensive understanding of nano-bio interactions in tumor microenvironments, which are characterized by dense leaky microvasculature and acidic extracellular pH (pHe ) values. Herein, we investigated the accumulation of ultrasmall renal-clearable gold NPs (AuNPs) with and without acidity targeting in xenograft mouse models of two prostate cancer types, PC-3 and LNCaP, with distinct microenvironments. Our results show that both sets of AuNPs could easily penetrate into the tumors but their uptake and retention were mainly dictated by the tumor microvasculature and the enhanced permeability and retention effect over the entire targeting process. On the other hand, increased tumor acidity indeed enhanced the uptake of AuNPs with acidity targeting, but only for a limited period of time. By making use of simple surface chemistry, these two effects can be synchronized in time for high tumor targeting, opening new possibilities to further improve the targeting efficiencies of nanomedicines.

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist.

The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit, COL6A1, has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury.