Calcium handling dysfunction and cardiac damage following acute ventricular preload challenge in the dystrophin-deficient mouse heart.

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and is caused by mutations in the dystrophin gene. Dystrophin deficiency is associated with structural and functional changes of the muscle cell sarcolemma and/or stretch-induced ion channel activation. In this investigation, we use mice with transgenic cardiomyocyte-specific expression of the GCaMP6f Ca2+ indicator to test the hypothesis that dystrophin deficiency leads to cardiomyocyte Ca2+ handling abnormalities following preload challenge. α-MHC-MerCreMer-GCaMP6f transgenic mice were developed on both a wild-type (WT) or dystrophic (Dmdmdx-4Cv) background. Isolated hearts of 3-7-mo male mice were perfused in unloaded Langendorff mode (0 mmHg) and working heart mode (preload = 20 mmHg). Following a 30-min preload challenge, hearts were perfused in unloaded Langendorff mode with 40 µM blebbistatin, and GCaMP6f was imaged using confocal fluorescence microscopy. Incidence of premature ventricular complexes (PVCs) was monitored before and following preload elevation at 20 mmHg. Hearts of both wild-type and dystrophic mice exhibited similar left ventricular contractile function. Following preload challenge, dystrophic hearts exhibited a reduction in GCaMP6f-positive cardiomyocytes and an increase in number of cardiomyocytes exhibiting Ca2+ waves/overload. Incidence of cardiac arrhythmias was low in both wild-type and dystrophic hearts during unloaded Langendorff mode. However, after preload elevation to 20-mmHg hearts of dystrophic mice exhibited an increased incidence of PVCs compared with hearts of wild-type mice. In conclusion, these data indicate susceptibility to preload-induced Ca2+ overload, ventricular damage, and ventricular dysfunction in male Dmdmdx-4Cv hearts. Our data support the hypothesis that cardiomyocyte Ca2+ overload underlies cardiac dysfunction in muscular dystrophy.NEW & NOTEWORTHY The mechanisms of cardiac disease progression in muscular dystrophy are complex and poorly understood. Using a transgenic mouse model with cardiomyocyte-specific expression of the GCaMP6f Ca2+ indicator, the present study provides further support for the Ca2+-overload hypothesis of disease progression and ventricular arrhythmogenesis in muscular dystrophy.

Cardiac Myocyte-Specific Overexpression of FASTKD1 Prevents Ventricular Rupture After Myocardial Infarction.

Background The mitochondrial mRNA-binding protein FASTKD1 (Fas-activated serine/threonine [FAST] kinase domain-containing protein 1) protects myocytes from oxidative stress in vitro. However, the role of FASTKD1 in the myocardium in vivo is unknown. Therefore, we developed cardiac-specific FASTKD1 transgenic mice to test the effects of this protein on experimental myocardial infarction (MI). Methods and Results Transgenic mouse lines with cardiac myocyte-specific overexpression of FASTKD1 to varying degrees were generated. These mice displayed normal cardiac morphological features and function at the gross and microscopic levels. Isolated cardiac mitochondria from all transgenic mouse lines showed normal mitochondrial function, ATP levels, and permeability transition pore activity. Male nontransgenic and transgenic mice from the highest-expressing line were subjected to 8 weeks of permanent coronary ligation. Of nontransgenic mice, 40% underwent left ventricular free wall rupture within 7 days of MI compared with 0% of FASTKD1-overexpressing mice. At 3 days after MI, FASTKD1 overexpression did not alter infarct size. However, increased FASTKD1 resulted in decreased neutrophil and increased macrophage infiltration, elevated levels of the extracellular matrix component periostin, and enhanced antioxidant capacity compared with control mice. In contrast, markers of mitochondrial fusion/fission and apoptosis remained unaltered. Instead, transcriptomic analyses indicated activation of the integrated stress response in the FASTKD1 transgenic hearts. Conclusions Cardiac-specific overexpression of FASTKD1 results in viable mice displaying normal cardiac morphological features and function. However, these mice are resistant to MI-induced cardiac rupture and display altered inflammatory, extracellular matrix, and antioxidant responses following MI. Moreover, these protective effects were associated with enhanced activation of the integrated stress response.

A Trinuclear High-Spin Iron(III) Complex with a Geometrically Frustrated Spin Ground State Featuring Negligible Magnetic Anisotropy and Antisymmetric Exchange.

The trinuclear high-spin iron(III) complex [Fe3Cl3(saltagBr)(py)6]ClO4 {H5saltagBr = 1,2,3-tris[(5-bromo-salicylidene)amino]guanidine} was synthesized and characterized by several experimental and theoretical methods. The iron(III) complex exhibits molecular 3-fold symmetry imposed by the rigid ligand backbone and crystallizes in trigonal space group P3̅ with the complex cation lying on a crystallographic C3 axis. The high-spin states (S = 5/2) of the individual iron(III) ions were determined by Mößbauer spectroscopy and confirmed by CASSCF/CASPT2 ab initio calculations. Magnetic measurements show an antiferromagnetic exchange between the iron(III) ions leading to a geometrically spin-frustrated ground state. This was complemented by high-field magnetization experiments up to 60 T, which confirm the isotropic nature of the magnetic exchange and negligible single-ion anisotropy for the iron(III) ions. Muon-spin relaxation experiments were performed and further prove the isotropic nature of the coupled spin ground state and the presence of isolated paramagnetic molecular systems with negligible intermolecular interactions down to 20 mK. Broken-symmetry density functional theory calculations are consistent with the antiferromagnetic exchange between the iron(III) ions within the presented trinuclear high-spin iron(III) complex. Ab initio calculations further support the absence of appreciable magnetic anisotropy (D = 0.086, and E = 0.010 cm-1) and the absence of significant contributions from antisymmetric exchange, as the two Kramers doublets are virtually degenerate (ΔE = 0.005 cm-1). Therefore, this trinuclear high-spin iron(III) complex should be an ideal candidate for further investigations of spin-electric effects arising exclusively from the spin chirality of a geometrically frustrated S = 1/2 spin ground state of the molecular system.

Suppression of estrogen receptor beta classical genomic activity enhances systemic and adipose-specific response to chronic beta-3 adrenergic receptor (ß3AR) stimulation.

White adipose tissue (WAT) dysfunction independently predicts cardiometabolic disease, yet there is a lack of effective adipocyte-targeting therapeutics. B3AR agonists enhance adipocyte mitochondrial function and hold potential in this regard. Based on enhanced sensitivity to B3AR-mediated browning in estrogen receptor (ER)alpha-null mice, we hypothesized that ERß may enhance the WAT response to the B3AR ligand, CL316,243 (CL). Methods: Male and female wild-type (WT) and ERß DNA binding domain knock-out (ERßDBDKO) mice fed high-fat diet (HFD) to induce obesity were administered CL (1 mg/kg) daily for 2 weeks. Systemic physiological assessments of body composition (EchoMRI), bioenergetics (metabolic chambers), adipocyte mitochondrial respiration (oroboros) and glucose tolerance were performed, alongside perigonadal (PGAT), subcutaneous (SQAT) and brown adipose tissue (BAT) protein expression assessment (Western blot). Mechanisms were tested in vitro using primary adipocytes isolated from WT mice, and from Esr2-floxed mice in which ERß was knocked down. Statistical analyses were performed using 2 × 2 analysis of variance (ANOVA) for main effects of genotype (G) and treatment (T), as well as GxT interactions; t-tests were used to determine differences between in vitro treatment conditions (SPSS V24). Results: There were no genotype differences in HFD-induced obesity or systemic rescue effects of CL, yet ERßDBDKO females were more sensitive to CL-induced increases in energy expenditure and WAT UCP1 induction (GxT, p < 0.05), which coincided with greater WAT B3AR protein content among the KO (G, p < 0.05). Among males, who were more insulin resistant to begin with (no genotype differences before treatment), tended to be more sensitive to CL-mediated reduction in insulin resistance. With sexes combined, basal WAT mitochondrial respiration trended toward being lower in the ERßDBDKO mice, but this was completely rescued by CL (p < 0.05). Confirming prior work, CL increased adipose tissue ERß protein (T, p < 0.05, all), an effect that was enhanced in WAT and BAT the female KO (GxT, p < 0.01). In vitro experiments indicated that an inhibitor of ERß genomic function (PHTPP) synergized with CL to further increase UCP1 mRNA (p = 0.043), whereas full ERß protein was required for UCP1 expression (p = 0.042). Conclusion: Full ERß activity appears requisite and stimulatory for UCP1 expression via a mechanism involving non-classical ERß signaling. This novel discovery about the role of ERß in adipocyte metabolism may have important clinical applications.

Intrinsically Disordered N-terminal Domain (NTD) of p53 Interacts with Mitochondrial PTP Regulator Cyclophilin D.

Mitochondrial permeability transition pore (mPTP) plays crucial roles in cell death in a variety of diseases, including ischemia/reperfusion injury in heart attack and stroke, neurodegenerative conditions, and cancer. To date, cyclophilin D is the only confirmed component of mPTP. Under stress, p53 can translocate into mitochondria and interact with CypD, triggering necrosis and cell growth arrest. However, the molecular details of p53/CypD interaction are still poorly understood. Previously, several studies reported that p53 interacts with CypD through its DNA-binding domain (DBD). However, using surface plasmon resonance (SPR), we found that both NTD-DBD, NTD and NTD (1-70) bind to CypD at ∼µM KD. In solution NMR, NTD binds CypD with µM affinity and mimics the pattern of FLp53 binding in chemical shift perturbation. In contrast, neither solution NMR nor fluorescence anisotropy detected DBD binding to CypD. Thus, instead of DBD, NTD is the major CypD binding site on p53. NMR titration and MD simulation revealed that NTD binds CypD with broad and dynamic interfaces dominated by electrostatic interactions. NTD 20-70 was further identified as the minimal binding region for CypD interaction, and two NTD fragments, D1 (residues 22-44) and D2 (58-70), can each bind CypD with mM affinity. Our detailed biophysical characterization of the dynamic interface between NTD and CypD provides novel insights on the p53-dependent mPTP opening and drug discovery targeting NTD/CypD interface in diseases.

Unconventional Pressure Dependence of the Superfluid Density in the Nodeless Topological Superconductor α-PdBi_{2}.

We investigated the superconducting properties of the topological superconductor α-PdBi_{2} at ambient and external pressures up to 1.77 GPa using muon spin rotation experiments. The ambient pressure measurements evince a fully gapped s-wave superconducting state in the bulk of the specimen. Alternating current magnetic susceptibility and muon spin rotation measurements manifest a continuous suppression of T_{c} with increasing pressure. In parallel, we observed a significant decrease of superfluid density by ∼20% upon application of external pressure. Remarkably, the superfluid density follows a linear relation with T_{c}, which was found before in some unconventional topological superconductors and hole-doped cuprates. This finding signals a possible crossover from Bose-Einstein to Bardeen-Cooper-Schrieffer like condensation in α-PdBi_{2}.

Magnetic Field Induced Quantum Spin Liquid in the Two Coupled Trillium Lattices of K_{2}Ni_{2}(SO_{4})_{3}.

Quantum spin liquids are exotic states of matter that form when strongly frustrated magnetic interactions induce a highly entangled quantum paramagnet far below the energy scale of the magnetic interactions. Three-dimensional cases are especially challenging due to the significant reduction of the influence of quantum fluctuations. Here, we report the magnetic characterization of K_{2}Ni_{2}(SO_{4})_{3} forming a three-dimensional network of Ni^{2+} spins. Using density functional theory calculations, we show that this network consists of two interconnected spin-1 trillium lattices. In the absence of a magnetic field, magnetization, specific heat, neutron scattering, and muon spin relaxation experiments demonstrate a highly correlated and dynamic state, coexisting with a peculiar, very small static component exhibiting a strongly renormalized moment. A magnetic field B≳4 T diminishes the ordered component and drives the system into a pure quantum spin liquid state. This shows that a system of interconnected S=1 trillium lattices exhibits a significantly elevated level of geometrical frustration.

Role of ERß in adipocyte metabolic response to wheel running following ovariectomy.

Estrogen receptor ß (ERb), one of the two major estrogen receptors, acts via genomic and non-genomic signaling pathways to affect many metabolic functions, including mitochondrial biogenesis and respiration. This study assessed the effect of ERb classical genomic activity on adipocyte-specific and -systemic metabolic responses to wheel running exercise in a rodent model of menopause. Female mice lacking the ERb DNA-binding domain (ERbDBDKO, n = 20) and WT (n = 21) littermate controls were fed a high-fat diet (HFD), ovariectomized (OVX), and randomized to control (no running wheel) and exercise (running wheel access) groups and were followed for 8 weeks. Wheel running did not confer protection against metabolic dysfunction associated with HFD+OVX in either ERbDBDKO or WT mice, despite increased energy expenditure. Unexpectedly, in the ERbDBDKO group, wheel running increased fasting insulin and surrogate measures of insulin resistance, and modestly increased adipose tissue inflammatory gene expression (P ≤ 0.05). These changes were not accompanied by significant changes in adipocyte mitochondrial respiration. It was demonstrated for the first time that female WT OVX mice do experience exercise-induced browning of white adipose tissue, indicated by a robust increase in uncoupling protein 1 (UCP1) (P ≤ 0.05). However, KO mice were completely resistant to this effect, indicating that full ERb genomic activity is required for exercise-induced browning. The inability to upregulate UCP1 with exercise following OVX may have resulted in the increased insulin resistance observed in KO mice, a hypothesis requiring further investigation.

Quantum spin-liquid states in an organic magnetic layer and molecular rotor hybrid.

The exotic properties of quantum spin liquids (QSLs) have continually been of interest since Anderson's 1973 ground-breaking idea. Geometrical frustration, quantum fluctuations, and low dimensionality are the most often evoked material's characteristics that favor the long-range fluctuating spin state without freezing into an ordered magnet or a spin glass at low temperatures. Among the few known QSL candidates, organic crystals have the advantage of having rich chemistry capable of finely tuning their microscopic parameters. Here, we demonstrate the emergence of a QSL state in [EDT-TTF-CONH2]2 +[[Formula: see text]] (EDT-BCO), where the EDT molecules with spin-1/2 on a triangular lattice form layers which are separated by a sublattice of BCO molecular rotors. By several magnetic measurements, we show that the subtle random potential of frozen BCO Brownian rotors suppresses magnetic order down to the lowest temperatures. Our study identifies the relevance of disorder in the stabilization of QSLs.

Subcellular NAMPT-mediated NAD+ salvage pathways and their roles in bioenergetics and neuronal protection after ischemic injury.

NAD+ is a cofactor required for glycolysis, tricarboxylic acid cycle, and complex I enzymatic reaction. In mammalian cells, NAD+ is predominantly synthesized through the salvage pathway, where nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme. Previously, we demonstrated that NAMPT exerts a neuroprotective effect in ischemia through the suppression of mitochondrial dysfunction. Mammalian cells maintain distinct NAD+ pools in the cytosol, mitochondria, and nuclei. However, it is unknown whether mitochondria have an intact machinery for NAD+ salvage, and if so, whether it plays a dominant role in bioenergetics, mitochondrial function, and neuronal protection after ischemia. Here, using mouse primary cortical neuron and cortical tissue preparations, and multiple technologies including cytosolic and mitochondrial subfractionation, viral over-expression of transgenes, molecular biology, and confocal microscopy, we provided compelling evidence that neuronal mitochondria possess an intact machinery of NAMPT-mediated NAD+ salvage pathway, and that NAMPT and nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) are localized in the mitochondrial matrix. By knocking down NMNAT1-3 and NAMPT with siRNA, we found that NMNAT3 has a larger effect on basal and ATP production-related mitochondrial respiration than NMNAT1-2 in primary cultured neurons, while NMNAT1-2 have a larger effect on glycolytic flux than NMNAT3. Using an oxygen glucose deprivation model, we found that mitochondrial, cytoplasmic, and non-subcellular compartmental over-expressions of NAMPT have a comparable effect on neuronal protection and suppression of apoptosis-inducing factor translocation. The current study provides novel insights into the roles of subcellular compartmental NAD+ salvage pathways in NAD+ homeostasis, bioenergetics, and neuronal protection in ischemic conditions.

Guidelines for evaluating myocardial cell death.

Cell death is a fundamental process in cardiac pathologies. Recent studies have revealed multiple forms of cell death, and several of them have been demonstrated to underlie adverse cardiac remodeling and heart failure. With the expansion in the area of myocardial cell death and increasing concerns over rigor and reproducibility, it is important and timely to set a guideline for the best practices of evaluating myocardial cell death. There are six major forms of regulated cell death observed in cardiac pathologies, namely apoptosis, necroptosis, mitochondrial-mediated necrosis, pyroptosis, ferroptosis, and autophagic cell death. In this article, we describe the best methods to identify, measure, and evaluate these modes of myocardial cell death. In addition, we discuss the limitations of currently practiced myocardial cell death mechanisms.

Western Diet-Fed, Aortic-Banded Ossabaw Swine: A Preclinical Model of Cardio-Metabolic Heart Failure.

The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile of this patient population. This report provides evidence supporting the hypothesis that Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure. This new preclinical animal model displays a distinctive constellation of findings that are conceivably useful to extending the understanding of how pre-existing cardio-metabolic syndrome can contribute to developing HF.

The novel cyclophilin-D-interacting protein FASTKD1 protects cells against oxidative stress-induced cell death.

Opening of the mitochondrial permeability transition (MPT) pore leads to necrotic cell death. Excluding cyclophilin D (CypD), the makeup of the MPT pore remains conjecture. The purpose of these experiments was to identify novel MPT modulators by analyzing proteins that associate with CypD. We identified Fas-activated serine/threonine phosphoprotein kinase domain-containing protein 1 (FASTKD1) as a novel CypD interactor. Overexpression of FASTKD1 protected mouse embryonic fibroblasts (MEFs) against oxidative stress-induced reactive oxygen species (ROS) production and cell death, whereas depletion of FASTKD1 sensitized them. However, manipulation of FASTKD1 levels had no effect on MPT responsiveness, Ca2+-induced cell death, or antioxidant capacity. Moreover, elevated FASTKD1 levels still protected against oxidative stress in CypD-deficient MEFs. FASTKD1 overexpression decreased Complex-I-dependent respiration and ΔΨm in MEFs, effects that were abrogated in CypD-null cells. Additionally, overexpression of FASTKD1 in MEFs induced mitochondrial fragmentation independent of CypD, activation of Drp1, and inhibition of autophagy/mitophagy, whereas knockdown of FASTKD1 had the opposite effect. Manipulation of FASTKD1 expression also modified oxidative stress-induced caspase-3 cleavage yet did not alter apoptotic death. Finally, the effects of FASTKD1 overexpression on oxidative stress-induced cell death and mitochondrial morphology were recapitulated in cultured cardiac myocytes. Together, these data indicate that FASTKD1 supports mitochondrial homeostasis and plays a critical protective role against oxidant-induced death.

TRPV4 increases cardiomyocyte calcium cycling and contractility yet contributes to damage in the aged heart following hypoosmotic stress.

Aims: Cardiomyocyte Ca2+ homeostasis is altered with aging via poorly-understood mechanisms. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an osmotically-activated Ca2+ channel, and there is limited information on the role of TRPV4 in cardiomyocytes. Our data show that TRPV4 protein expression increases in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in cardiomyocyte Ca2+ homeostasis following hypoosmotic stress and to assess the contribution of TRPV4 to cardiac contractility and tissue damage following ischaemia-reperfusion (I/R), a pathological condition associated with cardiomyocyte osmotic stress. Methods and results: TRPV4 protein expression increased in cardiomyocytes of Aged (24-27 months) mice compared with Young (3-6 months) mice. Immunohistochemistry revealed TRPV4 localization to microtubules and the t-tubule network of cardiomyocytes of Aged mice, as well as in left ventricular myocardium of elderly patients undergoing surgical aortic valve replacement for aortic stenosis. Following hypoosmotic stress, cardiomyocytes of Aged, but not Young exhibited an increase in action-potential induced Ca2+ transients. This effect was mediated via increased sarcoplasmic reticulum Ca2+ content and facilitation of Ryanodine Receptor Ca2+ release and was prevented by TRPV4 antagonism (1 µmol/L HC067047). A similar hypoosmotic stress-induced facilitation of Ca2+ transients was observed in Young transgenic mice with inducible TRPV4 expression in cardiomyocytes. Following I/R, isolated hearts of Young mice with transgenic TRPV4 expression exhibited enhanced contractility vs. hearts of Young control mice. Similarly, hearts of Aged mice exhibited enhanced contractility vs. hearts of Aged TRPV4 knock-out (TRPV4-/-) mice. In Aged, pharmacological inhibition of TRPV4 (1 µmol/L, HC067047) prevented hypoosmotic stress-induced cardiomyocyte death and I/R-induced cardiac damage. Conclusions: Our findings provide a new mechanism for hypoosmotic stress-induced cardiomyocyte Ca2+ entry and cell damage in the aged heart. These finding have potential implications in treatment of elderly populations at increased risk of myocardial infarction and I/R injury.

Hypoxia activates a neuropeptidergic pathway from the paraventricular nucleus of the hypothalamus to the nucleus tractus solitarii.

The paraventricular nucleus of the hypothalamus (PVN) contributes to both autonomic and neuroendocrine function. PVN lesion or inhibition blunts cardiorespiratory responses to peripheral chemoreflex activation, suggesting that the PVN is required for full expression of these effects. However, the role of efferent projections to cardiorespiratory nuclei and the neurotransmitters/neuromodulators that are involved is unclear. The PVN sends dense projections to the nucleus tractus solitarii (nTS), a region that displays neuronal activation following hypoxia. We hypothesized that acute hypoxia activates nTS-projecting PVN neurons. Using a combination of retrograde tracing and immunohistochemistry, we determined whether hypoxia activates PVN neurons that project to the nTS and examined the phenotype of these neurons. Conscious rats underwent 2 h normoxia (21% O2, n = 5) or hypoxia (10% O2, n = 6). Hypoxia significantly increased Fos immunoreactivity in nTS-projecting neurons, primarily in the caudal PVN. The majority of activated nTS-projecting neurons contained corticotropin-releasing hormone (CRH). In the nTS, fibers expressing the CRH receptor corticotropin-releasing factor receptor 2 (CRFR2) were colocalized with oxytocin (OT) fibers and were closely associated with hypoxia-activated nTS neurons. A separate group of animals that received a microinjection of adeno-associated virus type 2-hSyn-green fluorescent protein (GFP) into the PVN exhibited GFP-expressing fibers in the nTS; a proportion of these fibers displayed OT immunoreactivity. Thus, nTS CRFR2s appear to be located on the fibers of PVN OT neurons that project to the nTS. Taken together, our findings suggest that PVN CRH projections to the nTS may modulate nTS neuronal activation, possibly via OTergic mechanisms, and thus contribute to chemoreflex cardiorespiratory responses.

The still uncertain identity of the channel-forming unit(s) of the mitochondrial permeability transition pore.

Mitochondria from different organisms can undergo a sudden process of inner membrane unselective leakiness to molecules known as the mitochondrial permeability transition (MPT). This process has been studied for nearly four decades and several proteins have been claimed to constitute, or at least regulate the usually inactive pore responsible for this transition. However, no protein candidate proposed as the actual pore-forming unit has passed rigorous gain- or loss-of-function genetic tests. Here we review evidence for -and against- putative channel-forming components of the MPT pore. We conclude that the structure of the MPT pore still remains largely undefined and suggest that future studies should follow established technical considerations to unambiguously consolidate the channel forming constituent(s) of the MPT pore.

Implications of bond disorder in a S=1 kagome lattice.

Strong hydrogen bonds such as F···H···F offer new strategies to fabricate molecular architectures exhibiting novel structures and properties. Along these lines and, to potentially realize hydrogen-bond mediated superexchange interactions in a frustrated material, we synthesized [H2F]2[Ni3F6(Fpy)12][SbF6]2 (Fpy = 3-fluoropyridine). It was found that positionally-disordered H2F+ ions link neutral NiF2(Fpy)4 moieties into a kagome lattice with perfect 3-fold rotational symmetry. Detailed magnetic investigations combined with density-functional theory (DFT) revealed weak antiferromagnetic interactions (J ~ 0.4 K) and a large positive-D of 8.3 K with ms = 0 lying below ms = ±1. The observed weak magnetic coupling is attributed to bond-disorder of the H2F+ ions which leads to disrupted Ni-F···H-F-H···F-Ni exchange pathways. Despite this result, we argue that networks such as this may be a way forward in designing tunable materials with varying degrees of frustration.

Fascin2 regulates cisplatin-induced apoptosis in NRK-52E cells.

Previous studies have shown that the aging kidney has a marked loss of α(E)-catenin in proximal tubular epithelium. α-Catenin, a key regulator of the actin cytoskeleton, interacts with a variety of actin-binding proteins. Cisplatin-induced loss of fascin2, an actin bundling protein, was observed in cells with a stable knockdown of α(E)-catenin (C2 cells), as well as in aging (24 mon), but not young (4 mon), kidney. Fascin2 co-localized with α-catenin and the actin cytoskeleton in NRK-52E cells. Knockdown of fascin2 increased the susceptibility of tubular epithelial cells to cisplatin-induced injury. Overexpression of fascin2 in C2 cells restored actin stress fibers and attenuated the increased sensitivity of C2 cells to cisplatin-induced apoptosis. Interestingly, fascin2 overexpression attenuated cisplatin-induced mitochondrial dysfunction and oxidative stress in C2 cells. These data demonstrate that fascin2, a putative target of α(E)-catenin, may play important role in preventing cisplatin-induced acute kidney injury.