Cn Activity Research Articles

Facile synthesis of vinyl sulfoxides via external oxidant-free oxidative condensation of phenylglycinols with DMSO

Oxidative activation of CO, CN and CC bonds has recently emerged as a powerful method for the synthesis of valuable organic compounds. However, these strategies have often required the metal catalysts and strong external oxidants. Herein, we report a new protocol for the convenient construction of vinyl sulfoxides from phenylglycinols and DMSO under basic conditions. Notably, DMSO was used not only as a methyl sulfoxide (−SOMe) reagent, but also as an oxidizing agent. The present system features mild metal- and external oxidant-free conditions, broad scope, and excellent functionality tolerance.

Hierarchical differences in the encoding of amplitude modulation in the subcortical auditory system of awake nonhuman primates.

Sinusoidal amplitude modulation (SAM) is a key feature of complex sounds. Although psychophysical studies have characterized SAM perception, and neurophysiological studies in anesthetized animals report a transformation from the cochlear nucleus' (CN; brainstem) temporal code to the inferior colliculus' (IC; midbrain's) rate code, none have used awake animals or nonhuman primates to compare CN and IC's coding strategies to modulation-frequency perception. To address this, we recorded single-unit responses and compared derived neurometric measures in the CN and IC to psychometric measures of modulation frequency (MF) discrimination in macaques. IC and CN neurons often exhibited tuned responses to SAM in rate and spike-timing measures of modulation coding. Neurometric thresholds spanned a large range (2-200 Hz ΔMF). The lowest 40% of IC thresholds were less than or equal to psychometric thresholds, regardless of which code was used, whereas CN thresholds were greater than psychometric thresholds. Discrimination at 10-20 Hz could be explained by indiscriminately pooling 30 units in either structure, whereas discrimination at higher MFs was best explained by more selective pooling. This suggests that pooled CN activity was sufficient for AM discrimination. Psychometric and neurometric thresholds decreased as stimulus duration increased, but IC and CN thresholds were higher and more variable than behavior at short durations. This slower subcortical temporal integration compared with behavior was consistent with a drift diffusion model that reproduced individual differences in performance and can constrain future neurophysiological studies of temporal integration. These measures provide an account of AM perception at the neurophysiological, computational, and behavioral levels.NEW & NOTEWORTHY In everyday environments, the brain is tasked with extracting information from sound envelopes, which involves both sensory encoding and perceptual decision-making. Different neural codes for envelope representation have been characterized in midbrain and cortex, but studies of brainstem nuclei such as the cochlear nucleus (CN) have usually been conducted under anesthesia in nonprimate species. Here, we found that subcortical activity in awake monkeys and a biologically plausible perceptual decision-making model accounted for sound envelope discrimination behavior.

Enhancing visible light photocatalytic activity of holmium doped g-C3N4 and DFT theoretical insights

In the search of novel photocatalysts to increase the effect of visible light in photocatalysis, g-C3N4 (CN) has become a shining star. Rare earth metals have been used as dopant material to reinforce the photocatalytic activity of CN due to their unique electron configuration recently. In this present study, the pure and different amounts of Ho-doped g-C3N4 (HoCN) photocatalysts were successfully synthesized using urea as a precursor by the one-pot method. Morphological, structural, optical, and vibrational properties of the synthesized photocatalysts were characterized by SEM, EDX, XRD, TGA, XPS, FTIR, PL, TRPL, Raman, DRS, and BET analyses. In addition, theoretical calculations using density functional theory (DFT) were meticulously carried out to delve the changes in the structural and electronic structure of CN with holmium doping. According to calculations, the chemical potential, electrophilicity, and chemical softness are higher for HoCN, while HOMO–LUMO gap, dipole moment, and the chemical hardness are lower for the pure one. Thus, holmium doping becomes desirable with low chemical hardness which indicates more effectivity and smaller HOMO–LUMO gap designate high chemical reactivity. To determine the photocatalytic efficiency of the pure and doped CN photocatalysts, the degradation of methylene blue (MB) was monitored under visible light. The results indicate that holmium doping has improved the photocatalytic activities of CN samples. Most strikingly, this improvement is noticeable for the 0.2 mmol doped CN sample that showed two times better photocatalytic activity than the pure one.

Loss of ADAM15 in female mice does not worsen pressure overload cardiomyopathy, independent of ovarian hormones.

Cardiac hypertrophy is a common feature in several cardiomyopathies. We previously reported that loss of ADAM15 (disintegrin and metalloproteinase 15) worsened cardiac hypertrophy and dilated cardiomyopathy following cardiac pressure overload. Here, we investigated the impact of ADAM15 loss in female mice following cardiac pressure overload induced by transverse aortic constriction (TAC). Female Adam15-/- mice developed the same degree of cardiac hypertrophy, dilation, and dysfunction as the parallel female wild-type (WT) mice at 6 wk post-TAC. To determine if this is due to the protective effects of estrogen, which could mask the negative impact of Adam15 loss, WT and Adam15-/- mice underwent ovariectomy (OVx) 2 wk before TAC. Cardiac structure and function analyses were performed at 6 wk post-TAC. OVx similarly impacted females of both genotypes post-TAC. Calcineurin (Cn) activity was increased post-OVx-TAC, and more in Adam15-/- mice; however, this increase was not reflected in the total-to-phospho-NFAT levels. Integrin-α7 expression, which was upstream of Cn activation in male Adam15-/- -TAC mice, remained unchanged in female mice. However, activation of the mitogen-activated protein kinases (ERK, JNK, P38) was greater in Adam15-/--OVx-TAC than in WT-OVx-TAC mice. In addition, ADAM15 protein levels were significantly increased post-TAC in male but not in female WT mice. Myocardial fibrosis was comparable in non-OVx WT-TAC and Adam15-/- -TAC mice. OVx increased the perivascular fibrosis more in Adam15-/- compared with WT mice post-TAC. Our data demonstrate that loss of ovarian hormones did not fully replicate the male phenotype in the female Adam15-/- mice post-TAC. As ADAM15 levels were increased in males but not in females post-TAC, it is plausible that ADAM15 does not play a prominent role in post-TAC events in female mice. Our findings highlight the significance of factors other than sex hormones in mediating cardiomyopathies in females, which require a more thorough understanding.NEW & NOTEWORTHY Loss of ADAM15 in female mice, unlike the male mice, does not worsen the cardiomyopathy following cardiac pressure overload. Ovariectomy does not worsen the post-TAC cardiomyopathy in female Adam15-/- mice compared with female WT mice. Lack of deleterious impact of Adam15 deficiency in female mice is not because of the protective effects of ovarian hormones but could be due to a less prominent role of ADAM15 in cardiac response to post-TAC remodeling in female mice.

Magnetic Lipid-Based hybrid nanosystems: A combined stimuli- responsive nanocarriers for enriched chemotherapeutic potential of L-carnosine in induced breast Ehrlich ascites tumor model

Magnetic Lipid-Based Hybrid Nanosystems (M-LCNPs) is a novel nanoplatform that can respond to magnetic stimulus and are designed for delivering L-carnosine (CN), a challenging dipeptide employed in the treatment of breast cancer. CN exhibits considerable water solubility and undergoes in-vivo degradation, hence restricting its application. Consequently, it is anticipated that the developed M-LCNPs will enhance the effectiveness of CN. To ensure the physical stability of MNPs, they were initially coated with a mixture of oleic acid and oleylamine before being included in pegylated liquid crystalline nanoparticles (PLCNPs). The proposed M-LCNPs exhibited promising in-vitro characteristics, notably a small particle size (143.5 nm ± 1.25) and a high zeta potential (-39.5 mV ± 1.54), together with superparamagnetic behavior. The in-vitro release profile exhibited a prolonged release pattern. The IC50 values of M-LCNPs were 1.57 and 1.59 times lower than these of the CN solution after 24 and 48 hours, respectively. Female BALB/C female mice with an induced breast cancer (Ehrlich Ascites tumor [EAT] model) were used to study the influence of an external magnetic field on the chemotherapeutic activity and toxicity of CN loaded in the developed M-LCNPs.Stimuli-responsive M-LCNPs exhibited no apparent systemic toxicity in addition to enhanced chemotherapeutic efficacy compared to nontargeted M-LCNPs and CN solution, as evidenced by a reduction of % tumor growth (11.7%), VEGF levels (22.95 pg/g tissue), and cyclin D1 levels (27.61 ng/g tissue), and an increase in caspase-3 level (28.9 ng/g tissue). Ultimately, the developed stimuli-responsive CN loaded M-LCNPs presented a promising nanoplatform for breast cancer therapy.

Benchtop Nickel Catalysis Invigorated by Electron-Deficient Diene Ligands.

ConspectusDue to the rarity of precious metals like palladium, nickel catalysis is becoming an increasingly important player in organic synthesis, especially for the formation of bonds with sp3-hybridized carbon centers. Traditionally, catalytic processes involving active Ni(0) species have relied on Ni(COD)2 or in situ reduction of Ni(II) salts. However, Ni(COD)2 is an air- and temperature-sensitive material that requires use in an inert-atmosphere glovebox, and in situ reduction protocols of Ni(II) salts using metallic or organometallic reductants add additional complications to reaction development.This Account chronicles the development of air-stable Ni(0) precursors as replacements for Ni(COD)2 or in situ reduction. Based on Schrauzer's seminal discovery of Ni(COD)(DQ) as an air-stable zerovalent organonickel complex, our research laboratories at Scripps Research and Bristol Myers Squibb have developed a class of precatalysts based on the Ni(COD)(EDD) (EDD = electron-deficient diene) framework, relying on the steric and electronic properties of the supporting diene to render the metal center stable to air, moisture, and even silica gel but reactive to ligand substitution and redox changes.The stable Ni(0) complexes can be accessed through ligand exchange with Ni(COD)2, through reduction of Ni(acac)2 using DIBAL-H, or electrochemically via cathodic reduction of Ni(acac)2 to Ni(COD)2, followed by addition of an EDD ligand in one pot. As a toolkit, the complexes demonstrate reactivity that is equivalent or enhanced compared to Ni(COD)2, catalyzing C-C and C-N cross-couplings, Miyaura borylations, C-H activations, and other transformations. Since the initial report on Ni(COD)(DQ), its reactivity in C(sp2)-CN activation, metallophotoredox, and electric field-induced cross-coupling have also been demonstrated.By incorporating the precatalyst toolkit into reaction discovery campaigns, our laboratories have been able to perform C(sp3)-S(alkyl) couplings and metallonitrenoid carboamination, both of which represent challenging transformations that were inaccessible with traditional phosphine, nitrogen, or electron-deficient olefin ligands. Computational and experimental studies demonstrate how the quinone ligands are hemilabile, adopting η1(O)-bound geometries to relieve steric strain or stabilize transition states and intermediates; redox-active, able to transiently oxidize the metal center; and electron-withdrawing or -donating, depending on metal oxidation state and coordination geometry. These studies show how the ligands enable key steps in catalysis beyond imparting air-stability.Since our report documenting the catalytic activity of Ni(COD)(DQ), many other laboratories have also observed unique reactivity with this precatalyst. Ni(COD)(DQ) was found to offer superior reactivity to Ni(COD)2 in C-N cross coupling to form N,N-diaryl sulfonamides and in preparation of biaryls from aryl halides and benzene through a Ni-mediated, base-assisted homolytic aromatic substitution.

Construction of g- C3N4/Au/MgAl2O4 photocatalysts with different coupling methods to improve the photodegradation behavior and performance prediction

A novel g-C3N4/Au/MgAl2O4 (CN-Au-MAO) system have been developed to improve the photocatalytic activity of CN and MAO for the simulated sunlight -driven chlortetracycline hydrochloride (CTC-HCl) removal. The Au particles act as a surface plasmon resonance center to separate and accumulate electrons from the conduction band of CN and MAO, promoting the transfer of photo-generated carriers, thereby maintaining high oxidative capacities of MAO. The prepared photocatalysts revealed that the plasma resonance wavelength and photocatalytic efficiency of CN -Au -MAO photocatalysts strongly depend on the coupling order of CN, Au, and MAO. The effects of mass percentages of Au, CN and Au-CN, catalyst content, drug concentration and pH value on the degradation of CTC-HCl were explored in depth. The CN-Au-MAO photocatalysts exhibited a high photocatalytic efficiency of 92.56% toward the photodegradation of CTC-HCl with the optimum catalyst content of 1 g/L, drug concentration of 200 mg/L and pH= 11. The genetic algorithm was used to predict the photocatalytic activity of CN-Au-MAO photocatalyst, and the minimum data set that can effectively predict its photocatalytic activity was explored. The active species detection experiments, degradation pathways, and toxicity estimates were also performed. A reasonable mechanism of the CN-Au-MAO system was proposed. This work effectively solves the problem of coupling MAO with the noble metal particles, which makes MAO easy to hydrolyze, and the problem of predicting the effective minimum data set required for the photocatalytic activity through neural network algorithms.

Binding Modes of Carnostatine, Homocarnosine, and Ophidine to Human Carnosinase 1.

Carnosine (CAR), anserine (ANS), homocarnosine (H-CAR), and ophidine (OPH) are histidine-containing dipeptides that show a wide range of therapeutic properties. With their potential physiological effects, these bioactive dipeptides are considered as bioactive food components. However, such dipeptides display low stability due to their rapid degradation by human serum carnosinase 1 (CN1). A dimeric CN1 hydrolyzes such histidine-containing compounds with different degrees of reactivities. A selective CN inhibitor, carnostatine (CARN), was reported to effectively inhibit CN's activity. To date, the binding mechanisms of CAR and ANS have been recently reported, while no clear information about H-CAR, OPH, and CARN binding is available. Thus, in this work, molecular dynamics simulations were employed to elucidate the binding mechanism of H-CAR, OPH, and CARN. Among all, the amine end and imidazole ring are the main players for trapping all of the ligands in a pocket. OPH shows the poorest binding affinity, while CARN displays the tightest binding. Such firm binding is due to the longer amine chain and the additional hydroxyl (-OH) group of CARN. H-CAR and CARN are analogous, but the absence of the -OH moiety in H-CAR significantly enhances its mobility, resulting in the reduction in binding affinity. For OPH which is an ANS analogue, the methylated imidazole ring destroys the OPH-CN1 interaction network at this region, consequentially leading to the poor binding ability. An insight into how CN recognizes and binds its substrates obtained here will be useful for designing an effective strategy to prolong the lifetime of CAR and its analogues after ingestion.

Atomically dispersed vanadium on g-C3N4 for effective ciprofloxacin degradation via peroxymonosulfate activation: Insights on the nonradical pathway and V redox cycles

This work describes the preparation and characterization of atomically-dispersed V on graphitic carbon nitride (g-C3N4, CN) via a facile calcination method. The V atoms were found to coordinate with the –N and –O in the triazine units of g-C3N4. The catalytic activity of the as-prepared materials was evaluated in ciprofloxacin (CIP) degradation via peroxymonosulfate (PMS) activation. It was found that the presence of V (0.10 at%) noticeably enhanced the catalytic activity of CN, and the V-CN catalyst showed substantial tolerance towards pH changes, interfering species, various water sources, and different antibiotics. Chemical scavenging and electrochemical methods illustrated that the V-CN/PMS/CIP system encompassed of a nonradical electron-transfer pathway (50.0%), singlet oxygen (1O2) pathway (30.8%), sulfate radical (SO4•-) generation (11.5%), and other reactive species (7.7%), and the activation process was due to the V-redox cycles. Peculiarly, V(IV)/V(III) redox cycles were responsible for the nonradical electron-transfer pathway while V(V)/V(IV) redox cycles were behind the SO4•- and 1O2 generation. Additionally, comprehensive investigation on the catalytic affinity of V-CN towards different antibiotics elucidated that the electrochemical properties of the organic pollutant play a major role in the electron-transfer direction during nonradical activation. Lastly, the CIP degradation pathway was proposed, and the toxicity of its degradation intermediates was estimated. Overall, this work deepens the understanding on the potential of V-based materials in catalytic PMS activation.

Evaluation of the Antimicrobial Activity of Chitosan Nanoparticles against Listeria monocytogenes.

Chitosan is obtained from the deacetylation of chitin, and it is known to possess antimicrobial activity. It has attracted attention as it may be used for treating infections caused by different types of microorganisms due to its broad spectrum. Its application in the form of micro- or nanoparticles (CM/CN) has expanded its usage, as in this form, it retains its activity, and remain stable in aqueous solutions. However, inconsistencies in the results reported by different authors have been identified. In this communication, the antimicrobial activity of CN produced from different starting materials was tested against Listeria monocytogenes. It was observed that, even though all the starting materials were reported to have a molecular weight (MW) below 200 kDa and degree of deacetylation (DD) > 75%, the size of the CNs were significantly different (263 nm vs. 607 nm). Furthermore, these differences in sizes exerted a direct effect on the antimicrobial properties of the particles, as when testing the ones with the smallest size, i.e., 263 nm, a lower Minimum Inhibitory Concentration (MIC) was achieved, i.e., 0.04 mg/mL. Even though the largest particles, i.e., 607 nm, in individual experiments were able to achieve an MIC of 0.03 mg/mL, the results with CN presented great variation among replicates and up to 0.2 mg/mL were needed in other replicates. The starting material has a critical impact on the properties of the CN, and it must be carefully characterized and selected for the intended application, and MW and DD solely do not fully account for these properties.

Enrichment and activation of cyano in cobalt hexacyanoferrate for specific recovery of ultra-low concentrations of platinum

Adsorption recovery of ultra-low concentrations (1 ppm) of platinum (Pt) was challenging due to the inferior sensitivity response and poor specific affinity between sorbents and target ions. Herein, enrichment and activation of the cyano group (CN) on cobalt hexacyanoferrate (CoHCF) were achieved by crystal facets engineering to capture Pt(Ⅱ) efficiently and specifically. The Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and density-functional theory (DFT) calculations results revealed that the activity and density of CN on the (220) facets were higher than that on the (200) facet. The Pt(Ⅱ) adsorption efficiency on the CN-enriched and -activated CoHCF (CoHCF(220)) reached 92.5%, which was 1.56 times higher than that on the original CoHCF (59.2%). The specific adsorption of Pt(Ⅱ) was driven by the coordination interaction between Fe-CN– and Pt, leading to the Pt(Ⅱ)-Pd(Ⅱ) separation efficiency attained 98.95% within 20 min. In addition, CoHCF(220) equipped with Pt(Ⅱ) could be further chemically reduced as a photocatalyst for hydrogen evolution. This study suggested an attractive strategy for the practical recovery of Pt(Ⅱ) and comprehensive utilization of ultra-low concentration Pt-containing wastewater.

CuInS2 quantum-dot-modified g-C3N4 S-scheme heterojunction photocatalyst for hydrogen production and tetracycline degradation

CuInS2 quantum-dot (CIS QD)-modified g-C3N4 (CN) catalysts (CIS/CN) were prepared with the aid of an in-situ growth process. The as-obtained photocatalysts were explored by measuring their crystallinity, surface morphology, binding energy and light absorption activity. The photocatalytic efficiency of the photocatalysts was evaluated through photocatalytic water splitting for hydrogen production and tetracycline (TC) antibiotic degradation under the simulated solar light and visible light respectively. The optimized sample (10CIS/CN) showed the best photocatalytic activity: producing 102.4 µmol g−1 h−1 of hydrogen in 1 h, or degrading 52.16% of TC in 120 min, which were respectively 48 or 3.4 times higher than the photocatalytic activity of CN itself. The enhancement in the efficiency of the composite system was principally accredited to the enlargement of light absorption, the more effective in charge transfer and the dropping of the charge carrier pair recombination through a formed S-scheme heterojunctional interface. This work is an effort to adjust CN-based polysulfide QD for speedy photocatalysis. The enriched photocatalytic activity grants a new sense for adjusting the optical properties of CN.

The impact of sarcolipin ablation on calcineurin signalling and muscle phenotype with aging

Sarcolipin (SLN), a small protein inhibitor of the sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA), is dynamically upregulated in atrophic unloading and disease states where it promotes muscle health by activating calcineurin (Cn) and the dephosphorylation and subsequent nuclear translocation of nuclear factor of activated T-cells (NFAT). This study sought to examine how the ablation of SLN impacted Cn signalling, fibre type profile and muscle mass in both male and female mice with aging. Male and female, wild type (WT) and SLN knockout (SLNKO) mice were assessed at two age groups (young adult (4-6M) and older adult (18+M)) for muscle mass (soleus:body weight ratio, fibre type specific cross-sectional area), fibre type profile and protein expression (SLN, Cn, and NFAT). SLN content was significantly greater in WT females (p <00.1) and older animals (5<0.05) and absent from SLNKO. As SLN has been linked to Cn signalling previously, we hypothesized that the increased SLN content in female and aged animals may promote Cn signalling. While there was a trend for lower Cn expression with aging (p=0.10), neither sex nor genotype significantly impacted Cn expression. To examine activation of Cn, the ratio of inactive phosphorylated NFAT to total NFAT was assessed via Western Blotting. We found that aging significantly increased the activation of Cn (p<0.01) and there was a trend (p=0.10) towards greater NFATp/NFAT with SLN ablation signifying a reduction in Cn signalling. As Cn is a known regulator of muscle fibre type, we examined fibre type profile using immunofluorescence and found aging increased the percentage of type I fibres (p<0.001), which was witnessed more predominately in female mice regardless of genotype. Furthermore, when examining type II fibres, we found a significant sex by age interaction (p<0.05) in which both WT and SLNKO females displayed reduced type II fibres with aging while males did not display this apparent shift. With respect to muscle mass, aging, regardless of sex or genotype, was shown to significantly reduce relative muscle mass (p<0.001), however no significant reductions were found in total fibre count, or cross-sectional area of Type I or Type II fibres. In summary, this study found that WT female and aged animals display increased SLN content. Aligning with our hypothesis, there was a trend towards lower Cn signalling with SLN ablation, regardless of age or sex. However, this does not seem to be linked to changes in muscle fibre type or muscle mass, as SLNKO animals did not display significant differences from their WT counterparts. Further studies should seek to examine the role of SLN in both sex and aging further, with special focus on metabolic energy expenditure and SERCA protection. NSERC This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Multifunctional AuPd-cluster nanotheranostic agents with a cascade self-regulating redox tumor-microenvironment for dual-photodynamic synergized enzyme catalytic therapy.

Photodynamic therapy (PDT) has emerged as a promising strategy with higher selectivity and spatiotemporal control than conventional therapies. However, deep hypoxia in tumours has hampered the clinical use of PDT. In this study, a novel multifunctional cluster nanotheranostic agent (AuPd-BSA CN) was fabricated to generate a high amount of reactive oxygen species, regardless of oxygen dependence under 660 nm laser irradiation. The structure and properties of the AuPd-BSA CN were characterised using various technologies. The synthesised AuPd-BSA CN with high biocompatibility served as a superior photodynamic agent, showing prominent antitumour properties under laser irradiation. Additionally, the glucose oxidase-like activity of the AuPd-BSA CN synergistically enhanced the therapeutic performance. Notably, the intrinsic characteristics of the AuPd-BSA CN include dual-modal second near-infrared window fluorescence/photoacoustic imaging capabilities for monitoring and tracking the in vivo tumour therapeutic process. This work provides innovative insights into the AuPd-BSA CN as an "all-in-one" nanoplatform for cancer therapy.

Novel up-conversion N, S co-doped carbon dots/g-C3N4 photocatalyst for enhanced photocatalytic hydrogen evolution under visible and near-infrared light

In photocatalytic splitting water for hydrogen evolution, narrow light response range and fast electron-hole recombination of g-C3N4 (CN) limit its photocatalytic activity. In this article, the N, S co-doped carbon dots (NSCDs) with up-converted property were loaded on CN nanosheets by thermal polymerization to obtain NSCDs/CN composite catalyst. Characterization, electrochemical researches and hydrogen evolution tests suggest that the photocatalytic activity of CN is greatly promoted by the introduction of NSCDs. Under visible and near-infrared irradiation, the hydrogen evolution rate is 5033.1 μmol g−1 h−1 of NSCDs-5/CN, which is 8.3 times higher than that of CN. The performance improvement is mainly attributed to the increased specific surface area, elevated hydrophilic surface, increased light absorption and suppressed carrier recombination of CN after the introduction of NSCDs. This work unveils the mechanism of the hydrogen evolution activity improvement in NSCDs-5/CN, and also offers a new prospect in the design of high-performance CN-based photocatalysts.

Effect of calcineurin inhibitors on cognition in a canine model of Alzheimer’s disease

AbstractBackgroundCalcineurin (CN) is a Ca2+/calmodulin‐dependent phosphatase that regulates diverse cellular phenotypes through activation of NFAT transcription factor1. CN/NFAT signaling increases in Alzheimer’s disease (AD)2,3 and is associated with synaptic loss, neuron degeneration, neuroinflammation, amyloid‐β production, and cognitive decline4,5. Thus, calcineurin inhibitors (CNI) are attractive potential therapeutic to improve cognitive impairments associated with AD.Tacrolimus is an FDA‐approved CNI commonly prescribed for the prophylaxis of solid organ transplant rejection6. In mouse models of AD, tacrolimus ameliorates cognitive deficits7. Moreover, epidemiological studies suggest that tacrolimus reduced the incidence of dementia in kidney transplant patients, when compared to age‐matched controls8.Q134R, a hydroxyquinoline derivative with cytoprotective properties9, inhibits NFAT activity without suppressing CN activity. Q134R improves synapse function and reduce neuroinflammation in AD mouse models10.We hypothesized that chronic low dose tacrolimus and Q134R treatment will prevent cognitive decline over time in middle‐aged beagles, a natural model of human brain aging, amyloid‐β accumulation, and amyloid‐related cognitive impairment.MethodsCognitive outcomes were evaluated in 37 middle‐aged dogs at baseline and during follow‐up (years 1, 2 and 3). Spatial learning and working memory were evaluated using the landmark‐discrimination (1, 2 and 4cm) task and a delayed non‐matching to position (20‐, 70‐, and 110‐second delays) test. Dogs were ranked for cognition at baseline and randomized into one of three treatment groups: Control (n = 12; placebo), Q134R (n = 12; 8mg/day PO), and tacrolimus (n = 13; 0.075mg/kg/day PO).ResultsAccuracy at each landmark‐discrimination distance declined significantly among controls faster per year than both treatment groups. Control dogs declined 20% faster than tacrolimus dogs at all distances, and 15% faster than Q134R dogs, at the most difficult distance (4cm).Accuracy on the spatial working memory task declined in each year among controls faster than dogs in the active treatment groups. This effect tended to increase with treatment duration in tacrolimus dogs, whereas it attenuated in Q134R dogs.ConclusionOur findings suggest that both tacrolimus and Q134R have beneficial effects on cognitive outcomes in a canine model of AD, as dogs treated with these compounds showed improved learning, memory, attention, and working memory. Hence, inhibition of the CN pathway may reduce/delay cognitive impairment in AD.

Histopathological assessment of a two-stage reconstructive procedure of the infected Charcot foot.

Charcot neuropathic osteoarthropathy (CN) can be complicated by osteomyelitis (OM). Surgery is a standard procedure to treat OM including debridement and interposition of antibiotic-loaded cement (ABLC) spacer. The course of CN and OM was investigated on a histopathological level. Diabetic patients (n = 15) suffering from CN and midfoot OM underwent surgical debridement and interposition of ABLC was interposed. 6weeks later, ABLC was removed and bone samples were taken again. Histopathological Charcot Score (HCS), Histopathological Osteomyelitis Evaluation Score (HOES) and microbiological assessment were used to evaluate osteomyelitic and neuroosteoarthropathic activity at both time points. Interposition of ABLC leads to microbiological/histopathological eradication of OM in 73%/87% of patients. CN activity-measured by HCS-could be reduced from moderate to low activity by ABLC spacer and correlated with HOES. CN activity could be reduced by surgery. It can be suggested that neuroosteoarthropathic activity measured by HCS is triggered by OM.

Preparation of carbon nitride from different precursors through pyrolysis: Correlating the photocatalytic activity to the crystallinity and disorder

Crystallinity and disorder have been proven to significantly influence the activity of polymer photocatalysts. This work aimed to clarify the influences of crystallinity and disorder on photocatalytic activity of CN. Four different kinds of CN were synthesized through pyrolysis with different precursors. The adsorption and photocatalytic activities of as-prepared CN samples were in the decreasing order: crystalline-CN (C-CN) > synergetic-CN (S-CN) > disordered-CN (D-CN) > bulk-CN (B-CN). B-CN had a bulk structure, low specific surface area but high charge recombination efficiency, thus the worst activities. The adsorption capacity and photocatalytic activities of D-CN were 2.7 and 2.3 times higher than B-CN, respectively, owing to a 7.3 times larger surface area brought by disordered structure. The C-CN with highest crystallinity performed best in the adsorption and photocatalytic tests. Introducing urea in the CM complex broke the structure integrity, and the formed S-CN had a 1.0 times larger surface area, but 1.1 and 1.8 times decline in adsorption capacity and photocatalytic activities, respectively, comparing with C-CN. The results synergistically addressed that, (1) disordered and highly crystallized structures can both improve the specific surface area; (2) CN with higher crystallinity can be excited by light with longer wavelength and had reduced charge recombination efficiency; (3) CN with higher crystallinity performed better in the adsorption and photocatalytic tests. The results of this study demonstrate that crystallinity is the leading factor affecting the activity of CN, thus providing a promising route for the rational design of highly active CN photocatalysts.

Enhancement of photocatalytic oxidation of benzyl alcohol by edge-functionalized modified carbon nitride: A DFT evaluation

New dye functionalized polymeric carbon nitrides with increased visible light response were designed and fabricated. In this research, Rose Bengal (RB) was immobilized on g-C3N4 (CN) and carboxylated g-C3N4 (CCN) through the formation of a covalent bond. The covalent bonding of Rose Bengal to the CN or CCN resulted in the transfer of electrons from the dye to the semiconductor and the enhancement of the light harvesting performance, which promoted the photocatalytic efficiency. The photocatalytic activity of CN, CCN, and their hybrids with RB toward selective oxidation of benzyl alcohol was investigated under the visible light irradiation. The results obtained from the GC–MS analyses related to the oxidation reaction displayed the highest percentage of benzyl alcohol conversion and benzaldehyde selectivity for the hybrid structures compared to the bare RB, CN, CCN, or a mixture of RB and CN (or CCN). The effect of several parameters, including the amount of photocatalyst and promoter, irradiation time, and photocatalyst type, was studied and optimized. The recovery of RB-CCN (the most active catalyst) was surveyed in five runs, and the results verify that the activity is mostly maintained. Finally, the optimized structure, energy gap, and frontier orbitals of Rose Bengal/graphitic carbon nitride were investigated by DFT methods.

Low doses of BPF-induced hypertrophy in cardiomyocytes derived from human embryonic stem cells via disrupting the mitochondrial fission upon the interaction between ERβ and calcineurin A-DRP1 signaling pathway.

Bisphenol F (BPF) is a replacement to bisphenol A, which has been extensively used in industrial manufacturing. Its wide detection in various human samples raises increasing concern on its safety. Currently, whether a low dose of BPF compromises cardiac function is still unknown. This study provides the first evidence that low-dose BPF can induce cardiac hypertrophy by using cardiomyocytes derived from human embryonic stem cells (hES). Non-cytotoxic BPF increased cytosolic Ca 2+ influx ([Ca2+ ]c), which was most remarkable at low dose (7 ng/ml) rather than at higher doses. Significant changes in the morphological parameters of mitochondria and significant decreases in ATP production were induced by 7 ng/ml BPF, representing a classic hypertrophic cardiomyocyte. After eliminating the direct effects on mitochondrial fission-related DRP1 by administration of the DRP1 inhibitor Mdivi-1, we examined the changes in [Ca 2+ ]c levels induced by BPF, which enhanced the calcineurin (Cn) activity and induced the abnormal mitochondrial fission via the CnAβ-DRP1 signaling pathway. BPF triggered excessive Ca 2+ influx by disrupting the L-type Ca 2+channel in cardiomyocytes. The interaction between ERβ and CnAβ cooperatively involved in the BPF-induced Ca 2+ influx, which resulted in the abnormal mitochondrial fission and compromised the cardiac function. Our findings provide a feasible molecular mechanism for explaining low-dose BPF-induced cardiac hypertrophy in vitro, preliminarily suggesting that BPF may not be as safe as assumed in humans.