Multiple doping is widely used to improve the performance of a material, including its electrical transport, mechanical, and photovoltaic properties. In this paper, Sn–Se dual‐doped Li10GeP2S12 ...(LGPS, thio‐LISICON II analogue) electrolytes were synthesized via ball milling and sintering and compared with those Sn or Se single‐doped. Successful Sn and/or Se substitution expanded the unit cell and formed SnSe44− units, which were verified by X‐ray powder diffraction, energy‐dispersive X‐ray spectroscopy, and Raman spectroscopy. In contrast to the limited benefits of Se single doping and the negative effects of Sn single doping, Sn–Se dual doping demonstrated up to 53% enhancement in ionic conductivity. More importantly, Sn–Se dual‐doped LGPS showed an extremely low activation energy of 16 kJ/mol, which is one of the lowest known values for lithium ion conductors; as well as one of the widest electrochemical windows of 8 V. Sn–Se dual‐doped LGPS is a promising electrolyte for advanced all‐solid‐state batteries.
Conotoxins are widely distributed and important for studying ligand-gated ion channels. TxIB, a conotoxin consisting of 16 amino acids derived from
, is a unique selective ligand that blocks rat ...α6/α3β2β3 nAChR (IC
= 28 nM) without affecting other rat subtypes. However, when the activity of TxIB against human nAChRs was examined, it was unexpectedly found that TxIB had a significant blocking effect on not only human α6/α3β2β3 nAChR but also human α6/α3β4 nAChR, with an IC
of 537 nM. To investigate the molecular mechanism of this species specificity and to establish a theoretical basis for drug development studies of TxIB and its analogs, different amino acid residues between human and rat α6/α3 and β4 nAChR subunits were identified. Each residue of the human species was then substituted with the corresponding residue of the rat species via PCR-directed mutagenesis. The potencies of TxIB towards the native α6/α3β4 nAChRs and their mutants were evaluated through electrophysiological experiments. The results showed that the IC
of TxIB against hα6
/α3β4
was 22.5 μM, a 42-fold decrease in potency compared to the native hα6/α3β4 nAChR. Val-32 and Lys-61 in the human α6/α3 subunit and Leu-107 and Val-115 in the human β4 subunit, together, were found to determine the species differences in the α6/α3β4 nAChR. These results also demonstrate that the effects of species differences between humans and rats should be fully considered when evaluating the efficacy of drug candidates targeting nAChRs in rodent models.
Type I clathrates are a promising thermoelectric (TE) material for waste heat recovery applications. However, the TE figure-of-merit of type I clathrates still needs further improvement. In this ...study, Yb-doped Ba
8−
x
Yb
x
Ni
0.1
Zn
0.54
Ga
13.8
Ge
31.56
(0 ≤
x
≤ 0.5) type I clathrates were synthesized using a high-pressure technique. Energy dispersive spectrometry confirmed successful Yb doping. An increased Yb doping level reduces electrical resistivity and suppresses lattice thermal conductivity while keeping the Seebeck coefficient almost unchanged. TE figure-of-merit of Ba
7.7
Yb
0.3
Ni
0.1
Zn
0.54
Ga
13.8
Ge
31.56
type I clathrate was improved by 15% (0.91) at the highest measured temperature (900 K) compared with a Yb-free sample.
α4/6-conotoxin TxID, which was identified from
, simultaneously blocks rat (r) α3β4 and rα6/α3β4 nicotinic acetylcholine receptors (nAChRs) with IC
values of 3.6 nM and 33.9 nM, respectively. In ...order to identify the effects of loop2 size on the potency of TxID, alanine (Ala) insertion and truncation mutants were designed and synthesized in this study. An electrophysiological assay was used to evaluate the activity of TxID and its loop2-modified mutants. The results showed that the inhibition of 4/7-subfamily mutants +9ATxID, +10ATxID, +14ATxID, and all the 4/5-subfamily mutants against rα3β4 and rα6/α3β4 nAChRs decreased. Overall, ala-insertion or truncation of the 9th, 10th, and 11th amino acid results in a loss of inhibition and the truncation of loop2 has more obvious impacts on its functions. Our findings have strengthened the understanding of α-conotoxin, provided guidance for further modifications, and offered a perspective for future studies on the molecular mechanism of the interaction between α-conotoxins and nAChRs.
Synthesis of phosphoenolpyruvate (PEP) from oxaloacetate is an absolute requirement for gluconeogenesis from mitochondrial substrates. Generally, this reaction has solely been attributed to the ...cytosolic isoform of PEPCK (PEPCK-C), although loss of the mitochondrial isoform (PEPCK-M) has never been assessed. Despite catalyzing the same reaction, to date the only significant role reported in mammals for the mitochondrial isoform is as a glucose sensor necessary for insulin secretion. We hypothesized that this nutrient-sensing mitochondrial GTP-dependent pathway contributes importantly to gluconeogenesis. PEPCK-M was acutely silenced in gluconeogenic tissues of rats using antisense oligonucleotides both in vivo and in isolated hepatocytes. Silencing PEPCK-M lowers plasma glucose, insulin, and triglycerides, reduces white adipose, and depletes hepatic glycogen, but raises lactate. There is a switch of gluconeogenic substrate preference to glycerol that quantitatively accounts for a third of glucose production. In contrast to the severe mitochondrial deficiency characteristic of PEPCK-C knock-out livers, hepatocytes from PEPCK-M-deficient livers maintained normal oxidative function. Consistent with its predicted role, gluconeogenesis rates from hepatocytes lacking PEPCK-M are severely reduced for lactate, alanine, and glutamine, but not for pyruvate and glycerol. Thus, PEPCK-M has a direct role in fasted and fed glucose homeostasis, and this mitochondrial GTP-dependent pathway should be reconsidered for its involvement in both normal and diabetic metabolism.
Background: PEPCK-M is generally considered irrelevant for glucose production, although gluconeogenesis has never been characterized in its absence.
Results: PEPCK-M loss impaired gluconeogenesis from lactate, lowered plasma glucose, insulin, and triglycerides, reduced hepatic glycogen, and increased glycerol turnover.
Conclusion: Approximately a third of gluconeogenesis comes from PEPCK-M.
Significance: The nutrient-sensitive PEPCK-M has been overlooked and is potentially important for metabolic diseases such as diabetes.
Alterations in mitochondrial function have been implicated in the pathogenesis of insulin resistance and type 2 diabetes. However, it is unclear whether the reduced mitochondrial function is a ...primary or acquired defect in this process. To determine whether primary defects in mitochondrial β-oxidation can cause insulin resistance, we studied mice with a deficiency of long-chain acyl-CoA dehydrogenase (LCAD), a key enzyme in mitochondrial fatty acid oxidation. Here, we show that LCAD knockout mice develop hepatic steatosis, which is associated with hepatic insulin resistance, as reflected by reduced insulin suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. The defects in insulin action were associated with an almost equal to40% reduction in insulin-stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity and an almost equal to50% decrease in Akt2 activation. These changes were associated with increased PKCε activity and an aberrant 4-fold increase in diacylglycerol content after insulin stimulation. The increase in diacylglycerol concentration was found to be caused by de novo synthesis of diacylglycerol from medium-chain acyl-CoA after insulin stimulation. These data demonstrate that primary defects in mitochondrial fatty acid oxidation capacity can lead to diacylglycerol accumulation, PKCε activation, and hepatic insulin resistance.
Recent studies have demonstrated a strong relationship between aging-associated reductions in mitochondrial function, dysregulated intracellular lipid metabolism, and insulin resistance. Given the ...important role of the AMP-activated protein kinase (AMPK) in the regulation of fat oxidation and mitochondrial biogenesis, we examined AMPK activity in young and old rats and found that acute stimulation of AMPK-α2 activity by 5′-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) and exercise was blunted in skeletal muscle of old rats. Furthermore, mitochondrial biogenesis in response to chronic activation of AMPK with β-guanidinopropionic acid (β-GPA) feeding was also diminished in old rats. These results suggest that aging-associated reductions in AMPK activity may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with aging.
Nd sub(0.6)Fe sub(2)Co sub(22Sb) sub(12-x)Sn sub(x) (0 < or =, slant x < or =, slant 0.6 nominal) skutterudite compounds were synthesized by traditional heat treatment method. Sn substitution on Sb ...(24g) site was verified by X-ray powder diffraction, energy dispersive spectrometry, and Raman spectroscopy. It was determined that substituting Sb with Sn increases the Nd filling fraction. Along with the in situ nanoinclusions introduced by Sn, the thermoelectric behavior of Sn in Nd sub(0.6)Fe sub(2)Co sub( 2)Sb sub(12-x)Sn sub(x) differs from those seen in CoSb sub(3). Despite the increase of electrical resistivity, the enhanced Seebeck coefficient and suppressed lattice thermal conductivity resulted in a 30% improvement of ZT for Nd sub(0.6)Fe sub(2)Co sub( 2)Sb sub(11.6)Sn sub(0.4),4 compared with that of Sn-free sample. We hope our work can complement the knowledge of pnicogen-substituted p-type skutterudite family and demonstrate the ways to improve their properties through compositional modification as well as in situ formation of nanoinclusions.
By 2030, nearly half of Americans will have nonalcoholic fatty liver disease. In part, this epidemic is fueled by the increasing consumption of caloric sweeteners coupled with an innate capacity to ...convert sugar into fat via hepatic de novo lipogenesis. In addition to serving as substrates, monosaccharides also increase the expression of key enzymes involved in de novo lipogenesis via the carbohydrate response element-binding protein (ChREBP). To determine whether ChREBP is a potential therapeutic target, we decreased hepatic expression of ChREBP with a specific antisense oligonucleotide (ASO) in male Sprague-Dawley rats fed either a high-fructose or high-fat diet. ChREBP ASO treatment decreased plasma triglyceride concentrations compared with control ASO treatment in both diet groups. The reduction was more pronounced in the fructose-fed group and attributed to decreased hepatic expression of ACC2, FAS, SCD1, and MTTP and a decrease in the rate of hepatic triglyceride secretion. This was associated with an increase in insulin-stimulated peripheral glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp. In contrast, ChREBP ASO did not alter hepatic lipid content or hepatic insulin sensitivity. Interestingly, fructose-fed rats treated with ChREBP ASO had increased plasma uric acid, alanine transaminase, and aspartate aminotransferase concentrations. This was associated with decreased expression of fructose aldolase and fructokinase, reminiscent of inherited disorders of fructose metabolism. In summary, these studies suggest that targeting ChREBP may prevent fructose-induced hypertriglyceridemia but without the improvements in hepatic steatosis and hepatic insulin responsiveness.
Recent studies have suggested that n-3 fatty acids, abundant in fish oil, protect against high-fat diet-induced insulin resistance through peroxisome proliferator-activated receptor (PPAR)-alpha ...activation and a subsequent decrease in intracellular lipid abundance. To directly test this hypothesis, we fed PPAR-alpha null and wild-type mice for 2 weeks with isocaloric high-fat diets containing 27% fat from either safflower oil or safflower oil with an 8% fish oil replacement (fish oil diet). In both genotypes the safflower oil diet blunted insulin-mediated suppression of hepatic glucose production (P < 0.02 vs. genotype control) and PEPCK gene expression. Feeding wild-type mice a fish oil diet restored hepatic insulin sensitivity (hepatic glucose production HGP, P < 0.002 vs. wild-type mice fed safflower oil), whereas in contrast, in PPAR-alpha null mice failed to counteract hepatic insulin resistance (HGP, P = NS vs. PPAR-alpha null safflower oil-fed mice). In PPAR-alpha null mice fed the fish oil diet, safflower oil plus fish oil, hepatic insulin resistance was dissociated from increases in hepatic triacylglycerol and acyl-CoA but accompanied by a more than threefold increase in hepatic diacylglycerol concentration (P < 0.0001 vs. genotype control). These data support the hypothesis that n-3 fatty acids protect from high-fat diet-induced hepatic insulin resistance in a PPAR-alpha-and diacylglycerol-dependent manner.
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