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"Gray, Alexander"
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Control of the metal–insulator transition in vanadium dioxide by modifying orbital occupancy
External control of the conductivity of correlated oxides is one of the most promising schemes for realizing energy-efficient electronic devices. Vanadium dioxide (VO
2
), an archetypal correlated oxide compound, undergoes a temperature-driven metal–insulator transition near room temperature with a concomitant change in crystal symmetry. Here, we show that the metal–insulator transition temperature of thin VO
2
(001) films can be changed continuously from ∼285 to ∼345 K by varying the thickness of the RuO
2
buffer layer (resulting in different epitaxial strains). Using strain-, polarization- and temperature-dependent X-ray absorption spectroscopy, in combination with X-ray diffraction and electronic transport measurements, we demonstrate that the transition temperature and the structural distortion across the transition depend on the orbital occupancy in the metallic state. Our findings open up the possibility of controlling the conductivity in atomically thin VO
2
layers by manipulating the orbital occupancy by, for example, heterostructural engineering.
Bulk vanadium dioxide undergoes a metal–insulator transition near room temperature. It is now shown that by putting a thin layer of vanadium dioxide on a buffer, and varying the buffer’s thickness, the orbital occupancy in the metallic state and the transition temperature can be tuned.
Journal Article
Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK
Glucose starvation activates AMPK via an AMP/ADP-independent mechanism that involves fructose-1,6-bisphosphate and aldolase.
New insights into AMPK activation
AMPK is a central regulator of metabolic homeostasis, and its dysfunction may result in various diseases including diabetes, obesity, and cancer. AMPK is known to be activated under stressful conditions, including glucose starvation. It has been assumed that upon glucose deprivation AMPK activation occurs in the canonical AMP/ADP-dependent manner, with reduced metabolism of glucose causing falling ATP and increasing AMP and ADP. Here, Sheng-Cai Lin and colleagues show that this is not the case, and that glucose starvation activates AMPK via a different route, in an AMP/ADP-independent manner. During glycolysis, glucose is converted to fructose-1,6-bisphosphate (FBP), which is then processed by FBP aldolases. The authors show that the absence of glucose results in a reduction of FBP-bound aldolase, which triggers LKB1 phosphorylation and activation of AMPK. This study thus uncovers FBP as the critical metabolite that signals glucose availability and FBP aldolases as the sensors that relay the information to AMPK.
The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK)
1
, but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK
2
,
3
,
4
,
5
. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation
6
,
7
. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.
Journal Article
New Sulphated Flavonoids from Wissadula periplocifolia (L.) C. Presl (Malvaceae)
Wissadula periplocifolia (L.) C. Presl (Malvaceae) is commonly used in Brazil to treat bee stings and as an antiseptic. The antioxidant properties of its extracts have been previously demonstrated, thus justifying a phytochemical investigation for its bioactive phenolic constituents. This has yielded five new sulphated flavonoids: 8-O-sulphate isoscutellarein (yannin) (1a); 4′-O-methyl-7-O-sulphate isoscutellarein (beltraonin) (1b); 7-O-sulphate acacetin (wissadulin) (2a); 4′-O-methyl-8-O-sulphate isoscutellarein (caicoine) (2b) and 3′-O-methyl-8-O-sulphate hypolaetin (pedroin) (3b) along with the known flavonoids 7,4′-di-O-methyl-8-O-sulphate isoscutellarein (4), acacetin, apigenin, isoscutellarein, 4´-O-methyl isoscutellarein, 7,4′-di-O-methylisoscutellarein, astragalin and tiliroside. The compounds were isolated by column chromatography and identified by NMR (1H, 13C, HMQC, HMBC and COSY) and LC-HRMS. A cell based assay was carried out to evaluate the preliminary cytotoxic properties of the flavonoids against UVW glioma and PC-3M prostate cancer cells as well as non-tumour cell lines. The obtained results showed that acacetin, tiliroside, a mixture of acacetin + apigenin and the sulphated flavonoids 2a + 2b exhibited inhibitory activity against at least one of the cell lines tested. Among the tested flavonoids acacetin and tiliroside showed lower IC50 values, presenting promising antitumor effects.
Journal Article
Modulation-doping a correlated electron insulator
Correlated electron materials (CEMs) host a rich variety of condensed matter phases. Vanadium dioxide (VO
2
) is a prototypical CEM with a temperature-dependent metal-to-insulator (MIT) transition with a concomitant crystal symmetry change. External control of MIT in VO
2
—especially without inducing structural changes—has been a long-standing challenge. In this work, we design and synthesize modulation-doped VO
2
-based thin film heterostructures that closely emulate a textbook example of filling control in a correlated electron insulator. Using a combination of charge transport, hard X-ray photoelectron spectroscopy, and structural characterization, we show that the insulating state can be doped to achieve carrier densities greater than 5 × 10
21
cm
−3
without inducing any measurable structural changes. We find that the MIT temperature (T
MIT
) continuously decreases with increasing carrier concentration. Remarkably, the insulating state is robust even at doping concentrations as high as ~0.2 e
−
/vanadium. Finally, our work reveals modulation-doping as a viable method for electronic control of phase transitions in correlated electron oxides with the potential for use in future devices based on electric-field controlled phase transitions.
The metal-insulator transition in VO2 is concomitant with the structural transition, making purely electrical control challenging. Here the authors use a modulation-doped heterostructure to demonstrate modulation of the transition temperature with doping, without introducing structural changes.
Journal Article
Impact of uniform illumination in widefield microscopy and mesoscopy
Illumination uniformity is critical for widefield optical microscopy, especially for high-throughput and accurate quantitative imaging of biological specimens. While traditional Köhler illumination improves uniformity, it often fails to deliver homogeneous intensity across large fields of view. Existing optical and computational correction techniques remain inadequate for a broad range of quantitative imaging applications. Here, we implement a novel illumination device that we call the “effective uniform color-light integration device” (EUCLID), quantifying improvements in two widefield imaging modalities that require uniform illumination. For both imaging modalities, we demonstrate significantly improved precision of quantitative measurements compared to traditional Köhler illumination. The EUCLID device, which can also provide uniform spectral mixing, can be readily adapted to many other widefield imaging modalities to enhance imaging accuracy and reliability, with low cost and ease of implementation.
Journal Article
Antitrypanosomal and Antileishmanial Activities of Tacca leontopetaloides Tubers and Zanthoxylum zanthoxyloides Stem Bark
The phytochemical screening of extracts of Tacca leontopetaloides tubers has afforded the isolation of two novel chalcones, tarkalynins A and B, along with taccalonolide A and its 12-propanoate. The screening of Zanthoxylum zanthoxyloides stem bark yielded taraxerol acetate, dihydrochelerythrin and fagaramide. These compounds were obtained through column and thin-layer chromatography and identified using NMR and LC-HRMS. The compounds were tested against Trypanosoma brucei brucei s427 and its multi-drug-resistant clone B48, against Trypanosoma evansi, Trypanosoma equiperdum and Trypanosoma congolense, and against Leishmania mexicana. Cytotoxicity was tested against the human HEK293 cell line. The highest activities were observed with dihydrochelerythrin and fagaramide against T. b. brucei s427 and B48, T. evansi, and L. mexicana, with EC50 values of 1.37, 2.559, 1.09, and 5.44 µM and 17.8, 10.9, 10.9, and 13.3 µM, respectively. In addition, tarkalynin A and taraxerol acetate displayed promising activity against T. equiperdum (EC50 = 21.4 and 21.3 µM, respectively). None of these compounds showed significant cross-resistance with existing trypanocides (RF ≈ 1; p > 0.05). The compounds displayed low toxicity to human cells, with most exhibiting no growth inhibition at concentrations of 100, or even 300 µM. This report provides further evidence of the potential use of natural products for combating parasitic diseases.
Journal Article
Integrated machine learning analysis of proteomic and transcriptomic data identifies healing associated targets in diabetic wound repair
This study identified biomarkers that could be leveraged to classify the state of healing in diabetic wounds. Firstly, by collecting wound samples from diabetic mice at different time points and generating their protein profiles using standard techniques, we set to interrogate whether a small number of biomarkers could serve as sensors to monitor the healing stage. Least absolute shrinkage and selection operator (LASSO) was applied. Large-scale analysis of wound tissue proteins integrated with the respective wound sizes allowed to establish a correlation between the observed protein profile and wound closure. We further evaluated human subjects’ systemic serum proteomics for biomarkers. An additional wound healing model in diabetic mice was employed for microRNA quantitation at the same time points and similarly analyzed. Our analysis highlighted markers MMP-2, HGF, miR-1b and miR-107-3p in mice and Fractalkine and FGF-2 in humans that could correctly identify the extent of healing. By using proteomics from mice and human patients and complementary microRNA mouse data with computer regression models we can better predict molecular and protein deficits associated with impaired diabetic wound repair.
Journal Article
Isolation of a Novel Flavanonol and an Alkylresorcinol with Highly Potent Anti-Trypanosomal Activity from Libyan Propolis
Twelve propolis samples from different parts of Libya were investigated for their phytochemical constituents. Ethanol extracts of the samples and some purified compounds were tested against Trypanosoma brucei, Plasmodium falciparum and against two helminth species, Trichinella spiralis and Caenorhabditis elegans, showing various degrees of activity. Fourteen compounds were isolated from the propolis samples, including a novel compound Taxifolin-3-acetyl-4′-methyl ether (4), a flavanonol derivative. The crude extracts showed moderate activity against T. spiralis and C. elegans, while the purified compounds had low activity against P. falciparum. Anti-trypanosomal activity (EC50 = 0.7 µg/mL) was exhibited by a fraction containing a cardol identified as bilobol (10) and this fraction had no effect on Human Foreskin Fibroblasts (HFF), even at 2.0 mg/mL, thus demonstrating excellent selectivity. A metabolomics study was used to explore the mechanism of action of the fraction and it revealed significant disturbances in trypanosomal phospholipid metabolism, especially the formation of choline phospholipids. We conclude that a potent and highly selective new trypanocide may be present in the fraction.
Journal Article