External control of the conductivity of correlated oxides is one of the most promising schemes for realizing energy-efcient electronic devices. Vanadium dioxide (VO2), an archetypal correlated oxide ...compound, undergoes a temperature-driven metalinsulator transition near room temperature with a concomitant change in crystal symmetry. Here, we show that the metalinsulator transition temperature of thin VO2(001) lms can be changed continuously from 285 to 345 K by varying the thickness of the RuO2 buffer layer (resulting in different epitaxial strains). Using strain-, polarizationand 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 ndings open up the possibility of controlling the conductivity in atomically thin VO2 layers by manipulating the orbital occupancy by, for example, heterostructural engineering. PUBLICATION ABSTRACT
Strong interactions, or correlations, between the d or f electrons in transition-metal oxides lead to various types of metal-insulator transitions that can be triggered by external parameters such as ...temperature, pressure, doping, magnetic fields and electric fields. Electric-field-induced metallization of such materials from their insulating states could enable a new class of ultrafast electronic switches and latches. However, significant questions remain about the detailed nature of the switching process. Here, we show, in the canonical metal-to-insulator transition system V₂O₃, that ultrafast voltage pulses result in its metallization only after an incubation time that ranges from ∼150 ps to many nanoseconds, depending on the electric field strength. We show that these incubation times can be accounted for by purely thermal effects and that intrinsic electronic-switching mechanisms may only be revealed using larger electric fields at even shorter timescales.
Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and has a strong link to obesity. To better elucidate the role of visceral ...adiposity in this disease state, a full metabolic profile combined with analysis of secreted pro-inflammatory cytokines, metabolites, and lipid profiles were assessed in human ex vivo adipose tissue explants from obese and non-obese OAC patients. These data were then related to extensive clinical data including obesity status, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Real-time energy metabolism profiles were assessed using the seahorse technology. Adipose explant conditioned media was screened using multiplex ELISA to assess secreted levels of 54 pro-inflammatory mediators. Targeted secreted metabolite and lipid profiles were analysed using Ultra-High-Performance Liquid Chromatography coupled with Mass Spectrometry. Adipose tissue explants and matched clinical data were collected from OAC patients (
= 32). Compared to visceral fat from non-obese patients (
= 16), visceral fat explants from obese OAC patients (
= 16) had significantly elevated oxidative phosphorylation metabolism profiles and an increase in Eotaxin-3, IL-17A, IL-17D, IL-3, MCP-1, and MDC and altered secretions of glutamine associated metabolites. Adipose explants from patients with metabolic dysfunction correlated with increased oxidative phosphorylation metabolism, and increases in IL-5, IL-7, SAA, VEGF-C, triacylglycerides, and metabolites compared with metabolically healthy patients. Adipose explants generated from patients who had previously received neo-adjuvant chemotherapy (
= 14) showed elevated secretions of pro-inflammatory mediators, IL-12p40, IL-1α, IL-22, and TNF-β and a decreased expression of triacylglycerides. Furthermore, decreased secreted levels of triacylglycerides were also observed in the adipose secretome of patients who received the chemotherapy-only regimen FLOT compared with patients who received no neo-adjuvant treatment or chemo-radiotherapy regimen CROSS. For those patients who showed the poorest response to currently available treatments, their adipose tissue was associated with higher glycolytic metabolism compared to patients who had good treatment responses. This study demonstrates that the adipose secretome in OAC patients is enriched with mediators that could prime the tumour microenvironment to aid tumour progression and attenuate responses to conventional cancer treatments, an effect which appears to be augmented by obesity and metabolic dysfunction and exposure to different treatment regimes.
Accurate assays for the detection of antibodies to SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) are essential for the control of the COVID-19 (coronavirus disease 2019) pandemic. ...Here, we report antibody and antibody-avidity assays, relying on near-infrared-fluorescence amplification by nanostructured plasmonic gold substrates, for the simultaneous detection of antibodies to the S1 subunit of the spike protein and to the receptor binding domain of SARS-CoV-2 in human serum and saliva, and for quantifying immunoglobulin avidities against coronavirus antigens from SARS-CoV-2, SARS-CoV-1 and the common-cold viruses OC43, HKU1, NL63 and 229E. The antibody assay detected immunoglobulin M in 87% (52 of 60) COVID-19-positive serum samples collected 6 or more days after symptom onset (and the immunoglobulins M and G in all 33 samples collected at least 15 days after symptom onset), and correctly classified 456 out of the 457 COVID-19-negative serum samples tested (424 of them collected before the pandemic, including 73 that were positive for other viruses). We used the antibody-avidity assay to study antibody-maturation patterns, anamnestic responses, and cross-immunity to the common-cold coronaviruses.
Background:
Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. Epidermal growth factor receptor (EGFR) has been shown to be ...over-expressed in TNBC and represents a rational treatment target.
Methods:
We examined single agent and combination effects for afatinib and dasatinib in TNBC. We then determined IC50 and combination index values using Calcusyn. Functional analysis of single and combination treatments was performed using reverse phase protein array and cell cycle analysis. Finally, we determined the anticancer effects of the combination in vivo.
Results:
A total of 14 TNBC cell lines responded to afatinib with IC50 values ranging from 0.008 to 5.0 µM. Three cell lines, belonging to the basal-like subtype of TNBC, were sensitive to afatinib. The addition of afatinib enhanced response to the five other targeted therapies in HCC1937 and HDQP1 cells. The combination of afatinib with dasatinib caused the greatest growth inhibition in both cell lines. The afatinib/dasatinib combination was synergistic and/or additive in 13/14 TNBC cell lines. Combined afatinib/dasatinib treatment induced G1 cell cycle arrest. Reverse phase protein array results showed the afatinib/dasatinib combination resulted in efficient inhibition of both pERK(T202/T204) and pAkt(S473) signalling in BT20 cells, which was associated with the greatest antiproliferative effects. High baseline levels of pSrc(Y416) and pMAPK(p38) correlated with sensitivity to afatinib, whereas low levels of B-cell lymphoma 2 (Bcl2) and mammalian target of rapamycin (mTOR) correlated with synergistic growth inhibition by combined afatinib and dasatinib treatment. In vivo, the combination treatment inhibited tumour growth in a HCC1806 xenograft model.
Conclusions:
We demonstrate that afatinib combined with dasatinib has potential clinical activity in TNBC but warrants further preclinical investigation.
Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ ...localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.
The body condition score (BCS) of a dairy cow is an assessment of the proportion of body fat that it possesses, and it is recognized by animal scientists and producers as being an important factor in ...dairy cattle management. The scale used to measure BCS differs between countries, but low values always reflect emaciation and high values equate to obesity. The intercalving profile of BCS is a mirror image of the milk lactation profile. Cows lose condition for 50 to 100 d postcalving, because of homeorhetic changes that occur in the somatotropic axis and the sensitivity of peripheral tissues to insulin, and the upregulation of lipolytic pathways in adipose tissue. Management and feeding have little effect on early postcalving BCS loss (wk 1 to 4 postcalving) until the natural period of insulin resistance has passed and the somatotropic axis has recoupled. There is evidence, however, that management and diet can influence the timing of recoupling of the somatotropic axis and the sensitivity of peripheral tissues to insulin, and gene expression differences in adipose tissue 30 d in milk confirm an effect of energy intake on lipogenic enzymes. The BCS in which a cow calves, nadir BCS, and the amount of BCS she loses postcalving are associated with milk production, reproduction, and health. Body condition score may also be a valid indicator of animal welfare, but further research is required to determine the effect of BCS and BCS change on how a cow “feels.” Although the actual strength of the association may vary, there is relative consistency in the associations among calving and nadir BCS, and BCS change on milk production, postpartum anestrous, the likelihood of a successful pregnancy and days open, the risk of uterine infection, and the risk of metabolic disorders. For many production and health variables, the association with BCS is nonlinear, with an optimum calving BCS of 3.0 to 3.25 (5-point scale); lower calving BCS is associated with reduced production and reproduction, whereas calving BCS ≥3.5 (5-point scale) is associated with a reduction in early lactation dry matter intake and milk production and an increased risk of metabolic disorders. Ongoing research into the automation of body condition scoring suggests that it is a likely candidate to be incorporated into decision support systems in the near future to aid producers in making operational and tactical decisions.
Measuring the abundances of carbon and oxygen in exoplanet atmospheres is considered a crucial avenue for unlocking the formation and evolution of exoplanetary systems
. Access to the chemical ...inventory of an exoplanet requires high-precision observations, often inferred from individual molecular detections with low-resolution space-based
and high-resolution ground-based
facilities. Here we report the medium-resolution (R ≈ 600) transmission spectrum of an exoplanet atmosphere between 3 and 5 μm covering several absorption features for the Saturn-mass exoplanet WASP-39b (ref.
), obtained with the Near Infrared Spectrograph (NIRSpec) G395H grating of JWST. Our observations achieve 1.46 times photon precision, providing an average transit depth uncertainty of 221 ppm per spectroscopic bin, and present minimal impacts from systematic effects. We detect significant absorption from CO
(28.5σ) and H
O (21.5σ), and identify SO
as the source of absorption at 4.1 μm (4.8σ). Best-fit atmospheric models range between 3 and 10 times solar metallicity, with sub-solar to solar C/O ratios. These results, including the detection of SO
, underscore the importance of characterizing the chemistry in exoplanet atmospheres and showcase NIRSpec G395H as an excellent mode for time-series observations over this critical wavelength range
.
The Saturn-mass exoplanet WASP-39b has been the subject of extensive efforts to determine its atmospheric properties using transmission spectroscopy
. However, these efforts have been hampered by ...modelling degeneracies between composition and cloud properties that are caused by limited data quality
. Here we present the transmission spectrum of WASP-39b obtained using the Single-Object Slitless Spectroscopy (SOSS) mode of the Near Infrared Imager and Slitless Spectrograph (NIRISS) instrument on the JWST. This spectrum spans 0.6-2.8 μm in wavelength and shows several water-absorption bands, the potassium resonance doublet and signatures of clouds. The precision and broad wavelength coverage of NIRISS/SOSS allows us to break model degeneracies between cloud properties and the atmospheric composition of WASP-39b, favouring a heavy-element enhancement ('metallicity') of about 10-30 times the solar value, a sub-solar carbon-to-oxygen (C/O) ratio and a solar-to-super-solar potassium-to-oxygen (K/O) ratio. The observations are also best explained by wavelength-dependent, non-grey clouds with inhomogeneous coverageof the planet's terminator.
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