The binding and cytochrome P45051 (CYP51) inhibition properties of a novel antifungal compound, VT-1161, against purified recombinant Candida albicans CYP51 (ERG11) and Homo sapiens CYP51 were ...compared with those of clotrimazole, fluconazole, itraconazole, and voriconazole. VT-1161 produced a type II binding spectrum with Candida albicans CYP51, characteristic of heme iron coordination. The binding affinity of VT-1161 for Candida albicans CYP51 was high (dissociation constant Kd, ≤ 39 nM) and similar to that of the pharmaceutical azole antifungals (Kd, ≤ 50 nM). In stark contrast, VT-1161 at concentrations up to 86 μM did not perturb the spectrum of recombinant human CYP51, whereas all the pharmaceutical azoles bound to human CYP51. In reconstitution assays, VT-1161 inhibited Candida albicans CYP51 activity in a tight-binding fashion with a potency similar to that of the pharmaceutical azoles but failed to inhibit the human enzyme at the highest concentration tested (50 μM). In addition, VT-1161 (MIC = 0.002 μg ml(-1)) had a more pronounced fungal sterol disruption profile (increased levels of methylated sterols and decreased levels of ergosterol) than the known CYP51 inhibitor voriconazole (MIC = 0.004 μg ml(-1)). Furthermore, VT-1161 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. In summary, VT-1161 potently inhibited Candida albicans CYP51 and culture growth but did not inhibit human CYP51, demonstrating a >2,000-fold selectivity. This degree of potency and selectivity strongly supports the potential utility of VT-1161 in the treatment of Candida infections.
Efficient lower hybrid current drive (LHCD) is demonstrated at densities up to nover ¯_{e}≈1.5×10^{20} m^{-3} in diverted plasmas on the Alcator C-Mod tokamak by operating at increased plasma ...current-and therefore reduced Greenwald density fraction. This density exceeds the nominal "LH density limit" at nover ¯_{e}≈1.0×10^{20} m^{-3} reported previously, above which an anomalous loss of current drive efficiency was observed. The recovery of current drive efficiency to a level consistent with engineering scalings is correlated with a reduction in density shoulders and turbulence levels in the far scrape-off layer. Concurrently, rf wave interaction with the edge and/or scrape-off-layer plasma is reduced, as indicated by a minimal broadening of the wave frequency spectrum measured at the plasma edge. These results have important implications for sustaining steady-state tokamak operation and indicate a pathway forward for implementing efficient LHCD in a reactor.
Summary
Background
Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti‐fibrotic therapies are available; however, ...several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD.
Aim
To standardise definitions, diagnosis and treatment targets for anti‐fibrotic stricture therapies in Chron's disease.
Methods
An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting.
Results
Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre‐stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post‐prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24‐48 weeks is considered the appropriate endpoint in pharmacological trials.
Conclusions
Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design.
Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important ...means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here.
Key Points
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Tumour vascular function is key to tumour development and treatment
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Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function
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Thus DCE-MRI with pharmacokinetic models can assess novel treatments
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Many recent developments are advancing the accuracy of and information from DCE-MRI
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Establishing common methodology across multiple centres is challenging and requires accepted guidelines
Opportunity has investigated in detail rocks on the rim of the Noachian age Endeavour crater, where orbital spectral reflectance signatures indicate the presence of Fe(+3)-rich smectites. The ...signatures are associated with fine-grained, layered rocks containing spherules of diagenetic or impact origin. The layered rocks are overlain by breccias, and both units are cut by calcium sulfate veins precipitated from fluids that circulated after the Endeavour impact. Compositional data for fractures in the layered rocks suggest formation of Al-rich smectites by aqueous leaching. Evidence is thus preserved for water-rock interactions before and after the impact, with aqueous environments of slightly acidic to circum-neutral pH that would have been more favorable for prebiotic chemistry and microorganisms than those recorded by younger sulfate-rich rocks at Meridiani Planum.
AbstractObjectiveTo compare the effectiveness of sotrovimab (a neutralising monoclonal antibody) with molnupiravir (an antiviral) in preventing severe outcomes of covid-19 in adult patients infected ...with SARS-CoV-2 in the community and at high risk of severe outcomes from covid-19.DesignObservational cohort study with the OpenSAFELY platform.SettingWith the approval of NHS England, a real world cohort study was conducted with the OpenSAFELY-TPP platform (a secure, transparent, open source software platform for analysis of NHS electronic health records), and patient level electronic health record data were obtained from 24 million people registered with a general practice in England that uses TPP software. The primary care data were securely linked with data on SARS-CoV-2 infection and treatments, hospital admission, and death, over a period when both drug treatments were frequently prescribed in community settings.ParticipantsAdult patients with covid-19 in the community at high risk of severe outcomes from covid-19, treated with sotrovimab or molnupiravir from 16 December 2021.InterventionsSotrovimab or molnupiravir given in the community by covid-19 medicine delivery units.Main outcome measuresAdmission to hospital with covid-19 (ie, with covid-19 as the primary diagnosis) or death from covid-19 (ie, with covid-19 as the underlying or contributing cause of death) within 28 days of the start of treatment.ResultsBetween 16 December 2021 and 10 February 2022, 3331 and 2689 patients were treated with sotrovimab and molnupiravir, respectively, with no substantial differences in baseline characteristics. Mean age of all 6020 patients was 52 (standard deviation 16) years; 59% were women, 89% were white, and 88% had received three or more covid-19 vaccinations. Within 28 days of the start of treatment, 87 (1.4%) patients were admitted to hospital or died of infection from SARS-CoV-2 (32 treated with sotrovimab and 55 with molnupiravir). Cox proportional hazards models stratified by area showed that after adjusting for demographic information, high risk cohort categories, vaccination status, calendar time, body mass index, and other comorbidities, treatment with sotrovimab was associated with a substantially lower risk than treatment with molnupiravir (hazard ratio 0.54, 95% confidence interval 0.33 to 0.88, P=0.01). Consistent results were found from propensity score weighted Cox models (0.50, 0.31 to 0.81, P=0.005) and when restricted to people who were fully vaccinated (0.53, 0.31 to 0.90, P=0.02). No substantial effect modifications by other characteristics were detected (all P values for interaction >0.10). The findings were similar in an exploratory analysis of patients treated between 16 February and 1 May 2022 when omicron BA.2 was the predominant variant in England.ConclusionsIn routine care of adult patients in England with covid-19 in the community, at high risk of severe outcomes from covid-19, those who received sotrovimab were at lower risk of severe outcomes of covid-19 than those treated with molnupiravir.
The New Horizons spacecraft's encounter with the cold classical Kuiper Belt object (486958) Arrokoth (provisional designation 2014 MU
) revealed a contact-binary planetesimal. We investigated how ...Arrokoth formed and found that it is the product of a gentle, low-speed merger in the early Solar System. Its two lenticular lobes suggest low-velocity accumulation of numerous smaller planetesimals within a gravitationally collapsing cloud of solid particles. The geometric alignment of the lobes indicates that they were a co-orbiting binary that experienced angular momentum loss and subsequent merger, possibly because of dynamical friction and collisions within the cloud or later gas drag. Arrokoth's contact-binary shape was preserved by the benign dynamical and collisional environment of the cold classical Kuiper Belt and therefore informs the accretion processes that operated in the early Solar System.
Residual feed intake (RFI) and feed saved (FS) are important feed efficiency traits that have been increasingly considered in genetic improvement programs. Future sustainability of these genetic ...evaluations will depend upon greater flexibility to accommodate sparsely recorded dry matter intake (DMI) records on many more cows, especially from commercial environments. Recent multiple-trait random regression (MTRR) modeling developments have facilitated days in milk (DIM)-specific inferences on RFI and FS, particularly in modeling the effect of change in metabolic body weight (MBW). The MTRR analyses, using daily data on the core traits of DMI, MBW, and milk energy (MilkE), were conducted separately for 2,532 primiparous and 2,379 multiparous US Holstein cows from 50 to 200 DIM. Estimated MTRR variance components were used to derive genetic RFI and FS and DIM-specific genetic partial regressions of DMI on MBW, MilkE, and change in MBW. Estimated daily heritabilities of RFI and FS varied across lactation for both primiparous (0.05–0.07 and 0.11–0.17, respectively) and multiparous (0.03–0.13 and 0.10–0.17, respectively) cows. Genetic correlations of RFI across DIM varied (>0.05) widely compared with FS (>0.54) within either parity class. Heritability estimates based on average lactation-wise measures were substantially larger than daily heritabilities, ranging from 0.17 to 0.25 for RFI and from 0.35 to 0.41 for FS. The partial genetic regression coefficients of DMI on MBW (0.11 to 0.16 kg/kg0.75 for primiparous and 0.12 to 0.14 kg/kg0.75 for multiparous cows) and of DMI on MilkE (0.45 to 0.68 kg/Mcal for primiparous and 0.36 to 0.61 kg/Mcal for multiparous cows) also varied across lactation. In spite of the computational challenges encountered with MTRR, the model potentially facilitates an efficient strategy for harnessing more data involving a wide variety of data recording scenarios for genetic evaluations on feed efficiency.
A green and scalable method to synthesize organic luminophores with minimal aggregation caused quenching (ACQ) is reported where direct arylation is used to attach alkylated theobromine moieties onto ...luminophores. The resulting compounds demonstrated high photoluminescence quantum yields (PLQYs) in solution and as aggregates. The minimized ACQ can be ascribed to the large dihedral angles that theobromine moieties introduce into these molecules, preventing π-π interactions between the luminophores. Furthermore, the large dihedral angles promote the formation of hybridized local and charge-transfer states in these molecules. Finally, amplified spontaneous emission measurements were performed to explore their potential in lasers.
Green chemistry and a natural product together provide a cost-effective, safe and scalable solution to create luminophores with suppressed aggregation quenching in organic semiconductors.
The Atacama Cosmology Telescope was designed to measure small-scale anisotropies in the cosmic microwave background and detect galaxy clusters through the Sunyaev-Zel'dovich effect. The instrument is ...located on Cerro Toco in the Atacama Desert, at an altitude of 5190 m. A 6 m off-axis Gregorian telescope feeds a new type of cryogenic receiver, the Millimeter Bolometer Array Camera. The receiver features three 1000-element arrays of transition-edge sensor bolometers for observations at 148 GHz, 218 GHz, and 277 GHz. Each detector array is fed by free space millimeter-wave optics. Each frequency band has a field of view of approximately 22' X 26'. The telescope was commissioned in 2007 and has completed its third year of operations. We discuss the major components of the telescope, camera, and related systems, and summarize the instrument performance.
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