Formal Total Synthesis of Kendomycin by Way of Alkyne Metathesis/Gold Catalysis

In an attempt to study the ability of the latest generation of alkyne metathesis catalysts to process sterically hindered substrates, two different routes to the bacterial metabolite kendomycin (1) were explored. Whereas the cyclization of the overcrowded arylalkyne 39 and related substrates turned out to be impractical or even impossible, ring closure of the slightly relaxed diyne 45 was achieved in excellent yield under notably mild conditions with the aid of the molybdenum alkylidyne 2 endowed with triphenylsilanolate ligands. The resulting cycloalkyne 46 was engaged into a gold-catalyzed hydroalkoxylation, which led to benzofuran 47 that had already previously served as a late-stage intermediate en route to 1

Learning a second language via print: on the logical necessity of a fluent first language

How Deaf children should be taught to read has long been debated. Severely or profoundly Deaf children, who face challenges in acquiring language from its spoken forms, must learn to read a language they do not speak. We refer to this as learning a language via print. How children can learn language via print is not a topic regularly studied by educators, psychologists, or language acquisition theorists. Nonetheless, Deaf children can do this. We discuss how Deaf children can learn a written language via print by mapping print words and phrases to sign language sequences. However, established, time-tested curricula for using a signed language to teach the print forms of spoken languages do not exist. We describe general principles for approaching this task, how it differs from acquiring a spoken language naturalistically, and empirical evidence that Deaf children's knowledge of a signed language facilitates and advances learning a printed language.nstitute of Education Sciences (US Dept of Education) Education Research Training Granthttps://doi.org/10.3389/fcomm.2022.900399Published versio

The anomalous Cepheid XZ Ceti

XZ Ceti is the only known anomalous Cepheid in the Galactic field. Being the nearest and brightest such variable star, a detailed study of XZ Ceti may shed light on the behaviour of anomalous Cepheids whose representatives have been mostly detected in external galaxies. CCD photometric and radial velocity observations have been obtained. The actual period and amplitude of pulsation were determined by Fourier analysis. The long time scale behaviour of the pulsation period was studied by the method of the O-C diagram using the archival Harvard photographic plates and published photometric data. XZ Ceti differs from the ordinary classical Cepheids in several respects. Its most peculiar feature is cycle-to-cycle variability of the light curve. The radial velocity phase curve is not stable either. The pulsation period is subjected to strong changes on various time scales including a very short one. The ratio of amplitudes determined from the photometric and radial velocity observations indicates that this Cepheid performs an overtone pulsation, in accord with the other known anomalous Cepheid in our Galaxy, BL Boo (V19 in the globular cluster NGC 5466). Continued observations are necessary to study the deviations from regularity, to determine their time scale, as well as to confirm binarity of XZ Ceti and to study its role in the observed peculiar behaviour.Comment: 7 pages, 4 figures. accepted for Astron. Astrophy

Evaluating the accuracy of two: In situ optical sensors to estimate DOC concentrations for drinking water production

Two in situ optical sensors, a single-excitation fluorescence-based sensor (fDOM) mounted on a multi-parameter EXO2 sonde (YSI), and a stand-alone, multispectral absorbance-based instrument (spectro::lyser, scan Messtechnik GmbH), were evaluated for their capability to (i) estimate river dissolved organic carbon (DOC) concentrations and (ii) provide oversight of drinking water production. The sensors were deployed between March and November 2017 in the river Fyris, which drains a mixed forested and agricultural 2003 km$^{2}$ catchment and serves as a drinking water source by managed aquifer recharge. Grab samples were collected every 2 to 3 weeks and compared with logged sensor data collected at 15 minute intervals. The fDOM probe signal was used to estimate DOC concentrations in the range of 10.4 to 24.4 mg L$^{-1}$ using linear regression (R$^{2}$ = 0.71, RMSE = 2.5 mg L$^{-1}$), after correction for temperature, turbidity and inner-filter effects. Temporal changes in DOC character associated with the mixed land use landscape, as indicated by optical indices, reduced this sensor accuracy for estimating DOC concentration. Nevertheless, humic substance concentrations, the fraction of DOC that is preferentially removed during artificial infiltration, were well captured. The spectrolyser signal was used to establish a 2-component partial least square model that captured DOC fluctuations from 10.2 to 29.4 mg L$^{-1}$ (R$^{2}$ = 0.92; RMSE = 1.3 mg L$^{-1}$). This multiple-wavelength model (220 to 720 nm) effectively handled the changes in DOC composition while accurately estimating DOC concentrations. This study explores the advantages and limitations of optical sensors for their use in managed aquifer recharge and drinking water production in relation to DOC levels

Tidal disruption of NEAs - a case of P\v{r}\'ibram

This work studies the dynamical evolution of a possible meteor stream along the orbit of the P\v{r}\'{i}bram meteorite, which originated in the tidal disruption of the putative rubble-pile-like parent body during a close approach to the Earth. We assumed the disruption at the time when the ascending or descending node of the parent orbit was close to the Earth's orbit. In the last 5000 years, the P\v{r}\'{i}bram orbit has crossed the Earth orbit twice. It happened about 4200 years and 3300 years ago. In both cases, we modeled the release of particles from the simplified model of rotating asteroid, and traced their individual orbital evolution to the current date. It takes several hundred years to spread released meteoroids along the entire orbit of the parent body. Even today, the stream would be relatively narrow. Considering a model parent body with physical parameters of the asteroid Itokawa, the complete disintegration of the object produced 3.8$\times10^{11}$ meteoroid particles with diameter $\geq$ 1\,cm. The meteor activity observed from the Earth is revealed and justification of follow-up observation during suggested activity of the shower in the first two weeks of April is discussed. The Earth's tidal forces would disintegrate a fraction of NEA population into smaller objects. We evaluate the upper limit of mass of disintegrated asteroids within the mean NEA lifetime and the contribution of disrupted matter to the size distribution of the NEA.Comment: 8 pages, 10 figure

Inspiratory threshold loading reduces lipoperoxidation in obese and normal-weight subjects

Obesity is related to increased oxidative stress. Although low-intensity physical exercise reduces oxidative stress, obese subjects may show exercise intolerance. For these subjects, inspiratory threshold loading could be an alternative tool to reduce oxidative stress. We investigated the effects of inspiratory threshold loading on biomarkers of oxidative stress in obese and normal-weight subjects. Twenty obese (31.4 ± 6 years old, 10 men and 10 women, 37.5 ± 4.7 kg/m2) and 20 normal-weight (29.4 ± 8 years old, 10 men and 10 women, 23.2 ± 1.5 kg/m2) subjects matched for age and gender participated in the study. Maximal inspiratory pressure (MIP) was assessed by a pressure transducer. Blood sampling was performed before and after loading and control protocols to assess thiobarbituric acid reactive substances (TBARS), protein carbonylation, and reduced glutathione. Inspiratory threshold loading was performed at 60% MIP and maintained until task failure. The 30-min control protocol was performed at 0 cmH2O. Our results demonstrated that inspiratory threshold loading reduced TBARS across time in obese (6.21 ± 2.03 to 4.91 ± 2.14 nmol MDA/ml) and normal-weight subjects (5.60 ± 3.58 to 4.69 ± 2.80 nmol MDA/ml; p = 0.007), but no change was observed in protein carbonyls and glutathione in both groups. The control protocol showed no significant changes in TBARS and protein carbonyls. However, reduced glutathione was increased across time in both groups (obese: from 0.50 ± 0.37 to 0.56 ± 0.35 μmol GSH/ml; normal-weight: from 0.61 ± 0.11 to 0.81 ± 0.23 μmol GSH/ml; p = 0.002). These findings suggest that inspiratory threshold loading could be potentially used as an alternative tool to reduce oxidative stress in both normal-weight and obese individuals

Total Synthesis of an Exceptional Brominated 4-Pyrone Derivative of Algal Origin: An Exercise in Gold Catalysis and Alkyne Metathesis

A concise approach to the algal metabolite 1 is described, which also determines the previously unknown stereostructure of this natural product. Compound 1 is distinguished by a rare brominated 4-pyrone nucleus linked as a ketene–acetal to a polyunsaturated macrocyclic scaffold comprising an extra homoallylic bromide entity. The synthesis of 1 is based on the elaboration and selective functionalization of the linear precursor 23 endowed with no less than six different sites of unsaturation including the highly enolized oxo-alkanoate function. Key to success was the formation of the 2-alkoxy-4-pyrone ring by a novel gold-catalyzed transformation which engages only the acetylenic β-ketoester substructure of 23 but leaves all other π-bonds untouched. The synthesis was completed by a ring-closing alkyne metathesis to forge the signature cycloalkyne motif of 1 followed by selective bromination of the ketene–acetal site in the resulting product 27 without touching the skipped diene–yne substructure resident within the macrocyclic tether

Secretion of iron(III)-reducing metabolites during protein acquisition by the ectomycorrhizal fungus paxillus involutus

The ectomycorrhizal fungus Paxillus involutus decomposes proteins using a two-step mechanism, including oxidation and proteolysis. Oxidation involves the action of extracellular hydroxyl radicals (•OH) generated by the Fenton reaction. This reaction requires the presence of iron(II). Here, we monitored the speciation of extracellular iron and the secretion of iron(III)-reducing metabolites during the decomposition of proteins by P. involutus. X-ray absorption spectroscopy showed that extracellular iron was mainly present as solid iron(III) phosphates and oxides. Within 1 to 2 days, these compounds were reductively dissolved, and iron(II) complexes were formed, which remained in the medium throughout the incubation. HPLC and mass spectrometry detected five extracellular iron(III)-reducing metabolites. Four of them were also secreted when the fungus grew on a medium containing ammonium as the sole nitrogen source. NMR identified the unique iron(III)-reductant as the diarylcyclopentenone involutin. Involutin was produced from day 2, just before the elevated •OH production, preceding the oxidation of BSA. The other, not yet fully characterized iron(III)-reductants likely participate in the rapid reduction and dissolution of solid iron(III) complexes observed on day one. The production of these metabolites is induced by other environmental cues than for involutin, suggesting that they play a role beyond the Fenton chemistry associated with protein oxidation

Predicting survival from colorectal cancer histology slides using deep learning: A retrospective multicenter study

BACKGROUND: For virtually every patient with colorectal cancer (CRC), hematoxylin-eosin (HE)-stained tissue slides are available. These images contain quantitative information, which is not routinely used to objectively extract prognostic biomarkers. In the present study, we investigated whether deep convolutional neural networks (CNNs) can extract prognosticators directly from these widely available images. METHODS AND FINDINGS: We hand-delineated single-tissue regions in 86 CRC tissue slides, yielding more than 100,000 HE image patches, and used these to train a CNN by transfer learning, reaching a nine-class accuracy of >94% in an independent data set of 7,180 images from 25 CRC patients. With this tool, we performed automated tissue decomposition of representative multitissue HE images from 862 HE slides in 500 stage I-IV CRC patients in the The Cancer Genome Atlas (TCGA) cohort, a large international multicenter collection of CRC tissue. Based on the output neuron activations in the CNN, we calculated a "deep stroma score," which was an independent prognostic factor for overall survival (OS) in a multivariable Cox proportional hazard model (hazard ratio [HR] with 95% confidence interval [CI]: 1.99 [1.27-3.12], p = 0.0028), while in the same cohort, manual quantification of stromal areas and a gene expression signature of cancer-associated fibroblasts (CAFs) were only prognostic in specific tumor stages. We validated these findings in an independent cohort of 409 stage I-IV CRC patients from the "Darmkrebs: Chancen der Verhütung durch Screening" (DACHS) study who were recruited between 2003 and 2007 in multiple institutions in Germany. Again, the score was an independent prognostic factor for OS (HR 1.63 [1.14-2.33], p = 0.008), CRC-specific OS (HR 2.29 [1.5-3.48], p = 0.0004), and relapse-free survival (RFS; HR 1.92 [1.34-2.76], p = 0.0004). A prospective validation is required before this biomarker can be implemented in clinical workflows. CONCLUSIONS: In our retrospective study, we show that a CNN can assess the human tumor microenvironment and predict prognosis directly from histopathological images