Ball milling has been applied in numerous solvent‐free carbon‐carbon bond formations. In many cases, these transformations proved superior to the analogous reactions performed in solution. The ...reaction scope involves purely organic addition and coupling reactions, transformations involving metals (in stoichiometric and catalytic amounts) as well as asymmetric organocatalyses.
The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA-mutated (PIK3CAmut) breast cancer ...(BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib.
Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/HER2-), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2- advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay.
Patients with PIK3CAmut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CAmut BC. Among patients with double PIK3CAmut tumors (12% of all PIK3CAmut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CAmut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2- BC were not part of the therascreen panel.
PIK3CA mutations in BC are heterogenous and ~ 20% of patients with a known PIK3CA mutation, and 95% with a known double PIK3CAmut tumor, would not be captured by the therascreen panel. Finally, the clinical utility of PIK3CA mutations not present in the therascreen companion diagnostic assay or identified by other sequencing-based assays needs further investigation.
Identification of mycobacteria by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) requires not only a good protein extraction protocol but also an adequate ...cutoff score in order to provide reliable results. The aim of this study was to assess the cutoff scores proposed by the MALDI-TOF MS system for mycobacterial identification. A total of 693 clinical isolates from a liquid medium and 760 from a solid medium were analyzed, encompassing 67 different species of nontuberculous mycobacteria (NTM). MALDI-TOF MS identified 558 (80.5%) isolates from the liquid medium and 712 (93.7%) isolates from the solid medium with scores of ≥1.60. Among these, four (0.7%) misidentifications were obtained from the liquid medium and four (0.5%) from the solid medium. With regard to species diversity, MALDI-TOF MS successfully identified 64 (95.5%) different species, while PCR-reverse hybridization (GenoType
CM and AS assays) identified 24 (35.8%) different species. With MALDI-TOF MS scores of ≥2, all isolates were correctly identified, and with scores in the range from 1.60 to 1.99, most isolates were correctly identified, except for
,
,
,
, and
In conclusion, MALDI-TOF MS is a useful method for identifying a large diversity of NTM species. A score threshold of 1.60 proved useful for identifying almost all the isolates tested; only a few species required a higher score (≥2.00) to obtain a valid definitive identification.
Anti‐aldol products with up to >99 % enantiomeric excess (ee) have been obtained by proline catalysis in excellent yields under experimentally simple solvent‐free conditions. Efficient mixing of all ...the components is accomplished by applying a mechanochemical technique (ball milling). The catalysis is air and moisture tolerant and can be performed with non‐purified starting materials. Even mixtures of solely solid compounds react, giving (mostly solid) products through a partially homogeneous (honey‐like) intermediate melt. Since the reactant ratio is almost 1:1 (avoiding the common excess of ketone), the product isolation is easy leading to high aldol product yields.
Organocatalysis in a ball mill: Under experimentally simple solvent‐free conditions in a ball mill, anti‐aldol products with up to >99 % enantiomeric excess (ee) are formed (see scheme). The effects of concentration, water and impurities on the reaction outcome are also discussed.
Abstract
We use a conceptual recharge oscillator model to identify changes in El Niño and the Southern Oscillation (ENSO) statistics and dynamics during the observational record. The variability of ...ENSO has increased during the 20th century. The cross-correlation between sea surface temperature (SST) and warm water volume (WWV) has also changed during the observational record. From the 1970s onwards, the SST drives WWV anomalies with a lead-time of ten months and the WWV feedbacks onto the SST with a lead-time of eight months. This is reminiscent of a recharge-discharge mechanism of the upper ocean heat content. The full recharge-discharge mechanism is only observed from the 1970s onwards. This could be the result of the degradation of the quality of observations in the early part of the 20th century. However, it may also be a consequence of decadal changes in the coupling between WWV and SST. Additional analysis fitting the recharge oscillator model to the coupled state-of-the-art climate models indicates that ENSO properties show little decadal changes in the climate models. The disagreement in changes in ENSO properties between the reanalysis and the climate models can be due to errors in the available observational data or due to the models missing the low frequency variability and decadal wind trends. Longer and more reliable observational records would be required to validate our results.
Demineralization of dental hard tissue is a widespread problem and the main responsible for dental caries and dentin hypersensitivity. The most promising strategies to induce the precipitation of new ...mineral phase are the application of materials releasing gradually Ca
and PO
ions or mimicking the mineral phase of the host tissue. However, the design of formulations covering both processes is so far a challenge in preventive dentistry. In this work, we have synthesized innovative biomimetic amorphous calcium phosphate (ACP), which has been, for the first time, doped with fluoride ions (FACP) to obtain materials with enhanced anti-caries and remineralizing properties. Significantly, the doping with fluoride (F) did not vary the physico-chemical features of ACP but resulted in a faster conversion to the crystalline apatite phase in water, as observed by in-situ time-dependent Raman experiments. The efficacy of the as synthesized ACP and FACP samples to occlude dentinal tubules and induce enamel remineralization has been tested in vitro in human molar teeth. The samples showed good ability to partially occlude the tubules of acid-etched dentin and to restore demineralized enamel into its native structure. Results demonstrate that ACP and FACP are promising biomimetic materials in preventive dentistry to hinder demineralization of dental hard tissues.
COVID-19 has dramatically struck each section of our society: health, economy, employment, and mobility. This work presents a data-driven characterization of the impact of COVID-19 pandemic on public ...and private mobility in a mid-size city in Spain (Fuenlabrada). Our analysis used real data collected from the public transport smart card system and a Bluetooth traffic monitoring network, from February to September 2020, thus covering relevant phases of the pandemic. Our results show that, at the peak of the pandemic, public and private mobility dramatically decreased to 95% and 86% of their pre-COVID-19 values, after which the latter experienced a faster recovery. In addition, our analysis of daily patterns evidenced a clear change in the behavior of users towards mobility during the different phases of the pandemic. Based on these findings, we developed short-term predictors of future public transport demand to provide operators and mobility managers with accurate information to optimize their service and avoid crowded areas. Our prediction model achieved a high performance for pre- and post-state-of-alarm phases. Consequently, this work contributes to enlarging the knowledge about the impact of pandemic on mobility, providing a deep analysis about how it affected each transport mode in a mid-size city.
COVID-19 has become a major global issue with large social-economic and health impacts, which led to important changes in people's behavior. One of these changes affected the way people use public ...transport. In this work we present a data-driven analysis of the impact of COVID-19 on public transport demand in the Community of Madrid, Spain, using data from ticket validations between February and September 2020. This period of time covers all stages of pandemic in Spain, including de-escalation phases. We find that ridership has dramatically decreased by 95% at the pandemic peak, recovering very slowly and reaching only half its pre-pandemic levels at the end of September. We analyze results for different transport modes, ticket types, and groups of users. Our work corroborates that low-income groups are the most reliant on public transportation, thus observing significantly lower decreases in their ridership during pandemic. This paper also shows different average daily patterns of public transit demand during each phase of the pandemic in Madrid. All these findings provide relevant information for transit agencies to design responses to an emergence situation like this pandemic, contributing to extend the global knowledge about COVID-19 impact on transport comparing results with other cities worldwide.
•A data-driven analysis of the impact of COVID-19 on public transport demand in the Community of Madrid (Spain) is presented.•Results for different transport modes, ticket types, and groups of users are presented, covering all stages of pandemic.•Ridership has decreased by 95 % at the pandemic peak, recovering very slowly and reaching only half its pre-pandemic level.•Low-income groups are the most reliant on public transportation, observing significantly lower ridership decreases.
The mechanisms translating global circulation changes into rapid abrupt shifts in forest carbon capture in semi‐arid biomes remain poorly understood. Here, we report unprecedented multidecadal shifts ...in forest carbon uptake in semi‐arid Mediterranean pine forests in Spain over 1950–2012. The averaged carbon sink reduction varies between 31% and 37%, and reaches values in the range of 50% in the most affected forest stands. Regime shifts in forest carbon uptake are associated with climatic early warning signals, decreased forest regional synchrony and reduced long‐term carbon sink resilience. We identify the mechanisms linked to ocean multidecadal variability that shape regime shifts in carbon capture. First, we show that low‐frequency variations of the surface temperature of the Atlantic Ocean induce shifts in the non‐stationary effects of El Niño Southern Oscillation (ENSO) on regional forest carbon capture. Modelling evidence supports that the non‐stationary effects of ENSO can be propagated from tropical areas to semi‐arid Mediterranean biomes through atmospheric wave trains. Second, decadal changes in the Atlantic Multidecadal Oscillation (AMO) significantly alter sea–air heat exchanges, modifying in turn ocean vapour transport over land and land surface temperatures, and promoting sustained drought conditions in spring and summer that reduce forest carbon uptake. Third, we show that lagged effects of AMO on the winter North Atlantic Oscillation also contribute to the maintenance of long‐term droughts. Finally, we show that the reported strong, negative effects of ocean surface temperature (AMO) on forest carbon uptake in the last decades are unprecedented over the last 150 years. Our results provide new, unreported explanations for carbon uptake shifts in these drought‐prone forests and review the expected impacts of global warming on the profiled mechanisms.
We provide a description of regime shifts of forest carbon sinks in Mediterranean forests (Pinus halepensis Mill.) over 1950–2012. We demonstrate that non‐stationary effects of ocean surface temperature determine the onset of regime shifts of forest carbon uptake. ENSO effects regulated by ocean multidecadal variability (AMO–AMOC) are key in the emergence of multidecadal changes in forest carbon sink activity. The reported negative effects of ocean surface temperature (SST) trends on forest carbon uptake for the last decades are unprecedented over the last 150 years.
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