Tree rings reveal globally coherent signature of cosmogenic radiocarbon events in 774 and 993 CE

This study was funded by the WSL-internal COSMIC project (5233.00148.001.01), the ETHZ (Laboratory of Ion Beam Physics), the Swiss National Science Foundation (SNF Grant 200021L_157187/1), and as the Czech Republic Grant Agency project no. 17-22102s.Though tree-ring chronologies are annually resolved, their dating has never been independently validated at the global scale. Moreover, it is unknown if atmospheric radiocarbon enrichment events of cosmogenic origin leave spatiotemporally consistent fingerprints. Here we measure the 14C content in 484 individual tree rings formed in the periods 770–780 and 990–1000 CE. Distinct 14C excursions starting in the boreal summer of 774 and the boreal spring of 993 ensure the precise dating of 44 tree-ring records from five continents. We also identify a meridional decline of 11-year mean atmospheric radiocarbon concentrations across both hemispheres. Corroborated by historical eye-witness accounts of red auroras, our results suggest a global exposure to strong solar proton radiation. To improve understanding of the return frequency and intensity of past cosmic events, which is particularly important for assessing the potential threat of space weather on our society, further annually resolved 14C measurements are needed.Publisher PDFPeer reviewe

A Role for Proteomics in Identifying Targets for Radiosensitizing Strategies in Melanoma: The FKBP51 Paradigm

The treatment of metastatic melanoma is challenging and in the vast majority of cases unsuccessful. Melanoma cells are resistant to most standard therapeutics. We have recently demonstrated that FKBP51 regulates melanoma response to ionizing radiation (IR). To find out molecular targets for radiosensitizing strategies to apply in this neoplasm, we investigated the changes of protein profiles in irradiated melanoma depleted or not of FKBP51, by protein microarray approach. Among the multiple molecules that were found modulated in our cell model, the decrease of several pPKC isoforms in the FKBP51-depleted (IR-sensitive) melanoma appeared to us particularly interesting, because PKC is involved in radiation response. Therefore, PKC was chosen for further investigation. After validating by western blot proteomics results, we found that targeting PKC, with the pan PKC inhibitor LY317615 or enzastaurin, significantly enhanced IR-induced cell death. Most interestingly, enzastaurin combined with IR appeared to be effective in eliminating a subset of melanoma cells expressing a stemness marker. Our study highlighted a role for proteomics in finding useful targets to overcome melanoma resistance, and suggested a combination treatment, which deserves to be investigated in a clinical setting

Pediatric Slow-Progressive, but Not Non-Progressive Cerebellar Ataxia Delays Intra-Limb Anticipatory Postural Adjustments in the Upper Arm

We recently investigated the role of the cerebellum during development, reporting that children with genetic slow-progressive ataxia (SlowP) show worse postural control during quiet stance and gait initiation compared to healthy children (H). Instead, children with genetic non-progressive ataxia (NonP) recalled the behavior of H. This may derive from compensatory networks, which are hindered by disease progression in SlowP while free to develop in NonP. In the aim of extending our findings to intra-limb postural control, we recorded, in 10 NonP, 10 SlowP and 10 H young patients, Anticipatory Postural Adjustments (APAs) in the proximal muscles of the upper-limb and preceding brisk index finger flexions. No significant differences in APA timing occurred between NonP and H, while APAs in SlowP were delayed. Indeed, the excitatory APA in Triceps Brachii was always present but significantly delayed with respect to both H and NonP. Moreover, the inhibitory APAs in the Biceps Brachii and Anterior Deltoid, which are normally followed by a late excitation, could not be detected in most SlowP children, as if inhibition was delayed to the extent where there was overlap with a late excitation. In conclusion, disease progression seems to be detrimental for intra-limb posture, supporting the idea that inter- and intra-limb postures seemingly share the same control mechanism

A small mission for in situ exploration of a primitive binary near-Earth asteroid

We present a concept for a challenging in situ science mission to a primitive, binary near-Earth asteroid. A sub-400-kg spacecraft would use solar electric propulsion to rendezvous with the C-class binary asteroid (175706) 1996 FG3. A campaign of remote observations of both worlds would be followed by landing on the 1 km diameter primary to perform in situ measurements. The total available payload mass would be around 34 kg, allowing a wide range of measurement objectives to be addressed. This mission arose during 2004 from the activities of the ad-hoc Small Bodies Group of the DLR-led Planetary Lander Initiative. Although the particular mission scenario proposed here was not studied further per se, the experience was carried over to subsequent European asteroid mission studies, including first LEONARD and now the Marco Polo near-Earth asteroid sample return proposal for ESA’s Cosmic Vision programme. This paper may thus be of interest as much for insight into the life cycle of mission proposals as for the concept itself

First virtual screening and experimental validation of inhibitors targeting GES-5 carbapenemase

The worldwide spread of beta-lactamases with hydrolytic activity extended to last resort carbapenems is aggravating the antibiotic resistance problem and endangers the successful antimicrobial treatment of clinically relevant pathogens. As recently highlighted by the World Health Organization, new strategies to contain antimicrobial resistance are urgently needed. Class A carbapenemases include members of the KPC, GES and SFC families. These enzymes have the ability to hydrolyse penicillins, cephalosporins and carbapenems, while also being less susceptible to available beta-lactam inhibitors, such as clavulanic acid. The KPC family is the most prevalent. It is mostly found on plasmids in Klebsiella pneumoniae, meaning that great amounts of attention, in terms of inhibitor design and structural biology, have been dedicated to it, whereas no efforts have yet been dedicated to GES-type enzymes, despite their ability to rapidly and horizontally disseminate. We herein report the first in silico screening against GES-5, which is the most dangerous GES-type beta-lactamase, using a library of 800K commercially available candidates that all share drug-like properties, such as their MW, logP, rotatable bonds and HBA/HBD atoms. The best screening results were filtered to enrich the number of different chemotypes, and then submitted to molecular docking. The 34 most promising candidates were selected for in vitro validation in biochemical assays against recombinant GES-5. Six hits acted as inhibitors, in the high micromolar range, towards GES-5 and led to the identification of the first, novel chemotypes with inhibitory activity against this clinically relevant carbapenemase

Thresholds for warming-induced growth decline at elevational tree line

[1] A few tree ring studies indicate recent growth declines at northern latitudes. The precise causes are not well understood. Here we identify a temperature threshold for decline in a tree ring record from a well-established temperature-sensitive site at elevational tree line in northwestern Canada. The positive ring width/temperature relationship has weakened such that a pre-1965 linear model systematically overpredicts tree ring widths from 1965 to 1999. A nonlinear model shows an inverted U-shaped relationship between this chronology and summer temperatures, with an optimal July– August average temperature of 11.3°C based on a nearby station. This optimal value has been consistently exceeded since the 1960s, and the concurrent decline demonstrates that even at tree line, trees can be negatively affected when temperatures warm beyond a physiological threshold. If warming continues without significant gains in effective precipitation, the large-scale greening of recent decades could be replaced by large-scale browning. Such browning could slow or reverse carbon uptake by norther

Cognitive and Behavioral Outcome of Pediatric Low-Grade Central Nervous System Tumors Treated Only with Surgery: A Single Center Experience

Background: The present mono-institutional report aimed to describe the cognitive and behavioral outcomes of low-grade central nervous system (CNS) tumors in a cohort of children treated exclusively with surgical intervention. Methods: Medical records from 2000–2020 were retrospectively analyzed. We included 38 children (mean age at first evaluation 8 years and 3 months, 16 females) who had undergone presurgical cognitive–behavioral evaluation and/or at least 6 months follow-up. Exclusion criteria were a history of traumatic brain injury, stroke, cerebral palsy or cancer-predisposing syndromes. Results: The sample presented cognitive abilities and behavioral functioning in the normal range, with weaknesses in verbal working memory and processing speed. The obtained results suggest that cognitive and behavioral functioning is related to pre-treatment variables (younger age at symptoms’ onset, glioneuronal histological type, cortical location with preoperative seizures), timing of surgery and seizure control after surgery, and is stable when controlling for a preoperative cognitive and behavioral baseline. Younger age at onset is confirmed as a particular vulnerability in determining cognitive sequelae, and children at older ages or at longer postsurgical follow-up are at higher risk for developing behavioral disturbances. Conclusions: Timely treatment is an important factor influencing the global outcome and daily functioning of the patients. Preoperative and regular postsurgical cognitive and behavioral assessment, also several years after surgery, should be included in standard clinical practices

Intracellular accumulation of a mild-denatured monomer of the human PrP fragment 90–231, as possible mechanism of its neurotoxic effects

Because of high tendency of the prion protein (PrP) toaggregate, the exact PrP isoform responsible for prion diseasesas well as the pathological mechanism that it activatesremains still controversial. In this study, we show that a prefibrillar,monomeric or small oligomeric conformation of thehuman PrP fragment 90–231 (hPrP90–231), rather than solubleor fibrillar large aggregates, represents the neurotoxicspecies. In particular, we demonstrate that monomeric milddenaturedhPrP90–231 (incubated for 1 h at 53C) inducesSH-SY5Y neuroblastoma cell death, while, when structured inlarge aggregates, it is ineffective. Using spectroscopic andcellular techniques we demonstrate that this toxic conformer ischaracterized by a high exposure of hydrophobic regions thatfavors the intracellular accumulation of the protein. Inside the cells hPrP90–231 is mainly compartmentalized into the lysosomeswhere it may trigger pro-apoptotic ‘cell death’ signals.The PrP toxic conformation, which we have obtained inducinga controlled in vitro conformational change of the protein,might mimic mild-unfolding events occurring in vivo, in thepresence of specific mutations, oxidative reactions or proteolysis.Thus, in light of this model, we propose that noveltherapeutic strategies, designed to inhibit the interaction of thetoxic PrP with the plasmamembrane, could be beneficial toprevent the formation of intracellular neurotoxic aggregatesand ultimately the neuronal death.[...