Climate variability may delay post-fire recovery of boreal forest in southern Siberia, Russia

Prolonged dry periods and increased temperatures that result from anthropogenic cli-22 mate change have been shown to increase the frequency and severity of wildfires in the boreal 23 region. There is growing evidence that such changes in fire regime can reduce forest resilience 24 and drive shifts in post-fire plant successional trajectories. The response of post-fire vegetation 25 communities to climate variability is under-studied, despite being a critical phase determining 26 the ultimate successional conclusion. This study investigated the responses of post-fire recruited 27 species to climate change and inter-annual variability at 16 study sites that experienced high se-28 verity fire events, mostly in early 2000, within the Scots pine forest – steppe zone of south-eastern 29 Siberia, Russia. These sites were originally dominated by Scots pine; by 2018 they were recruited 30 by different successional species. Additionally, three mature Scots pine stands were included for 31 comparison. A Bayesian Additive Regression Trees (BART) approach was used to model the re-32 lationship between Landsat-derived Normalized Difference Vegetation Index (NDVI) time se-33 ries, temperature and precipitation in the 15 years after a stand replacing fire. Using the resulting 34 BART models, together with six projected climate scenarios with increased temperature and en-35 hanced inner-annual precipitation variability, we simulated NDVI at five-year intervals for 15 36 years post-fire. Our results show that the BART models performed well, with in-sample Pseudo-37 R2 varying from 0.49 to 0.95 for fire-disturbed sites. Increased temperature enhanced greenness 38 across all sites and across all three time periods since fire, exhibiting a positive feedback in a 39 warming environment. Repeatedly dry spring periods reduced NDVI at all the sites and wetter 40 summer periods following such dry springs could not compensate for this, indicating that a pro-41 longed dry spring has a strong impact consistently over the entire early developmental stages 42 from the initial five years to 15 years post-fire. Further, young forests showed higher climate 43 sensitivity compared to the mature forest, irrespective of species and projected climatic condi-44 tions. Our findings suggest that a dry spring not only increases fire risk, but also delays recovery 45 of boreal forests in southern Siberia. It also highlights the importance of changing rainfall sea-46 sonality as well as total rainfall in a changing climate for post-fire recovery of forest

The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing

Kinetoplastid parasites—trypanosomes and leishmanias—infect millions of humans and cause economically devastating diseases of livestock, and the few existing drugs have serious deficiencies. Benzoxaborole-based compounds are very promising potential novel anti-trypanosomal therapies, with candidates already in human and animal clinical trials. We investigated the mechanism of action of several benzoxaboroles, including AN7973, an early candidate for veterinary trypanosomosis. In all kinetoplastids, transcription is polycistronic. Individual mRNA 5'-ends are created by trans splicing of a short leader sequence, with coupled polyadenylation of the preceding mRNA. Treatment of Trypanosoma brucei with AN7973 inhibited trans splicing within 1h, as judged by loss of the Y-structure splicing intermediate, reduced levels of mRNA, and accumulation of peri-nuclear granules. Methylation of the spliced leader precursor RNA was not affected, but more prolonged AN7973 treatment caused an increase in S-adenosyl methionine and methylated lysine. Together, the results indicate that mRNA processing is a primary target of AN7973. Polyadenylation is required for kinetoplastid trans splicing, and the EC50 for AN7973 in T. brucei was increased three-fold by over-expression of the T. brucei cleavage and polyadenylation factor CPSF3, identifying CPSF3 as a potential molecular target. Molecular modeling results suggested that inhibition of CPSF3 by AN7973 is feasible. Our results thus chemically validate mRNA processing as a viable drug target in trypanosomes. Several other benzoxaboroles showed metabolomic and splicing effects that were similar to those of AN7973, identifying splicing inhibition as a common mode of action and suggesting that it might be linked to subsequent changes in methylated metabolites. Granule formation, splicing inhibition and resistance after CPSF3 expression did not, however, always correlate and prolonged selection of trypanosomes in AN7973 resulted in only 1.5-fold resistance. It is therefore possible that the modes of action of oxaboroles that target trypanosome mRNA processing might extend beyond CPSF3 inhibition

Birth weight and cognitive performance in older women: the Rancho Bernardo study

Low birth weight is associated with poorer cognitive function from infancy through early adulthood, but little is known about low birth weight and cognitive performance in the elderly. This study examines the association of birth weight with cognitive function in community-dwelling older women. Participants were 292 community-dwelling women aged 55–89 (median = 71 years) who attended a 1988–91 clinic visit when cognitive function was assessed, and responded to a 1991 mailed questionnaire assessing birth weight. All analyses were adjusted for age and education. Birth weight ranged from 2 to 12 pounds (lbs; mean = 7.4 ± 1.9). When birth weight was categorized into tertiles (2–6.9 lbs, 7–8 lbs, and 8.1–12.4 lbs), women in the lowest tertile had significantly lower (“poorer”) scores on Serial 7’s, a test of concentration and calculation (p < 0.05). Other birth weight categorizations (lowest quartile or quintile, or birth weight <5.5 lbs vs. 5.6–8.9 lbs and ≥9 lbs) did not improve the prediction of poor performance on Serial 7’s. Birth weight as a continuous variable was significantly and positively associated with Serial 7’s test scores (p = 0.04). Results suggest that small decrements in cognitive function tasks involving calculation may persist throughout life in women who were of relatively low birth weight. Although this association could be spurious, it deserves further evaluation

Novel minor groove binders cure animal African trypanosomiasis in an in vivo mouse model

Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa due to its huge impact on livestock health. Existing therapies including those based upon Minor Groove Binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places due to the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT, Trypanosoma congolense and T. vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative using 2 applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalised via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for animal African trypanosomiasis

Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development

Exact calculation of the skyrmion lifetime in a ferromagnetic Bose condensate

The tunneling rate of a skyrmion in ferromagnetic spin-1/2 Bose condensates through an off-centered potential barrier is calculated exactly with the periodic instanton method. The prefactor is shown to depend on the chemical potential of the core atoms, at which level the atom tunnels. Our results can be readily extended to estimate the lifetime of other topological excitations in the condensate, such as vortices and monopoles.Comment: 16 pages, 4 figures, to appear Phys. Rev.

Sub-Pixel Classification of MODIS EVI for Annual Mappings of Impervious Surface Areas

Regular monitoring of expanding impervious surfaces areas (ISAs) in urban areas is highly desirable. MODIS data can meet this demand in terms of frequent observations but are lacking in spatial detail, leading to the mixed land cover problem when per-pixel classifications are applied. To overcome this issue, this research develops and applies a spatio-temporal sub-pixel model to estimate ISAs on an annual basis during 2001–2013 in the Jakarta Metropolitan Area, Indonesia. A Random Forest (RF) regression inferred the ISA proportion from annual 23 values of MODIS MOD13Q1 EVI and reference data in which such proportion was visually allocated from very high-resolution images in Google Earth over time at randomly selected locations. Annual maps of ISA proportion were generated and showed an average increase of 30.65 km2/year over 13 years. For comparison, a series of RF per-pixel classifications were also developed from the same reference data using a Boolean class constructed from different thresholds of ISA proportion. Results from per-pixel models varied when such thresholds change, suggesting difficulty of estimation of actual ISAs. This research demonstrated the advantages of spatio-temporal sub-pixel analysis for annual ISAs mapping and addresses the problem associated with definitions of thresholds in per-pixel approaches

MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia

We identified mutations in the IL7Ra gene or in genes encoding the downstream signaling molecules JAK1, JAK3, STAT5B, N-RAS, K-RAS, NF1, AKT and PTEN in 49% of patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). Strikingly, these mutations (except RAS/NF1) were mutually exclusive, suggesting that they each cause the aberrant activation of a common downstream target. Expressing these mutant signaling molecules—but not their wild-type counterparts—rendered Ba/F3 cells independent of IL3 by activating the RAS-MEK-ERK and PI3K-AKT pathways. Interestingly, cells expressing either IL7Ra or JAK mutants are sensitive to JAK inhibitors, but respond less robustly to inhibitors of the downstream RAS-MEK-ERK and PI3K-AKT-mTOR pathways, indicating that inhibiting only one downstream pathway is not sufficient. Here, we show that inhibiting both the MEK and PI3K-AKT pathways synergistically prevents the proliferation of BaF3 cells expressing mutant IL7Ra, JAK and RAS. Furthermore, combined inhibition of MEK and PI3K/AKT was cytotoxic to samples obtained from 6 out of 11 primary T-ALL patients, including 1 patient who had no mutations in the IL7R signaling pathway. Taken together, these results suggest that the potent cytotoxic effects of inhibiting both MEK and PI3K/AKT should be investigated further as a therapeutic option using leukemia xenograft models.Leukemia advance online publication, 13 May 2016; doi:10.1038/leu.2016.83