Climate-driven flyway changes and memory-based long-distance migration.

Millions of migratory birds occupy seasonally favourable breeding grounds in the Arctic1, but we know little about the formation, maintenance and future of the migration routes of Arctic birds and the genetic determinants of migratory distance. Here we established a continental-scale migration system that used satellite tracking to follow 56 peregrine falcons (Falco peregrinus) from 6 populations that breed in the Eurasian Arctic, and resequenced 35 genomes from 4 of these populations. The breeding populations used five migration routes across Eurasia, which were probably formed by longitudinal and latitudinal shifts in their breeding grounds during the transition from the Last Glacial Maximum to the Holocene epoch. Contemporary environmental divergence between the routes appears to maintain their distinctiveness. We found that the gene ADCY8 is associated with population-level differences in migratory distance. We investigated the regulatory mechanism of this gene, and found that long-term memory was the most likely selective agent for divergence in ADCY8 among the peregrine populations. Global warming is predicted to influence migration strategies and diminish the breeding ranges of peregrine populations of the Eurasian Arctic. Harnessing ecological interactions and evolutionary processes to study climate-driven changes in migration can facilitate the conservation of migratory birds.

Taking the beat of the Arctic: are lemming population cycles changing due to winter climate?

Reports of fading vole and lemming population cycles and persisting low populations in some parts of the Arctic have raised concerns about the spread of these fundamental changes to tundra food web dynamics. By compiling 24 unique time series of lemming population fluctuations across the circumpolar region, we show that virtually all populations displayed alternating periods of cyclic/non-cyclic fluctuations over the past four decades. Cyclic patterns were detected 55% of the time (n = 649 years pooled across sites) with a median periodicity of 3.7 years, and non-cyclic periods were not more frequent in recent years. Overall, there was an indication for a negative effect of warm spells occurring during the snow onset period of the preceding year on lemming abundance. However, winter duration or early winter climatic conditions did not differ on average between cyclic and non-cyclic periods. Analysis of the time series shows that there is presently no Arctic-wide collapse of lemming cycles, even though cycles have been sporadic at most sites during the last decades. Although non-stationary dynamics appears a common feature of lemming populations also in the past, continued warming in early winter may decrease the frequency of periodic irruptions with negative consequences for tundra ecosystems.

LEAP2 is associated with impulsivity and reward sensitivity depending on the nutritional status and decreases with protein intake in humans.

AIM: Liver-expressed antimicrobial peptide 2 (LEAP2) dynamics in human plasma and its association with feeding behaviour remain poorly understood. Therefore, this study aims: (a) to investigate fasting LEAP2 in participants with normal weight or with overweight or mild obesity (OW/OB); (b) to study the association between fasting LEAP2 and anthropometric and metabolic traits, feeding behaviour, LEAP2 genetic variants and blood cell DNA methylation status; and (c) to ascertain postprandial changes in LEAP2 after high protein intake and the association with feeding behaviour and food intake. METHODS: Anthropometric and behavioural measures, genotyping, methylation profiling, plasma glucose and LEAP2 concentrations were assessed in 327 females and males. A subgroup of 123 participants received an ad libitum high-protein meal, and postprandial LEAP2 concentration and behavioural measures were assessed. RESULTS: LEAP2 concentration was higher in participants with OW/OB (p < 0.001) and in females (p < 0.001), and was associated with LEAP2 single nucleotide polymorphisms rs765760 (p = 0.012) and rs803223 (p = 0.019), but not with LEAP2 methylation status. LEAP2 concentration was directly related to glycaemia (p = 0.001) and fullness (p = 0.003) in participants with normal weight, whereas it was associated with body mass index (p = 0.018), waist circumference (p = 0.014) and motor impulsivity in participants with OW/OB (p = 0.005). A negative association with reward responsiveness was observed in participants with OW/OB (p = 0.023). LEAP2 concentration was inversely associated with food intake (p = 0.034) and decreased after a high-protein meal (p < 0.001), particularly in women (p = 0.002). CONCLUSION: Increased LEAP2 in participants with OW/OB is associated with behavioural characteristics of obesity. Our results show sexual dimorphism in LEAP2 concentration before and after food intake and highlight the role of LEAP2 in feeding regulation.

Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies.

Brain cancer is a formidable challenge for drug development, and drugs derived from many cutting-edge technologies are being tested in clinical trials. We manually characterized 981 clinical trials on brain tumors that were registered in ClinicalTrials.gov from 2010 to 2020. We identified 582 unique therapeutic entities targeting 581 unique drug targets and 557 unique treatment combinations involving drugs. We performed the classification of both the drugs and drug targets based on pharmacological and structural classifications. Our analysis demonstrates a large diversity of agents and targets. Currently, we identified 32 different pharmacological directions for therapies that are based on 42 structural classes of agents. Our analysis shows that kinase inhibitors, chemotherapeutic agents, and cancer vaccines are the three most common classes of agents identified in trials. Agents in clinical trials demonstrated uneven distribution in combination approaches; chemotherapy agents, proteasome inhibitors, and immune modulators frequently appeared in combinations, whereas kinase inhibitors, modified immune effector cells did not as was shown by combination networks and descriptive statistics. This analysis provides an extensive overview of the drug discovery field in brain cancer, shifts that have been happening in recent years, and challenges that are likely to come. SIGNIFICANCE STATEMENT: This review provides comprehensive quantitative analysis and discussion of the brain cancer drug discovery field, including classification of drug, targets, and therapies.

Nanoparticles in Clinical Trials: Analysis of Clinical Trials, FDA Approvals and Use for COVID-19 Vaccines.

Nanoparticles are heterologous small composites that are usually between 1 and 100 nanometers in size. They are applied in many areas of medicine with one of them being drug delivery. Nanoparticles have a number of advantages as drug carriers which include reduced toxic effects, increased bioavailability, and their ability to be modified for specific tissues or cells. Due to the exciting development of nanotechnology concomitant with advances in biotechnology and medicine, the number of clinical trials devoted to nanoparticles for drug delivery is growing rapidly. Some nanoparticles, lipid-based types, in particular, played a crucial role in the developing and manufacturing of the two COVID-19 vaccines-Pfizer and Moderna-that are now being widely used. In this analysis, we provide a quantitative survey of clinical trials using nanoparticles during the period from 2002 to 2021 as well as the recent FDA-approved drugs (since 2016). A total of 486 clinical trials were identified using the clinicaltrials.gov database. The prevailing types of nanoparticles were liposomes (44%) and protein-based formulations (26%) during this period. The most commonly investigated content of the nanoparticles were paclitaxel (23%), metals (11%), doxorubicin (9%), bupivacaine and various vaccines (both were 8%). Among the FDA-approved nanoparticle drugs, polymeric (29%), liposomal (22%) and lipid-based (21%) drugs were the most common. In this analysis, we also discuss the differential development of the diverse groups of nanoparticles and their content, as well as the underlying factors behind the trends.

Parasitoids indicate major climate-induced shifts in arctic communities.

Climatic impacts are especially pronounced in the Arctic, which as a region is warming twice as fast as the rest of the globe. Here, we investigate how mean climatic conditions and rates of climatic change impact parasitoid insect communities in 16 localities across the Arctic. We focus on parasitoids in a widespread habitat, Dryas heathlands, and describe parasitoid community composition in terms of larval host use (i.e., parasitoid use of herbivorous Lepidoptera vs. pollinating Diptera) and functional groups differing in their closeness of host associations (koinobionts vs. idiobionts). Of the latter, we expect idiobionts-as being less fine-tuned to host development-to be generally less tolerant to cold temperatures, since they are confined to attacking hosts pupating and overwintering in relatively exposed locations. To further test our findings, we assess whether similar climatic variables are associated with host abundances in a 22 year time series from Northeast Greenland. We find sites which have experienced a temperature rise in summer while retaining cold winters to be dominated by parasitoids of Lepidoptera, with the reverse being true for the parasitoids of Diptera. The rate of summer temperature rise is further associated with higher levels of herbivory, suggesting higher availability of lepidopteran hosts and changes in ecosystem functioning. We also detect a matching signal over time, as higher summer temperatures, coupled with cold early winter soils, are related to high herbivory by lepidopteran larvae, and to declines in the abundance of dipteran pollinators. Collectively, our results suggest that in parts of the warming Arctic, Dryas is being simultaneously exposed to increased herbivory and reduced pollination. Our findings point to potential drastic and rapid consequences of climate change on multitrophic-level community structure and on ecosystem functioning and highlight the value of collaborative, systematic sampling effort.

Flexibility in a changing arctic food web: Can rough-legged buzzards cope with changing small rodent communities?

Indirect effects of climate change are often mediated by trophic interactions and consequences for individual species depend on how they are tied into the local food web. Here we show how the response of demographic rates of an arctic bird of prey to fluctuations in small rodent abundance changed when small rodent community composition and dynamics changed, possibly under the effect of climate warming. We observed the breeding biology of rough-legged buzzards (Buteo lagopus) at the Erkuta Tundra Monitoring Site in southern Yamal, low arctic Russia, for 19 years (1999-2017). At the same time, data on small rodent abundance were collected and information on buzzard diet was obtained from pellet dissection. The small rodent community experienced a shift from high-amplitude cycles to dampened fluctuations paralleled with a change in species composition toward less lemmings and more voles. Buzzards clearly preferred lemmings as prey. Breeding density of buzzards was positively related to small rodent abundance, but the shift in small rodent community lead to lower numbers relative to small rodent abundance. At the same time, after the change in small rodent community, the average number of fledglings was higher relative to small rodent abundance than earlier. These results suggest that the buzzard population adapted to a certain degree to the changes in the major resource, although at the same time density declined. The documented flexibility in the short-term response of demographic rates to changes in structure and dynamics of key food web components make it difficult to predict how complex food webs will be transformed in a warmer Arctic. The degree of plasticity of functional responses is indeed likely to vary between species and between regions, depending also on the local food web context.

Reinforcement Strains in Reinforced Concrete Tensile Members Recorded by Strain Gauges and FBG Sensors: Experimental and Numerical Analysis.

Experimental and numerical studies have been carried out on reinforced concrete (RC) short tensile specimens. Double pull-out tests employed rectangular RC elements of a length determined not to yield any additional primary cracks. Tests were carried out with tensor strain gauges installed within a specially modified reinforcement bar and, alternatively, with fibre Bragg grating based optical sensors. The aim of this paper is to analyse the different experimental setups regarding obtaining more accurate and reliable reinforcement strain distribution data. Furthermore, reinforcement strain profiles obtained numerically using the stress transfer approach and the Model Code 2010 provided bond-slip model were compared against the experimental results. Accurate knowledge of the relation between the concrete and the embedded reinforcement is necessary and lacking to this day for less scattered and reliable prediction of cracking behaviour of RC elements. The presented experimental strain values enable future research on bond interaction. In addition, few double pull-out test results are published when compared to ordinary bond tests of single pull-out tests with embedded reinforcement. The authors summarize the comparison with observations on experimental setups and discuss the findings.

Vole abundance and reindeer carcasses determine breeding activity of Arctic foxes in low Arctic Yamal, Russia.

BACKGROUND: High latitude ecosystems are at present changing rapidly under the influence of climate warming, and specialized Arctic species at the southern margin of the Arctic may be particularly affected. The Arctic fox (Vulpes lagopus), a small mammalian predator endemic to northern tundra areas, is able to exploit different resources in the context of varying tundra ecosystems. Although generally widespread, it is critically endangered in subarctic Fennoscandia, where a fading out of the characteristic lemming cycles and competition with abundant red foxes have been identified as main threats. We studied an Arctic fox population at the Erkuta Tundra Monitoring site in low Arctic Yamal (Russia) during 10 years in order to determine which resources support the breeding activity in this population. In the study area, lemmings have been rare during the last 15 years and red foxes are nearly absent, creating an interesting contrast to the situation in Fennoscandia. RESULTS: Arctic fox was breeding in nine of the 10 years of the study. The number of active dens was on average 2.6 (range 0-6) per 100 km2 and increased with small rodent abundance. It was also higher after winters with many reindeer carcasses, which occurred when mortality was unusually high due to icy pastures following rain-on-snow events. Average litter size was 5.2 (SD = 2.1). Scat dissection suggested that small rodents (mostly Microtus spp.) were the most important prey category. Prey remains observed at dens show that birds, notably waterfowl, were also an important resource in summer. CONCLUSIONS: The Arctic fox in southern Yamal, which is part of a species-rich low Arctic food web, seems at present able to cope with a state shift of the small rodent community from high amplitude cyclicity with lemming dominated peaks, to a vole community with low amplitude fluctuations. The estimated breeding parameters characterized the population as intermediate between the lemming fox and the coastal fox ecotype. Only continued ecosystem-based monitoring will reveal their fate in a changing tundra ecosystem.