Integrin alpha-2 and beta-3 gene polymorphisms and breast cancer risk

Summary Integrins are cell surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Some of them, e.g. α_Vβ₃, α_IIbβ₃ and α₂β₁, have been suggested as key players for cancer development and tumor metastasis. Two polymorphisms in the gene for the α₂ component, ITGA2 807C>T and 1648G>A, have been associated with the cell-surface density of integrin α₂β₁. The 176T>C polymorphism in the ITGB3 gene, encoding the β₃ subunit of integrins α_IIbβ₃ and α_Vβ₃, modifies a variety of traits of β₃ expressing cells. To analyze the role of ITGA2 and ITGB3 polymorphisms for breast cancer risk and prognosis, we performed a case-control study including 500 female breast cancer patients and 500 healthy female age-matched control subjects. All study participants were of Caucasian origin (Austria, Middle-Europe). The ITGA2 1648_AA genotype was significantly associated with breast cancer (odds ratio 3.12; 95% confidence interval 1.11–8.77). Carriers of the most common ITGA2 haplotype (807C_1648G, ‘wildtype’) were at decreased risk for breast cancer (odds ratio 0.72; 95% confidence interval 0.53–0.98). A histological grade of 3 or 4 was found more often in ITGA2 807TT subjects (p=0.039 compared to CC+CT genotypes) and carriers of an ITGA2 1648A allele (p=0.017 compared to GG genotype). Carriers of the ITGA2 807C_1648G haplotype were less likely to have a histological grade 3 or 4 compared to non-carriers (p=0.003). The ITGB3 176T>C polymorphisms was not associated with breast cancer susceptibility. In a Cox-regression analysis, carriers of the homozygous ITGB3 176-CC genotype had a higher risk for metastasis (relative risk 2.3; 95% CI 1.3–4.2; p=0.005). We conclude that functional polymorphisms in integrin genes ITGA2 and ITGB3 influence the development and progression of breast cancer, respectively. The precise mechanism remains to be determined, but likely involves dysregulated signaling pathways.     

An in vitro comparative study upon the toxic properties of the venoms from Hemiscorpius lepturus, Androctonus crassicauda and Mesobuthus eupeus scorpions

The aim of the present study was to compare the toxic effects of the venoms from Hemiscorpius lepturus (H. lepturus), Androctonus crassicauda (A. crassicauda) and Mesobuthus eupeus (M. eupeus). For this purpose, three in vitro models were employed to compare the toxic effects of various concentrations of the venoms from these three scorpions, namely: hemolytic potential using human RBCs, phospholipase activity using Saubouraud's dextrose agar (SDA) supplemented with 2% egg yolk and lactate dehydrogenase (LDH) enzyme releasing effect using K562 leukemia cell line. In addition, the neutralizing effectiveness of the antivenom against these toxic properties was assessed. The results showed that, unlike the venoms from A. crassicauda and M. eupeus, the venom from H. lepturus produced dose-dependent lysis of human RBCs and showed phospholipase activity. However, all the tested venoms showed variable degrees of LDH releasing properties. The venom from H. lepturus had highest and the venom from M. eupeus had the lowest LDH releasing effect. The antivenom effectively inhibited all the tested toxicities. In conclusion, these results suggest that the venoms from the studied scorpions have variable toxic properties, which may explain the underlying reason for the differences in their clinical manifestations. In addition, the antivenom was effective in neutralizing all the tested toxic effects.     

The dorsal premotor cortex orchestrates concurrent speech and fingertapping movements

Human speech and hand use both involve highly specialized complex movement patterns. Whereas previous studies in detail characterized the cortical motor systems mediating speech and finger movements, the network that provides coordination of concurrent speech and hand movements so far is unknown. Using functional magnetic resonance imaging (fMRI), the present study investigated differential cortical networks devoted to speech or fingertapping, and regions mediating integration of these complex movement patterns involving different effectors. The conjunction contrasts revealing regions activated both during sole fingertapping and sole repetitive articulation or reading aloud showed contralateral regions at the border of ventral and dorsal motor cortex. In contrast, the analyses revealing regions showing a higher level of fMRI activation for concurrent movements of both effectors compared with sole hand movements or repetitive articulation or reading aloud showed distinct premotor activations, which were situated dorsal and caudal to the areas activated across speech and fingertapping tasks. These results indicate that the premotor cortex (PMC) subserves coordination of concurrent speech with hand movements. This integrative motor region is not identical with the area that shows overlapping activations for speech and fingertapping. Thus, concurrent performance of these complex movement patterns involving different effectors requires, in addition to somatotopic motor cortex activation, orchestration subserved by a distinct PMC area.     

Response of an Afro-Palearctic bird migrant to glaciation cycles

Migration allows animals to exploit spatially separated and seasonally available resources at a continental to global scale. However, responding to global climatic changes might prove challenging, especially for long-distance intercontinental migrants. During glacial periods, when conditions became too harsh for breeding in the north, avian migrants have been hypothesized to retract their distribution to reside within small refugial areas. Here, we present data showing that an Afro-Palearctic migrant continued seasonal migration, largely within Africa, during previous glacial–interglacial cycles with no obvious impact on population size. Using individual migratory track data to hindcast monthly bioclimatic habitat availability maps through the last 120,000 y, we show altered seasonal use of suitable areas through time. Independently derived effective population sizes indicate a growing population through the last 40,000 y. We conclude that the migratory lifestyle enabled adaptation to shifting climate conditions. This indicates that populations of resource-tracking, long-distance migratory species could expand successfully during warming periods in the past, which could also be the case under future climate scenarios.

Seasonality resulting from the tilted Earth orbiting the Sun is an important factor shaping the distribution of life on Earth (1). As seasonality increases toward the poles, year-round availability of resources declines (1, 2). Nonmobile species need to sustain survival throughout the season with the lowest resource availability, limiting population size outside of the peak of resources in the most resource-rich months during which breeding normally occur (3, 4). Migration allows animals to exploit the seasonal variation in resources (5–8). Every year, as the northern latitude winter approaches, billions of birds leave their breeding grounds, traveling thousands of kilometers to warmer, lower latitudes (5, 9). Comparable migrations are found in a wide range of taxa from small insects (10) to the largest of the whales (11), but seasonal migrations have been lost in much of the terrestrial megafauna, probably owing to human impacts (12).Migratory behavior is common across birds, although not all species migrate (13). The spatiotemporal schedules can be surprisingly fine tuned so that migratory species adjust the timing and migratory routes so to optimize the harvest of resources as they become available at continental scales (7). Because of the complex spatiotemporal schedules, migratory species are generally considered vulnerable (14). However, given the ability to track changes in habitat availability across the globe, migration likely represents an advantageous adaptation to exploit the changing distribution of seasonal resources over time, which would potentially be reflected in population size (15). The trait is often considered as plastic and changeable over short, decadal time scales (16, 17). Current migratory patterns derive from successful adjustments dating back to glacial periods when higher-latitude breeding grounds were unsuitable for breeding (18). During these glacial stages, populations of migrants retracted to the south and then expanded back to the north during interglacial periods (13, 15, 19, 20). Zink and Gardner (21) found that most currently long-distance migrants lacked suitable breeding area in North America during glacial maxima and suggested that a “migratory switch” would turn migrations off. That is, migratory populations would become sedentary to areas that were wintering grounds during warmer interglacial periods as indicated by the phylogeography of sedentary and migratory populations of chipping sparrows Spizella passerina (20). In contrast, Ponti et al. (22) found no support for a switch in long-distance migrants between Eurasia and Africa. While previous research (21–23) has explored the maintenance of migrations at breeding–wintering resolution, our study assesses migratory behavior at a higher temporal resolution (monthly estimates) and combines it with corresponding estimates of past population size inferred from whole-genome data, an independent line of evidence not combined with spatial prediction in previous studies.Inferring past migration patterns and population dynamics offer insights into future responses of migrant birds to accelerating climate change. Here, we combine independent lines of evidence from spatial models and genomics to explore the past migrations and shed light on this long-lasting debate on migratory behavior through shifting climates. We used direct tracking data of individual red-backed shrikes Lanius collurio (24), an Afro-Palearctic songbird with a complex, spatiotemporal, annual schedule that allows individuals to optimally exploit seasonal surplus of vegetation greenness across continents (7). Schedules consisting of alternating stationary and traveling periods are normally not captured in Species Distribution Models (SDMs), particularly not those inferring distributions of migrants in the past (15, 25, 26) or the future (27, 28). To capture these complex schedules, we used dynamic seasonal modeling, which takes into account the actual conditions experienced throughout the annual cycle (29) and paleoclimatic and vegetation conditions (30) at a fine spatiotemporal resolution to hindcast the potential seasonal distributions back to the previous interglacial, the Eemian. The habitat availability was based on modeled climate suitability and potential build-up of vegetation. Our paleoclimate data consisted of simulated monthly climatic conditions and photosynthetic activity spanning 120,000 y B.P. Moreover, we use genomics data to estimate effective population size back in time (31) to infer whether past species distribution and migration patterns have left imprints on population size (15). Together, estimated past spatiotemporal schedules and population dynamics shed light on previously unknown past migration patterns and population consequences for a long-distance migratory species.