Bumble bees (Bombus Latrielle) are significant pollinators of flowering plants due to their large body size, abundant setae, and generalist foraging strategies. However, shared setal coloration ...patterns among closely and distantly related bumble bee species makes identification notoriously difficult. The advent of molecular genetic techniques has increased our understanding of bumble bee evolution and taxonomy, and enables effective conservation policy and management. Individuals belonging to the North American Bombus fervidus species-complex (SC) are homogenous in body structure but exhibit significant body color phenotype variation across their geographic distribution. Given the uncertainty of the genealogical boundaries within the SC, some authors have synonymized all members of the B. fervidus SC within a single taxon, while others propose an alternative two taxa hypothesis. Operating under the phylogenetic species concept, our analysis supports the hypothesis that there are two independent lineages of bumble bees within the B. fervidus SC. With the current evidence, however, it is not possible to assign valid names to either of them, because both lineages include the color phenotypes found in the original species descriptions of B. fervidus and B. californicus. Cryptic speciation does not seem to be the product of Müllerian mimicry between the clades, because diverging coloration patterns are observed when the distribution of the clades overlaps. Furthermore, within each lineage there is evidence for strong population differentiation that is correlated with geographic distribution rather than color phenotype. In our study, we demonstrate the importance of obtaining a broad sample of multiple populations when conducting lower-level phylogenetic analyses. In addition to improving our knowledge of bumble bee diversification patterns, characterizing the evolutionary history of these pollinators provides the foundation needed to guide contemporary conservation assessments and management strategies.
Cell invasion through a dense three-dimensional (3D) matrix is believed to depend on the ability of cells to generate traction forces. To quantify the role of cell tractions during invasion in 3D, we ...present a technique to measure the elastic strain energy stored in the matrix due to traction-induced deformations. The matrix deformations around a cell were measured by tracking the 3D positions of fluorescent beads tightly embedded in the matrix. The bead positions served as nodes for a finite element tessellation. From the strain in each element and the known matrix elasticity, we computed the local strain energy in the matrix surrounding the cell. We applied the technique to measure the strain energy of highly invasive MDA-MB-231 breast carcinoma and A-125 lung carcinoma cells in collagen gels. The results were compared to the strain energy generated by non-invasive MCF-7 breast and A-549 lung carcinoma cells. In all cases, cells locally contracted the matrix. Invasive breast and lung carcinoma cells showed a significantly higher contractility compared to non-invasive cells. Higher contractility, however, was not universally associated with higher invasiveness. For instance, non-invasive A-431 vulva carcinoma cells were the most contractile cells among all cell lines tested. As a universal feature, however, we found that invasive cells assumed an elongated spindle-like morphology as opposed to a more spherical shape of non-invasive cells. Accordingly, the distribution of strain energy density around invasive cells followed patterns of increased complexity and anisotropy. These results suggest that not so much the magnitude of traction generation but their directionality is important for cancer cell invasion.
Bumble bees (Bombus) are vitally important pollinators of wild plants and agricultural crops worldwide. Fragmentary observations, however, have suggested population declines in several North American ...species. Despite rising concern over these observations in the United States, highlighted in a recent National Academy of Sciences report, a national assessment of the geographic scope and possible causal factors of bumble bee decline is lacking. Here, we report results of a 3-y interdisciplinary study of changing distributions, population genetic structure, and levels of pathogen infection in bumble bee populations across the United States. We compare current and historical distributions of eight species, compiling a database of >73,000 museum records for comparison with data from intensive nationwide surveys of >16,000 specimens. We show that the relative abundances of four species have declined by up to 96% and that their surveyed geographic ranges have contracted by 23–87%, some within the last 20 y. We also show that declining populations have significantly higher infection levels of the microsporidian pathogen Nosema bombi and lower genetic diversity compared with co-occurring populations of the stable (nondeclining) species. Higher pathogen prevalence and reduced genetic diversity are, thus, realistic predictors of these alarming patterns of decline in North America, although cause and effect remain uncertain.
Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur with HER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib ...has shown clinical activity against HER2-mutant tumors. To characterize the role of HER3 mutations in HER2-mutant tumors, we integrate computational structural modeling with biochemical and cell biological analyses. Computational modeling predicts that the frequent HER3E928G kinase domain mutation enhances the affinity of HER2/HER3 and reduces binding of HER2 to its inhibitor neratinib. Co-expression of mutant HER2/HER3 enhances HER2/HER3 co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT, resulting in enhanced growth, invasiveness, and resistance to HER2-targeted therapies, which can be reversed by combined treatment with PI3Kα inhibitors. Our results provide a mechanistic rationale for the evolutionary selection of co-occurring HER2/HER3 mutations and the recent clinical observations that HER3 mutations are associated with a poor response to neratinib in HER2-mutant cancers.
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•Co-occurring HER2/HER3 mutations promote oncogenesis and invasion via PI3K activation•HER3 mutations reduce sensitivity to HER2 inhibitors in HER2-mutant cancer cells•Tumors with HER2/HER3 mutations are sensitive to HER2 TKI + PI3Kα inhibitor
Hanker and Brown et al. demonstrate that co-occurring HER2 and HER3 mutations cooperatively activate HER2/HER3 and PI3K signaling in tumor cells, leading to enhanced growth, invasion, and resistance to HER2 inhibitors. HER2/HER3 double-mutant tumor models are sensitive to the combination of a HER2 TKI and a PI3Kα inhibitor.
Identifying drivers of dispersal limitation and genetic differentiation is a key goal in biogeography. We examine patterns of population connectivity and genetic diversity using restriction ...site‐associated DNA sequencing (RADseq) in two bumble bee species, Bombus vosnesenskii and Bombus bifarius, across latitude and altitude in mountain ranges from California, Oregon and Washington, U.S.A. Bombus vosnesenskii, which occurs across a broader elevational range at most latitudes, exhibits little population structure while B. bifarius, which occupies a relatively narrow higher elevation niche across most latitudes, exhibits much stronger population differentiation, although gene flow in both species is best explained by isolation with environmental niche resistance. A relationship between elevational habitat breadth and genetic diversity is also apparent, with B. vosnesenskii exhibiting relatively consistent levels of genetic diversity across its range, while B. bifarius has reduced genetic diversity at low latitudes, where it is restricted to high‐elevation habitat. The results of this study highlight the importance of the intersect between elevational range and habitat suitability in influencing population connectivity and suggest that future climate warming will have a fragmenting effect even on populations that are presently well connected, as they track their thermal niches upward in montane systems.
The T790M gatekeeper mutation in the EGFR is acquired by some EGFR-mutant non-small cell lung cancers (NSCLC) as they become resistant to selective tyrosine kinase inhibitors (TKI). As ...third-generation EGFR TKIs that overcome T790M-associated resistance become available, noninvasive approaches to T790M detection will become critical to guide management.
As part of a multi-institutional Stand-Up-To-Cancer collaboration, we performed an exploratory analysis of 40 patients with EGFR-mutant tumors progressing on EGFR TKI therapy. We compared the T790M genotype from tumor biopsies with analysis of simultaneously collected circulating tumor cells (CTC) and circulating tumor DNA (ctDNA).
T790M genotypes were successfully obtained in 30 (75%) tumor biopsies, 28 (70%) CTC samples, and 32 (80%) ctDNA samples. The resistance-associated mutation was detected in 47% to 50% of patients using each of the genotyping assays, with concordance among them ranging from 57% to 74%. Although CTC- and ctDNA-based genotyping were each unsuccessful in 20% to 30% of cases, the two assays together enabled genotyping in all patients with an available blood sample, and they identified the T790M mutation in 14 (35%) patients in whom the concurrent biopsy was negative or indeterminate.
Discordant genotypes between tumor biopsy and blood-based analyses may result from technological differences, as well as sampling different tumor cell populations. The use of complementary approaches may provide the most complete assessment of each patient's cancer, which should be validated in predicting response to T790M-targeted inhibitors.
Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2
) breast ...cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.
HER2
BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing.
experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples.
LTR tumors exhibited an increase in
copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab
Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of
correlated with a statistically shorter progression-free survival in patients with HER2
early breast cancer treated with adjuvant trastuzumab. Finally,
and/or
gene amplification correlated with a lower pathologic complete response in patients with HER2
early breast cancer treated with neoadjuvant anti-HER2 therapy.
Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors.
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The acute decline in global biodiversity includes not only the loss of rare species, but also the rapid collapse of common species across many different taxa. The loss of pollinating insects is of ...particular concern because of the ecological and economic values these species provide. The western bumble bee (
) was once common in western North America, but this species has become increasingly rare through much of its range. To understand potential mechanisms driving these declines, we used Bayesian occupancy models to investigate the effects of climate and land cover from 1998 to 2020, pesticide use from 2008 to 2014, and projected expected occupancy under three future scenarios. Using 14,457 surveys across 2.8 million km
in the western United States, we found strong negative relationships between increasing temperature and drought on occupancy and identified neonicotinoids as the pesticides of greatest negative influence across our study region. The mean predicted occupancy declined by 57% from 1998 to 2020, ranging from 15 to 83% declines across 16 ecoregions. Even under the most optimistic scenario, we found continued declines in nearly half of the ecoregions by the 2050s and mean declines of 93% under the most severe scenario across all ecoregions. This assessment underscores the tenuous future of
and demonstrates the scale of stressors likely contributing to rapid loss of related pollinator species throughout the globe. Scaled-up, international species-monitoring schemes and improved integration of data from formal surveys and community science will substantively improve the understanding of stressors and bumble bee population trends.
Huntington disease (HD), a hereditary neurodegenerative disorder, manifests as progressively impaired movement and cognition. Although early abnormalities of neuronal activity in striatum are well ...established in HD models, there are fewer in vivo studies of the cortex. Here, we record local field potentials (LFPs) in YAC128 HD model mice versus wild-type mice. In multiple cortical areas, limb sensory stimulation evokes a greater change in LFP power in YAC128 mice. Mesoscopic imaging using voltage-sensitive dyes reveals more extensive spread of evoked sensory signals across the cortical surface in YAC128 mice. YAC128 layer 2/3 sensory cortical neurons ex vivo show increased excitatory events, which could contribute to enhanced sensory responses in vivo. Cortical LFP responses to limb stimulation, visual and auditory input are also significantly increased in zQ175 HD mice. Results presented here extend knowledge of HD beyond ex vivo studies of individual neurons to the intact cortical network.
•Huntington disease mouse models show an augmented response to sensory input.•Mesoscale imaging in vivo reveals greater area of the cortex is activated.•Cortical neurons show aberrant excitatory events but no change in inhibition.
Abstract The leaf-mining microlepidopteran, Macrosaccus morrisella (Fitch) (Lepidoptera: Gracillariidae), has emerged as a new pest of soybean, Glycine max (L.) Merrill (Fabales: Fabaceae), in Canada ...and the United States, but little is known about its life history traits. Thus, this study was conducted to assess the immature developmental rate of M. morrisella, from egg to adult emergence, on soybean at different temperatures, and the longevity of adults supplied with water and/or honey at different temperatures. The time to 50% emergence of adults was 71.90, 36.33, 24.62, and 17.83 days at 15, 20, 25, and 30 °C, respectively. The lower developmental threshold of M. morrisella was estimated at 8.96 °C, with 425.04 degree-days required for egg-to-adult development. For adult longevity, time to 50% mortality at 25 °C was 15.00, 4.00, and 2.00 days when adults were provided with 25% (v/v) honey–water solution, water, or nothing, respectively. In a follow-up experiment, time to 50% mortality at 25 °C was 24.00, 6.00, 3.00, and 3.00 days when adults were provided with honey and water (offered separately), honey, water, or nothing, respectively, with a synergistic effect when honey and water were offered simultaneously as opposed to honey or water alone. Finally, when fed 25% (v/v) honey–water solution and maintained at 20, 25, and 30 °C, time to 50% mortality of adults was 26.50, 15.00, and 15.00 days. These results inform the understanding of the basic biology of M. morrisella and will help inform the future development of management programs for this insect in soybean.
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