Breast cancer exploits neural signaling pathways for bone-to-meninges metastasis.

The molecular mechanisms that regulate breast cancer cell (BCC) metastasis and proliferation within the leptomeninges (LM) are poorly understood, which limits the development of effective therapies. In this work, we show that BCCs in mice can invade the LM by abluminal migration along blood vessels that connect vertebral or calvarial bone marrow and meninges, bypassing the blood-brain barrier. This process is dependent on BCC engagement with vascular basement membrane laminin through expression of the neuronal pathfinding molecule integrin α6. Once in the LM, BCCs colocalize with perivascular meningeal macrophages and induce their expression of the prosurvival neurotrophin glial-derived neurotrophic factor (GDNF). Intrathecal GDNF blockade, macrophage-specific GDNF ablation, or deletion of the GDNF receptor neural cell adhesion molecule (NCAM) from BCCs inhibits breast cancer growth within the LM. These data suggest integrin α6 and the GDNF signaling axis as new therapeutic targets against breast cancer LM metastasis.

Evolution of species recognition when ecology and sexual selection favor signal stasis.

The process of reproductive character displacement involves divergence and/or the narrowing of variance in traits involved in species recognition, driven by interactions between taxa. However, stabilizing sexual selection may favor stasis and species similarity in these same traits if signals are optimized for transmission through the prevailing environment. Further, sexual selection may promote increased variability within species to facilitate individual recognition. Here we ask how the conflicting selection pressures of species recognition and sexual selection are resolved in a genus of Himalayan birds that sing exceptionally similar songs. We experimentally show that small differences in two traits (note shape and peak frequency) are both necessary and sufficient for species recognition. Song frequency shows remarkable clinal variation along the Himalayan elevational gradient, being most divergent where species co-occur, the classic signature of reproductive character displacement. Note shape shows no such clinal variation but varies more between individuals of an allopatric species than it does among individuals within species which co-occur. We argue that the different note shapes experience similar transmission constraints, and differences produced through species interactions spread back through the entire species range. Our results imply that reproductive character displacement is likely to be common.

The photoionization of methoxymethanol: Fingerprinting a reactive C2 oxygenate in a complex reactive mixture.

Methoxymethanol (CH3OCH2OH) is a reactive C2 ether-alcohol that is formed by coupling events in both heterogeneous and homogeneous systems. It is found in complex reactive environments-for example those associated with catalytic reactors, combustion systems, and liquid-phase mixtures of oxygenates. Using tunable synchrotron-generated vacuum-ultraviolet photons between 10.0 and 11.5 eV, we report on the photoionization spectroscopy of methoxymethanol. We determine that the lowest-energy photoionization process is the dissociative ionization of methoxymethanol via H-atom loss to produce [C2H5O2]+, a fragment cation with a mass-to-charge ratio (m/z) = 61.029. We measure the appearance energy of this fragment ion to be 10.24 ± 0.05 eV. The parent cation is not detected in the energy range examined. To elucidate the origin of the m/z = 61.029 (C2H5O2) fragment, we used automated electronic structure calculations to identify key stationary points on the cation potential energy surface and compute conformer-specific microcanonical rate coefficients for the important unimolecular processes. The calculated H-atom dissociation pathway results in a [C2H5O2]+ fragment appearance at 10.21 eV, in excellent agreement with experimental results.

Constructing a database of alien plants in the Himalaya to test patterns structuring diversity.

Differences in the number of alien plant species in different locations may reflect climatic and other controls that similarly affect native species and/or propagule pressure accompanied with delayed spread from the point of introduction. We set out to examine these alternatives for Himalayan plants, in a phylogenetic framework. We build a database of alien plant distributions for the Himalaya. Focusing on the well-documented regions of Jammu & Kashmir (west) and Bhutan (east) we compare alien and native species for (1) richness patterns, (2) degree of phylogenetic clustering, (3) the extent to which species-poor regions are subsets of species-rich regions and (4) continental and climatic affinities/source. We document 1470 alien species (at least 600 naturalised), which comprise ~14% of the vascular plants known from the Himalaya. Alien plant species with tropical affinities decline in richness with elevation and species at high elevations form a subset of those at lower elevations, supporting location of introduction as an important driver of alien plant richness patterns. Separately, elevations which are especially rich in native plant species are also rich in alien plant species, suggesting an important role for climate (high productivity) in determining both native and alien richness. We find no support for the proposition that variance in human disturbance or numbers of native species correlate with alien distributions. Results imply an ongoing expansion of alien species from low elevation sources, some of which are highly invasive.

Improved Peyronie's Disease Curvature Outcomes Using a Novel Collagenase Administration Protocol.

OBJECTIVE: To report outcomes of a novel collagenase clostridium histolyticum (CCH) injection protocol. METHODS: A prospective, sequential database was maintained of all Peyronie's men undergoing CCH injections since 2015. Our protocol has evolved to include changes with injection technique, timing, aggressive modeling/traction, and wrapping. Results of the "traditional" and "novel" techniques were compared using two definitions: "most recent" assessment and final assessments among men who "completed eight (injections) or were satisfied." RESULTS: A total of 509 men underwent greater than or equal to 1 CCH series (traditional, n = 280; novel n = 229). Baseline demographic/clinicopathologic characteristics were similar between groups. Results demonstrated significantly greater curve improvements with the novel technique ("most recent" median 30° vs 20° or 46% vs 28%; "completed eight or satisfied" 34° vs 20° or 58% vs 30%). Using the "completed eight or satisfied" definition, 94% vs 66% of men achieved greater than or equal to 20% improvement (odds ratio 7.6), and 60% vs 24% achieved greater than or equal to 50% improvements (odds ratio 5.0) in the novel cohort (all P < .0001). Importantly, the International Index of Erectile Function Erectile Function Domain score was unchanged, and subjective erectile function (50% vs 5%, P < .0001) and sensation improved (17% vs 8% improved, P = .01) with the new protocol. The novel cohort also reported higher rates of surgery prevention (53% vs 18%), restored/facilitated penetration (57% vs 21%), and hematomas (56% vs 26%), necessitating changes to wrapping procedures (all P < .0001). CONCLUSIONS: Use of the novel CCH protocol results in significant improvements with curvature without negatively impacting erectile function or sensation. Given its specialized nature, it is not recommended for low-volume CCH injectors.

Better to Divorce than Be Widowed: The Role of Mortality and Environmental Heterogeneity in the Evolution of Divorce.

AbstractDespite widespread interest in the evolution and implications of monogamy across taxa, less attention-especially theoretical-has been paid toward understanding the evolution of divorce (ending a socially monogamous pairing to find a new partner). Here, we develop a model of the evolution of divorce by females in a heterogeneous environment, where females assess territory quality as a result of their breeding success. Divorce results in females leaving poor territories disproportionally more often than good territories, while death of a partner occurs independent of territory quality, giving an advantage to divorce. Increasing environmental heterogeneity, a decreasing benefit of pair experience, and moderate survival rates favor the evolution of higher divorce rates, even in the absence of variance in individual quality and knowledge of available territories. Imperfect information about territory quality constrains the evolution of divorce, typically favoring divorce strategies that remain faithful to one's partner whenever successful reproduction occurs. Our model shows how feedbacks between divorce, widowhood, and the availability of territories are intricately linked in determining the evolutionary advantage of divorce. We detail testable predictions about populations that should be expected to divorce at high rates.

Effects of Plasticity on Elevational Range Size and Species Richness.

AbstractElevational ranges within many taxa are greater in the north temperate region than the tropics. Two hypotheses to explain the pattern are, first, that large elevational ranges in the temperate region arise because species have evolved broad tolerance curves in response to seasonality and, second, that a low diversification rate in the temperate region (speciation minus extinction) has led to relatively few species, each of which occupies a large elevational range in the absence of competitors (character release). We build a quantitative genetic model of selection on a phenotypic trait, whereby increased tolerance is modeled as arising from plasticity in the trait. We show that broad tolerances result in evolution of large elevational ranges because they induce shallower genotypic clines and hence reduced maladaptive gene flow. The evolution of large elevational ranges results in relatively few competing species arranged along the elevational gradient at a species carrying capacity. In such saturated communities, species have much elevational overlap. In contrast, in similar-sized communities that could accommodate many more species, the resulting character release is associated with smaller elevational overlaps. Empirical assessment of these predictions should contribute to assessing any role for ecological limits in driving the latitudinal diversity gradient in species richness.

Rapid evolutionary divergence of a songbird population following recent colonization of an urban area.

Colonization of a novel environment by a few individuals can lead to rapid evolutionary change, yet there is scarce evidence of the relative contributions of neutral and selective factors in promoting divergence during the early stages of colonization. Here we explore the role of neutral and selective forces in the divergence of a unique urban population of the dark-eyed junco (Junco hyemalis), which became established on the campus of the University of California at San Diego (UCSD) in the early 1980s. Previous studies based on microsatellite loci documented significant genetic differentiation of the urban population as well as divergence in phenotypic traits relative to nearby montane populations, yet the geographical origin of the colonization and the contributing factors remained uncertain. Our genome-wide single nucleotide polymorphism data set confirmed the marked genetic differentiation of the UCSD population, and we identified the coastal subspecies pinosus from central California as its sister group instead of the neighbouring mountain population. Demographic inference recovered a separation from pinosus as recent as 20-32 generations ago after a strong bottleneck, suggesting a role for drift in genetic differentiation. However, we also found significant associations between habitat variables and genome-wide variants linked to functional genes, some of which have been reported as potentially adaptive in birds inhabiting modified environments. These results suggest that the interplay between founder events and selection may result in rapid shifts in neutral and adaptive loci across the genome, and reveal the UCSD junco population as a case of contemporary evolutionary divergence in an anthropogenic environment.

Near-Surface Gas-Phase Methoxymethanol Is Generated by Methanol Oxidation over Pd-Based Catalysts.

Catalytic conversion of alcohols underlies many commodity and fine chemical syntheses, but a complete mechanistic understanding is lacking. We examined catalytic oxidative conversion of methanol near atmospheric pressure using operando small-aperture molecular beam time-of-flight mass spectrometry, interrogating the gas phase 500 µm above Pd-based catalyst surfaces. In addition to a variety of stable C1-3 species, we detected methoxymethanol (CH3OCH2OH)─a rarely observed and reactive C2 oxygenate that has been proposed to be a critical intermediate in methyl formate production. Methoxymethanol is observed above Pd, AuxPdy alloys, and oxide-supported Pd (common methanol oxidation catalysts). Experiments establish temperature and reactant feed ratio dependences of methoxymethanol generation, and calculations using density functional theory are used to examine the energetics of its likely formation pathway. These results suggest that future development of catalysts and microkinetic models for methanol oxidation should be augmented and constrained to accommodate the formation, desorption, adsorption, and surface reactions involving methoxymethanol.

Pan-PI3Ki targets multiple B-ALL microenvironment interactions that fuel systemic and CNS relapse.

The majority of adult patients with acute lymphoblastic leukemia (ALL) suffer relapse, and in patients with central nervous system (CNS) metastasis, prognosis is particularly poor. We recently demonstrated a novel route of ALL CNS metastasis dependent on PI3Kδ regulation of the laminin receptor integrin α6. B-ALL cells did not, however, rely on PI3Kδ signaling for growth. Here we show that broad targeting of PI3K isoforms can induce growth arrest in B-ALL, reducing systemic disease burden in mice treated with a single agent pan-PI3Ki, copanlisib. Moreover, we show that cellular stress activates PI3K/Akt-dependent survival pathways in B-ALL, exposing their vulnerability to PI3Kδ and pan-PI3Ki. The addition of a brief course of copanlisib to chemotherapy delivered the combined benefits of increased survival, decreased systemic disease, and reduced CNS metastasis. These data suggest the promising, multifaceted potential of pan-PI3Ki for B-ALL CNS prophylaxis, systemic disease control, and chemosensitization.

Leukaemia: a model metastatic disease.

In contrast to solid cancers, which often require genetic modifications and complex cellular reprogramming for effective metastatic dissemination, leukaemic cells uniquely possess the innate ability for migration and invasion. Dedifferentiated, malignant leukocytes retain the benign leukocytes' capacity for cell motility and survival in the circulation, while acquiring the potential for rapid and uncontrolled cell division. For these reasons, leukaemias, although not traditionally considered as metastatic diseases, are in fact models of highly efficient metastatic spread. Accordingly, they are often aggressive and challenging diseases to treat. In this Perspective, we discuss the key molecular processes that facilitate metastasis in a variety of leukaemic subtypes, the clinical significance of leukaemic invasion into specific tissues and the current pipeline of treatments targeting leukaemia metastasis.

Dispersal syndromes drive the formation of biogeographical regions, illustrated by the case of Wallace's Line.

AIM: Biogeographical regions (realms) reflect patterns of co-distributed species (biotas) across space. Their boundaries are set by dispersal barriers and difficulties of establishment in new locations. We extend new methods to assess these two contributions by quantifying the degree to which realms intergrade across geographical space and the contributions of individual species to the delineation of those realms. As our example, we focus on Wallace's Line, the most enigmatic partitioning of the world's faunas, where climate is thought to have little effect and the majority of dispersal barriers are short water gaps. LOCATION: Indo-Pacific. TIME PERIOD: Present day. MAJOR TAXA STUDIED: Birds and mammals. METHODS: Terrestrial bird and mammal assemblages were established in 1-degree map cells using range maps. Assemblage structure was modelled using latent Dirichlet allocation, a continuous clustering method that simultaneously establishes the likely partitioning of species into biotas and the contribution of biotas to each map cell. Phylogenetic trees were used to assess the contribution of deep historical processes. Spatial segregation between biotas was evaluated across time and space in comparison with numerous hard realm boundaries drawn by various workers. RESULTS: We demonstrate that the strong turnover between biotas coincides with the north-western extent of the region not connected to the mainland during the Pleistocene, although the Philippines contains mixed contributions. At deeper taxonomic levels, Sulawesi and the Philippines shift to primarily Asian affinities, resulting from transgressions of a few Asian-derived lineages across the line. The partitioning of biotas sometimes produces fragmented regions that reflect habitat. Differences in partitions between birds and mammals reflect differences in dispersal ability. MAIN CONCLUSIONS: Permanent water barriers have selected for a dispersive archipelago fauna, excluded by an incumbent continental fauna on the Sunda shelf. Deep history, such as plate movements, is relatively unimportant in setting boundaries. The analysis implies a temporally dynamic interaction between a species' intrinsic dispersal ability, physiographic barriers, and recent climate change in the genesis of Earth's biotas.

Urban birdsongs: higher minimum song frequency of an urban colonist persists in a common garden experiment.

Environmental changes caused by urbanization and noise pollution can have profound effects on acoustic communication. Many organisms use higher sound frequencies in urban environments with low-frequency noise, but the developmental and evolutionary mechanisms underlying these shifts are generally unknown. We used a common garden experiment to ask whether changes in minimum song frequency observed 30 years after a songbird colonized an urban environment are a consequence of behavioural flexibility. We captured male juvenile dark-eyed juncos, Junco hyemalis thurberi, from two populations (urban and mountain) soon after they reached independence (aged 25-40 days), raised them in identical indoor aviaries and studied their songs at an age of 3 years. We found that the large population difference in minimum frequency observed in the field persisted undiminished in the common garden despite the absence of noise. We also found some song sharing between the common garden and natal field populations, indicating that early song memorization before capture could contribute to the persistent song differences in adulthood. These results are the first to show that frequency shifts in urban birdsong are maintained in the absence of noise by genetic evolution and/or early life experiences.

Competition with insectivorous ants as a contributor to low songbird diversity at low elevations in the eastern Himalaya.

Competitive interactions between distantly related clades could cause complementary diversity patterns of these clades over large spatial scales. One such example might be ants and birds in the eastern Himalaya; ants are very common at low elevations but almost absent at mid-elevations where the abundance of other arthropods and insectivorous bird diversity peaks. Here, we ask if ants at low elevations could compete with birds for arthropod prey. Specifically, we studied the impact of the Asian weaver ant (Oecophylla smaragdina), a common aggressive ant at low elevations. Diet analysis using molecular methods demonstrate extensive diet overlap between weaver ants and songbirds at both low and mid-elevations. Trees without weaver ants have greater non-ant arthropod abundance and leaf damage. Experimental removal of weaver ants results in an increase in the abundance of non-ant arthropods. Notably, numbers of Coleoptera and Lepidoptera were most affected by removal experiments and were prominent components of both bird and weaver ant diets. Our results suggest that songbirds and weaver ants might potentially compete with each other for arthropod prey at low elevations, thereby contributing to lower insectivorous bird diversity at low elevations in eastern Himalaya. Competition with ants may shape vertebrate diversity patterns across broad biodiversity gradients.

Ecological Limits as the Driver of Bird Species Richness Patterns along the East Himalayan Elevational Gradient.

Variation in species richness across environmental gradients results from a combination of historical nonequilibrium processes (time, speciation, extinction) and present-day differences in environmental carrying capacities (i.e., ecological limits affected by species interactions and the abundance and diversity of resources). In a study of bird richness along the subtropical east Himalayan elevational gradient, we test the prediction that species richness patterns are consistent with ecological limits using data on morphology, phylogeny, elevational distribution, and arthropod resources. Species richness peaks at midelevations. Occupied morphological volume is roughly constant from low elevations to midelevations, implying that more species are packed into the same space at midelevations compared with low elevations. However, variance in beak length and differences in beak length between close relatives decline with elevation, which is a consequence of the addition of many small insectivores at midelevations. These patterns are predicted from resource distributions: arthropod size diversity declines from low elevations to midelevations, largely because many more small insects are present at midelevations. Weak correlations of species mean morphological traits with elevation also match predictions based on resources and habitats. Elevational transects in the tropical Andes, New Guinea, and Tanzania similarly show declines in mean arthropod size and mean beak length and, in these cases, likely contribute to declining numbers of insectivorous bird species richness along these gradients. The results imply that conditions for ecological limits are met, although historical nonequilibrium processes are likely to also contribute to the pattern of species richness.

PINK1-Dependent Mitophagy Regulates the Migration and Homing of Multiple Myeloma Cells via the MOB1B-Mediated Hippo-YAP/TAZ Pathway.

The roles of mitochondrial dysfunction in carcinogenesis remain largely unknown. The effects of PTEN-induced putative kinase 1 (PINK1)-dependent mitophagy on the pathogenesis of multiple myeloma (MM) are determined. The levels of the PINK1-dependent mitophagy markers PINK1 and parkin RBR E3 ubiquitin protein ligase (PARK2) in CD138+ plasma cells are reduced in patients with MM and correlate with clinical outcomes in myeloma patients. Moreover, the induction of PINK1-dependent mitophagy with carbonylcyanide-m-chlorophenylhydrazone (CCCP) or salinomycin, or overexpression of PINK1 leads to inhibition of transwell migration, suppression of myeloma cell homing to calvarium, and decreased osteolytic bone lesions. Furthermore, genetic deletion of pink1 accelerates myeloma development in a spontaneous X-box binding protein-1 spliced isoform (XBP-1s) transgenic myeloma mouse model and in VK*MYC transplantable myeloma recipient mice. Additionally, treatment with salinomycin shows significant antimyeloma activities in vivo in murine myeloma xenograft models. Finally, the effects of PINK1-dependent mitophagy on myeloma pathogenesis are driven by the activation of the Mps one binder kinase activator (MOB1B)-mediated Hippo pathway and the subsequent downregulation of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) expression. These data provide direct evidence that PINK1-dependent mitophagy plays a critical role in the pathogenesis of MM and is a potential therapeutic target.

Song playbacks demonstrate slower evolution of song discrimination in birds from Amazonia than from temperate North America.

Genetic data indicate differences in speciation rate across latitudes, but underlying causes have been difficult to assess because a critical phase of the speciation process is initiated in allopatry, in which, by definition, individuals from different taxa do not interact. We conducted song playback experiments between 109 related pairs of mostly allopatric bird species or subspecies in Amazonia and North America to compare the rate of evolution of male discrimination of songs. Relative to local controls, the number of flyovers and approach to the speaker were higher in Amazonia. We estimate that responses to songs of relatives are being lost about 6 times more slowly in Amazonia than in North America. The slow loss of response holds even after accounting for differences in song frequency and song length. Amazonian species with year-round territories are losing aggressive responses especially slowly. We suggest the presence of many species and extensive interspecific territoriality favors recognition of songs sung by sympatric heterospecifics, which results in a broader window of recognition and hence an ongoing response to novel similar songs. These aggressive responses should slow the establishment of sympatry between recently diverged forms. If male responses to novel allopatric taxa reflect female responses, then premating reproductive isolation is also evolving more slowly in Amazonia. The findings are consistent with previously demonstrated slower recent rates of expansion of sister taxa into sympatry, slower rates of evolution of traits important for premating isolation, and slower rates of speciation in general in Amazonia than in temperate North America.

Evolution of sexual cooperation from sexual conflict.

In many species that form pair bonds, males display to their mate after pair formation. These displays elevate the female's investment into the brood. This is a form of cooperation because without the display, female investment is reduced to levels that are suboptimal for both sexes. The presence of such displays is paradoxical as in their absence the male should be able to invest extra resources directly into offspring, to the benefit of both sexes. We consider that the origin of these displays lies in the exploitation of preexisting perceptual biases which increase female investment beyond that which is optimal for her, initially resulting in a sexual conflict. We use a combined population genetic and quantitative genetic model to show how this conflict becomes resolved into sexual cooperation. A cooperative outcome is most likely when perceptual biases are under selection pressures in other contexts (e.g., detection of predators, prey, or conspecifics), but this is not required. Cooperation between pair members can regularly evolve even when this provides no net advantage to the pair and when the display itself reduces a male's contributions to raising the brood. The findings account for many interactions between the sexes that have been difficult to explain in the context of sexual selection.

Regional influences on community structure across the tropical-temperate divide.

Many models to explain the differences in the flora and fauna of tropical and temperate regions assume that whole clades are restricted to the tropics. We develop methods to assess the extent to which biotas are geographically discrete, and find that transition zones between regions occupied by tropical-associated or temperate-associated biotas are often narrow, suggesting a role for freezing temperatures in partitioning global biotas. Across the steepest tropical-temperate gradient in the world, that of the Himalaya, bird communities below and above the freezing line are largely populated by different tropical and temperate biotas with links to India and Southeast Asia, or to China respectively. The importance of the freezing line is retained when clades rather than species are considered, reflecting confinement of different clades to one or another climate zone. The reality of the sharp tropical-temperate boundary adds credence to the argument that exceptional species richness in the tropics reflects species accumulation over time, with limited transgressions of species and clades into the temperate.