Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Shift from income breeding to capital breeding with latitude in the invasive Asian shore crab Hemigrapsus sanguineus.

Organisms vary in the timing of energy acquisition and use for reproduction. Thus, breeding strategies exist on a continuum, from capital breeding to income breeding. Capital breeders acquire and store energy for breeding before the start of the reproductive season, while income breeders finance reproduction using energy acquired during the reproductive season. Latitude and its associated environmental drivers are expected to heavily influence breeding strategy, potentially leading to latitudinal variation in breeding strategies within a single species. We examined the breeding strategy of the Asian shore crab Hemigrapsus sanguineus at five sites spanning nearly 10° of latitude across its invaded United States range. We hypothesized that the primary breeding strategy of this species would shift from income breeding to capital breeding as latitude increases. We found that though this species' breeding strategy is dominated by capital breeding throughout much of the range, income breeding increases in importance at lower latitudes. This latitudinal pattern is likely heavily influenced by the duration of the foraging and breeding seasons, which also vary with latitude. We also found that reproductive characteristics at the northern and southern edges of the invaded range were consistent with continued range expansion. We suggest that the reproductive flexibility of the Asian shore crab is a key facilitator of its continued invasion success. Our results highlight the influence of latitude on the breeding strategy of a species and emphasize the need for further research regarding the ecological importance and implications of flexibility in breeding strategies within species.

Does it pay to pay? A comparison of the benefits of open-access publishing across various sub-fields in biology.

Authors are often faced with the decision of whether to maximize traditional impact metrics or minimize costs when choosing where to publish the results of their research. Many subscription-based journals now offer the option of paying an article processing charge (APC) to make their work open. Though such "hybrid" journals make research more accessible to readers, their APCs often come with high price tags and can exclude authors who lack the capacity to pay to make their research accessible. Here, we tested if paying to publish open access in a subscription-based journal benefited authors by conferring more citations relative to closed access articles. We identified 146,415 articles published in 152 hybrid journals in the field of biology from 2013-2018 to compare the number of citations between various types of open access and closed access articles. In a simple generalized linear model analysis of our full dataset, we found that publishing open access in hybrid journals that offer the option confers an average citation advantage to authors of 17.8 citations compared to closed access articles in similar journals. After taking into account the number of authors, Journal Citation Reports 2020 Quartile, year of publication, and Web of Science category, we still found that open access generated significantly more citations than closed access (p < 0.0001). However, results were complex, with exact differences in citation rates among access types impacted by these other variables. This citation advantage based on access type was even similar when comparing open and closed access articles published in the same issue of a journal (p < 0.0001). However, by examining articles where the authors paid an article processing charge, we found that cost itself was not predictive of citation rates (p = 0.14). Based on our findings of access type and other model parameters, we suggest that, in the case of the 152 journals we analyzed, paying for open access does confer a citation advantage. For authors with limited budgets, we recommend pursuing open access alternatives that do not require paying a fee as they still yielded more citations than closed access. For authors who are considering where to submit their next article, we offer additional suggestions on how to balance exposure via citations with publishing costs.

Novel LIPA-Targeted Therapy for Treating Ovarian Cancer.

Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.

Dupilumab-Related Diabetes Mellitus With Reversal of Symptoms in a Non-genetically Predisposed Patient.

Dupilumab is a fully humanized monoclonal antibody that binds to IL-4 receptors and blocks IL-4 and IL-13 mediated T-helper 2 (Th2) responses. Dupilumab is estimated to be used by over 600,000 patients worldwide for the treatment of atopic dermatitis and other immunologic conditions. Recently, a 66-year-old male patient being treated for atopic dermatitis with dupilumab presented to the clinic with complaints of polyuria and polydipsia. Upon initial testing, the patient was found to have considerable hyperglycemia. Upon genetic testing, he showed no predisposition for autoimmune diabetes and was negative for type I diabetes mellitus-associated human leukocyte antigen (HLA) genes. After immediate cessation of dupilumab, and with subsequent insulin therapy, the patient was able to obtain glycemic control. Following taper and eventual cessation of insulin therapy and over the course of seven months, the patient was able to achieve a full resolution of symptoms and his glycosylated hemoglobin (HgBA1c) levels returned to normal ranges. This case represents only the second documented case of dupilumab-induced diabetes mellitus and is the first known documented case of dupilumab-induced diabetes mellitus in a non-genetically predisposed individual. This case also describes a previously unobserved spontaneous resolution of symptoms upon cessation of the drug. This case further illustrates the potential existence of immunogenic or immunomodulatory side effects of the monoclonal antibody dupilumab that can affect patients who are both genetically and non-genetically predisposed to autoimmune diabetes mellitus.

The Surgical Management of NCAA Division 1 College Football Injuries Post COVID-19: A Single Institution Retrospective Review.

ABSTRACT: Cohen, JL, Cade, WH, Harrah, TC, Costello II, JP, and Kaplan, LD. The surgical management of NCAA Division 1 college football injuries post COVID-19: A single institution retrospective review. J Strength Cond Res 38(5): 906-911, 2024-The unprecedented COVID-19 pandemic had a significant impact on college football operations, including athletes' training regimens. As a result of these changes, concern for increased injury susceptibility post COVID-19 regulations has become a point of discussion. The current study sought to evaluate the incidence of surgical injury among NCAA Division 1 college football players at the authors' institution during the first full season after start of the COVID-19 pandemic compared with previous years. Retrospective chart review was performed for all players who sustained injuries requiring surgery while a member of the NCAA Division 1 football program during the 2009-2021 seasons. A p -value of ≤0.05 was used to determine significance. A total of 23 surgical injuries occurred in 22 players during the 2021 season compared with 121 in 118 players in the 12 previous seasons combined ( p = 0.0178; RR = 1.47). There was a significant increase in shoulder injuries ( n = 13 vs. n = 31; p = <0.0001; RR = 3.05) and specifically a significant increase in labral tears ( n = 10 vs. n = 30; p = 0.0003; RR = 2.74). No difference was seen in knee injuries ( n = 10 vs. n = 77; p = 0.27; RR = 1.35) and specifically no difference in anterior cruciate ligament injuries ( n = 3 vs. n = 31; p = 0.77; RR = 1.17). This phenomenon is multifactorial in nature, but alterations to players' training and preparations because of the COVID-19 pandemic likely resulted in suboptimal conditioning, leading to the increased incidence of surgical injuries emphasizing the importance of adequate strength training and conditioning.

Intranasal insulin attenuates hypoxia-ischemia-induced short-term sensorimotor behavioral disturbances, neuronal apoptosis, and brain damage in neonatal rats.

There is a significant need for additional therapy to improve outcomes for newborns with acute Hypoxic-ischemic (HI) encephalopathy (HIE). New evidence suggests that insulin could be neuroprotective. This study aimed to investigate whether intranasal insulin attenuates HI-induced brain damage and neurobehavioral dysfunction in neonatal rats. Postnatal day 10 (P10), Sprague-Dawley rat pups were randomly divided into Sham + Vehicle, Sham + Insulin, HI + Vehicle, and HI + Insulin groups with equal male-to-female ratios. Pups either had HI by permanent ligation of the right common carotid artery followed by 90 min of hypoxia (8% O2) or sham surgery followed by room air exposure. Immediately after HI or Sham, pups were given fluorescence-tagged insulin (Alex-546-insulin)/vehicle, human insulin (25 µg), or vehicle in each nare under anesthesia. Shortly after administration, widespread Alex-546-insulin-binding cells were detected in the brain, primarily co-localized with neuronal nuclei-positive neurons on double-immunostaining. In the hippocampus, phospho-Akt was activated in a subset of Alex-546-insulin double-labeled cells, suggesting activation of the Akt/PI3K pathway in these neurons. Intranasal insulin (InInsulin) reduced HI-induced sensorimotor behavioral disturbances at P11. InInsulin prevented HI-induced increased Fluoro-Jade C+ degenerated neurons, cleaved caspase 3+ neurons, and volume loss in the ipsilateral brain at P11. There was no sex-specific response to HI or insulin. The findings confirm that intranasal insulin provides neuroprotection against HI brain injury in P10 rats associated with activation of intracellular cell survival signaling. If further pre-clinical research shows long-term benefits, intranasal insulin has the potential to be a promising non-invasive therapy to improve outcomes for newborns with HIE.

Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression.

The sparse vascularity of pancreatic ductal adenocarcinoma (PDAC) presents a mystery: What prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of noncanonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues. SIGNIFICANCE: We present a key mechanism of tumor angiosuppression, a process that sculpts the physiologic, cellular, and metabolic environment of PDAC. We further present a computational and experimental framework for the dissection of complex signaling cascades that propagate among multiple cell types in the tissue environment. This article is featured in Selected Articles from This Issue, p. 201.

Haploinsufficient Transcription Factors in Myeloid Neoplasms.

Many transcription factors (TFs) function as tumor suppressor genes with heterozygous phenotypes, yet haploinsufficiency generally has an underappreciated role in neoplasia. This is no less true in myeloid cells, which are normally regulated by a delicately balanced and interconnected transcriptional network. Detailed understanding of TF dose in this circuitry sheds light on the leukemic transcriptome. In this review, we discuss the emerging features of haploinsufficient transcription factors (HITFs). We posit that: (a) monoallelic and biallelic losses can have distinct cellular outcomes; (b) the activity of a TF exists in a greater range than the traditional Mendelian genetic doses; and (c) how a TF is deleted or mutated impacts the cellular phenotype. The net effect of a HITF is a myeloid differentiation block and increased intercellular heterogeneity in the course of myeloid neoplasia.

Evaluating physiochemical properties of FDA-approved orally administered drugs.

INTRODUCTION: Analyses of orally administered FDA-approved drugs from 1990 to 1993 enabled the identification of a set of physiochemical properties known as Lipinski's Rule of Five (Ro5). The original Ro5 and extended versions still remain the reference criteria for drug development programs. Since many bioactive compounds do not conform to the Ro5, we validated the relevance of and adherence to these rulesets in a contemporary cohort of FDA-approved drugs. AREAS COVERED: The authors noted that a significant proportion of FDA-approved orally administered parent compounds from 2011 to 2022 deviate from the original Ro5 criteria (~38%) or the Ro5 with extensions (~53%). They then evaluated if a contemporary Ro5 criteria (cRo5) could be devised to better predict oral bioavailability. Furthermore, they discuss many case studies showcasing the need for and benefit of increasing the size of certain compounds and cover several evolving strategies for improving oral bioavailability. EXPERT OPINION: Despite many revisions to the Ro5, the authors find that no single proposed physiochemical rule has universal concordance with absolute oral bioavailability. Innovations in drug delivery and formulation have dramatically expanded the range of physicochemical properties and the chemical diversity for oral administration.

Acute Batter's Shoulder With Concomitant Superior Labrum from Anterior to Posterior Injury in a Collegiate Baseball Player.

An 18-year-old collegiate baseball player sustained an acute batter's shoulder injury causing a posterior shoulder dislocation with type IX 360° superior labrum from anterior to posterior tear. To the authors' knowledge, this description of batter's shoulder is not within the literature. The patient ultimately underwent arthroscopic labral repair and has fully returned to sport. In understanding the complexity of the shoulder during the batter's swing, this case demonstrates an expansion to the previously described pathophysiology of batter's shoulder.

Outcomes in patients with clinically suspected pedal osteomyelitis based on bone marrow signal pattern on MRI.

Objective: confluent T1 hypointense marrow signal is widely accepted to represent osteomyelitis on MRI. Some authors have suggested that non-confluent bone marrow signal abnormality should be considered early osteomyelitis. The purpose of this study was to address this issue by comparing the rate of osteomyelitis and amputation based on T1 marrow signal characteristics. Materials and methods: a total of 112 patients who underwent MRI of the foot for the evaluation of possible osteomyelitis were included. Patients were assigned to confluent T1 hypointense, reticulated T1 hypointense, and normal bone marrow signal groups. Results: patients with confluent T1 hypointense signal on MRI had significantly higher rates of osteomyelitis and amputation at 2 and 14 months post-MRI than the reticulated T1 hypointense group ( p < 0.001 ). Six patients had normal T1 signal, 16.7 % of whom had osteomyelitis and underwent amputation by 2 months post-MRI. Of 61 patients with reticulated T1 hypointense signal, 19.7 % had a diagnosis of osteomyelitis at 2 months post-MRI and 30.8 % had a diagnosis of osteomyelitis at 14 months post-MRI; moreover, 14.8 % and 31.5 % underwent amputation by 2 and 14 months post-MRI, respectively. Of 45 patients with confluent T1 hypointense signal, 73.3 % of patients had osteomyelitis at 2 months post-MRI and 82.5 % had osteomyelitis at 14 months post-MRI. In this group, 66.7 % underwent amputation by 2 months post-MRI and 77.8 % underwent amputation by 14 months post-MRI. Conclusions: over half of the patients with suspected pedal osteomyelitis who had reticulated or normal T1 bone marrow signal on MRI healed with conservative measures. Therefore, we recommend terminology such as "osteitis", "reactive osteitis", or "nonspecific reactive change" to describe bone marrow edema-like signal and reticulated hazy T1 hypointense signal without associated confluent T1 hypointensity. Moreover, we recommend that the MRI diagnosis of osteomyelitis is reserved for confluent T1 hypointense bone signal in the area of concern.

Predicting diet in brachyuran crabs using external morphology.

Morphological traits have often been used to predict diet and trophic position of species across many animal groups. Variation in gut size of closely related animals is known to be a good predictor of dietary habits. Species that are more herbivorous or that persist on low-quality diets often have larger stomachs than their carnivorous counterparts. This same pattern exists in crabs and in most species, individuals exhibit external markings on the dorsal side of their carapace that appear to align with the position and size of their gut. We hypothesized that these external markings could be used as an accurate estimate of the crab's cardiac stomach size, allowing an approximation of crab dietary strategies without the need to sacrifice and dissect individual animals. We used literature values for mean diet and standardized external gut size markings taken from crab photographs across 50 species to show that percent herbivory in the diet increases non-linearly across species of brachyuran crab with the external estimate of gut size. We also used data from dissections in four species to show that external gut markings were positively correlated with gut sizes, though the strength of this correlation differed across species. We conclude that when rough approximations of diet quality such as percent herbivory will suffice, measuring external carapace markings in crabs presents a quick, free, non-lethal alternative to dissections. Our results also provide important insights into tradeoffs that occur in crab morphology and have implications for crab evolution.

Structurally Diverse Bench-Stable Nickel(0) Pre-Catalysts: A Practical Toolkit for In Situ Ligation Protocols.

A flurry of recent research has centered on harnessing the power of nickel catalysis in organic synthesis. These efforts have been bolstered by contemporaneous development of well-defined nickel (pre)catalysts with diverse structure and reactivity. In this report, we present ten different bench-stable, 18-electron, formally zero-valent nickel-olefin complexes that are competent pre-catalysts in various reactions. Our investigation includes preparations of novel, bench-stable Ni(COD)(L) complexes (COD=1,5-cyclooctadiene), in which L=quinone, cyclopentadienone, thiophene-S-oxide, and fulvene. Characterization by NMR, IR, single-crystal X-ray diffraction, cyclic voltammetry, thermogravimetric analysis, and natural bond orbital analysis sheds light on the structure, bonding, and properties of these complexes. Applications in an assortment of nickel-catalyzed reactions underscore the complementary nature of the different pre-catalysts within this toolkit.

Cell Competition Shapes Metastatic Latency and Relapse.

Cell competition, a fitness-sensing process, is essential for tissue homeostasis. Using cancer metastatic latency models, we show that cell competition results in the displacement of latent metastatic (Lat-M) cells from the primary tumor. Lat-M cells resist anoikis and survive as residual metastatic disease. A memodeled extracellular matrix facilitates Lat-M cell displacement and survival in circulation. Disrupting cell competition dynamics by depleting secreted protein and rich in cysteine (SPARC) reduced displacement from orthotopic tumors and attenuated metastases. In contrast, depletion of SPARC after extravasation in lung-resident Lat-M cells increased metastatic outgrowth. Furthermore, multiregional transcriptomic analyses of matched primary tumors and metachronous metastases from patients with kidney cancer identified tumor subclones with Lat-M traits. Kidney cancer enriched for these Lat-M traits had a rapid onset of metachronous metastases and significantly reduced disease-free survival. Thus, an unexpected consequence of cell competition is the displacement of cells with Lat-M potential, thereby shaping metastatic latency and relapse. SIGNIFICANCE: We demonstrate that cell competition within the primary tumor results in the displacement of Lat-M cells. We further show the impact of altering cell competition dynamics on metastatic incidence that may guide strategies to limit metastatic recurrences. This article is highlighted in the In This Issue feature, p. 1.

Incidence of Parkinson disease in North America.

Parkinson disease (PD) is the second most common age-related neurodegenerative condition diagnosed in North America. We recently demonstrated, using multiple epidemiological data sources, that the prevalence of PD diagnoses was greater than previously reported and currently used for clinical, research, and policy decision-making. Prior PD incidence estimates have varied, for unclear reasons. There is a need for improved estimates of PD incidence, not only for care delivery planning and future policy but also for increasing our understanding of disease risk. The objective of this study was thus to investigate the incidence of Parkinson disease across five epidemiological cohorts in North America in a common year, 2012. The cohorts contained data on 6.7 million person-years of adults ages 45 and older, and 9.3 million person-years of adults ages 65 and older. Our estimates of age-sex-adjusted incidence of PD ranged from 108 to 212 per 100,000 among persons ages 65 and older, and from 47 to 77 per 100,00 among persons ages 45 and older. PD incidence increased with age and was higher among males. We also found persistent spatial clustering of incident PD diagnoses in the U.S. PD incidence estimates varied across our data sources, in part due to case ascertainment and diagnosis methods, but also possibly due to the influence of population factors (prevalence of genetic risk factors or protective markers) and geographic location (exposure to environmental toxins). Understanding the source of these variations will be important for health care policy, research, and care planning.

Latitudinal and temporal variation in injury and its impacts in the invasive Asian shore crab Hemigrapsus sanguineus.

Nonlethal injury is a pervasive stress on individual animals that can affect large portions of a population at any given time. Yet most studies examine snapshots of injury at a single place and time, making the implicit assumption that the impacts of nonlethal injury are constant. We sampled Asian shore crabs Hemigrapsus sanguineus throughout their invasive North American range and from the spring through fall of 2020. We then documented the prevalence of limb loss over this space and time. We further examined the impacts of limb loss and limb regeneration on food consumption, growth, reproduction, and energy storage. We show that injury differed substantially across sites and was most common towards the southern part of their invaded range on the East Coast of North America. Injury also varied idiosyncratically across sites and through time. It also had strong impacts on individuals via reduced growth and reproduction, despite increased food consumption in injured crabs. Given the high prevalence of nonlethal injury in this species, these negative impacts of injury on individual animals likely scale up to influence population level processes (e.g., population growth), and may be one factor acting against the widespread success of this invader.

Metabolic rates of the Asian shore crab Hemigrapsus sanguineus in air as a function of body size, location, and injury.

Rapid warming in the Gulf of Maine may influence the success or invasiveness of the Asian shore crab, Hemigrapsus sanguineus. To better predict the effects of climate change on this invasive species, it is necessary to measure its energy dynamics under a range of conditions. However, previous research has only focused on the metabolism of this intertidal species in water. We sampled adult crabs from three different sites and measured their metabolic rates in the air. We show that metabolic rate increases with body mass and the number of missing limbs, but decreases with the number of regenerating limbs, possibly reflecting the timing of energy allocation to limb regeneration. Importantly, metabolic rates measured here in the air are ~4× higher than metabolic rates previously measured for this species in water. Our results provide baseline measurements of aerial metabolic rates across body sizes, which may be affected by climate change. With a better understanding of respiration in H. sanguineus, we can make more informed predictions about the combined effects of climate change and invasive species on the northeast coasts of North America.

Behavioral responses of a parasitoid fly to rapidly evolving host signals.

Animals eavesdrop on signals and cues generated by prey, predators, hosts, parasites, competing species, and conspecifics, and the conspicuousness of sexual signals makes them particularly susceptible. Yet, when sexual signals evolve, most attention is paid to impacts on intended receivers (potential mates) rather than fitness consequences for eavesdroppers. Using the rapidly evolving interaction between the Pacific field cricket, Teleogryllus oceanicus, and the parasitoid fly, Ormia ochracea, we asked how parasitoids initially respond to novel changes in host signals. We recently discovered a novel sexual signal, purring song, in Hawaiian populations of T. oceanicus that appears to have evolved because it protects the cricket from the parasitoid while still allowing males to attract female crickets for mating. In Hawaii, there are no known alternative hosts for the parasitoid, so we would expect flies to be under selection to detect and attend to the new purring song. We used complementary field and laboratory phonotaxis experiments to test fly responses to purring songs that varied in many dimensions, as well as to ancestral song. We found that flies strongly prefer ancestral song over purring songs in both the field and the lab, but we caught more flies to purring songs in the field than reported in previous work, indicating that flies may be exerting some selective pressure on the novel song. When played at realistic amplitudes, we found no preferences-flies responded equally to all purrs that varied in frequency, broadbandedness, and temporal measures. However, our lab experiment did reveal the first evidence of preference for purring song amplitude, as flies were more attracted to purrs played at amplitudes greater than naturally occurring purring songs. As purring becomes more common throughout Hawaii, flies that can use purring song to locate hosts should be favored by selection and increase in frequency.