Elevated [CO2] and temperature augment gas exchange and shift the fitness landscape in a montane forb.

Climate change is simultaneously increasing carbon dioxide concentrations ([CO2]) and temperature. These factors could interact to influence plant physiology and performance. Alternatively, increased [CO2] may offset costs associated with elevated temperatures. Furthermore, the interaction between elevated temperature and [CO2] may differentially affect populations from along an elevational gradient and disrupt local adaptation. We conducted a multifactorial growth chamber experiment to examine the interactive effects of temperature and [CO2] on fitness and ecophysiology of diverse accessions of Boechera stricta (Brassicaceae) sourced from a broad elevational gradient in Colorado. We tested whether increased [CO2] would enhance photosynthesis across accessions, and whether warmer conditions would depress the fitness of high-elevation accessions owing to steep reductions in temperature with increasing elevation in this system. Elevational clines in [CO2] are not as evident, making it challenging to predict how locally adapted ecotypes will respond to elevated [CO2]. This experiment revealed that elevated [CO2] increased photosynthesis and intrinsic water use efficiency across all accessions. However, these instantaneous responses to treatments did not translate to changes in fitness. Instead, increased temperatures reduced the probability of reproduction for all accessions. Elevated [CO2] and increased temperatures interacted to shift the adaptive landscape, favoring lower elevation accessions for the probability of survival and fecundity. Our results suggest that elevated temperatures and [CO2] associated with climate change could have severe negative consequences, especially for high-elevation populations.

Underrepresentation of racial and ethnic minority groups in gynecologic oncology: An analysis of over 250 trials.

OBJECTIVE: To describe the participation of racial and ethnic minority groups (REMGs) in gynecologic oncology trials. METHODS: Gynecologic oncology studies registered on ClinicalTrials.gov between 2007 and 2020 were identified. Trials with published results were analyzed based on reporting of race/ethnicity in relation to disease site and trial characteristics. Expected enrollment by race/ethnicity was calculated and compared to actual enrollment, adjusted for 2010 US Census population data. RESULTS: 2146 gynecologic oncology trials were identified. Of published trials (n = 252), 99 (39.3%) reported race/ethnicity data. Recent trials were more likely to report these data (36% from 2007 to 2009; 51% 2013-2015; and 53% from 2016 to 2018, p = 0.01). Of all trials, ovarian cancer trials were least likely to report race/ethnicity data (32.1% vs 39.3%, p = 0.011). Population-adjusted under-enrollment for Blacks was 7-fold in ovarian cancer, Latinx 10-fold for ovarian and 6-fold in uterine cancer trials, Asians 2.5-fold in uterine cancer trials, and American Indian and Alaska Native individuals 6-fold in ovarian trials. Trials for most disease sites have enrolled more REMGs in recent years - REMGs made up 19.6% of trial participants in 2007-2009 compared to 38.1% in 2016-2018 (p < 0.0001). CONCLUSION: Less than half of trials that published results reported race/ethnicity data. Available data reveals that enrollment of REMGs is significantly below expected rates based on national census data. These disparities persisted even after additionally adjusting for population size. Despite improvement in recent years, additional recruitment of REMGs is needed to achieve more representative and equitable participation in gynecologic cancer clinical trials.

The effect of global change on the expression and evolution of floral traits.

BACKGROUND: Pollinators impose strong selection on floral traits. Indeed, pollinator syndromes are the result of these strong selective forces, but other abiotic and biotic agents also drive the evolution of floral traits and influence plant reproduction. Global change is expected to have widespread effects on biotic and abiotic systems resulting in novel selection on floral traits under future conditions. SCOPE: Global change has depressed pollinator abundance and altered abiotic conditions, thereby exposing flowering plant species to novel suites of selective pressures. Here we consider how biotic and abiotic factors interact to shape the expression and evolution of various floral characteristics (the targets of selection), including floral size, color, physiology, reward quantity and quality, and longevity amongst other traits. We examine cases in which selection imposed by climatic factors conflicts with pollinator-mediated selection. Additionally, we explore how floral traits respond to environmental changes through phenotypic plasticity and how that can alter plant fecundity. In this review, we evaluate how global change may shift the expression and evolution of floral phenotypes. CONCLUSIONS: Floral traits evolve in response to multiple interacting agents of selection. Different agents can sometimes exert conflicting selection. For example, pollinators often prefer large flowers, but drought stress can favor the evolution of smaller flowers, and the size of floral organs can evolve as a trade-off between selection mediated by these opposing actors. Nevertheless, few studies have factorially manipulated abiotic and biotic agents of selection to disentangle their relative strengths and directions of selection. The literature has more often evaluated plastic responses of floral traits to stressors than it has considered how abiotic factors alter selection on these traits. Furthermore, global change will likely alter the selective landscape through changes in the abundance and community compositions of mutualists and antagonists and novel abiotic conditions. We encourage future work to consider a more holistic model of floral evolution, which will enable more robust predictions about floral evolution and plant reproduction as global change progresses.

Three-Month Symptom Profiles Among Symptomatic Adults With Positive and Negative Severe Acute Respiratory Syndrome Coronavirus 2 Tests: A Prospective Cohort Study From the INSPIRE Group.

BACKGROUND: Long-term symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are a major concern, yet their prevalence is poorly understood. METHODS: We conducted a prospective cohort study comparing adults with SARS-CoV-2 infection (coronavirus disease-positive [COVID+]) with adults who tested negative (COVID-), enrolled within 28 days of a Food and Drug Administration (FDA)-approved SARS-CoV-2 test result for active symptoms. Sociodemographic characteristics, symptoms of SARS-CoV-2 infection (assessed with the Centers for Disease Control and Prevention [CDC] Person Under Investigation Symptom List), and symptoms of post-infectious syndromes (ie, fatigue, sleep quality, muscle/joint pains, unrefreshing sleep, and dizziness/fainting, assessed with CDC Short Symptom Screener for myalgic encephalomyelitis/chronic fatigue syndrome) were assessed at baseline and 3 months via electronic surveys sent via text or email. RESULTS: Among the first 1000 participants, 722 were COVID+ and 278 were COVID-. Mean age was 41.5 (SD 15.2); 66.3% were female, 13.4% were Black, and 15.3% were Hispanic. At baseline, SARS-CoV-2 symptoms were more common in the COVID+ group than the COVID- group. At 3 months, SARS-CoV-2 symptoms declined in both groups, although were more prevalent in the COVID+ group: upper respiratory symptoms/head/eyes/ears/nose/throat (HEENT; 37.3% vs 20.9%), constitutional (28.8% vs 19.4%), musculoskeletal (19.5% vs 14.7%), pulmonary (17.6% vs 12.2%), cardiovascular (10.0% vs 7.2%), and gastrointestinal (8.7% vs 8.3%); only 50.2% and 73.3% reported no symptoms at all. Symptoms of post-infectious syndromes were similarly prevalent among the COVID+ and COVID- groups at 3 months. CONCLUSIONS: Approximately half of COVID+ participants, as compared with one-quarter of COVID- participants, had at least 1 SARS-CoV-2 symptom at 3 months, highlighting the need for future work to distinguish long COVID. CLINICAL TRIALS REGISTRATION: NCT04610515.

Local adaptation: Causal agents of selection and adaptive trait divergence.

Divergent selection across the landscape can favor the evolution of local adaptation in populations experiencing contrasting conditions. Local adaptation is widely observed in a diversity of taxa, yet we have a surprisingly limited understanding of the mechanisms that give rise to it. For instance, few have experimentally confirmed the biotic and abiotic variables that promote local adaptation, and fewer yet have identified the phenotypic targets of selection that mediate local adaptation. Here, we highlight critical gaps in our understanding of the process of local adaptation and discuss insights emerging from in-depth investigations of the agents of selection that drive local adaptation, the phenotypes they target, and the genetic basis of these phenotypes. We review historical and contemporary methods for assessing local adaptation, explore whether local adaptation manifests differently across life history, and evaluate constraints on local adaptation.

Fetal growth disorders in twin gestations.

PURPOSE OF REVIEW: Twin gestations account for approximately 3% of all births. Although there appear to be physiologic differences in the third trimester growth of twins compared with singleton gestations, reasons for this remain unclear. As growth-restricted fetuses and neonates are at increased risk for adverse outcomes, there is a clinical need to optimize our ability to delineate normally from pathologically grown twins. RECENT FINDINGS: Recent studies have addressed current limitations in the way growth restriction is diagnosed in twin gestations. Twin-specific fetal and neonatal growth charts have been shown to decrease the number of cases inappropriately labeled as growth restricted compared with singleton nomograms. In addition, individual growth assessment (IGA) is a promising method of diagnosing pathological growth using each fetus's growth potential rather than a comparison of the estimated fetal weight with population nomograms. SUMMARY: There is a recent focus on improving our understanding of physiologic and pathologic twin growth. The increased use of twin-specific growth curves is likely to result in a decrease in the incidence of FGR diagnosis among twin gestations and could improve the outcomes of twins currently misclassified as FGR. Future research will hopefully clarify the reasons behind differences seen in twin versus singleton third trimester twin growth.

Plasma Microbial Cell-free DNA Next-generation Sequencing in the Diagnosis and Management of Febrile Neutropenia.

BACKGROUND: Standard testing fails to identify a pathogen in most patients with febrile neutropenia (FN). We evaluated the ability of the Karius microbial cell-free DNA sequencing test (KT) to identify infectious etiologies of FN and its impact on antimicrobial management. METHODS: This prospective study (ClinicalTrials.gov; NCT02912117) enrolled and analyzed 55 patients with FN. Up to 5 blood samples were collected per subject within 24 hours of fever onset (T1) and every 2 to 3 days. KT results were compared with blood culture (BC) and standard microbiological testing (SMT) results. RESULTS: Positive agreement was defined as KT identification of ≥1 isolate also detected by BC. At T1, positive and negative agreement were 90% (9/10) and 31% (14/45), respectively; 61% of KT detections were polymicrobial. Clinical adjudication by 3 independent infectious diseases specialists categorized Karius results as: unlikely to cause FN (N = 0); definite (N = 12): KT identified ≥1 organism also found by SMT within 7 days; probable (N = 19): KT result was compatible with a clinical diagnosis; possible (N = 10): KT result was consistent with infection but not considered a common cause of FN. Definite, probable, and possible cases were deemed true positives. Following adjudication, KT sensitivity and specificity were 85% (41/48) and 100% (14/14), respectively. Calculated time to diagnosis was generally shorter with KT (87%). Adjudicators determined real-time KT results could have allowed early optimization of antimicrobials in 47% of patients, by addition of antibacterials (20%) (mostly against anaerobes [12.7%]), antivirals (14.5%), and/or antifungals (3.6%); and antimicrobial narrowing in 27.3% of cases. CLINICAL TRIALS REGISTRATION: NCT02912117. CONCLUSION: KT shows promise in the diagnosis and treatment optimization of FN.

Eco-evolutionary causes and consequences of rarity in plants: a meta-analysis.

Species differ dramatically in their prevalence in the natural world, with many species characterized as rare due to restricted geographic distribution, low local abundance and/or habitat specialization. We investigated the ecoevolutionary causes and consequences of rarity with phylogenetically controlled metaanalyses of population genetic diversity, fitness and functional traits in rare and common congeneric plant species. Our syntheses included 252 rare species and 267 common congeners reported in 153 peer-reviewed articles published from 1978 to 2020 and one manuscript in press. Rare species have reduced population genetic diversity, depressed fitness and smaller reproductive structures than common congeners. Rare species also could suffer from inbreeding depression and reduced fertilization efficiency. By limiting their capacity to adapt and migrate, these characteristics could influence contemporary patterns of rarity and increase the susceptibility of rare species to rapid environmental change. We recommend that future studies present more nuanced data on the extent of rarity in focal species, expose rare and common species to ecologically relevant treatments, including reciprocal transplants, and conduct quantitative genetic and population genomic analyses across a greater array of systems. This research could elucidate the processes that contribute to rarity and generate robust predictions of extinction risks under global change.

Genetic trade-offs and unexpected life history traits shape local adaptation in Trifolium repens.

Local adaptation has evolved in numerous taxa across the tree of life in response to divergent selection acting on populations that inhabit different environments (Briscoe Runquist et al., 2019; Hargreaves et al., 2019; Hereford, 2009). The genetic basis of local adaptation has intrigued researchers for decades. In their foundational reciprocal transplant study, Clausen and Hiesey (1960) evaluated the genetics of adaptation primarily using hybrid lines derived from crosses of low elevation and alpine Potentilla glandulosa (Rosaceae) ecotypes. Their work revealed that transgressive segregation can lead to a wider range of trait values than expressed by the parents, complex traits are often genetically correlated and evolve in tandem, and local adaptation is typically polygenic, that is, controlled by many loci of small effect (Clausen & Hiesey, 1960). Within the past 15 years, a burgeoning literature has investigated whether local adaptation evolves through genetic trade-offs, such that local alleles at a QTL (quantitative trait locus) or candidate gene have a fitness advantage in their home environment, but suffer a fitness cost when transplanted into a contrasting habitat type (Mitchell-Olds et al., 2007). Alternatively, local adaptation could arise through conditional neutrality, in which an allele native to one habitat type has elevated fitness in its home site relative to foreign alleles, but is not at a fitness disadvantage elsewhere. Conditional neutrality could maintain local adaptation if gene flow is spatially restricted (Hall et al., 2010). In a From the Cover article in this issue of Molecular Ecology, Wright et al. (2022) examined the genetic basis of local adaptation in white clover (Trifolium repens), discovering strong signatures of local adaptation, and revealing that both genetic trade-offs and conditional neutrality contribute to local adaptation. The most surprising and intriguing result to emerge from this study was that variation in a key antiherbivore defence did not appear to influence contemporary patterns of local adaptation. Rather, divergence in life history strategies was crucial, with early reproduction favoured in the southern garden and delayed reproduction and longer lifespans emerging in the north. These findings highlight the challenges of identifying the multivariate targets of divergent selection in locally-adapted systems, and reveal that not all traits that vary across populations contribute to adaptive differentiation. As studies continue to investigate local adaptation, experiments that manipulate environmental conditions and quantify the magnitude and direction of selection on traits will shed light on the processes that drive local adaptation.

Water and nutrient availability exert selection on reproductive phenology.

PREMISE: Global change has changed resource availability to plants, which could shift the adaptive landscape. We hypothesize that novel water and nutrient availability combinations alter patterns of natural selection on reproductive phenology in Boechera stricta (Brassicaceae) and influence the evolution of local adaptation. METHODS: We conducted a multifactorial greenhouse study using 35 accessions of B. stricta sourced from a broad elevational gradient in the Rocky Mountains. We exposed full siblings to three soil water and two nutrient availability treatment levels, reflecting current and projected future conditions. In addition, we quantified fitness (seed count) and four phenological traits: the timing of first flowering, the duration of flowering, and height and leaf number at flowering. RESULTS: Selection favored early flowering and longer duration of flowering, and the genetic correlation between these traits accorded with the direction of selection. In most treatments, we found selection for increased height, but selection on leaf number depended on water availability, with selection favoring more leaves in well-watered conditions and fewer leaves under severe drought. Low-elevation genotypes had the greatest fitness under drought stress, consistent with local adaptation. CONCLUSIONS: We found evidence of strong selection on these heritable traits. Furthermore, the direction and strength of selection on size at flowering depended on the variable measured (height vs. leaf number). Finally, selection often favored both early flowering and a longer duration of flowering. Selection on these two components of phenology can be difficult to disentangle due to tight genetic correlations.

The Boechera model system for evolutionary ecology.

Model systems in biology expand the research capacity of individuals and the community. Closely related to Arabidopsis, the genus Boechera has emerged as an important ecological model owing to the ability to integrate across molecular, functional, and eco-evolutionary approaches. Boechera species are broadly distributed in relatively undisturbed habitats predominantly in western North America and provide one of the few experimental systems for identification of ecologically important genes through genome-wide association studies and investigations of selection with plants in their native habitats. The ecologically, evolutionarily, and agriculturally important trait of apomixis (asexual reproduction via seeds) is common in the genus, and field experiments suggest that abiotic and biotic environments shape the evolution of sex. To date, population genetic studies have focused on the widespread species B. stricta, detailing population divergence and demographic history. Molecular and ecological studies show that balancing selection maintains genetic variation in ~10% of the genome, and ecological trade-offs contribute to complex trait variation for herbivore resistance, flowering phenology, and drought tolerance. Microbiome analyses have shown that host genotypes influence leaf and root microbiome composition, and the soil microbiome influences flowering phenology and natural selection. Furthermore, Boechera offers numerous opportunities for investigating biological responses to global change. In B. stricta, climate change has induced a shift of >2 weeks in the timing of first flowering since the 1970s, altered patterns of natural selection, generated maladaptation in previously locally-adapted populations, and disrupted life history trade-offs. Here we review resources and results for this eco-evolutionary model system and discuss future research directions.

Costs of reproduction under experimental climate change across elevations in the perennial forb Boechera stricta.

Investment in current reproduction can reduce future fitness by depleting resources needed for maintenance, particularly under environmental stress. These trade-offs influence life-history evolution. We tested whether climate change alters the future-fitness costs of current reproduction in a large-scale field experiment of Boechera stricta (Brassicaceae). Over 6 years, we simulated climate change along an elevational gradient in the Rocky Mountains through snow removal, which accelerates snowmelt and reduces soil water availability. Costs of reproduction were greatest in arid, lower elevations, where high initial reproductive effort depressed future fitness. At mid-elevations, initial reproduction augmented subsequent fitness in benign conditions, but pronounced costs emerged under snow removal. At high elevation, snow removal dampened costs of reproduction by prolonging the growing season. In most scenarios, failed reproduction in response to resource limitation depressed lifetime fecundity. Indeed, fruit abortion only benefited high-fitness individuals under benign conditions. We propose that climate change could shift life-history trade-offs in an environment-dependent fashion, possibly favouring early reproduction and short lifespans in stressful conditions.

Climate change alters plant-herbivore interactions.

Plant-herbivore interactions have evolved in response to coevolutionary dynamics, along with selection driven by abiotic conditions. We examine how abiotic factors influence trait expression in both plants and herbivores to evaluate how climate change will alter this long-standing interaction. The paleontological record documents increased herbivory during periods of global warming in the deep past. In phylogenetically corrected meta-analyses, we find that elevated temperatures, CO2 concentrations, drought stress and nutrient conditions directly and indirectly induce greater food consumption by herbivores. Additionally, elevated CO2 delays herbivore development, but increased temperatures accelerate development. For annual plants, higher temperatures, CO2 and drought stress increase foliar herbivory. Our meta-analysis also suggests that greater temperatures and drought may heighten florivory in perennials. Human actions are causing concurrent shifts in CO2 , temperature, precipitation regimes and nitrogen deposition, yet few studies evaluate interactions among these changing conditions. We call for additional multifactorial studies that simultaneously manipulate multiple climatic factors, which will enable us to generate more robust predictions of how climate change could disrupt plant-herbivore interactions. Finally, we consider how shifts in insect and plant phenology and distribution patterns could lead to ecological mismatches, and how these changes may drive future adaptation and coevolution between interacting species.

Outcomes of Bilateral Cataract Surgery in Infants 7 to 24 Months of Age Using the Toddler Aphakia and Pseudophakia Treatment Study Registry.

PURPOSE: To evaluate outcomes of bilateral cataract surgery in children aged 7 to 24 months and compare rates of adverse events (AEs) with other Toddler Aphakia and Pseudophakia Study (TAPS) registry outcomes. DESIGN: Retrospective clinical study at 10 Infant Aphakia Treatment Study (IATS) sites. Statistical analyses comparing this cohort with previously reported TAPS registry cohorts. PARTICIPANTS: Children enrolled in the TAPS registry between 2004 and 2010. METHODS: Children underwent bilateral cataract surgery with or without intraocular lens (IOL) placement at age 7 to 24 months with 5 years of postsurgical follow-up. MAIN OUTCOME MEASURES: Visual acuity (VA), occurrence of strabismus, AEs, and reoperations. RESULTS: A total of 40 children (76 eyes) who underwent bilateral cataract surgery with primary posterior capsulectomy were identified with a median age at cataract surgery of 11 months (7-23); 68% received a primary IOL. Recurrent visual axis opacification (VAO) occurred in 7.5% and was associated only with the use of an IOL (odds ratio, 6.10; P = 0.005). Glaucoma suspect (GS) was diagnosed in 2.5%, but no child developed glaucoma. In this bilateral cohort, AEs (8/40, 20%), including glaucoma or GS and VAO, and reoperations occurred in a similar proportion to that of the published unilateral TAPS cohort. When analyzed with children aged 1 to 7 months at bilateral surgery, the incidence of AEs and glaucoma or GS correlated strongly with age at surgery (P = 0.011/0.004) and glaucoma correlated with microcornea (P = 0.040) but not with IOL insertion (P = 0.15). CONCLUSIONS: Follow-up to age 5 years after bilateral cataract surgery in children aged 7 to 24 months reveals a low rate of VAO and very rare glaucoma or GS diagnosis compared with infants with cataracts operated at < 7 months of age despite primary IOL implantation in most children in the group aged 7 to 24 months. The use of an IOL increases the risk of VAO irrespective of age at surgery.

Climate change disrupts local adaptation and favours upslope migration.

Contemporary climate change is proceeding at an unprecedented rate. The question remains whether populations adapted to historical conditions can persist under rapid environmental change. We tested whether climate change will disrupt local adaptation and reduce population growth rates using the perennial plant Boechera stricta (Brassicaceae). In a large-scale field experiment conducted over five years, we exposed > 106 000 transplants to historical, current, or future climates and quantified fitness components. Low-elevation populations outperformed local populations under simulated climate change (snow removal) across all five experimental gardens. Local maladaptation also emerged in control treatments, but it was less pronounced than under snow removal. We recovered local adaptation under snow addition treatments, which reflect historical conditions. Our results revealed that low elevation populations risk rapid decline, whereas upslope migration could enable population persistence and expansion at higher elevation locales. Local adaptation to historical conditions could increase vulnerability to climate change, even for geographically widespread species.

Outcomes of Bilateral Cataracts Removed in Infants 1 to 7 Months of Age Using the Toddler Aphakia and Pseudophakia Treatment Study Registry.

PURPOSE: To evaluate outcomes of bilateral cataract surgery in infants 1 to 7 months of age performed by Infant Aphakia Treatment Study (IATS) investigators during IATS recruitment and to compare them with IATS unilateral outcomes. DESIGN: Retrospective case series review at 10 IATS sites. PARTICIPANTS: The Toddler Aphakia and Pseudophakia Study (TAPS) is a registry of children treated by surgeons who participated in the IATS. METHODS: Children underwent bilateral cataract surgery with or without intraocular lens (IOL) placement during IATS enrollment years 2004 through 2010. MAIN OUTCOME MEASURES: Visual acuity (VA), strabismus, adverse events (AEs), and reoperations. RESULTS: One hundred seventy-eight eyes (96 children) were identified with a median age of 2.5 months (range, 1-7 months) at the time of cataract surgery. Forty-two eyes (24%) received primary IOL implantation. Median VA of the better-seeing eye at final study visit closest to 5 years of age with optotype VA testing was 0.35 logarithm of the minimum angle of resolution (logMAR; optotype equivalent, 20/45; range, 0.00-1.18 logMAR) in both aphakic and pseudophakic children. Corrected VA was excellent (<20/40) in 29% of better-seeing eyes, 15% of worse-seeing eyes. One percent showed poor acuity (≥20/200) in the better-seeing eye, 12% in the worse-seeing eye. Younger age at surgery and smaller (<9.5 mm) corneal diameter at surgery conferred an increased risk for glaucoma or glaucoma suspect designation (younger age: odds ratio [OR], 1.44; P = 0.037; and smaller cornea: OR, 3.95; P = 0.045). Adverse events also were associated with these 2 variables on multivariate analysis (younger age: OR, 1.36; P = 0.023; and smaller cornea: OR, 4.78; P = 0.057). Visual axis opacification was more common in pseudophakic (32%) than aphakic (8%) eyes (P = 0.009). Unplanned intraocular reoperation occurred in 28% of first enrolled eyes (including glaucoma surgery in 10%). CONCLUSIONS: Visual acuity after bilateral cataract surgery in infants younger than 7 months is good, despite frequent systemic and ocular comorbidities. Although aphakia management did not affect VA outcome or AE incidence, IOL placement increased the risk of visual axis opacification. Adverse events and glaucoma correlated with a younger age at surgery and glaucoma correlated with the presence of microcornea.

Natural history collections document biological responses to climate change: A commentary on DeLeo et al. (2019), Effects of two centuries of global environmental variation on phenology and physiology of Arabidopsis thaliana.

Natural history collections can complement and enhance our research programs in a variety of ways. DeLeo et al. (2019) used herbarium records to study the changes in physiology and phenology in Arabidopsis thaliana (Brassicaceae) due to contemporary climate change. Here, we discuss their approach and results as well as highlight other ways in which herbarium and natural history museum records can be leveraged for future studies.The copyright holder of the image (the herbarium sheet of Arabidopsis thaliana) is the first author, Derek Denney. This article is a commentary on DeLeo et al, 26, 523-538.

Resource availability alters fitness trade-offs: implications for evolution in stressful environments.

PREMISE: Industrialization and human activities have elevated temperatures and caused novel precipitation patterns, altering soil moisture and nutrient availability. Predicting evolutionary responses to climate change requires information on the agents of selection that drive local adaptation and influence resource acquisition and allocation. Here, we examined the contribution of nutrient and drought stress to local adaptation, and we tested whether trade-offs across fitness components constrain or facilitate adaptation under resource stress. METHODS: We exposed 35 families of Boechera stricta (Brassicaceae) to three levels of water and two levels of nutrient supply in a factorial design in the greenhouse. We sourced maternal families from a broad elevational gradient (2499-3530 m a.s.l.), representing disparate soil moisture and nutrient availability. RESULTS: Concordant with local adaptation, maternal families from arid, low-elevation populations had enhanced fecundity under severe drought over those from more mesic, high-elevation sites. Furthermore, fitness trade-offs between growth and reproductive success depended on the environmental context. Under high, but not low, nutrient levels, we found a negative phenotypic relationship between the probability of reproduction and growth rate. Similarly, a negative phenotypic association only emerged between fecundity and growth under severe drought stress, not the benign water treatment levels, indicating that stressful resource environments alter the direction of trait correlations. Genetic covariances were broadly concordant with these phenotypic patterns. CONCLUSIONS: Despite high heritabilities in all fitness components across treatments, trade-offs between growth and reproduction could constrain adaptation to increasing drought stress and novel nutrient levels.

Cytokine signature associated with disease severity in chronic fatigue syndrome patients.

Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine's preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-ß was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

Single-Dose Neoadjuvant AKT Pathway Inhibitor Reduces Growth of Hepatocellular Carcinoma after Laser Thermal Ablation in Small-Animal Model.

BackgroundLocal recurrence following thermal ablation of hepatocellular carcinoma (HCC) larger than 2-3 cm remains a challenging clinical problem. Prior studies suggest that phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)-dependent protein kinase B (AKT) signaling mediates HCC cell survival caused by moderate heat stress in vitro, but these findings need in vivo validation.PurposeTo test the hypothesis that neoadjuvant inhibition of PI3K/mTOR/AKT signaling reduces HCC tumor growth in vivo after laser ablation and to evaluate the effects of moderate heat stress on molecular signaling and cellular function in HCC cells in vitro.Materials and MethodsHCC tumor-bearing mice were randomized to neoadjuvant PI3K/mTOR inhibitor (BEZ235) or control groups followed by an intentional partial laser ablation or sham ablation; there were at least nine mice per group. Postablation tumor growth was monitored up to 7 days. Tumor volumes were compared for drug or ablation groups by using two-way analysis of variance. N1S1 HCC cells pretreated with BEZ235 or control and subjected to moderate heat stress (45°C for 10 minutes) or control (37°C for 10 minutes) were analyzed by using mass spectrometry. Protein interaction networks were derived from protein expression analysis software, and cellular function activation state (Z-score) and fold-change in AKT phosphorylation were calculated.ResultsThere was a 37%-75% reduction in HCC tumor volume by day 7 after ablation in the BEZ235 plus ablation group (713 mm3 ± 417) compared with vehicle plus sham (1559 mm3 ± 552), vehicle plus ablation (1041 mm3 ± 591), and BEZ235 plus sham (1108 mm3 ± 523) groups (P < .001, P = .04, and P = .005, respectively). PI3K/mTOR inhibition prevented moderate heat stress-induced AKT signaling (Z-score, -0.2; P < .001) and isoform-specific AKT phosphorylation compared with the vehicle plus heat stress group. PI3K/mTOR inhibition prevented moderate heat stress-induced global effects on HCC molecular signaling and cellular function, including decreased cell survival, growth, and proliferation (Z-score, -0.3 to -3.2; P < .001) and increased apoptosis and cell death (Z-score, 0.4-1.1; P < .001).ConclusionModerate heat stress induces PI3K/mTOR/AKT-dependent global effects on hepatocellular carcinoma (HCC) cell survival, function, and death. Neoadjuvant PI3K/mTOR/AKT inhibition reduces postablation HCC tumor growth.© RSNA, 2019Online supplemental material is available for this article.See also the editorial by White in this issue.