Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer.

BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

Development and Validation of a Photonumeric Scale to Assess Marionette Lines.

BACKGROUND: A validated scale is needed for objective and reproducible comparisons of marionette lines before and after treatment in clinical studies. OBJECTIVE: To describe the development and validation of a 5-point photonumeric marionette lines scale. METHODS: The scale was developed to include an assessment guide, verbal descriptors, and real and morphed subject images for each scale grade. Intrarater and interrater reliability was evaluated in initial scale validation (web-based review) ( N = 51 ) and live-subject validation ( N = 75 ) studies, each completed during 2 sessions. RESULTS: In the initial scale validation study, intrarater agreement for 2 physician raters was near perfect (weighted kappa = 0.92 and 0.94). Interrater agreement was excellent during sessions 1 and 2 (intraclass correlation coefficients of 0.94 and 0.95, respectively). In the live-subject validation study, intrarater agreement for 3 physician raters showed a strong correlation (mean weighted kappa = 0.77). Interrater agreement was high during live-subject validation sessions 1 and 2 (intraclass correlation coefficients = 0.89 for both sessions). CONCLUSION: This new marionette lines scale is a validated and reliable scale for physician rating of marionette line severity.

Treating Glabellar Lines With Botulinum Toxin: Does Your Patient Need to Frown Steadily?

BACKGROUND: The variable relationship between the orbicularis supercilii and frontalis muscles may cause side effects with botulin toxin; steadily frowning is the usual recommendation. Eliminating the need to frown until all injections are over might enhance efficacy and lessen the neurotoxicity risks related to muscle exhaustion. OBJECTIVES: The goal of this study was to investigate whether the digital caliper-assessed distances between the medial and lateral corrugator injection sites and the midline differed significantly in patients persistently frowning from patients resting. METHODS: Seventy-six individuals with glabellar wrinkles treated with botulinum toxin in the authors' private practices for glabellar lines voluntarily contributed their retrospective data about the positions of injection sites. The investigators had freely chosen to inject the medial and lateral sections of the corrugator supercilii during persistent maximum frown or at rest. RESULTS: The mean differences in distances between the medial and lateral injection points and the estimated midline were clinically trivial (1.0 ± 1.28 and 1.5 ± 2.53 mm, respectively), although the distances between the relaxed and contracted medial and lateral injection sites exceeded 1.8 and 2.5 mm in 33.9% and 46.4% of patients, respectively. Distance differences, not significant before 40 years old, were statistically significant only for the lateral injections in older patients (on average, 1.9 ± 3.01 mm). CONCLUSIONS: The average distances from the medial and lateral injection points and the midline appear minimally different in patients who frown until all injections are over and, conversely, patients who rest. Persistently frowning might be advisable only in patients older than 40. Facial asymmetries may be a confounding factor.

Body Contouring Using a Combination of Pulsed Ultrasound and Unipolar Radio Frequency: A Prospective Pilot Study.

OBJECTIVE: To assess the efficacy and safety of a new non-invasive body contouring device in patients with localized fat in abdomen or in abdomen and hips. Additionally, we also evaluated the patient satisfaction with the procedure. METHODS: Prospective and non-randomized open label study. The patients underwent four sessions, separated by 1 week each, with the Alma PrimeX, a non-invasive body contouring device that combines pulsed non-focus ultrasound and a Unipolar radiofrequency. The primary end point was the mean change in fat tissue thickness, assessed by diagnostic ultrasound, from baseline to 3-months after the last treatment-session. RESULTS: Fifteen subjects were evaluated. As compared to pre-treatment thickness, Hodges-Lehmann median difference (95% CI) was - 85.3 (- 107.5 to - 62.0) mm, p = 0.0001; - 70.3 (- 95.0 to - 48.5) mm, p = 0.0001; - 100.0 (- 140.5 to - 49.5) mm, p = 0.0039; and - 71.8 (- 132.5 to - 23.0) mm, p = 0.0078 in infraumbilical, supraumbilical, right hip, and left hip, respectively. Pretreatment fat volume was significantly reduced from 32.9% to 31.2%, p = 0.0006. The median (interquartile range) degree of patient satisfaction was 4.0 (1.0-5.0), with 13 (86.7%) patients being "Highly satisfied" or "Satisfied" with the treatment results. The most common adverse event was discomfort, followed by erythema. All the adverse events were mild and were successfully resolved without treatment. CONCLUSIONS: Combine therapy of a Pulsed non-focus ultrasound and Unipolar radiofrequency using the non-invasive device Alma PrimeX was an effective and safe treatment for reducing fat tissue thickness in abdomen and hips in patients with localized fat. Patients' satisfaction with the procedure was high. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Increased polyamine levels and maintenance of γ-aminobutyric acid (Gaba) homeostasis in the gills is indicative of osmotic plasticity in killifish.

The Fundulus genus of killifish includes species that inhabit marshes along the U.S. Atlantic coast and the Gulf of Mexico, but differ in their ability to adjust rapidly to fluctuations in salinity. Previous work suggests that euryhaline killifish stimulate polyamine biosynthesis and accumulate putrescine in the gills during acute hypoosmotic challenge. Despite evidence that polyamines have an osmoregulatory role in euryhaline killifish species, their function in marine species is unknown. Furthermore, the consequences of hypoosmotic-induced changes in polyamine synthesis on downstream pathways, such as Æ´-aminobutyric acid (Gaba) production, have yet to be explored. Here, we examined the effects of acute hypoosmotic exposure on polyamine, glutamate, and Gaba levels in the gills of a marine (F. majalis) and two euryhaline killifish species (F. heteroclitus and F. grandis). Fish acclimated to 32 ppt or 12 ppt water were transferred to fresh water, and concentrations of glutamate (Glu), Gaba, and the polyamines putrescine (Put), spermidine (Spd), and spermine (Spm) were measured in the gills using high-performance liquid chromatography. F. heteroclitus and F. grandis exhibited an increase in gill Put concentration, but showed no change in Glu or Gaba levels following freshwater transfer. F. heteroclitus also accumulated Spd in the gills, whereas F. grandis showed transient increases in Spd and Spm levels. In contrast, gill Put, Spm, Glu, and Gaba levels decreased in F. majalis following freshwater transfer. Together, these findings suggest that increasing polyamine levels and maintaining Glu and Gaba levels in the gills may enable euryhaline teleosts to acclimate to shifts in environmental salinity.

Evaluación nutricional de cuidadores de pacientes hospitalizados.

Señor editor: La hospitalización de un miembro de la familia representa todo un fenómeno social y cultural. Esto afecta no sólo al enfermo, sino también al resto de los integrantes de la familia. La realización de las tareas del cuidador requiere un gasto de tiempo y dinero. Además del desgaste físico, psicológico y social que conlleva esta tarea, el cuidador puede presentar depresión y ansiedad.

Interspecific variation in hypoxia tolerance and hypoxia acclimation responses in killifish from the family Fundulidae.

Hypoxia is a pervasive stressor in aquatic environments, and both phenotypic plasticity and evolutionary adaptation could shape the ability to cope with hypoxia. We investigated evolved variation in hypoxia tolerance and the hypoxia acclimation response across fundulid killifishes that naturally experience different patterns of hypoxia exposure. We compared resting O2 consumption rate (MO2 ), and various indices of hypoxia tolerance [critical O2 tension (Pcrit), regulation index (RI), O2 tension (PO2 ) at loss of equilibrium (PLOE) and time to LOE (tLOE) at 0.6 kPa O2] in Fundulus confluentus, Fundulus diaphanus, Fundulus heteroclitus, Fundulus rathbuni, Lucania goodei and Lucania parva We examined the effects of chronic (28 days) exposure to constant hypoxia (2 kPa) or nocturnal intermittent hypoxia (12 h normoxia:12 h hypoxia) in a subset of species. Some species exhibited a two-breakpoint model in MO2  caused by early, modest declines in MO2  in moderate hypoxia. We found that hypoxia tolerance varied appreciably across species: F. confluentus was the most tolerant (lowest PLOE and Pcrit, longest tLOE), whereas F. rathbuni and F. diaphanus were the least tolerant. However, there was not a consistent pattern of interspecific variation for different indices of hypoxia tolerance, with or without taking phylogenetic relatedness into account, probably because these different indices are underlain by partially distinct mechanisms. Hypoxia acclimation generally improved hypoxia tolerance, but the magnitude of plasticity and responsiveness to different hypoxia patterns varied interspecifically. Our results therefore suggest that hypoxia tolerance is a complex trait that is best appreciated by considering multiple indices of tolerance.

Face and neck rejuvenation using an improved non-ablative fractional high power 1064-nm Q-switched Nd:YAG Laser: clinical results in 16 women.

OBJECTIVE: To evaluate the safety and efficacy of a specific treatment protocol using a new and improved non-ablative fractional high-power 1064-nm Q-switched Nd:YAG laser for face and neck rejuvenation. METHODS: Sixteen women, aged 30 to 60 years old, were selected to undergo three consecutive treatment sessions with this new laser at maximum energy (2,400 mJ/pulse, Clear Lift laser®-Harmony XL-Pro, Alma Lasers Ltd.). Face and neck were treated in eight patients, respectively. Each treatment used the same protocol. The efficacy was evaluated by the therapist (TS), the patient (PS), and two separate independent experts who were blind to the study (E1 and E2). RESULTS: According to E1 and E2, the mean reduction in signs of skin aging on a Global Esthetic Improvement Scale was 30-40%. Using a 0-10 points scale, TS and PS mean (range) satisfaction rates were 9.0 (8-10); 9.2 (6-10) for the face and 8.7 (8-10); 8.0 (3-10), for the neck, respectively. The procedure was practically painless, no significant adverse effects were observed, and the patients returned to their daily and work activities without downtime. CONCLUSION: This laser was safe and effective for face and neck minimally invasive rejuvenation, with excellent results using our usual routine use conditions.

Correction to: Concomitant Use of Hyaluronic Acid and Laser in Facial Rejuvenation.

The article Concomitant Use of Hyaluronic Acid and Laser in Facial Rejuvenation written by Urdiales-Gálvez et al. was originally published electronically on the publisher's internet portal (currently SpringerLink) on May 9, 2019, without open access.

Histopathological Changes After Experimental Skin Resurfacing Using an Improved Fractional High-Power 1064-nm Q-Switched Nd:YAG Laser

BACKGROUND: Several studies confirm microscopic changes in the cutaneous architecture following various rejuvenation techniques using non-ablative lasers. OBJECTIVE: To investigate the histological changes that occur after the application of an improved high-power 1064-nm fractional Q-switched Nd: YAG laser, using different focusing tips. MATERIAL AND METHODS: Experimental skin resurfacing of the retroauricular area in 15 female volunteers, in three treatment sessions of one pass each, using the Clear Lift® laser (Alma Lasers, Israel) and five different focusing tips. Biopsies were taken before and immediately after the first treatment session, one month after the first session, and one month after the third session. A total of 60 microscopic images were evaluated at a micrometric scale. RESULTS: The five tips used caused characteristic and similar histological changes in both the dermis and the epidermis. The signs of thermal damage and the formation of new collagen were observed at different depths, in accordance with the focal length of each tip. Neo-formation of collagen with the increase, reorganization and compaction of fibers began one month after the first treatment session, and was blindly confirmed, with all the tips used, one month after the third treatment session. CONCLUSION: The skin takes on a new conformation, with histological signs of skin rejuvenation, concordant with previous clinical observations. J Drugs Dermatol. 2019;18(12):1261-1266.

Concomitant Use of Hyaluronic Acid and Laser in Facial Rejuvenation.

BACKGROUND: Facial aging is a process that involves many different changes. Therefore, in many patients, it may be necessary to perform a combined treatment. Botulinum toxin A and dermal fillers are the two most popular nonsurgical cosmetic procedures performed globally to treat age-associated changes. However, there are not many studies reporting the concomitant use of dermal fillers and laser technology for facial rejuvenation. This review aims to assess the concomitant use of dermal hyaluronic acid (HA) fillers and laser technology for facial rejuvenation. METHODS: The present updated consensus recommendations are based on the experience and opinions of the authors and on a literature search. RESULTS: If a combined procedure (HA and light treatments) is to be performed, on the same day, the panel recommends starting always with the light treatments, avoiding skin manipulations after having injected HA. To customize the therapeutic management, it is crucial to establish a precise diagnosis of the photodamage and loss of volumes suffered by the patients. CONCLUSIONS: The currently available scientific evidence about the combined use of HA fillers and laser-radiofrequency-intense pulsed light (laser/RF/IPL) is limited and encompasses mainly small and nonrandomized studies. Nevertheless, most of these studies found that, on average, the concomitant use (same day) of laser and HA fillers for facial rejuvenation represents an effective and safe strategy which improves clinical results and patient's satisfaction. Future well-designed clinical studies are needed regarding the effectiveness and safety of combination filler/laser treatments. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Nutritional and meat quality characteristics of seven primal cuts from 9-month-old female veal calves: a preliminary study.

BACKGROUND: Beef is a highly nutritious and valuable food. In order to complete its nutritional information, this study determined the chemical and physicochemical parameters and fatty acid, amino acid and mineral contents in seven primal cuts from veal carcasses (shoulder clod (SC), inside round (IR), eye of round (ER), bottom round (BR), heel of round (HR), knuckle (KK) and tenderloin (TL)). RESULTS: The intramuscular fat content was higher and the cholesterol content was lower in TL than in the other cuts. The colour parameters also varied in the different primal cuts. The L* and b* values were highest in ER. Cooking losses were significantly (P < 0.001) affected by the cut of meat ranging from 20.85% in HR to 29.01% in ER. Determination of the shear force values permitted us to establish more tender muscle (TL with shear force 16.45 N cm-2 ) and less tender muscle (IR with shear force 47.27 N cm-2 ). The nutritional indices and fatty acid profile indicated that HR is the healthiest cut. All cuts evaluated provide important levels of dietary amino acids, although the contents of both essential and non-essential amino acids were highest in HR. Finally, K, Zn and Fe were affected by the type of veal cut. CONCLUSIONS: All primal cuts of veal provide important nutrients for human diets. The information of this research allows consumers to make healthful food choices, creating diets aimed at trying to correct deficiencies and providing objective data that differentiate between differently priced cuts of veal. © 2018 Society of Chemical Industry.

A comparative study between traditional fixation with miniplates and modified lag screws for the treatment of mandibular fractures.

OBJECTIVES: The objective of this study is to investigate two internal fixation surgical techniques for mandibular fractures in order to compare modified lag screw techniques with standard miniplates. MATERIALS AND METHODS: This is an observational prospective study. Three hundred eighteen patients were operated on for mandibular fractures. The patients were divided into two groups according to the type of surgical technique used: modified lag screws (155 patients) and traditional miniplates (163 patients). Analyses were made of sociodemographic and preoperative variables, the parameters related to the fracture type and postoperative data. RESULTS: There were no differences between the two groups regarding their sociodemographic characteristics. The modified lag screws were primarily used with double fractures, while conventional miniplates were more often used with simple fractures. The number of complications was higher with the miniplate technique. The unfavorable fractures had an OR of 5.75 due to postoperative complications; double fractures had an OR of 8.87 and simple fractures an OR of 19.53, which, in both cases, were lower with conventional miniplates than with modified lag screws. CONCLUSION: Modified lag screws provide a rigid fixation system that is as secure as miniplates, but with greater compression between the fragments, less postsurgical gap, faster ossification, and fewer postoperative complications. CLINICAL RELEVANCE: The modified screw technique is a safe tool that does not require any specific osteosynthesis materials not found in a basic traumatology kit and has a lower cost, due to the reduced amount of material used.

Treatment of Soft Tissue Filler Complications: Expert Consensus Recommendations.

BACKGROUND: Dermal fillers have been increasingly used in minimally invasive facial esthetic procedures. This widespread use has led to a rise in reports of associated complications. The aim of this expert consensus report is to describe potential adverse events associated with dermal fillers and to provide guidance on their treatment and avoidance. METHODS: A multidisciplinary group of experts in esthetic treatments convened to discuss the management of the complications associated with dermal fillers use. A search was performed for English, French, and Spanish language articles in MEDLINE, the Cochrane Database, and Google Scholar using the search terms "complications" OR "soft filler complications" OR "injectable complications" AND "dermal fillers" AND "Therapy". An initial document was drafted by the Coordinating Committee, and it was reviewed and modified by the experts, until a final text was agreed upon and validated. RESULTS: The panel addressed consensus recommendations about the classification of filler complications according to the time of onset and about the clinical management of different complications including bruising, swelling, edema, infections, lumps and bumps, skin discoloration, and biofilm formation. Special attention was paid to vascular compromise and retinal artery occlusion. CONCLUSIONS: Clinicians should be fully aware of the signs and symptoms related to complications and be prepared to confidently treat them. Establishing action protocols for emergencies, with agents readily available in the office, would reduce the severity of adverse outcomes associated with injection of hyaluronic acid fillers in the cosmetic setting. This document seeks to lay down a set of recommendations and to identify key issues that may be useful for clinicians who are starting to use dermal fillers. Additionally, this document provides a better understanding about the diagnoses and management of complications if they do occur. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Effects of pulses and microalgal proteins on quality traits of beef patties.

Physicochemical parameters (pH, colour and texture), proximate composition (moisture, protein, lipid and ash content), amino acid content, and taste profile of beef patties elaborated with soy (control), pulses (pea, lentil and bean) and microalgal (Chlorella and Spirulina) proteins were assessed. The pH, colour, ash content, total, essential and non-essential amino acids and amino acid content were significantly different among the beef patties studied. In this regard, beef patties prepared with pea protein presented the highest values for pH; whereas beef patties manufactured with pea also showed the highest values for lightness and patties elaborated with bean the highest values for redness. Similar textural parameters were observed among the six batches of beef patties manufactured. Regarding ash content, a significant higher content was observed in the beef patties prepared with soy compared to the other ones. On the other hand, the beef patties elaborated with bean and seaweeds showed the highest values for the total amino acids content. The inclusion of bean and seaweed proteins increased the concentrations of all amino acids in beef patties, being glutamic acids, lysine and aspartic acid the predominant amino acids. Regarding the taste analysis, a similar profile was found among the six batches of beef patties studied. Considering all studied parameters, beef patties elaborated with bean protein could be used as an alternative protein source respect to soy protein because of it showed a similar nutritional content and taste profile and higher amino acid content.

Impact of the soy protein replacement by legumes and algae based proteins on the quality of chicken rotti.

The addition of different protein sources (soy, bean, lentil, broad bean, Spirulina, and Chlorella) on nutritional, physicochemical and sensory properties of chicken rotti was evaluated. Significant changes were observed in physicochemical composition, textural properties and amino acid content of chicken rotti after adding the proteins from different sources, thus influencing the sensory acceptance and preference. Spirulina and Chlorella rotti presented a slight increase of pH and seaweed caused a decrease in some colour parameters. The highest lipids contents were found in chicken rotti added of with Spirulina and lentil proteins. Chicken rotti prepared with lentil protein also showed the highest values for ash content. Chicken rotti enriched with seaweed protein presented the highest total amino acid content. Principal component analysis showed that broad beans and lentils proteins as interesting ingredients to replace soy protein in chicken rotti.

Biomarkers of Aryl-hydrocarbon Receptor Activity in Gulf Killifish (Fundulus grandis) From Northern Gulf of Mexico Marshes Following the Deepwater Horizon Oil Spill.

Following the Deepwater Horizon oil spill, shorelines throughout the Barataria Basin of the northern Gulf of Mexico in Louisiana were heavily oiled for months with Macondo-252 oil, potentially impacting estuarine species. The Gulf killifish (Fundulus grandis) has been identified as a sentinel species for the study of site-specific effects of crude oil contamination on biological function. In November and December 2010, 4-5 months after the Macondo well was plugged and new oil was no longer spilling into the Gulf waters, Gulf killifish were collected across the Barataria Basin from 14 sites with varying degrees of oiling. Fish collected from oiled sites exhibited biological indications of exposure to oil, including increase in cytochrome P4501A (CYP1A) mRNA transcript and protein abundances in liver tissues. Immunohistochemistry revealed increases in gill, head kidney, and intestinal CYP1A protein at heavily oiled sites. Intestinal CYP1A protein was a sensitive indicator of exposure, indicating that intestinal tissue plays a key role in biotransformation of AHR ligands and that ingestion is a probable route of exposure, warranting additional consideration in future studies.

Preventing the Complications Associated with the Use of Dermal Fillers in Facial Aesthetic Procedures: An Expert Group Consensus Report.

BACKGROUND: The use of dermal fillers in minimally invasive facial aesthetic procedures has become increasingly popular of late, yet as the indications and the number of procedures performed increase, the number of complications is also likely to increase. Paying special attention to specific patient characteristics and to the technique used can do much to avoid these complications. Indeed, a well-trained physician can also minimize the impact of such problems when they do occur. METHODS: A multidisciplinary group of experts in aesthetic treatments reviewed the main factors associated with the complications that arise when using dermal fillers. A search of English, French and Spanish language articles in PubMed was performed using the terms "complications" OR "soft filler complications" OR "injectable complications" AND "dermal fillers". An initial document was drafted that reflected the complications identified and recommendations as to how they should be handled. This document was then reviewed and modified by the expert panel, until a final text was agreed upon and validated. RESULTS: The panel addressed consensus recommendations about the preparation, the procedure and the post-procedural care. The panel considered it crucial to obtain an accurate medical history to prevent potential complications. An additional clinical assessment, including standardized photography, is also crucial to evaluate the outcomes and prevent potential complications. Furthermore, the state of the operating theatre, the patient's health status and the preparation of the skin are critical to prevent superficial soft tissue infections. Finally, selecting the appropriate technique, based on the physician's experience, as well as the characteristics of the patient and filler, helps to ensure successful outcomes and limits the complications. CONCLUSIONS: This consensus document provides key elements to help clinicians who are starting to use dermal fillers to employ standard procedures and to understand how best to prevent potential complications of the treatment. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Natural selection canalizes expression variation of environmentally induced plasticity-enabling genes.

Many organisms survive fluctuating and extreme environmental conditions by manifesting multiple distinct phenotypes during adulthood by means of developmental processes that enable phenotypic plasticity. We report on the discovery of putative plasticity-enabling genes that are involved in transforming the gill of the euryhaline teleost fish, Fundulus heteroclitus, from its freshwater to its seawater gill-type, a process that alters both morphology and function. Gene expression that normally enables osmotic plasticity is inhibited by arsenic. Gene sets defined by antagonistic interactions between arsenic and salinity show reduced transcriptional variation among individual fish, suggesting unusually accurate and precise regulatory control of these genes, consistent with the hypothesis that they participate in a canalized developmental response. We observe that natural selection acts to preserve canalized gene expression in populations of killifish that are most tolerant to abrupt salinity change and that these populations show the least variability in their transcription of genes enabling plasticity of the gill. We found that genes participating in this highly canalized and conserved plasticity-enabling response had significantly fewer and less complex associations with transcriptional regulators than genes that respond only to arsenic or salinity. Collectively these findings, which are drawn from the relationships between environmental challenge, plasticity, and canalization among populations, suggest that the selective processes that facilitate phenotypic plasticity do so by targeting the regulatory networks that gives rise to the response. These findings also provide a generalized, conceptual framework of how genes might interact with the environment and evolve toward the development of plastic traits.

Reciprocal osmotic challenges reveal mechanisms of divergence in phenotypic plasticity in the killifish Fundulus heteroclitus.

The killifish Fundulus heteroclitus is an estuarine species with broad physiological plasticity, enabling acclimation to diverse stressors. Previous work suggests that freshwater populations expanded their physiology to accommodate low salinity environments; however, it is unknown whether this compromises their tolerance to high salinity. We used a comparative approach to investigate the mechanisms of a derived freshwater phenotype and the fate of an ancestral euryhaline phenotype after invasion of a freshwater environment. We compared physiological and transcriptomic responses to high- and low-salinity stress in fresh and brackish water populations and found an enhanced plasticity to low salinity in the freshwater population coupled with a reduced ability to acclimate to high salinity. Transcriptomic data identified genes with a conserved common response, a conserved salinity-dependent response and responses associated with population divergence. Conserved common acclimation responses revealed stress responses and alterations in cell-cycle regulation as important mechanisms in the general osmotic response. Salinity-specific responses included the regulation of genes involved in ion transport, intracellular calcium, energetic processes and cellular remodeling. Genes diverged between populations were primarily those showing salinity-specific expression and included those regulating polyamine homeostasis and the cell cycle. Additionally, when populations were matched with their native salinity, expression patterns were consistent with the concept of 'transcriptomic resilience', suggesting local adaptation. These findings provide insight into the fate of a plastic phenotype after a shift in environmental salinity and help to reveal mechanisms allowing for euryhalinity.