Avoiding dead ends: the experimental evolution of constraint as adaptation to environmental variation in Saccharomyces cerevisiae

Environmental unpredictability results in the evolution of bet-hedging traits, which maximize long-term fitness but are, by definition, suboptimal over short time scales. However, because suboptimal traits are expected to be purged by selection in the shorter term, the persistence of bet hedging remains perplexing. Here, we test the hypothesis that bet hedging persists through the evolution of constraint on short-term adaptation. We experimentally evolve Saccharomyces cerevisiae across two sequential treatments in which the frequency of extreme heat shocks decreases. We predict that experimental evolution under lower frequency heat shocks will result in greater adaptive constraint, or “purge-resistant” bet hedging. Constraint is assayed as evolutionary persistence of heat shock tolerance (HST) under constant benign conditions. As predicted, we find the retention of HST only in lines evolved under reduced frequency detrimental conditions. Results help explain the evolution of bet hedging, and challenge the traditional view that evolutionary constraint is inherently maladaptive.

Sequential Sterilization of Banana (Musa Spp.) Sucker Tip Reducing Microbial Contamination With Highest Establishment Percentage

Sterilization procedure was standardized for grand naine cultivar of banana using various sterilants in combinations and alone. The observations were recorded regularly with respect to presence of fungal, bacteria as well as percentages of culture establishment. Results indicated that a treatment combination No. 3 [Lactic acid (0.15 %) + Tween-20 (0.1 %) + 0.8 % Commercial bleach (30 Min.) followed by Sodium chlorite (0.3 %) (20 min)] gave the highest percentage of aseptic culture establishment in vitro condition. The present study also showed that, single step aseptic inoculation was unable to control endophytic contaminants while sequential treatments were good enough to reduce microbial load as well as increase culture survival. Bangladesh J. Bot. 50(4): 1151-1158, 2021 (December)

1-Naphthaleneacetic Acid (NAA) Reduces Sucker Growth in European Hazelnut (Corylus avellana L.)

Three 2-year field studies were conducted to evaluate 1-naphthaleneacetic acid (NAA) as a suppressant of suckers in European hazelnut (Corylus avellana L.). Treatments were basal-directed applications of NAA at 5, 10, and 20 g·L−1 a.i. applied once per season, and two sequential applications of NAA 10 g·L−1 a.i., 28 days apart, compared with 2,4-D (3.8 g·L−1 acid equivalent), and a nontreated control. Treatments were applied early in spring and repeated the following year. Both NAA and 2,4-D delayed sucker growth by 1.2- to 3.0-fold compared with the nontreated control, and response varied with experimental site and year. Sequential treatments of NAA significantly reduced sucker height and fresh weight 120 days after treatment. NAA applied in sequential treatments increased tree trunk cross-sectional area and canopy volume in two of the three experimental sites. Yield of hazelnuts increased when suckers were removed with NAA or 2,4-D compared with nontreated. Results indicate that NAA is an effective option to control suckers in hazelnuts and can help reduce herbicide and labor in sucker control.

Repeated percutaneous hepatic perfusion with melphalan can maintain long-term response in patients with liver cancers

Chemosaturation (CS; CHEMOSAT®, Delcath Systems Inc.) temporarily administers melphalan into the liver by percutaneous hepatic perfusion (PHP). CS-PHP can effectively control growth in liver tumors, but efficacy and tolerability of sequential treatments are unclear. We analyzed outcomes of sequential CS-PHP treatment. Patients with either unresectable intrahepatic metastases of ocular melanoma (OM, n = 9), cholangiocarcinoma (CCA, n = 3), or hepatocellular carcinoma (HCC, n = 1) were recruited retrospectively. Response was assessed by tomography imaging. Ten patients (mean age 60 years) with more than one CS-PHP treatment were included. CS-PHP was administered 2–6 times in the OM patients, 3 times in the CCA, and the HCC patient received 6 treatments. Overall response rate (ORR) to CS-PHP was 80%, and stable disease was achieved in one patient. Median hepatic progression-free survival (hPFS) was 336 days (range 0–354) for OM, 251 days for the CCA patient, and 256 days for the HCC patient. At the end of observation (153–701 days after first CS-PHP), 6/10 patients were still alive (5/9 with OM, 0 with CCA, and 1 with HCC). Death cases were not related to CS-PHP. Adverse events were mostly hematologic, grade I-IV, and self-resolving. The liver function was not deteriorated by CS-PHP. We conclude that repeated CS-PHP treatments were effective and well tolerated in the long term.

High potency of sequential therapy with only beta-lactam antibiotics

Evolutionary adaptation is a major source of antibiotic resistance in bacterial pathogens. Evolution-informed therapy aims to constrain resistance by accounting for bacterial evolvability. Sequential treatments with antibiotics that target different bacterial processes were previously shown to limit adaptation through genetic resistance trade-offs and negative hysteresis. Treatment with homogeneous sets of antibiotics is generally viewed to be disadvantageous, as it should rapidly lead to cross-resistance. We here challenged this assumption by determining the evolutionary response of Pseudomonas aeruginosa to experimental sequential treatments involving both heterogenous and homogeneous antibiotic sets. To our surprise, we found that fast switching between only β-lactam antibiotics resulted in increased extinction of bacterial populations. We demonstrate that extinction is favored by low rates of spontaneous resistance emergence and low levels of spontaneous cross-resistance among the antibiotics in sequence. The uncovered principles may help to guide the optimized use of available antibiotics in highly potent, evolution-informed treatment designs.

High potency of sequential therapy with only beta-lactam antibiotics

Evolutionary adaptation is a major source of antibiotic resistance in bacterial pathogens. Evolution- informed therapy aims to constrain resistance by accounting for bacterial evolvability. Sequential treatments with antibiotics that target different bacterial processes were previously shown to limit adaptation through genetic resistance trade-offs and negative hysteresis. Treatment with homogeneous sets of antibiotics is generally viewed to be disadvantageous, as it should rapidly lead to cross-resistance. We here challenged this assumption by determining the evolutionary response of Pseudomonas aeruginosa to experimental sequential treatments involving both heterogenous and homogeneous antibiotic sets. To our surprise, we found that fast switching between only β- lactam antibiotics resulted in increased extinction of bacterial populations. We demonstrate that extinction is favored by low rates of spontaneous resistance emergence and low levels of spontaneous cross-resistance among the antibiotics in sequence. The uncovered principles may help to guide the optimized use of available antibiotics in highly potent, evolution-informed treatment designs.

Randomized Phase II Trial Evaluating Two Sequential Treatments in First Line of Metastatic Pancreatic Cancer: Results of the PANOPTIMOX-PRODIGE 35 Trial

PURPOSE Metastatic pancreatic cancer (mPC) still harbors a dismal prognosis. Our previous trial (PRODIGE 4—ACCORD 11) demonstrated the superiority of 6-month chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) over gemcitabine for overall survival. The high limiting oxaliplatin-related neurotoxicity supports the evaluation of an oxaliplatin stop-and-go strategy and a sequential strategy in mPC. METHODS In this phase II study, patients were randomly assigned to receive either 6 months of FOLFIRINOX (arm A), 4 months of FOLFIRINOX followed by leucovorin plus fluorouracil maintenance treatment for controlled patients (arm B), or a sequential treatment alternating gemcitabine and fluorouracil, leucovorin, and irinotecan every 2 months (arm C). The primary end point was progression-free survival at 6 months. RESULTS Between January 2015 and November 2016, 276 patients (mean age: 63 years; range: 40-76 years) were enrolled (A: 91, B: 92, and C: 90). Grade 3 or 4 neurotoxicity occurred in 10.2% of patients in arm A and 19.8% in arm B. The median ratio of received dose/targeted dose of oxaliplatin was 83% in arm A and 92% in arm B. The 6-month progression-free survival was 47.1% in A, 42.9% in B, and 34.1% in C. The median overall survival was 10.1 months in arm A, 11.2 in arm B, and 7.3 in arm C. Median survival without deterioration in quality-of-life scores was higher in the maintenance arm (11.4 months) than in arms A and C (7.2 and 7.5 months, respectively). CONCLUSION Maintenance with leucovorin plus fluorouracil appears to be feasible and effective in patients with mPC controlled after 4 months of induction chemotherapy with FOLFIRINOX. Severe neurotoxicity was higher in the maintenance therapy arm, probably because of the higher cumulative dose of oxaliplatin.

Treating co-morbid insomnia and social anxiety disorder with sequential CBT protocols: a single-case experimental study

Background: Although insomnia disorder and social anxiety disorder are among the most prevalent psychiatric disorders, no studies have yet evaluated the use of sequential evidence-based treatment protocols in the population with co-morbid social anxiety disorder and insomnia disorder. Aims: This study aimed to investigate the effects of sequential treatments on co-morbid insomnia disorder and social anxiety disorder. As depression is a common co-morbid syndrome for both insomnia and social anxiety, a secondary aim was to examine depressive symptoms. Method: A single-case repeated crossover AB design was used. Ten participants between 18 and 59 years of age with co-morbid DSM-5 diagnoses of insomnia disorder and social anxiety disorder received sequential treatments with cognitive behavioural therapy (CBT). Seven participants completed the treatment course. The primary outcomes were symptoms of insomnia and social anxiety, and the secondary outcome was symptoms of depression. Results: The effects of CBT on people with co-morbid social anxiety disorder and insomnia disorder were mixed. The majority of participants improved their sleep quality and lessened symptoms of social anxiety and depression. However, participants differed in their degree of improvement concerning all three disorders. Conclusions: Sequential CBT treatments are potentially effective at decreasing symptoms of social anxiety and insomnia for people with co-morbid social anxiety disorder and insomnia disorder. The variation in outcome across participants makes firm conclusions about the treatment efficacy difficult to draw.

Junglerice (Echinochloa colona) Control with Sequential Applications of Glyphosate and Clethodim to Dicamba

Junglerice is becoming more prevalent in Tennessee, Arkansas and Mississippi row crop fields. The evolution of glyphosate-resistant junglerice populations is one reason for the increase. Another possible explanation is that glyphosate and clethodim grass activity is being antagonized by dicamba. This question has led to research to examine if sequential applications alleviate antagonism observed with dicamba plus glyphosate and/or clethodim mixtures and determine if 24 h, 72 h or 168 h sequential treatments of those herbicides can improve junglerice control. Glyphosate + clethodim applications provided >90% junglerice control. The observed levels of antagonism varied by whether the location of the test was in the greenhouse or the field and the timing of applications. In the greenhouse, clethodim + dicamba provided excellent control while in the field the same treatment showed over a 30% reduction in junglerice control compared with clethodim alone. However, control was restored by using a mixture of glyphosate + clethodim without dicamba. The environment at the time of application and relative glyphosate-resistance (GR) level of the junglerice influenced the overall control of these sequential applications. Clethodim applied first followed by dicamba at 72 or 168 h, better control was observed compared with applying dicamba followed by clethodim. Overall, mixing glyphosate + clethodim provided the most complete junglerice control regardless of timing. These data confirm that leaving dicamba out of the spray tank will mitigate herbicide antagonism on junglerice control. These data would also indicate that avoiding dicamba and glyphosate mixtures will also improve the consistency of control with glyphosate-susceptible junglerice.