Predicting long-term response to selection

Lande's equation for predicting the response of trait means to a shift in optimal trait values is tested using a stochastic simulation model. The simulated population is finite, and each individual has a finite number of loci. Therefore, selection may cause allele frequencies and distributions to change over time. Since the equation assumes constant genetic parameters, the degree to which such allelic changes affect predictions can be examined. Predictions are based only on information available at generation zero of directional selection. The quality of the predictions depends on the nature of allelic distributions in the original population. If allelic effects are approximately normally distributed, as assumed in Lande's Gaussian approximation to the continuum-of-alleles model, the predictions are very accurate, despite small changes in the G matrix. If allelic effects have a leptokurtic distribution, as is likely in Turelli's 'house-of-cards' approximation, the equation underestimates the rate of response and correlated response, and overestimates the time required for the trait means to reach their equilibrium values. Models with biallelic loci have limits as to the amount of trait divergence possible, since only two allelic values are available at each of a finite set of loci. If the new optimal trait values lie within these limits, predictions are good, if not, singularity in the G matrix results in suboptimal equilibria, despite the presence of genetic variance for each individual trait.     

Tumour expressions of hypoxic markers predict the response to neo-adjuvant chemotherapy in children with inoperable rhabdomyosarcoma

Objective: The study was to assess whether tumour expressions of hypoxia-inducible factor (HIF)-1α, glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX and vascular endothelial growth factor (VEGF) predict response to neo-adjuvant chemotherapy (naCHT) in children with inoperable rhabdomyosarcoma (RMS).

Methods: Immunohistochemical expressions of hypoxia markers were determined semi-quantitatively in tumour tissue microarray of 46 patients with embryonal RMS (RME) and 20 with alveolar (RMA), treated with CWS protocols (1992–2013).

Results: In paediatric RME, response to naCHT was influenced significantly by tumour expression of CA IX and GLUT-1. Patients with RMA with low expressions of analysed markers responded well to naCHT, while all poor-responders expressed highly hypoxia markers. Only 5.88% of RMA and 11.11% of RME tumours did not express any of the proteins. In both RME and RMA subgroups, most poor-responders demonstrated simultaneous high expression of ≥3 markers, while most patients expressing ≤2 markers responded well to naCHT. In the whole cohort, co-expression of ≥3 markers, was the only independent factor predicting poor-response to chemotherapy (odds ratio 14.706; 95% CI 1.72–125.75; p?=?0.014).

Conclusions: Immunohistochemical expression pattern of four endogenous markers of hypoxia, in tumour tissue at diagnosis, emerges as a promising tool to predict response to naCHT in children with inoperable RMS.     

Predicting the asymmetric response of a genetic switch to noise

We present a simple analytical tool which gives an approximate insight into the stationary behavior of nonlinear systems undergoing the influence of a weak and rapid noise from one dominating source, e.g. the kinetic equations describing a genetic switch with the concentration of one substrate fluctuating around a constant mean. The proposed method allows for predicting the asymmetric response of the genetic switch to noise, arising from the noise-induced shift of stationary states. The method has been tested on an example model of the lac operon regulatory network: a reduced Yildirim-Mackey model with fluctuating extracellular lactose concentration. We calculate analytically the shift of the system's stationary states in the presence of noise. The results of the analytical calculation are in excellent agreement with the results of numerical simulation of the noisy system. The simulation results suggest that the structure of the kinetics of the underlying biochemical reactions protects the bistability of the lactose utilization mechanism from environmental fluctuations. We show that, in the consequence of the noise-induced shift of stationary states, the presence of fluctuations stabilizes the behavior of the system in a selective way: Although the extrinsic noise facilitates, to some extent, switching off the lactose metabolism, the same noise prevents it from switching on.     

Predicting the magnitude of the reflex response to insertions in ubiquitin

The ability to predict the structural response of a protein to an insertion would be a significant advance for the fields of homology modeling and protein design. However, the effects of insertions on protein conformation are not well understood. Previous work has demonstrated that for two loops in ubiquitin, the primary determinant of the structural adaptation to insertions is the insertion site rather than the sequence of the insertion; this phenomenon was termed the reflex response of loops to insertions. We report herein the analysis of ubiquitin mutants with insertions in two other loops. This study demonstrates that the insertion site is the primary determinant of the response to insertions for these two new loops as well, which further supports the reflex response hypothesis. We also attempted to predict the relative magnitudes of the responses at each site but were unsuccessful. Using the additional data collected in this work, we have refined our predictive hypothesis.     

Impact of neoadjuvant chemoradiation on pathologic response and survival of patients with locally advanced rectal cancer

Background

The impact of neoadjuvant chemotherapy (CT) and radiotherapy (RT) on overall survival (OS) has been controversial. Some studies have pointed to an improvement in OS and disease-free survival (DFS) in patients with pathologic complete response (pCR).

Aim

To evaluate the therapeutic response and impact on survival of preoperative RT, alone or combined with CT, in patients with locally advanced rectal cancer (LARC).

Materials and methods

A set of 132 patients with LARC were treated preoperatively. GROUP 1: RT alone, 19 patients. GROUP 2: RT and concomitant oral CT (Capecitabine or UFT + leucovorin), 68 patients. GROUP 3: RT and concomitant CT with 5-FU in continuous infusion, 45 patients. 58.2% of patients were submitted to adjuvant CT.

Results

GROUP 1: no pCR, tumoral downstaging was 26.7%. GROUP 2: pCR in 16.9%; tumoral downstaging was 47.7%. GROUP 3: pCR in 11.9%; tumor downstaging was 52.4%. The loco-regional control (LRC) was 95%. The 5-year OS (p = 0.038) and DFS (p = 0.05) were significantly superior in patients treated with CT + RT. Patients with pCR had a significant increase on DFS (p = 0.019). Patients cT3–4 that had a tumoral downstaging to ypT0–2, showed an increase on DFS, OS and LRC.

Conclusions

CT combined with RT has increased tumoral response and survival rate. Nodal downstaging and pCR were higher in the GROUP 2. The 5-year OS and DFS were significantly superior in CT + RT arms. Patients with pathologic response showed a better DFS. Adjuvant CT had no impact on LRC, DFS nor on OS.     

Effects of neo-adjuvant chemotherapy for oesophago-gastric cancer on neuro-muscular gastric function

Delayed gastric emptying symptoms are often reported after chemotherapy. This study aims to characterise the effects of chemotherapy on gastric neuro-muscular function. Patients undergoing elective surgery for oesophago-gastric cancer were recruited. Acetylcholinesterase, nNOS, ghrelin receptor and motilin expressions were studied in gastric sections from patients receiving no chemotherapy (n?=?3) or oesophageal (n?=?2) or gastric (n?=?2) chemotherapy. A scoring system quantified staining intensity (0–3; no staining to strong). Stomach sections were separately suspended in tissue baths for electrical field stimulation (EFS) and exposure to erythromycin or carbachol; three patients had no chemotherapy; four completed cisplatin-based chemotherapy within 6?weeks prior to surgery. AChE expression was markedly decreased after chemotherapy (scores 2.3?±?0.7, 0.5?±?0.2 and 0?±?0 in non-chemotherapy, oesophageal- and gastric-chemotherapy groups (p?<?0.03 each) respectively. Ghrelin receptor and motilin expression tended to increase (ghrelin: 0.7?±?0.4 vs 2.0?±?0.4 and 1.2?±?0.2 respectively; p?=?0.04 and p?=?0.2; motilin: 0.7?±?0.5 vs 2.2?±?0.5 and 2.0?±?0.7; p?=?0.06 and p?=?0.16). Maximal contraction to carbachol was 3.7?±?0.7?g and 1.9?±?0.8?g (longitudinal muscle) and 3.4?±?0.4?g and 1.6?±?0.6 (circular) in non-chemotherapy and chemotherapy tissues respectively (p?<?0.05 each). There were loss of AChE and reduction in contractility to carbachol. The tendency for ghrelin receptors to increase suggests an attempt to upregulate compensating systems. Our study offers a mechanism by which chemotherapy markedly alters neuro-muscular gastric function.     

Sialyltransferase ST6GAL-1 mediates resistance to chemoradiation in rectal cancer

Locally advanced rectal cancer is typically treated with chemoradiotherapy followed by surgery. Most patients do not display a complete response to chemoradiotherapy, but resistance mechanisms are poorly understood. ST6GAL-1 is a sialyltransferase that adds the negatively charged sugar, sialic acid (Sia), to cell surface proteins in the Golgi, altering their function. We therefore hypothesized that ST6GAL-1 could mediate resistance to chemoradiation in rectal cancer by inhibiting apoptosis. Patient-derived xenograft and organoid models of rectal cancer and rectal cancer cell lines were assessed for ST6GAL-1 protein with and without chemoradiation treatment. ST6GAL-1 mRNA was assessed in untreated human rectal adenocarcinoma by PCR assays. Samples were further assessed by Western blotting, Caspase-Glo apoptosis assays, and colony formation assays. The presence of functional ST6GAL-1 was assessed via flow cytometry using the Sambucus nigra lectin, which specifically binds cell surface α2,6-linked Sia, and via lectin precipitation. In patient-derived xenograft models of rectal cancer, we found that ST6GAL-1 protein was increased after chemoradiation in a subset of samples. Rectal cancer cell lines demonstrated increased ST6GAL-1 protein and cell surface Sia after chemoradiation. ST6GAL-1 was also increased in rectal cancer organoids after treatment. ST6GAL-1 knockdown in rectal cancer cell lines resulted in increased apoptosis and decreased survival after treatment. We concluded that ST6GAL-1 promotes resistance to chemoradiotherapy by inhibiting apoptosis in rectal cancer cell lines. More research will be needed to further elucidate the importance and mechanism of ST6GAL-1-mediated resistance.     

Predicting the response of Cabomba caroliniana populations to biological control agent damage

Abstract  Cabomba caroliniana is a submerged aquatic plant from South America that is becoming a serious weed worldwide. It spreads by seed and by fragmentation and has an extremely wide climatic range, invading lakes and ponds from tropical (Darwin, Australia: latitude 12°) to cold temperate regions (Peterborough, Canada: latitude 45°). There are currently no effective methods of managing cabomba infestations and funding has been allocated to research biological methods. Surveys have examined cabomba in its native range and have identified several potential biological control agents. The most promising are a stem boring weevil ( Hydrotimetes natans ) and an aquatic moth ( Paracles spp.). Here we predict the change in cabomba populations after the introduction of the biological control agents. Our predictions are based on quantitative surveys of cabomba populations at three lakes in south-east Queensland, qualitative observations of cabomba in its native range, and conceptual knowledge of how the realised niche of cabomba might be affected by herbivore damage.     

Predicting the response of the deep-ocean microbiome to geochemical perturbations by hydrothermal vents

Submarine hydrothermal vents perturb the deep-ocean microbiome by injecting reduced chemical species into the water column that act as an energy source for chemosynthetic organisms. These systems thus provide excellent natural laboratories for studying the response of microbial communities to shifts in marine geochemistry. The present study explores the processes that regulate coupled microbial-geochemical dynamics in hydrothermal plumes by means of a novel mathematical model, which combines thermodynamics, growth and reaction kinetics, and transport processes derived from a fluid dynamics model. Simulations of a plume located in the ABE vent field of the Lau basin were able to reproduce metagenomic observations well and demonstrated that the magnitude of primary production and rate of autotrophic growth are largely regulated by the energetics of metabolisms and the availability of electron donors, as opposed to kinetic parameters. Ambient seawater was the dominant source of microbes to the plume and sulphur oxidisers constituted almost 90% of the modelled community in the neutrally-buoyant plume. Data from drifters deployed in the region allowed the different time scales of metabolisms to be cast in a spatial context, which demonstrated spatial succession in the microbial community. While growth was shown to occur over distances of tens of kilometers, microbes persisted over hundreds of kilometers. Given that high-temperature hydrothermal systems are found less than 100 km apart on average, plumes may act as important vectors between different vent fields and other environments that are hospitable to similar organisms, such as oil spills and oxygen minimum zones.     

Predicting microbial growth dynamics in response to nutrient availability

Developing mathematical models to accurately predict microbial growth dynamics remains a key challenge in ecology, evolution, biotechnology, and public health. To reproduce and grow, microbes need to take up essential nutrients from the environment, and mathematical models classically assume that the nutrient uptake rate is a saturating function of the nutrient concentration. In nature, microbes experience different levels of nutrient availability at all environmental scales, yet parameters shaping the nutrient uptake function are commonly estimated for a single initial nutrient concentration. This hampers the models from accurately capturing microbial dynamics when the environmental conditions change. To address this problem, we conduct growth experiments for a range of micro-organisms, including human fungal pathogens, baker’s yeast, and common coliform bacteria, and uncover the following patterns. We observed that the maximal nutrient uptake rate and biomass yield were both decreasing functions of initial nutrient concentration. While a functional form for the relationship between biomass yield and initial nutrient concentration has been previously derived from first metabolic principles, here we also derive the form of the relationship between maximal nutrient uptake rate and initial nutrient concentration. Incorporating these two functions into a model of microbial growth allows for variable growth parameters and enables us to substantially improve predictions for microbial dynamics in a range of initial nutrient concentrations, compared to keeping growth parameters fixed.