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Results for “balancing selection”

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PubMed2026

AI-Driven Multi-Omics Integration of Synthetic Colon Adenocarcinoma for Cluster-Guided PROTAC Candidate Design Targeting KRASG12D.

Colorectal cancer is a leading cause of cancer death, yet its molecular heterogeneity remains poorly translated into individualized treatment. We present a reproducible artificial intelligence (AI) framework that integrates multi-omics benchmarking, sample-level drug prioritization, E3 ubiquitin ligase selection, and shape-anchored Proteolysis Targeting Chimera (PROTAC) design for KRASG12D in colon adenocarcinoma (COAD). A controlled synthetic benchmark comprising 425 tumor and 41 simulated normal profiles, parameterized to match The Cancer Genome Atlas (TCGA) distributions, was used for pipeline verification. Among sixteen methods, the Balanced Latent Integration with Stability Selection (BLISS) model achieved the highest silhouette width (0.86) and competitive agreement (Adjusted Rand Index, ARI, 0.90). The pipeline was validated on real data: a TCGA COAD cohort (186 tumors) with independent Consensus Molecular Subtype (CMS) labels and a CPTAC cohort (104 tumors). Integration modestly recovered CMS (ARI 0.28), and stage, not molecular cluster, drove survival (log-rank p = 0.005 versus 0.81). Sample-level prioritization differed from cluster-level ranking in 82.6% of profiles, below chance (p < 0.0001), without indicating efficacy. Candidate NOVEL00489 showed a good MM-GBSA estimate, matching the reference ASP3082. Compounds are computational candidates requiring experimental validation. This establishes a transparent benchmark for in silico degrader generation in precision oncology.

Humans↗

PubMed1995

The use of microsoft excel as a user interface for biological simulations.

We used Microsoft Excel 4.0 for Windows running on a PC-486 to develop a user interface for two biological simulation models: a lung fluid balance model and a fractal model of the pulmonary circulation. The simulation programs were written in the C programming language, while the user interface was written in the macro language of Excel. The interface builds input data files for the simulation programs and provides a mechanism for displaying relevant information from output files produced from the simulations. Input fields are partially protected so that the user cannot modify certain portions of the spreadsheet. The Excel interface is used to build models from different available components and to select appropriate parameters for these models. The developed interface was also useful for running models in the batch mode. After selecting changes in lung fluid balance parameters, the interface allows users to find new steady state values by automatically running the model and adjusting initial conditions. Several different graphical options allow users to easily investigate the effects of selecting particular models and parameters. Techniques used in developing our user interface can be extended to most biological simulation programs which manipulate input and output data files.

Computer Graphics↗

PubMed2001

The emergence and epidemiology of resistance in the nucleoside-experienced HIV-infected population.

HIV drug resistance remains one of the most important influences on long-term therapeutic prospects. Resistance and therapeutic failure arises out of the selection and preservation of randomly generated genomic mutations that confer a replicative advantage in the presence of one or more antiretrovirals. The primary correlate to the time to emergence of a drug-resistant HIV variant is the extent of residual replication under selecting drug pressure, emphasizing the importance of full virological suppression to long-term therapy. Further contributions to the time to emergence are the degree of selective pressure exerted by a given drug, whereby greater potency forces earlier selection of mutant strains in balance with the extent of residual replication, and the degree of reduced drug susceptibility afforded by a particular mutation. Once evolved, drug-resistant strains can persist indefinitely as minority viral populations or archived genomes in latently infected CD4 cells, despite long-term withdrawal of the selecting drugs, to reemerge rapidly on rechallenge with those or any cross-resistant drug. Variable adherence to medication in the routine clinical setting has given rise to resistance mutations being observed in some 50-60% of those with detectable viral loads on therapy in countries where antiretroviral therapy has been widely available. Nucleoside reverse transcriptase inhibitor-associated mutations form the majority of these, and the long and almost universal use of zidovudine and stavudine has led to mutations selected by these drugs being the most common observed, along with the primary lamivudine resistance mutation M184V. Transmission of drug-resistant HIV in cases of new infection has also been widely studied, and although the extent is considerably lower than that in the treated population (typically 4-10% outside certain geographic areas), early data suggest that it is rising over time as the infected source population becomes more therapy-experienced. Once again, mutations from zidovudine or, to a lesser extent, stavudine exposure form the majority of mutations observed in cases of primary transmission. These data are a cause for concern, and imply that, as things stand, the use of a drug resistance test may become as important to the design of an effective first-line highly active antiretroviral therapy regimen as they have become for selecting new drugs on therapeutic failure.

Anti-HIV Agents↗

PubMed1992

Small-incision manual extracapsular cataract extraction using selective hydrodissection.

Hydrodissection is a technique in which balanced salt solution is injected through a cannula into various layers of a cataractous lens to separate the lens lamella in a nonspecific location. Selective hydrodissection allows separation of the lens lamella at different desired anatomical layers. The technique allows the smallest possible nucleus, ie, the hard-core nucleus, to be hydroexpressed as a separate entity, requiring, correspondingly, a relatively small capsulorhexis and limbal incision. Then, in a second maneuver, the epinucleus, which engulfs the hardcore nucleus to form the adult nucleus, also can be aspirated or hydroexpressed as a whole. Selective hydrodissection permits scleral incision and stitchless surgery in planned extracapsular cataract extraction and also may serve as an intermediate step for surgeons who wish to convert to or learn phacoemulsification techniques.

Cataract Extraction↗

PubMed1992

Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial.

Amitriptyline (AT) relieves some patients with postherpetic neuralgia (PHN). Many patients suffer side effects and better therapies are necessary. The aim of this study was to evaluate the efficacy of maprotiline (MT) (noradrenergic) compared to AT (mixed noradrenergic and serotonergic) in this disorder. Thirty-five patients entered a randomized, double-blind, crossover trial of these two agents. We found that MT relieved PHN in many patients but was not as effective as AT. Side effects were troublesome with both agents. Relief of steady pain, brief pain and pain on tactile stimulation occurred. Four groups of responses were identified. Some patients reported relief with both agents, some with neither agent and others with only one of the drugs. Most patients were not depressed and analgesia was observed to occur without change in depression ratings in most patients who responded. This result provides evidence that in some patients AT may act via a selective noradrenergic mechanism in relieving PHN and that individuals may differ in the balance and type of neurotransmitters inhibiting pain. Selective noradrenergic agents may be effective if AT fails.

Aged↗

PubMed2006

The role of neuropeptides in caterpillar nutritional ecology.

Plant diet strongly impacts the fitness of insect herbivores. Immediately, we think of plant defensive compounds that may act as feeding deterrents or toxins. We are, probably, less aware that plants also influence insect growth and fecundity through their nutritional quality. However, most herbivores respond to their environment and select the diet which optimizes their growth and development. This regulation of nutritional balance may occur on many levels: through selecting and ingesting appropriate plant tissue and nutrient digestion, absorption and utilization. Here, we review evidence of how nutritional requirements, particularly leaf protein to digestible carbohydrate ratios, affect caterpillar herbivores. We propose a model where midgut endocrine cells assess and integrate hemolymph nutritional status and gut content and release peptides which influence digestive processes. Understanding the effects of diet on the insect herbivore is essential for the rational design and implementation of sustainable pest management practices.

Animals↗

PubMedDate not supplied

OptDesign: extending optimizable k-dissimilarity selection to combinatorial library design.

Optimizable k-dissimilarity (OptiSim) selection entails drawing a series of subsamples of size k from a population and choosing the "best" candidate from each such subsample for inclusion in the selection set. By varying the size of the subsample, one can control the balance between representativeness and diversity in the selection set obtained. In the original formulation, a uniform random sampling from among valid candidates was used to draw the subsamples from a single target population. Here we describe in detail two key modifications that serve to extend the OptiSim methodology to vector selection for interdependent variables, specifically as applied to the design of combinatorial sublibraries. The first modification involves pivoting between variables: subsamples are drawn from each reagent pool in turn, with the viability of each candidate being evaluated in isolation as well as in terms of the products it will produce from complementary reagents already selected. The filters applied may be static or dynamic in nature, with molecular weight and hydrophobicity being examples of the former and structural diversity with respect to reagents already selected being an example of the latter. The second key modification is adding the ability to bias the selection of candidate reagents for inclusion in the subsamples. Taken together, these modifications support the efficient generation of multiblock and other sparse matrix designs that are both representative and diverse, and for which "backfilling" of designs edited to remove undesirable reagents or products is straightforward. The method is intrinsically fast and efficient, since enumeration of the full combinatorial is not required- only those candidates actually considered for inclusion need be evaluated. Moreover, because the subsample selection step is separate from the diversity-based selection of the "best" candidate, incorporating such bias in favor of a competing criterion such as low price provides a "natural," nonparametric mechanism for generating designs that are likely to be "good" in a double-objective, Pareto sense.

Journal Article↗

PubMed2003

Selection of fusion levels in scoliosis surgery.

Fusion levels are selected with the goal of having a balanced physiologic spine on the postoperative films. We have proposed an algorithm for selecting fusion levels based on the King-Moe scoliosis classification scheme and the flexibility of a compensatory curve. We propose the acronym TEAMS as a pneumonic. Curve type defines the region of the spine to be fused. The ends of the Cobb measurement around the region are the temporary endpoints. The endpoints are extended to avoid an apex due to the sagittal or frontal planes. The mobile disc is defined at the caudal end of the fusion area. Finally, the bending films, traction films, or intraoperative films are used to define the stable zone of Harrington that must contain the ends of the fusion mass. This scheme yields a simple, easily taught algorithm that results in reproducible endpoints for scoliosis fusion.

Adolescent↗

PubMed2004

Opposing natural selection from herbivores and pathogens may maintain floral-color variation in Claytonia virginica (Portulacaceae).

The maintenance of floral-color variation within natural populations is enigmatic because directional selection through pollinator preferences combined with random genetic drift should lead to the rapid loss of such variation. Fluctuating, balancing, and negative frequency-dependent selection mediated through pollinators have been identified as factors that may contribute to the maintenance of floral-color variation, and recently it has been suggested that indirect responses to selection on correlated characters through agents of selection other than pollinators may substantially shape the evolution of floral traits. Here, I provide empirical support for this latter view in Claytonia virginica (Portulacaceae) through a multiseason field study, a pollen supplementation study, and an artificial herbivory experiment. These studies show that most individuals fall into one of four discrete color classes, and suggest pollinator-mediated selection for increased floral redness in concurrent years. Floral color is also an indirect target of opposing directional selection via herbivores and pathogens that fluctuates through time. Taken together, these data suggest a novel mechanism by which floral-color variation may be maintained, and illustrate the importance of an inclusive, pluralistic view of selection when investigating the evolution of complex phenotypes.

Analysis of Variance↗

PubMed2005

Modelling approaches to dose estimation in children.

Most of the drugs on the market are originally developed for adults and dosage selection is based on an optimal balance between clinical efficacy and safety. The aphorism 'children are not small adults' not only holds true for the selection of suitable drugs and dosages for use in children but also their susceptibility to adverse drug reactions. Since children may not be subject to dose escalation studies similar to those carried out in the adult population, some initial estimation of dose in paediatrics should be obtained via extrapolation approaches. However, following such an exercise, well-conducted PK-PD or PK studies will still be needed to determine the most appropriate doses for neonates, infants, children and adolescents.

Adolescent↗

PubMedDate not supplied

[Bisyllabic words for speech audiometry: a new italian material].

Bisyllabic words are the most frequently used italian speech material in evaluating intelligibility function. The italian words presently used are those proposed by Bocca and Pellegrini in 1950. The Lists of these words do, however, present some problems with regard to phonemic balance and word familiarity. In speech audiometry testing, Lists are considered interchangeable if each individual List has the same phonemic balance. So as to avoid incorrect identification due to incomprehension of infrequently used words, we chose 200 of the most familiar bisyllabic words from the most recent, widely used occurrence vocabulary of the Italian Language. Secondly, we proceeded with phonemic balance of the speech material. The selected words were divided into ten lists of 20 words each, arranged in order to obtain the best phonemic balance within each individual List and among different Lists. The differences between the new and old speech material are presented and discussed.

Audiometry, Speech↗

PubMed1987

Zinc-induced peripheral anosmia and behavioral responses to novelty in mice: a quantitative-genetic analysis.

Adult male mice were made anosmic by intranasal flushing with a 5% zinc sulfate solution. Twelve behavioral variables were measured in treated as well as saline-irrigated control animals placed in a novel environment. The genetic underpinnings and the genotype-treatment interactions with regard to these behaviors were analyzed in a classical Mendelian cross between the inbred strains C57BL/6 and DBA/2 and in a full 4 X 4 diallel cross, replicated five times, between these strains and strains C3H/St an CPB-K. Based on the hypothesis of an evolutionary history of directional selection for a well-balanced information-processing system, one might expect directional dominance for decrease in exploration after anosmization. Although decreases were found for several behavioral phenotypes, only few and relatively unimportant genotype-treatment interactions were present. This absence of any kind of genetic variation for behavioral change after anosmization points to an extremely strong directional selection which has eliminated all less favorable alleles. The findings support the hypothesis of directional selection for an efficient olfactory information-processing system.

Animals↗

PubMed1989

Response to selection for milk yield and metabolic challenges in primiparous dairy cows.

The effect of selection for milk yield on lactation yield, net energy balance, and on plasma growth hormone, insulin, prolactin, nonesterified fatty acids and glucose was studied in two groups of primiparous Holstein cows of differing genetic merit. Net energy balance was calculated and serial blood samples were collected for a 7 hr period at 0, 45, 90 and 180 days postpartum. Growth hormone releasing factor (.2 microgram/kg BW) was administered after 2.5 hr at 0, 45 and 180 days postpartum, while epinephrine (.7 microgram/kg BW) was administered at 90 days postpartum. Milk yield was greater, net energy balance was decreased and plasma growth hormone was greater in genetically superior selection group cows compared to control cows. Growth hormone showed similar increases in both genetic groups in response to growth hormone releasing factor, while prolactin, insulin and glucose were not altered. Epinephrine stimulated an increase in plasma nonesterified fatty acids, glucose and insulin, but responses did not differ between genetic groups. Results indicate differences exist in production efficiency, net energy balance and plasma growth hormone concentration among dairy cattle as a result of selection for milk yield and suggest that selection pressure may act to alter homeorhetic control of nutrient metabolism.

Animals↗

PubMed1992

Considerations of dietary sodium/potassium/energy ratios of selected foods.

Various electrolytes and energy intakes have been shown to contribute to the risk of hypertension and other cardiovascular diseases. Further, dietary sodium (Na) and potassium (K) balance are important in both nonpharmacologic and pharmacologic management of various cardiovascular states. Emphasis is also given to weight reduction and electrolyte balance. As an aid to food selection to enhance K intake and decrease Na intake, we have categorized foods according to their electrolyte density as related to caloric content. More than 100 individual food items were assigned to one of four categories. Ratios of individual Na, K, and energy content were calculated, based on USDA-generated food nutrient values. Category 1 includes foods that are low in Na, high in K and low in energy: fresh or frozen vegetable sources with vitamins A and C. Category 2 contains foods low in Na relative to high K and high energy: most fruit, starchy vegetables, nuts, milk and meat products, and chocolate. Category 3 includes foods high in Na that are also high in K in relation to low energy: vegetables (canned, frozen in butter sauce or au gratin), most cheeses, cured or frozen meats. Category 4 contains foods high in Na and low in K relative to high energy: bread, rice, luncheon meats, commercial cookies and pastries, and fast food entrees. Commercial cereals could be differentiated by the guidelines, with bran cereals in Category 1, shredded wheat products in Category 2, fruit-containing cereals in Category 3, and presweetened or instant cereals in Category 4. Identification of the ratio of Na and K to content of foods, compared with relative energy ratio, is useful in selecting foods that will help meet specific dietary criteria for management of essential hypertension and other cardiovascular-renal states, both in the adult and pediatric populations.

Cardiovascular Diseases↗

PubMed2005

Nonsteroidal anti-inflammatory drugs, aspirin, and gastrointestinal prophylaxis: an ounce of prevention.

Because of the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs), NSAID-related gastrointestinal (GI) complications are recognized as the most prevalent drug toxicity in the United States. The withdrawal of 2 selective cyclooxygenase-2 (COX-2) inhibitors (agents specifically developed to reduce ulcer complications) from the US market owing to adverse cardiovascular events has made reducing ulcer risk more important than ever for patients receiving NSAID treatment. In addition, the impact of aspirin, implicated by itself as a cause of serious adverse GI events and in combination with NSAIDs as a source of incremental risk, remains under-appreciated. Balancing the cardiovascular risks of selective COX-2 inhibitors with the higher GI risks associated with conventional NSAIDs remains a major clinical challenge. Gastro-protective therapy, such as with a proton pump inhibitor, is beneficial in patients receiving NSAIDs, but despite current treatment recommendations, this "ounce of prevention" remains substantially underused for patients at risk.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1993

Congenital abnormalities of the goat.

Congenital abnormalities of genetic and environmental causes constitute a striking proportion of the afflictions seen in goats. These include a variety of malformations and metabolic diseases that could occur in all breeds but tend to exhibit predisposition in some breeds of goats. Genetic abnormalities for which the carrier state is detectable with the aid of enzymes and surface protein markers can be eliminated from goat populations, whereas common polygenic disorders including udder problems in does and gynecomastia in bucks are more difficult to eradicate because the mutant genes responsible for these traits generally do not declare themselves until inbreeding brings together a critical concentration of liability genes to create a crisis. A substantial reduction of common abnormalities in this species, such as intersexuality in dairy breeds, abortion in Angora breed, and arthritis in the Pygmy breed, will require a change in breeders' preference and selection practice. In making these changes, however, the beneficial traits will have to be balanced against the undesirable effects of the selected mutant genes (pleiotropy), which hold the key to success or failure of a breed under domestication.

Animals↗

PubMed2005

Structure-activity relationship study of some triazolinone based compounds with antagonistic balanced activity on angiotensin II receptor subtypes AT1 and AT2. A three-dimensional quantitative structure-activity relationship investigation.

Angiotensin II (AII) receptor antagonists have attracted much attention as anti-hypertensive agents in recent times following the discovery of side effects associated with angiotensin converting enzyme (ACE) inhibitors. Various lead structures of the compounds of this category are reported in the literature. Studying the structure-activity relationships (SAR) for such compounds has been a fascination for scientists and efforts have been made to identify the essential physico-chemical requirements for the angiotensin type 1 (AT1) receptor selective, angiotensin type 2 (AT2) receptor selective and some AT,/ AT2 balanced antagonistic activity compounds. With an aim to identify the structural requirements for balanced activity and differentiate between the features individually responsible for AT1 and AT2 antagonistic activities, a quantitative SAR (QSAR) analysis was carried out on a series of triazolinone based balanced AII receptor antagonists. The statistically significant equations with r > 0.88, chance < 0.01, q2 > 0.60 and F values at least three times greater than those reported were obtained for both AT1 and AT2 receptor subtypes antagonistic activities. A comparative study of the parameters responsible for AT1 and AT2 receptor antagonistic activities is carried out in order to identify the features that can be modulated to obtain balanced compounds. It has been observed that the most reliable equations obtained in the study show the contribution of hydrophobic parameters: logarithm of partition coefficient (logP), thermodynamic parameters: bend energy (Eb), and electronic parameters: electronic energy (Eelec) parameters towards AT1 anatgonistic activity, and thermodynamic parameters: total energy (E), steric parameters: principal moment of inertia along the Y-axis (PMIY) and electronic parameters: electronic energy (Eelec) parameters towards AT2 antagonistic activity. The parameter Eelec is common but its effect towards the two activities is opposite, negative for AT1 and positive for AT2.

Angiotensin II Type 2 Receptor Blockers↗

PubMed2006

Local adaptation, patterns of selection, and gene flow in the Californian serpentine sunflower (Helianthus exilis).

The traditional view of the species as the fundamental unit of evolution has been challenged by observations that in heterogeneous environments, gene flow may be too restricted to overcome the effects of local selection. Whether a species evolves as a cohesive unit depends critically on the dynamic balance between homogenizing gene flow among populations and potentially disruptive local adaptation. To examine this evolutionary balance between "global" gene flow and local selection, we studied northern Californian populations of Helianthus exilis, the serpentine sunflower, within a mosaic of contrasting serpentine and nonserpentine areas that differ considerably in soil chemistry and water availability. Local adaptation to riparian and serpentine habitats was studied in Helianthus exilis along with an analysis of gene flow patterns among populations within these habitats. Local adaptation was assessed in H. exilis during 2002 and 2003 using reciprocal transplant experiments at multiple locations within serpentine and riparian habitats. Effects of competition and germination date on the expression of local adaptation were also examined within the reciprocal transplant experiments. Local adaptation was detected in both years at the local site level and at the level of habitat. The analysis of the transplanted populations indicated that the patterns of selection differed considerably between riparian and serpentine sites. Differential survivorship occurred in serpentine habitats, whereas selection on reproductive output predominated in riparian habitats. Local adaptation was expressed only in the absence of competition. Local adaptation in terms of survivorship was most strongly expressed in treatments with delayed seed germination. Microsatellite markers were used to quantify population genetic parameters and examine the patterns of gene flow among sampled populations. Analysis of molecular markers revealed a system of population patches that freely exchange genes with each other. Strong selection seems to maintain ecotypic variation within this endemic sunflower species, while extensive gene flow among populations prevents local speciation between serpentine and riparian ecotypes.

Adaptation, Physiological↗