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At least 19 recordsLinked to original sources
PubMed2025

Evaluating selection at intermediate scales within genes provides robust identification of genes under positive selection in M. tuberculosis clinical isolates.

Multiple studies have reported genes in the M. tuberculosis (Mtb) genome that are under diversifying selection, based on genetic variants among Mtb clinical isolates. These might reflect adaptions to selection pressures associated with modern clinical treatment of TB. Many, but not all, of these genes under selection are related to drug resistance. Most of these studies have evaluated selection at the gene-level. However, positive selection can be evaluated on different scales, including individual sites (codons) and local regions within an ORF. In this paper, we use GenomegaMap, a Bayesian method for calculating selection, to evaluate selection of genes in the Mtb genome at all three levels. We present evidence that the intermediate analysis (windows of codons) yields the most credible list of candidate genes under selection (excluding PPE and PE_PGRS genes, which are predicted less reliably due to frequent sequencing errors). A further advantage of this approach is that it identifies specific regions within proteins that are under selective pressure, which is useful for structural and functional interpretation. In an analysis of two separate collections of Mtb clinical isolates (from Moldova; and a globally-representative set), we observed 53 and 173 significant genes under selection, with 36% overlap. The lists of genes under selection include many drug-resistance genes, as well as other genes that have previously been reported to be under selection (resR, phoR). The specific regions under selection identified within drug-resistance genes are shown to correspond to protein structural features known to be involved in resistance, supporting accuracy of the method. Positive selection in several ESX-1-related genes was also observed, suggesting adaptation to immune pressure.

adaptation↗
PubMed1975

In vitro selection and extended culture of antigen-specific T lymphocytes. II. Mechanisms of selection.

Functional selection of antigen-specific T lymphocytes can be achieved by culturing thymus-dependent (T) lymphocytes from immunized guinea pigs on "monolayers" of antigen-pulsed adherent peritoneal exudate cells (PEC) from nonimmune syngeneic donors. Several aspects of the in vitro selection of T lymphocyte-rich peritoneal exudate lymphocytes (PEL) were studied. It was shown that irradiated adherent PEC were equivalent to nonirradiated adherent PEC in supporting selection cultures, indicating that the lymphocytes harvested at the end of the selection culture derive from the immune donors of the PEL and not from the nonimmune donor of the adherent PEC. The relative importance of specific adherence and specific proliferation for achieving selection was determined by comparing the degree of selection obtained when nonadherent cells were discarded at 24 hr with that noted when the discard step was omitted. It was found that omitting the discard step markedly diminished the degree of selection. On the other hand, blocking proliferation with specific alloantisera after the discard step did not diminish the degree of selection, although it did diminish the cell yield. Thus, specific adherence to antigen-pulsed PEC appeared to be critical in the selection culture procedure. An estimate of the degree of enrichment obtained by the selection culture procedure was obtained by culturing selected cells in an excess of nonprimed PEL, so that auxiliary cells would not be limiting. Under these conditions, it appeared that selected cells were enrichied from 4- to 10-fold in antigen-responsive cells with respect to the initial cell population.

Animals↗
PubMed2026

Transition from Conventional to Genomic Selection (ssGBLUP) led to improve in accuracy gains and selection decisions in Sahiwal Cattle.

By using genome-wide markers to predict an individual's genetic potential, the introduction of Genomic Selection (GS) has transformed animal breeding. This greatly accelerated selection for complex traits by lowering reliance on drawn-out field trials, allowing for faster genetic gains in livestock. However, there is little research on the effects of genomic selection on Sahiwal cattle in India, and comparing it to the current culling or selection process is even more uncommon, particularly in nations with fewer genotyped animals. This study is an initial effort to address the aforementioned gaps in knowledge. Genomic selection was implemented in Sahiwal cattle for the 305 days milk yield using univariate animal model and the single-step Genomic Best Linear Unbiased Prediction (ssGBLUP) method. The Effective Population size (Ne) of the Sahiwal herd was calculated using genomic data and was reported for the previous generation to be 71.927. The heritability of 305 days milk yield was estimated as 0.177 ± 0.068. Genomic estimated breeding values (GEBVs) were predicted for each individual using ssGBLUP, yielding a mean prediction accuracy of 43.11%, compared with 40.88% obtained using conventional pedigree-based BLUP. Cross-validation further demonstrated superior predictive performance of ssGBLUP, with accuracies of 76.82% and 70.50% for ssGBLUP and PBLUP, respectively. To further check the effectiveness of the genomic selection methodology, we also compared the GEBVs obtained and compared it with the Expected Progeny Difference (EPD) which is being applied in our farm for culling decisions. It was seen that GEBVs obtained from ssGBLUP methodology were also in line with the conventionally used method of EPD. The use of genomic selection enables genetic studies with limited pedigree information. Additionally, the ssGBLUP methodology allows to check for pedigree errors, where family relationships are incorrectly recorded. The EPD and GEBVs were consistent with one another, indicating that genomic selection may also be utilised to support culling and selection decisions in a farm. Thus, in a conventional animal breeding program with constraint resources and an incomplete pedigree, we recommend employing the ssGBLUP model for regular genomic assessment and identification of suitable candidates to effectively carry out a genomic selection program.

Animals↗
PubMed2025

Positive selection and relaxed purifying selection contribute to rapid evolution of sex-biased genes in green seaweed Ulva.

BACKGROUND: The evolution of differences in gamete size and number between sexes is a cornerstone of sexual selection theories. The green macroalga Ulva, with incipient anisogamy and parthenogenetic gametes, provides a unique system to investigate theoretical predictions regarding the evolutionary pressures that drive the transition from isogamy to anisogamy, particularly in relation to gamete size differentiation and sexual selection. Its minimal gamete dimorphism and facultative parthenogenesis enable a rare window into early evolutionary steps toward anisogamy. RESULTS: By analyzing the expression profiles of sex-biased genes (SBGs) during gametogenesis, we found that SBGs evolve faster than unbiased genes, driven by higher rates of non-synonymous substitution (dN), indicating that SBGs are under stronger selective pressures. Mating type minus-biased genes (mt-BGs) exhibit higher dN/dS values than mating type plus-biased genes (mt+BGs), suggesting stronger selective pressures on mt-BGs, although this difference was not statistically significant (P = 0.08). Using branch-site and RELAX models, we found positive selection and relaxed purifying selection acting on a significant proportion of SBGs, particularly those associated with flagella function. CONCLUSIONS: This study highlights the selective pressures shaping anisogamy and provides insights into the molecular mechanisms underlying its evolution. The faster evolution of SBGs, particularly mt-BGs, and the positive selection on genes associated with motility, such as those related to flagella function, suggest the importance of enhanced gamete motility in the transition to anisogamy. These findings contribute to our understanding of sexual selection and the evolutionary forces that drive the differentiation of gamete size and number between sexes.

Selection, Genetic↗
PubMed1975

Selective and non-selective lymphocytotoxicity in human melanoma: observation on the effect of long-term culture and fetal bovine serum on target-cell sensitivity to lymphocytes.

In vitro cell mediated cytotoxicity (CMC) assays have been conducted in a human melanoma system with a 3H-proline retention technique. Melanoma target cells from long-term cultures ("cell lines") are found to exhibit increased susceptibility for lymphocyte cytotoxicity in comparison to the same target cells from short-term culture. The higher sensitivity of the "cell line" derived target cells is seen with lymphocytes, irrespective of diagnosis of the donor. In parallel experiments with the target cells grown in medium supplemented with fetal calf serum (FCS) and AB+ human serum (from a normal male doner), the melanoma target cells grown with FCS do not show any enhanced cytotoxicity, suggesting no causal relationship of such enhanced sensitivity of "cell line"-derived target cells to "heterologous melanoma antigens" that might have been acquired by the target cells following the use of FCS in tissue culture. In controlled assays of in vitro CMC, lymphocytes from melanoma patients (14/44) exhibited selective cytotoxicity (destruction of only one target-cell type) against the melanoma target cells, whereas only 3/97 control lymphocytes (other malignancies and normal donors) showed such melanoma-selective cytotoxicity. This difference is statistically significant at p less than 0.001. Non-selective cytotoxicity (destruction of two or more unrelated target cell types) was seen with lymphocytes from 9/44 melanoma patients, 13/51 patients with other malignancies and 8/46 normal donors. No correlation of selective cytotoxicity could be established with donors' age, sex, stage of disease, therapy or history of blood transfusion. Such a correlation may emerge as our series becomes larger. Despite the lack of any correlation between selective cytotoxicity and disease status, our study reaffirms the existence of selective cytotoxicity by melanoma patients' lymphocytes against melanoma target cells.

Animals↗
PubMed1979

Cardiovascular and adrenergic effects of cigarette smoking during immediate non-selective and selective beta adrenoceptor blockade in humans.

The cardiovascular and adrenergic responses to cigarette smoking during acute selective and non-selective beta adrenoceptor blockade were studied in seven young healthy volunteers in a double blind cross-over fashion. Heart rate, arterial blood pressure, forearm blood flow and plasma levels of adrenaline and noradrenaline were determined before and during the terminal 5 min period of 15 min smoking test. During smoking, plasma concentrations of adrenaline increased markedly and evenly by approximately 0.3 ng/ml in all three experimental sessions. Plasma concentrations of noradrenaline remained unchanged. Propranolol, a non-selective beta blocker, caused a marked rise in diastolic and mean blood pressure and forearm vascular resistance during smoking. This response was not seen in the control series or after selective beta-1 blockage with atenolol. This difference is attributable to propranolol's blockade of adrenaline's vasodilating effect mediated by beta-2 receptors in the resistance vessels. Furthermore, atenolol attenuated the systolic blood pressure and tachycardiac responses induced by cigarette smoking by comparison with placebo. This study suggests that selective beta-1 blockers are preferable in the management of patients who are habitual smokers.

Adult↗
PubMed1979

Divergent selection on locomotor activity in Drosophila melanogaster. I. Selection response.

Selection for high and low locomotor activity has been applied in two base populations of Drosophila melanogaster of distinct geographical origin. From each base population a high and a low line were selected, in which anesthesia was performed with ether. In addition, from one of the base populations a high line and a low line were selected under CO2 narcosis. Locomotor activity was measured in an apparatus consisting of rows of 20 tubes in a line. Heritabilities in the base populations determined in progeny tests were approximately 10%. Divergent directional selection was successful with realized heritabilities of similar value.

Animals↗
PubMed1979

Divergent selection on locomotor activity in Drosophila melanogaster. II. Test for reproductive isolation between selected lines.

Tests for reproductive isolation between lines selected for locomotor activity were performed. Three sets of selection lines were used, each consisting of lines selected for low and high locomotor activity from the same base population. Females preferred high-activity males in almost every case. However, in one of the sets temporary sexual isolation was found between flies of the high and low lines. This was accompanied in the low-activity females with a higher fertility when they were mated with their own males. After further selection the partial isolation disappeared.

Animals↗
PubMed1976

Specific selection of cytotoxic effector cells: the generation of cytotoxic T cells in rat thoracic duct lymphocyte populations positively or negatively selected for reactivity to specific strong histocompatibility alloantigens.

These studies consider the generation of cytotoxic T lymphocytes (CTL) from precursors (CTLP) present in rat thoracic duct lymphocytes after stimulation with strong alloantigens. Also, they explore the relationship between CTLP and "initiator" (I) lymphocytes responsible for specific GVH and MLI reactions. Positively selected TDL populations prepared in bulk MLI cultures show enriched GVH and MLI reactivity for the selecting major histocompatibility complex (MHC) haplotype, but no cytotoxic activity, raising the possibility that I and CTLP may belong to different subpopulations, and the latter failed to differentiate or to survive under these culture conditions. Restimulation of these cells in Marbrook culture vessels with the original priming haplotype under conditions suitable for generating killer cells in vitro resulted in greatly increased specific CTL activity with accelerated kinetics soon after priming and normal kinetics later. These findings indicate that "memory" killer cells can be generated in a previously stimulated lymphocyte population that had no overt cytotoxic activity. Restimulation with third party haplotypes failed to give CTL activity either to specific or to third party targets. Negatively selected TDL populations prepared by "filtration" through x-irradiated F1 rats, depleted of specific GVH and MLI responses, were also depleted of the ability to generate CTL in Marbrook cultures stimulated with the selecting haplotype. Stimulation with third party haplotypes, or with both third party and specific haplotypes together, gave CTL effective only against the third party target.

Animals↗
PubMed1977

Observations in man of hypoglycaemia during selective and non-selective beta-blockade.

The acute hypoglycaemic reaction is accompanied by a rise in systolic and a slight fall in diastolic blood pressure and a tachycardia. In contrast, during beta-blockade with propranolol there is a rise of both systolic and diastolic blood pressures and bradycardia. Restoration of blood glucose to normal is delayed. With metoprolol there is a lesser increase in diastolic blood pressure and a slight tachycardia. Restoration of the blood glucose to normal is little delayed. When patients liable to hypoglycaemia require a beta-blocking agent, it is suggested that a selective blocker such as metoprolol should be used.

Acute Disease↗
PubMed1976

Critical evaluation of the diagnostic value of systolic time intervals in the diagnosis of functional thyroid diseases. Comparison of results in a highly selected and a non-selected group of patients in relation to the blood PBI and T4I levels.

The value of measuring systolic time intervals for the diagnosis of functional thyroid disorders was studied. We were able to confirm that the systolic time intervals, namely the preejection period (PEP) are significantly shortened in hyperthyroidism and protracted in hypothyroidism. We were able to prove the rectilinear correlation between the PEP interval and Ig PBI in both highly selected and unselected groups of untreated patients with thyroid disorders. We were able to show much lower diagnostic value of other systolic intervals (as Q-S2) and indices (Weissler's index) compared to PEP. We are able to enumerate some pathological cardiovascular states, where the PEP interval is considerably influenced. With due respect to above-mentioned problems, we are convinced that the PEP measurement is of real diagnostic value in the bed-side diagnosis of thyroid disorders, moreover we believe it might help to solve some theoretical problems.

Electrocardiography↗
PubMed1979

[Action of grisin on the variability of an Acinomyces griseus culture and the use of the same antibiotic as a selection agent in the selection of active variants].

The effect of grisin on survival and variation of Actinomyces griseus producin grisin was studied. The efficiency of various concentrations of grisin on induction of variation according to the feature of the antibiotic production was compared. A possibility of increasing the productivity of strain. VNIIGenetics-115 by the use of the mutations of resistance to grisin is shown.

Anti-Bacterial Agents↗
PubMed1977

Ionic selectivity, saturation and block in gramicidin A channels: I. Theory for the electrical properties of ion selective channels having two pairs of binding sites and multiple conductance states.

A model for the gramicidin A channel is proposed which extends existing models by adding a specific cationic binding site at each entrance to the channel. The binding of ions to these outer channel sites is assumed to shift the energy levels of the inner sites and barriers and thereby alter the channel conductance. The resulting properties are analyzed theoretically for the simplest case of two inner sites and a single energy barrier. This for-site model (two outer and two inner) predicts that the membrane potential at zero current (Uo) should be a Goldman-Hodgkin-Katz equation with concentration-dependent permeability ratios. The coefficients of the concentration-dependent terms are shown to be related to the peak energy shifts of the barrier and to the binding constants of the outer sites. The thory also predicts the channel conductance in symmetrical solutions to exhibit three limiting behaviors, from which the properties of the outer and inner sites can be characterized. In two-cation symmetrical mixtures the conductance as a function of mole fraction is shown to have a minimum, and the related phenomenon of inhibition and block exerted by one ion on the other is explained explicitly by the theory. These various phenomena, having ion interactions in a multiply occupied channel as a common physical basis, are all related (by the theory) through a set of measurable parameters describing the properties of the system.

Electric Conductivity↗
PubMed2026

Impact of genomic selection for disease resistance on the spread of infection in a simulated aquaculture population.

BACKGROUND: In aquaculture, selection for disease resistance is typically based on mortality records from challenge tests performed on relatives of selection candidates. However, commercial success depends on limiting disease transmission, particularly the incidence and severity of outbreaks. It remains unclear whether selecting for lower mortality also reduces disease transmission. Both these outcomes are influenced by three underlying epidemiological host traits: susceptibility, infectivity, and infection-induced mortality. This simulation study evaluated the impact of genomic selection against mortality on disease transmission in a salmon population exposed to a pathogen with a fast transmission rate. METHODS: Mortality was assumed to be recorded on sibs of selection candidate, either as binary dead/alive status or as time to death during cohabitation/bath challenge tests. Phenotypes were simulated using a stochastic compartmental Susceptible-Infected-Removed epidemiological model, with genetic variation for the three underlying traits. Scenarios were explored by varying the genetic correlations between the three underlying traits. Challenge test designs varied in the number of groups, group sizes, and family distribution across groups. For comparison, a reference scenario with direct selection on the underlying traits was included. Genomic selection was applied over 10 discrete generations, and its impact on disease transmission was assessed using the basic reproductive ratio (R0). RESULTS: When selection was based on dead/alive status, R0 was highly sensitive to both the genetic correlations between the three underlying traits and the challenge test design. In contrast, selection based on time to death consistently reduced R0 across all scenarios (often to below 1 within four generations), regardless of trait correlations or test design. Selection on time to death primarily produced fish with reduced susceptibility to infection, while selection on dead/alive status produced fish with increased resistance and endurance to infection, delaying onset of infection or death without necessarily limiting transmission. Direct selection on the underlying epidemiological traits was the most efficient approach to reduce both mortality and transmission. CONCLUSIONS: Genomic selection for disease resistance, when measured as time to death in cohabitation or bath challenge tests conducted until mortality naturally levels off, reduces both mortality and disease spread. Breeding programs may benefit from challenge test designs that enable estimation of genetic parameters for the underlying traits affecting disease transmission and survival.

Animals↗
PubMed1979

The importance of choice of agonist in studies designed to predict beta 2 : beta 1 adrenoceptor selectivity of antagonists from pA2 values on guinea-pig trachea and atria.

1. pA2 values have been obtained for propranolol, butoxamine, H35/25 and atenolol on guinea-pig isolated trachea and atria (rate) using noredrenaline (beta 1-selective), isoprenaline (non-selective) and fenoterol (beta 2-selective) as agonists. 2. pA2 values varied with the agonist used on trachea but not on atria and, therefore, trachea : atria selectivity values varied with the agonist used. 3. It is suggested that the best estimate of the selectivity of an antagonist between beta 2- and beta 1-adrenoceptors is obtained by comparing its pA2 value obtained on trachea using a beta 2-selective agonist with that obtained on atria using a beta 1-selective agonist. The reasons for this are discussed. 4. The quantitative values for beta 2 : beta 1 selectivity obtained using the above pA2 values were butoxamine 17.0 H35/25 13.5, propranolol 2.75 and atenolol 0.036, i.e. butoxamine and H35/25 were beta 2-selective, propranolol was non-selective and atenolol was beta 1-selective. 5. The results support the hypotheses that guinea-pig trachea contains a mixture of beta 1- and beta 2-adrenoceptors and that guinea-pig atria contain only beta 1-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed2025

Selecting candidate Neisseria gonorrhoeae strains for oropharyngeal gonorrhoea human challenge: a genomics-based analysis of clinical isolates.

BACKGROUND: Neisseria gonorrhoeae is a human pathogen of major public health importance due to its increasing global prevalence and antimicrobial resistance (AMR). Evidence suggests that oropharyngeal infection plays a key role in N gonorrhoeae transmission and AMR; however, our understanding of oropharyngeal gonorrhoea pathogenesis is poor. A controlled human infection model (CHIM) for oropharyngeal gonorrhoea will improve understanding of infection and accelerate urgently needed novel gonorrhoea prevention and therapeutic strategies. As the first step in the development of this CHIM, we describe a systematic approach to CHIM strain selection that leverages genomics and clinical data. METHODS: In this genomics-based analysis, we applied a systematic N gonorrhoeae challenge strain selection strategy incorporating genomic and clinical data to a primary dataset of clinical isolates of N gonorrhoeae collected from adult patients in Victoria, Australia, between Jan 1 and Dec 31, 2017, and July 1, 2019, and June 30, 2021. This selection strategy used clinical, phenotypic, and genomic characteristics to define a set of eight criteria that aimed to ensure the contemporary global clinical relevance of the candidate strains; select strains that would be applicable for the assessment of current and future gonorrhoea vaccines; and maximise participant safety by reducing the risk of disseminated gonococcal infection and clinically significant AMR. We applied these criteria to our primary dataset to generate a panel of potential challenge strains. From this final dataset of potential challenge strains, we predetermined that we would select up to ten isolates to proceed to the next stage of detailed phenotypic characterisation for final N gonorrhoeae CHIM strain selection. FINDINGS: 5881 isolates comprised the primary dataset. After application of the selection criteria, most of the isolates (5795 [98·6%] of 5881) were excluded, mostly due to having clinically significant AMR and poor contemporary global clinical relevance. The remaining 86 N gonorrhoeae challenge strain candidates comprised five multilocus sequence types and six N gonorrhoeae multiantigen sequence types, many of which were represented by a single isolate. Of these 86 strains, five isolates were selected to maximise coverage of the phylogenetically distinct groups within the 86 candidate challenge strains and ensure representation of strains collected from various anatomical sites. INTERPRETATION: We transparently describe a novel, systematic, and rational genomics-based strategy for oropharyngeal gonorrhoea CHIM strain selection that improves the efficiency and transparency of CHIM strain selection and enables identification of contemporary and clinically relevant potential challenge strains. A final N gonorrhoeae challenge strain will be selected from the subset of five shortlisted candidates after detailed phenotypic assessment. FUNDING: Medical Research Future Fund, Australian National Health and Medical Research Council and Australian Government Research Training Program.

Humans↗