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Results for “Feature selection stability”

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PubMed1992

A bootstrap resampling procedure for model building: application to the Cox regression model.

A common problem in the statistical analysis of clinical studies is the selection of those variables in the framework of a regression model which might influence the outcome variable. Stepwise methods have been available for a long time, but as with many other possible strategies, there is a lot of criticism of their use. Investigations of the stability of a selected model are often called for, but usually are not carried out in a systematic way. Since analytical approaches are extremely difficult, data-dependent methods might be an useful alternative. Based on a bootstrap resampling procedure, Chen and George investigated the stability of a stepwise selection procedure in the framework of the Cox proportional hazard regression model. We extend their proposal and develop a bootstrap-model selection procedure, combining the bootstrap method with existing selection techniques such as stepwise methods. We illustrate the proposed strategy in the process of model building by using data from two cancer clinical trials featuring two different situations commonly arising in clinical research. In a brain tumour study the adjustment for covariates in an overall treatment comparison is of primary interest calling for the selection of even 'mild' effects. In a prostate cancer study we concentrate on the analysis of treatment-covariate interactions demanding that only 'strong' effects should be selected. Both variants of the strategy will be demonstrated analysing the clinical trials with a Cox model, but they can be applied in other types of regression with obvious and straightforward modifications.

Brain Neoplasms↗

PubMed2025

RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.

TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Amyotrophic lateral sclerosis↗

PubMed1989

Universality and structure of the N-end rule.

Our previous work has shown that, in the yeast Saccharomyces cerevisiae, any of the eight stabilizing amino-terminal residues confers a long (greater than 20 h) half-life on a test protein beta-galactosidase (beta gal), whereas 12 destabilizing amino-terminal residues confer on beta gal half-lives from less than 3 min to 30 min. We now show that an analogous single-residue code (the N-end rule) operates in an in vitro system derived from mammalian reticulocytes. We also show that the N-end rule has a hierarchical structure. Specifically, amino-terminal Glu and Asp (and also Cys in reticulocytes) are secondary destabilizing residues in that they are destabilizing through their ability to be conjugated to primary destabilizing residues such as Arg. Amino-terminal Gln and Asn are tertiary destabilizing residues in that they are destabilizing through their ability to be converted, via selective deamidation, into secondary destabilizing residues Glu and Asp. Furthermore, in reticulocytes, distinct types of the N-end-recognizing activity are shown to be specific for three classes of primary destabilizing residues: basic (Arg, Lys, His), bulky hydrophobic (Phe, Leu, Trp, Tyr), and small uncharged (Ala, Ser, Thr). Features of the N-end rule in reticulocytes suggest that the exact form of the N-end rule may depend on the cell's physiological state, thereby providing a mechanism for selective destruction of preexisting proteins upon cell differentiation.

Amino Acid Sequence↗

PubMed2026

Seed shattering habit in millets and the secrets of the abscission layer - a comprehensive review.

Though seed shattering continues to be a significant barrier affecting yield stability and harvesting efficiency in millets and other grasses, millets are increasingly acknowledged as climate-resilient, nutrient-rich 2007cereal crops with the potential to strengthen global nutritional and food security under the combined pressures of climate change, population growth, and limited natural resources. Since strong artificial selection favoured non-shattering phenotypes during domestication, seed shattering, an adaptive trait in wild species that promotes seed dispersal through the formation and activation of specialised abscission layers, became a distinguishing feature of cultivated cereals. With a focus on the morphological, physiological, hormonal, and genetic modulation of the abscission zone, this article summarizes the state of the art regarding seed shattering in millets. Abscission layer morphology, location, and lignification vary greatly among grasses, from well-defined lignified zones in rice and sorghum to non-lignified and anatomically subtle zones in Setaria and Panicum species. Cell wall-modifying enzymes like polygalacturonases, cellulases, expansins, and pectin methylesterases that mediate middle lamella degradation are modulated by coordinated hormonal signalling involving auxin, ethylene, and abscisic acid, which controls the timing and progression of cell separation at the physiological level. Domestication-related genes, including SH1, qSH1, SH4, and LES1, demonstrate convergent evolutionary mechanisms controlling abscission layer development in a variety of grass lineages at the molecular level. Understanding these regulatory networks has been greatly enhanced by recent developments in transcriptomics, functional genomics, and genome sequencing in both model species and underused millets. The role of millets as climate-smart cereals for sustainable future agriculture is reinforced by the integration of anatomical, physiological, and genetic insights, which offer a solid basis for targeted breeding and genome-editing strategies intended to improve seed retention, enhance yield stability, and increase harvest efficiency.

Abscission Layer↗

PubMed1992

Breast masses. Mammographic and sonographic evaluation.

Asymmetric breast tissue can nearly always be distinguished from a true mass by means of mammographic evaluation. Stellate masses from early invasive breast cancer are often extremely subtle so that optimal technique and meticulous interpretation are essential. Benign stellate masses such as post-biopsy scarring and fat necrosis frequently have a characteristic appearance. A radial scar is usually indistinguishable from malignancy on the mammogram. Nearly all circumscribed masses are benign and are usually cysts, fibroadenomas, or intramammary lymph nodes. A few circumscribed masses represent in situ or invasive carcinoma or both. Characteristics that may allow a definitively benign diagnosis for a circumscribed mass include the presence of fat and certain calcification patterns on the mammogram and features of a simple cyst on the sonogram. Management decisions for other circumscribed masses will depend on characteristics such as shape, margins, calcification, multiplicity, size, stability, and sonographic features as well as patient age and risk factors. Most nonspecific circumscribed masses should be followed rather than biopsied as they are commonly present on mammograms and have a change of malignancy of less than 5%. Even when biopsied on the basis of interval change, most small circumscribed cancers will not have metastasized to the regional nodes. For palpable breast masses, selection of mammography or ultrasonography as the primary imaging modality will depend on patient's age and risk factors.

Breast Diseases↗

PubMed1975

Presynaptic events in meiocytes of Lilium longiflorum and their relation to crossing-over: a preselection hypothesis.

We are proposing a "Preselection Hypothesis" to account for the regulation of crossing-over in eukaryotic organisms. The hypothesis characterized meiosis in terms of three major physiological stages: (1) a presynaptic stage when pairs of homologous DNA stretches are selected so as to become trapped within the synaptinemal complex during synapsis, (2) an alignment of homologous chromosomes and stabilization of paired bivalents via the synaptinemal complex, and (3) a scission and rejoining of DNA stretches leading to the formation of chiasmata and crossovers. The hypothesis centers on the first stage and is based on evidence for the occurrence of significant cytological and biochemical changes prior to synapsis. The major feature of the hypothesis is that crossing-over occurs only in trapped DNA stretches. Thus, potential crossing-over sites, though not crossing-over itself, are determined well before chromosomes pair. Since, to a large degree, crossovers are distributed randomly along the length of each chromosome, the preselection process must result in a random assortment of trapped DNA stretches, the assortment differing from one meiocyte to another.

Chromosomes↗

PubMed2026

DHX9 Inhibition Enhances Paclitaxel Sensitivity by Inducing Mitotic Failure in Ovarian and Endometrial Cancers.

Recurrent high-grade serous ovarian carcinoma (HGSOC) and endometrial cancer remain major clinical challenges with limited effective treatment options. DExH-box helicase 9 (DHX9), a DNA/RNA helicase essential for genomic stability, has not yet been explored as a therapeutic target in gynecologic cancers. In this study, we show that a selective DHX9 inhibitor (DHX9i) suppresses proliferation in a subset of HGSOC and endometrial cancer cell lines by inducing DNA damage, chromosomal instability, and mitotic failure. This effect was independent of microsatellite instability status and prior resistance to platinum or PARP inhibitors. Genomic analysis indicated that DHX9i resistance was unlikely to be driven by single-gene mutations but was instead associated with copy-number alterations in mitotic spindle and microtubule-regulating genes in both HGSOC and endometrial cancer. Transcriptomic profiling further revealed consistent alterations in microtubule- and spindle-associated pathways in DHX9i-resistant models following DHX9i treatment. Mechanistically, DHX9i induced mitotic defects in DHX9i-sensitive models, whereas resistant lines maintained mitotic integrity. Given the convergence of resistance-associated features on microtubule-related pathways, we combined DHX9i with the microtubule-stabilizing agent paclitaxel to enhance mitotic stress. This combination triggered mitotic disruption and enhanced cytotoxicity in DHX9i-resistant cells. In vivo, the combination led to sustained tumor regression and prolonged survival in both DHX9i-sensitive and DHX9i-resistant models without notable toxicity. Overall, our findings define genomic, transcriptomic, and phenotypic characteristics associated with differential responses to DHX9i and support the clinical evaluation of the DHX9i-paclitaxel combination as a therapeutic strategy in recurrent gynecologic cancers.

Female↗

PubMed2026

Bacteriophages Control Epiphytic Pseudomonas syringae Populations in Highbush Blueberry Leaves.

The Pseudomonas syringae complex (Psc) is a group of globally distributed phytopathogens responsible for substantial agricultural losses. Although bacteriophage-based biocontrol has shown promise against Psc, no studies have examined phages targeting blueberry-tropic Psc lineages. Here, we isolated phages infecting Psc strains from diseased highbush blueberry (Vaccinium corymbosum), and evaluated their suitability for biocontrol using a multi-stage screening pipeline incorporating host-range analysis, comparative genomics, environmental stability testing, in vitro antibacterial efficacy assays and ex planta validation. Twelve of the isolated phages exhibited favourable host-range characteristics. Genomic analyses revealed substantial phylogenetic diversity among these candidates but simultaneously identified multiple clonal groups, reducing the collection to eight non-redundant phages spanning five distinct genera. Candidate phages generally retained infectivity under environmentally relevant conditions and exhibited heterogeneous but largely favourable stability profiles. Planktonic killing assays uncovered considerable variation in antibacterial efficacy, but phage performance appeared to be driven by infection compatibility and host-specific factors rather than properties intrinsic to individual phages. Notably, the jumbo phageCB10 emerged as a particularly promising candidate due to its strong antibacterial activity (median GRC = 0.943), favourable environmental stability and unique genomic features. Cocktails containing the most effective candidates produced substantial and longitudinally sustained reductions in epiphytic colonization of detached blueberry leaves by Psc, exceeding five orders of magnitude at peak efficacy and demonstrating robust activity in a biologically relevant ex planta system. Importantly, in vitro antibacterial efficacy was predictive of performance in our ex planta model (r = 0.67; p = 0.0003), supporting the utility of tiered screening approaches for candidate selection. Taken together, these findings establish a framework for the systematic identification and evaluation of phages targeting Psc, and support the development of phage-based interventions for managing plant diseases.

Pseudomonas syringae↗

PubMedDate not supplied

[Conformational transitions of DNA in concentrated neutral salt solutions].

Salt anions can be arranged in lyotropic series of the action of conformational stability of DNA. This effect is universal for proteins and DNA. It is explained by the salt changes of transfer free energy of macromolecular inner groups to the solvent. Effect mechanism is the combination of anion direct interaction with the exposed inner groups and in indirect way through the changes of water structure. Individual features of the salt effect on DNA are the induced transitions in DNA duplex and the changes of differential stability of AT- and GC-base pairs. An important role in these phenomena plays the dehydration of DNA in the reduction of water activity in concentrated salt solutions. Local changes in medium polarity, hydration level of DNA molecule at different stages of their functioning can explain the regulatory role in intracellular processes, as well as selectivity and specificity of the action of individual ions in the cell.

Circular Dichroism↗

PubMed1992

Cutaneous T-cell lymphoma. Evaluation of pretreatment skin biopsy specimens by a panel of pathologists.

BACKGROUND AND DESIGN: Cutaneous T-cell lymphoma (CTCL) frequently presents a difficult diagnostic challenge for the clinician and pathologist. To assess the diagnostic validity of conventional histopathologic findings in CTCL, pretreatment skin biopsy specimens were scored prospectively and independently by a panel of five to seven dermatopathologists and pathologists. Scores were compared with disease outcome. Repeatability of these scores was examined among observers and for the same observer. The study population consisted of 165 subjects, initially referred for suspected mycosis fungoides or Sézary syndrome. Ninety-two patients determined to have CTCL have been followed up for 6.3 +/- 3.5 years (mean +/- SD) and are categorized according to disease outcome: 22 are in complete remission, 35 are in partial remission, three have progressive lymphoma, 15 died of disease, 13 died of other causes, and four were unavailable for follow-up. Seventy-three patients determined not to have CTCL have been followed up for 5.3 +/- 3.2 years without subsequent clinicopathologic evidence of CTCL. These longitudinal data allowed comparisons of the clinical course with the original histologic interpretations. RESULTS: Data showed that the histologic scores rendered by the pathology panel did not correlate with stage of disease and were not an accurate predictor of clinical outcome, because the histologic ratings did not discriminate between patients who eventually had complete remission and those with either progressive lymphoma or who have died of disease. The results also substantiate the low inherent reliability of histopathologic findings in CTCL. Large differences existed among pathologists in scoring the study populations and repeated reading of selected cases by the same panel member resulted in a change of diagnosis 15% of the time. Among the histologic features evaluated, only the presence of mitoses in the infiltrating cells showed a trend toward an unfavorable outcome. CONCLUSION: Pathologic diagnosis in the CTCL disease spectrum should be interpreted with caution and then only in conjunction with the clinical evaluation. As expected, the use of an average value from a panel of readers added a component of stability to the histologic interpretation.

Biopsy↗

PubMed1991

Kinetics of rapid RNA evolution in vitro.

A rapidly acquired partial resistance to the replicase antagonist, ethidium bromide (EB), seen by Spiegelman and coresearchers in Q beta RNA variants competitively replicating under defined conditions in vitro, reflected existence of a pool of mutant RNA molecules, preadapted to EB, and their cross-propagation from the pre-EB optimum species, MDV-1, and from other kindred variants, some of which remained undetected, according to this quantitative analysis of midivariant RNA replication kinetics. DNAlike features of their evolution, such as the cloning of variants from an MDV-1 subtype and a compliance with the fundamental theorem of natural selection, resulted from the suppression, both real and apparent, of intrinsic RNA heterogeneity through sampling and detection methods, and also by the ascendency of self-propagation over cross-propagation with advancement of a superior variant. The deficit in mean polymer fitness, compared with optimum levels, determines the lower limit of this heterogeneity. Stability conditions for frequency equilibrium and strategies for counteracting viral drug resistance have been considered.

Biological Evolution↗

PubMed2026

Yeast Rad55-Rad57-SHU paralog complex dynamically promotes Rad51 filament formation.

Homologous recombination (HR) is an important DNA repair pathway that safeguards genome integrity. During HR, the Rad51 nucleoprotein filaments catalyze strand invasion into a homologous duplex DNA. Filament formation requires a conserved family of Rad51 paralogs that act as tumor suppressors in humans. By capturing six distinct states using cryo-electron microscopy, we reveal that the Saccharomyces cerevisiae Rad51 paralog complex, composed of the Rad55-Rad57 heterodimer and the SHU (Psy3-Csm2-Shu1-Shu2) complex, selectively brings Rad51 to single-stranded DNA to seed filament formation. Rad51 itself is a transient yet integral component of this machinery which binds along the Rad57 subunit to complete a high-affinity DNA-binding site. We also uncover a dual-nucleotide regulatory mechanism: a structural ADP molecule stabilizes the complex, while a second, catalytic ATPase site at the Rad57-Rad51 interface promotes the release of the paralog complex. These structural and mechanistic features provide a blueprint for understanding the function of Rad51 paralogs across eukaryotes.

Saccharomyces cerevisiae Proteins↗

PubMed2026

NCBoost v2: a classifier for non-coding single-nucleotide variants in Mendelian diseases.

MOTIVATION: The current diagnostic rate of rare diseases through whole-genome sequencing has stabilized at around 30% on average, highlighting the need for improved computational scores to identify pathogenic variants. In 2019, we developed NCBoost, a supervised-learning approach that mined a comprehensive set of sequence constraint features and proved particularly well suited to identifying high-effect pathogenic non-coding variants in genetic diseases. Since its first release, the substantial increase in the number of variants available for training, as well as the enhanced capacity to detect purifying selection signals from large-scale genome sequencing projects, motivated an update of NCBoost. RESULTS: We implemented NCBoost v2, a pathogenicity score for non-coding single-nucleotide variants, trained on the largest set of curated pathogenic variants in monogenic Mendelian diseases available to date. It leverages conservation features computed from recent large-scale genomic consortia such as Zoonomia and gnomAD, and incorporates recent splice-altering predictive scores. NCBoost v2 outperformed alternative state-of-the-art methods in a variety of scenarii, providing more consistent scores across non-coding genomic regions and fine-tuning the scoring of pathogenic splice-altering variants in Mendelian disease genes. AVAILABILITY AND IMPLEMENTATION: NCBoost v2 software is implemented in Python 3.10 and is freely available under the GNU General Public License Version 3 at https://doi.org/10.5281/zenodo.16029049 and https://github.com/RausellLab/NCBoost-2, together with precomputed scores for the human genome assembly GRCh38.

Polymorphism, Single Nucleotide↗

PubMed1992

New IS10 transposition vectors based on a gram-positive replication origin.

We describe below a set of plasmid-based vehicles which can be used for delivery of IS10-derived transposons into Gram- bacteria. These vehicles replicate via a Gram+ plasmid origin that is inactive in Escherichia coli; they are easily maintained in Bacillus subtilis. Transposons are introduced by electroporation or transformation with the plasmid, and as in previous delivery systems, transpositions are selected with the appropriate antibiotic. This system should be particularly useful in situations where the standard delivery vehicles, based on bacteriophage lambda, are inappropriate. The system described incorporates a number of useful features: a variety of antibiotic markers (Er, Cm, Km or Tc), a polylinker containing restriction sites for rare-cutting endonucleases to facilitate physical mapping of chromosomal insertions, a mutant transposase that confers a relaxation in insertion specificity and positioning of the transposase-encoding gene outside of the transposing segment to ensure the stability of insertions once isolated.

Bacillus subtilis↗

PubMed1989

[A new general orthopedic universal intramedullary nail for the tibia. Clinical development and experiences].

The new AO-Universal-Nail was developed through intensive cooperation between fundamental research, technicians and clinical application. We are now able to transfer the concept of a Universal-Nail (initially for the femur) to the tibia as well. The existing technique of the medullary nail was maintained as far as possible. Special features to be highlighted: The new AO-bend obtains better impact behavior and a more anatomical stabilization of the bone cavity. The tapered tip eases the gliding of the tip of the nail along the inner wall of the dorsal corticalis and past the fracture. Proximal locking is obtained through three transverse extending holes. They offer many choices for optimal placement of the locking bolts. Interlocking from anterior to posterior has been logically abandoned, due to danger for nerves and vessels. Distal looking offers a large selection for stabilization through one a.p.-hole and two transverse holes for the locking bolts. The design from anterior to posterior entables the protection of the soft tissue. The Universal-nail can either be inserted with or without interlocking. A free decision is possible during the operation. The new AO-Universal-Nail for the tibia (as for the femur) maintained reliable aspects and was consequently converted to meet new demands and findings. The basic fundamentals of the AO, namely the observance and application of biomechanical principles and safe operation procedure were attained through simple instrumentation and have been proved successful for clinical application.

Fracture Fixation, Intramedullary↗

PubMed1985

Common features of polyomavirus mutants selected on PCC4 embryonal carcinoma cells.

The genomic rearrangements of six polyomavirus mutants selected on PCC4 embryonal carcinoma cells have been compared and their common characteristics pointed out. All mutants show a duplication which includes at least the adenovirus type 5 (Ad5) E1A-like enhancer core sequence plus a deletion of variable size and location. The presence of the second enhancer core sequence, the SV40-like enhancer, is not required for expression of the PyEC PCC4 phenotype. Two of these mutants are also able to express polyomavirus T antigen on F9 and LT1 cells. Multiadaptation seems to require the duplication of the Ad5 E1A-like core sequence, the maintenance of the SV40-like core sequence and a local change in DNA stability.

Animals↗

PubMed1979

Electrophrenic respiration: report of six cases.

The development of electrophrenic respiration has permitted freedom from mechanical ventilation for patients who have irreversible respiratory failure in association with high-cervical spinal cord or brainstem lesions. There are three basic criteria for successful diaphragm pacing: (1) the need for long-term mechanical ventilatory assistance, (2) a functionally intact phrenic nerve-diaphragm axis, and (3) chest wall stability. Inability to achieve satisfactory pacing can be due to malfunction of equipment, instability of the chest wall, or inadequate neuromuscular responsiveness. These features of diaphragm pacing are exemplified in a series of six patients. Three achieved independence from mechanical ventilatory assistance with full-time phrenic pacing. In one patient, only limited electrophrenic respiration was achieved, and in another the method was entirely unsuccessful. Although functioning well, pacing systems were removed from the sixth patient because of infection. Diaphragm pacing can be a valuable form of respiratory support for carefully selected patients.

Adolescent↗

PubMed1990

Placing patients in the queue for coronary revascularization: evidence for practice variations from an expert panel process.

A panel of 16 cardiologists and cardiac surgeons rated 438 case scenarios for the maximum acceptable delay prior to revascularization, using a scale with seven interventional time frames and two nodes for designating dubious or inappropriate cases. If consensus was defined as agreement by 12 or more panelists, only 1.4 percent of the case scenarios showed consensus on a single rating. Dividing the scale into three broad clinical categories (revascularize promptly, place on a waiting list, or no intervention), 11.4 percent of scenarios showed all 16 panelists agreeing on a single category, rising to 59.4 percent of scenarios if agreement by 12 panelists was accepted as a consensus. The mean difference between the panelists' highest and lowest urgency ratings yielded waiting time differences of two weeks for scenarios of very unstable angina, and more than three months for those with stable angina. However, in a regression model, individual panelist factors on average had less effect than clinical features such as severity and stability of angina, or stenosis of major coronary arteries. These findings strongly support the need for consensus criteria to ensure that triage practices are consistent and fair, and also suggest that widespread adoption of a standardized approach to revascularization priorities may be feasible.

Coronary Artery Bypass↗