Consider a sequence of Markov processes $X^1, X^2,...$ with state space $E$, where $X^N$ has a strong drift to $D \subseteq E$, such that $Φ(X^N)$ is slow for some appropriate $Φ: E\to D$. Using the method of martingale problems, we give a limit result, such that $Φ(X^N) \xRightarrow{N\to\infty} Z$ in the space of càdlàg paths, and $X^N \xRightarrow{N\to\infty} X$ in measure. \\ We apply the general limit result to models for copy number variation of genetic elements in a diploid Moran model of size $N$. The population by time $t$ is described by $X^N \in \mathcal P(\mathbb N_0)$, where $X^N_k$ is the frequency of individuals with copy number $k$, and $Φ: \mathcal P(\mathbb
Jun Tsukiji, Shiro Koizume, Tomoko Takahashi
et al.
Background: Impaired smell/taste sensation (dysosmia/dysgeusia) are common manifestations of coronavirus disease 2019 (COVID-19). Scattered peripheral chemoreceptors and directly innervating central nerves from the brain to the receptors are responsible systems for perception in the human body. The shared neurotransmitter serotonin (5-HT) and neuroimmune modulators of the kynurenine (Kyn) pathway (KP) are metabolites derived from tryptophan (Trp). The synthesis of KP metabolites is initiated by the rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can activate Trp metabolism. Therefore, we investigated whether serum metabolites of Trp and IDO/TDO activity could serve as biomarkers for assessing smell/taste impairment (dysosmia/dysgeusia) in patients during the acute phase of COVID-19. Methods: We conducted a retrospective case-control study. Among patients admitted with acute COVID-19 to our hospital between September 13, 2021, and September 30, 2023, those whose chief complaints included dysosmia/dysgeusia at admission were identified. These symptoms were confirmed by the attending physician for COVID-19. Patients were stratified based on the presence or absence of dysosmia and/or dysgeusia.In both patient groups, serum concentrations of Trp, 5-HT, Kyn, kynurenic acid (KYNA), and quinolinic acid (QUIN) were measured using enzyme-linked immunosorbent assay. IDO/TDO activity was expressed as Kyn–Trp ratio (KTR). The relationships between these biomarkers and dysosmia/dysgeusia, as well as other clinical parameters and outcomes, were evaluated. Results: Of 520 patients admitted with COVID-19, 95 met the inclusion and exclusion criteria. Among them, 26 patients with dysosmia/dysgeusia (group A) and 26 patients without these symptoms (group B) were analyzed. No significant intergroup difference was observed in the average timepoint at blood sampling after COVID-19 onset (post-day from onset: pdo) (4.69 ± 2.51 days in group A vs. 3.62 ± 2.22 in group B). Group A showed significantly lower Trp levels [median 9.70 μg/mL (range 4.59–13.89) vs. 10.40 (7.52–13.34), p = 0.031], and higher KTR [61.34 (40.47–384.2) vs. 53.52 (26.13–86.64), p < 0.037] and QUIN levels [574.39 nM (100.39–11909) vs. 443.65 (83.09–998.3), p < 0.0169]. No significant differences were observed in 5-HT or KYNA levels between groups. Almost all cases of dysosmia involved anosmia/hyposmia and were significantly correlated with non-vaccination status with mRNA vaccine (p = 0.017). In contrast, dysgeusia exhibited heterogeneous manifestations, primarily ageusia or hypogeusia, followed by hypersensitivity to salty taste, and was not correlated with vaccination status. Conclusion: Clinically, serum KTR and QUIN levels may serve as useful biomarkers for assessing dysgeusia/dysomia during acute COVID-19. Furthermore, vaccination may play an important preventive role, particularly against dysosmia.
The process of mismatch repair was first postulated to explain the results of experiments on genetic recombination and bacterial mutagenesis. Mismatch repair has long been known to play a major role in two cellular processes: (1) the repair of errors made during DNA replication or as the result of some types of chemical damage to DNA and DNA precursors; and (2) the processing of recombination intermediates to yield new configurations of genetic markers. More recent studies have suggested that mismatch repair may also be crucial for (1) the regulation of recombination events between divergent DNA sequences that could result in different types of genetic instability (Rayssiguier et al. 1989; Selva et al. 1995; Datta et al. 1996), (2) some types of nucleotide excision repair responsible for repair of physicallchemical damage to DNA (Karran and Marinus 1982; Fram et al. 1985; Feng et al. 1991; Mellon and Champe 1996), and (3) participating in a cell-cycle checkpoint control system by recognizing certain types of DNA damage and triggering cell-cycle arrest or other responses to DNA damage (Hawn et al. 1995; Anthoney et al. 1996). The most extensively characterized general mismatch repair system is the Escherichia coli MutHLS system, which repairs a broad spectrum of mispaired bases and has been reconstituted with purified enzymes. Eukaryotes are known to contain a mismatch repair system that has at least some components that are highly related to key components of the bacterial MutHLS mismatch repair system. The observation that defects in mismatch repair genes are linked to both inherited cancer susceptibility and some sporadic cancers has generated considerable interest in the gene products that function in eukaryotic mismatch repair. The goal of this review is to discuss recent studies on the mechanisms of MutHLSlike mismatch repair in the yeast Saccharomyces cerevisiae and in humans and to relate insights derived from these studies to human cancer genetics. Given space constraints, i t is difficult to cover everything known about mismatch repair or to reference all of the relevant work that has been done in this area. However, a brief overview of the E. coli MutHLS pathway is presented below to allow comparison of the E. coli and eukaryotic mismatch repair pathways and proteins. For more detailed information, particularly related to bacterial mismatch repair, base-specific mismatch repair systems, and cancer genetics, see other recent reviews (Modrich 1991; Eshleman and Markowitz 1995; Fishel and Kolodner 1995; Friedberg et al. 1995; Kolodner 1995; Marra and Boland 1995; Modrich and Lahue 1996).
Mariana A. Londe, Luciana S. Pessoa, Carlos E. Andrade
et al.
A random-key genetic algorithm is an evolutionary metaheuristic for discrete and global optimization. Each solution is encoded as a vector of N random keys, where a random key is a real number randomly generated in the continuous interval [0, 1). A decoder maps each vector of random keys to a solution of the optimization problem being solved and computes its cost. The benefit of this approach is that all genetic operators and transformations can be maintained within the unitary hypercube, regardless of the problem being addressed. This enhances the productivity and maintainability of the core framework. The algorithm starts with a population of P vectors of random keys. At each iteration, the vectors are partitioned into two sets: a smaller set of high-valued elite solutions and the remaining non-elite solutions. All elite elements are copied, without change, to the next population. A small number of random-key vectors (the mutants) is added to the population of the next iteration. The remaining elements of the population of the next iteration are generated by combining, with the parametrized uniform crossover of Spears and DeJong (1991), pairs of solutions. This chapter reviews random-key genetic algorithms and describes an effective variant called biased random-key genetic algorithms.
Optimal path planning involves finding a feasible state sequence between a start and a goal that optimizes an objective. This process relies on heuristic functions to guide the search direction. While a robust function can improve search efficiency and solution quality, current methods often overlook available environmental data and simplify the function structure due to the complexity of information relationships. This study introduces Genetic Informed Trees (GIT*), which improves upon Effort Informed Trees (EIT*) by integrating a wider array of environmental data, such as repulsive forces from obstacles and the dynamic importance of vertices, to refine heuristic functions for better guidance. Furthermore, we integrated reinforced genetic programming (RGP), which combines genetic programming with reward system feedback to mutate genotype-generative heuristic functions for GIT*. RGP leverages a multitude of data types, thereby improving computational efficiency and solution quality within a set timeframe. Comparative analyses demonstrate that GIT* surpasses existing single-query, sampling-based planners in problems ranging from R^4 to R^16 and was tested on a real-world mobile manipulation task. A video showcasing our experimental results is available at https://youtu.be/URjXbc_BiYg
Sean Campbell, Courtney C. White, Amanda M. Alexander
et al.
Delay is an inherent feature of genetic regulatory networks. It represents the time required for the assembly of functional regulator proteins. The protein production process is complex, as it includes transcription, translocation, translation, folding, and oligomerization. Because these steps are noisy, the resulting delay associated with protein production is distributed (random). We here consider how distributed delay impacts the dynamics of bistable genetic circuits. We show that for a variety of genetic circuits that exhibit bistability, increasing the noise level in the delay distribution dramatically stabilizes the metastable states. By this we mean that mean residence times in the metastable states dramatically increase. Relevance to Life Sciences. Bistable genetic regulatory networks are ubiquitous in living organisms. Evolutionary processes seem to have tuned such networks so that they switch between metastable states when it is important to do so, but small fluctuations do not cause unwanted switching. Understanding how evolution has tuned the stability of biological switches is an important problem. In particular, such understanding can guide the design of forward-engineered synthetic bistable genetic regulatory networks. Mathematical Content. We use two methods to explain this stabilization phenomenon. First, we introduce and simulate stochastic hybrid models that depend on a switching-rate parameter. These stochastic hybrid models allow us to unfold the distributed-delay models in the sense that, in certain cases, the distributed-delay model can be viewed as a fast-switching limit of the corresponding stochastic hybrid model. Second, we generalize the three-states model, a symbolic model of bistability, and analyze this extension.
Valeria Sarahi Ocaranza-Joya, Olimpia Chong-Carrillo, Martín Alonso Aréchiga-Palomera
et al.
Purpose: To analyze the development of scientific information produced worldwide on the genus Ambystoma and identify existing trends and knowledge gaps.
Methodological design: We analyzed publications registered in the Scopus database containing the word “Ambystoma” in the title. The results were systematized using the Excel ® program to exclude non-scientific records and categorized by subject area, species, authorship, and institutional affiliation. VOSviewer software was used to visualize collaboration networks between authors.
Results: The analysis identified Ambystoma mexicanum (axolotl) as the most studied species, mainly due to its utility as a model organism. Most research originated from North America, particularly the United States, with limited international collaboration. Studies focused on areas such as genetics, ecology, and morphophysiology.
Research limitations: The study excluded publications that did not explicitly mention Ambystoma in the title, potentially overlooking broader research contributions related to the genus.
Findings: The findings highlight the need for increased international collaboration and a more comprehensive research focus on lesser-known Ambystoma species. Diversifying research efforts can enhance conservation strategies and improve scientific understanding of this genus.
Blepharipoda liberata Shen, 1949, is a distinctive benthic crustacean found in the low tidal zone of the beach in Rizhao, Shandong, China. This study presents the first record of the complete mitochondrial genome of B. liberata. The mitochondrial genome was found to be 15,766 base pairs in length and contained 13 protein-coding genes, two ribosomal RNA genes, and 22 transfer RNA genes. The overall nucleotide composition was characterized by A 38.18%, T 35.94%, C 15.44%, and G 10.43%, with a high A + T content of 74.12%. Phylogenetic analysis indicated that B. liberata is closely related to other species within the Hippoidea family. This research marks the first acquisition of the complete mitochondrial genome of B. liberata, thereby providing valuable insights for future studies focused on the conservation and management of this species.
Audre Preena Maria Sundar Raj, Gayathri Selvakumar, James Clement
et al.
Abstract Aging, a complex biological process, entails sequential changes in organisms that elevate the risk of frailty, disease, and mortality, affecting individuals at the level of cellular, organ, and organism. This process is influenced by genetic diversity, socioeconomic status, healthcare infrastructure, lifestyle choices, and cultural practices. Gerontology delves into the factors shaping longevity, aging processes, and aging from both evolutionary and individual perspectives. Centenarians and supercentenarians serve as models for studying exceptional longevity, offering insights into the aging process and resistance to age-related diseases. This research investigates common genetic variations (SNPs) shared among 3 centenarians and 18 supercentenarians, individuals aged 110 years or older. 754,520 SNPs were found to be common among all the 21 samples. Utilizing SNPnexus, a genetic variant annotation tool, we annotated coding variants and assessed potential disease susceptibilities associated with these variants. Ensembl was used as an annotation system, we annotated 1,607,122 variants, and found 11,348 coding variants. Among them, 4980 had non-synonymous variants, and 110 variants were observed to have deleterious effects. These deleterious SNPs were linked with 79 genes among them 16 novel variants were identified in 9 genes. The population frequency comparison using the 1000 Genomes Project and gnomAD revealed that a subset of these common, non-synonymous SNPs and deleterious SNPs had minor allele frequencies (MAF) below 1% or were absent entirely, suggesting potential rare variants specific to this cohort. In addition, we also found statistically significant (p < 0.05) 148 enriched pathways, among them the top enriched pathways such as extracellular matrix (ECM) remodeling, signal transduction, disease-associated pathways, sensory processing and metabolism of proteins and RNA. These preliminary findings may help prioritize candidate variants and genes for future studies on larger cohorts with appropriate controls can help in understanding the genetic basis of exceptional longevity.
AbstractOne hundred years ago, the first book with the phrase “Animal Genetics” in its title was published. It was written by F.A.E. Crew, then Lecturer in Genetics and foundation Director of the Department of Research in Animal Breeding at the University of Edinburgh. The 352 pages of text provide a most interesting summary of the knowledge of animal genetics at that time. It is impressive to see the extent to which the understanding of genetics had developed in just a couple of decades since the rediscovery of Mendelism. There was, for example, recognition that genes are borne on chromosomes; that XX/XY sex determination provides a very satisfactory explanation for most of the relevant evidence; that sex‐linked inheritance has a practical application; that variation in quantitative traits is determined by the combined action of many genes and many non‐genetic factors; that inbreeding results in substantial decreases in fecundity and fertility due to homozygosity for undesirable alleles; that crossing between lines or breeds gives rise to hybrid vigour (heterosis); and that many disorders are inherited in a Mendelian fashion, and hence can be controlled by informed breeding. There is, however, no mention of Fisher's 1918 paper nor of Wright's recently published inbreeding coefficient and coefficient of relationship. Crew's book inspired the next generation of geneticists, such as Fred Hutt, who travelled from Canada to Edinburgh to do a PhD with Crew, and who later published his own very influential book with the same title, which was dedicated to Crew.
Alassane Baneye Maiga, Ibrahim Pamanta, Salia Bamba
et al.
ABSTRACT Background Congenital muscular dystrophies (CMDs) are diverse early‐onset conditions affecting skeletal muscle and connective tissue. This group includes collagen VI‐related dystrophies such as Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM), caused by mutations in the COL6A1, COL6A2 and COL6A3 genes. We report a consanguineous Malian family with three siblings affected by UCMD due to a novel homozygous splice site variant in the COL6A1 gene. Methods After obtaining consent, three affected siblings and their relatives underwent physical examinations by specialists and laboratory tests where possible. DNA was extracted from peripheral blood for genetic testing, including Whole Exome Sequencing (WES). Putative variants were confirmed through Sanger Sequencing and assessed for pathogenicity using in silico tools. Results The three siblings and their healthy parents, from a consanguineous marriage, presented with early‐onset progressive muscle weakness, walking difficulty, proximal motor deficits, severe muscle atrophy, hypotonia, skeletal deformities, joint hyperlaxity, ankyloses at the elbows and knees, keloid scars and dental crowding. No cardiac involvement was detected and creatine kinase (CK) levels were normal. All had low serum calcium levels, treated with oral supplements. Needle myography indicated myopathic patterns. WES identified a novel splice site variant in the first intron of COL6A1 (c.98‐1G>C), which segregated with the disease within the family. This variant is predicted to cause exon 2 skipping in COL6A1, with a high CADD score of 33 and Splice AI predicting it as deleterious. Conclusion We identified a novel COL6A1 variant in a consanguineous family, highlighting the need for further studies in larger African cohorts to enhance genetic epidemiology and prepare for future therapeutic research.
Farhad Jeddi, Elnaz Faghfuri, Sahar Mehranfar
et al.
Abstract DNA methylation is an important molecular modification that plays a key role in the expression of cancer genes. Evaluation of epigenetic changes, hypomethylation and hypermethylation, in specific genes are applied for cancer diagnosis. Numerous studies have concentrated on describing DNA methylation patterns as biomarkers for cancer diagnosis monitoring and predicting response to cancer therapy. Various techniques for detecting DNA methylation status in cancers are based on sodium bisulfite treatment. According to the application of these methods in research and clinical studies, they have a number of advantages and disadvantages. The current review highlights sodium bisulfite treatment-based techniques, as well as, the advantages, drawbacks, and applications of these methods in the evaluation of human cancers.
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cytology
IntroductionHybrid poplars are industrial trees in China. An understanding of the molecular mechanism underlying wood formation in hybrid poplars is necessary for molecular breeding. Although the division and differentiation of vascular cambial cells is important for secondary growth and wood formation, the regulation of this process is largely unclear.MethodsIn this study, mPagGRF15 OE and PagGRF15-SRDX transgenic poplars were generated to investigate the function of PagGRF15. RNA-seq and qRT-PCR were conducted to analyze genome-wide gene expression, while ChIP‒seq and ChIP-PCR were used to identified the downstream genes regulated by PagGRF15.Results and discussionWe report that PagGRF15 from hybrid poplar (Populus alba × P. glandulosa), a growth-regulating factor, plays a critical role in the regulation of vascular cambium activity. PagGRF15 was expressed predominantly in the cambial zone of vascular tissue. Overexpression of mPagGRF15 (the mutated version of GRF15 in the miR396 target sequence) in Populus led to decreased plant height and internode number. Further stem cross sections showed that the mPagGRF15 OE plants exhibited significant changes in vascular pattern with an increase in xylem and a reduction in phloem. In addition, cambium cell files were decreased in the mPagGRF15 OE plants. However, dominant suppression of the downstream genes of PagGRF15 using PagGRF15-SRDX showed an opposite phenotype. Based on the RNA-seq and ChIP-seq results, combining qRT-PCR and ChIP-PCR analysis, candidate genes, such as WOX4b, PXY and GID1.3, were obtained and found to be mainly involved in cambial activity and xylem differentiation. Accordingly, we speculated that PagGRF15 functions as a positive regulator mediating xylem differentiation by repressing the expression of the WOX4a and PXY genes to set the pace of cambial activity. In contrast, PagGRF15 mediated the GA signaling pathway by upregulating GID1.3 expression to stimulate xylem differentiation. This study provides valuable information for further studies on vascular cambium differentiation mechanisms and genetic improvement of the specific gravity of wood in hybrid poplars.
Lucia Verrillo, Rosita Di Palma, Alberto de Bellis
et al.
Neuroplasticity is a crucial property of the central nervous system to change its activity in response to intrinsic or extrinsic stimuli. This is mainly achieved through the promotion of changes in the epigenome. One of the epi-drivers priming this process is suberoylanilide hydroxamic acid (SAHA or Vorinostat), a pan-histone deacetylase inhibitor that modulates and promotes neuroplasticity in healthy and disease conditions. Knowledge of the specific molecular changes induced by this epidrug is an important area of neuro-epigenetics for the identification of new compounds to treat cognition impairment and/or epilepsy. In this review, we summarize the findings obtained in cellular and animal models of various brain disorders, highlighting the multiple mechanisms activated by SAHA, such as improvement of memory, learning and behavior, and correction of faulty neuronal functioning. Supporting this evidence, <i>in vitro</i> and <i>in vivo</i> data underline how SAHA positively regulates the expression of neuronal genes and microtubule dynamics, induces neurite outgrowth and spine density, and enhances synaptic transmission and potentiation. In particular, we outline studies regarding neurodevelopmental disorders with pharmaco-resistant seizures and/or severe cognitive impairment that to date lack effective drug treatments in which SAHA could ameliorate defective neuroplasticity.