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Cancer cells change phenotype through cancer evolution; some phenotype changes are caused by underlying genetic mutations, but many are due to non-genetic mechanisms. We suggest separating non-genetic phenotype changes into two distinct mechanisms: changes induced by microenvironmental stimuli (that we term 'phenotypic plasticity') and changes induced by stochastic cell-intrinsic effects (that we term 'phenotypic noise'). We discuss how lineage tracing methods – either experimental or those that make use of sporadic mutations to mark lineages – can be used to distinguish between phenotypic plasticity and noise. Distinguishing between phenotypic plasticity and noise guides mechanistic work to determine the molecular causes of phenotype change, and will ultimately accelerate efforts to control or prevent phenotype changes that enable cancer cells to resist therapies. Non-genetic alterations can produce changes in a cell's phenotype. In cancer, these phenomena can influence a cell's fitness by conferring access to heritable, beneficial phenotypes. Herein, we argue that current discussions of 'phenotypic plasticity' in cancer evolution ignore a salient feature of the original definition: namely, that it occurs in response to an environmental change. We suggest 'phenotypic noise' be used to distinguish non-genetic changes in phenotype that occur independently from the environment. We discuss the conceptual and methodological techniques used to identify these phenomena during cancer evolution. We propose that the distinction will guide efforts to define mechanisms of phenotype change, accelerate translational work to manipulate phenotypes through treatment, and, ultimately, improve patient outcomes. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to compare the histological outcomes of three distinct de-epithelialization methods used in (connective tissue grafts) CTG harvested from the palate. Materials and methods: An experimental study using nine cadaver head specimens was carried out to compare 3 different de-epithelialization techniques for CTG. Eighteen samples were randomly allocated to three study groups: bone scraper, diamond bur and extraoral removal with a scalpel. The main outcome variable was the graft surface percentage without epithelium remains. Additionally, the time employed, and the graft thickness were also measured. Results: Sixteen CTGs were analyzed. The extraoral scalpel group presented a total surface area with no epithelium of 58.84% (22.68) and a mean de-epithelialization time of 3.7 min; the intraoral diamond bur group had 88.24% (41.3) of the surface with no epithelium and took 1.455 min, and the intraoral bone scraper showed 97.98% (5.99) of surface without epithelium and a mean time of 0.815 min (P < 0.05). Histological analysis showed significant differences between the bone scraper and the extraoral group (P = 0.009). Conclusion: The de-epithelialization technique with a bone scraper seems to be the most effective and fastest de-epithelialization technique for CTG. These findings need to be confirmed in future clinical studies with larger samples. Clinical relevance: The use of bone scrapers, could be a simple, effective and fast technique to de-epithelialize connective tissue grafts harvested from the palatal area for both novice and experienced surgeons. [ABSTRACT FROM AUTHOR]

Dispersal is critical to population persistence, colonization and connectivity which are all critical components of invasive success. While individual propensity to disperse varies within populations, the underlying mechanisms promoting individual dispersal remain unclear. Collectively, dispersal is influenced by the environment and individual phenotype. Here we investigated individual dispersal propensity in the Trinidadian guppy, Poecilia reticulata , and related individual variation in dispersal behaviour to phenotype and social/environmental conditions. Namely, we addressed the effect of sex ratio (social/environmental factor) on the tendency for individuals to disperse across physical barriers via jumping behaviour. Jumping is vital for the dispersal of many aquatic species and has been anecdotally linked to the guppy's global invasive success. We found similar jumping behaviour for males and females, with population sex ratio not influencing the magnitude of male or female dispersal. Further, we found consistent among-individual variation in jumping probability; individual differences explained 17.46% and 7.92% of total variation in jumping probability for males and females, respectively. These results strongly indicate that sex ratio does not influence jumping behaviour, suggesting that species invasions are mediated by a nonrandom subset of individuals with greater dispersal tendencies. Overall, this study stresses the need to move the focus of invasion biology from the species level to incorporate information on individual variation in behaviour. • Guppies differ in individual propensity to disperse over physical barriers. • Sex ratio does not influence jumping behaviour. • Species invasions are mediated by individuals with greater dispersal tendencies. [ABSTRACT FROM AUTHOR]

In the era of precision medicine, accurate disease phenotype prediction for heterogeneous diseases, such as cancer, is emerging due to advanced technologies that link genotypes and phenotypes. However, it is difficult to integrate different types of biological data because they are so varied. In this study, we focused on predicting the traits of a blood cancer called Acute Myeloid Leukemia (AML) by combining different kinds of biological data. We used a recently developed method called Omics Generative Adversarial Network (GAN) to better classify cancer outcomes. The primary advantages of a GAN include its ability to create synthetic data that is nearly indistinguishable from real data, its high flexibility, and its wide range of applications, including multi-omics data analysis. In addition, the GAN was effective at combining two types of biological data. We created synthetic datasets for gene activity and DNA methylation. Our method was more accurate in predicting disease traits than using the original data alone. The experimental results provided evidence that the creation of synthetic data through interacting multi-omics data analysis using GANs improves the overall prediction quality. Furthermore, we identified the top-ranked significant genes through statistical methods and pinpointed potential candidate drug agents through in-silico studies. The proposed drugs, also supported by other independent studies, might play a crucial role in the treatment of AML cancer. The code is available on GitHub; https://github.com/SabrinAfroz/omicsGAN_codes?fbclid=IwAR1-/stuffmlE0hyWgSu2wlXo6dYlKUei3faLdlvpxTOOUPVlmYCloXf4Uk9ejK4I • Proposing a Generative Adversarial Network (GAN) to classify cancer outcomes more accurately. • Generated synthetic datasets for gene expression and DNA methylation. • Identified potential candidate drug agents through in-silico studies. • The proposed drugs might play a vital role in the treatment of AML cancer. [ABSTRACT FROM AUTHOR]

Vibrio harveyi is commonly found in salt and brackish water and is recognized as a serious bacterial pathogen in aquaculture worldwide. In this study, we cloned the ferric uptake regulator (fur) gene from V. harveyi wild‐type strain HA_1, which was isolated from diseased American eels (Anguilla rostrata) and has a length of 450 bp, encoding 149 amino acids. Then, a mutant strain, HA_1‐Δfur, was constructed through homologous recombination of a suicide plasmid (pCVD442). The HA_1‐Δfur mutant exhibited weaker biofilm formation and swarming motility, and 18‐fold decrease (5.5%) in virulence to the American eels; compared to the wild‐type strain, the mutant strain showed time and diameter differences in growth and haemolysis, respectively. Additionally, the adhesion ability of the mutant strain was significantly decreased. Moreover, there were 15 different biochemical indicators observed between the two strains. Transcriptome analysis revealed that 875 genes were differentially expressed in the Δfur mutant, with 385 up‐regulated and 490 down‐regulated DEGs. GO and KEGG enrichment analysis revealed that, compared to the wild‐type strain, the type II and type VI secretion systems (T2SS and T6SS), amino acid synthesis and transport and energy metabolism pathways were significantly down‐regulated, but the ABC transporters and biosynthesis of siderophore group non‐ribosomal peptides pathways were up‐regulated in the Δfur strain. The qRT‐PCR results further confirmed that DEGs responsible for amino acid transport and energy metabolism were positively regulated, but DEGs involved in iron acquisition were negatively regulated in the Δfur strain. These findings suggest that the virulence of the Δfur strain was significantly decreased, which is closely related to phenotype changing and gene transcript regulation. [ABSTRACT FROM AUTHOR]

While DNA serves as the fundamental genetic blueprint for an organism, it is not a static entity. Gene expression, the process by which genetic information is utilized to create functional products like proteins, can be modulated by a diverse range of environmental factors. Epigenetic mechanisms, including DNA methylation, histone modification, and microRNAs, play a pivotal role in mediating the intricate interplay between the environment and gene expression. Intriguingly, alterations in the epigenome have the potential to be inherited across generations. Alcohol use disorder (AUD) poses significant health issues worldwide. Alcohol has the capability to induce changes in the epigenome, which can be inherited by offspring, thus impacting them even in the absence of direct alcohol exposure. This review delves into the impact of alcohol on the epigenome, examining how its effects vary based on factors such as the age of exposure (adolescence or adulthood), the duration of exposure (chronic or acute), and the specific sample collected (brain, blood, or sperm). The literature underscores that alcohol exposure can elicit diverse effects on the epigenome during different life stages. Furthermore, compelling evidence from human and animal studies demonstrates that alcohol induces alterations in epigenome content, affecting both the brain and blood. Notably, rodent studies suggest that these epigenetic changes can result in lasting phenotype alterations that extend across at least two generations. In conclusion, the comprehensive literature analysis supports the notion that alcohol exposure induces lasting epigenetic alterations, influencing the behavior and health of future generations. This knowledge emphasizes the significance of addressing the potential transgenerational effects of alcohol and highlights the importance of preventive measures to minimize the adverse impact on offspring. [Display omitted] • Chronic ethanol consumption alters the epigenome, such as DNA methylation. • Ethanol consumption before gestation affects offspring. • Ethanol alters behavior in offspring who were not prenatally exposed. [ABSTRACT FROM AUTHOR]

Absorptive hypercalciuria (AH) is a prevalent cause of kidney stones, and the adenylate cyclase 10 (ADCY10) gene is a rare causative gene of AH. This study aims to investigate the genotypic and phenotypic characteristics of patients with AH caused by ADCY10 gene mutations. Whole-exome sequencing and Sanger sequencing were performed on the probands and their family members, respectively. Clinical and genetic data of patients with AH caused by ADCY10 gene mutations were collected and analysed retrospectively from the present study and published literature. Two female patients (6 years old and 1 year old) with multiple bilateral kidney stones were found to have a heterozygous c.3304T>C mutation and a heterozygous c.1726C>T mutation in the ADCY10 gene. Urinary metabolite analysis revealed that urine calcium / creatinine ratios were 0.95 mmol/mmol and 1.61 mmol/mmol, respectively. Both patients underwent thiazide intake postoperatively, and upon reexamination, urine calcium decreased to within the normal range. A total of 61 patients with AH were reported from previous and present studies. The sex ratio was 7:5 for males to females, and the mean age of onset was 23.61±20.08 years. A total of 16 ADCY10 gene mutations were identified, including seven missense (43.75%), five splicing (31.25%), two frameshift (12.50%) and two nonsense mutations (12.50%). Only two cases were identified as homozygous mutations (c.1205_1206del), and the others were heterozygous mutations. In summary, we identified two novel ADCY10 gene candidate pathogenic variants in Chinese pediatric patients, which expands the mutational spectrum of the ADCY10 gene and provides a potential diagnostic and therapeutic target. [ABSTRACT FROM AUTHOR]

Background: The Rh blood group system is characterized by its complexity and polymorphism, encompassing 56 different antigens. Accurately predicting the presence of the C antigen using genotyping methods has been challenging. The objective of this study was to evaluate the accuracy of various genotyping methods for predicting the Rh C and to identify a suitable method for the Chinese Han population. Methods: In total, 317 donors, consisting 223 D+ (including 20 with the Del phenotype) and 94 D− were randomly selected. For RHC genotyping, 48C and 109bp insertion were detected on the Real-time PCR platform and −292 substitution was analyzed via restriction fragment length polymorphism (RFLP). Moreover, the promoter region of the RHCE gene was sequenced to search for other nucleotide substitutions between RHC and RHc. Agreement between prediction methods was evaluated using the Kappa statistic, and comparisons between methods were conducted via the χ2 test. Results: The analysis revealed that the 48C allele, 109bp insertion, a specific pattern observed in RFLP results, and wild-type alleles of seven single nucleotide polymorphisms (SNPs) were in strong agreement with the Rh C, with Kappa coefficients exceeding 0.8. However, there were instances of false positives or false negatives (0.6% false negative rate for 109bp insertion and 5.4-8.2% false positive rates for other methods). The 109bp insertion method exhibited the highest accuracy in predicting the Rh C, at 99.4%, compared to other methods (P values≤0.001). Although no statistical differences were found among other methods for predicting Rh C (P values>0.05), the accuracies in descending order were 48C (94.6%) > rs586178 (92.7%) > rs4649082, rs2375313, rs2281179, rs2072933, rs2072932, and RFLP (92.4%) > rs2072931 (91.8%). Conclusions: None of the methods examined can independently and accurately predict the Rh C. However, the 109bp insertion test demonstrated the highest accuracy for predicting the Rh C in the Chinese Han population. Utilizing the 109bp insertion test in combination with other methods may enhance the accuracy of Rh C prediction. [ABSTRACT FROM AUTHOR]

AbstractAsthma is a heterogeneous disease with multiple phenotypes that have variable risk factors and therapeutic responses. Airway hyperreactivity, inflammation and airway remodeling are hallmarks of asthma. Asthmatics exhibiting an increase in airway T2 inflammation is now classify as having T2-“high” asthma. Type 2 cytokines, IL-4, IL-5, and IL-13, along with other inflammatory mediators, lead to increased eosinophilic inflammation along with elevated FeNO in this endotype. There is no clear definition for T2-“low” asthma. Biomarkers can help identify different phenotypes and endotypes, treatment response to standard treatment or potential therapeutic targets particularly for biologics. As our knowledge of phenotypes and endotypes improved, biologics have increasingly integrated into treatment strategies for severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers may help to identify subsets of patients who will benefit from these treatments. However, only a few inflammatory biomarkers have validated for clinical application. As knowledge emerges, the goal would be to provide individualized care to asthmatic patients. [ABSTRACT FROM AUTHOR]

Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. CSS can easily be misdiagnosed as other syndromes or disorders with a similar clinical picture because of their genetic and phenotypic heterogeneity. We describde the genotype-phenotype correlation of one patient from a healthy Chinese family with a novel genotype underlying CSS, who was first diagnosed in the ophthalmology department as early-onset high myopia (eoHM). Comprehensive ophthalmic tests as well as other systemic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. Real-time quantitative PCR (RT-qPCR) technology was used to detect the relative mRNA expression levels of candidate genes between proband and normal family members. The pathogenicity of the identified variant was determined by The American College of Medical Genetics and Genomics (ACMG) guidelines. STRING protein-protein interactions (PPIs) network analysis was used to detect the interaction of candidate gene-related proteins with high myopia gene-related proteins. The patient had excessive eoHM, cone-rod dystrophy, coarse face, excessive hair growth on the face, sparse scalp hair, developmental delay, intellectual disability, moderate hearing loss, dental hypoplasia, patent foramen ovale, chronic non-atrophic gastritis, bilateral renal cysts, cisterna magna, and emotional outbursts with aggression. The genetic assessment revealed that the patient carries a de novo heterozygous frameshift insertion variant in the ARID1B c.3981dup (p.Glu1328ArgfsTer5), which are strongly associated with the typical clinical features of CSS patients. The test results of RT-qPCR showed that mRNA expression of the ARID1B gene in the proband was approximately 30% lower than that of the normal control in the family, suggesting that the variant had an impact on the gene function at the level of mRNA expression. The variant was pathogenic as assessed by ACMG guidelines. Analysis of protein interactions in the STRING online database revealed that the ARID1A protein interacts with the high myopia gene-related proteins FGFR3, ASXL1, ERBB3, and SOX4, whereas the ARID1A protein antagonizes the ARID1B protein. Therefore, in this paper, we are the first to report a de novo heterozygous frameshift insertion variant in the ARID1B gene causing CSS with excessive eoHM. Our study extends the genotypic and phenotypic spectrums for ARID1B-CSS and supplies evidence of significant association of eoHM with variant in ARID1B gene. As CSS has high genetic and phenotypic heterogeneity, our findings highlight the importance of molecular genetic testing and an interdisciplinary clinical diagnostic workup to avoid misdiagnosis as some disorders with similar manifestations of CSS. [ABSTRACT FROM AUTHOR]

As links between genotype and phenotype, small-molecule metabolites are attractive biomarkers for disease diagnosis, prognosis, classification, drug screening and treatment, insight into understanding disease pathology and identifying potential targets. Metabolomics technology is crucial for discovering targets of small-molecule metabolites involved in disease phenotype. Mass spectrometry-based metabolomics has implemented in applications in various fields including target discovery, explanation of disease mechanisms and compound screening. It is used to analyze the physiological or pathological states of the organism by investigating the changes in endogenous small-molecule metabolites and associated metabolism from complex metabolic pathways in biological samples. The present review provides a critical update of high-throughput functional metabolomics techniques and diverse applications, and recommends the use of mass spectrometry-based metabolomics for discovering small-molecule metabolite signatures that provide valuable insights into metabolic targets. We also recommend using mass spectrometry-based metabolomics as a powerful tool for identifying and understanding metabolic patterns, metabolic targets and for efficacy evaluation of herbal medicine. [ABSTRACT FROM AUTHOR]

Background: Macrophages are key inflammatory immune cells that orchestrate the initiation and progression of autoimmune diseases. The characters of macrophage in diseases are determined by its phenotype in response to the local microenvironment. Ficolins have been confirmed as crucial contributors to autoimmune diseases, with Ficolin-2 being particularly elevated in patients with autoimmune diseases. However, whether Ficolin-A stimulates macrophage polarization is still poorly understood. Methods: We investigated the transcriptomic expression profile of murine bone marrow-derived macrophages (BMDMs) stimulated with Ficolin-A using RNA-sequencing. To further confirm a distinct phenotype activated by Ficolin-A, quantitative RT-PCR and Luminex assay were performed in this study. Additionally, we assessed the activation of underlying cell signaling pathways triggered by Ficolin-A. Finally, the impact of Ficolin-A on macrophages were investigated in vivo through building Collagen-induced arthritis (CIA) and Dextran Sulfate Sodium Salt (DSS)-induced colitis mouse models with Fcna-/- mice. Results: Ficolin-A activated macrophages into a pro-inflammatory phenotype distinct to LPS-, IFN-γ- and IFN-γ + LPS-induced phenotypes. The transcriptomic profile induced by Ficolin-A was primarily characterized by upregulation of interleukins, chemokines, iNOS, and Arginase 1, along with downregulation of CD86 and CD206, setting it apart from the M1 and M2 phenotypes. The activation effect of Ficolin-A on macrophages deteriorated the symptoms of CIA and DSS mouse models, and the deletion of Fcna significantly alleviated the severity of diseases in mice. Conclusion: Our work used transcriptomic analysis by RNA-Seq to investigate the impact of Ficolin-A on macrophage polarization. Our findings demonstrate that Ficolin-A induces a novel pro-inflammatory phenotype distinct to the phenotypes activated by LPS, IFN-γ and IFN-γ + LPS on macrophages. [ABSTRACT FROM AUTHOR]

Cats with a distinctive white hair pattern of unknown molecular cause have been discovered in the Finnish domestic cat population. Based on the unique appearance of these cats, we have named this phenotype salmiak (“salty licorice”). The use of a commercially available panel test to genotype four salmiak‐colored cats revealed the absence of all known variants associated with white‐haired phenotypic loci: full White (W), Spotting (Ws) and the Birman white Gloves associated (wg) allele of the KIT proto‐oncogene (KIT) gene. Whole‐genome sequencing on two salmiak‐colored cats was conducted to search for candidate causal variants in the KIT gene. Despite a lack of coding variants, visual inspection of the short read alignments revealed a large ~95 kb deletion located ~65 kb downstream of the KIT gene in the salmiak cats. Additional PCR genotyping of 180 domestic cats and three salmiak‐colored cats confirmed the homozygous derived variant genotype fully concordant with the salmiak phenotype. We suggest the newly identified variant be designated as wsal for “w salmiak”. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusions Mutations in ganglioside‐induced differentiation‐associated protein 1 (GDAP1) cause axonal or demyelinating Charcot–Marie–Tooth disease (CMT) with autosomal dominant or recessive inheritance. In this study, we aim to report the genotypic and phenotypic features of GDAP1‐related CMT in a Chinese cohort.Clinical, neurophysiological, genetic data, and available muscle/brain imaging information of 28 CMT patients with GDAP1 variants were retrospectively collected.We identified 16 GDAP1 pathogenic variants, among which two novel variants c.980dup(p.L328FfsX25) and c.480+4T>G were first reported. Most patients (16/28) presented with AR or AD CMT2K phenotype. Clinical characteristics in our cohort demonstrated that the AR patients presented earlier onset, more severe phenotype compared with the AD patients. Considerable intra‐familial phenotypic variability was observed among three AD families. Muscle atrophy and fatty infiltration in the lower extremity were detected by Muscle magnetic resonance imaging (MRI) scans in four patients. MRI showed two AR patients showed more severe muscle involvement of the posterior compartment than those of the anterolateral compartment in the calf. One patient carrying Q38*/H256R variants accompanied with mild periventricular leukoaraiosis.In this study, we conducted an analysis of clinical features of the GDAP1‐related CMT patients, expanded the mutation spectrum in GDAP1 by reporting two novel variants, and presented the prevalent occurrence of the H256R mutation in China. The screening of GDAP1 should be particularly emphasized in Chinese patients with CMT2, given the incomplete penetrance and pathogenic inheritance patterns involving dominant and recessive modes. [ABSTRACT FROM AUTHOR]

Background: Astragalus membranaceus var. mongholicus (Astragalus), acknowledged as a pivotal "One Root of Medicine and Food", boasts dual applications in both culinary and medicinal domains. The growth and metabolite accumulation of medicinal roots during the harvest period is intricately regulated by a transcriptional regulatory network. One key challenge is to accurately pinpoint the harvest date during the transition from conventional yield content of medicinal materials to high and to identify the core regulators governing such a critical transition. To solve this problem, we performed a correlation analysis of phenotypic, transcriptome, and metabolome dynamics during the harvesting of Astragalus roots. Results: First, our analysis identified stage-specific expression patterns for a significant proportion of the Astragalus root genes and unraveled the chronology of events that happen at the early and later stages of root harvest. Then, the results showed that different root developmental stages can be depicted by co-expressed genes of Astragalus. Moreover, we identified the key components and transcriptional regulation processes that determine root development during harvest. Furthermore, through correlating phenotypes, transcriptomes, and metabolomes at different harvesting periods, period D (Nov.6) was identified as the critical period of yield and flavonoid content increase, which is consistent with morphological and metabolic changes. In particular, we identified a flavonoid biosynthesis metabolite, isoliquiritigenin, as a core regulator of the synthesis of associated secondary metabolites in Astragalus. Further analyses and experiments showed that HMGCR, 4CL, CHS, and SQLE, along with its associated differentially expressed genes, induced conversion of metabolism processes, including the biosynthesis of isoflavones and triterpenoid saponins substances, thus leading to the transition to higher medicinal materials yield and active ingredient content. Conclusions: The findings of this work will clarify the differences in the biosynthetic mechanism of astragaloside IV and calycosin 7-O-β-D-glucopyranoside accumulation between the four harvesting periods, which will guide the harvesting and production of Astragalus. [ABSTRACT FROM AUTHOR]

A new variant of Methanothermobacter wolfeii was isolated from an anaerobic digester using enrichment cultivation in anaerobic conditions. The new isolate was taxonomically identified via 16S rRNA gene sequencing and tagged as M. wolfeii BSEL. The whole genome of the new variant was sequenced and de novo assembled. Genomic variations between the BSEL strain and the type strain were discovered, suggesting evolutionary adaptations of the BSEL strain that conferred advantages while growing under a low concentration of nutrients. M. wolfeii BSEL displayed the highest specific growth rate ever reported for the wolfeii species (0.27 ± 0.03 h-1) using carbon dioxide (CO2) as unique carbon source and hydrogen (H2) as electron donor. M. wolfeii BSEL grew at this rate in an environment with ammonium (NH4+) as sole nitrogen source. The minerals content required to cultivate the BSEL strain was relatively low and resembled the ionic background of tap water without mineral supplements. Optimum growth rate for the new isolate was observed at 64°C and pH 8.3. In this work, it was shown that wastewater from a wastewater treatment facility can be used as a low-cost alternative medium to cultivate M. wolfeii BSEL. Continuous gas fermentation fed with a synthetic biogas mimic along with H2 in a bubble column bioreactor using M. wolfeii BSEL as biocatalyst resulted in a CO2 conversion efficiency of 97% and a final methane (CH4) titer of 98.5%v, demonstrating the ability of the new strain for upgrading biogas to renewable natural gas. [ABSTRACT FROM AUTHOR]

Polygenetic Risk Scores are used to evaluate an individual's vulnerability to developing specific diseases or conditions based on their genetic composition, by taking into account numerous genetic variations. This article provides an overview of the concept of Polygenic Risk Scores (PRS). We elucidate the historical advancements of PRS, their advantages and shortcomings in comparison with other predictive methods, and discuss their conceptual limitations in light of the complexity of biological systems. Furthermore, we provide a survey of published tools for computing PRS and associated resources. The various tools and software packages are categorized based on their technical utility for users or prospective developers. Understanding the array of available tools and their limitations is crucial for accurately assessing and predicting disease risks, facilitating early interventions, and guiding personalized healthcare decisions. Additionally, we also identify potential new avenues for future bioinformatic analyzes and advancements related to PRS. [ABSTRACT FROM AUTHOR]

Background: For patients with weak or discrepant RhD RBC phenotypes, RHD genotyping is employed to determine need for RhD‐negative management. However, many RHD variants are type D‐negative or D‐positive. Serological recognition rates (RRs) of weak and partial RHD variants are poorly characterized. Study Design and Methods: Four US studies employing RHD genotyping for weak or discrepant RhD phenotypes provided data for race/ethnicity‐specific serological recognition. Three studies used microplate, and 1 used gel and tube; 2 had anti‐D data. We obtained White and Hispanic/Latino allele frequencies (AFs) of weak D types 1, 2, and 3 single‐nucleotide variants (SNVs) from the Genome Aggregation Database (gnomAD, v4.0.0) and devised Hardy–Weinberg‐based formulas to correct for gnomAD's overcount of hemizygous RHD SNVs as homozygous. We compiled common partial RHD AF from genotyped cohorts of US Black or sickle cell disease subjects. From variant AF, we calculated hemizygous‐plus‐homozygous genetic prevalences. Serological prevalence: genetic prevalence ratios yielded serological RRs. Results: Overall RRs of weak D types 1–3 were 17% (95% confidence interval 12%–24%) in Whites and 12% (5%–27%) in Hispanics/Latinos. For eight partial RHD variants in Blacks, overall RR was 11% (8%–14%). However, DAR RR was 80% (38%–156%). Compared to microplate, gel–tube recognition was higher for type 2 and DAU5 and lower for type 4.0. Anti‐D was present in 6% of recognized partial RHD cases, but only in 0.7% of estimated total genetic cases. Discussion: Based on AF, >80% of patients with weak or partial RHD variants were unrecognized serologically. Although overall anti‐D rates were low, better detection of partial RHD variants is desirable. [ABSTRACT FROM AUTHOR]

Background: Decades following the introduction of vincristine as treatment for haematological malignancies, vincristine-induced peripheral neuropathy (VIPN) remains a pervasive, untreatable side-effect. However there remains a gap in understanding the characteristics of VIPN in adults. This study presents a comprehensive phenotyping of VIPN. Methods: Adult patients (n = 57; age = 59.8 ± 14.6) were assessed cross-sectionally following completion of vincristine (months post treatment = 16.3 ± 15.6, cumulative dose = 7.6 ± 4.4), with a subset of 20 patients assessed prospectively during treatment. Patient reported measures (EORTC-QLQ-CIPN20, R-ODS) were used to profile symptoms and disability. Neurological assessment was undertaken using the Total Neuropathy Score and nerve conduction studies. Sensory threshold and fine motor tasks were also undertaken. Comparisons of data between timepoints were calculated using paired-sample t tests or Wilcoxon matched-pairs signed-rank test. Comparisons between outcome measures were calculated with independent sample t tests or Mann–Whitney U tests for non-parametric data. Results: The majority of patients developed VIPN by mid-treatment (77.8%, 7.0 ± 3.3 weeks post baseline) with the prevalence remaining stable by end-of-treatment (75%, 8.1 ± 1.7 weeks post mid-treatment). By 3 months post-completion, 50% of patients still reported VIPN although there were significant improvements on neurological grading and functional assessment (P < 0.05). VIPN presented with sensorimotor involvement in upper and lower limbs and was associated with decreased sensory and motor nerve amplitudes, reduced fine-motor function and increased disability. Conclusion: VIPN in adults presents as a sensorimotor, upper- and lower-limb neuropathy that significantly impacts disability and function. Neuropathy recovery occurs in a proportion of patients; however, VIPN symptoms may persist and continue to affect long-term quality of life. [ABSTRACT FROM AUTHOR]

Loss-of-function mutation of ABCC9 , the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9 -related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction. [ABSTRACT FROM AUTHOR]

RFC1 disease, caused by biallelic repeat expansion in RFC1 , is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson's coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I–V β = −1.06, P < 0.001; lobules VI–VII β = −0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion. [ABSTRACT FROM AUTHOR]

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1 – GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally. Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function or gain-of-function properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 patients (from 23 families) harbouring 17 of these variants. All patients had global developmental impairment, mostly moderate (9/25) or severe (12/25). Twelve patients had seizures, including focal motor (6/12), unknown onset motor (4/12), focal impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12) and generalized tonic-clonic (1/12) or atonic (1/12) seizures. The epilepsy syndrome was classified as developmental and epileptic encephalopathy in eight patients, developmental encephalopathy without seizures in 13 patients, and intellectual disability with epilepsy in four patients. Limb muscular hypotonia was reported in 13/25, and hypertonia in 10/25. Movement disorders were reported in 14/25, with hyperekplexia or non-epileptic erratic myoclonus being the most prevalent feature (8/25). Correlating receptor functional phenotype with clinical features revealed clinical features for GRIA3 -associated NDDs and distinct NDD phenotypes for loss-of-function and gain-of-function variants. Gain-of-function variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age: 1 month), hypertonic and more often had movement disorders, including hyperekplexia. Patients with loss-of-function variants were older at the time of seizure onset (median age: 16 months), hypotonic and had sleeping disturbances. Loss-of-function and gain-of-function variants were disease-causing in both sexes but affected males often carried de novo or hemizygous loss-of-function variants inherited from healthy mothers, whereas affected females had mostly de novo heterozygous gain-of-function variants. [ABSTRACT FROM AUTHOR]

Polyploid organisms are common and can be found across the tree of life. A key question is to understand how and why these polyploid lineages become established and persist in populations, particularly since they are predicted to have a low probability of success. While the collection of papers in this special issue addresses broad questions on the evolutionary ecology of polyploids, ultimately, these studies also highlight the myriad ways that we are examining what drives the success of polyploid lineages. In this paper we consider where we've been and the challenges that we face, and then propose several directions that will allow us to continue to propel the field towards our ultimate goal of understanding the rules that govern the establishment and persistence of polyploid populations. We conclude that developing this rule set will require a combination of model systems for which we have detailed knowledge of the phylogenetic and population genetic history, expanding our perspective beyond plants to include greater taxonomic breadth, and conducting studies in ecologically relevant settings. Additionally, we argue that future research on the evolutionary ecology of polyploidy should focus on integrating theory and empirical research, providing mechanistic linkages between the effects of whole genome duplication and population demography, and build a predictive framework to understand how anthropogenic change will impact polyploid organisms. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to analyse clinical and radiological features (phenotypes) to predict revision risk after functional endoscopic sinus surgery in patients with chronic rhinosinusitis with nasal polyps. Method: Phenotype characteristics of the patients with chronic rhinosinusitis with nasal polyps who underwent functional endoscopic sinus surgery were analysed retrospectively. Results: The rates of asthma, aspirin sensitivity, smoking and a positive prick test result were significantly higher in revision functional endoscopic sinus surgery cases (p < 0.001, 0.001, < 0.001 and < 0.001, respectively). Multivariate analysis demonstrated that only gender, pre-operative nasal steroid use, pre-operative systemic steroid use, intra-operative systemic steroid use and smoking were significant risk factors for revision functional endoscopic sinus surgery (p = 0.034, 0.001, 0.010, 0.007 and 0.001, respectively). In addition, only eosinophilia and aspirin sensitivity were significant risk factors for multiple revision functional endoscopic sinus surgery procedures (p = 0.043 and 0.005, odds ratio = 2.4 and 5.2). Conclusion: Beyond the endotype of chronic rhinosinusitis with nasal polyps, defining clinical and radiological factors enables a valid prediction of patients at high risk of revision functional endoscopic sinus surgery. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the distribution of coronal plane alignment of the knee (CPAK) classification and functional knee phenotypes in a Chinese osteoarthritis (OA) population and to compare different lower limb alignment targets according to the distribution characteristics to find suitable total knee arthroplasty (TKA) bone cut strategies for the Chinese OA patients. Methods: The computed tomography (CT) images were retrospectively collected and the three‐dimensional (3D) models were reconstructed from 434 Chinese OA patients, including 93 males and 341 females, with a mean age of 66.4 ± 9.3 years. Femoral mechanical angle (FMA), tibial mechanical angle (TMA) and mechanical hip–knee–ankle angle (mHKA) were measured on the 3D models. Arithmetic hip–knee–ankle angle (aHKA) was calculated using FMA plus TMA, and joint line obliquity was calculated as 180 + TMA–FMA. The CPAK according to MacDessi and the functional knee phenotypes according to Hirschmann were performed. In addition, the suitable TKA bone cut strategies were explored according to the phenotypes and based on the characteristics of different alignment targets, such as mechanical alignment, anatomic alignment (AA), kinematic alignment, restricted KA (rKA) and adjusted MA (aMA). Statistical differences were determined using the independent‐samples t‐test or the two independent‐samples Wilcoxon test, with p < 0.05 considered statistically significant. Results: The Chinese OA population showed a varus alignment tendency (mHKA = 172.1° ± 7.2°), to which the TMA was a major contributor (TMA = 84.7° ± 4.4° vs. FMA = 91.3° ± 3.2°). The mHKA was on average 3.9° more varus than the aHKA. A total of 140 functional knee phenotypes were found and 45.6% were concentrated in VARFMA3°–NEUFMA0° to VARTMA3°–NEUTMA0°. More than 70% of patients had different FMA and TMA phenotypes. There were 92.9% of CPAK distributed in types I to IV, with type I accounting for 53.9%. The FMA phenotypes were less changed if the aMA and rKA were chosen, and the TMA phenotypes were less changed if the AA and rKA were chosen. Conclusion: Compared with the CPAK, the functional knee phenotypes were more suitable for the Chinese OA population with a wide distribution and a varus tendency, and it seemed more appropriate to choose aMA and rKA as TKA alignment targets for resection. Level of Evidence: Level Ⅲ. [ABSTRACT FROM AUTHOR]

Background: The metabolically healthy obese (MHO) phenotype is associated with an increased risk of coronary heart disease (CHD) in the general population. However, association of metabolic health and obesity phenotypes with CHD risk in adult cancer survivors remains unclear. We aimed to investigate the associations between different metabolic health and obesity phenotypes with incident CHD in adult cancer survivors. Methods: We used National Health Insurance Service (NHIS) to identify a cohort of 173,951 adult cancer survivors aged more than 20 years free of cardiovascular complications. Metabolically healthy nonobese (MHN), MHO, metabolically unhealthy nonobese (MUN), metabolically unhealthy obese (MUO) phenotypes were created using as at least three out of five metabolic health criteria along with obesity (body mass index ≥ 25.0 kg/m2). We used Cox proportional hazards model to assess CHD risk in each metabolic health and obesity phenotypes. Results: During 1,376,050 person‐years of follow‐up, adult cancer survivors with MHO phenotype had a significantly higher risk of CHD (hazard ratio [HR] = 1.52; 95% confidence intervals [CI]: 1.41 to 1.65) as compared to those without obesity and metabolic abnormalities. MUN (HR = 1.81; 95% CI: 1.59 to 2.06) and MUO (HR = 1.92; 95% CI: 1.72 to 2.15) phenotypes were also associated with an increased risk of CHD among adult cancer survivors. Conclusions: Adult cancer survivors with MHO phenotype had a higher risk of CHD than those who are MHN. Metabolic health status and obesity were jointly associated with CHD risk in adult cancer survivors. [ABSTRACT FROM AUTHOR]

Beckwith–Wiedemann syndrome (BWS) is an epigenetic overgrowth syndrome. Despite its distinctive growth pattern, the detailed growth trajectories of children with BWS remain largely unknown. We retrospectively analyzed 413 anthropometric measurements over an average of 4.4 years of follow‐up in 51 children with BWS. We constructed sex‐specific percentile curves for height, weight, and head circumference using a generalized additive model for location, scale, and shape. Males with BWS exhibited greater height at all ages evaluated, weight before the age of 10, and head circumference before the age of 9 than those of the general population. Females with BWS showed greater height before the age of 7, weight before the age of 4.5, and head circumference before the age of 7 than those of the general population. At the latest follow‐up visit at a mean 8.4 years of age, bone age was significantly higher than chronological age. Compared to paternal uniparental disomy (pUPD), males with imprinting center region 2‐loss of methylation (IC2‐LOM) had higher standard deviation score (SDS) for height and weight, while females with IC2‐LOM showed larger SDS for head circumference. These disease‐specific growth charts can serve as valuable tools for clinical monitoring of children with BWS. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) has a high prevalence and a major impact on health-related quality of life (HRQL). COPD exacerbations are an important cause of morbidity and mortality, affecting cardiovascular risk, and are associated with poorer health status. The aim of this study was to assess the association between cardiovascular risk (CVR) and HRQL, according to exacerbator or non-exacerbator phenotype. We undertook a cross-sectional, observational, descriptive study of 107 patients with COPD. Patients with two or more moderate exacerbations or one severe exacerbation in the previous year were considered as exacerbators. The CVR was calculated with the Framingham scale and SCORE (Systematic Coronary Risk Evaluation) and the HRQL was assessed with the generic questionnaire Short Form-36 Health Survey (SF-36), the St George Respiratory Questionnaire (SGRQ) and the COPD Assessment Test (CAT). Statistical analysis was done with SPSS version 26.0 for Windows. The SF-36 and the SGRQ showed lower values for the exacerbator phenotype, indicating a poorer quality of life. The CAT questionnaire showed values above 10 for the exacerbator phenotype, and lower values in the non-exacerbator group. After categorizing the sample according to their median age (65 years), we found a greater deterioration in HRQL in patients under 65 years of age according to the SF-36, the SGRQ and the CAT. We also detected differences in HRQL between non-exacerbator patients with a high CVR according to the Framingham (≥ 20%) and SCORE (≥ 5%) scales compared to those without this risk. A tendency towards worse HRQL was observed in non-exacerbator patients with a high CVR, which was statistically significant for the SGRQ impact domain on the SCORE scale. The CAT also showed a worse quality of life in non-exacerbator patients with a high CVR, which was significant in the Framingham model (Framingham high risk 8.41 vs non-high risk 6.05, p < 0.01). These differences were not observed in exacerbator patients. Our findings confirm that a high CVR influences HRQL in patients with COPD, especially in non-exacerbator patients with a high CVR, measured according to the SGRQ and the CAT. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Vascular smooth muscle cells (VSMCs) are commonly used as seed cells in tissue‐engineered vascular constructions. However, their variable phenotypes and difficult to control functions pose challenges. This study aimed to overcome these obstacles using a three‐dimensional culture system.Calf VSMCs were administered tumor necrosis factor‐alpha (TNF‐α) before culturing in two‐ and three‐dimensional well plates and polyglycolic acid (PGA) scaffolds, respectively. The phenotypic markers of VSMCs were detected by immunofluorescence staining and western blotting, and the proliferation and migration abilities of VSMCs were detected by CCK‐8, EDU, cell counting, scratch, and Transwell assays.TNF‐α rapidly decreased the contractile phenotypic markers and elevated the synthetic phenotypic markers of VSMCs, as well as markedly increasing the proliferation and migration ability of VSMCs under two‐ and three‐dimensional culture conditions.TNF‐α can rapidly induce a phenotypic shift in VSMCs and change their viability on PGA scaffolds. [ABSTRACT FROM AUTHOR]

The Ornate Moth, Utetheisa ornatrix, has served as a model species in chemical ecology studies for decades. Like in the widely publicized stories of the Monarch and other milkweed butterflies, the Ornate Moth and its relatives are tropical insects colonizing whole continents assisted by their chemical defenses. With the recent advances in genomic techniques and evo-devo research, it is becoming a model for studies in other areas, from wing pattern development to phylogeography, from toxicology to epigenetics. We used a genomic approach to learn about Utetheisa's evolution, detoxification, dispersal abilities, and wing pattern diversity. We present an evolutionary genomic analysis of the worldwide genus Utetheisa, then focusing on U. ornatrix. Our reference genome of U. ornatrix reveals gene duplications in the regions possibly associated with detoxification abilities, which allows them to feed on toxic food plants. Finally, comparative genomic analysis of over 100 U. ornatrix specimens from the museum with apparent differences in wing patterns suggest the potential roles of cortex and lim3 genes in wing pattern formation of Lepidoptera and the utility of museum-preserved collection specimens for wing pattern research. [ABSTRACT FROM AUTHOR]

Developmental delay (DD), or intellectual disability (ID) is a very large group of early onset disorders that affects 1–2% of children worldwide, which have diverse genetic causes that should be identified. Genetic studies can elucidate the pathogenesis underlying DD/ID. In this study, whole-exome sequencing (WES) was performed on 225 Chinese DD/ID children (208 cases were sequenced as proband-parent trio) who were classified into seven phenotype subgroups. The phenotype and genomic data of patients with DD/ID were further retrospectively analyzed. There were 96/225 (42.67%; 95% confidence interval [CI] 36.15–49.18%) patients were found to have causative single nucleotide variants (SNVs) and small insertions/deletions (Indels) associated with DD/ID based on WES data. The diagnostic yields among the seven subgroups ranged from 31.25 to 71.43%. Three specific clinical features, hearing loss, visual loss, and facial dysmorphism, can significantly increase the diagnostic yield of WES in patients with DD/ID (P = 0.005, P = 0.005, and P = 0.039, respectively). Of note, hearing loss (odds ratio [OR] = 1.86%; 95% CI = 1.00-3.46, P = 0.046) or abnormal brainstem auditory evoked potential (BAEP) (OR = 1.91, 95% CI = 1.02–3.50, P = 0.042) was independently associated with causative genetic variants in DD/ID children. Our findings enrich the variation spectrums of SNVs/Indels associated with DD/ID, highlight the value genetic testing for DD/ID children, stress the importance of BAEP screen in DD/ID children, and help to facilitate early diagnose, clinical management and reproductive decisions, improve therapeutic response to medical treatment. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine–metabolic disorder in women of reproductive age. Diagnosis is based on the evidence-based international guideline 2018 and the Rotterdam Consensus to classify PCOS phenotypes. This study aims to characterize the biodemographic, clinical, metabolic, and reproductive variables and their relationship with PCOS phenotypes in a population from the Ecuadorian Andes. Methodology: A cross-sectional study was conducted with a non-random consecutive sample of 92 women who attended the outpatient gynecology and endocrinology clinic at the Hospital of the Technical University of Loja (UTPL)—Santa Inés, Loja, Ecuador, between January 2022 and July 2023. Descriptive statistics, mean calculations, standard deviation, parametric and nonparametric tests, odds ratios (OR), confidence intervals (CI), and p-values were employed. Results: The average age was 22 ± 3.4 years, with a predominantly mestizo, urban, single, highly educated, and medium–high socioeconomic level population. It was identified that phenotypes A + B are at a higher risk of developing oligomenorrhea and hypertriglyceridemia compared to phenotypes C + D, with statistically significant differences (p < 0.05). Furthermore, in terms of reproductive variables, phenotypes A + B exhibit a significantly higher frequency of elevated anti-Müllerian hormone (AMH) compared to phenotypes C + D, also with statistical significance (p < 0.05). Conclusions: The classical phenotypes A and B of PCOS are the most common in Ecuadorian Andean women and carry a higher risk of insulin resistance, anovulation, metabolic disorders, and elevated triglyceride levels compared to phenotypes C and D. Ethnic diversity and sociocultural habits influence the prevalence and clinical manifestations of these phenotypes. [ABSTRACT FROM AUTHOR]

Background: Kenny–Caffey syndrome type 2 (KCS2) is an extremely rare inherited disorder characterized by proportionate short stature, skeletal defects, ocular and dental abnormalities, and transient hypocalcemia. It is caused by variants in FAM111A gene. Diagnosis of KCS2 can be challenging because of its similarities to other syndromes, the absence of clear hallmarks and the deficient number of genetically confirmed cases. Here, we aimed to further delineate and summarize the genotype and phenotype of KCS2, in order to get a better understanding of this rare disorder, and promote early diagnosis and intervention. Methods: We present clinical and genetic characteristics of eight newly affected individuals with KCS2 from six families, including one family with three individuals found to be a father‐to‐daughter transmission, adding to the limited literature. Furthermore, we performed a review of genetically confirmed KCS2 cases in PubMed, MEDLINE and CNKI databases. Results: There were six females and two males in our cohort. All the patients presented with short stature (100.0%). Clinical manifestations included ocular defects such as hypermetropia (5/8), dental problems such as defective dentition (3/8) and dental caries (3/8), skeletal and brain anomalies such as delayed closure of anterior fontanelle (6/8), cerebral calcification (3/8), cortical thickening (3/8) and medullary stenosis (4/8) of tubular bones. Endocrinologic abnormalities included hypoparathyroidism (5/8) and hypocalcemia (3/8). One male patient had micropenis and microorchidism. All cases harboured missense variants of FAM111A, and nucleotides c.1706 arose as a mutational hotspot, with seven individuals harbouring a c.1706G>A (p.Arg569His) variant, and one child harbouring a c.1531T>C (p.Tyr511His) variant. Literature review yielded a total of 46 patients from 20 papers. Data analysis showed that short stature, hypoparathyroidism and hypocalcemia, ocular and dental defects, skeletal features including cortical thickening and medullary stenosis of tubular bones, and seizures/spasms were present in more than 70% of the reported KCS2 cases. Conclusion: We provide detailed characteristics of the largest KCS2 group in China and present the first genetically confirmed instance of father‐to‐daughter transmission of KCS2. Our study confirms that Arg569His is the hot spot variant and summarizes the typical phenotypes of KCS2, which would help early diagnosis and intervention. [ABSTRACT FROM AUTHOR]

The role of DNA methylation in mollusks is just beginning to be understood. This review synthesizes current knowledge on this potent molecular hallmark of epigenetic control in gastropods—the largest class of mollusks and ubiquitous inhabitants of diverse habitats. Their DNA methylation machinery shows a high degree of conservation in CG maintenance methylation mechanisms, driven mainly by DNMT1 homologues, and the presence of MBD2 and MBD2/3 proteins as DNA methylation readers. The mosaic-like DNA methylation landscape occurs mainly in a CG context and is primarily confined to gene bodies and housekeeping genes. DNA methylation emerges as a critical regulator of reproduction, development, and adaptation, with tissue-specific patterns being observed in gonadal structures. Its dynamics also serve as an important regulatory mechanism underlying learning and memory processes. DNA methylation can be affected by various environmental stimuli, including as pathogens and abiotic stresses, potentially impacting phenotypic variation and population diversity. Overall, the features of DNA methylation in gastropods are complex, being an essential part of their epigenome. However, comprehensive studies integrating developmental stages, tissues, and environmental conditions, functional annotation of methylated regions, and integrated genomic-epigenomic analyses are lacking. Addressing these knowledge gaps will advance our understanding of gastropod biology, ecology, and evolution. [ABSTRACT FROM AUTHOR]

• Male patients with less severe SMA subtypes have higher incidence ratio and symptom vulnerability. • The SMNΔ7 mouse model does not exhibit sex differences in incidence ratio. • The SMNΔ7 mouse model continues to show consistency in phenotypic severity across sexes. • Sex-specific vulnerabilities in SMA patients are not present in one of the most common mouse models of SMA. Spinal muscular atrophy (SMA) is an autosomal recessive disease that affects 1 out of every 6,000-10,000 individuals at birth, making it the leading genetic cause of infant mortality. In recent years, reports of sex differences in SMA patients have become noticeable. The SMNΔ7 mouse model is commonly used to investigate pathologies and treatments in SMA. However, studies on sex as a contributing biological variable are few and dated. Here, we rigorously investigated the effect of sex on a series of characteristics in SMA mice of the SMNΔ7 model. Incidence and lifespan of 23 mouse litters were tracked and phenotypic assessments were performed at 2-day intervals starting at postnatal day 6 for every pup until the death of the SMA pup(s) in each litter. Brain weights were also collected post-mortem. We found that male and female SMA incidence does not differ significantly, survival periods are the same across sexes, and there was no phenotypic difference between male and female SMA pups, other than for females exhibiting lesser body weights at early ages. Overall, this study ensures that sex is not a biological variable that contributes to the incidence ratio or disease severity in the SMNΔ7 mouse model. [ABSTRACT FROM AUTHOR]

Background: This exploratory study evaluated the presence of sensitization-associated and neuropathic-like symptoms and identified their association with pressure sensitivity, pain, and disability in patients with cervical dystonia (CD). Methods: Thirty-one patients with CD (74.2% women, age: 61.2 years, SD 10.1) participated. Data collected included clinical variables, the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), the Central Sensitization Inventory (CSI), the Self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), the Hospital Anxiety and Depression Scale (HADS) and the Pittsburgh Sleep Quality Index (PSQI), as well as widespread pressure pain thresholds (PPTs). Results: Patients with CD with pain (n = 20, 64.5%) showed higher scores on the TWSTRS disability subscale and the CSI (p < 0.001), and lower PPTs (p < 0.05). Fifteen patients (15/31, 48%) showed sensitization-associated symptoms (CSI ≥ 40), whereas five of the patients with pain (5/20, 25%) exhibited neuropathic-like symptoms (S-LANSS ≥ 12). The CSI and S-LANSS were positively associated with the TWSTRS, HADS-A and HADS-D, and negatively associated with PPTs. HADS-D and S-LANSS explained 72.5% of the variance of the CSI (r2: 0.725), whereas CSI explained 42.3% of the variance of the S-LANSS (r2: 0.423). Conclusions: Pain is an important source of disability in CD, and may be a consequence of different mechanisms, including sensitization. [ABSTRACT FROM AUTHOR]

Cancer medicines often have narrow therapeutic windows; toxicity can be severe and sometimes fatal, but inadequate dose intensity reduces efficacy and survival. Determining the optimal dose for each patient is difficult, with body‐surface area used most commonly for chemotherapy and flat dosing for tyrosine kinase inhibitors, despite accumulating evidence of a wide range of exposures in individual patients with many receiving a suboptimal dose with these strategies. Therapeutic drug monitoring (measuring the drug concentration in a biological fluid, usually plasma) (TDM) is an accepted and well validated method to guide dose adjustments for individual patients to improve this. However, implementing TDM in routine care has been difficult outside a research context. The development of genotyping of various proteins involved in drug elimination and activity has gained prominence, with several but not all Guideline groups recommending dose reductions for particular variant genotypes. However, there is increasing concern that dosing recommendations are based on limited data sets and may lead to unnecessary underdosing and increased cancer mortality. This Review discusses the evidence surrounding genotyping and TDM to guide decisions around best practice. [ABSTRACT FROM AUTHOR]

Temperature variation is affecting fish biodiversity worldwide, causing changes in geographic distribution, phenotypic structure, and even species extinction. Incubation is a critical stage for stenothermic species, which are vulnerable to large temperature fluctuations, and its effects on the phenotype at later developmental stages are understudied, despite the fact that the phenotype being essential for organism ecology and evolution. In this study, we tested the effects of heat shocks during the embryonic period on the phenotype of Arctic charr (Salvelinus alpinus). We repeatedly quantified multiple phenotypic traits, including morphology, development, and behavior, over a period of 4 months, from hatching to juvenile stage in individuals that had experienced heat shocks (+ 5°C on 24 h, seven times) during their embryonic stage and those that had not. We found that heat shocks led to smaller body size at hatching and a lower sociability. Interestingly, these effects weakened throughout the development of individuals and even reversed in the case of body size. We also found an accelerated growth rate and a higher body condition in the presence of heat shocks. Our study provides evidence that heat shocks experienced during incubation can have long‐lasting effects on an individual's phenotype. This highlights the importance of the incubation phase for the development of ectothermic organisms and suggests that temperature fluctuations may have significant ecological and evolutionary implications for Arctic charr. Given the predicted increase in extreme events and the unpredictability of temperature fluctuations, it is critical to further investigate their effects on development by examining fluctuations that vary in frequency and intensity. [ABSTRACT FROM AUTHOR]

Introduction: There is evidence that the apico‐coronal implant position and the mucosal phenotype can affect the extent of peri‐implant bone loss. This clinical trial analyzes the bone remodeling and marginal bone loss that occur around conical‐connection implants placed equicrestally and subcrestally, assessing the effect of the peri‐implant soft‐tissue phenotype. Methods: Fifty‐one patients received 56 implants of distinct diameters (3.5 mm Ø n = 6; 4.3 mm Ø n = 41; 5 mm Ø n = 9) in the posterior part of the maxilla or mandible. The implants were placed equicrestally, 1 mm subcrestally and >1 mm subcrestally, depending on the initial supracrestal tissue height (STH). After 3 months of non‐submerged healing, single metal‐ceramic screw‐retained implant‐supported crowns were placed. Longitudinal measurements of STH, mucosal thickness and keratinized mucosa width (KMW) were made at the time of implant placement (T0), crown placement (T1), and after 3 (T2) and 6 months (T3) of prosthetic loading. At each of these points, a radiographic evaluation of bone remodeling and marginal bone loss was also performed. Results: STH was significantly greater for implants placed >1 mm subcrestally than for those placed 1 mm subcrestally. After 12 months of follow‐up, a very significant (p < 0.001) loss of KMW was observed, in addition to a marginal bone loss of 0.08 ± 0.1, 0.15 ± 0.2, and 0.14 ± 0.2 mm in the groups placed equicrestally, 1 mm subcrestally and >1 mm subcrestally, respectively. After the multiple linear regression, marginal bone loss was found to depend primarily on KMW (β = −0.43), while also being affected by STH (β = 0.32) and implant diameter (β = −0.28). Conclusions: Marginal bone loss may be influenced by the position with respect to the bone crest, as well as the KMW, STH, and implant diameter. However, more well‐controlled studies are needed to verify these above‐mentioned findings with different implant designs and connections. [ABSTRACT FROM AUTHOR]

Our understanding of plant functional trait variation among populations and how this relates to local adaptation to environmental conditions is largely shaped by above‐ground traits. However, we might expect below‐ground traits linked to resource acquisition and conservation to vary among populations that experience different environmental conditions. Alternatively, below‐ground traits might be highly plastic in response to growing conditions, such as availability of soil resources and association with symbiont arbuscular mycorrhizal fungi (AMF).We assessed (i) the strength of among‐population variation in above‐ and below‐ground traits, (ii) the effects of growing conditions on among‐population variation and (iii) whether variation among populations is linked to source environment conditions, in a globally distributed perennial Plantago lanceolata. Using seeds from 14 populations across three continents, we grew plants in a common garden experiment and measured leaf and root traits linked to resource acquisition and water conservation. We included two sets of experimental treatments (high or low water availability; with and without AMF inoculation), which enabled us to assess trait responses to growing conditions.Across treatments, the percentage of root trait variation explained by populations and continents was 9%–26%, compared to 7%–20% for leaf trait variation. From principal component analysis (PCA), the first PC axis for both root and leaf traits largely reflected plant size, while the second PC broadly captured mass allocation. Root mass allocation (PC 2) was related to mean annual temperature and mean moisture index, indicating that populations from cooler, wetter environments had longer, thinner roots. However, we found little support for a relationship between source environment and leaf trait PCs, root system size (PC1) or individual traits. Water availability and AMF inoculation effects on size were consistent among populations, with larger plants under AMF inoculation, and less mass allocation to leaves under lower water availability.Plantago lanceolata shows substantial population‐level variation in a suite of root traits, but that variation is only partially linked to the source environmental variables studied. Despite considerable differences in source abiotic environments, geographically separated populations have retained a strong and similar capacity for phenotypic plasticity both above and below‐ground. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

Organisms exhibit reversible physiological adjustments as a response to rapidly changing environments. Yet such plasticity of the phenotype is gradual and may lag behind environmental fluctuations, thereby affecting long‐term average performance of the organisms. By supplying energy and essential compounds for optimal tissue building, food determines the range of possible phenotypic changes and potentially the rate at which they occur. Here, we assess how differences in the dietary supply of essential lipids modulate the phenotypic plasticity of an ectotherm facing thermal fluctuations. We use three phytoplankton strains to create a gradient of polyunsaturated fatty acid and sterol supply for Daphnia magna under constant and fluctuating temperatures. We used three different fluctuation periodicities to unravel the temporal dynamics of gradual plasticity and its long‐term consequences for D. magna performance measured as juvenile somatic growth rate. In agreement with gradual plasticity theory, we show that in D. magna, fluctuation periodicity determines the differential between observed growth rates and those expected from constant conditions. Most importantly, we show that diet modulates both the size and the direction of the growth rate differential. Overall, we demonstrate that the nutritional context is essential for predicting ectotherm consumers' performance in fluctuating thermal environments. [ABSTRACT FROM AUTHOR]

Crustose coralline algae (CCA) are a highly diverse group of habitat‐forming, calcifying red macroalgae (Rhodophyta) with unique adaptations to diverse irradiance regimes. A distinctive CCA phenotype adaptation, which allows them to maximize photosynthetic performance in low light, is their content of a specific group of light‐harvesting pigments called phycobilins. In this study, we assessed the potential of noninvasive hyperspectral imaging (HSI) in the visible spectrum (400–800 nm) to describe the phenotypic variability in phycobilin content of an Antarctic coralline, Tethysphytum antarcticum (Hapalidiales), from two distinct locations. We validated our measurements with pigment extractions and spectrophotometry analysis, in addition to DNA barcoding using the psbA marker. Targeted spectral indices were developed and correlated with phycobilin content using linear mixed models (R2 = 0.64–0.7). Once applied to the HSI, the models revealed the distinct phycoerythrin spatial distribution in the two site‐specific CCA phenotypes, with thin and thick crusts, respectively. This study advances the capabilities of hyperspectral imaging as a tool to quantitatively study CCA pigmentation in relation to their phenotypic plasticity, which can be applied in laboratory studies and potentially in situ surveys using underwater hyperspectral imaging systems. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a multifaceted disease that encompasses diverse clinical phenotypes. The diversity of PD could be subtyped based on the temporal dynamic status of cardiac sympathetic innervation; (1) initially, denervated myocardium (peripheral nervous system-predominant; PNS-predominant), (2) preserved myocardium (central nervous system-predominant; CNS-predominant), and (3) preserved myocardium who developed cardiac sympathetic denervation (CSD) on the subsequent imaging (Converter; delayed cardiac denervation). This study assessed how the cardiac denervation could reflect the pathobiology. We investigated whether this phenotyping could help predict the motor progression trajectory of PD. Methods: Cardiac sympathetic innervation was evaluated using initial and sequential 123I-meta-iodobenzylguanidine myocardial scintigraphy and patients were stratified into three groups as above. Motor severity and progression were evaluated in each patient. The association between subtypes and dopaminergic nigrostriatal degeneration was analyzed. The influence of cardiac denervation on motor progression was also investigated. Results: Among the enrolled 195 patients, 144 PD subjects were defined as PNS-predominant, 16 as Converter, and 35 as CNS-predominant. The most severe nigrostriatal degeneration was observed in the PNS-predominant group and the dopaminergic degeneration was the most asymmetric in the CNS-predominant group. Positive linear trends of nigrostriatal degeneration and its asymmetric degeneration of striatum and globus pallidus were found across the patterns of cardiac sympathetic innervation (PNS-predominant vs. Converter vs. CNS-predominant). It indicated an increasing degree of asymmetric degeneration among the groups. A longitudinal estimation of motor progression revealed distinct cardiac denervation trajectories for each subtype. Conclusions: These results implicated that the subtypes of CSD might indicate a predominant origin and spreading pattern of pathobiology. [ABSTRACT FROM AUTHOR]

Key message: Exogenous SL positively regulates pepper DS by altering the root morphology, photosynthetic character, antioxidant enzyme activity, stomatal behavior, and SL-related gene expression. Drought stress (DS) has always been a problem for the growth and development of crops, causing significant negative impacts on crop productivity. Strigolactone (SL) is a newly discovered class of plant hormones that are involved in plants’ growth and development and environmental stresses. However, the role of SL in response to DS in pepper remains unknown. DS considerably hindered photosynthetic pigments content, damaged root architecture system, and altered antioxidant machinery. In contrast, SL application significantly restored pigment concentration modified root architecture system, and increased relative chlorophyll content (SPAD). Additionally, SL treatment reduced oxidative damage by reducing hydrogen peroxide (H2O2) (24–57%) and malondialdehyde (MDA) (79–89%) accumulation in pepper seedlings. SL-pretreated pepper seedlings showed significant improvement in antioxidant enzyme activity, proline accumulation, and soluble sugar content. Furthermore, SL-related genes (CcSMAX2, CcSMXL6, and CcSMXL3) were down-regulated under DS. These findings suggest that the foliar application of SL can alleviate the adverse effects of drought tolerance by up-regulating chlorophyll content and activating antioxidant defense mechanisms. [ABSTRACT FROM AUTHOR]

Background: While migraine is markedly prevalent in women, gender-related phenotype differences were rarely assessed. For this reason, we investigated, through a multicenter observational cross-sectional study, based on an online questionnaire, gender-related differences in stress factors, emotions, and pain perception in migraine patients and controls and their impact on migraine severity. Methods: The study was designed as an online questionnaire. The link was emailed to healthy subjects (C) and migraine patients (MIG) (age 18–75, education ≥ 13 years) recruited during the first visit in 8 Italian Headache Centers adhering to Italian Society for Headache Study (SISC). The questionnaire included personal/social/work information, the Perceived Stress Scale, the Romance Quality Scale, the Emotion Regulation Questionnaire, the Beck Anxiety Inventory, the Body Perception Questionnaire, the pain perception, and a self-assessment of migraine severity in the last 3 months. Results: 202 MIG and 202 C completed the survey. Independently from gender, migraine was characterized by higher pain sensitivity and more severe partner relationships. The female gender, in MIG, exhibited higher anxiety scores, body awareness, and reduced emotional suppression. Body awareness and emotional suppression were discriminating factors between genders in control and migraine groups without relevant influence on disease features. Perceived perception of migraine severity was similar between genders. Conclusion: Gender-related emotional and stress factors did not contribute to delineate a distinct phenotype in migraine men and women. The possible impact of emotional and stress factors characterizing genders could be considered for a single case–tailored therapeutic approach. [ABSTRACT FROM AUTHOR]

Summary: Background: Obesity is a heterogeneous disease with variable treatment response. Identification of the unique constellation of contributors to obesity may allow for targeted interventions and improved outcomes. Objective: Identify empirically derived phenotypes of pediatric patients with obesity based on appetitive and psychological correlates of obesity. Methods: This cross‐sectional study included patients aged 5–12 years who were treated in a weight management clinic and completed standard intake questionnaires including Child Eating Behavior Questionnaire (CEBQ), Vanderbilt ADHD Scale and Pediatric Symptom Checklist. Phenotypes were elicited using latent profile analysis of 12 indicators: eight CEBQ subscales, inattention, hyperactivity/impulsivity, internalizing and externalizing symptoms. Results: Parents/guardians of 384 patients (mean age 9.8 years, mean BMI 30.3 kg/m2) completed the intake questionnaires. A 4‐phenotype model best fits the data. Hedonic Impulsive phenotype (42.5%) exhibited high food enjoyment and hyperactivity/impulsivity. Inattentive Impulsive phenotype (27.4%) exhibited overall low food approach and high food avoid behaviours, and highest inattention. Hedonic Emotional phenotype (20.8%) scored the highest on food enjoyment, internalizing and externalizing symptoms. Picky Eating phenotype (9.3%) scored the lowest on food approach, inattention, hyperactivity/impulsivity, internalizing and externalizing symptoms. Conclusion: Appetitive traits and psychological symptoms appear to cluster in distinct patterns, giving rise to four unique phenotypic profiles, which, if replicated, may help inform the development of tailored treatment plans. [ABSTRACT FROM AUTHOR]

The genotype–phenotype relationship in PWS patients is important for a better understanding of the clinical phenotype and clinical characteristics of different genotypes of PWS in children. We aimed to explore the influence of specific gene changes on the clinical symptoms of PWS and the value of early screening and early intervention of the condition. All data in this study were extracted from the database of the XiaoPang Weili Rare Disease Care Center. The collected information included basic demographics, maternal pregnancy information, endocrine abnormalities, growth and development abnormalities, and other clinical phenotypes. The relationships between genotypes and phenotypes in the major categories of PWS were analyzed. A total of 586 PWS cases with confirmed molecular diagnosis and genotyping were included in this study. Among them, 83.8% belonged to the deletion type, 10.9% the uniparental disomy (UPD) type, and 5.3% the imprinting defect (ID) type. Age‐wide comparison among the three groups: The rate of hypopigmentation in the deletion group was higher than that in the UPD group (88.8% vs. 60.9%; p < 0.05); A total of 62 patients (14.2%) had epilepsy; and no statistical significance was found among the three groups (p = 0.110). Age‐wide comparison between the deletion and non‐deletion types: the rate of skin hypopigmentation and epilepsy in the deletion group was significantly higher than that in the non‐deletion group (88.8% vs. 68.4%, p < 0.001; 15.9% vs. 7.6%, p = 0.040). The intergroup comparison for the >2‐year age group: there were significant intergroup differences in the language development delay among the three groups (p < 0.001). The incidence of delayed language development was the highest in the deletion group, followed by the UPD group, and the lowest in the ID group. The rates of obesity and hyperphagia in the deletion group were also higher than those in the non‐deletion group (71.1% vs. 58.9%, p = 0.041; 75.7% vs. 62.0%, p = 0.016). There are significant differences in the rates of skin hypopigmentation and language developmental delay among the deletion, UPD, and ID genotypes. The patients with deletion type had significantly higher rates of lighter skin color, obesity, hyperphagia, language developmental delay, and epilepsy. The results of this study will help clinicians better understand the impact of different PWS molecular etiologies on specific phenotypes. [ABSTRACT FROM AUTHOR]

Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. This study summarizes the clinical, imaging, and molecular data of these patients for five years. The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1 , and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042). [ABSTRACT FROM AUTHOR]

Background: Primary cutaneous lymphoma represents 0.2%–3% of all feline lymphomas, with nonepitheliotropic lymphomas being the most common. In humans and dogs, subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) is a primary nonepitheliotropic lymphoma with a T‐cell phenotype developing in the subcutis and often mimicking inflammation. Objective: The aim of this report is to describe pathological, phenotypical and clonal features of SPTCL in cats. Animals: Six cats with SPTCL were included in this study. Materials and Methods: Skin biopsies were formalin‐fixed, routinely processed and stained. Histological and immunohistochemical investigation for anti‐CD18, CD204, CD79a, CD20, CD3, FeLVp27and FeLVgp70 and clonality assessment were performed. Results: Four male and two female domestic shorthair cats, mean age 11.2 years, developed SPTCL in the abdominal (three), inguinal (two) and thoracic (one) regions. Variably pleomorphic neoplastic lymphoid cells were present in the panniculus in percentages, expanding the septa (six of six) and extending into fat lobules in one of six cats. Tumours were associated with elevated numbers of neutrophils (five of six), lesser macrophages (six of six) and variable necrosis (six of six). Neoplastic cells expressed CD3+ (six of six), with clonal T‐cell receptor rearrangement detected in five of six cats. Conclusions and Clinical Relevance: This is the first description of SPTCL in cats. Lesions can be confused with panniculitis, leading to delay in diagnosis and therapy. Awareness of this neoplastic disease is relevant to avoid misdiagnoses and to gain greater knowledge about the disease in cats. [ABSTRACT FROM AUTHOR]