Mutations Research Articles

Rehabilitating Amputated Hallux with Dental Implant–Supported Double Magnet in Y-Bar–Retained Prosthesis

ABSTRACT Introduction Loss of hallux leads to aesthetic deficit and functional loss, with active push-off, weight-bearing ability, and pronation all being affected. Rehabilitation can be surgical or prosthetic; however, surgical alternatives can be unpredictable in terms of aesthetics and is not cost-effective. Therefore, prosthetic rehabilitation is often favored. However, loss of all 3 phalanges makes prosthetic rehabilitation challenging due to minimal scope of retention from the residual limb. Materials and Methods This technique presents a solution to this challenge, with an implant-supported, magnet-retained silicone prosthesis, having a novel abutment design, to provide dual (magnetic and frictional) retention. Conclusions The prosthetic design improved retention, facilitated easy handling by the patient, and prevented stress concentration on implant-bone interface. Clinical Relevance The prosthetic innovation improved retention during standing and walking, and increased the patient’s confidence to perform daily activities without fear of dislodgement.

Exploring Extracellular Vesicle Surface Protein Markers Produced by Glioblastoma Tumors: A Characterization Study Using In Vitro 3D Patient-Derived Cultures

Background/Objectives: Glioblastoma (GBM) is an aggressive brain cancer with limited treatment options. Extracellular vesicles (EVs) derived from GBM cells contain important biomarkers, such as microRNAs, proteins, and DNA mutations, which are involved in tumor progression, invasion, and resistance to treatment. Identifying surface markers on these EVs is crucial for their isolation and potential use in noninvasive diagnosis. This study aimed to use tumor-derived explants to investigate the surface markers of EVs and explore their role as diagnostic biomarkers for GBM. Methods: Tumor explants from nine GBM patients without IDH1/IDH2 mutations or 1p-19q co-deletion were cultured to preserve both tumor viability and cytoarchitecture. EVs were collected from the tumor microenvironment using differential centrifugation, filtration, and membrane affinity binding. Their surface protein composition was analyzed through multiplex protein assays. RNA-Seq data from TCGA and GTEx datasets, along with in silico single-cell RNA-seq data, were used to assess EV surface biomarker expression across large GBM patient cohorts. Results: The in vitro model successfully replicated the tumor microenvironment and produced EVs with distinct surface markers. Biomarker analysis in large datasets revealed specific expression patterns unique to GBM patients compared with healthy controls. These markers demonstrated potential as a GBM-specific signature and were correlated with clinical data. Furthermore, in silico single-cell RNA-seq provided detailed insights into biomarker distribution across different cell types within the tumor. Conclusions: This study underscores the efficacy of the tumor-derived explant model and its potential to advance the understanding of GBM biology and EV production. A key innovation is the isolation of EVs from a model that faithfully mimics the tumor’s original cytoarchitecture, offering a deeper understanding of the cells involved in EV release. The identified EV surface markers represent promising targets for enhancing EV isolation and optimizing their use as diagnostic tools. Moreover, further investigation into their molecular cargo may provide crucial insights into tumor characteristics and evolution.

Striate palmoplantar keratoderma: a novel DSG1 mutation, combined with an LDLR mutation.

Palmoplantar keratoderma (PPK) is a heterogeneous group of disorders characterized by abnormal thickening of the skin on the palms and soles. Striate palmoplantar keratoderma (SPPK) is commonly caused by heterozygous mutations in the desmoglein-1 (DSG1) gene. This study aimed to report a case of a 36-year-old Chinese female patient with SPPK caused by a novel DSG1 gene mutation, along with her family history, and explore its potential relationship with other genetic variants. Whole-exome sequencing was performed on the patient and their family members to identify the pathogenic mutation, which was validated by Sanger sequencing. Histological and electron microscopy analyses were conducted to examine the pathological characteristics of skin tissue.of skin tissue. A frameshift mutation, c.1285del, in exon 10 of the DSG1 gene was identified, leading to a loss of protein function and resulting in SPPK. This mutation was also detected in two other family members with similar phenotypes. Additionally, a classical splicing variant, c.313+2dup, in the low-density lipoprotein receptor (LDLR) gene associated with hypercholesterolemia was identified in the patient; however, no direct association with SPPK was observed. This study was the first to report a novel mutation in the DSG1 gene associated with SPPK and suggested a potential role of the LDLR gene variant in SPPK patients, providing new insights for further research into the genetic mechanisms underlying SPPK.

New evidence of vascular defects in neurodegenerative diseases revealed by single cell RNA sequencing.

Neurodegenerative diseases (NDs) involve the progressive loss of neuronal structure or function in the brain and spinal cord. Despite their diverse etiologies, NDs manifest similar pathologies. Emerging research identifies vascular defects as a previously neglected hallmark of NDs. The development and popularization of single-cell RNA sequencing (scRNA-seq) technologies have significantly advanced our understanding of brain vascular cell types and their molecular characteristics, including gene expression changes at the single-cell level in NDs. These unprecedented insights deepen our understanding of the pathogenic mechanisms underlying NDs. However, the occurrence and role of vascular defects in disease progression remain largely unexplored. In this paper, we systematically summarize recent advances in the structure and organization of the central nervous system vasculature in mice, healthy individuals, and patients with NDs, focussing primarily on disease-specific alterations in vascular cell types or subtypes. Combining scRNA-seq with pathology evidence, we propose that vascular defects, characterized by disruptions in cell types and structural integrity, may serve as common early features of NDs. Finally, we discuss several pathways through which vascular defects in NDs lead to neuronal degeneration. A deeper understanding of the causes and contributions of vascular defects to NDs aids in elucidating the pathogenic mechanisms and developing meaningful therapeutic interventions.

Antibiotic resistance mediated by gene amplifications

AbstractApart from horizontal gene transfer and sequence-altering mutational events, antibiotic resistance can emerge due to the formation of tandem repeats of genomic regions. This phenomenon, also known as gene amplification, has been implicated in antibiotic resistance in both laboratory and clinical scenarios, where the evolution of resistance via amplifications can affect treatment efficacy. Antibiotic resistance mediated by gene amplifications is unstable and consequently can be difficult to detect, due to amplification loss in the absence of the selective pressure of the antibiotic. Further, due to variable copy numbers in a population, amplifications result in heteroresistance, where only a subpopulation is resistant to an antibiotic. While gene amplifications typically lead to resistance by increasing the expression of resistance determinants due to the higher copy number, the underlying mechanisms of resistance are diverse. In this review article, we describe the various pathways by which gene amplifications cause antibiotic resistance, from efflux and modification of the antibiotic, to target modification and bypass. We also discuss how gene amplifications can engender resistance by alternate mutational outcomes such as altered regulation and protein structure, in addition to just an increase in copy number and expression. Understanding how amplifications contribute to bacterial survival following antibiotic exposure is critical to counter their role in the rise of antimicrobial resistance.

Role of HOXA10 in pathologies of the endometrium.

HOXA10 belongs to the homeobox gene family and is essential for uterine biogenesis, endometrial receptivity, embryo implantation, and stromal cell decidualization. Available evidence suggests that the expression of HOXA10 is dysregulated in different endometrial disorders like endometrial hyperplasia, endometrial cancer, adenomyosis, endometriosis, recurrent implantation failure, and unexplained infertility. The downregulation of HOXA10 occurs by genetic changes in the HOXA10 gene, methylation of the HOXA10 locus, or selected miRNAs. Endocrine disruptors and organic pollutants also cause the reduced expression of HOXA10 in these conditions. In vivo experiments in mouse models and in vitro studies in human cell lines demonstrate that downregulation of HOXA10 leads to endometrial epithelial cell proliferation, failure of stromal cell decidualization, altered expression of genes involved in cell cycle regulation, immunomodulation, and various signaling pathways. These disruptions are speculated to cause infertility associated with the disorders of the endometrium.

Bexotegrast Shows Dose-dependent Integrin αvβ6 Receptor Occupancy in Lungs of Participants with Idiopathic Pulmonary Fibrosis: A Phase 2, Open-Label Clinical Trial.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by dyspnea and loss of lung function. Transforming growth factor-beta (TGF-β) activation mediated by αv integrins is central to the pathogenesis of IPF. Bexotegrast (PLN 74809) is an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1 integrins under investigation for the treatment of IPF. Positron emission tomography (PET) using an αvβ6-specific PET tracer could confirm target engagement of bexotegrast in the lungs of participants with IPF. Objectives: This Phase 2 study (NCT04072315) evaluated αvβ6 receptor occupancy in the lung, as assessed by changes from baseline in αvβ6 PET tracer uptake, following single dose administration of bexotegrast to participants with IPF. Methods: In this open-label, single-center, single-arm study, adults with IPF received up to 2 single doses of bexotegrast, ranging from 60 to 320 mg with or without background IPF therapy (pirfenidone or nintedanib). At baseline and approximately 4 hours after each orally administered bexotegrast dose, a 60-minute dynamic PET/CT scan was conducted following administration of an αvβ6-specific PET probe ([18F]FP-R01-MG-F2). αvβ6 receptor occupancy by bexotegrast was estimated from the changes in PET tracer uptake following bexotegrast. Pharmacokinetics, safety, and tolerability of bexotegrast were also assessed. Results: Eight participants completed the study. Total and unbound plasma bexotegrast concentrations increased in a dose-dependent manner, and regional PET volume of distribution (VT) values decreased in a dose- and concentration-dependent manner. The VT data fit a simple saturation model, producing an unbound bexotegrast EC50 estimate of 3.32 ng/mL. Estimated maximum receptor occupancy was 35%, 53%, 71%, 88%, and 92% following single 60, 80, 120, 240, and 320-mg doses of bexotegrast, respectively. No treatment-emergent adverse events related to bexotegrast were reported. Conclusions: Dose- and concentration-dependent αvβ6 receptor occupancy by bexotegrast was observed by PET imaging, supporting once-daily 160 to 320 mg dosing to evaluate efficacy in clinical trials of IPF. Trial registration number: NCT04072315 Primary source of funding: Pliant Therapeutics, Inc. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Biallelic loss-of-function variants in GON4L cause microcephaly and brain structure abnormalities.

We identified two homozygous truncating variants in GON4L [NM_001282860.2:c.62_63del, p.(Gln21Argfs*12) and c.5517+1G>A] in two unrelated families who presented prenatal-onset growth impairment, microcephaly, characteristic face, situs inversus, and developmental delay. The frameshift variant is predicted to invoke nonsense-mediated mRNA decay of all five known GON4L isoforms resulting in the complete loss of GON4L function. The splice site variant located at a region specific to the longer isoforms; therefore, defects of long GON4L isoforms may explain the phenotypes observed in the three patients. Knockdown of Gon4l in rat PC12 cells suppressed neurite outgrowth in vitro. gon4lb knockdown and knockout zebrafish successfully recapitulated the patients' phenotypes including craniofacial abnormalities. We also observed situs inversus in gon4lb-knockout zebrafish embryo. To our knowledge, the relationship between craniofacial abnormalities or situs inversus and gon4lb has not been reported before. Thus, our data provide evidence that GON4L is involved in craniofacial and left-right patterning during development.

Implementing palliative and end of life care for people with dementia.

Dementia is characterised by memory loss, behavioural changes and decline of cognitive, social and physical functions and is a life-limiting condition. At the point of diagnosis it is classed as a palliative condition, yet there is limited public and healthcare professional awareness that, once diagnosed, a person will either die of dementia or die with dementia. This article discusses how the recognition and timing of the need for palliative dementia care is pivotal in providing person-centred care. The authors explore factors such as optimal prognostication, advance care planning, staff education and accessing support from palliative and end of life care teams and Admiral Nurses. The authors also use a fictional case study to demonstrate best practice in palliative dementia care.

A nanofibrous polycaprolactone/collagen neural guidance channel filled with sciatic allogeneic schwann cells and platelet-rich plasma for sciatic nerve repair.

Sciatic nerve damage, a common condition affecting approximately 2.8% of the US population, can lead to significant disability due to impaired nerve signal transmission, resulting in loss of sensation and motor function in the lower extremities. In this study, a neural guidance channel was developed by rolling a nanofibrous scaffold produced via electrospinning. The scaffold's microstructure, biocompatibility, biodegradation rate, porosity, mechanical properties, and hemocompatibility were evaluated. Platelet-rich plasma (PRP) activated with 30,000 allogeneic Schwann cells (SCs) was injected into the lumen of the channels following implantation into a rat model of sciatic nerve injury. Recovery of motor function, sensory function, and muscle re-innervation was assessed using the sciatic function index (SFI), hot plate latency time, and gastrocnemius muscle wet weight loss. Results showed mean hot plate latency times of Autograft: 7.03, PCL/collagen scaffolds loaded with PRP and SCs (PCLCOLPRPSCs): 8.34, polymer-only scaffolds (PCLCOL): 10.66, and untreated animals (Negative Control): 12.00. The mean SFI values at week eight were Autograft: -49.30, PCLCOLPRPSCs: -64.29, PCLCOL: -75.62, and Negative Control: -77.14. The PCLCOLPRPSCs group showed a more negative SFI compared to the Autograft group but performed better than both the PCLCOL and Negative Control groups. These findings suggest that the developed strategy enhanced sensory and functional recovery compared to the negative control and polymer-only scaffold groups.

Optimizing Chronotherapy in Psychiatric Care: The Impact of Circadian Rhythms on Medication Timing and Efficacy

In many medical settings, medications are typically administered in the morning or evening, aligning with patients’ daily routines. This practice does not stem from chronotherapy, which involves scheduling drug administration to enhance its effectiveness, but rather from the way clinical operations are structured. The timing of drug administration can significantly affect a medication’s effectiveness and side effects, with the impact varying by up to ten times based on circadian rhythms. Disorders such as major depression, bipolar disorder, and schizophrenia are linked to disruptions in these rhythms. Recent studies have found that circadian dysfunctions, including genetic and neurohumoral changes, underlie many psychiatric conditions. Issues such as an altered glucocorticoid rhythm due to impaired HPA axis function, disturbed melatonin balance, and sleep disturbances have been noted in psychotic disorders. Furthermore, mood disorders have been associated with changes in the expression of circadian rhythm genes such as Clock, Bmal1, and Per. Considering that the absorption, biodistribution, effects on target organs, half-life, metabolism, and elimination of drugs are all influenced by the body’s circadian rhythms, this narrative review explores the optimal timing of medication administration to maximize efficacy and minimize side effects in the treatment of psychiatric disorders. By closely monitoring circadian variations in cortisol, melatonin, and key clock genes, as well as by deepening our understanding of the metabolisms and pharmacokinetics of antipsychotic medications, we propose a chronotherapy approach for psychiatric patients that could significantly enhance patient care.

USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer.

The chromatin-remodeling enzyme SMARCA5 plays a key role in DNA-templated events including transcription, DNA replication, and DNA repair. Loss of function of the SMARCA5 can cause neurodevelopmental disorder and Williams syndrome. However, the molecular mechanism underlying the regulation of SMARCA5 in prostate cancer remains largely elusive. Here, we report that the deubiquitinating enzyme USP3 directly interacts with SMARCA5 and removes K63-linked polyubiquitination of SMARCA5 to maintain its stability, which promotes DNA damage repair and chemotherapy resistance. Depletion of USP3 or SMARCA5 promoted PCa cells sensitive to docetaxel and overexpression of USP3 restored the cells resistance to docetaxel treatment in SMARCA5 silenced cells in vitro and vivo. Clinically, USP3 was significantly up-regulated in prostate cancer tissues and positively associated with SMARCA5 expression. Collectively, our findings uncover a novel molecular mechanism for the USP3-SMARCA5 axis in regulating DSB repair with an important role in chemotherapy response in human prostate cancers, highlighting that targeting USP3-SMARCA5 axis could be a valuable strategy to treat USP3/SMARCA5-overexpressing chemotherapy-resistant patients and improve drug treatment.

The E3 ligase OsPUB33 controls rice grain size and weight by regulating the OsNAC120-BG1 module.

Grain size and weight are important determinants of crop yield. Although the ubiquitin pathway has been implicated in the grain development in rice (Oryza sativa), the underlying genetic and molecular mechanisms remain largely unknown. Here, we report that the Plant U-box (PUB) E3 ubiquitin ligase OsPUB33 interferes with the OsNAC120-BG1 module to control rice grain development. Functional loss of OsPUB33 triggers elevated photosynthetic rates and greater sugar translocation, leading to enhanced cell proliferation and accelerated grain filling. These changes cause enlarged spikelet hulls, thereby increasing final grain size and weight. OsPUB33 interacts with transcription factor OsNAC120, resulting in its ubiquitination and degradation. Unlike OsPUB33, OsNAC120 promotes grain size and weight: OsNAC120-overexpression plants harbor large and heavy grains, whereas osnac120 loss-of-function mutants produce small grains. Genetic interaction analysis supports that OsPUB33 and OsNAC120 function at least partially in a common pathway to control grain development, but have opposite functions. Additionally, OsNAC120 transcriptionally activates BIG GRAIN1 (BG1), a prominent modulator of grain size, whereas OsPUB33 impairs the OsNAC120-mediated regulation of BG1. Collectively, our findings uncover an important molecular framework for the control of grain size and weight by the OsPUB33-OsNAC120-BG1 regulatory module and provide promising targets for improving crop yield.

Unraveling Uncertainty: The Impact of Biological and Analytical Variation on the Prediction Uncertainty of Categorical Prediction Models.

Interest in prediction models, including machine learning (ML) models, based on laboratory data has increased tremendously. Uncertainty in laboratory measurements and predictions based on such data are inherently intertwined. This study developed a framework for assessing the impact of biological and analytical variation on the prediction uncertainty of categorical prediction models. Practical application was demonstrated for the prediction of renal function loss (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) and 31-day mortality (advanced ML model) in 6360 emergency department patients. Model outcome was calculated in 100 000 simulations of variation in laboratory parameters. Subsequently, the percentage of discordant predictions was calculated with the original prediction as reference. Simulations were repeated assuming increasing levels of analytical variation. For the ML model, area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity were 0.90, 0.44, and 0.96, respectively. At base analytical variation, the median [2.5th-97.5th percentiles] percentage of discordant predictions was 0% [0%-28.8%]. In addition, 7.2% of patients had >5% discordant predictions. At 6× base analytical variation, the median [2.5th-97.5th percentiles] percentage of discordant predictions was 0% [0%-38.8%]. In addition, 11.7% of patients had >5% discordant predictions. However, the impact of analytical variation was limited compared with biological variation. AUROC, sensitivity, and specificity were not affected by variation in laboratory parameters. The impact of biological and analytical variation on the prediction uncertainty of categorical prediction models, including ML models, can be estimated by the occurrence of discordant predictions in a simulation model. Nevertheless, discordant predictions at the individual level do not necessarily affect model performance at the population level.

EXECUTER1 and singlet oxygen signaling: A reassessment of nuclear activity.

Chloroplasts are recognized as environmental sensors, capable of translating environmental fluctuations into diverse signals to communicate with the nucleus. Among the reactive oxygen species produced in chloroplasts, singlet oxygen (1O2) has been extensively studied due to its dual roles, encompassing both damage and signaling activities, and the availability of conditional mutants overproducing 1O2 in chloroplasts. In particular, investigating the Arabidopsis (Arabidopsis thaliana) mutant known as fluorescent (flu) has led to the discovery of EXECUTER1 (EX1), a plastid 1O2 sensor residing in the grana margin of the thylakoid membrane. 1O2-triggered EX1 degradation is critical for the induction of 1O2-responsive nuclear genes (SOrNGs). However, a recent study showed that EX1 relocates from chloroplasts to the nucleus upon 1O2 release, where it interacts with WRKY18 and WRKY40 (WRKY18/40) transcription factors to regulate SOrNG expression. In this study, we challenge this assertion. Our confocal microscopy analysis and subcellular fractionation assays demonstrate that EX1 does not accumulate in the nucleus. While EX1 appears in nuclear fractions, subsequent thermolysin treatment assays indicate that it adheres to the outer nuclear region rather than localizing inside the nucleus. Furthermore, luciferase complementation imaging and yeast two-hybrid assays reveal that EX1 does not interact with nuclear WRKY18/40. Consequently, our study refines the current model of 1O2 signaling by ruling out the nuclear relocation of intact EX1 as a means of communication between the chloroplast and nucleus.

Effect of Lingual Nerve Block and Localised Somatosensory Abnormalities in Patients With Burning Mouth Syndrome-A Randomised Crossover Double-Blind Trial.

To investigate the effect of a lingual nerve block on spontaneous pain in patients with burning mouth syndrome (BMS) and to estimate associated somatosensory abnormalities by quantitative sensory testing (QST). A standardised QST battery including cold detection threshold (CDT), warmth detection threshold (WDT), thermal sensory limen (TSL), paradoxical heat sensation (PHS), cold pain threshold (CPT), heat pain threshold (HPT), mechanical pain threshold (MPT), wind-up ratio (WUR) and pressure pain threshold (PPT) was performed at the oral mucosa of the most painful site and intraoral control site in 20 BMS patients, and at the tongue and cheek mucosa in 22 age- and gender-matched healthy controls. The effect of a lingual nerve block on spontaneous burning pain reported by the BMS patients on a 0-10 cm visual analogue scale (VAS) was investigated in a randomised double-blind crossover design using (1 mL) lidocaine (lido) or saline (sal) with an interval of 1 week. The BMS patients were grouped into 'central' and 'peripheral' mechanisms based on the effect of the lingual nerve injections. For each BMS patient, Z-scores and Loss/Gain scores were computed. Differences among groups and sites were analysed using a two-way ANOVA. Differences within group were assessed by paired t-test. The 20 BMS patients were characterised on the basis of VAS changes (ΔLido-ΔSal) as a peripheral BMS subgroup (n = 9) with pain relief more than 1 cm on the VAS and a central BMS subgroup (n = 11) with pain relief less than 1 cm. BMS patients (n = 20) had lower sensitivity to thermal stimuli (i.e., CDT, WDT, TSL, CPT, HPT and PPT) and higher sensitivity to mechanical stimuli (i.e., PPT) compared with controls (p ≤ 0.007). Based on Loss/Gain coding, L1G0 (loss of thermal somatosensory function with no somatosensory gain, 55.0%) was the most frequent coding in the BMS group, which was higher than 11.4% in the control group (p < 0.001). Surprisingly, there was no significant difference between the peripheral and central BMS subgroups with regard to the Z-scores of any of the nine QST parameters (p > 0.097). The results of the lingual nerve blocks demonstrated two distinct phenotypes with either peripheral or central mechanisms but no direct impact on somatosensory function. Overall, somatosensory function in BMS patients seems abnormal in the painful areas compared to matched controls with a conspicuous loss of thermosensory function.

Germline copy number variants and endometrial cancer risk.

Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10-63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.

The role of genetic and epigenetic modifications as potential biomarkers in the diagnosis and prognosis of thyroid cancer

Thyroid cancer (TC) is the most common endocrine cancer, which contributes to more than 43,600 deaths and 586,000 cases worldwide every year. Among the TC types, PTC and FTC comprise 90% of all TCs. Genetic modifications in genes are responsible for encoding proteins of mitogen-associated protein kinase cascade, which is closely related with numerous cellular mechanisms, including controlling programmed cell death, differentiation, proliferation, gene expression, as well as in genes encoding the PI3K (phosphatidylinositol 3-kinase)/protein kinase B (AKT) cascade, which has contribution in controlling cell motility, adhesion, survival, and glucose metabolism, have been associated with the TC pathogenesis. Various genetic modifications including BRAF mutations, RAS mutations, RET mutations, paired-box gene 8/peroxisome proliferator-activated receptor-gamma fusion oncogene, RET/PTC rearrangements, telomerase reverse transcriptase mutations, neurotrophic tyrosine receptor kinase fusion genes, TP53 mutations, and eukaryotic translation initiation factor 1A X-linked mutations can effectively serve as potential biomarkers in both diagnosis and prognosis of TC. On the other hand, epigenetic modifications can lead to aberrant functions or suppression of a range of signalling cascades, which can ultimately result in cancer. Various studies have observed the link between epigenetic modification and multiple cancers including TC. It has been reported that several epigenetic alterations including histone modifications, aberrant DNA methylation, and epigenetic modulations of non-coding RNAs can play significant roles as potential biomarkers in the diagnosis and prognosis of TC. Therefore, a good understanding regarding the genetic and epigenetic modifications is not only essential for the diagnosis and prognosis of TC, but also for the development of novel therapeutics. In this review, most of the major TC-related genetic and epigenetic modifications and their potential as biomarkers for TC diagnosis and prognosis have been extensively discussed.

Hyperspectral Leaf Reflectance Detects Interactive Genetic and Environmental Effects on Tree Phenotypes, Enabling Large-Scale Monitoring and Restoration Planning Under Climate Change.

Plants respond to rapid environmental change in ways that depend on both their genetic identity and their phenotypic plasticity, impacting their survival as well as associated ecosystems. However, genetic and environmental effects on phenotype are difficult to quantify across large spatial scales and through time. Leaf hyperspectral reflectance offers a potentially robust approach to map these effects from local to landscape levels. Using a handheld field spectrometer, we analyzed leaf-level hyperspectral reflectance of the foundation tree species Populus fremontii in wild populations and in three 6-year-old experimental common gardens spanning a steep climatic gradient. First, we show that genetic variation among populations and among clonal genotypes is detectable with leaf spectra, using both multivariate and univariate approaches. Spectra predicted population identity with 100% accuracy among trees in the wild, 87%-98% accuracy within a common garden, and 86% accuracy across different environments. Multiple spectral indices of plant health had significant heritability, with genotype accounting for 10%-23% of spectral variation within populations and 14%-48% of the variation across all populations. Second, we found gene by environment interactions leading to population-specific shifts in the spectral phenotype across common garden environments. Spectral indices indicate that genetically divergent populations made unique adjustments to their chlorophyll and water content in response to the same environmental stresses, so that detecting genetic identity is critical to predicting tree response to change. Third, spectral indicators of greenness and photosynthetic efficiency decreased when populations were transferred to growing environments with higher mean annual maximum temperatures relative to home conditions. This result suggests altered physiological strategies further from the conditions to which plants are locally adapted. Transfers to cooler environments had fewer negative effects, demonstrating that plant spectra show directionality in plant performance adjustments. Thus, leaf reflectance data can detect both local adaptation and plastic shifts in plant physiology, informing strategic restoration and conservation decisions by enabling high resolution tracking of genetic and phenotypic changes in response to climate change.

Comparative transcriptome analysis of low- and high-latitude populations of Charybdis japonica under temperature stress

Global climate change has caused rapid temperature changes in marine environments. Understanding how marine organisms respond to temperature changes can help predict their richness of future biodiversity. In this study, we examined the gene expression levels and the difference in the pathways that are responsive to acute temperature stress in low- and high-latitude populations of the shore swimming crab, Charybdis japonica. The two populations of C. japonica were exposed to low- and high-temperature stresses (15°C and 28°C) and used for transcriptome sequencing. Genetic regulatory ability changes were compared to determine the diverse response of the two crab populations to temperature change. The gene expression levels and functional enrichment analysis showed that the low-latitude crab regulated more genes (938) that were mainly enriched in DNA replication and metabolic pathways, whereas the high-latitude crab regulated less genes (309) that were mainly enriched in genetic information processing at low-temperature stress. Furthermore, the low-latitude crab regulated less genes (33) that were mainly enriched in genetic information processing, whereas the high-latitude crab regulated more genes (280) that were mainly enriched in signal transduction and cellular process at high-temperature stress. These results implied that the low-latitude population was more resilient to high-temperature stress, while the high-latitude population was more resilient to low-temperature stress. This study enhances our understanding of how different geographic C. japonica populations respond to varying temperature environments in their living zone, which could be helpful for predicting future biodiversity trends of intertidal crustaceans under global climate change.