Molecular Response Research Articles

Aldehyde dehydrogenase-2 deficiency aggravates neuroinflammation, nociception, and motor impairment in a mouse model of multiple sclerosis

Aldehyde dehydrogenase-2 deficiency (ALDH2∗2) found in 36 % of Han Chinese, affects approximately 8 % of the world population. ALDH2 is a mitochondrial key enzyme in detoxifying reactive aldehydes to less reactive forms. Studies demonstrate a potential link between ALDH2∗2 mutation and neurodegenerative diseases. Multiple sclerosis (MS) is an incurable and disabling neurodegenerative autoimmune disease that induces motor, and cognitive impairment, and hypersensitivity, including chronic pain. Accumulating evidence suggests that reactive aldehydes, such as 4-hydroxynonenal (4-HNE), contribute to MS pathogenesis. Here, using knock-in mice carrying the inactivating point mutation in ALDH2, identical to the mutation found in Han Chinese, we showed that the impairment in ALDH2 activity heightens motor disabilities, and hypernociception induced by experimental autoimmune encephalomyelitis (EAE). The deleterious clinical signs are followed by glial cell activation in the spinal cord and increased 4-HNE levels in the spinal cord and serum. Importantly, the pharmacological ALDH2 activation by Alda-1 ameliorates EAE-induced hypernociception and motor impairment in both wild-type and ALDH2∗2KI mice. Reduced hypernociception was associated with less early growth response protein 1 (EGR1), neuronal and glial activation, and reactive aldehyde accumulation in the spinal cord and serum. Taken together, our data suggest that the mitochondrial enzyme ALDH2 plays a role in regulating clinical, cellular, and molecular responses associated with EAE. This indicates that ALDH2 could serve as a molecular target for MS control, with ALDH2 activators, like Alda-1 as potential neuroprotective candidates. Furthermore, ALDH2∗2 carriers may be at increased risk of developing more accentuated MS symptoms.

Outcomes of pregnancy in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors.

Young female patients with chronic myeloid leukemia (CML) often face challenges becoming pregnant due to the teratogenicity of tyrosine kinase inhibitors (TKIs). The authors conducted a nationwide survey of female patients with CML who experienced pregnancy between 2002 and 2020. Information for 70 pregnancies in 49 patients was obtained. There were three types of pregnancies: CML onset during pregnancy (n=9), unplanned pregnancy mostly during treatment with a TKI (n=25), and planned pregnancy during treatment-free remission (TFR) or treatment with interferon-alpha (IFN-α) (n=36). The median duration from CML diagnosis to pregnancy in patients with planned pregnancy was significantly longer than that in patients with unplanned pregnancy (10.6 years vs. 4.1 years, p<.001). In 48 pregnancies that resulted in childbirth, TFR and treatment with IFN-α were chosen in 26 and 17 pregnancies, respectively. Sustained major or deeper molecular response was observed in 18 of 26 pregnancies with TFR. The patients who fulfilled the requirements for TKI therapy discontinuation by European LeukemiaNet recommendations achieved a TFR rate of 77% in pregnancy. Treatment with IFN-α might be effective for patients who are in complete cytogenetic response or deeper response (response rate, 76%). Pregnancy by TFR or treatment with IFN-α could be a safe and feasible way for patients with CML. However, a substantial duration of treatment with a TKI before conception may be needed for planned pregnancy. Planning and evaluation for pregnancy should be considered at the time of CML onset for female patients with childbearing potential.

Molecular depiction and functional delineation of E3 ubiquitin ligase MARCH5 in yellowtail clownfish (Amphiprion clarkii)

Membrane-associated Ring-CH 5 (MARCH5) is a mitochondrial E3 ubiquitin ligase playing a key role in the regulation of mitochondrial dynamics. In mammals, MARCH5 negatively regulates mitochondrial antiviral signaling (MAVS) protein aggregation during viral infection and hampers downstream type I interferon signaling to prevent excessive immune activation. However, its precise functional role in the teleost immune system remains unclear. This study investigated the molecular characteristics and immune response of the MARCH5 ortholog in Amphiprion clarkii (A. clarkii; AcMARCH5). The predicted AcMARCH5 protein sequence consists of 287 amino acids with a molecular weight of 32.02 kDa and a theoretical isoelectric point of 9.11. It contains four C-terminal transmembrane (TM) domains and an N-terminal RING cysteine-histidine (CH) domain, which directly regulates ubiquitin transfer. Multiple sequence alignment revealed a high level of conservation between AcMARCH5 and its orthologs in other vertebrate species. Under normal physiological conditions, AcMARCH5 showed the highest mRNA expression in the muscle, brain, and kidney tissues of A. clarkii. Upon stimulation with polyinosinic:polycytidylic acid (Poly I:C), lipopolysaccharide (LPS), and Vibrio harveyi, AcMARCH5 expression was drastically modulated. Functional assays showed that overexpression of AcMARCH5 in fathead minnow (FHM) cells downregulated antiviral gene expression, accompanied by enhanced viral hemorrhagic septicemia virus (VHSV) replication. In murine macrophages, AcMARCH5 overexpression markedly reduced the production of pro-inflammatory cytokines in response to poly I:C treatment. Additionally, AcMARCH5 exhibited an anti-apoptotic effect in H2O2-treated FHM cells. Collectively, these results suggest that AcMARCH5 may play a role in maintaining cellular homeostasis under disease and stress conditions in A. clarkii.

Defining the molecular response to ischemia-reperfusion injury and remote ischemic preconditioning in human kidney transplantation

Background Ischemia-reperfusion injury (IRI) inevitably occurs during kidney transplantation and extended ischemia is associated with delayed graft function and poor outcomes. Remote ischemic preconditioning (RIPC) is a simple, noninvasive procedure aimed at reducing IRI and improving graft function. Experimental studies have implicated the kynurenine pathway as a protective mechanism behind RIPC. Methods First, paired biopsies from 11 living kidney donors were analyzed to characterize the acute transcriptomic response to IRI. Second, 16 living kidney donors were subjected to either RIPC (n = 9) or no pretreatment (n = 7) to evaluate the impact of RIPC on the transcriptomic response to IRI. Finally, the effect of RIPC on plasma metabolites was analyzed in 49 healthy subjects. Results There was a robust immediate response to IRI in the renal transcriptomes of living-donor kidney transplantation, including activation of the mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) pathways. Preconditioning with RIPC did not significantly alter the transcriptomic response to IRI or the concentration of plasma metabolites. Conclusions The present data validate living-donor kidney transplantation as a suitable model for mechanistic studies of IRI in human kidneys. The failure of RIPC to alter transcriptomic responses or metabolites in the kynurenine pathway raises the question of the robustness of the standard procedure used to induce RIPC, and might explain the mixed results in clinical trials evaluating RIPC as a method to attenuate IRI.

Deciphering Acclimation to Sublethal Combined and Sequential Abiotic Stresses in Arabidopsis thaliana.

Plants are frequently exposed to environmental challenges. Responses to sub-lethal abiotic stress combinations are complex and often distinct from responses to individual stresses and remain poorly understood. Investigating traits and molecular factors mediating acclimation to stress combinations is essential for the development of climate change-resilient field crops. Here, we studied the morphological, physiological, and molecular responses of Arabidopsis thaliana to i) co-occurring high temperature and drought and ii) flooding followed by drought, both of which have increased in frequency due to climate change, and the individual component stresses: high temperature, drought and flooding. A set of 15 physiological and morphological traits were assessed during single and combined stresses. By combining these comprehensive trait analyses with transcriptome characterization, we established the generally additive negative effects of simultaneous or sequential stresses on plant morphology and physiology compared to the corresponding individual stresses. Although drought had a mild effect on various growth, morphological and physiological traits in both stress combinations, a unique transcriptome signature emerged upon combination with high temperature simultaneously or flooding sequentially. Molecular processes identified as important for multi-stress resilience included plastid-nucleus communication, ABA signaling and photo-acclimation. Based on the RNA-seq data, a set of 39 genes was identified as potential multi-stress response regulators. Mutants were tested to validate the contribution of these genes to plant survival and phenotypic acclimation under combined stress. We confirmed the involvement of several genes in regulating phenotypic acclimation traits. Among the identified factors were EARLY FLOWERING 6 (ELF6) and ARABIDOPSIS TÓXICOS EN LEVADURA 80 (ATL80), with substantial effects on plant growth, leaf development and plant survival (wilting) during high-temperature drought and post-submergence drought, respectively.

A field study of the molecular response of brown macroalgae to heavy metal exposure: An (epi)genetic approach

Our understanding of the relative contribution of genetic and epigenetic mechanisms to organismal response to stress is largely biased towards specific taxonomic groups (e.g. seed plants) and environmental stresses (e.g. drought and salinity). In previous work, we found intraspecific differences in heavy metal (HM) uptake capacity in the brown macroalgae Fucus vesiculosus. The molecular mechanisms underlying these differences, however, remained unknown. Here, we evaluated the concentrations of HMs, and characterized the genetic (single nucleotide polymorphisms) and epigenetic (cytosine DNA methylation) variability in reciprocal transplants of F. vesiculosus between two polluted and two unpolluted sites on the NW Spanish coast after 90 days. Genetic and epigenetic differentiation did not explain the phenotypic differentiation observed, possibly due to the combined effect of multiple environmental factors acting on the algae in their natural habitats. Nonetheless, we provide further evidence of intraspecific genetic differentiation in F. vesiculosus at short spatial scales, as well as first evidence of population-specific epigenetic changes in brown macroalgae in response to changes in environmental conditions (i.e. transplantation ex situ). We propose that both genetic and, to some extent, epigenetic mechanisms might impinge upon the adaptive potential of this species to environmental change, but this needs to be further addressed.

Deciphering lipoprotein(a) atherogenicity with use of high-throughput proteomics

Abstract Background Accumulating observational and genetic evidence suggests that lipoprotein(a) [Lp(a)], is significantly more atherogenic than other apolipoprotein-B containing particles. Systemic inflammation is thought to mediate the atherogenic effects of Lp(a). Previous studies have predominantly focused on single inflammatory biomarkers, an approach that fails to capture the broader molecular response to elevated Lp(a) levels. Purpose The aim of this study was to derive a proteome-wide signature of plasma Lp(a) concentrations and subsequently identify the pathways through which Lp(a) influences the risk of coronary artery disease (CAD). Methods This study included 41,123 UK Biobank participants with baseline Lp(a) measurements who also underwent a proteomic assessment. Relative concentration of 2,920 proteins was quantified in EDTA plasma samples using a high-throughput proximity extension assay. Lp(a)-associated proteins were identified in linear regression models, adjusting for age, sex, body mass index, race, smoking status, estimated glomerular filtration rate, medication use, and apolipoprotein B. Proteins linked with Lp(a) concentration were then evaluated for their association with incident CAD risk using Cox proportional hazards models. Significant traits were further included in pathway enrichment analysis. Results Out of 2,920 analyzed proteins (Figure 1), 140 showed a positive association with Lp(a) concentration, while 336 exhibited a negative association after adjustment for multiple testing (False discovery rate &amp;lt; 0.05). The strongest positive associations were observed for apolipoprotein F, group 10 secretory phospholipase A, and C4b-binding protein beta chain. The strongest negative associations were observed for asporin, aminoacylase-1, and retinol-binding protein 5. Among 140 proteins positively associated with Lp(a), 49 were associated with an increased risk of CAD. Conversely, among the 336 proteins negatively associated with Lp(a), 10 were associated with a decreased risk of CAD. Pathway enrichment analysis (Figure 2) indicated that proteins linked with both Lp(a) levels and CAD risk predominantly upregulated pathways related to peptide-ligand receptor signalling, platelet degranulation, neutrophil degranulation, and cytosolic calcium response. Conversely, pathways related to HDL remodeling, PI3K/AKT, KIT, and nuclear receptor signalling were downregulated. Conclusions The greater atherogenic potential of Lp(a) may be attributable to the modulation of several molecular pathways, particularly those involving platelet and neutrophil responses, cell signalling, and lipoprotein metabolism.

Cardiovascular events in CML patients treated with nilotinib: validation of the HFA-ICOS baseline risk score

Abstract Background The therapeutic landscape of chronic myeloid leukaemia (CML) has been transformed by tyrosine kinase inhibitors (TKI). Nilotinib, a potent 2nd generation TKI, showed higher rates of major molecular response than imatinib, however was associated with higher rates of cardiovascular (CV) toxicity. Objectives To describe the CV events associated with nilotinib in a real-world CML population and assess the predictive value of the HFA-ICOS baseline risk score in clinical practice. Methods The HFA-ICOS baseline risk was calculated (low, medium, high /very high) for patients with CML treated with nilotinib between 2006 and 2021. The incidence of all CV events, ischaemic events and Major CV Adverse Events (MACE) were reviewed and compared among the different risk groups. Results A total of two hundred and twenty-nine eligible patients were included in the analysis. The incidence of CV events, ischaemic events, and MACE, while on nilotinib, were 20.9% (95% CI: 15.7% to 26.2%), 12.7% (95% CI: 8.4% to 16.9%), and 12.2% (95% CI: 7.9% to 16.5%) respectively, following a median duration of treatment with nilotinib of 34.4 months for the entire cohort. Patients with a higher HFA-ICOS baseline risk score had higher rates of all CV events (low: 11.2%, medium: 28.2% [HR: 2.8, 95% CI: 1.2 to 6.2], high/very high: 32.4% [HR: 3.5, 95% CI: 1.8 to 6.8]), ischaemic events (low: 5.2%, medium: 17.9% [HR: 3.7, 95% CI: 1.2 to 10.9] , high/very high: 21.6% [HR: 3.7, 95% CI: 1.4 to 9.7]) and MACE (low: 7.8% , medium: 10.3% [HR:1.2, 95% CI: 0.38 to 4.1], high/very high: 20.2% [HR: 2.2, 95% CI: 0.9 to 5.3]). The predictive tool presented an 89% NPV, and an area under the ROC curve: 0.65 for all CV events, an NPV of 95% and AUC 0.68 for ischaemic events and NPV 92% and AUC 0.62 for MACE. Conclusions The HFA-ICOS risk stratification tool has been shown to be an efficient discriminator at low, medium and high/very high risk of developing cardiovascular events, with an overall positive trend towards increasing cardiotoxicity rates with rising risk categories. This study provides evidence to support the use of this predictive tool in nilotinib treated patients, as it also underscores the potential for further improvement in the overall discriminatory ability of the model.

Time-Course Transcriptome Analysis Reveals Distinct Transcriptional Regulatory Networks in Resistant and Susceptible Grapevine Genotypes in Response to White Rot.

Grapevine (Vitis vinifera L.) is a globally significant economic crop. However, its widely cultivated varieties are highly susceptible to white rot disease. To elucidate the mechanisms of resistance in grapevine against this disease, we utilized time-ordered gene co-expression network (TO-GCN) analysis to investigate the molecular responses in the grapevine varieties 'Guifeimeigui' (GF) and 'Red Globe' (RG). An assessment of their resistance demonstrated that GF is highly resistant to white rot, whereas RG is highly susceptible. We conducted transcriptome sequencing and a TO-GCN analysis on leaf samples from GF and RG at seven time points post-infection. Although a significant portion of the differentially expressed genes related to disease resistance were shared between GF and RG, the GF variety rapidly activated its defense mechanisms through the regulation of transcription factors during the early stages of infection. Notably, the gene VvLOX3, which is a key enzyme in the jasmonic acid biosynthetic pathway, was significantly upregulated in GF. Its upstream regulator, Vitvi08g01752, encoding a HD-ZIP family transcription factor, was identified through TO-GCN and yeast one-hybrid analyses. This study provides new molecular insights into the mechanisms of grapevine disease resistance and offers a foundation for breeding strategies aimed at enhancing resistance.

CDK4/6 inhibition initiates cell cycle arrest by nuclear translocation of RB and induces a multistep molecular response

CDK4/6 inhibitors are standard of care in the treatment of metastatic breast cancer. Treatment regimen consists of a combination with endocrine therapy, since their therapeutic efficacy as monotherapy in most clinical trials was rather limited. Thus, understanding the molecular mechanisms that underlie response to therapy might allow for the development of an improved therapy design. We analyzed the response to the CDK4/6 inhibitor palbociclib in bladder cancer cells over a 48-hour time course using RNA sequencing and identified a multi-step mechanism of response. We next translated these results to the molecular mechanism in bladder cancer cells upon PD treatment. The initial step is characterized by translocation of the RB protein into the nucleus by activation of importin α/β, a mechanism that requires the NLS sequence. In parallel, RB is proteolyzed in the cytoplasm, a process regulated by gankyrin and the SCF complex. Only hypophosphorylated RB accumulates in the nucleus, which is an essential step for an efficient therapy response by initiating G1 arrest. This might explain the poor response in RB negative or mutated patients. At later stages during therapy, increased expression of the MiT/TFE protein family leads to lysosomal biogenesis which is essential to maintain this response. Lastly, cancer cells either undergo senescence and apoptosis or develop mechanisms of resistance following CDK4/6 inhibition.

Multi-omics approaches for abiotic stress tolerance in rice (Oryza sativa L.)

Rice, one of the world's staple crops, faces significant challenges due to abiotic stresses such as drought, salinity and extreme temperatures, which threaten global food security. Traditional breeding methods have limitations in developing stress-tolerant rice varieties within a short time frame. Thus, there is a growing interest in employing multi-omics approaches, integrating genomics, transcriptomics, proteomics, metabolomics and epigenomics, to unravel the complex molecular mechanisms underlying abiotic stress tolerance in rice. In contrast to a single-omics method, this combination of multi-dimensional approaches provides an extensive understanding of cellular dynamics under abiotic stress conditions. This review discusses recent advances in multi-omics technologies and their applications in dissecting the molecular responses of rice to abiotic stresses. It highlights the integration of multi-omics data to identify critical genes, pathways and regulatory networks involved in stress responses and tolerance mechanisms.Furthermore, it explores the potential of multi-omics-assisted breeding strategies for developing stress-tolerant rice varieties with improved agronomic traits. The challenges and future perspectives in utilizing multi-omics approaches to enhance rice's abiotic stress tolerance are also discussed. Overall, multi-omics approaches offer a comprehensive platform to understand the molecular basis of stress tolerance in rice and accelerate the development of resilient varieties to ensure global food security.

Impact of Sublethal Insecticides Exposure on Vespa magnifica: Insights from Physiological and Transcriptomic Analyses

Insecticides are widely used to boost crop yields, but their effects on non-target insects like Vespa magnifica are still poorly understood. Despite its ecological and economic significance, Vespa magnifica has been largely neglected in risk assessments. This study employed physiological, biochemical, and transcriptomic analyses to investigate the impact of sublethal concentrations of thiamethoxam, avermectin, chlorfenapyr, and β-cypermethrin on Vespa magnifica. Although larval survival rates remained unchanged, both pupation and fledge rates were significantly reduced. Enzymatic assays indicated an upregulation of superoxide dismutase and catalase activity alongside a suppression of peroxidase under insecticide stress. Transcriptomic analysis revealed increased adenosine triphosphate-related processes and mitochondrial electron transport activity, suggesting elevated energy expenditure to counter insecticide exposure, potentially impairing essential functions like flight, hunting, and immune response. The enrichment of pathways such as glycolysis, hypoxia-inducible factor signaling, and cholinergic synaptic metabolism under insecticide stress highlights the complexity of the molecular response with notable effects on learning, memory, and detoxification processes. These findings underscore the broader ecological risks of insecticide exposure to non-target insects and highlight the need for further research into the long-term effects of newer insecticides along with the development of strategies to safeguard beneficial insect populations.

Quantitative Proteomic Analysis of Brassica Napus Reveals Intersections Between Nutrient Deficiency Responses.

Macronutrients such as nitrogen (N), phosphorus (P), potassium (K) and sulphur (S) are critical for plant growth and development. Field-grown canola (Brassica napus L.) is supplemented with fertilizers to maximize plant productivity, while deficiency in these nutrients can cause significant yield loss. A holistic understanding of the interplay between these nutrient deficiency responses in a single study and canola cultivar is thus far lacking, hindering efforts to increase the nutrient use efficiency of this important oil seed crop. To address this, we performed a comparative quantitative proteomic analysis of both shoot and root tissue harvested from soil-grown canola plants experiencing either nitrogen, phosphorus, potassium or sulphur deficiency. Our data provide critically needed insights into the shared and distinct molecular responses to macronutrient deficiencies in canola. Importantly, we find more conserved responses to the four different nutrient deficiencies in canola roots, with more distinct proteome changes in aboveground tissue. Our results establish a foundation for a more comprehensive understanding of the shared and distinct nutrient deficiency response mechanisms of canola plants and pave the way for future breeding efforts.

Drought Tolerance in Plants: Physiological and Molecular Responses.

Drought, a significant environmental challenge, presents a substantial risk to worldwide agriculture and the security of food supplies. In response, plants can perceive stimuli from their environment and activate defense pathways via various modulating networks to cope with stress. Drought tolerance, a multifaceted attribute, can be dissected into distinct contributing mechanisms and factors. Osmotic stress, dehydration stress, dysfunction of plasma and endosome membranes, loss of cellular turgidity, inhibition of metabolite synthesis, cellular energy depletion, impaired chloroplast function, and oxidative stress are among the most critical consequences of drought on plant cells. Understanding the intricate interplay of these physiological and molecular responses provides insights into the adaptive strategies plants employ to navigate through drought stress. Plant cells express various mechanisms to withstand and reverse the cellular effects of drought stress. These mechanisms include osmotic adjustment to preserve cellular turgor, synthesis of protective proteins like dehydrins, and triggering antioxidant systems to counterbalance oxidative stress. A better understanding of drought tolerance is crucial for devising specific methods to improve crop resilience and promote sustainable agricultural practices in environments with limited water resources. This review explores the physiological and molecular responses employed by plants to address the challenges of drought stress.

Genome-wide identification of CAMTA genes and their expression dependence on light and calcium signaling during seedling growth and development in mung bean

BackgroundCalmodulin-binding transcription activator (CAMTA) is comprised of a group of transcription factors and plays an important role in the Ca2+ signaling pathway, mediating various molecular responses via interactions with other transcription factors and binding to the promoter region of specific genes. Mung beans (Vigna radiata) are one of the most commonly consumed commodities in Asia. To date, CAMTA proteins have not been characterized in this important crop plant.ResultsEight paralogous VrCAMTA genes were identified and found to be distributed on five of the 11 chromosomes. The proteins possessed CG-1 DNA-binding domains with bipartite NLS signals, ankyrin domains, CaM-binding IQ motifs, and CaM-binding domain (CaMBD). The 2 kb upstream regions of VrCAMTA genes contained sequence motifs of abscisic acid-responsive elements (ABRE) and ethylene-responsive elements (ERE), and binding sites for transcription factors of the bZIP and bHLH domains. Analysis of RNA-seq data from a public repository revealed ubiquitous expression of the VrCAMTA genes, as VrCAMTA1 was expressed at the highest level in seedling leaves, whereas VrCAMTA8 was expressed at the lowest level, which agreed with the RT-qPCR analysis performed on the first true leaves. On day four after leaf emergence, all VrCAMTA genes were upregulated, with VrCAMTA1 exhibiting the highest degree of upregulation. In darkness on day 4, upregulation was not observed in most VrCAMTA genes, except VrCAMTA7, for which a low degree of upregulation was found, whereas no difference was found in VrCAMTA8 expression between light and dark conditions. Treatment with calcium ionophores enhanced VrCAMTA expression under light and/or dark conditions at different times after leaf emergence, suggesting that calcium signaling is involved in the light-induced upregulation of VrCAMTA gene expression.ConclusionsThe expression dependence of nearly all VrCAMTA genes on light and calcium signaling suggests their possible differential but likely complementary roles during the early stages of mung bean growth and development.

Treatment-free remission after discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a systematic review and meta-analysis

BackgroundTreatment-free remission (TFR) is a new long-term goal for treating selected patients with chronic myeloid leukemia in the chronic phase (CML-CP). Still, the appropriate group in which TFR can be attempted and the factors influencing it have not yet been identified. This meta-analysis aimed to explore TFR in CML-CP patients who achieved a deep molecular response (DMR) before Tyrosine kinase inhibitors (TKIs) discontinuation and to explore possible factors influencing TFR and the safety of discontinuation.MethodsWe performed a systematic review and single-arm meta-analysis with a systematic search of published literature up to September 2023 in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The assessment was performed using the MINORS scale. Random-effects models were used to calculate outcome metrics, including overall mean TFR rates at 12 and 24 months and subgroup differences. Data synthesis and analysis were done by Stata17.0 software.ResultsA total of 19 single-arm trials involving 2336 patients were included in this meta-analysis, with an overall mean TFR rate of 59% [95CI:0.56–0.63] at 12 months and 55% [95CI:0.52–0.59] at 24 months, and no CML-related deteriorations or deaths reported during the TFR period. Our subgroup analysis showed that better TFR was associated with prior interferon therapy (P = 0.003), and molecular response depth MR5.0 (P = 0.020).ConclusionOur study demonstrated that prior interferon therapy and attainment of a molecular response depth of MR5.0 or greater were associated with higher TFR rates, with patients who attained MR5.0 or greater achieving a TFR rate of up to 62% in the second year after TKI discontinuation. Considering the high heterogeneity of the included trials, the above influences still require further validation and more detailed subgroup analysis in future discontinuation trials.Systematic review registration:https://www.crd.york.ac.uk/prospero/ (Registration No. CRD42023471334).

Evaluating the performance of multi-omics integration: a thyroid toxicity case study.

Multi-omics data integration has been repeatedly discussed as the way forward to more comprehensively cover the molecular responses of cells or organisms to chemical exposure in systems toxicology and regulatory risk assessment. In Canzler etal. (Arch Toxicol 94(2):371-388. https://doi.org/10.1007/s00204-020-02656-y ), we reviewed the state of the art in applying multi-omics approaches in toxicological research and chemical risk assessment. We developed best practices for the experimental design of multi-omics studies, omics data acquisition, and subsequent omics data integration. We found that multi-omics data sets for toxicological research questions were generally rare, with no datasets comprising more than two omics layers adhering to these best practices. Due to these limitations, we could not fully assess the benefits of different data integration approaches or quantitatively evaluate the contribution of various omics layers for toxicological research questions. Here, we report on a multi-omics study on thyroid toxicity that we conducted in compliance with these best practices. We induced direct and indirect thyroid toxicity through Propylthiouracil (PTU) and Phenytoin, respectively, in a 28-day plus 14-day recovery oral rat toxicity study. We collected clinical and histopathological data and six omics layers, including the long and short transcriptome, proteome, phosphoproteome, and metabolome from plasma, thyroid, and liver. We demonstrate that the multi-omics approach is superior to single-omics in detecting responses at the regulatory pathway level. We also show how combining omics data with clinical and histopathological parameters facilitates the interpretation of the data. Furthermore, we illustrate how multi-omics integration can hint at the involvement of non-coding RNAs in post-transcriptional regulation. Also, we show that multi-omics facilitates grouping, and we assess how much information individual and combinations of omics layers contribute to this approach.

Developing forebrain synapses are uniquely vulnerable to sleep loss

Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood. Importantly, problems with sleep are common in neurodevelopmental disorders including autism spectrum disorder (ASD). Moreover, early life sleep disruption in animal models causes long-lasting changes in adult behavior. Divergent plasticity engaged during sleep necessarily implies that developing and adult synapses will show differential vulnerability to SD. To investigate distinct sleep functions and mechanisms of vulnerability to SD across development, we systematically examined the behavioral and molecular responses to acute SD between juvenile (P21 to P28), adolescent (P42 to P49), and adult (P70 to P100) mice of both sexes. Compared to adults, juveniles lack robust adaptations to SD, precipitating cognitive deficits in the novel object recognition task. Subcellular fractionation, combined with proteome and phosphoproteome analysis revealed the developing synapse is profoundly vulnerable to SD, whereas adults exhibit comparative resilience. SD in juveniles, and not older mice, aberrantly drives induction of synapse potentiation, synaptogenesis, and expression of perineuronal nets. Our analysis further reveals the developing synapse as a putative node of convergence between vulnerability to SD and ASD genetic risk. Together, our systematic analysis supports a distinct developmental function of sleep and reveals how sleep disruption impacts key aspects of brain development, providing insights for ASD susceptibility.

Characterization of cellular and molecular immune components of the painted white sea urchin Lytechinus pictus in response to bacterial infection.

Sea urchins are basal deuterostomes that share key molecular components of innate immunity with vertebrates. They are a powerful model for the study of innate immune system evolution and function, especially during early development. Here we characterize the morphology and associated molecular markers of larval immune cell types in a newly developed model sea urchin, Lytechinus pictus. We then challenge larvae through infection with an established pathogenic Vibrio and characterize phenotypic and molecular responses. We contrast these to the previously described immune responses of the purple sea urchin Strongylocentrotus purpuratus. The results revealed shared cellular morphologies and homologs of known pigment cell immunocyte markers (PKS, srcr142) but a striking absence of subsets of perforin-like macpf genes in blastocoelar cell immunocytes. We also identified novel patterning of cells expressing a scavenger receptor cysteine rich (SRCR) gene in the coelomic pouches of the larva (the embryonic stem cell niche). The SRCR signal becomes further enriched in both pouches in response to bacterial infection. Collectively, these results provide a foundation for the study of immune responses in L. pictus. The characterization of the larval immune system of this rapidly developing and genetically enabled sea urchin species will facilitate more sophisticated studies of innate immunity and the crosstalk between the immune system and development.

Transcriptomic Analysis Reveals Dynamics of Gene Expression in Liver Tissue of Spotted Sea Bass Under Acute Thermal Stress.

The spotted sea bass (Lateolabrax maculatus), a eurythermal species, exhibits strong adaptability to temperature variations and presents an ideal model for studying heat stress-responsive mechanisms in fish. This study examined the liver transcriptome of spotted sea bass over a 24-h period following exposure to elevated temperatures, rising from 25 to 32°C. The results revealed significant alterations in gene expression in response to this thermal stress. Specifically, we identified 1702, 1199, 3128, and 2636 differentially expressed genes at 3, 6, 12, and 24h post-stress, respectively. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify specific gene modules responsive to heat stress, containing hub genes such as aco2, eci2, h6pd, suclg1, fgg, fga, fgb, f2, and apoba, which play central roles in the heat stress response. Enrichment analyses via KEGG and GSEA indicated that upregulated differentially expressed genes (DEGs) are predominantly involved in protein processing in the endoplasmic reticulum, while downregulated genes are primarily associated with the AGE-RAGE signaling pathways. Additionally, 272 genes exhibited differential alternative splicing, primarily through exon skipping, underscoring the complexity of transcriptomic adaptations. These findings provide deeper insights into the molecular responses to thermal stress and are crucial for advancing the breeding of heat-resistant strains of spotted sea bass.