Multiple Alterations Research Articles

The effects of changes in the coastline and water depth on tidal prism and water exchange of the Laizhou Bay, China

Laizhou Bay’s coastline has undergone multiple alterations due to human activities such as land reclamation and port construction. These changes in the coastline have led to modifications in the bay’s hydrodynamic conditions, which, in turn, can impact the marine environment and potentially result in a decline in biodiversity. To date, there has been no comprehensive study focusing on the coastline changes and hydrodynamic variations in Laizhou Bay. Therefore, this study utilizes coastline and water depth data from four time points—1990, 2003, 2013, and 2023—to establish a two-dimensional tidal current model of Laizhou Bay using Delft3D. Based on the good agreement between the simulated tidal current results and the observed data, this study further investigates the changes in tidal prism and water exchange in Laizhou Bay. The results indicate that tidal currents dominate the bay, with significant influences of topographic changes on the velocity and direction of tidal flows. The Eulerian residual current velocity is substantially lower than the tidal current velocity. Both tidal and residual currents play a role in controlling the distribution of materials within Laizhou Bay. Over the past three decades (1990-2023), the tidal prism in Laizhou Bay has shown a downward trend, with the tidal prism during spring, intermediate, and neap tides in 2023 reduced by 2.03%, 6.36%, and 10.19%, respectively, compared to 1990. The water exchange capacity has also weakened, with the half-exchange time being 71 days in 1990, increasing to 73 days in 2003 and 81 days in 2013, and showing a slight increase of 1 day in 2023 compared to 2013. Thus, changes in the coastline and water depth of Laizhou Bay can alter its hydrodynamic conditions, significantly impacting the tidal prism and water exchange, leading to a decrease in tidal prism and exchange rate, an increase in the water exchange period, a slower dispersion rate of pollutants, and a reduced water environmental carrying capacity. This research provides a scientific reference for protecting the marine environment and coastal management in Laizhou Bay.

Emotional dysregulation following prenatal stress is associated with altered prefrontal cortex responsiveness to an acute challenge in adolescence

Exposure to prenatal stress (PNS) has the potential to elicit multiple neurobiological alterations and increase the susceptibility to psychiatric disorders. Moreover, gestational stress may sensitize the brain toward an altered response to subsequent challenges. Here, we investigated the effects of PNS in rats and assessed whether these animals exhibit an altered brain responsiveness to an acute stress (AS) during adolescence. From gestational day 14 until delivery, Sprague Dawley dams were exposed to PNS or left undisturbed. During adolescence (PND38 to PND41), offspring were tested in the social interaction and splash test. At PND44 half of the animals were exposed to 5 min of forced swim stress. Males and Females exposed to PNS showed reduced sociability and increased anhedonic-like behavior. At the molecular level, exposure of adolescent rats to AS produced increased activation of the amygdala and ventral and dorsal hippocampus. Regarding the prefrontal cortex (PFC), we observed a pronounced activation in PNS males exposed to AS. Cell-type specific transcriptional analyses revealed a significant imbalance in the activation of PFC excitatory and inhibitory neurons in PNS males and females exposed to AS. Furthermore, stressed males exhibited disrupted HPA-axis function, while females showed impairments in the modulation of antioxidant genes. Our study shows that PNS induces emotional dysregulation and alters the responsiveness of the PFC to an acute stressor. Moreover, the disruption of excitatory and inhibitory balance during adolescence could influence the ability to respond to challenging events that may contribute to precipitate a full-blown pathologic condition.

Single-cell CRISPR screening characterizes transcriptional deregulation in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of leukemia caused by accumulation of multiple genetic alterations in T-cell progenitors. However, for many genes it remains unknown how their mutations contribute to disease development. We therefore performed two single-cell CRISPR screens in primary pro-T cells ex vivo to study the transcriptional impact of loss-of-function alterations in T-ALL and correlate this with effects on cell fitness. The various perturbations were clustered based on their effects on E2F/MYC or STAT/NOTCH signatures, which play a defining role in driving T-cell proliferation. Many of the perturbations resulted in positive effects on the STAT and NOTCH signatures and were predicted to behave as haploinsufficient tumor suppressors in T-ALL. Additionally, Spi1 was identified as an essential gene for pro-T-cell survival, associated with deregulation of the MYC signature and epigenetic consequences. In contrast, Bcl11b was identified as a strong tumor suppressor gene in immature T lymphocytes, associated with deregulation of NF-kB and JAK/STAT signaling. We found a correlation between BCL11B expression level and JAK/STAT pathway mutations in T-ALL patients and demonstrated oncogenic cooperation between Bcl11b inactivation and JAK3 hyperactivation in pro-T cells. Altogether, these single-cell CRISPR screens in pro-T cells provide fundamental insights into the mechanisms of transcriptional deregulation caused by genetic alterations in T-ALL.

Molecular Markers in Follicular and Oncocytic Thyroid Carcinomas: Clinical Application of Molecular Genetic Testing.

Oncocytic thyroid carcinoma (OTC) was previously considered a variant of follicular thyroid carcinoma (FTC) but has recently been reclassified as a separate form of thyroid cancer. This study aimed to demonstrate that FTC and OTC are fundamentally distinct entities that can potentially be differentiated preoperatively through cytology and/or molecular testing. A retrospective chart review of patients diagnosed with FTC and OTC operated upon at two university health centers from January 2016 to September 2023 (n = 3219) was conducted. Molecular testing results were correlated with histopathologic diagnosis. Fifty patients met the inclusion criteria. FTC was identified in 27 (54.0%) patients, and OTC in 23 (46.0%) patients. Patients with OTC were older (61.8 years) than FTC patients (51.2 years) (p = 0.013). Moreover, aggressive tumors were found in 39.1% (9/23) of OTCs compared to 11.1% (3/27) of FTCs (p = 0.021). Amongst Bethesda category III and IV nodules, 17 out of 20 (85.0%) OTC cytology reports demonstrated an oncocytic subtype compared to only 5 out of 24 FTC cytology reports (20.8%) (p = 0.002). On molecular testing, the EIF1AX alteration was exclusively present in OTCs while the PAX8/PPARy and PTEN alterations were exclusively found in FTCs. Copy number alterations (CNAs) were found to be more prevalent in OTC (66.7%) compared to FTC (33.3%), and they were not indicative of tumor aggressiveness. Within the OTC group, all three patients who had a TP53 alteration were diagnosed with aggressive cancer. Lastly, the OTCs exhibited a higher frequency of multiple alterations on molecular testing (66.7%) compared to FTCs (33.3%). To our knowledge, this is the largest study to date comparing the clinical application of abnormalities found on molecular testing for FTC and OTC. It further demonstrates the distinct clinicopathological and molecular characteristics of OTC.

Sarcopenia and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Narrative Review

The primary objective of modern medicine is to extend human life expectancy. Currently, the majority of hospital patients across various clinical settings are elderly or advanced-age individuals, often with multiple comorbidities and age-related alterations in peripheral tissues. One such alteration is sarcopenia, a progressive decline in muscle mass, strength, and function, which significantly increases the risk of disability and mortality in older adults. Sarcopenia is associated with numerous adverse outcomes, and its underlying mechanisms are the subject of ongoing research. This narrative review discusses the epidemiology, pathophysiology, and diagnostic criteria for sarcopenia. It also examines the connections between sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting potential treatment approaches for the coexistence of these two pathologies.

New mechanistic insights of nanoplastics synergistic cadmium induced overactivation of trypsin: Joint analysis from protein multi-level conformational changes and computational modeling

Nanoplastics (NPs) are emerging global contaminants that can exacerbate the animal toxicity and cytotoxicity of cadmium (Cd). However, the mechanisms by which NPs influence the toxic effects of Cd on key functional proteins within the body remain unknown. In this study, trypsin, a protein that is prone to coexist with NPs in the digestive tract, was selected as the target protein. The effects and mechanisms of NPs on Cd2+-induced structural damage at multiple levels and alterations in the biological function of trypsin were investigated using multi-spectroscopy techniques, enzyme activity assays, and computational modeling. Results indicated that the Cd2+-induced decrease and red shift of the trypsin backbone peak were exacerbated by the presence of NPs, leading to more serve backbone loosening. Furthermore, compared to Cd2+, NPs@Cd2+ caused a more pronounced reduction in the α-helix content of trypsin. These structural changes led to the opening of the trypsin pocket and the overactivation of the enzyme (NPs@Cd2+: 227.22%; Cd2+: 53.35%). Ultimately, the formation of a “protein corona” around NPs@Cd2+ and the metal contact of Cd2+ to the trypsin surface were identified as the mechanisms by which NPs enhanced the protein toxicity of Cd2+. This study elucidates, for the first time, the effects and underlying mechanisms of NPs on the toxicity of key functional proteins of Cd2+. These findings offer novel mechanistic insights and critical evidence essential for evaluating the risks associated with NPs.

Growth Phase Contribution in Dictating Drug Transport and Subcellular Accumulation inside Escherichia coli.

Depending upon nutrient availability, bacteria transit to multiple growth phases. The transition from the active to nongrowing phase results in reduced drug efficacy and, in some cases, even multidrug resistance. However, due to multiple alterations in the cell envelope, probing the drug permeation kinetics during growth phases becomes perplexing, especially across the Gram-negative bacteria's complex dual membrane envelope. To advance the understanding of drug permeation during the life cycle of Gram-negative bacteria, we sought to address two underlying objectives: (a) how changes are occurring inside the bacterial envelope during growth and (b) how the drug permeation and accumulation vary across both the membranes and in subcellular compartments during growth. Both objectives are met with the help of nonlinear optical technique second-harmonic generation spectroscopy (SHG). Specifically, using SHG, we probed the transport kinetics and accumulation of a quaternary ammonium compound (QAC), malachite green, inside Escherichia coli in various growth phases. Further insight about another QAC molecule, propidium iodide, is accomplished using fluorescence microscopy. Results indicate that actively growing cells have faster drug transport and higher cytoplasmic accumulation than slow- or nongrowing cells. In this regard, the rpoS gene plays a crucial role in limiting drug transport across the saturation phase cultures. Moreover, within a particular growth phase, membrane permeability undergoes gradual changes much before the subsequent growth phase commences. These outcomes signify the importance of reporting the growth phase and rate in drug efficacy studies.

Hyperglycemia and Venous Thromboembolism.

Patients with diabetes mellitus (DM) have chronically increased blood glucose and multiple physiologic alterations that place them at elevated risk for vascular disease. Traditionally, this vascular risk has mainly referred to chronic atherosclerosis and embolic arterial disease. Retrospective studies have suggested an increased risk of a pulmonary embolism (PE) and deep vein thrombosis (DVT), collectively termed venous thromboembolism (VTE), in patients with DM, but this association has been difficult to demonstrate with comorbidities such as obesity in meta-analysis. Clinical studies have demonstrated worse outcomes for patients with DM who suffer from VTE. In vitro studies show multiple physiologic abnormalities with chronic inflammation, endothelial dysfunction, dysfunction in the coagulation cascade, as well as other changes that drive a vicious cycle of hypercoagulability. Aggressive medical management of DM can improve vascular outcomes, and some anti-hyperglycemic therapies may modify VTE risk as well. Anticoagulation strategies are similar for patients with DM, but with some added considerations, such as high rates of comorbid renal dysfunction. More research is needed to definitively categorize DM as a risk factor for VTE and elucidate specific therapeutic strategies.

The value of preoperative molecular testing in the management of Bethesda V and Bethesda VI thyroid tumors.

The incidence of thyroid cancer has increased over recent years due to the fact that several diagnostic tools, such as neck ultrasound and fine-needle aspiration, are being ever more widely adopted. Lately, another modality which might provide significant information preoperatively on the aggressiveness of a thyroid tumor, its prognosis, and its recurrence rate is molecular testing. We reviewed the literature with regard to the role of preoperative molecular testing in patients with Bethesda V and Bethesda VI thyroid nodules and its impact on choice of the optimal treatment strategy. Several molecular mutations and alterations are associated with thyroid cancer and its biological behavior, such as BRAF-V600E, RET, and TERT promoter. Although the value of preoperative molecular testing for indeterminate nodules (Bethesda III and Bethesda IV) have been analyzed in numerous studies, the impact of preoperative molecular testing on Bethesda V and Bethesda VI thyroid nodules is not adequately described in the current literature. The preoperative recognition of specific molecular mutations, such as BRAFV600E and TERT promoter mutation, might provide more individualized management for thyroid cancer patients by altering the surgical approach and the extent of surgery for patients diagnosed with a more aggressive or iodine-resistant subtype of thyroid cancer.Thyroid cancer is characterized by multiple genetic mutations and alterations and, as a result, preoperative molecular testing of malignant nodules could be a very useful tool for surgeons, enabling them to decide on the most appropriate surgical approach for each patient.

Miocene magmatism in Northern Tunisia and its geodynamic implications

The Nefza igneous rocks in Northern Tunisia belong to the Miocene magmatic belt extending from Northern Tunisia to Morocco and consist mainly of Serravallian–Tortonian granodiorite and rhyodacite (~ 14–8 Ma) and Messinian basalts (~ 8–6 Ma). Differences in geochemical composition between units have been interpreted to be the result of geodynamic processes in the upper mantle below the Western Mediterranean area, but their implications for Northern Tunisia are unclear due to limited data. In this contribution, we present an updated geodynamic model for Northern Tunisia based on new petrographic and whole-rock geochemical results from the Nefza magmatic suite from outcrop and OB45 drill core samples. Petrographic observations show that rhyodacites display a microlithic texture with quartz, plagioclase, K-feldspar, biotite, and glass, whilst granodiorite contains plagioclase, quartz and exhibits fine-grained texture with a 2–3 mm crystal size. The Nefza magmatic rocks are overprinted by multiple weathering and alteration processes with loss of ignition (LOI) ranging between 0.88 and more than 5 wt%. The linear relationships between mobile elements (Ca, Na, P, K, Mg, Si), large-ion lithophile elements (LILE), and LOI suggest element mobilisation during alteration. Major and trace element compositions show the Nefza magmatic rocks plot in the rhyolite, dacite, and trachydacite fields for felsic rocks and plot in the basalt and trachybasalt fields for mafic rocks. Granodiorite and rhyodacite rocks exhibit negative Eu anomalies and a LILE enrichment (Rb, Ba, Pb) relative to high-field-strength elements (HFSE: Nb, Ta, Hf, Zr, REE). Mafic rocks enriched in LILE show geochemical characteristics between calc-alkaline and alkaline trends. Comparison with nearby regions suggests that the generation of calc-alkaline magmas resulted from the partial melting of the lithospheric mantle due to slab break-off or tearing in Eastern Algeria. The upward flow of asthenospheric material through the widening tear in the sinking slab leads to partial melting of the mantle and shallowing of the lithosphere–asthenosphere boundary, ultimately leading to the formation of alkaline magma. The Nefza geochemical variations underscore Mediterranean upper mantle heterogeneity, offering crucial insights into Mediterranean geodynamics. More studies are needed to constrain mantle dynamics and the region’s complex geological history.

The Frequency of Risk Factors for Cleft Lip and Palate in Mexico: A Systematic Review.

Cleft lip and palate is an anomaly that affects both women and men. It is considered to be among the most frequent congenital abnormalities and is related to modifications in chromosomal DNA and multiple genetic alterations. This anomaly can also be associated with various environmental factors, such as tobacco and alcohol consumption, medication use, and exposure to different environmental and industrial toxic substances. The objective of this study was to document the frequency of risk factors related to cleft lip and palate through a systematic review of Mexican studies. In this systematic review, a bibliographic search was conducted following PRISMA guidelines in the databases Scielo, ScienceDirect, PubMed, and EBSCO. Keywords related to cleft lip and palate, epidemiology, and risk factors were used. In all, 3 independent reviewers (J.A.S.L., S.L.V., and N.M.F.) selected and evaluated a total of 17 articles included in this analysis, achieving a coefficient of κ = 0.84. The analysis revealed that the highest frequency of conducted studies was in the State of Mexico. The most common risk factors identified were environmental, pharmacological, consumption habits, and gynecological factors. Identifying the main risk factors for cleft lip and palate in the Mexican population will enable the implementation of preventive measures aimed at reducing exposure to these factors. Additionally, early intervention can improve the quality of life for individuals affected by this condition.

The impact of sex on gene expression in the brain of schizophrenic patients: a systematic review and meta-analysis of transcriptomic studies

BackgroundSchizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society despite its relatively low prevalence. Sex-based differences have been described in schizophrenia epidemiology, symptomatology and outcomes. Different studies explored the impact of schizophrenia in the brain transcriptome, however we lack a consensus transcriptomic profile that considers sex and differentiates specific cerebral regions.MethodsWe performed a systematic review on bulk RNA-sequencing studies of post-mortem brain samples. Then, we fulfilled differential expression analysis on each study and summarized their results with regions-specific meta-analyses (prefrontal cortex and hippocampus) and a global all-studies meta-analysis. Finally, we used the consensus transcriptomic profiles to functionally characterize the impact of schizophrenia in males and females by protein-protein interaction networks, enriched biological processes and dysregulated transcription factors.ResultsWe discovered the sex-based dysregulation of 265 genes in the prefrontal cortex, 1.414 genes in the hippocampus and 66 genes in the all-studies meta-analyses. The functional characterization of these gene sets unveiled increased processes related to immune response functions in the prefrontal cortex in male and the hippocampus in female schizophrenia patients and the overexpression of genes related to neurotransmission and synapses in the prefrontal cortex of female schizophrenia patients. Considering a meta-analysis of all brain regions available, we encountered the relative overexpression of genes related to synaptic plasticity and transmission in females and the overexpression of genes involved in organizing genetic information and protein folding in male schizophrenia patients. The protein-protein interaction networks and transcription factors activity analyses supported these sex-based profiles.ConclusionsOur results report multiple sex-based transcriptomic alterations in specific brain regions of schizophrenia patients, which provides new insight into the role of sex in schizophrenia. Moreover, we unveil a partial overlapping of inflammatory processes in the prefrontal cortex of males and the hippocampus of females.

YAP/TAZ interacts with RBM39 to confer resistance against indisulam

The Hippo pathway and its downstream effectors, Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), are essential for cell growth and organ development. Emerging evidence revealed that the Hippo pathway and YAP/TAZ are frequently dysregulated by multiple genetic alterations in solid cancers including head and neck squamous cell carcinoma (HNSCC); however, the YAP/TAZ-nuclear interactome remains unclear. RNA-binding motif protein 39 (RBM39) enhances transcriptional activity of several transcription factors and also regulates mRNA splicing. Indisulam degrading RBM39 induces alternative splicing, leading to cell death. However, clinical trials of indisulam have failed to show effectiveness. Therefore, clarifying the resistance mechanism against splicing inhibitors is urgently required. In this study, we identified RBM39 as a novel YAP/TAZ-interacting molecule by proteome analysis. RBM39 promoted YAP/TAZ transcriptional activity. We further elucidated that indisulam reduces RBM39/YAP/TAZ-mediated integrin or collagen expression, thereby inactivating focal adhesion kinase (FAK) important for cell survival. Moreover, indisulam also induced alternative splicing of cell cycle- or DNA metabolism-related genes. YAP/TAZ hyperactivation delayed indisulam-induced RBM39 degradation, which restored the integrin/collagen expression to activate FAK, and alternative splicing, thereby conferring resistance against indisulam in vitro and in vivo. Our findings may aid to develop a novel cancer therapy focusing on YAP/TAZ/RBM39 interaction.

The Utility of Lipidomic Analysis in Colorectal Cancer Diagnosis and Prognosis-A Systematic Review of Recent Literature.

Colorectal cancer (CRC) is among the most prevalent and lethal malignancies. Lipidomic investigations have revealed numerous disruptions in lipid profiles across various cancers. Studies on CRC exhibit potential for identifying novel diagnostic or prognostic indicators through lipidomic signatures. This review examines recent literature regarding lipidomic markers for CRC. PubMed database was searched for eligible articles concerning lipidomic biomarkers of CRC. After selection, 36 articles were included in the review. Several studies endeavor to establish sets of lipid biomarkers that demonstrate promising potential to diagnose CRC based on blood samples. Phosphatidylcholine, phosphatidylethanolamine, ceramides, and triacylglycerols (TAGs) appear to offer the highest diagnostic accuracy. In tissues, lysophospholipids, ceramides, and TAGs were among the most altered lipids, while unsaturated fatty acids also emerged as potential biomarkers. In-depth analysis requires both cell culture and animal studies. CRC involves multiple lipid metabolism alterations. Although numerous lipid species have been suggested as potential diagnostic markers, the establishment of standardized methods and the conduct of large-scale studies are necessary to facilitate their clinical application.

Single-cell genomics details the maturation block in BCP-ALL and identifies therapeutic vulnerabilities in DUX4-r cases

AbstractB-cell progenitor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy and is driven by multiple genetic alterations that cause maturation arrest and accumulation of abnormal progenitor B cells. Current treatment protocols with chemotherapy have led to favorable outcomes but are associated with significant toxicity and risk of side effects, highlighting the necessity for highly effective, less toxic, targeted drugs, even in subtypes with a favorable outcome. Here, we used multimodal single-cell sequencing to delineate the transcriptional, epigenetic, and immunophenotypic characteristics of 23 childhood BCP-ALLs belonging to the BCR::ABL1+, ETV6::RUNX1+, high hyperdiploid, and recently discovered DUX4-rearranged (DUX4-r) subtypes. Projection of the ALL cells along the normal hematopoietic differentiation axis revealed a diversity in the maturation pattern between the different BCP-ALL subtypes. Although the BCR::ABL1+, ETV6::RUNX1+, and high hyperdiploidy cells mainly showed similarities to normal pro-B cells, DUX4-r ALL cells also displayed transcriptional signatures resembling mature B cells. Focusing on the DUX4-r subtype, we found that the blast population displayed not only multilineage priming toward nonhematopoietic cells, myeloid, and T-cell lineages, but also an activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling that sensitized the cells to PI3K inhibition in vivo. Given the multilineage priming of DUX4-r blasts with aberrant expression of myeloid marker CD371 (CLL-1), we generated chimeric antigen receptor T cells, which effectively eliminated DUX4-r ALL cells in vivo. These results provide a detailed characterization of BCP-ALL at the single-cell level and reveal therapeutic vulnerabilities in the DUX4-r subtype, with implications for the understanding of ALL biology and new therapeutic strategies.

Utility of Targeted Sequencing Compared to FISH for Detection of Chronic Lymphocytic Leukemia Copy Number Alterations.

Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNAs) and somatic mutations that are central to disease prognosis, risk stratification, and mechanisms of therapy resistance. Fluorescence in situ hybridization (FISH) panels are widely used in clinical applications as the gold standard for screening prognostic chromosomal abnormalities in CLL. DNA sequencing is an alternative approach to identifying CNAs but is not an established method for clinical CNA screening. We sequenced DNA from 509 individuals with CLL or monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, using a targeted sequencing panel of 59 recurrently mutated genes in CLL and additional amplicons across regions affected by clinically relevant CNAs [i.e., del(17p), del(11q), del(13q), and trisomy 12]. We used the PatternCNV algorithm to call CNA and compared the concordance of calling clinically relevant CNAs by targeted sequencing to that of FISH. We found a high accuracy of calling CNAs via sequencing compared to FISH. With FISH as the gold standard, the specificity of targeted sequencing was >95%, sensitivity was >86%, positive predictive value was >90%, and negative predictive value was >84% across the clinically relevant CNAs. Using targeted sequencing, we were also able to identify other common CLL-associated CNAs, including del(6q), del(14q), and gain 8q, as well as complex karyotype, defined as the presence of 3 or more chromosomal abnormalities, in 26 patients. In a single and cost-effective assay that can be performed on stored DNA samples, targeted sequencing can simultaneously detect CNAs, somatic mutations, and complex karyotypes, which are all important prognostic features in CLL.

Identifying genomic regions associated with C4 photosynthetic activity and leaf anatomy in Alloteropsis semialata.

C4 photosynthesis is a complex trait requiring multiple developmental and metabolic alterations. Despite this complexity, it has independently evolved over 60 times. However, our understanding of the transition to C4 is complicated by the fact that variation in photosynthetic type is usually segregated between species that diverged a long time ago. Here, we perform a genome-wide association study (GWAS) using the grass Alloteropsis semialata, the only known species to have C3, intermediate, and C4 accessions that recently diverged. We aimed to identify genomic regions associated with the strength of the C4 cycle (measured using δ13C), and the development of C4 leaf anatomy. Genomic regions correlated with δ13C include regulators of C4 decarboxylation enzymes (RIPK), nonphotochemical quenching (SOQ1), and the development of Kranz anatomy (SCARECROW-LIKE). Regions associated with the development of C4 leaf anatomy in the intermediate individuals contain additional leaf anatomy regulators, including those responsible for vein patterning (GSL8) and meristem determinacy (GIF1). The parallel recruitment of paralogous leaf anatomy regulators between A. semialata and other C4 lineages implies the co-option of these genes is context-dependent, which likely has implications for the engineering of the C4 trait into C3 species.

The effect of early life cytomegalovirus infection on the immune profile of children

Cytomegalovirus (CMV) infection has a life-long impact on the immune system, particularly on memory T cells. However, the effect of early life CMV infection on the phenotype and functionality of T cells in infants and especially longitudinal changes occurring during childhood have not been explored in detail.The phenotype and functionality of peripheral blood CD8+ and CD4+ T cells from children infected with CMV in early life (< 6 months of age) was analyzed using high-dimensional flow cytometry. Samples from CMV IgG-seropositive (CMV+) children were collected at 6 months and 6 years of age and compared to samples from CMV-seronegative (CMV-) children.Early life CMV infection caused multiple alterations within T cells. These include downregulation of CD28 expression and upregulation of CD57 expression within both CD27+ early and CD27- late effector memory CD8+ and CD4+ T-cells at 6 months of age. Of these changes, only alterations within the highly differentiated late effector memory compartment persisted at the age of 6 years.Early life CMV-infection has a distinct impact on developing CD8+ and CD4+ memory T cell compartments. It appears to induce both temporary as well as longer-lasting alterations, which may affect the functionality of the immune system throughout life.

Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease: A Systems Biology Analysis.

Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1α and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1/HK2, ALDOA, ENO2, PKM, LDHA/LDHB, MCT4, PDHA1, PDK1/3, MPC1/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1α, a transcriptional coactivator for transcription factors PPARα, ERRα, and ERRγ, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention.

LPS-related muscle loss is associated with the alteration of Bacteroidetes abundance, systemic inflammation, and mitochondrial morphology in a weaned piglet model.

We previously demonstrated that lipopolysaccharide (LPS) injection-induced immune stress could impair muscle growth in weaned piglets, but the precise mechanisms behind this remain elusive. Here, we found that chronic immune stress induced by LPS resulted in a significant reduction of 36.86% in the total muscle mass of piglets at 5 d post-treatment compared with the control group. At 1 d, prior to muscle mass loss, multiple alterations were noted in response to LPS treatment. These included a reduction in the abundance of Bacteroidetes, an increase in serum concentrations of pro-inflammatory cytokines, compromised mitochondrial morphology, and an upregulation in the expression of dynamin-related protein 1 (Drp1), a critical protein involved in mitochondrial fission. We highlight a strong negative correlation between Bacteroidetes abundance and the levels of serum pro-inflammatory cytokines, corroborated by in vivo intervention strategies in the musculature of both pig and mouse models. Mechanistically, the effects of Bacteroidetes on inflammation and muscle mass loss may involve the signaling pathway of the tauro-β-muricholic acid-fibroblast growth factor 15. Furthermore, the induction of overexpression of inflammatory cytokines, achieved without LPS treatment through oral administration of recombinant human IL-6 (rhIL-6), led to increased levels of circulating cytokines, subsequently causing a decrease in muscle mass. Notably, pre-treatment with Mdivi-1, an inhibitor of Drp-1, markedly attenuated the LPS-induced elevation in reactive oxygen species levels and rescued the associated decline in muscle mass. Collectively, these data indicate that LPS-induced muscle mass loss was linked to the reduction of Bacteroidetes abundance, increased inflammation, and the disruption of mitochondrial morphology. These insights offer promising avenues for the identification of potential therapeutic targets aimed at mitigating muscle mass loss.