Search Results (25,489)

Beginning in 2022, following widespread infection and vaccination among the global population, the SARS-CoV-2 virus mainly evolved to evade immunity derived from vaccines and past infections. This review covers the convergent evolution of structural, nonstructural, and accessory proteins in SARS-CoV-2, with a specific look at common mutations found in long-lasting infections that hint at the virus potentially reverting to an enteric sarbecovirus type. Full article

Acute myeloid leukemia (AML) has a poor survival rate for both pediatric and adult patients due to its frequent relapse. To elucidate the bioenergetic principle underlying AML relapse, we investigated the transcriptional regulation of mitochondrial–nuclear dual genomes responsible for metabolic plasticity in treatment-resistant blasts. Both the gain and loss of function results demonstrated that NFκB2, a noncanonical transcription factor (TF) of the NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) family, can control the expression of TFAM (mitochondrial transcription factor A), which is known to be essential for metabolic biogenesis. Furthermore, genetic tracking and promoter assays revealed that NFκB2 is in the mitochondria and can bind the specific “TTGGGGGGTG” region of the regulatory D-loop domain to activate the light-strand promoter (LSP) and heavy-strand promoter 1 (HSP1), promoters of the mitochondrial genome. Based on our discovery of NFκB2′s novel function of regulating mitochondrial–nuclear dual genomes, we explored a novel triplet therapy including inhibitors of NFκB2, tyrosine kinase, and mitochondrial ATP synthase that effectively eliminated primary AML blasts with mutations of the FMS-related receptor tyrosine kinase 3 (FLT3) and displayed minimum toxicity to control cells ex vivo. As such, effective treatments for AML must include strong inhibitory actions on the dual genomes mediating metabolic plasticity to improve leukemia prognosis. Full article

Background and aims: Brain metastases are prevalent in the late stages of malignant melanoma. Multimodal therapy remains challenging. Patient-derived organoids (PDOs) represent a valuable pre-clinical model, faithfully recapitulating key aspects of the original tumor, including the heterogeneity and the mutational status. This study aimed to establish PDOs from melanoma brain metastases (MBM-PDOs) and to test the feasibility of using them as a model for in vitro targeted-therapy drug testing. Methods: Surgical resection samples from eight patients with melanoma brain metastases were used to establish MBM-PDOs. The samples were enzymatically dissociated followed by seeding into low-attachment plates to generate floating organoids. The MBM-PDOs were characterized genetically, histologically, and immunohistologically and compared with the parental tissue. The MBM-PDO cultures were exposed to dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) followed by a cell viability assessment. Results: Seven out of eight cases were successfully cultivated, maintaining the histological, immunohistological phenotype, and the mutational status of the parental tumors. Five out of seven cases harbored BRAF V600E mutations and were responsive to BRAF and MEK inhibitors in vitro. Two out of seven cases were BRAF wild type: one case harboring an NRAS mutation and the other harboring a KIT mutation, and both were resistant to BRAF and MEK inhibitor therapy. Conclusions: We successfully established PDOs from melanoma brain metastases surgical specimens, which exhibited a consistent histological and mutational profile with the parental tissue. Using FDA-approved BRAF and MEK inhibitors, our data demonstrate the feasibility of employing MBM-PDOs for targeted-therapy in vitro testing. Full article

Adult-onset cases of idiopathic hypogonadotropic hypogonadism (IHH) are characterized by partial or normal puberty development until adolescence and by the impairment of the hypothalamic–pituitary–gonadal (HPG) axis in adulthood. WDR11 and DCC genes are known to be involved in axonal development, particularly of hypothalamic GnRH neurons, and ciliogenesis. We report a female case of adult-onset hypogonadism and cerebellar ataxia, in which we identified two gene mutations. A panel of 48 genes was set up to search for variants in the causative genes of CHH. The variants found were analyzed following the American College of Medical Genetics and Genomics (ACMG) criteria to define their pathogenicity. We identified a missense heterozygous variant in the WDR11 gene NM_018117.12:c.2306T>G (p.Met769Arg) and a mutation in a second gene DCC resulting in amino acid substitutions NM_005215.4:c.3533C>T (p.Ser1178Phe). These variants were classified as being of uncertain clinical significance. We assume that there is a link between the variants found and the impairment of the gonadotrophic and neurological phenotype of the patient. Therefore, we propose the genetic test to identify the best therapeutic approach to identify infertility in female patients with IHH; we believe it is necessary to test WDR11 and DCC genes in larger populations with the same condition to introduce it in future protocols of assessment. Full article

The innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation and progression. Several studies support the idea that innate immunity, through the release of pro- and/or anti-inflammatory cytokines and tumor growth factors, plays a significant role in the pathogenesis, progression, and prognosis of cutaneous malignant melanoma (MM). Cutaneous melanoma is the most common skin cancer, with an incidence that rapidly increased in recent decades. Melanoma is a highly immunogenic tumor, due to its high mutational burden. The metastatic form retains a high mortality. The advent of immunotherapy revolutionized the therapeutic approach to this tumor and significantly ameliorated the patients’ clinical outcome. In this review, we will recapitulate the multiple roles of innate immune cells in melanoma and the related implications for immunotherapy. Full article

The thermal and dynamic effects of the special topography of the Qinghai–Tibet Plateau have a significant impact on rainfall in China. Utilizing NCEP/NCAR monthly reanalysis data alongside precipitation observations from 1936 monitoring stations across China spanning from 1966 to 2022, this study establishes a location index for the thermal low-pressure center situated over the Qinghai–Tibet Plateau. Temporal variations in the location index and summer (July) precipitation patterns in China were studied. Over the past six decades, thermal low-pressure centers have been predominantly positioned near 90° E and 32.5° N within a geopotential height of 4360 gpm, with their distribution extending from east to west rather than from south to north. The longitudinal and latitudinal position indices showed the same linear trend, with a negative trend before the 21st century, and then began to turn positive. Mutation analysis highlights pronounced weakening mutations occurring in 1981 and 1973, with the longitudinal index transitioning from an interannual cycle of approximately 6–8 years, while the latitudinal index displays quasi-cyclic oscillations of 5 and 8 and 12–14 years. Strong negative correlations are evident between the location indices and precipitation along the southeastern edge of the Qinghai–Tibet Plateau and in southern China, contrasting with the positive correlations observed in the central-eastern plateau, northwest, north, and the Huang-Huai region of China. The center of the thermal low is located to the east and north, corresponding to the deeper surface thermal low in most areas east of China, and the stronger transport of warm and wet air from the southwest wind, leading to greater convergence of southwest wind and northwest wind in China’s northern region. The south of the Yangtze River is controlled by the strengthening West Pacific subtropical high and South Asia high, resulting in a significant decrease in precipitation, and the warm and humid air from the southwest on the west side of the West Pacific subtropical high is also transported to the north, increasing the precipitation in most parts of the north. Full article

The kiwifruit, Actinidia genus, has emerged as a nutritionally rich and economically significant crop with a history rooted in China. This review paper examines the global journey of the kiwifruit, its genetic diversity, and the role of advanced breeding techniques in its cultivation and improvement. The expansion of kiwifruit cultivation from China to New Zealand, Italy, Chile and beyond, driven by the development of new cultivars and improved agricultural practices, is discussed, highlighting the fruit’s high content of vitamins C, E, and K. The genetic resources within the Actinidia genus are reviewed, with emphasis on the potential of this diversity in breeding programs. The review provides extensive coverage to the application of modern omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, which have revolutionized the understanding of the biology of kiwifruit and facilitated targeted breeding efforts. It examines both conventional breeding methods and modern approaches, like marker-assisted selection, genomic selection, mutation breeding, and the potential of CRISPR-Cas9 technology for precise trait enhancement. Special attention is paid to interspecific hybridization and cisgenesis as strategies for incorporating beneficial traits and developing superior kiwifruit varieties. This comprehensive synthesis not only sheds light on the current state of kiwifruit research and breeding, but also outlines the future directions and challenges in the field, underscoring the importance of integrating traditional and omics-based approaches to meet the demands of a changing global climate and market preferences. Full article

The emergence of drug-resistance-inducing mutations in Hepatitis C virus (HCV) coupled with genotypic heterogeneity has made targeting NS3/4A serine protease difficult. In this work, we investigated the mutagenic variations in the binding pocket of Genotype 3 (G3) HCV NS3/4A and evaluated ligands for efficacious inhibition. We report mutations at 14 positions within the ligand-binding residues of HCV NS3/4A, including H57R and S139P within the catalytic triad. We then modelled each mutational variant for pharmacophore-based virtual screening (PBVS) followed by covalent docking towards identifying a potential covalent inhibitor, i.e., cpd-217. The binding stability of cpd-217 was then supported by molecular dynamic simulation followed by MM/GBSA binding free energy calculation. The free energy decomposition analysis indicated that the resistant mutants alter the HCV NS3/4A–ligand interaction, resulting in unbalanced energy distribution within the binding site, leading to drug resistance. Cpd-217 was identified as interacting with all NS3/4A G3 variants with significant covalent docking scores. In conclusion, cpd-217 emerges as a potential inhibitor of HCV NS3/4A G3 variants that warrants further in vitro and in vivo studies. This study provides a theoretical foundation for drug design and development targeting HCV G3 NS3/4A. Full article

The pathogenic expansion of the intronic GGGGCC hexanucleotide located in the non-coding region of the C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation leads to the accumulation of toxic RNA foci and dipeptide repeats (DPRs), as well as reduced levels of the C9orf72 protein. Thus, both gain and loss of function are coexisting pathogenic aspects linked to C9orf72-ALS/FTD. Synaptic alterations have been largely described in C9orf72 models, but it is still not clear which aspect of the pathology mostly contributes to these impairments. To address this question, we investigated the dynamic changes occurring over time at the synapse upon accumulation of poly(GA), the most abundant DPR. Overexpression of this toxic form induced a drastic loss of synaptic proteins in primary neuron cultures, anticipating autophagic defects. Surprisingly, the dramatic impairment characterizing the synaptic proteome was not fully matched by changes in network properties. In fact, high-density multi-electrode array analysis highlighted only minor reductions in the spike number and firing rate of poly(GA) neurons. Our data show that the toxic gain of function linked to C9orf72 affects the synaptic proteome but exerts only minor effects on the network activity. Full article

The first line of defense against invading pathogens usually relies on innate immune systems. In this context, the recognition of exogenous RNA structures is primordial to fight, notably, against RNA viruses. One of the most efficient immune response pathways is based on the sensing of RNA double helical motifs by the oligoadenylate synthase (OAS) proteins, which in turn triggers the activity of RNase L and, thus, cleaves cellular and viral RNA. In this contribution, by using long-range molecular dynamics simulations, complemented with enhanced sampling techniques, we elucidate the structural features leading to the activation of OAS by interaction with a model double-strand RNA oligomer mimicking a viral RNA. We characterize the allosteric regulation induced by the nucleic acid leading to the population of the active form of the protein. Furthermore, we also identify the free energy profile connected to the active vs. inactive conformational transitions in the presence and absence of RNA. Finally, the role of two RNA mutations, identified as able to downregulate OAS activation, in shaping the protein/nucleic acid interface and the conformational landscape of OAS is also analyzed. Full article

Glioblastoma cell lines derived from different patients are widely used in tumor biology research and drug screening. A key feature of glioblastoma is the high level of inter- and intratumor heterogeneity that accounts for treatment resistance. Our aim was to investigate whether intratumor heterogeneity is maintained in cell models. Single-cell RNA sequencing was used to investigate the cellular composition of a tumor sample and six patient-derived glioblastoma cell lines. Three cell lines preserved the mutational profile of the original tumor, whereas three others differed from their precursors. Copy-number variation analysis showed significantly rearranged genomes in all the cell lines and in the tumor sample. The tumor had the most complex cell composition, including cancer cells and microenvironmental cells. Cell lines with a conserved genome had less diverse cellularity, and during cultivation, a relative increase in the stem-cell-derived progenitors was noticed. Cell lines with genomes different from those of the primary tumors mainly contained neural progenitor cells and microenvironmental cells. The establishment of cell lines without the driver mutations that are intrinsic to the original tumors may be related to the selection of clones or cell populations during cultivation. Thus, patient-derived glioblastoma cell lines differ substantially in their cellular profile, which should be taken into account in translational studies. Full article

The seepage characteristics of clay core walls are crucial for the seepage safety of core rockfill dams, with the permeability coefficient in the unsaturated zone being nonlinear. To accurately determine the unsaturated seepage parameters in clay core rockfill dams, this paper first proposes an enhanced reptile search algorithm (ERSA) by applying three improvement strategies: Arnold’s cat chaotic map, nonlinear evolutionary factor, and adaptive Cauchy–Gaussian mutation with variable weight. Then, by integrating the ERSA with the unsaturated seepage finite element method, an inverse modeling approach is developed. This approach is applied to an actual rockfill dam with operational monitoring data to determine the unsaturated seepage parameters of the clay core. Results indicate that the ERSA outperforms the original RSA in test functions, and the calculation results of the seepage parameters determined through inversion are consistent with the monitoring data, showing an overall mean absolute error of 1.086 m. The inverse modeling approach provides a valuable reference for determining unsaturated seepage parameters in similar clay core rockfill dams. Full article

The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are involved in key metabolic processes in human cells, regulating differentiation, proliferation, and oxidative damage response. IDH mutations have been associated with tumor development and progression in various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, and other tumor types and have become crucial markers in molecular classification and prognostic assessment. The intratumoral and serum levels of D-2-hydroxyglutarate (D-2-HG) could serve as diagnostic biomarkers for identifying IDH mutant (IDHmut) tumors. As a result, an increasing number of clinical trials are evaluating targeted treatments for IDH1/IDH2 mutations. Recent studies have shown that the focus of these new therapeutic strategies is not only the neomorphic activity of the IDHmut enzymes but also the epigenetic shift induced by IDH mutations and the potential role of combination treatments. Here, we provide an overview of the current knowledge about IDH mutations in solid tumors, with a particular focus on available IDH-targeted treatments and emerging results from clinical trials aiming to explore IDHmut tumor-specific features and to identify the clinical benefit of IDH-targeted therapies and their combination strategies. An insight into future perspectives and the emerging roles of circulating biomarkers and radiomic features is also included. Full article

Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Treatment is not uniform, with management varying from observation to stem cell transplant. The aim of our retrospective review is to describe the treatment and outcomes of a cohort of patients with JMML or Noonan Syndrome-associated Myeloproliferative Disorder (NS-MPD) to provide management guidance for this rare and heterogeneous disease. We report on 22 patients with JMML or NS-MPD managed at three institutions in the Texas Medical Center. Of patients with known genetic mutations and cytogenetics, 6 harbored germline mutations, 12 had somatic mutations, and 9 showed cytogenetic abnormalities. Overall, 14/22 patients are alive. Spontaneous clinical remission occurred in one patient with somatic NRAS mutation, as well as two with germline PTPN11 mutations with NS-MPD, and two others with germline PTPN11 mutations and NS-MPD remain under surveillance. Patients with NS-MPD were excluded from treatment analysis as none required chemotherapeutic intervention. All patients (5/5) treated with 5-azacitidine alone and one of the four treated with 6-mercaptopurine monotherapy had a reduction in mutant variant allele frequency. Transformation to acute myeloid leukemia was seen in two patients who both died. Among patients who received transplants, 7/13 are alive, and relapse post-transplant occurred in 3/13 with a median time to relapse of 3.55 months. This report provides insight into therapy responses and long-term outcomes across different genetic subsets of JMML and lends insight into the expected time to spontaneous resolution in patients with NS-MPD with germline PTPN11 mutations. Full article

The formation of embryonic axes is a critical step during animal development, which contributes to establishing the basic body plan in each particular organism. Wnt signaling pathways play pivotal roles in this fundamental process. Canonical Wnt signaling that is dependent on β-catenin regulates the patterning of dorsoventral, anteroposterior, and left–right axes. Non-canonical Wnt signaling that is independent of β-catenin modulates cytoskeletal organization to coordinate cell polarity changes and asymmetric cell movements. It is now well documented that components of these Wnt pathways biochemically and functionally interact to mediate cell–cell communications and instruct cellular polarization in breaking the embryonic symmetry. The dysfunction of Wnt signaling disrupts embryonic axis specification and proper tissue morphogenesis, and mutations of Wnt pathway genes are associated with birth defects in humans. This review discusses the regulatory roles of Wnt pathway components in embryonic axis formation by focusing on vertebrate models. It highlights current progress in decoding conserved mechanisms underlying the establishment of asymmetry along the three primary body axes. By providing an in-depth analysis of canonical and non-canonical pathways in regulating cell fates and cellular behaviors, this work offers insights into the intricate processes that contribute to setting up the basic body plan in vertebrate embryos. Full article