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Results for “driver mutations”

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At least 235 records · Page 13Linked to original sources

PubMed2003

Genome-wide-array-based comparative genomic hybridization reveals genetic homogeneity and frequent copy number increases encompassing CCNE1 in fallopian tube carcinoma.

Fallopian tube carcinoma (FTC) is a rare, poorly studied and aggressive cancer, associated with poor survival. Since tumorigenesis is related to the acquisition of genetic changes, we used genome-wide array comparative genomic hybridization to analyse copy number aberrations occurring in FTC in order to obtain a better understanding of FTC carcinogenesis and to identify prognostic events and targets for therapy. We used arrays of 2464 genomic clones, providing approximately 1.4 Mb resolution across the genome to map genomic DNA copy number aberrations quantitatively from 14 FTC onto the human genome sequence. All tumors showed a high frequency of copy number aberrations with recurrent gains on 3q, 6p, 7q, 8q, 12p, 17q, 19 and 20q, and losses involving chromosomes 4, 5q, 8p, 16q, 17p, 18q and X. Recurrent regions of amplification included 1p34, 8p11-q11, 8q24, 12p, 17p13, 17q12-q21, 19p13, 19q12-q13 and 19q13. Candidate, known oncogenes mapping to these amplicons included CMYC (8q24), CCNE1 (19q12-q21) and AKT2 (19q13), whereas PIK3CA and KRAS, previously suggested to be candidate driver genes for amplification, mapped outside copy number maxima on 3q and 12p, respectively. The FTC were remarkably homogeneous, with some recurrent aberrations occurring in more than 70% of samples, which suggests a stereotyped pattern of tumor evolution.

Carcinoma↗

PubMed2003

Targeted gene expression in Drosophila dopaminergic cells using regulatory sequences from tyrosine hydroxylase.

Dopamine (DA) is the only catecholaminergic neurotransmitter in the fruit fly Drosophila melanogaster. Dopaminergic neurons have been identified in the larval and adult central nervous system (CNS) in Drosophila and other insects, but no specific genetic tool was available to study their development, function, and degeneration in vivo. In Drosophila as in vertebrates, the rate-limiting step in DA biosynthesis is catalyzed by the enzyme tyrosine hydroxylase (TH). The Drosophila TH gene (DTH) is specifically expressed in all dopaminergic cells and the corresponding mutant, pale (ple), is embryonic lethal. We have performed ple rescue experiments with modified DTH transgenes. Our results indicate that partially redundant regulatory elements located in DTH introns are required for proper expression of this gene in the CNS. Based on this study, we generated a GAL4 driver transgene, TH-GAL4, containing regulatory sequences from the DTH 5' flanking and downstream coding regions. TH-GAL4 specifically expresses in dopaminergic cells in embryos, larval CNS, and adult brain when introduced into the Drosophila genome. As a first application of this driver, we observed that in vivo inhibition of DA release induces a striking hyperexcitability behavior in adult flies. We propose that TH-GAL4 will be useful for studies of the role of DA in behavior and disease models in Drosophila.

Animals↗

PubMed2001

Reduced placental 11beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms.

11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2) inactivates cortisol to cortisone. In the placenta 11beta-HSD2 activity is thought to protect the fetus from the deleterious effects of maternal glucocorticoids. Patients with apparent mineralocorticoid excess owing to mutations in the 11beta-HSD2 gene invariably have reduced birth weight, and we have recently shown reduced placental 11beta-HSD2 activity in pregnancies complicated by intrauterine growth restriction. This is reflected in the literature by evidence of hypercortisolemia in the fetal circulation of small babies. In this study we have determined the levels of placental 11beta-HSD2 mRNA expression across normal gestation (n = 86 placentae) and in pregnancies complicated by intrauterine growth restriction (n = 19) and evaluated the underlying mechanism for any aberrant 11beta-HSD2 mRNA expression in intrauterine growth restriction. 11beta-HSD2 mRNA expression increased more than 50-fold across gestation, peaking at term. Placental 11beta-HSD2 mRNA levels were significantly decreased in intrauterine growth restriction pregnancies when compared with gestationally matched, appropriately grown placentae [e.g. at term DeltaCt (11beta-hydroxysteroid dehydrogenase type 2/18S) 12.8 +/- 0.8 (mean +/- SE) vs. 10.2 +/- 0.2, respectively, P < 0.001]. These differences were not attributable to changes in trophoblast mass in intrauterine growth restriction placentae, as assessed by parallel analyses of cytokeratin-8 mRNA expression. No mutations were found in the 11beta-HSD2 gene in the intrauterine growth restriction cohort, and imprinting analysis revealed that the 11beta-HSD2 gene was not imprinted. Although the underlying cause is unknown, 11beta-HSD2 gene expression is reduced in intrauterine growth restriction pregnancies. These data highlight the important role of 11beta-HSD2 in regulating fetal growth, a known factor in determining fetal morbidity but also the subsequent development of cardiovascular disease in adulthood.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed2000

Replicon vectors derived from Sindbis virus and Semliki forest virus that establish persistent replication in host cells.

Alphavirus replicon vectors are well suited for applications where transient, high-level expression of a heterologous gene is required. Replicon vector expression in cells leads to inhibition of host macromolecular synthesis, culminating in eventual cell death by an apoptotic mechanism. For many applications, including gene expression studies in cultured cells, a longer duration of transgene expression without resulting cytopathic effects is useful. Recently, noncytopathic Sindbis virus (SIN) variants were isolated in BHK cells, and the mutations responsible were mapped to the protease domain of nonstructural protein 2 (nsP2). We report here the isolation of additional variants of both SIN and Semliki Forest virus (SFV) replicons encoding the neomycin resistance gene that can establish persistent replication in BHK cells. The SIN and SFV variant replicons resulted from previously undescribed mutations within one of three discrete regions of the nsP2 gene. Differences among the panel of variants were observed in processing of the nonstructural polyprotein and in the ratios of subgenomic to genomic RNAs. Importantly, high-level expression of a heterologous gene was retained with most replicons. Finally, in contrast to previous studies, efficient packaging was obtained with several of the variant replicons. This work expands the utility of noncytopathic replicons and the understanding of how alphavirus replicons establish persistent replication in cultured cells.

Genetic Vectors↗

PubMed2026

KEAP1 loss-of-function suppresses immunogenic ferroptosis and limits PD-1 blockade efficacy through an NRF2-FSP1 pathway.

Loss-of-function mutations in Kelch-like ECH-associated protein 1 (KEAP1) frequently occur in lung adenocarcinoma and are associated with poor prognosis and limited benefit from immunotherapy. However, the mechanisms linking KEAP1 deficiency to immune evasion remain elusive. We combined clinical data analysis, in vivo tumor models, and in vitro co-culture systems to investigate how KEAP1 deficiency shapes dendritic cell (DC) biology and response to PD-1 blockade. Ferroptosis induction assays, damage-associated molecular patterns (DAMPs) quantification, cytokine profiling, and mechanistic interrogation of the FSP1-CoQ10 axis were performed to delineate pathways.KEAP1 mutations correlated with poor response to PD-1 blockade and reduced DC infiltration. In mice, KEAP1-deficient tumors exhibited accelerated growth and reduced DC and CD8+ T-cell infiltration, consistent with an immune-cold phenotype. Mechanistically, KEAP1 loss impaired DC function in vitro, as evidenced by reduced maturation, phagocytosis, and naïve CD8+ T-cell priming capacity. This defect was linked to two mechanisms. First, KEAP1-deficient tumor cells resisted ferroptosis and failed to release immunogenic DAMPs, including extracellular ATP, HMGB1, and calreticulin. Second, KEAP1 deficiency reprogrammed the cytokine secretion profile, with downregulation of CCL2, IL-6, CXCL1, and CXCL2, thereby diminishing DC recruitment and inflammatory signaling. Notably, inhibition of the FSP1-CoQ10 antioxidant axis restored ferroptosis-associated immunogenic cell death. Our study identifies KEAP1 deficiency as a driver of immune-cold tumor microenvironments and resistance to PD-1 blockade, acting through impaired ferroptosis-induced immunogenic cell death and disrupted DC function. Genetic FSP1 deletion restored ferroptosis-associated immunogenicity and DC activation in KEAP1-deficient cells, supporting FSP1 as a potential therapeutic target for further in vivo evaluation.

DAMPs↗

PubMed2005

Cell-nonautonomous induction of ovarian and uterine serous cystadenomas in mice lacking a functional Brca1 in ovarian granulosa cells.

Women with germline mutations in BRCA1 have a 40% risk of developing ovarian cancer by age 70 and are also predisposed to cancers of the fallopian tubes. Given that ovulatory activity is a strong risk factor for sporadic ovarian cancer, we hypothesized that reduced BRCA1 expression might predispose to gynecological cancers indirectly, by influencing ovarian granulosa cells. These cells secrete sex steroids that control the ovulatory cycle and influence the growth of ovarian epithelial tumors. Granulosa cells also secrete mullerian inhibiting substance (MIS), a hormone that inhibits both the formation of female reproductive organs in male embryos and the proliferation of ovarian epithelial tumor cells. We tested this hypothesis by using the Cre-lox system to inactivate the Brca1 gene in mouse ovarian granulosa cells. A truncated form of the Fsh receptor promoter served as the Cre driver. Here, we show that indeed, inactivation of the Brca1 gene in granulosa cells led to the development of cystic tumors in the ovaries and uterine horns. These tumors carried normal Brca1 alleles, supporting the view that Brca1 may influence tumor development indirectly, possibly through an effector secreted by granulosa cells.

Animals↗

PubMed2001

Carbonic anhydrase: in the driver's seat for bicarbonate transport.

Carbonic anhydrases are a widely expressed family of enzymes that catalyze the reversible reaction: CO(2) + H(2)O <=> HCO(3)(-) + H(+). These enzymes therefore both produce HCO(3)(-) for transport across membranes and consume HCO(3)(-) that has been transported across membranes. Thus these enzymes could be expected to have a key role in driving the transport of HCO(3)(-) across cells and epithelial layers. Plasma membrane anion exchange proteins (AE) transport chloride and bicarbonate across most mammalian membranes in a one-for-one exchange reaction and act as a model for our understanding of HCO(3)(-) transport processes. Recently it was shown that AE1, found in erythrocytes and kidney, binds carbonic anhydrase II (CAII) via the cytosolic C-terminal tail of AE1. To examine the physiological consequences of the interaction between CAII and AE1, we characterized Cl(-)/HCO(3)(-) exchange activity in transfected HEK293 cells. Treatment of AE1-transfected cells with acetazolamide, a CAII inhibitor, almost fully inhibited anion exchange activity, indicating that endogenous CAII activity is essential for transport. Further experiments to examine the role of the AE1/CAII interaction will include measurements of the transport activity of AE1 following mutation of the CAII binding site. In a second approach a functionally inactive CA mutant, V143Y, will be co-expressed with AE1 in HEK293 cells. Since over expression of V143Y CAII would displace endogenous wild-type CAII from AE1, a loss of transport activity would be observed if binding to the AE1 C-terminus is required for transport.

Animals↗

PubMed1996

Mitochondrial D-loop "signatures" produced by low-stringency single specific primer PCR constitute a simple comparative human identity test.

We have developed a technique called "LSSP-PCR" (low-stringency single specific primer PCR) that detects single or multiple mutations in DNA. A purified DNA fragment is submitted to PCR by using a single primer specific for one of the extremities of the fragment, under conditions of very low stringency. The primer hybridizes specifically to its complementary extremity and nonspecifically to multiple sites within the fragment, in a sequence-dependent manner. A complex set of reaction products is thus created that, when separated by electrophoresis, constitutes a unique "gene signature." We here report the application of LSSP-PCR to the detection of sequence variation in the control (D-loop) region of human mtDNA, which is known to differ significantly between unrelated individuals. We prepared human DNA samples from blood and amplified a 1024-bp portion of the mtDNA control region, using primers L15996 and H408. The amplified mtDNA fragments were then reamplified under LSSP-PCR conditions by using L15996 or H408 as drivers to produce complex signatures that always differed between unrelated individuals and yet were highly reproducible. In contrast, all mother-child pairs tested were identical, as expected from the matrilineal inheritance of mtDNA. Thus, the use of LSSP-PCR to produce D-loop signatures constitutes a powerful new technique for mtDNA-based comparative identity testing.

Base Sequence↗

PubMed2026

Distinct molecular profiles of indeterminate and malignant thyroid nodules in patients under 21 years of age.

Although uncommon, thyroid nodules (TN) in pediatric and young adult patients carry higher malignancy risk and often present with a high burden of metastatic disease than adults. The molecular features underlying this distinct clinical behavior remain unclear. We analyzed Afirma Genomic Sequencing Classifier (GSC) data from 283,621 TN, comparing patients <21 and ≥21 years. Cytology (Bethesda), GSC benign (B) vs suspicious (S) calls, and Afirma Xpression Atlas (XA) variant/fusion profiles were evaluated in GSC-S and Bethesda V/VI samples. Genome-wide expression was used to derive pathway signatures and thyroid cancer-related scores: BRAF-RAS score (BRS), ERK, follicular and epithelial-to-mesenchymal transition (FMT, EMT) and thyroid differentiation scores (TDS). Among 2,397 patients <21 (median age 18.9; 81.4% female) and 281,224 adults ≥21 (median age 59.8; 77.1% female), <21 samples showed more Bethesda V/VI cytology (14.5% vs 5.0%; p<0.0001) and a lower GSC-B rate (43.5% vs 68.8%; p<0.0001). In GSC-S samples, total variant detection was higher in <21 (45.3% vs 37.4%), with enriched BRAF p.V600E, TSHR, and DICER1 variants, while HRAS variants were more common in adults (all p<0.01). Gene fusions involving RET, NTRK3 and ALK were enriched in <21 (14.5% vs 5.5%; p<0.0001). TERT promoter mutations were absent in <21 yrs GSC-S and Bethesda V/VI samples (vs 4.2% and 9.3% in adults). GSC-S <21 showed cell-cycle pathway enrichment. RET/NTRK/ALK-positive <21 demonstrated enrichment of angiogenesis and EMT pathways, higher ERK/EMT/FMT scores, and lower BRS/TDS scores vs genotyped-matched adults. These molecular differences provide mechanistic insight into the more invasive phenotype in pediatric and young adult TN.

BRAF↗

PubMed2025

Clinical, Morphologic, and Molecular Findings in Neurotrophic Tyrosine Receptor Kinase 3 (NTRK3) Fusion Spitz Neoplasms.

Neurotrophic tyrosine receptor kinase 3 (NTRK3) fusions are a relatively common driver of Spitz neoplasms. This subset of Spitz neoplasms may have smaller cells without the typical abundant glassy eosinophilic cytoplasm seen in most Spitz neoplasms. This can make it difficult to recognize them as belonging to the Spitz family and potentially result in misdiagnosis as melanoma. In this study, we assessed the clinical, morphologic, and genomic features of 60 NTRK3 fusion Spitz neoplasms (13 previously reported and 47 new cases) and performed a comprehensive review of the literature. We identified 5 characteristic morphologic patterns: (1) conventional Spitz nevus (SN) or Spitz tumor (ST), (2) spindle cell nevus of Reed, (3) spindle cell tumor of Reed, (4) dysplastic SN, and (5) exclusively spindle cell variant of SN/ST. The most common fusion partners were MYO5A and ETV6. DNA copy number changes were infrequent (18% of cases), with an average of 1 copy number variant per case. Among 54 cases tested for a TERT promoter mutation, all were negative. One case had a homozygous deletion of 9p21. The majority of cases were diagnosed as SN or Reed nevi (n = 37), rather than ST or Reed tumor (n = 23), and none were diagnosed as Spitz melanoma. Among the 30 patients with outcome data, none experienced recurrence following excision (mean follow-up time was 15 months). NTRK3 fusions can produce morphologic variants of Spitz neoplasms that may be difficult to recognize as belonging to the Spitz family. Familiarity with these morphologic patterns can facilitate identification of the NTRK3 fusion, optimizing classification and distinction from melanoma.

Humans↗

PubMed2026

A HUWE1 regulatory helix gates ASCL1 degradation through its C-terminal phospho-degron in small cell lung cancer.

Lineage-defining transcription factors are key oncogenic drivers but remain difficult to target pharmacologically due to the absence of ligandable pockets. The molecular rules governing substrate recognition by large HECT ubiquitin ligases also remain incompletely understood, limiting efforts to exploit these enzymes for targeted protein degradation. Here we combine genome-wide CRISPR knockout screening with base editor tiling screens at amino acid resolution, both coupled to an endogenous knock-in reporter of the SCLC lineage oncogenic transcription factor ASCL1, to systematically interrogate the mechanisms governing its degradation. These complementary screens unbiasedly identify the HECT ubiquitin ligase HUWE1 as the dominant regulator of ASCL1 stability in small cell lung cancer (SCLC) and resolve a conserved C-terminal phospho-degron centered on Ser207 and terminal Trp/Phe residues that are required for HUWE1 docking and ubiquitin-mediated degradation. Unexpectedly, base editor screening further uncovers a previously unrecognized regulatory module within HUWE1: a short negatively charged helix that functions as an autoinhibitory gate controlling access of phospho-degron substrates to HUWE1. Charge-flipping mutations within this regulatory helix relieve autoinhibition and accelerate degradation of multiple HUWE1 phospho-degron substrates, including ASCL1 and the canonical HUWE1 substrate DDIT4. Stabilization of ASCL1 through degron disruption paradoxically impairs SCLC proliferation, revealing that dynamic proteasome-coupled turnover is required for transcription factor function. Together, these findings reveal molecular rules governing HUWE1 phospho-degron recognition and identify a regulatory gate controlling substrate engagement. They also illustrate a generalizable strategy for resolving degradation mechanisms of undruggable transcription factors in their endogenous cellular context.

ASCL1↗

PubMed2005

Loss- and gain-of-function analysis of the lipid raft proteins Reggie/Flotillin in Drosophila: they are posttranslationally regulated, and misexpression interferes with wing and eye development.

Reggie/Flotillin proteins are upregulated after optic nerve dissection and evolutionary highly conserved components of lipid rafts. Whereas many biochemical and cell culture studies suggest an involvement in the assembly of multiprotein complexes at cell contact sites, not much is known about their biological in vivo functions. We therefore set out to study the expression pattern and the effects of loss- and gain-of-function in the Drosophila melanogaster model system. We found that in flies these proteins are mainly expressed in axons at the root of fiber tracts, in places where strong fasciculation is required, e.g. at the neck of the peduncle of the mushroom bodies and in the optic chiasms. Despite their evolutionary conservation which implies fundamental and important functions, a P-element-induced null mutant (KG00210) of reggie1/flotillin2 (reggie1/flo2) in D. melanogaster shows no apparent phenotypic defects. This was even more surprising as we show that in this reggie1/flo2 null mutant the paralogous Reggie2/Flo1 protein is unstable and degraded, while the transcript is still present. The requirement of Reggie1/Flo2 for Reggie2/Flo1 stabilization is confirmed by misexpression experiments. Reggie2/Flo1 can only be misexpressed when Reggie1/Flo2 is provided as well. Conversely, Reggie1/Flo2 immunoreactivity can be detected, when its transgene is misexpressed alone. Using appropriate Gal4 driver lines, misexpression of Reggie1/Flo2 alone or together with Reggie2/Flo1 in the eye imaginal disc results in a specific and severe mislocalization of cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) (while DE-Cadherin is unaffected) and in differentiation defects pointing to impaired signaling. In the wing imaginal disc, global overexpression of Reggie/Flotillin proteins leads to a significant extension of the Wingless signal and severely disrupts normal wing development. Our data support the notion that Reggie/Flotillin proteins are implicated in signaling processes at cellular contact sites.

Animals↗

PubMed2026

Lipid metabolic reprogramming of tumor-associated macrophages drives resistance to immune checkpoint blockade in lung cancer: a narrative review of mechanisms and therapeutic strategies.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), have shown remarkable efficacy in non-small cell lung cancer (NSCLC); however, many patients still develop resistance to immunotherapy. Although small cell lung cancer (SCLC) is also an important histological type of lung cancer, NSCLC accounts for the majority of lung cancer cases. Current research on ICI development, first-line treatment efficacy, and the mechanisms of lipid metabolism in tumor-associated macrophages (TAMs) is predominantly focused on NSCLC. In patients with advanced NSCLC, objective response rates (ORRs) with PD-1/PD-L1 inhibitor monotherapy remain limited. Only in patients with high PD-L1 expression [tumor proportion score (TPS) ≥50%] and without sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements does the ORR increase to approximately 40-45%. TAMs are a key component of the immunosuppressive tumor microenvironment (TME). Lipid metabolic reprogramming profoundly influences the functional and transcriptional features of TAMs. This review aims to integrate relevant evidence, elucidate how TAM lipid metabolism promotes immunosuppression and resistance to ICIs, and outline potential therapeutic strategies. METHODS: We searched PubMed/MEDLINE, Web of Science, and Scopus for publications up to June 2026 using terms combining lung cancer, TAMs, lipid metabolism, and immune checkpoint blockade/resistance. Mechanistic, translational, and clinically relevant studies were selected by author consensus. KEY CONTENT AND FINDINGS: Lipid uptake, de novo lipogenesis, fatty acid oxidation (FAO), cholesterol remodeling, and eicosanoid metabolism are not independent processes in TAMs. Lipid metabolic reprogramming in TAMs ultimately suppresses type I interferon (IFN-I) signaling, upregulates PD-L1 expression, and impairs the function of CD8+ T cells with stem-like features, thereby establishing an immunosuppressive TME and leading to resistance to ICIs. In lung cancer, hypoxia, high lactate levels, and tobacco exposure further shape the lipid phenotype of TAMs, such as lipid raft enrichment and lipid-laden macrophage subsets like SPP1+ macrophages. Different driver genomic backgrounds differentially impact tumor cell-intrinsic metabolism and the lipid metabolic programs of myeloid cells. In preclinical models, interventions targeting these metabolic axes, including TAM-directed delivery systems, have demonstrated potential therapeutic benefit when combined with anti-PD-1/PD-L1 therapy. CONCLUSIONS: Targeting TAM lipid metabolism to convert immunologically cold tumors into more inflamed, ICI-responsive tumors is a promising strategy to overcome resistance in NSCLC. Identification of predictive biomarkers of therapeutic response and development of cell-selective drug delivery systems come to be major challenges.

Non-small cell lung cancer (NSCLC)↗

PubMed2005

Whole-genome analyses of speciation events in pathogenic Brucellae.

Despite their high DNA identity and a proposal to group classical Brucella species as biovars of Brucella melitensis, the commonly recognized Brucella species can be distinguished by distinct biochemical and fatty acid characters, as well as by a marked host range (e.g., Brucella suis for swine, B. melitensis for sheep and goats, and Brucella abortus for cattle). Here we present the genome of B. abortus 2308, the virulent prototype biovar 1 strain, and its comparison to the two other human pathogenic Brucella species and to B. abortus field isolate 9-941. The global distribution of pseudogenes, deletions, and insertions supports previous indications that B. abortus and B. melitensis share a common ancestor that diverged from B. suis. With the exception of a dozen genes, the genetic complements of both B. abortus strains are identical, whereas the three species differ in gene content and pseudogenes. The pattern of species-specific gene inactivations affecting transcriptional regulators and outer membrane proteins suggests that these inactivations may play an important role in the establishment of host specificity and may have been a primary driver of speciation in the genus Brucella. Despite being nonmotile, the brucellae contain flagellum gene clusters and display species-specific flagellar gene inactivations, which lead to the putative generation of different versions of flagellum-derived structures and may contribute to differences in host specificity and virulence. Metabolic changes such as the lack of complete metabolic pathways for the synthesis of numerous compounds (e.g., glycogen, biotin, NAD, and choline) are consistent with adaptation of brucellae to an intracellular life-style.

Bacterial Proteins↗

PubMed2026

Spatiotemporal patterns of Rift Valley fever virus in Africa: a retrospective genomic epidemiology and phylodynamic modelling study.

BACKGROUND: Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing outbreaks in humans and ruminants across Africa and the Arabian Peninsula. Originally restricted to the Great Rift Valley, RVFV has expanded geographically, prompting its classification by WHO as a pathogen of pandemic potential. We investigated the evolutionary and spatial dynamics of RVFV across Africa. METHODS: We used genomic data generated at the International Livestock Research Institute Nairobi genomic laboratory (BioProject PRJNA1106221) and combined with publicly available datasets retrieved from the National Center for Biotechnology (NCBI) GenBank nucleotide database. In retrieving RVFV genome sequences from the NCBI GenBank, we applied the search terms "Rift Valley fever virus segment L AND 6404[SLEN]", "Rift Valley fever virus segment M AND 3885[SLEN]", and "Rift Valley fever virus segment S AND 1520:1690[SLEN]" for L (Large), M (Medium), and S (Small) segments, respectively. For sequences without additional spatiotemporal information, we searched PubMed to extract the associated sequence metadata. We performed molecular clock analysis, phylogenetic inference, phylodynamic modelling (continuous phylogeographic reconstruction), and landscape phylogeography on the three RVFV genome segments (L, M, and S). We aimed to assess evolutionary rates, dispersal patterns, and environmental drivers. Focus was placed on lineage C, the most widely distributed variant. FINDINGS: The global dataset used in this study consisted of large (n=236), medium (n=237), and small (n=247), which were further filtered to exclude potential reassortants and vaccine strains. Genome sequences retrieved from NCBI GenBank database comprised large (n=180), medium (n=184), and small (n=202). The genome sequences from retrospective human and livestock isolates comprised large (n=56), medium (n=53), and small (n=45) collected in Burundi (2018), Kenya (2007, 2018, 2019, 2021, and 2022), and Rwanda (2018 and 2022). Our dataset revealed that RVFV exhibited low overall genetic diversity. Lineage C, however, showed evidence of active evolution, with substitution rates ranging from 3·58 × 10-4 to 9·76 × 10-4 substitutions per site per year. This lineage probably originated in Zimbabwe in the mid-1970s and has since expanded across eastern and southern Africa. Phylogeographic reconstructions revealed rapid spread, with diffusion coefficients exceeding 50 000 km2 per year. INTERPRETATION: Lineage C appears capable of establishing endemic transmission in new regions, with ongoing diversification observed during interepidemic periods. These observations reinforce the value of continuous genomic surveillance, particularly during cryptic transmission phases when adaptive mutations might emerge. Although further evidence is needed, observed trends in climate variability and land-use change point to the potential benefit of targeted surveillance in settings that could be at increased risk, including urban centres and wetlands. FUNDING: This work was supported by the German Federal Ministry for Economic Cooperation and Development, the Rockefeller Foundation, and the Africa Centres for Disease Control and Prevention.

Rift Valley fever virus↗

PubMed2004

Temporal requirement for hedgehog signaling in ventral telencephalic patterning.

Hedgehog signaling is required for multiple aspects of brain development, including growth, the establishment of both dorsal and ventral midline patterning and the generation of specific cell types such as oligodendrocytes and interneurons. To identify more precisely when during development hedgehog signaling mediates these events, we directed the removal of hedgehog signaling within the brain by embryonic day 9 of development, using a FoxG1(Cre) driver line to mediate the removal of a conditional smoothened null allele. We observed a loss of ventral telencephalic patterning that appears to result from an initial lack of specification of these structures rather than by changes in proliferation or cell death. A further consequence of the removal of smoothened in these mice is the near absence of both oligodendrocytes and interneurons. Surprisingly, the dorsal midline appears to be patterned normally in these mutants. Together with previous analyses, the present results demonstrate that hedgehog signaling in the period between E9.0 and E12 is essential for the patterning of ventral regions and the generation of cell types that are thought to largely arise from them.

Animals↗

PubMed2026

Phylogeographic epidemiology of Dabie bandavirus in East Asia: divergent transmission networks and genotype‑linked clinical severity.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS), caused by Dabie bandavirus (SFTSV), exhibits geographically decoupled incidence and fatality patterns across East Asia. We aimed to elucidate the distinct ecological drivers and phylogeographic dynamics underlying this inland-coastal epidemiological divergence. METHODS: Integrating 1820 high-quality global genomes of SFTSV with well-characterized clinical cohorts (936 patients) and nationwide surveillance data (27,457 cases) from China, we constructed a comprehensive analytical framework. Ecological modeling, Bayesian phylogeography, and genotype-phenotype association analyses were employed to trace the evolutionary trajectories and clinical implications of the virus. RESULTS: A pronounced "inland-high-incidence vs. coastal-high-fatality" pattern of SFTS was identified. The incidence of SFTS exhibited divergent sensitivities to meteorological factors; inland transmission was sensitive to thermal fluctuations, whereas coastal dynamics were constrained by a sunshine threshold (> 200 h/month). In contrast, spatial divergence in clinical severity correlated with the distribution of regional viral genetic structures. Inland regions mainly co-circulated genotypes A, C, and D, while coastal regions were dominated by genotype B. Zhejiang province was identified as a genetic hub with significantly higher recombination frequencies than inland regions (11.0% vs. 3.5%, P < 0.001). Bayesian phylogeographic inference indicated frequent lineage exchange of Zhejiang province in China with the Republic of Korea and Japan. Clinically, genotypes B and D were associated with elevated mortality in coastal and inland regions, respectively, suggesting that the severe coastal phenotype is shaped by its genotype B-dominated structure. Additionally, the RdRp-N828S mutation emerged as a robust molecular correlate of fatal outcomes, warranting further functional validation. CONCLUSIONS: Divergent meteorological factors and plausible maritime transmission networks may underlie the geographically decoupled epidemiology of SFTS. These findings highlight that risk assessment must extend beyond incidence alone and provide a phylogeographically informed framework for targeted surveillance and genotype-specific interventions in high-risk hotspots.

Humans↗

PubMed2007

Complex interference in the eye developmental pathway by Drosophila NF-YA.

The CCAAT motif-binding factor NF-Y consists of three different subunits, NF-YA, NF-YB, and NF-YC, all of which are required for formation of the NF-Y complex and DNA-binding. NF-YA contains a DNA binding domain in its C-terminal region. We established transgenic fly lines carrying the UAS-HA-dNF-YA or UAS-dNF-YAIR and showed over-expression or knockdown with various GAL4 drivers to be lethal at various developmental stages, suggesting that dNF-YA participate in various gene regulatory pathways during Drosophila development. Expression of dNF-YA with eyeless-GAL4 mainly resulted in lethality with a headless phenotype in pharate-adults. Reduction of the eyeless gene dose enhanced the dNF-YA-induced phenotype, while reduction of the Distal-less gene dose suppressed the phenotype. On the other hand, crossing the dNF-YA over-expressing flies with Notch mutant resulted in no apparent effect on the phenotype. These results suggest that dNF-YA can disturb eye disc specification, but not eye disc growth.

Amino Acid Sequence↗