In many species, both morphological and molecular traits related to sex and reproduction evolve faster in males than in females. Ultimately, rapid male evolution relies on the acquisition of genetic ...variation associated with differential reproductive success. Many newly evolved genes are associated with novel functions that might enhance male fitness. However, functional evidence of the adaptive role of recently originated genes in males is still lacking. The Sperm dynein intermediate chain multigene family, which encodes a Sperm dynein intermediate chain presumably involved in sperm motility, originated from complex genetic rearrangements in the lineage that leads to Drosophila melanogaster within the last 5.4 million years since its split from Drosophila simulans. We deleted all the members of this multigene family resident on the X chromosome of D. melanogaster by chromosome engineering and found that, although the deletion does not result in a reduction of progeny number, it impairs the competence of the sperm in the presence of sperm from wildtype males. Therefore, the Sperm dynein intermediate chain multigene family contributes to the differential reproductive success among males and illustrates precisely how quickly a new gene function can be incorporated into the genetic network of a species.
Drosophila melanogaster plays an important role in molecular, genetic, and genomic studies of heredity, development, metabolism, behavior, and human disease. The initial reference genome sequence ...reported more than a decade ago had a profound impact on progress in Drosophila research, and improving the accuracy and completeness of this sequence continues to be important to further progress. We previously described improvement of the 117-Mb sequence in the euchromatic portion of the genome and 21 Mb in the heterochromatic portion, using a whole-genome shotgun assembly, BAC physical mapping, and clone-based finishing. Here, we report an improved reference sequence of the single-copy and middle-repetitive regions of the genome, produced using cytogenetic mapping to mitotic and polytene chromosomes, clone-based finishing and BAC fingerprint verification, ordering of scaffolds by alignment to cDNA sequences, incorporation of other map and sequence data, and validation by whole-genome optical restriction mapping. These data substantially improve the accuracy and completeness of the reference sequence and the order and orientation of sequence scaffolds into chromosome arm assemblies. Representation of the Y chromosome and other heterochromatic regions is particularly improved. The new 143.9-Mb reference sequence, designated Release 6, effectively exhausts clone-based technologies for mapping and sequencing. Highly repeat-rich regions, including large satellite blocks and functional elements such as the ribosomal RNA genes and the centromeres, are largely inaccessible to current sequencing and assembly methods and remain poorly represented. Further significant improvements will require sequencing technologies that do not depend on molecular cloning and that produce very long reads.
The evolutionarily conserved family of Bucentaur (BCNT) proteins exhibits a widespread distribution in animal and plants, yet its biological role remains largely unknown. Using Drosophila ...melanogaster as a model organism, we investigated the in vivo role of the Drosophila BCNT member called YETI. We report that loss of YETI causes lethality before pupation and defects in higher-order chromatin organization, as evidenced by severe impairment in the association of histone H2A.V, nucleosomal histones and epigenetic marks with polytene chromosomes. We also find that YETI binds to polytene chromosomes through its conserved BCNT domain and interacts with the histone variant H2A.V, HP1a and Domino-A (DOM-A), the ATPase subunit of the DOM/Tip60 chromatin remodeling complex. Furthermore, we identify YETI as a downstream target of the Drosophila DOM-A. On the basis of these results, we propose that YETI interacts with H2A.V-exchanging machinery, as a chaperone or as a new subunit of the DOM/Tip60 remodeling complex, and acts to regulate the accumulation of H2A.V at chromatin sites. Overall, our findings suggest an unanticipated role of YETI protein in chromatin organization and provide, for the first time, mechanistic clues on how BCNT proteins control development in multicellular organisms.
The evolutionarily conserved family of Bucentaur (BCNT) proteins exhibits a widespread distribution in animal and plants, yet its biological role remains largely unknown. Using Drosophila ...melanogaster as a model organism, we investigated the in vivo role of the Drosophila BCNT member called YETI. We report that loss of YETI causes lethality before pupation and defects in higher order chromatin organization, evidenced by severe impairment in the association of histone H2A.V, nucleosomal histones and epigenetic marks with polytene chromosomes. We also find that YETI binds to polytene chromosomes through its conserved BCNT domain and interacts with the histone variant H2A.V, HP1a and Domino-A (DOM-A), the ATPase subunit of the DOM/Tip60 chromatin remodeling complex. Furthermore, we identify YETI as a novel downstream target of the Drosophila DOM-A. Based on these results, we propose that YETI interacts with H2A.V-exchanging machinery, as a chaperone or as a new subunit of the DOM/Tip60 remodeling complex, and contributes to regulate the accumulation of H2A.V at chromatin sites. Overall, our findings suggest an unanticipated role of YETI protein in chromatin organization and provide for the first time mechanistic clues on how BCNT proteins may control development in multicellular organisms.
Poly ADP-ribose polymerase inhibitors (PARPi) have transformed ovarian cancer (OC) treatment, primarily for tumours deficient in homologous recombination repair. Combining VEGF-signalling inhibitors ...with PARPi has enhanced clinical benefit in OC. To study drivers of efficacy when combining PARP inhibition and VEGF-signalling, a cohort of patient-derived ovarian cancer xenografts (OC-PDXs), representative of the molecular characteristics and drug sensitivity of patient tumours, were treated with the PARPi olaparib and the VEGFR inhibitor cediranib at clinically relevant doses. The combination showed broad anti-tumour activity, reducing growth of all OC-PDXs, regardless of the homologous recombination repair (HRR) mutational status, with greater additive combination benefit in tumours poorly sensitive to platinum and olaparib. In orthotopic models, the combined treatment reduced tumour dissemination in the peritoneal cavity and prolonged survival. Enhanced combination benefit was independent of tumour cell expression of receptor tyrosine kinases targeted by cediranib, and not associated with change in expression of genes associated with DNA repair machinery. However, the combination of cediranib with olaparib was effective in reducing tumour vasculature in all the OC-PDXs. Collectively our data suggest that olaparib and cediranib act through complementary mechanisms affecting tumour cells and tumour microenvironment, respectively. This detailed analysis of the combined effect of VEGF-signalling and PARP inhibitors in OC-PDXs suggest that despite broad activity, there is no dominant common mechanistic inter-dependency driving therapeutic benefit.
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•Water, sediment and Procambarus clarkii were sampled in Candia Lake.•Fibers and fragments of PP and PET were found in biotic and abiotic compartments.•The number of items/g was ...predicted only by the specimen’s total weight.•Procambarus clarkii could be a good candidate bioindicator for MP pollution.
Microplastic pollution has become pervasive. Identifying a bioindicator species to track the occurrence and effects of microplastics (MPs) on ecosystems is crucial for determining their impact on the environment. The digestive tract of Procambarus clarkii was thought to be of interest for investigating MPs accumulation in freshwater organisms. Our hypothesis was that the same type of MPs found in abiotic compartments (water and sediment) could be found in P. clarkii, which would make it an ideal candidate for use as a bioindicator of MP pollution in freshwater ecosystems. Water, sediment, and P. clarkii specimens were collected from four sites in a lentic ecosystem (Lake Candia; northwestern Italy) for two consecutive years (2021–2022). The mean MPs abundance was 1.75 ± 0.95 items/m3 in 2021 and 2 ± 0.81 items/m3 in 2022 in the water samples and 6.75 ± 1.5 items/kg and 8 ± 0.81 items/kg in the sediment samples in 2021 and 2022, respectively. In 2021, the average was 0.06 ± 0.07 items/g in the males and 0.05 ± 0.05 items/g in the females; in 2022, the average was 0.04 ± 0.05 items/g and 0.05 ± 0.06 items/g in the males and the females, respectively. MP fibers and fragments (black, white, blue, light blue) of polypropylene and polyethylene terephthalate were found in the biotic and the abiotic compartments. The generalized linear mixed model revealed that the number of items/g was predicted only by total weight: the lowest number of items/g was recorded for crayfish with the highest weight probably due to the feeding habits of P. clarkii. Our findings suggest that the invasive P. clarkii (smaller individuals, in particular) could be a good candidate bioindicator for MP pollution since the same type of MP items were recorded in the abiotic compartments. Further research is needed to better understand the feeding behavior of P. clarkii and the dynamics of MPs in aquatic ecosystems.
In lung adenocarcinoma (AD), the main lung cancer subtype, different driver genetic alterations can be targeted with specific small-molecule inhibitors 1, whereas KRAS mutations, which occur in about ...30% of AD cases, have been traditionally considered undruggable. In this work, we performed an integrative functional genomic analysis, combining in vitro dependency data within a large collection of cancer cell lines, gene druggability information and patients’ transcriptomics and mutational data. ...we integrated our A549 dataset with the lung cancer DepMap data and used RNA-sequencing data to filter for expressed genes. SEE PDF To identify dependency genes that were preferentially associated with the KRAS-mutated genetic background, we mined the dependency profiles of KRAS-mutated and KRAS wild-type lung cancer cell lines, extracting 1374 genes having a significantly different CERES score (Fig. 1c).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BH3 mimetics, targeting the Bcl-2 family anti-apoptotic proteins, represent a promising therapeutic opportunity in cancers. ABT-199, the first specific Bcl-2 inhibitor, was approved by FDA for the ...treatment of several hematological malignancies. We have recently discovered IS21, a novel pan BH3 mimetic with preclinical antitumor activity in several tumor types. Here, we evaluated the efficacy of IS21 and other BH3 mimetics, both as single agents and combined with the currently used antineoplastic agents in T-cell acute lymphoblastic leukemia, ovarian cancer, and melanoma. IS21 was found to be active in T-cell acute lymphoblastic leukemia, melanoma, lung, pancreatic, and ovarian cancer cell lines. Bcl-xL and Mcl-1 protein levels predicted IS21 sensitivity in melanoma and ovarian cancer, respectively. Exploring IS21 mechanism of action, we found that IS21 activity depends on the presence of BAX and BAK proteins: complexes between Bcl-2 and Bcl-xL proteins and their main binding partners were reduced after IS21 treatment. In combination experiments, BH3 mimetics sensitized leukemia cells to chemotherapy, ovarian cancer cells and melanoma models to PARP and MAPK inhibitors, respectively. We showed that this enhancing effect was related to the potentiation of the apoptotic pathway, both in hematologic and solid tumors. In conclusion, our data suggest the use of inhibitors of anti-apoptotic proteins as a therapeutic strategy to enhance the efficacy of anticancer treatment.
Abstract
Background
Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses on prolonging patients’ (pts) overall survival (OS) and improving their quality of life. Eribulin ...is a microtubule inhibitor that increases OS in pre-treated MBC pts. The most common adverse events (AEs) are asthenia, neutropenia and peripheral neuropathy (PN).
Methods
PAINTER is a single arm, phase IV study, aimed at evaluating the tolerability of eribulin in MBC pts. Secondary objectives were the description of treatment efficacy and safety, the assessment of the incidence and severity of PN and its association with genetic polymorphisms. Genomic DNA was isolated from blood samples and 15 Single Nucleotide Polymorphisms (SNPs) were genotyped by Taqman specific assays. The association between PN and SNPs were evaluated by Fisher exact test.
Results
Starting from May 2014 until June 2018 180 pts were enrolled in this study by 20 Italian centers. 170 of these pts could be evaluated for efficacy and toxicity and 159 for polymorphisms analysis. The median age of pts was 60 years old and the biological subtypes were luminal type (64.7%), Her2 positive (18.3%) and triple negative (17%). Pts were pretreated with a median of 5 lines for MBC. The median follow up of this study was 15.4 months with a median number of 4.5 cycles administered (minimum–maximum 1–23). The median overall survival was 12 months. 48.8% of pts experienced a dose reduction, mainly for neutropenia (23.9%) and liver toxicity (12%). 65 pts (38.2%) reported at least one severe toxicity. Neutropenia and neurotoxicity were the most frequent severe AEs (15.3% and 14.7%, respectively); other reported toxicities were osteo-muscular, abdominal or tumor site pain (19.4%), liver toxicity (6.6%), pulmonary toxicity (6.5%) and dermatological toxicity (3.6%). Among the 15 evaluated SNPs, an association with PN was found for rs2233335 and rs7214723.
Conclusions
Eribulin is a well-tolerated treatment option in MBC. Schedule and dosage modifications were common, but toxicity rarely led to treatment discontinuation. SNPs rs2233335 (G/T and T/T) in the
NDRG1
gene and rs7214723 (CC and CT) in the
CAMKK1
gene were associated with PN. These findings, if validated, could allow a tailored treatment with eribulin in cancer patients.
Trial registration
: ClinicalTrials.gov ID: NCT02864030.
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•No microplastic items were found in water and zooplankton samples.•Low microplastic items were found in sediment, tadpoles, and fish.•Young fish resulted more contaminated by ...microplastic items.•Shape, color, and chemical type of microplastics were the same in all compartments.•Salvelius fontinalis could be a good bioindicator of microplastic pollution.
Microplastic (MP) pollution is a major environmental concern for mountain ecosystem and for high-mountain lakes in particular, which are recognized indicators of global change. In this study, the presence of MPs was assessed in abiotic (water and sediment) and biotic (zooplankton, tadpoles, fish) compartments of two high-mountain lakes (Upper Lake Balma and Lower Lake Balma) in the Cottian Alps (northwest Italy). No MPs were found in water and zooplankton samples, whereas the mean MPs in sediment samples was 1.33 ± 0.67 items/m3 and 1.75 ± 0.62 items/m3 in Lower and Upper Lake Balma, respectively. The mean MPs in tadpoles of Rana temporaria was 0.33 ± 0.58 items/individual and 0.66 ± 0.58 items/individual in Lower and Upper Lake Balma, respectively. The mean number of MPs items found in the gastrointestinal tract (GIT) of fish (Salvelinus fontinalis) was considerably higher in specimens from the Lower (0.45 items/g GIT) than in those from the Upper Lake (0.20 items/g GIT). There was a negative relationship between fish size (weight and age) and MPs abundance in the GIT of fish, indicating that young fish accumulated more MP items probably due to the high prey ingestion rate compared to adults. The same MPs color (blue, white, black), shape (fibers and fragments), and chemical type (polypropylene and polyethylene) were found in the compartments of both lakes. Our findings suggest the use of S. fontinalis as an indicator of MP pollution in high-mountain lakes. Further studies are needed to better understand the sources and the effects of MPs in these remote ecosystems.
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