Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade.

The MRE11 nuclease is essential during DNA damage recognition, homologous recombination, and replication. BRCA2 plays important roles during homologous recombination and replication. Here, we show that effecting an MRE11 blockade using a prototypical inhibitor (Mirin) induces synthetic lethality (SL) in BRCA2-deficient ovarian cancer cells, HeLa cells, and 3D spheroids compared to BRCA2-proficient controls. Increased cytotoxicity was associated with double-strand break accumulation, S-phase cell cycle arrest, and increased apoptosis. An in silico analysis revealed Mirin docking onto the active site of MRE11. While Mirin sensitises DT40 MRE11+/- cells to the Top1 poison SN-38, it does not sensitise nuclease-dead MRE11 cells to this compound confirming that Mirin specifically inhibits Mre11 nuclease activity. MRE11 knockdown reduced cell viability in BRCA2-deficient PEO1 cells but not in BRCA2-proficient PEO4 cells. In a Mirin-resistant model, we show the downregulation of 53BP1 and DNA repair upregulation, leading to resistance, including in in vivo xenograft models. In a clinical cohort of human ovarian tumours, low levels of BRCA2 expression with high levels of MRE11 co-expression were linked with worse progression-free survival (PFS) (p = 0.005) and overall survival (OS) (p = 0.001). We conclude that MRE11 is an attractive SL target, and the pharmaceutical development of MRE11 inhibitors for precision oncology therapeutics may be of clinical benefit.

Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71.

Different viruses belonging to distinct viral families, such as enterovirus 71, rely on the host methyltransferase METTL3 for the completion of fundamental cytoplasmic stages of their life cycle. Modulation of the activity of this enzyme could therefore provide a broad-spectrum approach to interfere with viral infections caused by viruses that depend on its activity for the completion of their viral cycle. With the aim to identify antiviral therapeutics with this effect, a series of new nucleoside analogues was rationally designed to act as inhibitors of human METTL3, as a novel approach to interfere with a range of viral infections. Guided by molecular docking studies on the SAM binding pocket of the enzyme, 24 compounds were prepared following multiple-step synthetic protocols, and evaluated for their ability to interfere with the replication of different viruses in cell-based systems, and to directly inhibit the activity of METTL3. While different molecules displayed moderate inhibition of the human methyltransferase in vitro, multiple novel, potent and selective inhibitors of enterovirus 71 were identified.

Microplastics and the functional traits of fishes: A global meta-analysis.

Over the years, concern about the effects of microplastics has grown. Here, we answered the main question "What are the impacts of microplastics on the functional traits of fish species?" through a meta-analysis. The general impact of microplastic exposure on the functional traits of fishes and specifically on eight variables, namely, behaviour, development, fecundity, feeding, growth, health, hatching and survival was explored. Subgroup analyses were performed to detect correlations between the impact of microplastics and the following factors: species, life stage, habitat, water column habitat, day of exposure to microplastics and microplastic size, type and shape. A meta-regression analysis allowed understanding the correlation between the impact of microplastics and the size of organisms. Generally, microplastics have a negative effect on the functional traits of fishes. Feeding and behaviour, followed by growth showed the greatest impact. Among the subgroup analysis, four of the eight variables considered showed a significant difference between groups: species, life stage, microplastic shape and days of exposure to microplastics. Depending on their life stage, organisms may be more sensitive to microplastic pollution. Changes in growth rates, development of early life stage and behavioural patterns in fishes may have a negative effect on the structure and functions of aquatic ecosystem in the long term and consequently affect the ability of aquatic ecosystems to provide ecosystem services and sustain human communities.

Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections.

Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2'-C-methyl-adenosine, 2-CMA, and 7-deaza-2'C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against Zika virus when applied in combination with an indirect antiviral agent, a l-dideoxy bicyclic pyrimidine nucleoside analogue, which potently inhibits vaccinia and measles viruses in vitro by targeting a host pathway. Our findings provide a solid basis for further development of an antiviral therapy for Zika virus infections, possibly exploiting a dual approach combining two different agents, one targeting the viral polymerase (direct-acting antiviral), the second targeting a host-directed autophagy mechanism.

Data presenting the synthesis of three novel stimuli responsive hyperbranched polymers synthesised via RAFT polymerisation and the bio conjugation of folic acid.

The data presented in this manuscript presents the characterisation spectra of three hyperbranched polymers as discussed in the paper "Folic Acid and Rhodamine Labelled pH Responsive Hyperbranched Polymers: synthesis, characterisation and cell uptake studies" [1]. Characterisation of polymers was performed via 1H Nuclear Magnetic Resonance (1H NMR) and Size Exclusion Chromatography (SEC). pH responsive characteristics were observed via Dynamic Light Scattering (DLS). The data for characterisation of folate conjugated hyperbranched polymer is presented as 1H NMR, Ultra Violet Visible (UV-VIS) spectra and DLS measurements. Further data is presented detailing the experiments for the synthesis of monomers 2-propyl acrylic acid (PAA) and disulfide diacrylate (DSDA), with the full synthesis of folic acid-poly (ethylene glycol) (PEG) linker, rhodamine B ethylenediamine linker and bioconjugation reactions also detailed.

First report of Heleomyzidae (Diptera) recovered from the inner cavity of an intact human femur.

One of the main characteristics of the Mafia of Gargano is their use of ritual murders: they shoot their victims in the face and then conceal the corpses in the numerous natural ravines present in the Gargano area. Skeletal remains are often recovered in a poor state of preservation under particular conditions related to the environmental situation. Humidity, temperature and environmental contaminants could be considered very important for forensic examinations and are strictly related to the bone preservation status. One of the most important analyses is the identification of the victim: the success rate is linked to the condition of the bones. During military investigations in the Gargano area, several bones were recovered and analyzed in a karst ravine about 30 m deep. The forensic examination highlighted the presence of fly puparia from an intact human femur. The colonization of the inner bone cavity by a species of the Heleomyzidae family is described for the first time. Puparia, despite not being identified at the species level, are described and illustrated and their potential role in the degradation of the victim's DNA is discussed. This work increases our knowledge about the effects of Diptera in the taphonomic process underlying the need of a multidisciplinary approach to skeletal investigations.