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De Vivo, M.

Publications and source records attributed to De Vivo, M..

9 recordsLinked to original sources

How many are you? Open data and bioinformatics reveal species misidentification and potential introgression in Chordodes (Phylum Nematomorpha)

The potential usage of genomic open data can help us to understand patterns in biodiversity. They can also be helpful for identifying morphologically similar species. An example of taxon in which this can be useful is Nematomorpha, one of the less studied animal phyla, for which data has started to be available recently and where species identification can be hard. In this study, I planned initially to evaluate the usage of mitochondrial data for population analyses using an RNA sequencing (RNA-seq) dataset labelled as belonging to Chordodes fukuii. After surprising results using extracted sequences from the barcoding gene cytochrome c oxidase subunit I (COXI), I evaluated species delimitation using a mix of a previously released double-digest restriction-site-associated DNA sequencing (ddRADseq) SRA dataset plus the RNA-seq one. PCA, R analyses through "adegenet" and ADMIXTURE confirmed the presence of two species in the RNA-seq dataset, which should be labelled as C. formosanus and C. japonensis; however, some individuals labelled as C. japonensis according to COXI clustered with C. formosanuss specimens or had some C. formosanus ancestry when more data was used, indicating potential introgression or incomplete lineage sorting. The study shows how previously released data can be used for evaluating species delimitation, potential previous demographic events and potential needs in DNA barcoding and genomics for avoiding future misidentification of morphologically similar species.

bioinformatics↗

CDC42 Inhibitors Alter Patterns of Vessel Arborization in Skin and Tumors in vivo

Tumors that arise in the epidermis must develop a vascular supply to grow beyond a millimeter in depth. This process requires CDC42 GTPases such as CDC42, RhoJ and RhoQ. Despite this dependence on angiogenesis for growth, melanoma tumors are minimally responsive to current anti-angiogenesis agents, highlighting the need for more effective drugs in this class. Here we integrate antibody infusion, optical tissue clearing, multiphoton imaging, and three-dimensional semi-automated tracing to develop a quantitative approach to measure changes in vascular architecture in skin and skin tumors. This new approach uncovered differences in vessel arborization in the skin of RhoJ KO mice as compared to wild-type mice. Furthermore, novel small molecules that inhibit CDC42 GTPases inhibited both tumor growth and vessel branching within tumors to a similar degree as Braf inhibitors, which are commonly used to treat melanoma. In contrast to Braf inhibitors, however, which only affected tumor vasculature, CDC42 inhibitors affected vascularization in both tumor and normal skin without apparent toxicity to endothelial or stromal cells. These novel CDC42 inhibitors similarly blocked vessel branching in human cell-based micro-physiological models of normal and tumor vessels. RNA sequencing revealed reduced expression of multiple angiogenesis-related genes in drug-treated skin. Taken together, these studies identify a new class of pharmacologic agents that inhibit vessel branching in both normal skin and tumors with potential utility for treating skin cancer and skin diseases characterized by pathologic angiogenesis.

cancer biology↗

Targeting the conserved active site of splicing machines with specific and selective small molecule modulators

The self-splicing group II introns are bacterial and organellar ancestors of the nuclear spliceosome and retro-transposable elements of pharmacological and biotechnological importance. Integrating enzymatic, crystallographic, and simulation studies, we demonstrate how these introns recognize small molecules through their conserved active site. These RNA-binding small molecules selectively inhibit the two steps of splicing by adopting distinctive poses at different stages of catalysis, and by preventing crucial active site conformational changes that are essential for splicing progression. Our data exemplify the enormous power of RNA binders to mechanistically probe vital cellular pathways. Most importantly, by proving that the evolutionarily-conserved RNA core of splicing machines can recognize small molecules specifically, our work puts solid bases for the rational design of splicing modulators not only against bacterial and organellar introns, but also against the human spliceosome, which is a validated drug target for the treatment of congenital diseases and cancers.

biochemistry↗

Testing the efficacy of different molecular tools for parasite conservation genetics: a case study using horsehair worms (Phylum Nematomorpha)

In recent years, parasite conservation has become a globally significant issue. Because of this, there is a need for standardised methods for inferring population status and possible cryptic diversity. However, given the lack of molecular data for some groups, it is challenging to establish procedures for genetic diversity estimation. Therefore, universal tools, such as double digest restriction-site associated DNA sequencing (ddRADseq), could be useful when conducting conservation genetic studies on rarely studied parasites. Here, we generated a ddRADseq dataset that includes all three described Taiwanese horsehair worms (Phylum Nematomorpha), possibly one of the most understudied animal groups. Additionally, we produced data for a fragment of the cytochrome c oxidase subunit I (COXI) for said species. We used the COXI dataset in combination with previously published sequences of the same locus for inferring the effective population size (Ne) trends and possible population structure. We found that a larger and geographically broader sample size combined with more sequenced loci resulted in a better estimation of changes in Ne. We were able to detect demographic changes associated with Pleistocene events in all the species. Furthermore, the ddRADseq dataset for Chordodes formosanus did not reveal a genetic structure based on geography, implying a great dispersal ability, possibly due to its hosts. We showed that different molecular tools can be used to reveal genetic structure and demographic history at different historical times and geographical scales, which can help with conservation genetic studies in rarely studied parasites.

zoology↗

microRNA165 and 166 modulate salt stress response of the Arabidopsis root.

In plants, developmental plasticity allows for the modulation of organ growth in response to environmental cues. Being in contact with soil, roots are the first organ responding to soil abiotic stresses such as high salt concentration. In the root, plasticity relies on changes in the activity of the apical meristem, the region at the tip of the root where a set of self-renewing undifferentiated stem cells sustains growth. We show that salt stress promotes root meristem cells differentiation via reducing the dosage of the microRNAs miR165 and 166. By means of genetic, molecular and computational analysis, we show that the levels of miR165 and 166 respond to high salt concentration, and that miR165 and 166-dependent PHB modulation is fundamental for the response of root growth to this stress. Salt dependent reductions of miR165 and 166 causes rapid increase of the Arabidopsis homeobox protein PHABULOSA (PHB) expression and production of the root meristem pro-differentiation hormone cytokinin. Our data provide direct evidence of how the miRNA-dependent modulation of transcription factors dosage mediates plastic development in plants. In plants, development must be both robust - to ensure appropriate growth - and plastic - to enable the adaptation to external cues. Plastic development largely depends on the modulation of gene expression, controlling the concentration of developmental factors, such as hormones, transcription factors (TFs) and signalling molecules (Garcia-Molina et al, 2013; Hofhuis & Heidstra, 2018; Lopez-Ruiz et al, 2020; Schroder et al, 2021). A classic example of plant developmental plasticity is the adaptation of plant growth to high salt conditions, a stress that inhibits shoot and root development (Flowers et al, 1997). Roots are the first organs sensing salt concentration in soil, where high salt reduces meristem activity and root growth (Dinneny et al, 2008; Geng et al, 2013; Jiang et al, 2016). It has been suggested that the regulation of several plant hormones and miRNAs mediate the plant response to salt stress (Dolata et al, 2016; Geng et al, 2013; Iglesias et al, 2014; Jiang et al, 2016; Nishiyama et al, 2011; Yan et al, 2016). However, the molecular interplays mediating the adaptation of plant roots to salt stress are still vague. Post-embryonic root growth is supported by the activity of the root meristem, a region located at the root tip where self-renewing stem cells divide asymmetrically in the stem cell niche (SCN), originating transit-amplifying daughter cells that divide in the division zone (DZ) (Di Mambro et al, 2018). Once these cells reach a developmental boundary denominated transition zone (TZ), they stop dividing and start to elongate in the so-called elongation/differentiation zone (EDZ) (Di Mambro et al, 2018). A dynamic balance between cell division and cell differentiation ensures continuous root growth, maintaining a fixed number of cells in the DZ. Alterations in this dynamic equilibrium promote or inhibit root growth (Di Mambro et al, 2018; Salvi et al, 2020). microRNA molecules (miRNA) play a key role in the control of root meristem development (Bertolotti et al, 2021a; Skopelitis et al, 2012). Maturation of plant miRNAs depends on the activity of a multiprotein complex comprising the DICER-LIKE1 (DCL1), HYPONASTIC LEAVES1 (HYL1) and SERRATE (SE) proteins that cut pre-miRNA transcripts into 21 nucleotides mature miRNA (Yan et al, 2016). Among miRNAs, miR165 and 166 have been shown to be main regulator of root development (Carlsbecker et al, 2010; Dello Ioio et al, 2012). miR165 and miR166 are pleiotropic regulators of plant developmental processes. miR165 and 166 family consists of nine independent loci (MIR165 A-B and MIR166 A-G) that drive expression of pre-miR165 and 166 in different tissues and at different developmental stages (Miyashima et al, 2011). miR165/166 activity is crucial in the control of robust development, restricting the expression of the HOMEODOMAIN LEUCINE ZIPPER III (HD-ZIPIII), including PHABULOSA (PHB) and PHAVOLUTA (PHV), which are involved in root and shoot development, vascular growth, and leaf and embryo polarity (Carlsbecker et al, 2010; Dello Ioio et al, 2012; Di Ruocco et al, 2017; Grigg et al, 2009; McConnell et al, 2001; Skopelitis et al, 2017; Williams et al, 2005). In the root, miR165/166 regulate meristem homeostasis and radial patterning (Carlsbecker et al, 2010; Dello Ioio et al, 2012); pre-miR165a, pre-miR166a and b transcription is promoted by the SCARECROW (SCR) and SHORTROOT (SHR) transcription factors (Carlsbecker et al, 2010) and, thanks to the cell-to-cell mobility, mature miR165 and 166 forms diffuse to patterns both the root vasculature and the ground tissue (Carlsbecker et al, 2010; Miyashima et al, 2011; Skopelitis et al, 2018; Vaten et al, 2011; Bertolotti et al, 2021b). In the root meristem the miR165-166-PHB module promotes the synthesis of the plant hormone cytokinin, an important player in root developmental plasticity regulating cell differentiation rate of meristematic cells via the activation of the ARABIDOPSIS HISTIDINE KINASE3 (AHK3)/ARABIDOPSIS RESPONSE REGULATOR 1/12 (ARR1/12) pathway (Dello Ioio et al, 2007,2008). Here, we show that in response to salt stress miR165 and 166 modulates PHB expression to adjust root meristem activity. Salt exposure results in changes in cytokinin biosynthesis, which further regulates the miR165/166-PHB module. Hence, in addition to the above-described miRNA activity in controlling root robust development, we provide clear evidence that, in response to environmental cues, miRNAs are crucial also in the control of root plastic development, modulating the dosage of transcription factors.

plant biology↗

Backtracking of influenza polymerase upon consecutive incorporation of nucleoside analogue T1106 directly observed by high resolution cryo-electron microscopy

The broad-spectrum antiviral pseudobase T705, a fluorinated pyrazinecarboxamide, is incorporated via its triphosphate form into nascent viral RNA by viral RNA-dependent RNA polymerases. Since it mimics guanine or adenine it can act as a mutagen, whereas consecutive incorporation leads to chain termination. Here we examine the structural basis for incorporation and stalling for the case of influenza polymerase, using T1106-TP, the nucleotide form of T1105, the de-fluoro analogue of T705. We used a specially designed template that allows single T1106-MP incorporation at a defined site followed by consecutive T1106-MP incorporation and stalling four nucleotides later, as demonstrated by biochemical analysis. A high-resolution cryoEM structure of influenza A/H7N9 polymerase, stalled after transcribing this template, revealed that the entire product-template duplex has backtracked by five nucleotides. Consequently, the singly incorporated T1106-MP resides at the +1 position and forms an unexpected wobble base-pair with a U in the template. The relative stability of the canonical and wobble T1106:U base-pairs in different contexts is investigated by molecular dynamics simulations. Using a different template and influenza B polymerase we also observe stalling after double incorporation of T1106-MP and structural analysis showed again that backtracking occurs, this time by four nucleotides. These results show that, at least in early elongation, consecutive T1106-MP incorporation into the product destabilises the proximal end of the product-template duplex, promoting irreversible backtracking until a more favourable overall configuration is achieved. These results give new insight into the unusual mechanism of chain termination by pyrazinecarboxamide base analogues.

molecular biology↗

Utilisation of Oxford Nanopore sequencing to generate six complete gastropod mitochondrial genomes as part of a biodiversity curriculum

High-throughput sequencing has enabled genome skimming approaches to produce complete mitochondrial genomes (mitogenomes) for species identification and phylogenomics purposes. In particular, the portable sequencing device from Oxford Nanopore Technologies (ONT) has the potential to facilitate hands-on training from sampling to sequencing and interpretation of mitogenomes. In this study, we present the results from sampling and sequencing six gastropod mitogenomes (Aplysia argus, Cellana orientalis, Cellana toreuma, Conus ebraeus, Conus miles and Tylothais aculeata) from a graduate level biodiversity course. The students were able to produce mitochondrial genomes from sampling to annotation using existing protocols and programs. Approximately 4Gb of sequence was produced from 15 Flongle and two R9.4 Flowcells, averaging 235Mb and N50=4.4kb per Flowcell. Five of the six 14.1-18kb mitogenomes were circlised containing all 13 core protein coding genes. Additional Illumina sequencing reveal that the ONT assemblies were able to span over highly AT rich sequence in the control region that was otherwise missing in Illumina-assembled mitogenomes, but still contained a base error of one every 70.8-346.7bp with the majority occurring at homopolymer regions. Our findings suggest that ONT are portable and can be used to rapidly produce mitogenomes at low cost and tailored to genomics-based training in biodiversity research.

ecology↗

Structure-based Design of CDC42 Effector Interaction Inhibitors For the Treatment of Cancer

CDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. Here we use computer-aided drug design to discover a new chemical entity (ARN22089) that targets CDC42 GTPases and blocks CDC42 effector interactions without affecting the binding between closely related GTPases (RAC1, RAS, RAL) and their downstream effectors. Our lead compound has broad activity against a panel of cancer cell lines, inhibits S6 phosphorylation and MAPK activation, activates pro-inflammatory and apoptotic signaling, and blocks tumor growth and angiogenesis in three-dimensional vascularized microtumor models (VMT) in vitro. In addition, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenografts in vivo. Taken together, this work identifies a promising new class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.

molecular biology↗

Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms

Brutons tyrosine kinase (Btk) is a key component for B-cell maturation and activation. Btk loss-of-function mutations cause human X-linked agammaglobulinemia (XLA). In contrast, constitutive Btk signaling drives several B-cell neoplasms, which may be treated with tyrosine kinase inhibitors (TKIs). Here, we uncovered the molecular mechanism by which a subset of XLA mutations in the SH2 domain strongly perturbs Btk activation. Using a combination of molecular dynamics (MD) simulations and small-angle X-ray scattering (SAXS), we discovered an allosteric interface between the SH2 and kinase domain to which multiple XLA mutations map and which is required for Btk activation. As allosteric interactions provide unique targeting opportunities, we developed an engineered repebody protein binding to the Btk SH2 domain and able to disrupt the SH2-kinase interaction. The repebody prevented activation of wild-type and TKI-resistant Btk, inhibited Btk-dependent signaling and proliferation of malignant B-cells. Therefore, the SH2-kinase interface is critical for Btk activation and a targetable site for allosteric inhibition.

cancer biology↗