Biology subjects

Fischer, M.

Publications and source records attributed to Fischer, M..

At least 73 records · Page 4Linked to original sources

bioRxiv2021

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7s role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.

genomics↗

bioRxiv2021

pUL36 de-ubiquitinase activity augments both the initiation and progression of lytic virus infection in IFN-primed cells

The conserved, structural HSV-1 tegument protein pUL36 is essential for both virus entry and assembly. While its N-terminal de-ubiquitinase (DUB) activity is dispensable for infection in cell culture, it is required for efficient virus spread in vivo by acting as a potent viral immune evasin. Here, we show that the pUL36 DUB activity was required to overcome interferon-(IFN)-mediated suppression of both plaque initiation and progression to productive infection. Immediately upon virus entry, incoming tegument-derived pUL36-DUB activity helped the virus to escape intrinsic antiviral resistance and efficiently initiate lytic virus replication in IFN-primed cells. Subsequently, de novo expressed pUL36-DUB augmented the efficiency of productive infection and virus yield. Interestingly, removal of IFN shortly after inoculation only resulted in a partial rescue of plaque formation, indicating that an IFN-induced defense mechanism eliminates invading virus particles unless counteracted by pUL36-DUB activity. Taken together, we demonstrated that the pUL36 DUB disarms IFN-induced antiviral responses at two levels, namely, to protect the infectivity of invading virus as well as to augment productive virus replication in IFN-primed cells. Author SummaryHSV-1 is an ubiquitous human pathogen that is responsible for common cold sores but may also cause life-threatening disease. pUL36 is an essential and conserved protein of infectious herpesvirus virions with a unique de-ubiquitinating (DUB) activity. The pUL36 DUB is dispensable for efficient virus infection in cell culture but represents an important viral immune evasin in vivo. Here, we showed that tegument-derived DUB activity delivered by the invading virus particles is required to overcome IFN-induced host resistance and to initiate efficient lytic infection. De novo expressed pUL36 DUB subsequently augments productive infection and virus yield. These data indicate that the pUL36 DUB antagonizes the activity of yet unidentified IFN-inducible E3 ligases to facilitate productive infection at multiple levels. Our findings underscore the therapeutic potential of targeting conserved herpesvirus DUBs to prevent or treat herpesvirus disease.

microbiology↗

bioRxiv2020

RRM2 is a target for synthetic lethal interactions with replication stress checkpoint addiction in high-risk neuroblastoma

Neuroblastoma is a pediatric tumor originating from the sympathetic nervous system responsible for 10-15 percent of all childhood cancer deaths. Half of all neuroblastoma patients present with high-risk disease at diagnosis. Despite intensive multi-modal therapies nearly 50 percent of high-risk cases relapse and die of their disease. In contrast to the overall paucity of mutations, high-risk neuroblastoma nearly invariably present with recurrent somatic segmental chromosome copy number variants. For several focal aberrations (e.g. MYCN and LIN28B amplification), the direct role in tumor formation has been established. However, for recurrent aberrations, such as chromosome 2p and 17q gains, the identification of genes contributing to tumor initiation or progression has been challenging due to the scarcity of small segmental gains or amplifications. In this study, we identified and functionally evaluated the ribonucleotide reductase regulatory subunit 2 (RRM2) as a top-ranked 2p putative co-driver and therapeutic target in high-risk neuroblastoma enforcing replicative stress resistance. In vitro knock down and pharmacological RRM2 inhibition highlight RRM2 dependency in neuroblastoma cells, further supported by the finding that co-overexpression of RRM2 in a d{beta}h-MYCN transgenic zebrafish line increased tumor penetrance with 80% and accelerated tumor formation. Given the critical role of RRM2 in replication fork progression and regulation of RRM2 through ATR/CHK1 signaling, we tested combined RRM2 and ATR/CHK1 small molecule inhibition with triapine and BAY1895344/prexasertib respectively, and observed strong synergism, in particular for combined RRM2 and CHK1 inhibition. Transcriptome analysis following combinatorial drugging revealed HEXIM1 as one of the strongest upregulated genes. Using programmable DNA binding of dCas9 with a promiscuous biotin ligase, RRM2 promotor bound proteins were identified including HEXIM1 and NurRD complex members, supporting a cooperative role for HEXIM1 upregulation together with CHK1 inhibition in further attenuating RRM2 expression levels. We evaluated the impact of combined RRM2/CHK1 inhibition in vivo, with treatment of a murine xenograft model showing rapid and complete tumor regression, without tumor regrowth upon treatment arrest. In conclusion, we identified RRM2 as a novel dependency gene in neuroblastoma and promising target for synergistic drug combinations with small compounds targeting DNA checkpoint regulators.

cancer biology↗

bioRxiv2020

PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors.

Majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms. Here we show that p53-regulating PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded by PPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstrated PPM1D genetic dependency in TP53 wild-type neuroblastoma cell lines, and shRNA PPM1D knockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressing PPM1D showed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1-mutations, Pten-deletions and p53-accumulation, adenocarcinomas and PHOX2B-expressing neuroblastomas establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.

cancer biology↗

bioRxiv2020

X-ray mediated scintillation increases synaptic activity via Cerium-doped LSO and Channelrhodopsin-2

Optogenetics is a widely used tool for studying neural circuits. However, non-invasive methods for light delivery in the brain are needed to avoid physical damage typically caused by intracranial insertion of light guides. An innovative strategy could employ X-ray activation of radioluminescent particles (RLPs) to emit localized light. We previously reported that RLPs composed of cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light, are biocompatible with neuronal function and synaptic transmission. However, little is known about the consequences of acute X-ray exposure on synaptic function and long-term plasticity. Furthermore, modulation of neuronal or synaptic function by X-ray induced radioluminescence from RLPs has not yet been demonstrated. Here we show that 30 minutes of X-ray exposure at a rate of 0.042 Gy/second caused no change in the strength of basal glutamatergic transmission during extracellular dendritic field recordings in mouse hippocampal slices. Additionally, long-term potentiation (LTP), a robust measure of synaptic integrity, was able to be induced after X-ray exposure and expressed at a magnitude not different from control conditions (absence of X-rays). This is important as synaptic plasticity is critical to learning and memory. Next, we used molecular and electrophysiological approaches to determine if X-ray dependent radioluminescence emitted from RLPs can activate light sensitive proteins. We found that X-ray stimulation of RLPs elevated cAMP levels in HEK293T cells expressing OptoXR, a chimeric opsin receptor that combines the extracellular light-sensitive domain of channelrhodopsin-2 (ChR2) with an intracellular second messenger signaling cascade. This demonstrates that X-ray radioluminescence from LSO:Ce particles can activate OptoXR. Next, we tested whether X-ray activation of the RLPs can enhance synaptic activity in whole-cell recordings from hippocampal neurons expressing ChR2, both in cell culture and acute hippocampal slices. Importantly, X-ray radioluminescence caused an increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in both systems, indicating activation of ChR2 and excitation of neurons. Together, our results show that X-ray activation of LSO:Ce particles can heighten cellular and synaptic function. The combination of LSO:Ce inorganic scintillators and X-rays is therefore a viable method for optogenetics as an alternative to more invasive light delivery methods.

neuroscience↗

bioRxiv2020

SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma

The pediatric extra-cranial tumor neuroblastoma (NB) is characterised by a low mutation burden while copy number alterations are present in most high-risk cases. We identified SOX11 as a strong lineage dependency transcription factor in adrenergic NB based on recurrent chromosome 2p focal gains and amplifications, its specific expression in the normal sympatho-adrenal lineage and adrenergic NBs and its regulation by multiple adrenergic specific cis-interacting (super-)enhancers. Adrenergic NBs are strongly dependent on high SOX11 expression levels for growth and proliferation. Through genome-wide DNA-binding and transcriptome analysis, we identified and validated functional SOX11 target genes, several of which implicated in chromatin remodeling and epigenetic modification. SOX11 controls chromatin accessibility predominantly affecting distal adrenergic lineage-specific enhancers marked by binding sites of the adrenergic core regulatory circuitry. During normal sympathoblast differentiation we find expression of SOX11 prior to members of the adrenergic core regulatory circuitry. Given the broad control of SOX11 of multiple epigenetic regulatory complexes and its presumed pioneer factor function, we propose that adrenergic NB cells have co-opted the normal role of SOX11 as a crucial regulator of chromatin accessibility and cell identity.

cancer biology↗

bioRxiv2020

Landscape management for grassland multifunctionality

Land-use intensification has contrasting effects on different ecosystem services, often leading to land-use conflicts. While multiple studies have demonstrated how landscape-scale strategies can minimise the trade-off between agricultural production and biodiversity conservation, little is known about which land-use strategies maximise the landscape-level supply of multiple ecosystem services (landscape multifunctionality), a common goal of stakeholder communities. We combine comprehensive data collected from 150 German grassland sites with a simulation approach to identify landscape compositions, with differing proportions of low-, medium-, and high-intensity grasslands, that minimise trade-offs between the six main grassland ecosystem services prioritised by local stakeholders: biodiversity conservation, aesthetic value, productivity, carbon storage, foraging, and regional identity. Results are made accessible through an online tool that provides information on which compositions best meet any combination of user-defined priorities (https://neyret.shinyapps.io/landscape_composition_for_multifunctionality/). Results show that an optimal landscape composition can be identified for any pattern of ecosystem service priorities. However, multifunctionality was similar and low for all landscape compositions in cases where there are strong trade-offs between services (e.g. aesthetic value and fodder production), where many services were prioritised, and where drivers other than land use played an important role. We also found that if moderate service levels are deemed acceptable, then strategies in which both high and low intensity grasslands are present can deliver landscape multifunctionality. The tool presented can aid informed decision-making by predicting the impact of future changes in landscape composition, and by allowing for the relative roles of stakeholder priorities and biophysical trade-offs to be understood by scientists and practitioners alike. HighlightsO_LIAn online tool identifies optimal landscape compositions for desired ecosystem services C_LIO_LIWhen the desired services are synergic, the optimum is their common best landscape composition C_LIO_LIWhen the desired services trade-off, a mix of grassland intensity is most multifunctional C_LIO_LISuch tools could support decision-making processes and aid conflict resolution C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/208199v5_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@3273f6org.highwire.dtl.DTLVardef@5b3a5aorg.highwire.dtl.DTLVardef@153f526org.highwire.dtl.DTLVardef@103cbea_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2020

Dissecting the DNA binding landscape and gene regulatory network of p63 and p53

The transcription factor (TF) p53 is the best-known tumor suppressor, but its ancient sibling p63 ({Delta}Np63) is a master regulator of epidermis development and a key oncogenic driver in squamous cell carcinomas (SCC). Despite multiple gene expression studies becoming available in recent years, the limited overlap of reported p63-dependent genes has made it difficult to decipher the p63 gene regulatory network (GRN). In particular, analyses of p63 response elements differed substantially among the studies. To address this intricate data situation, we provide an integrated resource that enables assessing the p63-dependent regulation of any human gene of interest. Here, we use a novel iterative de novo motif search approach in conjunction with extensive publicly available ChIP-seq data to achieve a precise global distinction between p53 and p63 binding sites, recognition motifs, and potential co-factors. We integrate all these data with enhancer:gene associations to predict p63 target genes and identify those that are commonly de-regulated in SCC and, thus, may represent candidates for therapeutic interventions.

genomics↗

bioRxiv2020

Genetic ablation of SOD1G37R selectively from corticofugal projection neurons protects corticospinal neurons from degeneration without affecting ALS onset and progression

While clinical evidence of combined degeneration of the bulbar and spinal motor neurons (MN) together with the corticospinal neurons (CSN) is required to diagnose Amyotrophic Lateral Sclerosis (ALS), preclinical studies have mostly concentrated on MN, leaving aside the CSN and their contribution to ALS onset and progression. Recent studies carried on ALS patients suggest that the disease may initiate in the motor cortex and spread to its projection targets, along the corticofugal axonal projections (including CSN), either via altered neuronal excitability and subsequent excitotoxicity, or via prion-like propagation of misfolded proteins. We recently provided first experimental arguments in favour of the corticofugal hypothesis of ALS, demonstrating that CSN and other subcerebral projection neurons were toxic in a context of ALS. Here, we aimed to determine how CSN may be detrimental to their downstream targets, and what governs their degeneration. To answer these questions, we took advantage of the FloxedSOD1G37R mouse model of ALS that allows genetic ablation of the mutant transgene in selected cells upon Cre-mediated recombination, and crossed it to the CrymCreERT2 mouse line that we purposely designed to genetically target CSN and other corticofugal projection neurons (CFuPN) populations. We demonstrate that excision of the mutant SOD1G37R transgene from the CSN is sufficient to prevent their death, suggesting that CSN degeneration mostly relies on cell-intrinsic mechanisms. However, genetic ablation of SOD1G37R transgene from the corticofugal neurons had no effect on disease onset and survival. The data thus indicate that the toxicity of CFuPN in the context of ALS, and corticofugal propagation of the disease, are not mediated by the presence of misfolded mutant proteins, but more likely by other aspects of the cortical pathology, possibly hyperexcitability.

neuroscience↗

bioRxiv2019

Geometry of Ranked Nearest Neighbour Interchange Space of Phylogenetic Trees

AO_SCPLOWBSTRACTC_SCPLOWIn this paper we study the graph of ranked phylogenetic trees where the adjacency relation is given by a local rearrangement of the tree structure. Our work is motivated by tree inference algorithms, such as maximum likelihood and Markov Chain Monte Carlo methods, where the geometry of the search space plays a central role for efficiency and practicality of optimisation and sampling. We hence focus on understanding the geometry of the space (graph) of ranked trees, the so-called ranked nearest neighbour interchange (RNNI) graph. We find the radius and diameter of the space exactly, improving the best previously known estimates. Since the RNNI graph is a generalisation of the classical nearest neighbour interchange (NNI) graph to ranked phylogenetic trees, we compare geometric and algorithmic properties of the two graphs. Surprisingly, we discover that both geometric and algorithmic properties of RNNI and NNI are quite different. For example, we establish convexity of certain natural subspaces in RNNI which are not convex is NNI. Our results suggest that the complexity of computing distances in the two graphs is different.

bioinformatics↗

bioRxiv2019

Enhancer hijacking determines intra- and extrachromosomal circular MYCN amplicon architecture in neuroblastoma

MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA. The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyzed the MYCN amplicon structure and its chromatin landscape. This revealed two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplified a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons was characterized by high structural complexity, lacked key local enhancers, and instead contained distal chromosomal fragments, which harbored CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.

cancer biology↗

bioRxiv2019

Plant traits are poor predictors of long-term ecosystem functioning

Earth is home to over 350,000 vascular plant species1 that differ in their traits in innumerable ways. Yet, a handful of functional traits can help explaining major differences among species in photosynthetic rate, growth rate, reproductive output and other aspects of plant performance2-6. A key challenge, coined "the Holy Grail" in ecology, is to upscale this understanding in order to predict how natural or anthropogenically driven changes in the identity and diversity of co-occurring plant species drive the functioning of ecosystems7, 8. Here, we analyze the extent to which 42 different ecosystem functions can be predicted by 41 plant traits in 78 experimentally manipulated grassland plots over 10 years. Despite the unprecedented number of traits analyzed, the average percentage of variation in ecosystem functioning that they jointly explained was only moderate (32.6%) within individual years, and even much lower (12.7%) across years. Most other studies linking ecosystem functioning to plant traits analyzed no more than six traits, and when including either only six random or the six most frequently studied traits in our analysis, the average percentage of explained variation in across-year ecosystem functioning dropped to 4.8%. Furthermore, different ecosystem functions were driven by different traits, with on average only 12.2% overlap in significant predictors. Thus, we did not find evidence for the existence of a small set of key traits able to explain variation in multiple ecosystem functions across years. Our results therefore suggest that there are strong limits in the extent to which we can predict the long-term functional consequences of the ongoing, rapid changes in the composition and diversity of plant communities that humanity is currently facing.

ecology↗

bioRxiv2019

Absence of subcerebral projection neurons delays disease onset and extends survival in a mouse model of ALS

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of adulthood that affects voluntary motricity and rapidly leads to full paralysis and death. ALS arises from the combined degeneration of motoneurons in the spinal cord and brain stem, responsible for muscle denervation, and corticospinal projection neurons (CSN), responsible for emergence of the upper motor neuron syndrome. Recent studies carried on ALS patients suggest that the disease may initiate in the motor cortex and spread to its projection targets. However, this "corticofugal hypothesis" of ALS has not yet been specifically challenged. Here, we provide a direct test of this hypothesis by genetically removing subcerebral projection neurons (SubCerPN), including CSN, in Sod1G86R mice, a mouse model of ALS. Ablation of the transcription factor Fezf2, leading to the complete absence of all SubCerPN, delays disease onset, reduces weight loss and motor impairment, and increases survival without modifying disease duration. Importantly absence of SubCerPN and CSN also limits pre-symptomatic hyperreflexia. Together, our results demonstrate that major corticofugal tracts are critical to ALS onset, and that SubCerPN and CSN in particular may carry detrimental signals to their downstream targets. In its whole, this study provides first experimental arguments in favour of the corticofugal hypothesis of ALS.

neuroscience↗

bioRxiv2019

Rare species perform worse than common species under changed climate

Predicting how species, particularly rare and endangered ones, will react to climate change is a major current challenge in ecology. Rare species are expected to have a narrower niche width than common species. However, we know little whether they are also less able to cope with new climatic conditions. To simulate climate change, we transplanted 35 plant species varying in rarity to five botanical gardens in Switzerland, differing in altitude. For each species we calculated the difference in climate between their natural habitats and the novel climate of the respective botanical garden. We found that rare species had generally lower survival and biomass production than common species. Moreover, rare plant species survived less when the amount of precipitation differed more from the one in their natural range, indicating a higher susceptibility to climate change. Common species, in contrast, survived equally well under all climates and even increased their biomass under wetter or drier conditions. Our study shows that rarer species are less able to cope with changes in climate compared to more widespread ones, which might even benefit from these changes. This indicates that already rare and endangered plant species might suffer strongly from future climate change.

ecology↗

bioRxiv2019

Context dependency of biotic interactions and its relation to plant rarity

AimBiotic interactions can determine rarity and commonness of species, however evidence that rare and common species respond differently to biotic stress is scarce. This is because biotic interactions are notoriously context-dependent and traits leading to success in one habitat might be costly or unimportant in another. We aim to identify plant characteristics that are related to biotic interactions and may drive patterns of rarity and commonness, taking environmental context into account.\n\nLocationSwitzerland\n\nMethodsIn a multi-species experiment, we compared the response to biotic interactions of 19 rare and 21 widespread congeneric plant species in Switzerland, while also accounting for variation in environmental conditions of the species origin.\n\nResultsOur results restrict the long-standing hypothesis that widespread species are superior competitors to rare species to only those species originating from resource rich habitats, in which competition is usually strong. Tolerance to herbivory and ambient herbivore damage on the other hand, did not differ between widespread and rare species. In accordance to the resource-availability hypothesis, widespread species from resource rich habitats where more damaged by herbivores (less defended) than widespread species from resource poor habitats - such a growth-defense tradeoff was lacking in rare species. This indicates that the evolutionary important tradeoff between traits increasing competitive-ability and defence is present in widespread species but may have been lost in rare species.\n\nMain conclusionsOur results indicate that biotic interactions, above all competition, might indeed set range limits, and underlines the importance of including context-dependency in studies comparing traits of common and rare or invasive and non-invasive species.

ecology↗

bioRxiv2019

Transcriptomic changes due to early, chronic ethanol exposure during cortical development implicates arealization, cell-type specification, Axon Guidance and Synaptogenesis as primary determinants of Fetal Alcohol Spectrum Disorders

Fetal alcohol spectrum disorders (FASD) are described by a cluster of deficits following in utero alcohol exposure, whose effects disproportionately target the cerebral cortex. In vitro and in vivo models of FASD have successfully recapitulated multiple facets of clinical presentations, including morphological and behavioral deficits, but far less is understood regarding the molecular and genetic bases of FASD. In this study, we utilize an in vitro human pluripotent stem cell-based (hPSC) model of corticogenesis to probe the effect of early, chronic alcohol exposure on the transcriptome of developing cortical neurons. We here identify a relatively limited number of significantly altered biological pathways, including regional patterning, cell-type specification, axon guidance and synaptic function. Significant upregulation of WNT signaling-related transcripts, to the exclusion of other secreted morphogens was also observed in alcohol exposed cultures. Lastly, an overall alcohol-associated shift towards an increased caudal profile, at the expense of rostral molecular identity was observed, representing a potentially previously underappreciated FASD phenotype.

neuroscience↗

bioRxiv2019

The results of biodiversity-ecosystem functioning experiments are realistic

A large body of research shows that biodiversity loss can reduce ecosystem functioning, thus providing support for the conservation of biological diversity1-4. Much of the evidence for this relationship is drawn from biodiversity-ecosystem functioning experiments (hereafter: biodiversity experiments), in which biodiversity loss is simulated by randomly assembling communities of varying species diversity, and ecosystem functions are measured5-9. This random assembly has led some ecologists to question the relevance of biodiversity experiments to real-world ecosystems, where community assembly may often be non-random and influenced by external drivers, such as climate or land-use intensification10-18. Despite these repeated criticisms, there has been no comprehensive, quantitative assessment of how experimental and real-world plant communities really differ, and whether these differences invalidate the experimental results. Here, we compare data from two of the largest and longest-running grassland biodiversity experiments globally (Jena Experiment, Germany; BioDIV, USA) to related real-world grassland plant communities in terms of their taxonomic, functional, and phylogenetic diversity and functional-trait composition. We found that plant communities of biodiversity experiments have greater variance in these compositional features than their real-world counterparts, covering almost all of the variation of the real-world communities (82-96%) while also containing community types that are not currently observed in the real world. We then re-analysed a subset of experimental data that included only ecologically-realistic communities, i.e. those comparable to real-world communities. For ten out of twelve biodiversity-ecosystem functioning relationships, biodiversity effects did not differ significantly between the full dataset of biodiversity experiments and the ecologically-realistic subset of experimental communities. This demonstrates that the results of biodiversity experiments are largely insensitive to the inclusion/exclusion of unrealistic communities. By bridging the gap between experimental and real-world studies, these results demonstrate the validity of inferences from biodiversity experiments, a key step in translating their results into specific recommendations for real-world biodiversity management.

ecology↗

bioRxiv2019

Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease clinically defined as the combined degeneration of corticospinal and corticobulbar neurons (CSN), and bulbar and spinal motor neurons (MN). A growing body of evidence points to the motor cortex, where CSN are located, as the potential initiation site of ALS. However, little is known about the spatiotemporal dynamics of CSN degeneration and the molecular pathways involved. Here, we show in the Sod1G86R mouse model of ALS that CSN loss precedes MN degeneration and that CSN and MN degenerations are somatotopically related, highlighting the relevance of CSN to ALS onset and progression. To gain insights into the molecular mechanisms that selectively trigger CSN degeneration, we purified CSN from the motor and somatosensory cortex of adult mice and analysed their transcriptome from presymptomatic ages to disease end-stage. Significant RNA metabolism and splicing alterations, novel in the context of Sod1 mutation, were identified, including mis-splicing events that largely trigger genes involved in neuronal functions. Together, the data indicate that CSN dysfunction and degeneration upon mutant Sod1 expression involve alterations of RNA metabolism and splicing, emphasizing shared mechanisms across various ALS-related genes.

neuroscience↗