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The article titled "Theme 07 - Pre-Clinical Therapeutic Strategies" was written by a large group of authors and published in the journal Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. The article discusses various pre-clinical therapeutic strategies for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The authors present a comprehensive review of the current research in this field, including potential therapeutic targets and approaches. [Extracted from the article]

FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the Forkhead Box G1 ( FOXG1 ) gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, we report a patient with a de novo pathogenic single nucleotide deletion c.946del (p.Leu316Cysfs*10) of the FOXG1 gene that causes a premature protein truncation. To study this variant in vivo, we generated and characterized Foxg1 c946del mice that recapitulate hallmarks of the human disorder. Accordingly, heterozygous Foxg1 c946del mice display neurological symptoms with aberrant neuronal networks and increased seizure susceptibility. Gene expression profiling identified increased oligodendrocyte- and myelination-related gene clusters. Specifically, we showed that expression of the c946del mutant and of other pathogenic FOXG1 variants correlated with overexpression of proteolipid protein 1 ( Plp1 ), a gene linked to white matter disorders. Postnatal administration of Plp1 -targeting antisense oligonucleotides (ASOs) in Foxg1 c946del mice improved neurological deficits. Our data suggest Plp1 as a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients.

The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals' genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3θ and TDP-43, which regulates nuclear-cytoplasmic shuttling. Neuronal 14-3-3θ levels were increased in sporadic ALS and FTD with TDP-43 pathology. Pathogenic TDP-43 showed increased interaction with 14-3-3θ, resulting in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, resembling pathological changes in disease. Harnessing this increased affinity of 14-3-3θ for pathogenic TDP-43, we devised a gene therapy vector targeting TDP-43 pathology, which mitigated functional deficits and neurodegeneration in different ALS/FTD mouse models expressing mutant or non-mutant TDP-43, including when already symptomatic at the time of treatment. Our study identified 14-3-3θ as a mediator of cytoplasmic TDP-43 localization with implications for ALS/FTD pathogenesis and therapy., Competing Interests: Declaration of interests Y.D.K. and L.M.I. are inventors, and A.v.H. and W.S.L. are contributors to patents covering the gene therapy vectors presented here that have been licensed to Celosia Therapeutics (Australia), of which L.M.I. is a co-founder. Celosia Therapeutics was not involved in design, data generation/analysis, or funding of this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Reperfusion therapy is generally recommended in acute high-risk pulmonary embolism (HR-PE), but several population-based studies report that it is underused. Data on epidemiology, management and outcomes of HR-PE in Portugal are scarce., Objective: To determine the reperfusion rate in HR-PE patients, the reasons for non-reperfusion, and how it influences outcomes., Methods: In this retrospective cohort study of consecutive HR-PE patients admitted to a thromboembolic disease referral center between 2008 and 2018, independent predictors for non-reperfusion were assessed by multivariate logistic regression. PE-related mortality and long-term MACE (cardiovascular mortality, PE recurrence and chronic thromboembolic disease) were calculated according to the Kaplan-Meier method. Differences stratified by reperfusion were assessed using the log-rank test., Results: Of 1955 acute PE patients, 3.8% presented with hemodynamic instability. The overall reperfusion rate was 50%: 35 patients underwent systemic thrombolysis, one received first-line percutaneous embolectomy and one rescue endovascular treatment. Independent predictors of non-reperfusion were: age, with >75 years representing 12 times the risk of non-treatment (OR 11.9, 95% CI 2.7-52.3, p=0.001); absolute contraindication for thrombolysis (31.1%), with recent major surgery and central nervous system disease as the most common reasons (OR 16.7, 95% CI 3.2-87.0, p<0.001); and being hospitalized (OR 7.7, 95% CI 1.4-42.9, p=0.020). At a mean follow-up of 2.5±3.3 years, the survival rate was 33.8%. Although not reaching statistical significance for hospital mortality, mortality in the reperfusion group was significantly lower at 30 days, 12 months and during follow-up (relative risk reduction of death of 64% at 12 months, p=0.013). Similar results were found for MACE., Conclusions: In this population, the recommended reperfusion therapy was performed in only 50% of patients, with advanced age and absolute contraindications to fibrinolysis being the main predictors of non-reperfusion. In this study, thrombolysis underuse was associated with a significant increase in short- and long-term mortality and events., (Copyright © 2023 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Multiple effects, operating either on the long-term (soil-engineering effects) or on the short-term during plant life (microclimate modification or resources pre-emption), can act simultaneously and determine the outcome of plant-plant interactions. These diverse effects have not been disentangled along a gradient of metal/metalloid pollution, although this is crucial for understanding the dominant species turnover along the gradient, and thus the driving processes of facilitation recurrently found in metalliferous ecosystems, which could help improving ecological restoration of these degraded ecosystems. Here, we experimentally assessed different short-term effects of two dominant forbs of highly polluted habitats (Hutchinsia alpina and Arenaria multicaulis, tolerant to metal stress) and two grasses of less polluted habitats (Agrostis capillaris and Festuca rubra, less tolerant to metal stress) on target plant species (the same as the dominant species mentioned above) transplanted along a large metal pollution gradient. Additionally, in highly polluted environments, we differentiated short- from long-term effects of the two metallicolous forbs, which had different abilities to concentrate metals in their leaves. In line with other studies along metal gradients, variation of short-term interactions appeared to follow the Stress Gradient Hypothesis for plants less adapted to metal pollution (p = 0.030), with positive interactions dominating in most severe areas. Regarding long-term effects, the species with highest leaf metal-accumulation showed no negative effect contrary to the Elemental allelopathy Hypothesis. Long-term effects of the species with lower leaf-metal accumulation could not be determined because of the occurrence of an unexpected difference in micro-habitat conditions (soil depth and humidity) for this species along the metal pollution gradient. Increasing short-term facilitation along metal pollution gradients, which confirmed previous studies, is promising for improving conditions and restoring the most polluted environments. However, long-term results stressed the difficulty to quantify these effects given that these areas are highly fragmented and heterogeneous., Competing Interests: Declaration of competing interest None of the authors have a conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction and Objectives: The true prevalence of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE) in the Portuguese population remains unknown. We aimed to assess the prevalence and predictors of CTEPH two years after a symptomatic high- (HR) or intermediate-high risk (IHR) PE., Methods: We conducted a retrospective cohort study of patients admitted with PE between 2014 and 2019 to a Portuguese referral center for pulmonary hypertension., Results: In this single-center registry of 969 patients admitted with PE (annual incidence of 46/100000 population), 194 had HR (5.4%) and IHR (14.7%) PE. After excluding patients who died or had no follow-up in the first three months, 129 patients were included in the analysis. The overall prevalence of suspected CTEPH by clinical assessment, Doppler echocardiography and V/Q lung scan was 6.2% (eight patients). CTEPH was confirmed by right heart catheterization in four of these (3.1%). Increased pulmonary artery systolic pressure (PASP) at admission (OR 1.12; 95% CI 1.04-1.22; p=0.005) and the presence of varicose veins in the lower limbs (OR 7.47; 95% CI 1.53-36.41; p=0.013) were predictors of CTEPH. PASP >60 mmHg at admission identified patients with CTEPH at follow-up with sensitivity and specificity of 83.3% and 76.3%, respectively. All patients diagnosed with CTEPH had at least two radiological findings suggestive of CTEPH at the index event., Conclusions: In our cohort, the prevalence of CTEPH in survivors of severe forms of acute PE was 6.2%. PASP above 60 mmHg and supporting radiological findings on the index computed tomography scan are highly suggestive of acute-on-chronic CTEPH., (Copyright © 2023 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best-performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD, and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective in diagnosing the specific neurodegenerative disease.

Disentangling competitive-response and -effect abilities has strongly improved our understanding of the role of competition for the diversity and composition of plant communities. Much less is known about the relative importance of facilitative-effect and -response abilities in harsh ecosystems. Here, we aim to fill this gap by simultaneously assessing the facilitative-response and -effect abilities of different species and ecotypes in former mining sites in the French Pyrenees, both in naturally occurring communities and in a common-garden designed on a slag heap. The response of two ecotypes of the target species Festuca rubra with contrasting metal-stress tolerances and the facilitative effects of two ecotypes with contrasting metal-stress tolerances of four different metallicolous nurse species were assessed. The results revealed that the response of the Festuca ecotype with lower metal-stress tolerance shifted from competitive (RII = -0.24) to facilitative (RII = 0.29) as pollution increased, consistently with the stress-gradient-hypothesis. The Festuca ecotype with high metal-stress tolerance did not show any facilitative response. Regarding facilitative effect ability assessed in the common-garden, nurse ecotypes from highly polluted habitats (RII = 0.04) had a significantly higher facilitative effects than ecotypes from less polluted habitats (RII = -0.05). Metal-intolerant target ecotypes of Festuca rubra were the most sensitive to the positive effects of neighbours, while metal-tolerant nurse ecotypes were the best benefactors. Facilitative-response ability appeared to be driven by a trade-off between stress-tolerance and facilitative response of target ecotypes. In contrast, facilitative-effect ability was positively correlated to the stress-tolerance of nurse plants. The results of this study show that the highest restoration success of highly metal-stressed systems should be found when highly stress-tolerant nurse ecotypes are associated with less stress-tolerant target ecotypes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Spinal cord injury (SCI) occurs when the spinal cord is damaged from either a traumatic event or disease. SCI is characterised by multiple injury phases that affect the transmission of sensory and motor signals and lead to temporary or long-term functional deficits. There are few treatments for SCI. Estrogens and estrogenic compounds, however, may effectively mitigate the effects of SCI and therefore represent viable treatment options. This review systematically examines the pre-clinical literature on estrogen and estrogenic compound neuroprotection after SCI. Several estrogens were examined by the included studies: estrogen, estradiol benzoate, Premarin, isopsoralen, genistein, and selective estrogen receptor modulators. Across these pharmacotherapies, we find significant evidence that estrogens indeed offer protection against myriad pathophysiological effects of SCI and lead to improvements in functional outcomes, including locomotion. A STRING functional network analysis of proteins modulated by estrogen after SCI demonstrated that estrogen simultaneously upregulates known neuroprotective pathways, such as HIF-1, and downregulates pro-inflammatory pathways, including IL-17. These findings highlight the strong therapeutic potential of estrogen and estrogenic compounds after SCI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The relationship between competition and productivity in plant communities is unclear, and this is likely to be due to (1) a confusion in the literature between productivity and biomass, (2) the lack of studies assessing variation in competition in all combinations of biomass and productivity. We assessed the outcome of plant-plant interactions by removing the neighbors around five focal species in 14 herbaceous communities with contrasting biomasses and productivities: meadows with high biomass and productivity, heathlands with high biomass and low productivity, understory communities of deciduous forests with low biomass and high productivity and calcareous grasslands with low biomass and low productivity. Competition intensity was quantified with the relative interaction index (RII) calculated for both survival and growth of the transplanted targets assessed with the increase in leaf number. To examine which traits better explain variation in competition and what drives variation in diversity, we also quantified litter decomposition rate, species composition and diversity and six morphological traits related to plant size and growth rate for eight dominant species of each community. Our main questions were: (1) Is competition mostly related to biomass or productivity? (2) Which traits of the community dominants better explain variation in competition? (3) Is variation in competition and related traits correlated with variation in diversity? Competition for survival significantly increased with increasing community biomass (but not productivity). In addition, competition for survival increased with the size traits and competitive effects of the dominant species of the communities, whereas diversity decreased. Competition for growth also increased with increasing productivity, but only for high-biomass communities. Additionally, the increase in competition for growth with increasing soil fertility, as measured with litter decomposition rate, was only due to an increase in target growth in plots without neighbors and was unrelated to community competitive effects and species diversity. The results of our study illustrate how the confusion between productivity and biomass could have contributed to the long-standing debate on variation in competition along productivity gradients and its consequence for diversity., (© 2022 The Ecological Society of America.)

Alzheimer's disease (AD) is the most common form of dementia. There is no treatment and AD models have focused on a small subset of genes identified in familial AD. Microarray studies have identified thousands of dysregulated genes in the brains of patients with AD yet identifying the best gene candidates to both model and treat AD remains a challenge. We performed a meta-analysis of microarray data from the frontal cortex (n = 697) and cerebellum (n = 230) of AD patients and healthy controls. A two-stage artificial intelligence approach, with both unsupervised and supervised machine learning, combined with a functional network analysis was used to identify functionally connected and biologically relevant novel gene candidates in AD. We found that in the frontal cortex, genes involved in mitochondrial energy, ATP, and oxidative phosphorylation, were the most significant dysregulated genes. In the cerebellum, dysregulated genes were involved in mitochondrial cellular biosynthesis (mitochondrial ribosomes). Although there was little overlap between dysregulated genes between the frontal cortex and cerebellum, machine learning models comprised of this overlap. A further functional network analysis of these genes identified that two downregulated genes, ATP5L and ATP5H, which both encode subunits of ATP synthase (mitochondrial complex V) may play a role in AD. Combined, our results suggest that mitochondrial dysfunction, particularly a deficit in energy homeostasis, may play an important role in AD., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Hyperphosphorylated microtubule-associated protein tau has been implicated in dementia, epilepsy, and other neurological disorders. In contrast, site-specific phosphorylation of tau at threonine 205 (T205) by the kinase p38γ was shown to disengage tau from toxic pathways, serving a neuroprotective function in Alzheimer's disease. Using a viral-mediated gene delivery approach in different mouse models of epilepsy, we show that p38γ activity-enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38γ-mediated phosphorylation of tau at T205 is essential for this protection in epilepsy, as a lack of this critical interaction reinstates pathological features and accelerates epilepsy in vivo. Hence, our work provides a scope to harness p38γ as a future therapy applicable to acute neurological conditions.

In Alzheimer's disease (AD), where amyloid-β (Aβ) and tau deposits in the brain, hyperexcitation of neuronal networks is an underlying disease mechanism, but its cause remains unclear. Here, we used the Collaborative Cross (CC) forward genetics mouse platform to identify modifier genes of neuronal hyperexcitation. We found LAMP5 as a novel regulator of hyperexcitation in mice, critical for the survival of distinct interneuron populations. Interestingly, synaptic LAMP5 was lost in AD brains and LAMP5 interneurons degenerated in different AD mouse models. Genetic reduction of LAMP5 augmented functional deficits and neuronal network hypersynchronicity in both Aβ- and tau-driven AD mouse models. To this end, our work defines the first specific function of LAMP5 interneurons in neuronal network hyperexcitation in AD and dementia with tau pathology., (© 2022. The Author(s).)

The leukodystrophy Hypomyelination with Brainstem and Spinal cord involvement and Leg spasticity (HBSL) is caused by recessive mutations of the DARS1 gene, which encodes the cytoplasmic aspartyl-tRNA synthetase. HBSL is a spectrum disorder with disease onset usually during early childhood and no available treatment options. Patients display regression of previously acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Gene-function studies in mice revealed that homozygous Dars1 deletion is embryonically lethal, suggesting that successful modelling of HBSL requires the generation of disease-causing genocopies in mice. In this study, we introduced the pathogenic DARS1 M256L mutation located on exon nine of the murine Dars1 locus. Despite causing severe illness in humans, homozygous Dars1 M256L mice were only mildly affected. To exacerbate HBSL symptoms, we bred Dars1 M256L mice with Dars1-null 'enhancer' mice. The Dars1 M256L/- offspring displayed increased embryonic lethality, severe developmental delay, reduced body weight and size, hydrocephalus, anophthalmia, and vacuolization of the white matter. Remarkably, the Dars1 M256L/- genotype affected energy metabolism and peripheral organs more profoundly than the nervous system and resulted in reduced body fat, increased respiratory exchange ratio, reduced liver steatosis, and reduced hypocellularity of the bone marrow. In summary, homozygous Dars1 M256L and compound heterozygous Dars1 M256L/- mutation genotypes recapitulate some aspects of HBSL and primarily manifest in developmental delay as well as metabolic and peripheral changes. These aspects of the disease might have been overlooked in HBSL patients with severe neurological deficits but could be included in the differential diagnosis of HBSL in the future., (© 2022. The Author(s).)

Polluted sites are ubiquitous worldwide but how plant partition their biomass between different organs in this context is unclear. Here, we identified three possible drivers of biomass partitioning in our controlled study along pollution gradients: plant size reduction (pollution effect) combined with allometric scaling between organs; early deficit in root surfaces (pollution effect) inducing a decreased water uptake; increased biomass allocation to roots to compensate for lower soil resource acquisition consistent with the optimal partitioning theory (plant response). A complementary meta-analysis showed variation in biomass partitioning across published studies, with grass and woody species having distinct modifications of their root: shoot ratio. However, the modelling of biomass partitioning drivers showed that single harvest experiments performed in previous studies prevent identifying the main drivers at stake. The proposed distinction between pollution effects and plant response will help to improve our knowledge of plant allocation strategies in the context of pollution., (© 2022. The Author(s).)

Since the fifties, organochlorine pesticides (OCPs) had been used in agriculture to protect vegetables. Two decades after their ban by the Stockholm convention in 2001, OCPs are still present in agricultural soils inducing vegetable contamination with concentrations above Maximum Residue Level (MRL). This is a major concern for a 5 km 2 peri-urban vegetable growing valley located in the south west of France. In the present work, the sampling method was developed to clarify the spatial distribution of one OCP, Dieldrin, and its relationship with soil properties at the scale of study area. A total of 99 soil samples was collected for physicochemical analyses and Dieldrin concentrations. Results show Dieldrin concentrations in soils up to 204 μg kg -1 . The horizontal distribution of this pesticide is heterogeneous at the study area scale but homogeneous in each reference plot studied. About 85% of the contamination was located in the top soil layers (0-40 cm depth), but Dieldrin may still be quantified at a depth of 80 cm. Among all soil physicochemical parameters analysed, SOM was the most significantly related (P < 10 -4 ) with Dieldrin concentrations, once different grain size fractions were considered. Moreover, results indicate a 33 times higher Dieldrin concentration and/or extractability for coarse sand than for other grain size fractions. These results show that the developed sampling method is adapted for the study area scale as it helps understanding the factors influencing the spatial distribution of Dieldrin. Historical amendments are the predominant factor for the horizontal contamination and deep ploughing for the vertical contamination. Also, the variations of coarse sand repartition in soils prevents identification of relationships between SOM and Dieldrin contamination in bulk soil. Further investigation is required to explain these relationships but these results highlight why no clear relationship between OCPs and SOM was previously identified., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Genetically modified (GM) mice are widely used in biomedical research because they can address complex questions in an in-vivo setting that could not otherwise be addressed in-vitro. Microinjection of zygotes remains the most common technique to generate GM animals to date. Here, we describe the targeted insertion (knock-in) of transgenes by microinjection of 1-cell or 2-cell stage embryos into the murine Rosa26 safe harbor., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Acute pulmonary embolism is one of the main causes of cardiovascular mortality. Treatment should be guided according to mortality risk stratification, but an individualised and multidisciplinary approach is often required. Concomitant persistent hypoxaemia can be present in cases of intracardiac shunt. In this report, we describe a 46-year-old woman with a history of surgery, presenting with pulmonary embolism with refractory hypoxaemia and simultaneous ischaemic stroke. Fibrinolysis was successfully performed, and the patient made a full recovery. Additional investigations identified a patent foramen ovale, which was later closed. She had no recurrent thrombotic events., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

An 88-year-old male patient presented with left ptosis, diplopia, muscle weakness of the lower limbs, dysphagia for solids, dysphonia and constipation. On investigation, he was found to have myasthenia gravis (MG). Further evaluation for the possible cause of MG, with CT scan, revealed that the patient had concomitant prostatic cancer. The patient was given steroids and pyridostigmine, with consequent resolution of his neurological symptoms. This is a rare case of MG associated with prostatic cancer., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Hyperphosphorylation of the neuronal tau protein contributes to Alzheimer's disease (AD) by promoting tau pathology and neuronal and cognitive deficits. In contrast, we have previously shown that site-specific tau phosphorylation can inhibit toxic signals induced by amyloid-β (Aβ) in mouse models. The post-synaptic mitogen-activated protein (MAP) kinase p38γ mediates this site-specific phosphorylation on tau at Threonine-205 (T205). Using a gene therapeutic approach, we draw on this neuroprotective mechanism to improve memory in two Aβ-dependent mouse models of AD at stages when advanced memory deficits are present. Increasing activity of post-synaptic kinase p38γ that targets T205 in tau reduced memory deficits in symptomatic Aβ-induced AD models. Reconstitution experiments with wildtype human tau or phosphorylation-deficient tauT205A showed that T205 modification is critical for downstream effects of p38γ that prevent memory impairment in APP-transgenic mice. Furthermore, genome editing of the T205 codon in the murine Mapt gene showed that this single side chain in endogenous tau critically modulates memory deficits in APP-transgenic Alzheimer's mice. Ablating the protective effect of p38γ activity by genetic p38γ deletion in a tau transgenic mouse model that expresses non-pathogenic tau rendered tau toxic and resulted in impaired memory function in the absence of human Aβ. Thus, we propose that modulating neuronal p38γ activity serves as an intrinsic tau-dependent therapeutic approach to augment compromised cognition in advanced dementia.

Alterations in DNA methylation occur during development, but the mechanisms by which they influence gene expression remain uncertain. There are few examples where modification of a single CpG dinucleotide directly affects transcription factor binding and regulation of a target gene in vivo. Here, we show that the erythroid transcription factor GATA-1 - that typically binds T/AGATA sites - can also recognise CGATA elements, but only if the CpG dinucleotide is unmethylated. We focus on a single CGATA site in the c-Kit gene which progressively becomes unmethylated during haematopoiesis. We observe that methylation attenuates GATA-1 binding and gene regulation in cell lines. In mice, converting the CGATA element to a TGATA site that cannot be methylated leads to accumulation of megakaryocyte-erythroid progenitors. Thus, the CpG dinucleotide is essential for normal erythropoiesis and this study illustrates how a single methylated CpG can directly affect transcription factor binding and cellular regulation.

Percutaneous endovascular procedures (PEPs) are increasingly common in clinical practice. Percutaneous closure devices (PCD) ensure safe and immediate haemostasis, reducing the length of hospitalisation and improving patient comfort. Infectious complications are rare. We present the case of a 65-year-old man who was admitted to hospital because of fever and weight loss. He had a history of carotid arterial disease, having been submitted to a PEP 3 weeks before. On admission, he presented feverishly. Anaemia and elevated inflammatory parameters were detected on basic chemistry. Blood cultures isolated methicillin-sensitive Staphylococcus aureus and antibiotic therapy was started. He maintained fever and developed signs of right lower limb ischemia. Bacterial endocarditis was ruled out. Positron emission tomography (PET)-scan revealed inflammatory activity involving the right femoral artery (RFA). Bacterial femoral endarteritis was confirmed on surgical exploration, which documented the presence of infected PCD and occlusion of RFA. After surgery, apyrexia and improvement of ischaemic signs were achieved., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment and no cure. Mutations in profilin 1 were identified as a cause of familial ALS (fALS) in 2012. We investigated the functional impact of mutant profilin 1 expression in spinal cords during mouse development. We developed a novel mouse model with the expression of profilin 1 C71G under the control of the Hb9 promoter, targeting expression to α-motor neurons in the spinal cord during development. Embryos of transgenic mice showed evidence of a significant reduction of brachial nerve diameter and a loss of Mendelian inheritance. Despite the lack of transgene expression, adult mice presented with significant motor deficits. Transgenic mice had a significant reduction in the number of motor neurons in the spinal cord. Further analysis of these motor neurons in aged transgenic mice revealed reduced levels of TDP-43 and ChAT expression. Although profilin 1 C71G was only expressed during development, adult mice presented with some ALS-associated pathology and motor symptoms. This study highlights the effect of profilin 1 during neurodevelopment and the impact that this may have in later ALS., (Copyright © 2019 Brettle, Stefen, Djordjevic, Fok, Chan, van Hummel, van der Hoven, Przybyla, Volkerling, Ke, Delerue, Ittner and Fath.)

Background and Aims: Large, persistent seed banks contribute to the invasiveness of non-native plants, and maternal plant size is an important contributory factor. We explored the relationships between plant vegetative size (V) and soil seed bank size (S) for the invasive shrub Ulex europaeus in its native range and in non-native populations, and identified which other factors may contribute to seed bank variation between native and invaded regions., Methods: We compared the native region (France) with two regions where Ulex is invasive, one with seed predators introduced for biological control (New Zealand) and another where seed predators are absent (La Réunion). We quantified seed bank size, plant dimensions, seed predation and soil fertility for six stands in each of the three regions., Key Results: Seed banks were 9-14 times larger in the two invaded regions compared to native France. We found a positive relationship between current seed bank size and actual plant size, and that any deviation from this relationship was probably due to large differences in seed predation and/or soil fertility. We further identified three possible factors explaining larger seed banks in non-native environments: larger maternal plant size, lower activity of seed predators and higher soil fertility., Conclusions: In highlighting a positive relationship between maternal plant size and seed bank size, and identifying additional factors that regulate soil seed bank dynamics in non-native ranges, our data offer a number of opportunities for invasive weed control. For non-native Ulex populations specifically, management focusing on 'S' (i.e. the reduction of the seed bank by stimulating germination, or the introduction of seed predators as biological control agents) and/or on 'V' (i.e. by cutting mature stands to reduce maternal plant biomass) offers the most probable combination of effective control options., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Development of organisms that live on contaminated soils depends on toxicity as well as several physical and chemical soil properties. We aimed to identify plant bioassays most responsive to contaminants and not to confounding factors due to soil type differences. We implemented a multi-site approach in seven contaminated sites and used different ordinary plant bioassays (fourteen-day-shoot biomass and five-day-root and shoot elongation). Most of the sites were contaminated with polycyclic aromatic hydrocarbons (PAHs), and soils were sampled from areas of both high and low contamination. Bioassays were performed on ninety soil samples and were carried out with six model species. We performed analyses of regulatory PAHs and their derivatives content in the samples. Fourteen-day-shoot biomass responses depended on the site's origin, with an intricate response of plants that faced contrasted soil pH and organic matter content and various contaminant levels. Five-day-shoot and root lengths were informative when considering the most heavily PAH-contaminated site, since both measures exhibited a close dose-dependent response to PAHs but not to soil pH or organic matter content. For the other sites, elongation tests revealed tenuous effects somehow related to the presence of PAHs or their derivatives. We propose that tests based on plant development during their autotrophic phase (the fourteen-day-shoot biomass test in this study) are likely more sensitive to environmental stressors but less specific for contaminant-induced effects. Comparatively, tests based on early and heterotrophic plant development could be particularly more specific for soil contaminants, but the associated responses may be of low sensitivity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The importance of competition in low productive habitats is still debated. Studies which simultaneously evaluate preemption of resources and consequences for population dynamics are needed for a comprehensive view of competitive outcomes. We cultivated two emblematic species of European heathlands (Calluna vulgaris and Molinia caerulea) in a nursery for 2 years at two fertility levels, reproducing the productivity gradient found in phosphorus (P)-depleted heathlands in southwest France. The second year, we planted Ulex europaeus seedlings, a ubiquitous heathland species, under the cover of the two species to evaluate its ability to regenerate. Half of the seedlings were placed in tubes for exclusion of competitor roots. We measured the development of the competitors aboveground and belowground and their interception of resources (light, water, inorganic P). Ulex seedlings' growth and survival were also measured. Our results on resources interception were consistent with species distribution in heathlands. Molinia, which dominates rich heathlands, was the strongest competitor for light and water in the rich soil. Calluna, which dominates poor heathlands, increased its root allocation in the poor soil, decreasing water and inorganic P availability. However, the impact of total competition and root competition on Ulex seedlings decreased in the poor soil. Other mechanisms, especially decrease of water stress under neighbouring plant cover, appeared to have more influence on the seedlings' response. We found no formal contradiction between Tilman and Grime's theories. Root competition has a primary role in acquisition of soil resources in poor habitats. However, the importance of competition decreases with decreasing fertility.