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Biology subjects

Wells, T.

Publications and source records attributed to Wells, T..

13 recordsLinked to original sources

Setting priorities for the acquisition of primary plant occurrence data

AimEffective implementation of the Global Biodiversity Framework and Global Strategy for Plant Conservation depends on accurate species distribution data. Current vascular plant distribution data, while crucial for understanding terrestrial ecosystems, is often sparse and biased and requires significant expansion. This study developed a scalable approach to prioritize areas for plant occurrence data acquisition, adaptable to national priorities and providing a framework for botanical institutions to coordinate efforts and allocate resources. LocationGlobal. MethodsUsing a Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) analysis, we prioritized areas based on: (a) ecosystem service value; (b) floristic value threatened by climate or land-use change; and (c) uncertainty in species richness estimates, stratified by biome and region. Regional prioritization maps for Africa & Madagascar; East, South and Southeast Asia; Siberia and the Russian Far East; South America; and North & Central America were reviewed by botanical experts for validation. Scalability was assessed by comparing regional and global analyses. ResultsData-driven priority maps, divided into tree-dominated and grassland/deforested areas, largely received expert support. High similarity between global and regional maps demonstrated scalability. Main conclusionsOur approach provides a framework for supporting national implementation of the Global Biodiversity Framework. Variables and their weights can be tailored to national or local needs. The methods flexibility and adaptability extend to other taxonomic groups and objectives, such as protected area selection By prioritizing data acquisition, whether field-based or digital, this research promotes the efficient use of resources. A key advantage of this approach is its capacity to systematically translate expert opinion into explicit and quantitative criteria, which in turn facilitates clear communication with policymakers and funders.

plant biology↗

Classification of Urticaceae based on morphology and phylogenetic inference

The Urticaceae (ca. 2600 species) were first formally recognized by Jussieu in the 18th century and last comprehensively monographed by Weddell in the 19th century. Since Weddells work, family delimitation has been modified and many genera described in a fragmented manner. Over the past two decades, numerous molecular studies have supported the inclusion of Cecropiaceae within Urticaceae and identified paraphyly in several genera, notably Laportea, Urera, Boehmeria, Parietaria, Pellionia, and Pouzolzia. However, few studies have translated these molecular insights into a revised taxonomy. This study aimed to provide a robust, updated classification for Urticaceae by: a) increasing taxon and genomic locus sampling through the integration of newly generated sequence data with previously published datasets; and b) incorporating morphological data to support a revised delimitation of tribes and genera, and to establish a new linear sequence for the family. We also sought to identify remaining taxonomic challenges. Using Sanger and Angiosperms353 sequence data, we constructed a phylogenetic framework for 57 out of 59 currently accepted genera. We also assessed the phylogenetic informativeness of 57 morphological characters by mapping them onto the phylogeny. Our analyses support the delimitation of 61 monophyletic genera and an infrafamilial classification comprising seven tribes, two of which we describe as new: Myriocarpeae and Leukosykeae. We provide a revised linear sequence for the family. Our classification reinstates several names previously treated as synonyms (Fleurya, Leptocnide, Margarocarpus, Polychroa, Scepocarpus, Sceptrocnide), places several genera in synonymy (Hemistylus and Rousselia under Pouzolzia; Hesperocnide under Urtica; Gesnouinia and Soleirolia under Parietaria), and proposes the recognition of two new genera, Muimar gen. nov. and Pouzolziella gen. nov., to accommodate Boehmeria nivea and Pouzolzia australis, respectively. Mapping morphological characters onto the phylogeny indicates that while most states are homoplastic at the family level, their combination is valuable for recognizing genera. Geographic character mapping suggests a high degree of spatial conservatism at the genus rank. Our dated ultrametric tree suggests an origin for Urticaceae in Indomalaya during the mid-Cretaceous, followed by establishment in the Laurasian boreotropical flora and subsequent dispersal to the neotropics and Africa. Once classified within an evolutionary framework we believe that the Urticaceae represent a valuable study system in evolutionary biology for investigating transitions across biomes, the drivers of floral trait evolution, and intrinsic speciation mechanisms. New tribes: --Leukosykeae, Myriocarpeae New genera: --Muimar, Pouzolziella

evolutionary biology↗

Artificial intelligence-augmented drug discovery identifies gefitinib as a potential treatment for ALS

Amyotrophic lateral sclerosis (ALS) is characterised by motor neuron (MN) death; however, astrocytes play a key role in disease pathogenesis. Developments in the field of artificial intelligence (AI) have the potential to impact drug discovery in multiple ways, including the rapid identification of drug repurposing candidates. A combination of natural language processing and deep learning algorithms was used to generate a knowledge graph based on scientific literature, omics and chemical databases, and other public sources with the aim to identify drug repurposing candidates for ALS. The aim of the study was to determine the effect of a cancer compound identified by AI, gefitinib, on MN survival, and to decipher its mode of action inin vitroandin vivomodels of ALS. We used co-cultures of healthy motor neurons with ALS patient-derived astrocytes (iAstrocytes), obtained through a semi-direct conversion protocol, to assess the neuroprotective properties of gefitinib. Compound treatment led to a significant rescue of MNs cultured with ALS iAstrocytes and a significant reduction in the levels of cleaved TDP-43 fragments in ALS iAstrocytes. Our data suggest that gefitinib-mediated activation of autophagy decreased the 35 kDa fragments of TDP-43. In a proof-of-conceptin vivostudy in SOD1G93Amice, gefitinib treatment significantly delayed the onset of neurological symptoms, thus showing the potential of AI-augmented drug discovery for neurodegenerative disorders.Significance StatementThis study presents an AI-augmented method of identifying potential repurposing candidates for disease with an unprecedented speed. The AI’s results were validatedin vitrousing iAstrocytes differentiated from induced neuronal progenitor cells (iNPCs), which are pathophysiologically relevant models suitable for studying neurodegeneration. iNPCs recapitulate many pathological hallmarks of the disease and they retain the ageing phenotype of the patient that they are obtained from. TDP-43 proteinopathy is one of the disease hallmarks observed in patients and is present in 97% of ALS patients. Here, we show gefitinib, a repurposing candidate identified by AI, improves survival of MNs in a co-culture with patient-derived astrocytes and can modulate TDP-43 proteinopathy.

neuroscience↗

Maximising the translational potential of neurophysiology in amyotrophic lateral sclerosis: a study on compound muscle action potentials

Transgenic mouse models of amyotrophic lateral sclerosis, such as the widely used SOD1G93A mouse, enable investigation of disease mechanisms and testing of novel therapeutic interventions. However, treatments that have been considered successful in mice have often failed to translate into human benefit in clinical trials, particularly when relying on the so-called survival read-out. Compound muscle action potentials (CMAPs), are a simple neurophysiological test that measures the summation of muscle fibre depolarisation in response to maximal stimulation of the innervating nerve. CMAPs can be measured in both mice and humans and decline with motor axon loss in ALS, making them a potential translational read-out of disease progression which could help bridge the preclinical and clinical divide. Herein we assess the translational potential of CMAPs and ascertain at what time points human and mouse data aligned most closely. We extracted data from 18 human studies and compared with results generated from SOD1G93A and control mice at different ages across different muscles. We found that the relative CMAP amplitude difference between SOD1G93A and control mice in tibialis anterior and gastrocnemius muscles at 70 days of age was most similar to the relative difference between baseline ALS patient CMAP measurements and healthy controls in the abductor pollicis brevis (APB) muscle. We also found that the relative decline in SOD1G93A tibialis anterior CMAP amplitude between 70-140 days was similar to that observed in 12 month human longitudinal studies in APB. Our findings suggest CMAP amplitudes can provide a translational window, from which to make comparisons between the SOD1G93A model and human ALS patients. CMAPs are easy to perform and can help determine the most clinically relevant starting/end points for preclinical studies and provide a basis for predicting potential clinical effect sizes.

neuroscience↗

The 5:2 diet does not increase adult hippocampal neurogenesis or enhance spatial memory in mice

New neurones are generated throughout life in the mammalian brain in a process known as adult hippocampal neurogenesis (AHN). Since this phenomenon grants a high degree of neuroplasticity influencing learning and memory and mood related behaviour, identifying factors that regulate AHN may be important for ameliorating age-related cognitive decline and neurodegeneration. Calorie restriction (CR), in the absence of malnutrition, has been shown to enhance AHN and improve hippocampal-dependent memory, mediated by the stomach hormone, ghrelin. Intermittent fasting (IF), a dietary strategy offering more flexibility than conventional CR, also promotes aspects of AHN. The 5:2 diet is a popular form of IF linked to a range of health benefits, however its effects on AHN and spatial memory are not well characterised. We hypothesised that the 5:2 diet would enhance AHN in a ghrelin-dependent manner. To assess this, we used immunohistochemistry to quantify new adult-born neurones and new neural stem cells (NSCs) in the hippocampal DG of adolescent and adult wild-type and mice lacking the ghrelin receptor following six weeks on a 5:2 diet. We report an age-related decline in neurogenic processes and identify a novel role for ghrelin-receptor in regulating the formation of new adult born NSCs in an age-dependent manner. However, the 5:2 diet did not affect new neurone or NSC formation in the DG. Consistent with this finding the 5:2 diet did not alter performance on a spatial learning and memory task. These data suggest that the 5:2 diet used in this study does not increase AHN or improve associated spatial memory function. HighlightsO_LI5:2 diet does not increase adult hippocampal neurogenesis C_LIO_LI5:2 diet does not enhance spatial memory performance C_LIO_LIThere is an age-related decline in adult hippocampal neurogenesis C_LIO_LIGhrelin-receptor regulates new neural stem cell and new neurone number in an age-related manner C_LIO_LIGhrelin-receptor is required for intact spatial memory C_LI

neuroscience↗

Acyl ghrelin attenuates neurochemical and motor deficits in the 6OHDA model of Parkinsons disease

The feeding-related hormone, acyl-ghrelin, protects dopamine neurons in murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-based models of experimental Parkinsons disease (PD). However, the potential protective effect of acyl-ghrelin on substantia nigra pars compacta (SNpc) dopaminergic neurones and consequent behavioural correlates in the more widely used 6-hydroxydopamine (6-OHDA) rat medial forebrain bundle (MFB) lesion model of PD are unknown. To address this question, acyl-ghrelin levels were raised directly by mini-pump infusion for 7-days prior to unilateral injection of 6-OHDA into the MFB with assessment of amphetamine-induced rotations on days 27 and 35, and immunohistochemical analysis of dopaminergic neurone survival. While acyl-ghrelin treatment was insufficient to elevate food intake or body weight, it attenuated amphetamine-induced circling behaviour and SNpc dopamine neurone loss induced by 6-OHDA. These data support the notion that elevating circulating acyl-ghrelin may be a valuable approach to slow or impair progression of neurone loss in PD. HighlightsO_LIAcyl-ghrelin attenuates SNpc dopamine cell loss in rat 6-OHDA-lesion model of PD C_LIO_LIAcyl-ghrelin attenuates motor deficits in rat 6-OHDA-lesion model of PD C_LI

neuroscience↗

Molnupiravir combined with different repurposed drugs further inhibits SARS-CoV-2 infection in human nasal epithelium in vitro

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in late 2019, has caused a worldwide pandemic with unprecedented economic and societal impact. Currently, several vaccines are available, and multitudes of antiviral treatments have been proposed and tested. Although many of the vaccines show high clinical efficacy, they are not equally accessible worldwide. Additionally, due to the continuous emergence of new virus variants, and generally short duration of immunity, the development of safe and effective antiviral treatments remains of the utmost importance. Since the emergence of SARS-CoV-2, substantial efforts have been undertaken to repurpose existing and approved drugs for accelerated clinical testing and potential emergency use authorizations. However, drug-repurposing using high throughput screenings in cellular assays, often identify hits that later prove ineffective in clinical studies. Our approach was to evaluate the activity of compounds that have either been tested clinically or already undergone extensive preclinical profiling, using a standardized in vitro model of human nasal epithelium. Secondly, we evaluated drug combinations using sub-maximal doses of each active single compound. Here, we report the antiviral effects of 95 single compounds and 30 combinations. The data show that selected drug combinations including 10 M of molnupiravir, a viral RNA-dependent RNA polymerase (RdRp) inhibitor, effectively inhibit SARS-CoV-2 replication. This indicates that such combinations are worthy of further evaluation as potential treatment strategies against coronavirus disease 2019 (COVID-19).

microbiology↗

Archaeogenomics of a ~2,100-year-old Egyptian leaf provides a new timestamp on date palm domestication

O_LIThe date palm (Phoenix dactylifera) has been a cornerstone of Middle Eastern and North African agriculture for millennia. It is presumed that date palms were first domesticated in the Persian Gulf and subsequently introduced into North Africa, where their evolution in the latter region appears to have been influenced by gene flow from the wild relative P. theophrasti, which is restricted to Crete and Turkey. However, the timing of gene flow from P. theophrasti to P. dactylifera remains unknown due to the limited archaeobotanical evidence of P. theophrasti and their exclusion from population genomic studies. C_LIO_LIWe addressed this issue by investigating the relatedness and ancestry of a ~2,100-year-old P. dactylifera leaf from Saqqara (Egypt), combining genome sequencing of this ancient specimen with a broad sample of date palm cultivars and closely related species. C_LIO_LIThe ancient Saqqara date palm shares close genetic ancestry with North African date palm populations. We find clear genomic admixture between the Saqqara date palm, P. theophrasti and the closest known relative P. sylvestris. C_LIO_LIOur study highlights that gene flow from P. theophrasti and P. sylvestris to North African date palms had already occurred at least ~2,100 years ago, providing a minimum timestamp for hybridisation between species. C_LI

evolutionary biology↗

Identification of Chlorophyll a-b Binding Protein AB96 as a novel TGFbeta1 binding agent.

The discovery of compounds and proteins from plants has greatly contributed to modern medicine, especially in malaria where both quinine and artemisinin have been the cornerstone of therapeutics. Here we describe the first known plant-derived cytokine binding agent. Chlorophyll a-b binding protein AB96, present to varying levels in the leaves of all chlorophyll-containing plants, binds to active TGF{beta}1. Active TGF{beta}1 contributes to the pathology of many infectious and neoplastic diseases and therefore, by inhibiting these processes, chlorophyll a-b binding protein opens up new approaches with therapeutic potential.

immunology↗

Structure-function analyses of dual-BON domain protein DolP identifies phospholipid binding as a new mechanism for protein localisation

The Gram-negative outer membrane envelops the bacterium and functions as a permeability barrier against antibiotics, detergents and environmental stresses. Some virulence factors serve to maintain the integrity of the outer membrane, including DolP (formerly YraP) a protein of unresolved structure and function. Here we reveal DolP is a lipoprotein functionally conserved among Gram-negative bacteria and that loss of DolP increases membrane fluidity. We present the NMR solution structure for DolP, which is composed of two BON domains that form an interconnected opposing pair. The C-terminal BON domain binds to anionic phospholipids through an extensive membrane:protein interface providing evidence of subcellular localization of these phospholipids within the outer membrane. This interaction is essential for DolP function and is required for sub-cellular localization of the protein to the cell division site. The structure of DolP provides a new target for developing therapies that disrupt the integrity of the bacterial cell envelope.

biochemistry↗

High proportion of multiple copies of Plasmodium falciparum Plasmepsin-2 gene in African isolates: Is piperaquine resistance emerging in Africa?

Emergence of Plasmodium falciparum resistance to antimalarial drugs is currently the primary rationale supporting the development of new and well-tolerated drugs. In 2014-2015, a phase 2b clinical study was conducted to evaluate the efficacy of a single oral dose of Artefenomel (OZ439)-piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria. Blood samples collected before treatment offered the opportunity to investigate the proportion of multidrug resistant parasite genotypes including P. falciparum Kelch13 mutations and copy number variation of both P. falciparum plasmepsin2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. Validated Kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated to PPQ resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (>30%).\n\nOur findings sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to decipher the genetic background associated with PPQ resistance in Africa by investigating in vitro susceptibilities to PPQ of isolates with multiple copies of the Pfpm2 gene and the urgent need to assess the risk of development of PPQ resistance, along with the efficacy of both current frontline therapies and new antimalarial combinations.

microbiology↗

Mammalian Cell Entry domains are required for bile resistance and virulence in Salmonella

MCE domains were first reported in Mycobacteria as having a role in Mammalian Cell Entry, with subsequent studies showing their importance during infection. Here, we have examined the function of MCE proteins in Salmonella Typhimurium during mammalian infection. We report that MCE proteins are required for Salmonella virulence, but that this is not related to decreased adherence, entry or survival in mammalian cells. Instead, we reveal that MCE proteins are required for Salmonella bile resistance, in particular to withstand bile salts such as cholate and deoxycholate. Based on our previous work in Escherichia coli, and other studies that have reported roles for MCE proteins in membrane biogenesis, we propose that Salmonella lacking MCE domains have a defective outer membrane that results in bile sensitivity and decreased virulence in vivo. These results suggest that MCE domains mediate fundamental aspects of bacterial membrane physiology as opposed to a proposed direct role in mammalian cell entry, explaining their conservation across both pathogenic and non-pathogenic bacteria.

microbiology↗

Circulating unacylated-ghrelin impairs hippocampal neurogenesis and memory in mice and is altered in human Parkinson’s disease dementia

Blood-borne factors regulate adult hippocampal neurogenesis (AHN) and cognition in mammals, albeit via mechanisms that are poorly understood. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in GOAT-/- mice that lack acyl-ghrelin (AG) but have high levels of UAG, were rescued by treatment with AG. This unexpected finding suggests that the post-translational acylation of ghrelin is an important modulator of neurogenesis and memory in adult mammals. To determine whether this paradigm is relevant to humans we analysed circulating AG:UAG levels in Parkinsons disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients and healthy controls. Uniquely, the ratio of plasma AG:UAG was reduced in the PDD cohort and correlated with cognitive performance. Our results identify UAG as a novel regulator of neurogenesis and cognition, and AG:UAG as a circulating diagnostic biomarker of dementia. The findings extend our understanding of adult brain plasticity regulation by circulating factors and suggest that manipulating the post-translational acylation of plasma ghrelin may offer therapeutic opportunities to ameliorate cognitive decline.\n\nHighlightsO_LICirculating UAG impairs markers of neurogenesis and plasticity\nC_LIO_LIGOAT-/-mice have impaired neurogenesis and spatial memory\nC_LIO_LICirculating acyl-ghrelin (AG) rescues spatial memory deficit in GOAT-/-mice\nC_LIO_LICirculating AG:UAG ratio is reduced in Parkinsons disease dementia\nC_LI

neuroscience↗