Miracle-dz/UniFAR-FTUs huggingface dataset:
Characterizing the genetic basis of copper toxicity in Drosophila reveals a complex pattern of allelic, regulatory, and behavioral variation

A range of heavy metals are required for normal cell function and homeostasis. Equally, the anthropogenic release of heavy metals into soil and water sources presents a pervasive health threat. Copper is one such metal; it functions as a critical enzymatic cofactor, but at high concentrations is toxic, and can lead to the production of reactive oxygen species. Using a combination of quantitative trait locus (QTL) mapping and RNA sequencing in the Drosophila Synthetic Population Resource (DSPR), we demonstrate that resistance to the toxic effects of ingested copper in D. melanogaster is genetically complex, and influenced by allelic and expression variation at multiple loci. Additionally, we find that copper resistance is impacted by variation in behavioral avoidance of copper and may be subject to life-stage specific regulation. Multiple genes with known copper-specific functions, as well as genes that are involved in the regulation of other heavy metals were identified as potential candidates to contribute to variation in adult copper resistance. We demonstrate that nine of 16 candidates tested by RNAi knockdown influence adult copper resistance, a number of which may have pleiotropic effects since they have previously been shown to impact the response to other metals. Our work provides new understanding of the genetic complexity of copper resistance, highlighting the diverse mechanisms through which copper pollution can negatively impact organisms. Additionally, we further support the similarities between copper metabolism and that of other essential and nonessential heavy metals.
Dopaminergic Neuromodulation of Spike Timing Dependent Plasticity in Mature Adult Rodent and Human Cortical Neurons

Synapses in the cerebral cortex constantly change and this dynamic property regulated by the action of neuromodulators such as dopamine (DA), is essential for reward learning and memory. DA modulates spike-timing-dependent plasticity (STDP), a cellular model of learning and memory, in juvenile rodent cortical neurons. However, it is unknown whether this neuromodulation also occurs at excitatory synapses of cortical neurons in mature adult mice or in humans. Cortical layer V pyramidal neurons were recorded with whole cell patch clamp electrophysiology and an extracellular stimulating electrode was used to induce STDP. DA was either bath-applied or optogenetically released in slices from mice. Classical STDP induction protocols triggered non-Hebbian excitatory synaptic depression in the mouse or no plasticity at human cortical synapses. DA reverted long term synaptic depression to baseline in mouse or elicited long term synaptic potentiation in human cortical synapses. Furthermore, when DA was applied during a STDP protocol it depressed presynaptic inhibition in the mouse but not in the human cortex. Thus, DA modulates excitatory synaptic plasticity differently in human versus mouse cortex. The data strengthens the importance of DA in gating cognition in humans, and may inform on therapeutic interventions to recover brain function from diseases.
CoV-AbDab: the Coronavirus Antibody Database

The emergence of a novel strain of betacoronavirus, SARS-CoV-2, has led to a pandemic that has been associated with hundreds of thousands of deaths. Research is ongoing around the world to create vaccines and therapies to minimise rates of disease spread and mortality. Crucial to these efforts are molecular characterisations of neutralising antibodies to SARS-CoV-2. Such antibodies would be valuable for measuring vaccine efficacy, diagnosing exposure, and developing effective biotherapeutics. Here, we describe our new database, CoV-AbDab, which already contains data on over 380 published/patented antibodies and nanobodies known to bind to at least one betacoronavirus. This database is the first consolidation of antibodies known to bind SARS-CoV-2 and other betacoronaviruses such as SARS-CoV-1 and MERS-CoV. We supply relevant metadata such as evidence of cross-neutralisation, antibody/nanobody origin, full variable domain sequence (where available) and germline assignments, epitope region, links to relevant PDB entries, homology models, and source literature. Our preliminary analysis exemplifies a spectrum of potential applications for the database, including identifying characteristic germline usage biases in receptor-binding domain antibodies and contextualising the diagnostic value of the SARS-CoV binding CDRH3s through comparison to over 500 million antibody sequences from SARS-CoV serologically naive individuals. Community submissions are invited to ensure CoV-AbDab is efficiently updated with the growing body of data analysing SARS-CoV-2. CoV-AbDab is freely available and downloadable on our website at http://opig.stats. ox.ac. uk/webapps/coronavirus.
Habitat loss causes long transients in small trophic chains

Transients in ecology are extremely important since they determine how equilibria are approached. The debate on the dynamic stability of ecosystems has been largely focused on equilibrium states. However, since ecosystems are constantly changing due to climate conditions or to perturbations such as the climate crisis or anthropogenic actions (habitat destruction, deforestation, or defaunation), it is important to study how dynamics can proceed till equilibria. In this contribution we investigate dynamics and transient phenomena in small food chains using mathematical models. We are interested in the impact of habitat loss in ecosystems with vegetation undergoing facilitation. We provide a thorough dynamical study of a small food chain system given by three trophic levels: vegetation, herbivores, and predators. The dynamics of the vegetation alone suffers a saddle-node bifurcation, causing extremely long transients. The addition of a herbivore introduces a remarkable number of new phenomena. Specifically, we show that, apart from the saddle node involving the extinction of the full system, a transcritical and a supercritical Hopf-Andronov bifurcation allow for the coexistence of vegetation and herbivores via non-oscillatory and oscillatory dynamics, respectively. Furthermore, a global transition given by a heteroclinic bifurcation is also shown to cause a full extinction. The addition of a predator species to the previous systems introduces further complexity and dynamics, also allowing for the coupling of different transient phenomena such as ghost transients and transient oscillations after the heteroclinic bifurcation. Our study shows how the increase of ecological complexity via addition of new trophic levels and their associated nonlinear interactions may modify dynamics, bifurcations, and transient phenomena.
Limited transgenerational effects of environmental temperatures on thermal performance of a cold-adapted salmonid

The capacity of ectotherms to cope with rising temperatures associated with climate change is a significant conservation concern as the rate of warming is likely too fast for adaptation to occur in some populations. Transgenerational plasticity, if present, could potentially buffer some of the negative impacts of warming on future generations. We examined transgenerational plasticity in lake trout to assess their inter-generational potential to cope with anticipated warming. We acclimated adult lake trout to cold or warm temperatures for several months, then bred them to produce offspring from parents of matched and mismatched temperatures. At the fry stage, offspring were also acclimated to cold or warm temperatures and their thermal performance was assessed by measuring their critical thermal maximum and metabolic rate during an acute temperature challenge. Overall, transgenerational plasticity was evident: thermal performance of offspring reflected both maternal and paternal environmental conditions, and offspring performed better when their environment matched that of their parents. There was little variation in offspring critical thermal maximum or peak metabolic rate, although cold-acclimated offspring from warm-acclimated parents exhibited elevated standard metabolic rates, suggesting that transgenerational effects can be detrimental when parent and offspring environments mismatch. These results demonstrate both the occurrence and limitations of transgenerational plasticity in a coldwater salmonid in response to elevated temperature, as well as potential ecological risks associated with transgenerational plasticity when an environmental change experienced by the parents does not persist with the next generation.
Higher Prevalence of Bacteroides fragilis in Crohn’s Disease Exacerbations and Strain-Dependent Increase of Epithelial Resistance

Bacteroides fragilis has previously been linked to Crohn’s disease (CD) exacerbations, but results are inconsistent and underlying mechanisms unknown. This study investigates the epidemiology of B. fragilis and its virulence factors bft (enterotoxin) and ubiquitin among 181 CD patients and the impact on the intestinal epithelial barrier in vitro. The prevalence of B. fragilis was significantly higher in active (n=69/88, 78.4%) as compared to remissive (n=58/93, 62.4%, p=0.018) CD patients. Moreover, B. fragilis was associated with intestinal strictures. Interestingly, the intestinal barrier function, as examined by transepithelial electrical resistance (TEER) measurements of Caco-2 monolayers, improved when exposed to secretomes of bft-positive (increased TEER ∼160%, p<0.001) but not when exposed to bft- negative strains. Whole metagenome sequencing and metabolomics, respectively, identified 19 coding sequences and two metabolites that discriminated TEER-increasing from non-TEER-increasing strains. This study revealed a higher B. fragilis prevalence during exacerbation. Surprisingly, bft-positive secretomes improved epithelial resistance.
Endocannabinoids and Dopamine Balance Basal Ganglia Output

The entopeduncular nucleus is one of the basal ganglia’s output nuclei, thereby controlling basal ganglia information processing. Entopeduncular nucleus neurons integrate GABAergic inputs from the striatum and the globus pallidus and glutamatergic inputs from the subthalamic nucleus. We show that endocannabinoids and dopamine interact to modulate the long-term plasticity of all the primary afferents to the entopeduncular nucleus. Our results suggest that dopamine-endocannabinoids interplay determines the balance of the direct or indirect dominance of entopeduncular nucleus output. Furthermore, we demonstrate that, despite the lack of axon collaterals, information is transferred between neighboring neurons in the entopeduncular nucleus via endocannabinoids diffusion. These results transform the prevailing view of the entopeduncular nucleus as a feedforward “relay” nucleus to an intricate control unit, which may play a vital role in the process of action selection.
The legacy of C4 evolution in the hydraulics of C3 and C4 grasses

The anatomical reorganization required for optimal C4 photosynthesis should also impact plant hydraulics. Most C4 plants possess large bundle-sheath cells and high vein density, which should also lead to higher leaf hydraulic conductance (Kleaf) and capacitance. Paradoxically, the C4 pathway reduces water demand and increases water-use-efficiency, creating a potential mis-match between supply capacity and demand in C4 plant water relations. We use phylogenetic analyses, physiological measurements, and models to examine the reorganization of hydraulics in closely-related C4 and C3 grasses. Evolutionarily young C4 lineages have higher Kleaf, capacitance, turgor-loss-point, and lower stomatal conductance than their C3 relatives. In contrast, species from older C4 lineages show decreased Kleaf and capacitance, indicating that over time, C4 plants have evolved to optimize hydraulic investments while maintaining C4 anatomical requirements. The initial “over-plumbing” of C4 plants disrupts the positive correlation between maximal assimilation rate and Kleaf, decoupling a key relationship between hydraulics and photosynthesis generally observed in vascular plants.
Nitrogen Use Efficiency and Nitrogen Fertilizer Recovery of Durum Wheat Genotypes as Affected by Interspecific Competition

A better understanding of the genotype response to N fertilization under weed competition is necessary to identify varieties that exhibit high N use effi ciency even when weeds compete for available N. Such varieties may be more suitable for low input or organic systems. Th is study assessed the variations in nitrogen use effi ciency (NUE) (and its components) and the recovery of 15 N-labeled fertilizer in three durum wheat (Triticum durum Desf.) genotypes (one landrace and two varieties that diff er in terms of plant growth, grain yield potential, and adaptability to stressful environments) grown in the presence or absence of interspecifi c competition and varying soil N availability (0 or 80 kg N ha –1 fertilization). Th e results showed that wheat genotypes had diff erent grain yield potentials and the yields were similar when plants were grown in conditions of low N availability and in presence of interspecifi c competition. Diff erences among genotypes in N uptake effi ciency were very small, and the low NUE value observed for the landrace seemed to be due to its reduced ability to use absorbed N for increasing grain yield compared with the two varieties. Furthermore, the genotypes showed diff erent competitive abilities against competitor, and seemed to depend on the genotypes’ ability to reduce resource availability (N) for their competitors rather than on their ability to tolerate a reduction in contested resources due to competitors.
Recurrent evolution of two competing haplotypes in an insect DNA virus

Hosts and viruses are constantly evolving in response to each other: as hosts attempt to suppress the virus, the virus attempts to evade and suppress the host’s immune system. This arms race results in the evolution of novel pathways in both the host and virus to gain the upper hand. Here we describe the coevolution between Drosophila species and a common and virulent DNA virus. We identify two distinct viral types that differ 100-fold in viral titer in infected individuals, with similar effects across multiple species. Our analysis suggests that one of the viral types appears to have recurrently evolved at least 4 times in the past ∼30,000 years, including in another geographically distinct species, due to the high effective mutation rate which increases with titer. The higher titer viral type is associated with suppression of the host immune system and an increased transmission rate compared to the low viral titer type. Both types are maintained in all populations, likely due to an increased virulence in the high titer type creating a trade-off between effective transmission and virulence and resulting in nearly equal reproduction rates (R0) in both types. Together these results suggest that the reciprocal selective pressures caused by the co-evolution between host and virus has resulted in this recurrently evolving relationship.
Dual Role of a Rubisco Activase in Metabolic Repair and Carboxysome Organization

Rubisco, the key enzyme of CO2 fixation in photosynthesis, is prone to inactivation by inhibitory sugar phosphates. Inhibited Rubisco undergoes conformational repair by the hexameric AAA+ chaperone Rubisco activase (Rca) in a process that is not well understood. Here we performed a structural and mechanistic analysis of cyanobacterial Rca, a close homolog of plant Rca. In the Rca:Rubisco complex, Rca is positioned over the Rubisco catalytic site under repair and pulls the N-terminal tail of the large Rubisco subunit (RbcL) into the hexamer pore. Simultaneous displacement of the C-terminus of the adjacent RbcL opens the catalytic site for inhibitor release. An alternative interaction of Rca with Rubisco is mediated by C-terminal domains that resemble the small Rubisco subunit. These domains, together with the N-terminal AAA+ hexamer, ensure that Rca is packaged with Rubisco into carboxysomes. Cyanobacterial Rca is a dual-purpose protein with functions in Rubisco repair and carboxysome organization.
Persistent epigenetic reprogramming of sweet taste by diet

Diets high in sugar persistently alter sensory responses to sweetness through the actions of the PRC2 complex to promote obesity. Diets rich in sugar, salt, and fat alter taste perception and food preference, contributing to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here, we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of Drosophila melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.
Acute exercise following skill practice promotes motor memory consolidation in Parkinson’s disease

Acute cardiovascular exercise has shown to promote neuroplastic processes, and thus to improve the consolidation of newly acquired motor skills in healthy adults. First results suggest that this concept may be transferred to populations with motor and cognitive dysfunctions. In this context, Parkinson’s disease (PD) is highly relevant since patients demonstrate deficits in motor learning. Hence, in the present study we sought to explore the effect of a single post-practice exercise bout on motor memory consolidation in PD patients. For this purpose, 17 PD patients (Hoehn and Yahr: 1 – 2.5, age: 60.1 ± 7.9 y) practiced a whole-body task followed by either (i) a moderate-intense bout of cycling, or (ii) seated rest for a total of 30 minutes. The motor task required the participants to balance on a tiltable platform (stabilometer) for 30 seconds. During skill practice, patients performed 15 trials followed by a retention test 1 day and 7 days later. We calculated time in balance (platform within ± 5° from horizontal) for each trial and within- and between-group differences in memory consolidation (i.e. offline learning = skill change from last acquisition block to retention tests) were analyzed. Groups revealed similar improvements during skill practice (F4,60 = .316, p = .866), but showed differences in offline learning, which was only evident after 7 days (F1,14 = 5.602, p = .033). Our results suggest that a single post-practice exercise bout is effective in enhancing long-term motor memory consolidation in a population with motor learning impairments. This may point at unique promoting effects of exercise on dopamine neurotransmission involved in memory formation. Future studies should investigate the potential role of exercise-induced effects on the dopaminergic system. Highlights Acute exercise enhanced motor memory consolidation in PD Effects were evident only at 7-day retention Results may indicate unique exercise-effects on the dopaminergic system Findings show promising potential of exercise for motor rehabilitation
The role of incoherent feedforward circuits in regulating precision of event timing

Triggering of cellular events often relies on the level of a key gene product crossing a critical threshold. Achieving precision in event timing in spite of noisy gene expression facilitates high-fidelity functioning of diverse processes from biomolecular clocks, apoptosis and cellular differentiation. Here we investigate the role of an incoherent feedforward circuit in regulating the time taken by a bacterial virus (bacteriophage lambda) to lyse an infected Escherichia coli cell. Lysis timing is the result of expression and accumulation of a single lambda protein (holin) in the E. coli cell membrane up to a critical threshold level, which triggers the formation of membrane lesions. This easily visualized process provides a simple model system for characterizing event-timing stochasticity in single cells. Intriguingly, lambda’s lytic pathway synthesizes two functionally opposite proteins: holin and antiholin from the same mRNA in a 2:1 ratio. Antiholin sequesters holin and inhibits the formation of lethal membrane lesions, thus creating an incoherent feedforward circuit. We develop and analyze a stochastic model for this feedforward circuit that considers correlated bursty expression of holin/antiholin, and their concentrations are diluted from cellular growth. Interestingly, our analysis shows the noise in timing is minimized when both proteins are expressed at an optimal ratio, hence revealing an important regulatory role for antiholin. These results are in agreement with single cell data, where removal of antiholin results in enhanced stochasticity in lysis timing.
Let it bud: an ultrastructural study of Cryptococcus neoformans surface during budding events

Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals. It is surrounded by three concentric structures that separate the cell from the extracellular space: the plasma membrane, the cell wall and the polysaccharide capsule. Although several studies have revealed the chemical composition of these structures, little is known about their ultrastructural organization and remodeling during C. neoformans budding event. Here, by combining the state-of-the-art in light and electron microscopy techniques we describe the morphological remodeling that occurs synergistically among the capsule, cell wall and plasma membrane during budding in C. neoformans. Our results show that the cell wall deforms to generate a specialized budding region at one of the cell’s poles. This region subsequently begins to break into layers that are slightly separated from each other and with thick tips. We also observe a reduction in density of the capsular polysaccharide around these specialized regions. Daughter cells present a distinct spatial organization, with polysaccharide fibers aligned in the direction of budding. In addition, to control the continuous openings between mother and daughter cells, the latter developed a strategy to shield themselves by forming multilamellar membrane structures in conjunction with their capsules. Together, our findings provide compelling ultrastructural evidence for a dynamic C. neoformans surface remodeling during budding and may have important implications for future studies exploring these remodeled specialized regions as drug-targets against cryptococcosis.