Miracle-dz/UniFAR-FTUs huggingface dataset:
ATP2, the essential P4-ATPase of malaria parasites, catalyzes lipid-dependent ATP hydrolysis in complex with a Cdc50 β-subunit

Efficient mechanisms of lipid transport are indispensable for the Plasmodium malaria parasite along the different stages of its intracellular life-cycle. Gene targeting approaches have recently revealed the irreplaceable role of the Plasmodium-encoded type 4 P-type ATPases (P4-ATPases or lipid flippases), ATP2, together with its potential involvement as antimalarial drug target. In eukaryotic membranes, P4-ATPases assure their asymmetric phospholipid distribution by translocating phospholipids from the outer to the inner leaflet. As ATP2 is a yet putative transporter, in this work we have used a recombinantly-produced P. chabaudi ATP2, PcATP2, to gain insights into the function and structural organization of this essential transporter. Our work demonstrates that PcATP2 heterodimerizes with two of the three Plasmodium-encoded Cdc50 proteins: PcCdc50B and PcCdc50A, indispensable partners for most P4-ATPases. Moreover, the purified PcATP2/PcCdc50B complex catalyses ATP hydrolysis in the presence of phospholipids containing either phosphatidylserine, phosphatidylethanolamine or phosphatidylcholine head groups, and that this activity is upregulated by phosphatidylinositol 4-phosphate. Overall, our work provides the first study of the function and quaternary organization of ATP2, a promising antimalarial drug target candidate.
Hippocampal hyperactivity in a rat model of Alzheimer’s disease

Neuronal network dysfunction is a hallmark of Alzheimer’s disease (AD). However, the underlying pathomechanisms remain unknown. We analyzed the hippocampal micronetwork in a rat model of AD at an early disease stage at the beginning of extracellular amyloid beta (Aβ) deposition. We established two-photon Ca2+-imaging in vivo in the hippocampus of rats and found hyperactivity of CA1 neurons. Patch-clamp recordings in brain slices in vitro revealed changes in the passive properties and intrinsic excitability of CA1 pyramidal neurons. Furthermore, we observed increased neuronal input resistance and prolonged action potential width in CA1 pyramidal neurons. Surprisingly, all parameters measured to quantify synaptic inhibition and excitation onto CA1 pyramidal neurons were intact suggesting a cell immanent deficit. Our data support the view that altered intrinsic excitability of CA1 neurons may precede inhibitory dysfunction at an early stage of disease progression.
Root economics spectrum and construction costs in Mediterranean woody plants: the role of symbiotic associations and the environment

Quantifying the functional variation of fine root traits and their interactions with symbiotic organisms is an uprising research topic to understand the overarching trade-off between maximizing resource acquisition or conservation (root economics spectrum -RES-). The currency of root traits economy is based on the carbon required to construct them; however, we lack a clear understanding of this question. Our main aim was to quantify construction costs (CC) of fine roots (<2 mm) and their underlying components (concentration of carbon, minerals and organic nitrogen) in 60 Mediterranean woody species with contrasting symbiotic association types (ectomycorrhizas, arbuscular and ericoid mycorrhizas and N-Fixing nodules). We examined (1) if the CC depended on the symbiotic type, and if they were associated with morphological traits; (2) the relation of each component of the CC with the root structure for each symbiotic type; and (3) whether soil water and nutrient availability determined differences in CC across sites and symbiotic types. The multivariate analysis of root traits showed a main plane of covariation accordingly to the RES expectations, with contrasting symbiotic types at both ends of the spectrum. We found a significant relationship between root CC and RES; interestingly the slopes of this relationship differed among symbiotic types, which was mainly due to the different role that each specific components of CC plays across them. In addition, independently of the symbiotic type, the CC decreased linearly with the nutrient availability and quadratic with the water availability. Synthesis. Our study demonstrates that woody plants have different strategies in their root carbon investment, which depend on their position along the economics spectrum (RES) and on their main symbiotic association preference. The intrinsic components of the cost of root production varied across species with contrasting symbiotic associations, pointing to a trade-off between structural and metabolic compounds. We also found that root CC are strongly modulated by soil resource availability, following a non-linear pattern with water availability. Thus, CC shifts from high to low at the most arid sites, which points to a strong role of symbiotic associations in this shift.
Activation of the myeloid checkpoint inhibitor LILRB3 (ILT5) elicits profound immununomodulation

Despite advances in identifying the key immunoregulatory roles of the human leukocyte immunoglobulin (Ig)-like receptor (LILR) family members, the function of the inhibitory receptor LILRB3 (ILT5, CD85a, LIR3) remains unclear. Studies indicate a predominant myeloid expression; however, high homology within the LILR family and a relative paucity of reagents have hindered progress. To investigate its function and potential immunomodulatory capacity, a panel of LILRB3-specific monoclonal antibodies (mAb) was generated. LILBR3-specific mAb bound to discrete epitopes in either Ig-like domain two or four. LILRB3 ligation on primary human monocytes by agonistic mAb resulted in phenotypic and functional changes, leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Importantly, agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells. Our findings reveal powerful immunoregulatory functions of LILRB3 and identify it as an important myeloid immune checkpoint receptor.
Toward in vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

The human ether-a-go-go-related voltage-gated cardiac ion channel (commonly known as hERG) conducts the rapid outward repolarizing potassium current in cardiomyocytes (IKr). Inadvertent blockade of this channel by drug-like molecules represents a key challenge in pharmaceutical R&D due to frequent overlap between the structure-activity relationships of hERG and many primary targets. Building on our previous work, together with recent cryo-EM structures of hERG, we set about to better understand the energetic and structural basis of promiscuous blocker-hERG binding in the context of Biodynamics theory. We propose a two-step blocker binding process consisting of: Diffusion of a single fully solvated blocker copy into a large cavity lined by the intracellular cyclic nucleotide binding homology domain (the initial capture step). Occupation of this cavity is a necessary but insufficient condition for ion current disruption. Translocation of the captured blocker along the channel axis (the IKr disruption step), such that: The head group, consisting of a quasi-linear moiety, projects into the open pore, accompanied by partial de-solvation of the binding interface. One tail moiety packs along a kink between the S6 helix and proximal C-linker helix adjacent to the intra-cellular entrance of the pore, likewise accompanied by mutual de-solvation of the binding interface (noting that the association barrier is comprised largely of the total head + tail group de-solvation cost). Blockers containing a highly planar moiety that projects into a putative constriction zone within the closed channel become trapped upon closing, as do blockers terminating prior to this region. A single captured blocker molecule may associate and dissociate from the pore many times before exiting the CNBHD cavity. Lastly, we highlight possible flaws in the current hERG safety index (SI) and propose an alternate in vivo-relevant strategy factoring in: Benefit/risk. The predicted arrhythmogenic fractional hERG occupancy (based on action potential simulations of the undiseased human ventricular cardiomyocyte). Alteration of the safety threshold due to underlying disease. Risk of exposure escalation toward the predicted arrhythmic limit due to patient-to-patient pharmacokinetic variability, drug-drug interactions, overdose, and use for off-label indications in which the hERG safety parameters may differ from their on-label counterparts.
Eye-movement related brain potentials during assisted navigation in real-world

Conducting neuroscience research in the real world remains challenging because of movement- and environment-related artifacts as well as missing control over stimulus presentation. The present study demonstrated that it is possible to investigate the neuronal correlates underlying visuo-spatial information processing during real-world navigation. Using mobile EEG allowed for extraction of saccade- and blink-related potentials as well as gait-related EEG activity. In combination with source-based cleaning of non-brain activity and unfolding of overlapping event-related activity, brain activity of naturally behaving humans was revealed even in a complex and dynamic city environment.
Slow oscillation-spindle coupling is negatively associated with emotional memory formation following stress

Both stress and sleep enhance emotional memory. They also interact, with the largest effect of sleep on emotional memory being seen when stress occurs shortly before or after encoding. Slow wave sleep (SWS) is critical for long-term episodic memory, facilitated by the temporal coupling of slow oscillations and sleep spindles. Prior work in humans has shown these associations for neutral information in non-stressed participants. Whether coupling interacts with stress to facilitate emotional memory formation is unknown. Here, we addressed this question by reanalyzing an existing dataset of 64 individuals. Participants underwent a psychosocial stressor (32) or comparable control (32) prior to the encoding of 150-line drawings of neutral, positive, and negative images. All participants slept overnight with polysomnography, before being given a surprise memory test the following day. In the stress group, time spent in SWS was positively correlated with memory for images of all valences. Results were driven by those who showed a high cortisol response to the stressor, compared to low responders. The amount of slow oscillation-spindle coupling during SWS was negatively associated with neutral and emotional memory in the stress group only. The association with emotional memory was significantly stronger than for neutral memory within the stress group. These results suggest that stress around the time of initial memory formation impacts the relationship between slow wave sleep and memory.
Genomics of Ocular Chlamydia trachomatis After 5 Years of SAFE Interventions for Trachoma in Amhara, Ethiopia

Background To eliminate trachoma as a public health problem, the WHO recommends the SAFE strategy. As part of the SAFE strategy in the Amhara Region, Ethiopia, the Trachoma Control Program distributed over 124 million doses of antibiotic between 2007 and 2015. Despite these interventions, trachoma remained hyperendemic in many districts and a considerable level of Chlamydia trachomatis (Ct) infection was evident. Methods We utilised residual material from Abbott m2000 Ct diagnostic tests to sequence 99 ocular Ct samples from Amhara and investigated the role of Ct genomic variation in the continued transmission of Ct following 5 years of SAFE. Findings Sequences were typical of ocular Ct, at the whole-genome level and in tissue tropism-associated genes. There was no evidence of macrolide-resistance in this Ct population. Polymorphism in a region around ompA gene was associated with village-level TF prevalence. Additionally, greater ompA diversity at the district-level was associated with increased Ct infection prevalence. Interpretation We found no evidence for Ct genomic variation contributing to continued transmission of Ct after treatment, adding to previous evidence that azithromycin does not drive acquisition of macrolide resistance alleles in Ct. Increased Ct infection in villages and in districts with more ompA variants requires longitudinal investigation to understand what impact this may have on treatment success and host immunity. Funding European Commission; Neglected Tropical Disease Support Center; International Trachoma Initiative
Transduction catalysis: doxorubicin accelerates and enhances rAAV-mediated gene expression in the cortex of mouse, cat and monkey

Rapid and efficient gene transduction via recombinant adeno-associated viruses (rAAVs) is highly desirable across many basic and clinical research domains. Here we report vector co-infusion with doxorubicin, a clinical anti-cancer drug, markedly enhanced rAAV-mediated gene expression in cerebral cortex across mammalian species (cat, mouse, and macaque), acting throughout the time-period examined and detectable at just three days post-transfection. This enhancement showed serotype generality, being common to rAAV serotypes 2, 8, 9 and PHP.eB tested, and was observed both locally, and at remote locations consistent with doxorubicin undergoing retrograde axonal transport. All these effects were observed at doses matching human blood plasma levels in clinical therapy, and lacked detectable cytotoxicity as assessed by cell morphology, activity, apoptosis and behavioral testing. Altogether, this study identifies an effective means to improve the capability and scope of in vivo rAAV applications, accelerating and augmenting gene transduction at doxorubicin concentrations paralleling medical practice. Highlights Anti-cancer drug doxorubicin doubles the rate of rAAV-mediated transgene expression Doxorubicin enhancement generalizes across rAAV serotypes and animal species The effect is observed in both locally and retrogradely infected cortical neurons The effective dosage is free from cytotoxicity and matches clinical settings
Paternal obesity and epigenetic inheritance of breast cancer: The role of systemic effects and transmission to the second generation

Background While genetics explains some familial breast cancer cases, we showed that environmentally-induced epigenetic inheritance of breast cancer can also occur in rodent models. We previously reported that paternal consumption of a high-fat diet and ensuing obesity increased breast cancer susceptibility in the offspring (F1). Nevertheless, it is still unclear whether paternal-induced programming of breast cancer in daughters is associated with systemic alterations or mammary epithelium-specific factors. It also remains to be determined whether the ancestrally programmed breast cancer predisposition in F1 progeny can be transmitted to subsequent generations. Methods Male mice (F0) were fed either a control (CO) diet or an obesity-inducing diet (OID) for seven weeks and then mated with female mice (F0) reared on a CO diet. The resulting offspring (F1), also exclusively fed CO diet, were either used for mammary gland and tumor transplantation surgeries or to generate the F2 generation. To induce the mammary tumors, female mice were treated with 7,12 dimethylbenz[a]anthracene (DMBA). Total RNA extracted from F0 or F1 males sperm was used for small RNA-Seq analysis. Results Mammary glands from F1 CO female offspring exhibited enhanced development when transplanted into OID females [OID(CO-MG)], as shown by higher mammary gland area, epithelial branching and elongation, compared to CO females that received a CO mammary gland [CO(CO-MG)]. Similarly, mammary tumors from F1 CO female offspring transplanted into OID females [OID(CO.T)] displayed improved growth with a higher proliferation/apoptosis rate. We also found that granddaughters (F2) from the OID grand-paternal germline showed accelerated tumor growth compared to COxCO granddaughters (F2). Transmission of breast cancer predisposition to the F2 generation through OID male germline was associated with alterations in specific sperm tRNA fragments (tRF) in both F0 and F1 males. Conclusions Our findings indicate that systemic metabolic and mammary stromal alterations are the most significant contributors to paternal programming of mammary gland development and cancer predisposition in female offspring rather than mammary epithelium confined factors. Our data also show breast cancer predisposition in OID daughters can be transmitted to subsequent generations and could explain some familial cancers, if confirmed in humans.
Long identical sequences found in multiple bacterial genomes reveal frequent and widespread exchange of genetic material between distant species

Horizontal transfer of genomic elements is an essential force that shapes microbial genome evolution. Horizontal Gene Transfer (HGT) occurs via various mechanisms and has been studied in detail for a variety of systems. However, a coarse-grained, global picture of HGT in the microbial world is still missing. One reason is the difficulty to process large amounts of genomic microbial data to find and characterise HGT events, especially for highly distant organisms. Here, we exploit the fact that HGT between distant species creates long identical DNA sequences in genomes of distant species, which can be found efficiently using alignment-free methods. We analysed over 90 000 bacterial genomes and thus identified over 100 000 events of HGT. We further developed a mathematical model to analyse the statistical properties of those long exact matches and thus estimate the transfer rate between any pair of taxa. Our results demonstrate that long-distance gene exchange (across phyla) is very frequent, as more than 8% of the bacterial genomes analysed have been involved in at least one such event. Finally, we confirm that the function of the transferred sequences strongly impact the transfer rate, as we observe a 3.5 order of magnitude variation between the most and the least transferred categories. Overall, we provide a unique view of horizontal transfer across the bacterial tree of life, illuminating a fundamental process driving bacterial evolution.
Influenza-induced activation of recruited alveolar macrophages during the early inflammatory phase drives lung injury and lethality

Severe respiratory virus infections initiate a robust host immune response that contributes to disease severity. Immunomodulatory strategies that limit virus-initiated inflammation are of critical importance. In this study, we compared the host response to influenza A virus (IAV) infection in susceptible animals (wild-type, WT) to resilient mice (Vimentin-/- mice). We identified distinct gene expression patterns in recruited monocyte-derived alveolar macrophages (MoAMs) associated with three phases (Infiltrating, Early Inflammatory, Late Inflammatory) that evolve in sequence over the course of IAV infection. We report a core set of pro-inflammatory genes involved in the WT MoAM Early Inflammatory response that is suppressed in Vim-/- MoAMs. Moreover, we identify CEBPB, Jun-AP1, and IRF transcriptions factors as regulators of this attenuated inflammatory response. We performed causal experiments using bone-marrow chimeras to credential that Vim-/- MoAMs with suppressed pro-inflammatory genes confer protection from influenza-induced mortality in WT susceptible mice. Taken together, these data support the notion that vimentin plays a causal role in determining the pro-inflammatory function of recruited MoAMs and drives IAV-induced lung injury.
Growth stage-based response of wheat (Triticum aestivum L.) to kinetin under water-deficit environment: pigments and gas exchange attributes

Plant growth regulator, kinetin, is known to modulate the key physiological processes under abiotic stresses in different crops. However, kinetin-mediated response at different growth stages of crop plants is lagging behind. Therefore, a field experiment was conducted to appraise the potential role of exogenously applied kinetin in alleviating the effects of water scarcity on wheat. Three levels of kinetin (0, 75, and 150 mg/L) were used either as seed treatment or foliar spray at the vegetative or the post-anthesis stage. Water deficit markedly reduced shoot fresh mass, plant chlorophyll level, flag leaf photosynthesis, stomatal conductance, and transpiration rate. Degradation of chlorophyll a was greater in plants subjected to post-anthesis water-deficit conditions. However, plants growing under continuous water-deficit conditions had significantly lower concentration of chlorophyll b than those treated with water scarcity at the post-anthesis stage or receiving normal irrigation. Inhibited photosynthesis of wheat in response to post-anthesis water-deficit conditions was largely due to non-stomatal factors. In contrast, stomatal factors were the main constraints for photosynthesis in plants growing under continuous scarcity of water. Plants subjected to continuous water starvation had markedly lower grain yield than those subjected to water-deficit conditions at post-anthesis stage. Application of kinetin before seed sowing or at the post-anthesis stage significantly reduced the negative effects of drought on flag leaf chlorophyll and stomatal conductance. Lower level of kinetin (75 mg/L) was found to be more effective in mitigating the inhibitory effects of water shortage on photosynthesis and growth, and improved grain yield under water scarcity.
Occurrence and Significance of Bacteria in Wood

The review covers investigations on wood-inhabiting bacteria and their significance in wood quality carried out in the Hamburg Institute, with some additional literature. It addresses bacteria isolated from various woody tissues, their action on pits and woody cell walls, examples for wood discolouration by bacteria, the degradation of wood in soil and water environments and of timber treated with preservatives, methods for decay measurement, the efficacy of preservatives, trends to detoxify treated timber waste and aspects of bacteria äs bioprotectants.
Evidence of Progenitor Cell Lineage Rerouting in the Adult Mouse Hippocampus After Status Epilepticus

Cell lineage in the adult hippocampus comprises multipotent and neuron-committed progenitors. In the present work, we fate-mapped neuronal progenitors using Dcx-CreERT2 and CAG-CAT-EGFP double-transgenic mice (cDCX/EGFP). We show that three days after tamoxifen-mediated recombination in cDCX/EGFP adult mice, GFP+ cells in the dentate gyrus co-expresses DCX and about 6% of these cells are proliferative neuronal progenitors. After 30 days, 20% of GFP+ generated from these progenitors differentiate into GFAP+ astrocytes. Administration of the chemoconvulsants kainic acid (KA) or pilocarpine (PL) led to a significant increase in the number of GFP+ cells in both ipsi and contralateral dentate gyrus. However, while PL favored the differentiation of neurons in both ipsi- and contralateral sides, KA stimulated neurogenesis only in the contralateral side. In the ipsilateral side, KA injection led to an unexpected increase of astrogliogenesis in the Dcx-lineage. These different effects of KA and PL in the Dcx-lineage are associated with distinct alterations of the parvalbuminergic plexus and inflammatory responses in the hippocampi. Finally, we also observed a small number of GFP+/GFAP+ cells displaying radial-glia morphology ipsilaterally 3 days after KA administration, indicating that Dcx-progenitors could regress to a multipotent stage. Altogether, our data suggest that cell lineage in the adult hippocampus is not unidirectional and can be modulated by environmental signals.