Miracle-dz/UniFAR-FTUs huggingface dataset:
Modelling the contribution of iodised salt in industrially processed foods to iodine intake in Macedonia

Evidence from the 1950s showed that Macedonia was iodine deficient. After the introduction of mandatory universal salt iodisation, the country saw a steady increase in iodine intake and decline in goitre prevalence, earning iodine-deficiency free status in 2003. Iodine status assessments in 2007 and 2016 showed adequate iodine intake among school age children (median urinary iodine concentration of 241 µg/L and 236 µg/L respectively). Macedonia participated in the 2019 piloting of the Iodine Global Network Programme Guidance on the use of iodised salt in industrially processed foods to better understand salt and iodised salt intake from food sources other than household salt. Aggregated data from the 2017 Household Consumption and Expenditure Survey (HCES) was used to determine household salt consumption, to identify widely-consumed, salt-containing industrially processed foods and estimate typical daily intake of these foods. The salt content of these foods was estimated using national standards and the Danish food composition database. The percentage of this salt that was iodised was assessed using customs data for salt imports. Although the study has its limitations, including a relatively small selection of foods, the results indicate potential iodine intake from iodised household salt and iodised salt in the selected foods of above 300% of the Estimated Average Requirement and over 220% of the Recommended Nutrient Intake for adults. This was approximately 50% of the tolerable safe Upper Level for iodine intake. The study confirmed high daily salt intake (11.2 grams from household salt only). Successful salt reduction would be expected to reduce iodine intake, however, modelling with 10% and 30% reduction implied this is unlikely to put any population group at risk of deficiency. It is recommended that design and implementation of salt iodisation and salt reduction policies are harmonized, alongside continued regular iodine status monitoring for different population groups.
Thermodynamic Assessment of the Miscibility Gaps and the Metastable Liquidi in the Zn–Bi, Zn–Pb, and Zn–Tl Systems

Abstract In monotectic systems, there are thermodynamic restrictions on compositions and temperatures below the monotectic where the equilibrium solid cannot form directly from the undercooled homogeneous liquid. In this region, the solid can form only after liquid–liquid phase separation has occurred. As suggested by earlier research, the thermodynamic restrictions on the solidification process may be useful to control the micro structure of rapidly solidified materials. Thus, it could be commercially important to understand the thermodynamic limitations on the formation of the solid in monotectic systems. The liquid miscibility gaps, metastable liquidi, and spinodal curves in the binary Zn–Bi, Zn–Pb, and Zn–Tl systems were assessed by using a subregular solution model to describe the Gibbs energies of the liquid phases. The present results were compared and discussed with other experimental and assessed data available in the literature.
NirA Is an Alternative Nitrite Reductase from Pseudomonas aeruginosa with Potential as an Antivirulence Target

The emergence of widespread antimicrobial resistance has led to the need for development of novel therapeutic interventions. Antivirulence strategies are an attractive alternative to classic antimicrobial therapy; however, they require identification of new specific targets which can be exploited in drug discovery programs. ABSTRACT The opportunistic pathogen Pseudomonas aeruginosa produces an arsenal of virulence factors causing a wide range of diseases in multiple hosts and is difficult to eradicate due to its intrinsic resistance to antibiotics. With the antibacterial pipeline drying up, antivirulence therapy has become an attractive alternative strategy to the traditional use of antibiotics to treat P. aeruginosa infections. To identify P. aeruginosa genes required for virulence in multiple hosts, a random library of Tn5 mutants in strain PAO1-L was previously screened in vitro for those showing pleiotropic effects in the production of virulence phenotypes. Using this strategy, we identified a Tn5 mutant with an insertion in PA4130 showing reduced levels of a number of virulence traits in vitro. Construction of an isogenic mutant in this gene presented results similar to those for the Tn5 mutant. Furthermore, the PA4130 isogenic mutant showed substantial attenuation in disease models of Drosophila melanogaster and Caenorhabditis elegans as well as reduced toxicity in human cell lines. Mice infected with this mutant demonstrated an 80% increased survival rate in acute and agar bead lung infection models. PA4130 codes for a protein with homology to nitrite and sulfite reductases. Overexpression of PA4130 in the presence of the siroheme synthase CysG enabled its purification as a soluble protein. Methyl viologen oxidation assays with purified PA4130 showed that this enzyme is a nitrite reductase operating in a ferredoxin-dependent manner. The preference for nitrite and production of ammonium revealed that PA4130 is an ammonia:ferredoxin nitrite reductase and hence was named NirA. IMPORTANCE The emergence of widespread antimicrobial resistance has led to the need for development of novel therapeutic interventions. Antivirulence strategies are an attractive alternative to classic antimicrobial therapy; however, they require identification of new specific targets which can be exploited in drug discovery programs. The host-specific nature of P. aeruginosa virulence adds complexity to the discovery of these types of targets. Using a sequence of in vitro assays and phylogenetically diverse in vivo disease models, we have identified a PA4130 mutant with reduced production in a number of virulence traits and severe attenuation across all infection models tested. Characterization of PA4130 revealed that it is a ferredoxin-nitrite reductase and hence was named NirA. These results, together with attenuation of nirA mutants in different clinical isolates, high level conservation of its gene product in P. aeruginosa genomes, and the lack of orthologues in human genomes, make NirA an attractive antivirulence target.
The CP110-CEP97-CEP290 module orchestrates a centriolar satellite dependent response to proteotoxic stress

Protein degradation at the centrosome, the primary microtubule organizing centre of the cell, is critical to a myriad of cellular processes. Perturbation of the ubiquitin proteasome system causes the formation of an inclusion, or aggresome, at the centrosome. By systematic microscopy analysis, we have placed a subset of centrosomal proteins within the aggresome. Centriolar satellites, proteinaceous granules found in the vicinity of centrosomes, also became incorporated into this structure. Through high-resolution quantitative analysis, we have defined aggresome assembly at the centrosome, demonstrating a requirement for satellites in this process. Furthermore, a module consisting of CP110-CEP97-CEP290 was required to recruit aggresome components early in the pathway and senescent cells were defective in aggresome formation due to limiting amounts of CP110. Finally, satellites and the CP110-CEP97-CEP290 module were required for the aggregation of mutant huntingtin. The accumulation of protein aggregates is central to the pathology of a range of human disorders. These data thereby reveal new roles for CP110, its interactors, and centriolar satellites in controlling cellular proteostasis and the aggregation of disease relevant proteins.
Developmental Accumulation of Gene Body and Transposon Non-CpG Methylation in the Zebrafish Brain

DNA methylation predominantly occurs at CG dinucleotides in vertebrate genomes; however, non-CG methylation (mCH) is also detectable in vertebrate tissues, most notably in the nervous system. In mammals it is well established that mCH is targeted to CAC trinucleotides by DNMT3A during nervous system development where it is enriched in gene bodies and associated with transcriptional repression. However, the conservation of developmental mCH accumulation and its deposition by DNMT3A is largely unexplored and has yet to be functionally demonstrated in other vertebrates. In this study, by analyzing DNA methylomes and transcriptomes of zebrafish brains, we identified enrichment of mCH at CAC trinucleotides (mCAC) at defined transposon motifs as well as in developmentally downregulated genes associated with developmental and neural functions. We further generated and analyzed DNA methylomes and transcriptomes of developing zebrafish larvae and demonstrated that, like in mammals, mCH accumulates during post-embryonic brain development. Finally, by employing CRISPR/Cas9 technology, we unraveled a conserved role for Dnmt3a enzymes in developmental mCAC deposition. Overall, this work demonstrates the evolutionary conservation of developmental mCH dynamics and highlights the potential of zebrafish as a model to study mCH regulation and function during normal and perturbed development.
Human cytomegalovirus infection changes the pattern of surface markers of small extracellular vesicles isolated from first trimester placental histocultures

Currently, research on the use of non-invasive biomarkers as diagnosis and prognosis tools during pathological pregnancies is in full development. Among these, placenta-derived small extracellular vesicles (sEVs) are considered as serious candidates, since their composition is modified during many pregnancy pathologies. Moreover, sEVs are found in maternal serum and can thus be easily purified from a simple blood sample. In this study, we describe the isolation of sEVs from a histoculture model of first trimester placental explants. Using bead-based multiplex cytometry and electron microscopy combined with biochemical approaches, we characterized these sEVs and defined their associated markers and ultrastructure. We next examined the consequences of infection by human cytomegalovirus on sEVs secretion and characteristics. We observed that infection led to increased levels of expression of several surface markers, without any impact on the secretion and integrity of sEVs. Our findings open the prospect for the identification of new predictive biomarkers for the severity and outcome of this congenital infection early during pregnancy, which are still sorely lacking.
Cell cycle corruption in a pre-leukemic ETV6-RUNX1 model exposes RUNX1 addiction as a therapeutic target in acute lymphoblastic leukemia

The ETV6-RUNX1 onco-fusion arises in utero, initiating a clinically silent pre-leukemic state associated with the development of pediatric B-acute lymphoblastic leukemia (B-ALL). We characterize the ETV6-RUNX1 regulome by integrating chromatin immunoprecipitation- and RNA-sequencing and show that ETV6-RUNX1 functions primarily through competition for RUNX1 binding sites and transcriptional repression. In pre-leukemia, this results in ETV6-RUNX1 antagonization of cell cycle regulation by RUNX1 as evidenced by mass cytometry analysis of B-lineage cells derived from ETV6-RUNX1 knock-in human pluripotent stem cells. In frank leukemia, knockdown of RUNX1 or its co-factor CBFβ results in cell death suggesting sustained requirement for RUNX1 activity which is recapitulated by chemical perturbation using an allosteric CBFβ-inhibitor. Strikingly, we show that RUNX1 addiction extends to other genetic subtypes of pediatric B-ALL and also adult disease. Importantly, inhibition of RUNX1 activity spares normal hematopoiesis. Our results implicate chemical intervention in the RUNX1 program as an exciting therapeutic opportunity in ALL.
Adsorption of As(III) Ions onto Iron-Containing Waste Sludge

The adsorption performance of a low-cost adsorbent (IS), viz. an iron-containing waste sludge arising during a hot-dip galvanizing process, towards the removal of As(III) ions from synthetic aqueous solutions and natural underground water was examined. The adsorption process was best described by the pseudo-second-order kinetic equation. The equilibrium adsorption data were well described by the Langmuir model. The value of the dimensional separation factor, RL, indicated favourable adsorption. The maximum adsorption capacity of IS was 625 μg As(III)/g. The variation in the extent of adsorption with temperature was used to evaluate the thermodynamic parameters for the adsorption process. The values of ΔH0 and ΔG0 obtained demonstrated that the adsorption process was exothermic and spontaneous. The studied material exhibited an excellent As(III) ion adsorption performance from both synthetic solutions and a natural water sample. Moreover, no secondary contaminated substances arise if the exhausted adsorbent is recycled (e.g. in glass applications).
Quantitative cross-species translators of cardiac myocyte electrophysiology: Model training, experimental validation, and applications

Animal experimentation is key in the evaluation of cardiac efficacy and safety of novel therapeutic compounds. However, inter-species differences in the mechanisms regulating excitation-contraction coupling can limit the translation of experimental findings from animal models to human physiology, and undermine the assessment of drugs’ efficacy and safety. Here, we built a suite of translators for quantitatively mapping electrophysiological responses in ventricular myocytes across species. We trained these statistical operators using a broad dataset obtained by simulating populations of our biophysically detailed computational models of action potential and Ca2+ transient in mouse, rabbit, and human. We then tested our translators against experimental data describing the response to stimuli, such as ion channel block, change in beating rate, and β-adrenergic challenge. We demonstrate that this approach is well suited to predicting the effects of perturbations across different species or experimental conditions, and suggest its integration into mechanistic studies and drug development pipelines.
HIV Reverse Transcriptase Pre-Steady-State Kinetic Analysis of Chain Terminators and Translocation Inhibitors Reveals Interactions between Magnesium and Nucleotide 3′-OH

Deoxythymidine triphosphate analogs with various 3′ sugar groups (-OH (dTTP), -H, -N3, -NH2, -F, -O-CH3, no group (2′,3′-didehydro-2′,3′-dideoxythymidine triphosphate (d4TTP)), and those retaining the 3′-OH but with 4′ additions (4′-C-methyl, 4′-C-ethyl) or sugar ring modifications (D-carba dTTP) were evaluated using pre-steady-state kinetics in low (0.5 mM) and high (6 mM) Mg2+ with HIV reverse transcriptase (RT). Analogs showed diminished incorporation rates (k) compared to dTTP ranging from about 2-fold (3′-H, -N3, and d4TTP with high Mg2+) to >10-fold (3′-NH2 and 3′-F with low Mg2+), while 3′-O-CH3 dTTP incorporated much slower than other analogs. Illustrating the importance of interactions between Mg2+ and the 3′-OH, k using 5 μM dTTP and 0.5 mM Mg2+ was only modestly slower (1.6-fold) than with 6 mM Mg2+, while analogs with 3′ alterations incorporated 2.8-5.1-fold slower in 0.5 mM Mg2+. In contrast, 4′-C-methyl and D-carb dTTP, which retain the 3′-OH, were not significantly affected by Mg2+. Consistent with these results, analogs with 3′ modifications were better inhibitors in 6 mM vs. 0.5 mM Mg2+. Equilibrium dissociation constant (Kd) and kpol determinations for dTTP and analogs lacking a 3′-OH indicated that low Mg2+ caused a several-fold greater reduction in kpol with the analogs but had little effect on Kd, results consistent with a role for 3′-OH/Mg2+ interactions in catalysis rather than nucleotide binding. Overall, results emphasize the importance previously unreported interactions between Mg2+ and the 3′-OH of the incoming nucleotide and suggest inhibitors with 3′-OH groups may have advantages in the low free Mg2+ in physiological settings.
Mechanisms of punctuated vision in fly flight

To guide locomotion, animals control their gaze via movements of their eyes, head, and/or body, but how the nervous system controls gaze during complex motor tasks remains elusive. Notably, eye movements are constrained by anatomical limits, which requires resetting eye position. By studying tethered, flying flies (Drosophila) in a virtual reality flight simulator, we show that ballistic head movements (saccades) reset eye position, are stereotyped and leverage elastic recoil of the neck joint, enabling mechanically assisted redirection of gaze. Head reset saccades were of proprioceptive origin and interrupted smooth movements for as little as 50 ms, enabling punctuated, near-continuous gaze stabilization. Wing saccades were modulated by head orientation, establishing a causal link between neck signals and execution of body saccades. Furthermore, we demonstrate that head movements are gated by behavioral state. We propose a control architecture for biological and bio-inspired active vision systems with limits in sensor range of motion.
Invasive garlic mustard demonstrates stronger relationships with pathotrophic than mycorrhizal fungi

24 Garlic mustard (Alliaria petiolata) has long been known to degrade mycorrhizal 25 mutualisms in soils it invades and may also promote the abundance of microbial pathogens 26 harmful to native plants or alter saprotrophic communities to disrupt nutrient cycling. Phenology 27 of other invasive species, like Lepidium latifolium and Lonicera maackii, plays a role in their 28 interactions with soil microbial communities, and so we may expect garlic mustard phenology to 29 influence its effects on native soil microbiomes as well. Here, we investigate differences in 30 fungal, bacterial, and archaeal community structure, as well as the abundance of key functional 31 groups, between garlic mustard present, absent, and removed treatments in central-Illinois forest 32 soils across different stages of the garlic mustard life cycle. Across its phenology, garlic mustard 33 present soils had different overall fungal community structure and greater abundance of 34 pathotrophic fungi than soils where garlic mustard was absent or removed. However, abundance 35 of ectomycorrhizal and saprotrophic fungi as well as bacterial and archaeal community structure 36 were similar between treatments and did not interact with garlic mustard phenology. The most 37 abundant overall fungal taxon was a plant pathogen, Entorrhiza aschersoniana, that was greatest 38 in garlic mustard present soils, particularly while the plants were flowering. These results 39 support the hypothesis that invasive plants form active relationships with microbial pathogens 40 that could contribute to their overall success in invading ecosystems. 41 42
Absence of electroencephalographic evidence of implicit action-effect intentional binding with varying effect probability

The subjective experience of an attraction in time of an action, and the event caused by the action, is known as the intentional binding phenomenon. Intentional binding is a robust phenomenon and has previously been associated with subjective sense of agency, but recent studies have shown that binding can take place in the absence of action intentions. In this study, we tested possible electrophysiological equivalents to the intentional binding phenomenon under a simple action-effect task, where pressing of a button caused tones to occur at different pitches or delays with different probabilities. Changing the probabilities of the effect of an action has in some previous studies shown to influence the intentional binding phenomenon. We tested whether changes in action-effect probability gave rise to differences in movement related cortical potentials (MRCP) slopes, peak latency and auditory event related potential (aERP) changes of amplitude or latency of the N1, P2, P3 and N4 components of the central aERP, of which some has been related to sense of agency or intentional binding. We also tested differences in MRCP across the whole scalp prior to movements, and to differences in aERP across the whole scalp after the tone is played. We found no electrophysiological indications of intentional binding when action-effect contingencies were changed in accordance with conditions that have given rise to intentional binding in previous experiments. Our results are in line with several recent studies that have questioned whether intentional binding follows all voluntary actions and can be related to sense of agency at all.
A Wolf in Another Wolf’s Clothing: Post-Genomic Regulation Dictates Venom Profiles of Medically-Important Cryptic Kraits in India

The Common Krait (Bungarus caeruleus) shares a distribution range with many other ‘phenotypically-similar’ kraits across the Indian subcontinent. Despite several reports of fatal envenoming by other Bungarus species, commercial Indian antivenoms are only manufactured against B. caeruleus. It is, therefore, imperative to understand the distribution of genetically-distinct lineages of kraits, compositional differences in their venoms, and the consequent impact of venom variation on the (pre)clinical effectiveness of antivenom therapy. To address this knowledge gap, we conducted phylogenetic and comparative venomics investigations of kraits in Southern and Western India. Phylogenetic reconstructions using mitochondrial markers revealed a new species of krait, Romulus’ krait (B. romulusi), in Southern India. Additionally, we find that kraits with 17 mid-body dorsal scale rows in Western India do not represent a subspecies of the Sind Krait (B. sindanus walli) as previously believed, but are genetically very similar to B. sindanus in Pakistan. Furthermore, venom proteomics and comparative transcriptomics revealed completely contrasting venom profiles. While the venom gland transcriptomes of all three species were highly similar, venom proteomes and toxicity profiles differed significantly, suggesting the prominent role of post-genomic regulatory mechanisms in shaping the venoms of these cryptic kraits. In vitro venom recognition and in vivo neutralisation experiments revealed a strong negative impact of venom variability on the preclinical performance of commercial antivenoms. While the venom of B. caeruleus was neutralised as per the manufacturer’s claim, performance against the venoms of B. sindanus and B. romulusi was alarming, highlighting the need for regionally-effective antivenoms in India.