Miracle-dz/UniFAR-FTUs huggingface dataset:
Merit overrules theory of mind when young children share resources with others

Non-windfall approaches to sharing demonstrate pre-schoolers’ sensitivity to merit-based distributions of resources. However, such studies have not considered (1) whether epistemic aspects of task performance, such as the relative accuracy of a co-worker, influences pre-schoolers’ rates of sharing; and (2) how children’s emerging social understanding may impact resource allocations in high- and low-merit situations. These issues are of theoretical importance as they may provide new information about the scope of pre-schooler’s merit-based sharing behaviours. Moreover, as social understanding has been related to both increases and decreases in pre-schoolers’ levels of sharing, providing a merit-based assessment of this relationship would allow for a concurrent assessment of recent conflicting findings. In this study, three- and four-year-olds (N = 131) participated in an unexpected transfer task which was followed by a resource generation picture card naming task with a reliable or unreliable (high- or low-merit) co-worker (a hand puppet). The results showed that children engage in more generous rates of sharing with a high-merit co-worker. This suggests that merit-based sharing is apparent in young children and extends to epistemic aspects of task performance. However, such sharing was constrained by a self-serving bias. Finally, we were not able to detect an effect of children’s performance on the false belief task on sharing behaviours in the high- or low-merit trials, suggesting that these behaviours may not be modulated by social understanding during early childhood.
Correction: The ACT domain in chloroplast precursor–phosphorylating STY kinases binds metabolites and allosterically regulates kinase activity.

Protein import of nucleus-encoded proteins into plant chloroplasts is a highly regulated process, requiring fine-tuning mechanisms especially during chloroplast differentiation. One way of altering import efficiency is phosphorylation of chloroplast transit peptides in the cytosol. We recently investigated the role of three serine/threonine/tyrosine (STY) kinases, STY8, STY17, and STY46, in precursor phosphorylation. These three kinases have a high degree of similarity and harbor a conserved aspartate kinase-chorismate mutase-tyrA (prephenate dehydrogenase) (ACT) domain upstream of the kinase domain. The ACT domain is a widely distributed structural motif known to be important for allosteric regulation of many enzymes. In this work, using biochemical and biophysical techniques in vitro and in planta, including kinase assays, microscale thermophoresis, size exclusion chromatography, as well as site-directed mutagenesis approaches, we show that the ACT domain regulates autophosphorylation and substrate phosphorylation of the STY kinases. We found that isoleucine and S-adenosylmethionine bind to the ACT domain, negatively influencing its autophosphorylation ability. Moreover, we investigated the role of the ACT domain in planta and confirmed its involvement in chloroplast differentiation in vivo Our results provide detailed insights into the regulation of enzyme activity by ACT domains and establish that it has a role in binding amino acid ligands during chloroplast biogenesis.
Pathogenesis and pathophysiology of autosomal dominant sleep‐related hypermotor epilepsy with S284L‐mutant α4 subunit of nicotinic ACh receptor

The mechanisms causing spontaneous epileptic seizures, including carbamazepine‐resistant/zonisamide ‐sensitive seizures and comorbidity in autosomal dominant sleep‐related hypermotor epilepsy (ADSHE) are unclear. This study investigated functional abnormalities in thalamocortical transmission in transgenic rats bearing rat S286L‐mutant Chrna4 (S286L‐TG) of α4 subunit of the nicotinic ACh receptor (nAChR) that corresponds to the human S284L‐mutant CHRNA4.
Identification of a major locus determining a pigmentation defect in cultivated gilthead seabream (Sparus aurata).

The gilthead seabream (Sparus aurata) is an important cultivated species in the Mediterranean area. A major problem for the gilthead seabream aquaculture sector derives from the high frequency of phenotypic abnormalities, including discolorations. In this study, we applied a whole-genome resequencing approach to identify a genomic region affecting a pigmentation defect that occurred in a cultivated S. aurata population. Two equimolar DNA pools were constructed using DNA extracted from 30 normally coloured and 21 non-pigmented fish collected among the offspring of the same broodstock nucleus. Whole-genome resequencing reads from the two DNA pools were aligned to the S. aurata draft genome and variant calling was performed. A whole-genome heterozygosity scan from single pool sequencing data highlighted a peak of reduced heterozygosity of approximately 5 Mbp on chromosome 6 in the non-pigmented pool that was not present in the normally coloured pool. The comparison of the non-pigmented with the normally coloured fish using a whole-genome FST analysis detected three main regions within the coordinates previously detected with the heterozygosity analysis. The results support the presence of a major locus affecting this discoloration defect in this fish population. The results of this study have practical applications, including the possibility of eliminating this defect from the breeding stock, with direct economic advantages derived from the reduction of discarded fry. Other studies are needed to identify the candidate gene and the causative mutation, which could add information to understand the complex biology of fish pigmentation.
Profiling cysteine reactivity and oxidation in the endoplasmic reticulum.

The endoplasmic reticulum (ER) is the initial site of biogenesis of secretory pathway proteins, including proteins localized to the ER, Golgi, lysosomes, intracellular vesicles, plasma membrane, and extracellular compartments. Proteins within the secretory pathway contain a high abundance of disulfide bonds to protect against the oxidative extracellular environment. These disulfide bonds are typically formed within the ER by a variety of oxidoreductases, including members of the protein disulfide isomerase (PDI) family. Here, we establish chemoproteomic platforms to identify oxidized and reduced cysteine residues within the ER. Subcellular fractionation methods were utilized to enrich for the ER and significantly enhance the coverage of ER-localized cysteine residues. Reactive-cysteine profiling ranked ~900 secretory pathway cysteines by reactivity with an iodoacetamide-alkyne probe, revealing functional cysteines annotated to participate in disulfide bonds, or S-palmitoylation sites within proteins. Through application of a variation of the OxICAT protocol for quantifying cysteine oxidation, the percentages of oxidation for each of ~700 ER-localized cysteines were calculated. Lastly, perturbation of ER function, through chemical induction of ER stress, was used to investigate the effect of initiation of the unfolded protein response (UPR) on ER-localized cysteine oxidation. Together, these studies establish a platform for identifying reactive and functional cysteine residues on proteins within the secretory pathway, as well as for interrogating the effects of diverse cellular stresses on ER-localized cysteine oxidation.
Plasma concentrations of pemafibrate with co-administered drugs predicted by physiologically based pharmacokinetic modeling in virtual populations with renal/hepatic impairment

Abstract Pharmacokinetic profiles of pemafibrate with virtual drug and/or disease interactions were assessed by creating a detailed physiologically based pharmacokinetic (PBPK) model. Passive diffusion clearance in liver was experimentally determined as 0.013 mL/min/106 human hepatocytes. In vitro intrinsic clearance values for pemafibrate by cytochromes P450 2C8, 2C9, and 3A4 were 54, 26, and 16 μL/min/mg protein, respectively. Values for the effective permeability and the intrinsic clearance of hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 were optimized in a simulator platform. This PBPK model was subsequently validated using reported maximum pemafibrate plasma concentration and area under the curve values in reported interaction studies in healthy subjects co-administered with rifampicin. For subjects with Child-Pugh A and B liver cirrhosis, the intrinsic clearance of hepatic uptake of pemafibrate by OATP1B1 were modeled using 53% and 31% of that of healthy subjects, respectively. Virtual co-administrations of rifampicin and sacubitril (OATP1B inhibitors) in subjects with renal impairment and liver cirrhosis resulted in 11- to 13-folds (rifampicin) and 1.1- to 1.3-folds (sacubitril) increased plasma exposures of pemafibrate. The current PBPK model and simulations revealed different pharmacokinetic profiles for pemafibrate following co-administration of rifampicin or sacubitril in virtual subjects with or without renal/hepatic impairment.
Relationship between Foot Pain/Deformities and Risk of Fall in Patients with Rheumatoid Arthritis

Objective: Patients with rheumatoid arthritis (RA) have an increased risk of falls. Foot pain/ deformities affect the majority of patients with RA. The objective of this study was to determine the influence of foot pain/deformities on risk of fall in patients with RA. Methods: This study comprised 89 patients (75 females, 14 males) with RA. Patients were queried about pain in the hip, knee and foot. The diagnoses of foot deformities were based on clinical and radiographic evaluation. Patients’ risk of fall was assessed using the Tinetti Performance Oriented Mobility Assessment . Results: Mean age and disease duration of the patients were 46.84 ± 13.20 and 7.82 ± 7.01 years, respectively. Twelve (13%) patients had risk of fall. The patients with risk of fall had a higher numeric rating scale (NRS) for foot pain (4.08 ± 1.44 vs 2.62 ± 2.51; p = 0.012) and number of foot deformities (1.41 ± 1.67 vs 0.55 ± 1.11; p = 0.009) than those without risk of fall. There were correlations between the TPOMA scores and NRS for foot pain (r = -0.264; p = 0.013) and number of foot deformities (r = -0.374; p = 0.001). Conclusion: The results of this study demonstrate that RA patients with foot pain/deformities have higher risk of fall . We suggest that early diagnosis and better control of disease activity will prevent foot pain/deformities in order to reduce the risk and the burden of falls.
Photolysis of 3‐(1‐acyl‐5‐aryl‐3‐pyrazolinyl)coumarins—Effective Fluorescence Decay

Photophysical characteristics of new 3‐(1‐acyl‐5‐aryl‐3‐pyrazolinyl)coumarins have been measured. These coumarin derivatives are found to be effective fluorophores and show high values of quantum yields of fluorescence both in nonpolar and in polar solvents. The 3‐(1‐acyl‐5‐aryl‐3‐pyrazolinyl)coumarins turned to be photosensitive compounds and undergo photolysis under irradiation in the range of 310–465 nm. Photolysis is suggested to include retro‐cyclization and retro‐condensation steps. The process is accompanied by a sharp drop of fluorescence that can be of interest for the creation of new media in optical recording of information.
The effector mechanism of siRNA spherical nucleic acids

Significance Although small interfering RNAs (siRNAs) are promising agents for treating many diseases, cellular delivery difficulties have prevented their widespread application. The use of spherical nucleic acids (SNAs) as single-entity gene regulation agents could overcome this limitation, since SNAs naturally and rapidly enter over 50 cell types. Consequently, siRNA-SNAs have been extensively used for effecting knockdown in both research and clinical settings. However, the mechanism of gene regulation by siRNA-SNAs is not well understood. Herein, we study cytosolic processing of siRNA-SNAs and how it leads to gene knockdown. Informed by this mechanism, we designed an SNA architecture with an order-of-magnitude-higher siRNA density. Importantly, this higher density reduces the cellular toxicity of SNAs without loss in RNA interference performance. Spherical nucleic acids (SNAs) are nanostructures formed by chemically conjugating short linear strands of oligonucleotides to a nanoparticle template. When made with modified small interfering RNA (siRNA) duplexes, SNAs act as single-entity transfection and gene silencing agents and have been used as lead therapeutic constructs in several disease models. However, the manner in which modified siRNA duplex strands that comprise the SNA lead to gene silencing is not understood. Herein, a systematic analysis of siRNA biochemistry involving SNAs shows that Dicer cleaves the modified siRNA duplex from the surface of the nanoparticle, and the liberated siRNA subsequently functions in a way that is dependent on the canonical RNA interference mechanism. By leveraging this understanding, a class of SNAs was chemically designed which increases the siRNA content by an order of magnitude through covalent attachment of each strand of the duplex. As a consequence of increased nucleic acid content, this nanostructure architecture exhibits less cell cytotoxicity than conventional SNAs without a decrease in siRNA activity.
Nondestructive sex-specific monitoring of early embryonic development rate in white layer chicken eggs using visible light transmission

ABSTRACT 1. Sex-specific variations in early embryonic development rates may pre-empt later variations in embryonic development through to pipping and hatching. Given that erythropoiesis (blood production) can be equated with early embryonic growth rate, it was hypothesised that blood pigment haemoglobin can act as a specific spectral fingerprint for changes in growth rate. Moreover, by measuring longitudinal, rather than lateral, spectral transmission through the egg, a more consistent spectrum with a higher signal-to-noise ratio could be captured. 2. Longitudinal visible transmission (T575/T598 ratio), which is sensitive to haemoglobin, was used to monitor sex-specific early embryonic development rate in white layer chicken eggs from d 0 to 8 of incubation. The sex of these eggs was subsequently confirmed two days after hatching. 3. Embryonic development was detectable from d 3 (72 h) of incubation, 36 h earlier than previously reported lateral spectral measurements, supporting the greater sensitivity of longitudinal measurements. 4. At d 3, the mean T575/T598 ratio for male embryos was significantly lower (P < 0.001) (i.e. higher absorbance of haemoglobin) than for female embryos, which was thought to be due to sex-differences in early embryogenesis. On the other hand, female embryos had a significantly lower (P < 0.05) mean T575/T598 ratio than male embryos at d 7 of incubation, presumably due to the combined effects of oestrogen synthesis receptors and enzymes on erythropoiesis in female embryos at this time. 5. In conclusion, the proposed methodology has the sensitivity to differentiate sex-specific embryonic development rates during early incubation and the potentiality to advance precision incubation management and poultry research.
Versatile and robust genome editing with Streptococcus thermophilus CRISPR1-Cas9

Targeting definite genomic locations using CRISPR-Cas systems requires a set of enzymes with unique protospacer adjacent motif (PAM) compatibilities. To expand this repertoire, we engineered nucleases, cytosine base editors, and adenine base editors from the archetypal Streptococcus thermophilus CRISPR1-Cas9 (St1Cas9) system. We found that St1Cas9 strain variants enable targeting to five distinct A-rich PAMs and provide a structural basis for their specificities. The small size of this ortholog enables expression of the holoenzyme from a single adeno-associated viral vector for in vivo editing applications. Delivery of St1Cas9 to the neonatal liver efficiently rewired metabolic pathways, leading to phenotypic rescue in a mouse model of hereditary tyrosinemia. These robust enzymes expand and complement current editing platforms available for tailoring mammalian genomes.
Cryo-EM reveals the architecture of the dimeric cytochrome P450 CYP102A1 enzyme and conformational changes required for redox partner recognition

Cytochrome P450 family 102 subfamily A member 1 (CYP102A1) is a self-sufficient flavohemeprotein and a highly active bacterial enzyme capable of fatty acid hydroxylation at a >3,000 min−1 turnover rate. The CYP102A1 architecture has been postulated to be responsible for its extraordinary catalytic prowess. However, the structure of a functional full-length CYP102A1 enzyme remains to be determined. Herein, we used a cryo-EM single-particle approach, revealing that full-length CYP102A1 forms a homodimer in which both the heme and FAD domains contact each other. The FMN domain of one monomer was located close to the heme domain of the other monomer, exhibiting a trans configuration. Moreover, full-length CYP102A1 is highly dynamic, existing in multiple conformational states, including open and closed states. In the closed state, the FMN domain closely contacts the FAD domain, whereas in the open state, one of the FMN domains rotates away from its FAD domain and traverses to the heme domain of the other monomer. This structural arrangement and conformational dynamics may facilitate rapid intraflavin and trans FMN-to-heme electron transfers (ETs). Results with a variant having a 12-amino-acid deletion in the CYP102A1 linker region, connecting the catalytic heme and the diflavin reductase domains, further highlighted the importance of conformational dynamics in the ET process. Cryo-EM revealed that the Δ12 variant homodimer is conformationally more stable and incapable of FMN-to-heme ET. We conclude that closed-to-open alternation is crucial for redox partner recognition and formation of an active ET complex for CYP102A1 catalysis.
Using Machine Learning in Psychiatry: The Need to Establish a Framework That Nurtures Trustworthiness.

The rapid embracing of artificial intelligence in psychiatry has a flavor of being the current "wild west"; a multidisciplinary approach that is very technical and complex, yet seems to produce findings that resonate. These studies are hard to review as the methods are often opaque and it is tricky to find the suitable combination of reviewers. This issue will only get more complex in the absence of a rigorous framework to evaluate such studies and thus nurture trustworthiness. Therefore, our paper discusses the urgency of the field to develop a framework with which to evaluate the complex methodology such that the process is done honestly, fairly, scientifically, and accurately. However, evaluation is a complicated process and so we focus on three issues, namely explainability, transparency, and generalizability, that are critical for establishing the viability of using artificial intelligence in psychiatry. We discuss how defining these three issues helps towards building a framework to ensure trustworthiness, but show how difficult definition can be, as the terms have different meanings in medicine, computer science, and law. We conclude that it is important to start the discussion such that there can be a call for policy on this and that the community takes extra care when reviewing clinical applications of such models.
Transcriptional Differences in Peanut (Arachis hypogaea L.) Seeds at the Freshly Harvested, After-ripening and Newly Germinated Seed Stages: Insights into the Regulatory Networks of Seed Dormancy Release and Germination

Seed dormancy and germination are the two important traits related to plant survival, reproduction and crop yield. To understand the regulatory mechanisms of these traits, it is crucial to clarify which genes or pathways participate in the regulation of these processes. However, little information is available on seed dormancy and germination in peanut. In this study, seeds of the variety Luhua No.14, which undergoes nondeep dormancy, were selected, and their transcriptional changes at three different developmental stages, the freshly harvested seed (FS), the after-ripening seed (DS) and the newly germinated seed (GS) stages, were investigated by comparative transcriptomic analysis. The results showed that genes with increased transcription in the DS vs FS comparison were overrepresented for oxidative phosphorylation, the glycolysis pathway and the tricarboxylic acid (TCA) cycle, suggesting that after a period of dry storage, the intermediates stored in the dry seeds were rapidly mobilized by glycolysis, the TCA cycle, the glyoxylate cycle, etc.; the electron transport chain accompanied by respiration was reactivated to provide ATP for the mobilization of other reserves and for seed germination. In the GS vs DS pairwise comparison, dozens of the upregulated genes were related to plant hormone biosynthesis and signal transduction, including the majority of components involved in the auxin signal pathway, brassinosteroid biosynthesis and signal transduction as well as some GA and ABA signal transduction genes. During seed germination, the expression of some EXPANSIN and XYLOGLUCAN ENDOTRANSGLYCOSYLASE genes was also significantly enhanced. To investigate the effects of different hormones during seed germination, the contents and differential distribution of ABA, GAs, BRs and IAA in the cotyledons, hypocotyls and radicles, and plumules of three seed sections at different developmental stages were also investigated. Combined with previous data in other species, it was suggested that the coordination of multiple hormone signal transduction nets plays a key role in radicle protrusion and seed germination.
In vitro drug discovery models for Mycobacterium tuberculosis relevant for host infection

ABSTRACT Introduction: Tuberculosis is the leading cause of death from infectious disease. Current drug therapy requires a combination of antibiotics taken over >6 months. An urgent need for new agents that can shorten therapy is required. In order to develop new drugs, simple in vitro assays are required that can identify efficacious compounds rapidly and predict in vivo activity in the human. Areas covered: This review focusses on the most relevant in vitro assays that can be utilized in a drug discovery program and which mimic different aspects of infection or disease. The focus is largely on assays used to test >1000s of compounds reliably and robustly. However, some assays used for 10s to 100s of compounds are included where the utility outweighs the low capacity. Literature searches for high throughput screening, models and in vitro assays were undertaken. Expert opinion: Drug discovery and development in tuberculosis is extremely challenging due to the requirement for predicting drug efficacy in a disease with complex pathology in which bacteria exist in heterogeneous states in inaccesible locations. A combination of assays can be used to determine profiles against replicating, non-replicating, intracellular and tolerant bacteria.