Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical effect and safety profile of pegzilarginase in patients with arginase 1 deficiency

Hyperargininemia in patients with arginase 1 deficiency (ARG1‐D) is considered a key driver of disease manifestations, including spasticity, developmental delay, and seizures. Pegzilarginase (AEB1102) is an investigational enzyme therapy which is being developed as a novel arginine lowering approach. We report the safety and efficacy of intravenously (IV) administered pegzilarginase in pediatric and adult ARG1‐D patients (n = 16) from a Phase 1/2 study (101A) and the first 12 weeks of an open‐label extension study (102A). Substantial disease burden at baseline included lower‐limb spasticity, developmental delay, and previous hyperammonemic episodes in 75%, 56%, and 44% of patients, respectively. Baseline plasma arginine (pArg) was elevated (median 389 μM, range 238‐566) on standard disease management. Once weekly repeat dosing resulted in a median decrease of pArg of 277 μM after 20 cumulative doses (n = 14) with pArg in the normal range (40 to 115 μM) in 50% of patients at 168 hours post dose (mean pegzilarginase dose 0.10 mg/kg). Lowering pArg was accompanied by improvements in one or more key mobility assessments (6MWT, GMFM‐D & E) in 79% of patients. In 101A, seven hypersensitivity reactions occurred in four patients (out of 162 infusions administered). Other common treatment‐related adverse events (AEs) included vomiting, hyperammonemia, pruritus, and abdominal pain. Treatment‐related serious AEs that occurred in five patients were all observed in 101A. Pegzilarginase was effective in lowering pArg levels with an accompanying clinical response in patients with ARG1‐D. The improvements with pegzilarginase occurred in patients receiving standard treatment approaches, which suggests that pegzilarginase could offer benefit over existing disease management.
Locus-specific paramutation in Zea mays is maintained by a PICKLE-like chromodomain helicase DNA-binding 3 protein controlling development and male gametophyte function

Paramutations represent directed and meiotically-heritable changes in gene regulation leading to apparent violations of Mendelian inheritance. Although the mechanism and evolutionary importance of paramutation behaviors remain largely unknown, genetic screens in maize (Zea mays) identify five components affecting 24 nucleotide RNA biogenesis as required to maintain repression of a paramutant purple plant1 (pl1) allele. Currently, the RNA polymerase IV largest subunit represents the only component also specifying proper development. Here we identify a chromodomain helicase DNA-binding 3 (CHD3) protein orthologous to Arabidopsis (Arabidopsis thaliana) PICKLE as another component maintaining both pl1 paramutation and normal somatic development but without affecting overall small RNA biogenesis. In addition, genetic tests show this protein contributes to proper male gametophyte function. The similar mutant phenotypes documented in Arabidopsis and maize implicate some evolutionarily-conserved gene regulation while developmental defects associated with the two paramutation mutants are largely distinct. Our results show that a CHD3 protein responsible for normal plant ontogeny and sperm transmission also helps maintain meiotically-heritable epigenetic regulatory variation for specific alleles. This finding implicates an intersection of RNA polymerase IV function and nucleosome positioning in the paramutation process.
Capture of Carbon Dioxide Using Aqueous Ammonia in a Lab-Scale Stirred-Tank Scrubber

A pH-stat stirred-tank scrubber for capturing carbon dioxide using aqueous ammonia was used to explore the effects of process variables on the absorption of carbon dioxide. In order to maintain the pH value of the solution, aqueous ammonia was automatically introduced into the tank through the action of a pH-controller. The process variables were the pH of the solution, gas-flow rate, gas concentration and stirring speed. The absorption rate and mass-transfer coefficient could be determined by means of mass balance at a steady-state. It was found that the liquid-flow rate was 0.50-58.33 ml/min; the removal efficiency was in the range of 30.1-100% and the loading of CO2 was in the range of 0.02425-0.5661 mol-CO2/mol-NH3. The results also showed that the absorption rate was in the range of 5.14x10-5 to 6.27x10-4 mol/s-L, while the mass-transfer coefficient was in the range of 0.015 to 0.14 1/s. The effects of mixing on the absorption rate, mass-transfer coefficient and loading of CO2 were also discussed in this work.
Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 Virus

The prolonged treatment of immunosuppressed (IS) individuals with anti-influenza monotherapies may lead to the emergence of drug-resistant variants. Herein, we evaluated oseltamivir and polymerase inhibitors combinations against influenza A/H3N2 infections in an IS mouse model. Mice were IS with cyclophosphamide and infected with 3 × 103 PFU of a mouse-adapted A/Switzerland/9715293/2013 (H3N2) virus. Forty-eight hours post-infection, the animals started oseltamivir, favipiravir or baloxavir marboxil (BXM) as single or combined therapies for 10 days. Weight losses, survival rates and lung viral titers (LVTs) were determined. The neuraminidase (NA) and polymerase genes from lung viral samples were sequenced. All untreated animals died. Oseltamivir and favipiravir monotherapies only delayed mortality (the mean day to death (MDD) of 21.4 and 24 compared to 11.4 days for those untreated) while a synergistic improvement in survival (80%) and LVT reduction was observed in the oseltamivir/favipiravir group compared to the oseltamivir group. BXM alone or in double/triple combination provided a complete protection and significantly reduced LVTs. Oseltamivir and BXM monotherapies induced the E119V (NA) and I38T (PA) substitutions, respectively, while no resistance mutation was detected with combinations. We found that the multiple dose regimen of BXM alone provided superior benefits compared to oseltamivir and favipiravir monotherapies. Moreover, we suggest the potential for drug combinations to reduce the incidence of resistance.
Clinical and Electrophysiological Hints to TMS in De Novo Patients with Parkinson’s Disease and Progressive Supranuclear Palsy

Background: Transcranial magnetic stimulation (TMS) can non-invasively probe cortical excitability in movement disorders, although clinical significance is still controversial, especially at early stages. We compare single-pulse TMS in two prototypic synucleinopathy and tauopathy—i.e., Parkinson’s disease (PD) and Progressive Supranuclear Palsy (PSP), respectively—to find neurophysiological differences and identify early measures associated with cognitive impairment. Methods: 28 PD and 23 PSP de novo patients were age-matched with 28 healthy controls, all right-handed and drug-free. Amplitude and latency of motor evoked potentials (MEP), central motor conduction time, resting motor threshold (rMT), and cortical silent period (CSP) were recorded through a figure-of-eight coil from the First Dorsal Interosseous muscle (FDI), bilaterally. Results: Mini Mental Examination and Frontal Assessment Battery (FAB) scored worse in PSP; PD had worse FAB than controls. Higher MEP amplitude from right FDI in PD and PSP than controls was found, without difference between them. CSP was bilaterally longer in patients than controls, but similar between patient groups. A positive correlation between FAB and rMT was observed in PSP, bilaterally. Conclusions: Despite the small sample size, PD and PSP might share, at early stage, a similar global electrocortical asset. rMT might detect and possibly predict cognitive deterioration in PSP.
Associations between Adherence to Combinations of 24-h Movement Guidelines and Overweight and Obesity in Japanese Preschool Children

The interactions between movement behaviors (physical activity, screen time, and sleep) affect the health of preschool children. Therefore, we examined the status of adherence to combinations of 24-hour movement guidelines (24-h MG) in Japanese preschool children and determined the associations between overweight/obesity and adherence to these 24-h MG. This cross-sectional study was conducted with 421 children aged 3–5 years (216 boys and 199 girls) living in the northeastern region of Japan. To evaluate the 24-h MG, physical activity over one week was measured using a three-axis accelerometer. For screen time and sleep duration, a questionnaire survey was conducted. Children who failed to meet all the 24-h MG had a higher probability of overweight/obesity than those who met all the 24-h MG (odds ratio 1.139, 95% confidence interval: 1.009, 1.285). The percentage of adherence to the 24-h MG was 91.6% for physical activity, 82.5% for sleep duration, and 33.7% for screen time, and only 21.5% of the children adhered to all three areas of the guidelines. Our findings have important implications for developing public health policies and effective intervention programs for preschool children.
Fault-Tolerant Cooperative Control for Multiple Vehicle Systems Based on Topology Reconfiguration

In this article, the fault-tolerant synchronization and time-varying tracking control problem is investigated for nonlinear multivehicle systems (MVSs) in the presence of partial loss-of-control-effectiveness (LoCE) faults. Based on the graph theory, a two-level fault-tolerant cooperative control framework is proposed, namely, the low-level distributed nominal control scheme and the high-level topology reconfiguration protocols. The low-level scheme is developed to guarantee system performances in the fault-free scenario. With the low-level scheme, the high-level topology reconfiguration protocols, each of which corresponds to one partial LoCE fault scenario, are then proposed to mitigate the fault impact by adjusting the underlying topology. Accordingly, without modifying the structure or the design parameter of the low-level control scheme, the proposed framework can guarantee the synchronization and tracking errors of the MVS asymptotically convergent to zero in both fault-free and fault scenarios. Finally, the effectiveness of the proposed control method is verified via a simulation study of three degree-of-freedom helicopters.
Tyrosine-based Signals Converge on Daple•PARD3 Complex to Fine-tune Polarized Planar Cell Migration

Polarized distribution of organelles and molecules inside a cell is vital for a range of cellular processes and its loss is frequently encountered in disease. Polarization during planar cell migration is a special condition in which cellular orientation is triggered by cell-cell contact. Here, we demonstrate that the multi-modular signaling scaffold Daple (CCDC88C) is a component of cell junctions in epithelial cells which serves like a cellular ‘compass’ for establishing and maintaining contact-triggered planar polarity via its interaction with the polarity regulator PARD3. This interaction, mediated by Daple’s PDZ-binding motif (PBM) and the third PDZ domain of PARD3, is fine-tuned by two tyrosine phosphoevents on Daple’s PBM that are triggered by a multitude of growth factors. Hypophosphorylation strengthens the interaction, whereas hyperphosphorylation disrupts it. These findings reveal an unexpected role of Daple within the planar cell polarity pathway as a platform for signal integration and gradient sensing for tyrosine-based signals. Highlights Daple localizes to cell junctions via its PDZ binding motif (PBM) Junction-localized Daple regulates planar cell migration Daple’s PBM directly binds the polarity regulator PARD3 The Daple•PARD3 interface senses gradients of tyrosine-based signals
Integrated Reporting and Earnings Management

This study examines whether the introduction of integrated reporting affects earnings management. According to the International Integrated Reporting Framework, published by the International Integrated Reporting Council in 2013, integrated reporting is intended not only to improve the quality of information available to external parties, but also to improve internal decision making. Introducing integrated reporting is expected to correct companies’ short-term orientation and promote long-term value creation. Using data from Japan, where a large number of companies are voluntarily practicing integrated reporting, we find that firms are more likely to report conservative earnings after the introduction of integrated reporting, in terms of both accrual-based earnings management and real earnings management. We also find that the effect of integrated reporting on earnings management appears approximately two years or more after the introduction of integrated reporting. This evidence is consistent with practitioners’ point that integrated reporting is a continuous improvement process, and so takes several years to improve internal decision making. Finally, our findings provide evidence for standard setters and regulators who are interested in the merits of integrated reporting that integrated reporting promotes decision making with a long-term focus, resulting in more conservative earnings management.
From correlation to causality: the case of Subdoligranulum

ABSTRACT Gut microbes are considered as major factors contributing to human health. Nowadays, the vast majority of the data available in the literature are mostly exhibiting negative or positive correlations between specific bacteria and metabolic parameters. From these observations, putative detrimental or beneficial effects are then inferred. Akkermansia muciniphila is one of the unique examples for which the correlations with health benefits have been causally validated in vivo in rodents and humans. In this study, based on available metagenomic data in overweight/obese population and clinical variables that we obtained from two cohorts of individuals (n = 108) we identified several metagenomic species (MGS) strongly associated with A. muciniphila with one standing out: Subdoligranulum. By analyzing both qPCR and shotgun metagenomic data, we discovered that the abundance of Subdoligranulum was correlated positively with microbial richness and HDL-cholesterol levels and negatively correlated with fat mass, adipocyte diameter, insulin resistance, levels of leptin, insulin, CRP, and IL6 in humans. Therefore, to further explore whether these strong correlations could be translated into causation, we investigated the effects of the unique cultivated strain of Subdoligranulum (Subdoligranulum variabile DSM 15176 T) in obese and diabetic mice as a proof-of-concept. Strikingly, there were no significant difference in any of the hallmarks of obesity and diabetes measured (e.g., body weight gain, fat mass gain, glucose tolerance, liver weight, plasma lipids) at the end of the 8 weeks of treatment. Therefore, the absence of effect following the supplementation with S. variabile indicates that increasing the intestinal abundance of this bacterium is not translated into beneficial effects in mice. In conclusion, we demonstrated that despite the fact that numerous strong correlations exist between a given bacteria and health, proof-of-concept experiments are required to be further validated or not in vivo. Hence, an urgent need for causality studies is warranted to move from human observations to preclinical validations.
Interrupting Neuron—Tumor Interactions to Overcome Treatment Resistance

Simple Summary Solid cancers take advantage of the surrounding tissue to stimulate their own growth, to promote their spread, and to escape anticancer immune responses and treatments. Neurons are an important newly identified target for tumors because they can provide all of these benefits and are found throughout the body. Neurons communicate using chemical signals, many of which can be recognized and leveraged by tumor cells. Tumors, in turn, manipulate neurons by sending local signals that drive the growth of neurons into the body of the tumor. In tandem with local signaling, tumors transmit protein and RNA messengers within extracellular vesicles that travel through the bloodstream and other bodily fluids. This long-range tumor signaling is a growing area of research that allows for new diagnostic and therapeutic approaches. Ongoing clinical trials will uncover methods of disrupting tumor–neuron communication for the benefit of patients. Abstract Neurons in the tumor microenvironment release neurotransmitters, neuroligins, chemokines, soluble growth factors, and membrane-bound growth factors that solid tumors leverage to drive their own survival and spread. Tumors express nerve-specific growth factors and microRNAs that support local neurons and guide neuronal growth into tumors. The development of feed-forward relationships between tumors and neurons allows tumors to use the perineural space as a sanctuary from therapy. Tumor denervation slows tumor growth in animal models, demonstrating the innervation dependence of growing tumors. Further in vitro and in vivo experiments have identified many of the secreted signaling molecules (e.g., acetylcholine, nerve growth factor) that are passed between neurons and cancer cells, as well as the major signaling pathways (e.g., MAPK/EGFR) involved in these trophic interactions. The molecules involved in these signaling pathways serve as potential biomarkers of disease. Additionally, new treatment strategies focus on using small molecules, receptor agonists, nerve-specific toxins, and surgical interventions to target tumors, neurons, and immune cells of the tumor microenvironment, thereby severing the interactions between tumors and surrounding neurons. This article discusses the mechanisms underlying the trophic relationships formed between neurons and tumors and explores the emerging therapies stemming from this work.
Impact of Different Lipid Ligands on the Stability and IgE-Binding Capacity of the Lentil Allergen Len c 3

Previously, we isolated the lentil allergen Len c 3, belonging to the class of lipid transfer proteins, cross-reacting with the major peach allergen Pru p 3 and binding lipid ligands. In this work, the allergenic capacity of Len c 3 and effects of different lipid ligands on the protein stability and IgE-binding capacity were investigated. Impacts of pH and heat treating on ligand binding with Len c 3 were also studied. It was shown that the recombinant Len c 3 (rLen c 3) IgE-binding capacity is sensitive to heating and simulating of gastroduodenal digestion. While being heated or digested, the protein showed a considerably lower capacity to bind specific IgE in sera of allergic patients. The presence of lipid ligands increased the thermostability and resistance of rLen c 3 to digestion, but the level of these effects was dependent upon the ligand’s nature. The anionic lysolipid LPPG showed the most pronounced protective effect which correlated well with experimental data on ligand binding. Thus, the Len c 3 stability and allergenic capacity can be retained in the conditions of food heat cooking and gastroduodenal digestion due to the presence of certain lipid ligands.
Patient‐reported outcome measures ( PROMs): making sense of individual PROM scores and changes in PROM scores over time

Patient‐reported outcome measures (PROMs) are increasingly being used in nephrology care. However, in contrast to well‐known clinical measures such as blood pressure, health‐care professionals are less familiar with PROMs and the interpretation of PROM scores is therefore perceived as challenging. In this paper, we provide insight into the interpretation of PROM scores by introducing the different types and characteristics of PROMs, and the most relevant concepts for the interpretation of PROM scores. Concepts such as minimal detectable change, minimal important change and response shift are explained and illustrated with examples from nephrology care.
Assessing the reliability of an online behavioural laterality battery: A pre-registered study

ABSTRACT Studies of cerebral lateralization often involve participants completing a series of perceptual tasks under laboratory conditions. This has constrained the number of participants recruited in such studies. Online testing can allow for much larger sample sizes but limits the amount of experimental control that is feasible. Here we considered whether online testing could give valid and reliable results on four tasks: a rhyme decision visual half-field task, a dichotic listening task, a chimeric faces task, and a finger tapping task. We recruited 392 participants, oversampling left-handers, who completed the battery twice. Three of the tasks showed evidence of both validity and reliability, insofar as they showed hemispheric advantages in the expected direction and test-retest reliability of at least r = . 75. The reliability of the rhyme decision task was less satisfactory (r = .62). We also confirmed a prediction that extreme left-handers were more likely to depart from typical lateralization. Lateralization across the two language tasks (dichotic listening and rhyme judgement) was weakly correlated, but unrelated to lateralization on the chimeric faces task. We conclude that three of the tasks, dichotic listening, chimeric faces and finger tapping, show considerable promise for online evaluation of cerebral lateralization.
Prevalence and clinical correlates of self-harm and suicidality during admission of children in a mental health inpatient unit

Abstract Background Self-harm and suicidality are common presentations in children and adolescents requiring a mental health inpatient admission. Although there are several studies on adolescents, there is relatively limited research into childhood self-harm and suicidality during such admissions. Methods A retrospective electronic file review was conducted on all children discharged from a national mental health inpatient children’s unit over a 6-year period. Several independent variables were compared between self-harm/suicidal and non-self-harm/non-suicidal children. Separate analyses investigated changes in self-harm/suicidality, functional outcomes, and risk assessment ratings between admission and discharge. Results A total of 105 children were included in this study. During admission, 65.7% of them reported self-harm thoughts, 61% engaged in self-harm, 50.5% expressed suicidal thoughts, and 14.3% engaged in suicidal behavior. Thoughts and acts of self-harm were associated with previous self-harm, longer admissions, and Attention Deficit Hyperactivity Disorder. Suicidality overlapped with self-harm and was strongly predicted by previous self-harm. The prevalence of self-harm and suicidal thoughts and acts significantly decreased during admission. Children in the non-self-harm group had marginally better functional outcomes upon discharge compared to those in the self-harm group. Children and parents/caregivers were similarly satisfied with treatment, irrespective of children’s self-harm/suicidality. Conclusions Self-harm and suicidality were widespread among children admitted to hospital. Better understanding of the mechanisms and factors related to self-harm and suicidality in this age group could help mitigate associated risks and improve existing safety strategies.