Miracle-dz/UniFAR-FTUs huggingface dataset:
Eradication of Measurable Residual Disease in AML: A Challenging Clinical Goal

Simple Summary Relapse is still a major problem in AML because it occurs in about 60–80% of patients, even those who have previously achieved complete remission (CR), defined by the presence of ≤5% bone marrow (BM) leukemic cells. Thus, since CR is unable to predict the relapse risk, significantly more sensitive techniques aimed at identifying AML cells in BM or peripheral blood, a parameter termed measurable residual disease (MRD), have been developed. Among them, RT-qPCR, which analyses appropriate molecular markers, and multiparameter flow cytometry (MFC), which analyses aberrantly expressed antigens, have been identified as the methods of choice for MRD detection. Nowadays, various studies that assessed MRD by these techniques have provided compelling evidence that MRD positivity (MRD+) after standard induction/consolidation chemotherapy and before allo-HSCT is predictive of a very poor clinical outcome. In addition, other studies, which showed that MRD+ clearance even at late time points of the course of the disease may improve the disease clinical outcome, have further strengthened the relevance of MRD+. Thus, a complete MRD eradication, potentially attainable through novel innovative treatments, has emerged as an un-met clinical need in AML and is expected to improve our patients’ prognosis. Abstract In non-promyelocytic (non-M3) AML measurable residual disease (MRD) detected by multi-parameter flow cytometry and molecular technologies, which are guided by Consensus-based guidelines and discover very low leukemic cell numbers far below the 5% threshold of morphological assessment, has emerged as the most relevant predictor of clinical outcome. Currently, it is well-established that MRD positivity after standard induction and consolidation chemotherapy, as well as during the period preceding an allogeneic hematopoietic stem cell transplant (allo-HSCT), portends to a significantly inferior relapse-free survival (RFS) and overall survival (OS). In addition, it has become absolutely clear that conversion from an MRD-positive to an MRD-negative state provides a favorable clinical outcome similar to that associated with early MRD negativity. Thus, the complete eradication of MRD, i.e., the clearance of the few leukemic stem cells—which, due to their chemo-radiotherapy resistance, might eventually be responsible of disease recurrence—has become an un-met clinical need in AML. Nowadays, this goal might potentially be achieved thanks to the development of novel innovative treatment strategies, including those targeting driver mutations, apoptosis, methylation patterns and leukemic proteins. The aim of this review is to analyze these strategies and to suggest any potential combination able to induce MRD negativity in the pre- and post-HSCT period.
Maternal Work–Life Balance and Children’s Social Adjustment: The Mediating Role of Perceived Stress and Parenting Practices

The participation of women with young children in the Japanese labor force has increased dramatically in recent years, bringing growing potential for conflict between work and family roles amid inadequate social systems, such as childcare support. Thus, work–life balance (WLB) of mothers may influence their children’s mental health and lifestyle. This study aims to clarify the relationship between parents’ WLB and children’s mental health, as well as the underlying factors of parental stress and nurturing attitude. The study is based on a questionnaire survey administered in 2019 to fifth-grade elementary school students and their caregivers in Aichi Prefecture, Japan. The regression results indicated that the higher the work–family negative spillover, the higher the child’s externalizing and internalizing problems, and the higher the positive spillover, the lower the problems and the higher the prosocial behaviors. Path analysis indicates that maternal WLB is negatively and positively related to children’s behavior through maternal stress and parenting practices. The study suggests that maternal WLB is related to children’s emotional and behavioral problems. WLB may impact children’s emotional and behavioral problems through parents’ mental health and involvement with their children, particularly because of work arrangements changing with the COVID-19 pandemic.
Studies of Conformational Changes of Tubulin Induced by Interaction with Kinesin Using Atomistic Molecular Dynamics Simulations

The transition between strong and weak interactions of the kinesin head with the microtubule, which is regulated by the change of the nucleotide state of the head, is indispensable for the processive motion of the kinesin molecular motor on the microtubule. Here, using all-atom molecular dynamics simulations, the interactions between the kinesin head and tubulin are studied on the basis of the available high-resolution structural data. We found that the strong interaction can induce rapid large conformational changes of the tubulin, whereas the weak interaction cannot. Furthermore, we found that the large conformational changes of the tubulin have a significant effect on the interaction of the tubulin with the head in the weak-microtubule-binding ADP state. The calculated binding energy of the ADP-bound head to the tubulin with the large conformational changes is only about half that of the tubulin without the conformational changes.
Usual Protein Intake Amount and Sources of Nursing Home Residents with (Risk of) Malnutrition and Effects of an Individualized Nutritional Intervention: An enable Study

Nursing home (NH) residents with (risk of) malnutrition are at particular risk of low protein intake (PI). The aim of the present analysis was (1) to characterize usual PI (total amount/day (d) and meal, sources/d and meal) of NH residents with (risk of) malnutrition and (2) to evaluate the effects of an individualized nutritional intervention on usual PI. Forty residents (75% female, 85 ± 8 years) with (risk of) malnutrition and inadequate dietary intake received 6 weeks of usual care followed by 6 weeks of intervention. During the intervention phase, an additional 29 ± 11 g/d from a protein-energy drink and/or 2 protein creams were offered to compensate for individual energy and/or protein deficiencies. PI was assessed with two 3-day-weighing records in each phase and assigned to 4 meals and 12 sources. During the usual care phase, mean PI was 41 ± 10 g/d. Lunch and dinner contributed 31 ± 11% and 32 ± 9% to daily intake, respectively. Dairy products (median 9 (interquartile range 6–14) g/d), starchy foods (7 (5–10) g/d) and meat/meat products (6 (3–9) g/d) were the main protein sources in usual PI. During the intervention phase, an additional 18 ± 10 g/d were consumed. Daily PI from usual sources did not differ between usual care and intervention phase (41 ± 10 g/d vs. 42 ± 11 g/d, p = 0.434). In conclusion, daily and per meal PI were very low in NH residents with (risk of) malnutrition, highlighting the importance of adequate intervention strategies. An individualized intervention successfully increased PI without affecting protein intake from usual sources.
AB-Kefir Reduced Body Weight and Ameliorated Inflammation in Adipose Tissue of Obese Mice Fed a High-Fat Diet, but Not a High-Sucrose Diet

Consumption of different types of high-calorie foods leads to the development of various metabolic disorders. However, the effects of multi-strain probiotics on different types of diet-induced obesity and intestinal dysbiosis remain unclear. In this study, mice were fed a control diet, high-fat diet (HFD; 60% kcal fat and 20% kcal carbohydrate), or western diet (WD; 40% kcal fat and 43% kcal carbohydrate) and administered with multi-strain AB-Kefir containing six strains of lactic acid bacteria and a Bifidobacterium strain, at 109 CFU per mouse for 10 weeks. Results demonstrated that AB-Kefir reduced body weight gain, glucose intolerance, and hepatic steatosis with a minor influence on gut microbiota composition in HFD-fed mice, but not in WD-fed mice. In addition, AB-Kefir significantly reduced the weight and size of adipose tissues by regulating the expression of CD36, Igf1, and Pgc1 in HFD-fed mice. Although AB-Kefir did not reduce the volume of white adipose tissue, it markedly regulated CD36, Dgat1 and Mogat1 mRNA expression. Moreover, the abundance of Eubacterium_coprostanoligenes_group and Ruminiclostridium significantly correlated with changes in body weight, liver weight, and fasting glucose in test mice. Overall, this study provides important evidence to understand the interactions between probiotics, gut microbiota, and diet in obesity treatment.
Hemophilic arthropathy: Current knowledge and future perspectives

Hemophilia A and B are rare X‐linked inherited bleeding disorders caused by complete or partial deficiency in or the absence of coagulation factors VIII and IX. Recurrent joint bleeding (hemarthrosis) is the most frequent clinical manifestation of severe hemophilia. Unless appropriately managed, even subclinical hemarthrosis can lead to the development of hemophilic arthropathy, a disabling condition characterized by joint remodelling, chronic pain, and a reduced quality of life, and eventually requires joint replacement. Given the lack of specific treatments to reduce blood‐induced synovitis, the prevention of bleeding is pivotal to the maintenance of joint health. Prophylactic coagulation factor replacement therapy using extended half‐life recombinant drugs has significantly improved patients' quality of life by reducing the burden of intravenous injections, and the more recent introduction of nonreplacement therapies such as subcutaneous emicizumab injections has improved treatment adherence and led to the greater protection of patients with hemophilia A. However, despite these advances, chronic arthropathy is still a significant problem. The introduction of point‐of‐care ultrasound imaging has improved the diagnosis of acute hemarthrosis and early hemophilic arthropathy, and allowed the better monitoring of progressive joint damage, but further research into the underlying mechanisms of the disease is required to allow the development of more targeted treatment. In the meantime, patient management should be based on the risk factors for the onset and progression of arthropathy of each individual patient, and all patients should be collaboratively cared for by multidisciplinary teams of hematologists, rheumatologists, orthopedic surgeons, and physiotherapists at comprehensive hemophilia treatment centers.
Plumbagin, a Natural Product with Potent Anticancer Activities, Binds to and Inhibits Dihydroorotase, a Key Enzyme in Pyrimidine Biosynthesis

Dihydroorotase (DHOase) is the third enzyme in the de novo biosynthesis pathway for pyrimidine nucleotides, and an attractive target for potential anticancer chemotherapy. By screening plant extracts and performing GC–MS analysis, we identified and characterized that the potent anticancer drug plumbagin (PLU), isolated from the carnivorous plant Nepenthes miranda, was a competitive inhibitor of DHOase. We also solved the complexed crystal structure of yeast DHOase with PLU (PDB entry 7CA1), to determine the binding interactions and investigate the binding modes. Mutational and structural analyses indicated the binding of PLU to DHOase through loop-in mode, and this dynamic loop may serve as a drug target. PLU exhibited cytotoxicity on the survival, migration, and proliferation of 4T1 cells and induced apoptosis. These results provide structural insights that may facilitate the development of new inhibitors targeting DHOase, for further clinical anticancer chemotherapies.
Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes

Mutations in splicing factors are recurrent somatic alterations identified in myelodysplastic syndromes (MDS) and they frequently coincide with mutations in epigenetic factors. About 25% of patients present concurrent mutations in such pathways, suggesting a cooperative role in the pathogenesis of MDS. We focused on the splicing factor U2AF1 involved in the recognition of the 3′ splice site during pre-mRNA splicing. Using a CRISPR/Cas9 system, we created heterozygous mice with a carboxy-terminal truncated U2af1 allele (U2af1mut/+), studied the U2af1mut/+ hematopoietic system, and did not observe any gross differences in both young (12–13 weeks) and old (23 months) U2af1mut/+ mice, except for a reduction in size of approximately 20%. However, hematopoietic stem/progenitor cells lacked reconstitution capacity in transplantation assays and displayed an aberrant RNA splicing by RNA sequencing. We also evaluated U2af1mut/+ in conjunction with Tet2-deficiency. Novel double mutant U2af1mut/+ Tet2−/− mice showed increased monogranulocytic precursors. Hematopoietic stem/progenitor cells were also enhanced and presented functional and transcriptomic alterations. Nonetheless, U2af1mut/+ Tet2−/− mice did not succumb to MDS disease over a 6-month observation period. Collectively, our data suggest that cooperation between mutant U2af1 and Tet2 loss is not sufficient for MDS initiation in mice.
Effect of Morphological Characteristics and Biomineralization of 3D-Printed Gelatin/Hyaluronic Acid/Hydroxyapatite Composite Scaffolds on Bone Tissue Regeneration

The use of porous three-dimensional (3D) composite scaffolds has attracted great attention in bone tissue engineering applications because they closely simulate the major features of the natural extracellular matrix (ECM) of bone. This study aimed to prepare biomimetic composite scaffolds via a simple 3D printing of gelatin/hyaluronic acid (HA)/hydroxyapatite (HAp) and subsequent biomineralization for improved bone tissue regeneration. The resulting scaffolds exhibited uniform structure and homogeneous pore distribution. In addition, the microstructures of the composite scaffolds showed an ECM-mimetic structure with a wrinkled internal surface and a porous hierarchical architecture. The results of bioactivity assays proved that the morphological characteristics and biomineralization of the composite scaffolds influenced cell proliferation and osteogenic differentiation. In particular, the biomineralized gelatin/HA/HAp composite scaffolds with double-layer staggered orthogonal (GEHA20-ZZS) and double-layer alternative structure (GEHA20-45S) showed higher bioactivity than other scaffolds. According to these results, biomineralization has a great influence on the biological activity of cells. Hence, the biomineralized composite scaffolds can be used as new bone scaffolds in bone regeneration.
Phytochemicals as Therapeutic Interventions in Peripheral Artery Disease

Peripheral artery disease (PAD) affects over 200 million people worldwide, resulting in significant morbidity and mortality, yet treatment options remain limited. Among the manifestations of PAD is a severe functional disability and decline, which is thought to be the result of different pathophysiological mechanisms including oxidative stress, skeletal muscle pathology, and reduced nitric oxide bioavailability. Thus, compounds that target these mechanisms may have a therapeutic effect on walking performance in PAD patients. Phytochemicals produced by plants have been widely studied for their potential health effects and role in various diseases including cardiovascular disease and cancer. In this review, we focus on PAD and discuss the evidence related to the clinical utility of different phytochemicals. We discuss phytochemical research in preclinical models of PAD, and we highlight the results of the available clinical trials that have assessed the effects of these compounds on PAD patient functional outcomes.
Photo-Selective Nets and Pest Control: Searching Behavior of the Codling Moth Parasitoid Mastrus ridens (Hymenoptera: Ichneumonidae) under Varying Light Quantity and Quality Conditions

Simple Summary Although substantial studies exists evaluating the effects of photo-selective nets (PSN) on physiological and morphological aspects of crops in different parts of the world, there is a paucity of studies regarding the effects of PSN on the searching behavior of natural enemies of insect pests. Cydia pomonella is a major insect pest of apples worldwide and the parasitoid Mastrus ridens is an important natural enemy of this pest. We evaluated the effects of pearl and red PSN and black standard nets (SN) on the searching behavior of this parasitoid. The host localization ability of the parasitoid was significantly affected by the net color. The females found their hosts faster under the pearl and red PSN compared to the black SN. However, no effects were found in terms of parasitism or the initial behavior of the parasitoid. Even though parasitism was not affected, host localization was delayed under black SN compared to the other PSN. Therefore, it is necessary to carry out further studies in field conditions to verify whether parasitism or other parameters could be affected. Abstract Photo-selective nets (PSN) are used to manipulate the physiology of fruit crops. Besides their advantages to the crop, PSN potentially affect insect pests and their natural enemies. We aimed to assess the effects of these production systems on the searching behavior of the codling moth parasitoid, Mastrus ridens. We hypothesized that PSN and black standard nets (SN) affect the behavior of the parasitoid by delaying host localization and reducing parasitism. Laboratory experiments were carried out in closed cages under four treatment conditions: black SN, pearl PSN, red PSN, and no PSN as control (uncovered cages). Our results showed that the host localization of M. ridens was delayed under black SN and enhanced by pearl and red PSN. The PSN and the black SN did not affect the parasitism levels. In addition, the initial behavior of the parasitoid during the first 30 min of the bioassays was not affected by treatments. However, females spent most of the time walking around the arena, grooming, or resting, regardless of the color of the net. Parasitism was not affected under the PSN or the black SN; however, this must be verified in field conditions.
Attention Components and Spelling Accuracy: Which Connections Matter?

Attention and working memory are cross-domain functions that regulate both behavioural and learning processes. Few longitudinal studies have focused on the impact of these cognitive resources on spelling skills in the early phase of learning to write. This longitudinal study investigates the contributions of attention and working memory processes to spelling accuracy and handwriting speed in 112 primary school children (2nd, 3rd, and 4th grade; age range: 7.6–9.4 years) learning to write in the Italian transparent orthography. Standardised batteries were used to assess their attention and working memory skills, as well as their spelling. Homophone and non-homophone errors were measured, as they may involve different attentional and working memory processes. The results showed that, for 2nd grade children, selective attention shifting, planning, and inhibition predicted non-homophone errors, whereas sequential working memory predicted homophone errors and writing speed was explained by planning and selective attention. In 3rd grade, only homophone errors were predicted by planning and inhibition. No significant relationships were found in 4th grade, nor in the transition across grades. Dynamic and diversified roles of attentional and working memory processes in predicting different writing skills in early primary school years emerged, with a gradual decrease in the attention–writing relationship with age.
Transcriptome Profiling of Starvation in the Peripheral Chemosensory Organs of the Crop Pest Spodoptera littoralis Caterpillars

Simple Summary Starvation increases olfactory sensitivity in a manner that enhances the search for food in animals, including insects. However, the molecular mechanisms via which starvation modulates olfactory receptor neuron function are poorly understood. In this study, we sequenced and compared the whole transcriptomes of the main olfactory organs (antennae and palps) of fed and starved caterpillars from the species Spodoptera littoralis. We revealed that transcripts involved in several biological processes are regulated upon starvation. These processes include glucose metabolism, immune defense, foraging activity, and olfaction. In this last process, we evidenced regulation of chemosensory proteins and odorant-degrading enzymes, known to play a role in the dynamics and the sensitivity of the olfactory receptor neuron response. Our results identify new elements in the cascade of olfactory neuron modulation, in addition to insulin, GABA, and short neuropeptide F signaling. Abstract Starvation is frequently encountered by animals under fluctuating food conditions in nature, and response to it is vital for life span. Many studies have investigated the behavioral and physiological responses to starvation. In particular, starvation is known to induce changes in olfactory behaviors and olfactory sensitivity to food odorants, but the underlying mechanisms are not well understood. Here, we investigated the transcriptional changes induced by starvation in the chemosensory tissues of the caterpillar Spodoptera littoralis, using Illumina RNA sequencing. Gene expression profiling revealed 81 regulated transcripts associated with several biological processes, such as glucose metabolism, immune defense, response to stress, foraging activity, and olfaction. Focusing on the olfactory process, we observed changes in transcripts encoding proteins putatively involved in the peri-receptor events, namely, chemosensory proteins and odorant-degrading enzymes. Such modulation of their expression may drive fluctuations in the dynamics and the sensitivity of the olfactory receptor neuron response. In combination with the enhanced presynaptic activity mediated via the short neuropeptide F expressed during fasting periods, this could explain an enhanced olfactory detection process. Our observations suggest that a coordinated transcriptional response of peripheral chemosensory organs participates in the regulation of olfactory signal reception and olfactory-driven behaviors upon starvation.
The Impact of Coil Position and Number on Wireless System Performance for Electric Vehicle Recharging

Recently, most transportation systems have used an integrated electrical machine in their traction scheme, resulting in a hybrid electrified vehicle. As a result, an energy source is required to provide the necessary electric power to this traction portion. However, this cannot be efficient without a reliable recharging method and a practical solution. This study discusses the wireless recharge solutions and tests the system’s effectiveness under various external and internal conditions. Moreover, the Maxwell tool is used in this research to provide a complete examination of the coils’ position, size, number, and magnetic flux evolution when the coils are translated. In addition, the mutual inductance for each of these positions is computed to determine the ideal conditions for employing the wireless recharge tool for every charging application. A thorough mathematical analysis is also presented, and the findings clearly demonstrate the relationship between the magnet flux and the various external conditions employed in this investigation.