Miracle-dz/UniFAR-FTUs huggingface dataset:
Fludarabine, High-Dose Cytarabine and Idarubicin-Based Induction May Overcome the Negative Prognostic Impact of FLT3-ITD in NPM1 Mutated AML, Irrespectively of FLT3-ITD Allelic Burden

Simple Summary The prognostic relevance of molecular aberrations in acute myeloid leukemia (AML) has been prevalently tested in patients receiving conventional 3+7 induction. Recently, there has been a renewed interest in intensified inductions, but very few data are available on the impact of the most frequent genetic alterations with these alternative treatments. We analyzed a large multicentric cohort of younger AML patients harboring NPM1 and FLT3-ITD mutations receiving an intensified fludarabine-containing regimen (FLAI). Our data suggest that in NPM1 mut patients, FLAI may overcome the prognostic influence of co-mutated FLT3-ITD. The increased efficacy of this treatment seems to reduce the need for early consolidation with allogeneic transplant in double-mutated patients. Our data strongly support FLAI as an ideal backbone for combination with innovative targeted drugs, in order to further improve patients’ outcome. Abstract The mutations of NPM1 and FLT3-ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an NPM1 mutation reduces the negative prognostic impact of FLT3-ITD in patients treated with conventional “3+7” induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the NPM1 and/or FLT3-ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both NPM1mut (p < 0.05) and ELN 2017 risk score (p < 0.05) were significant predictors of survival. NPM1-mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant FLT3-ITD (p = 0.372), irrespective of FLT3-ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with NPM1mut and question the role of HSCT in 1st CR in NPM1mut patients with concomitant FLT3-ITD.
Sterols and Triterpenes: Antiviral Potential Supported by In-Silico Analysis

The acute respiratory syndrome caused by the novel coronavirus (SARS-CoV-2) caused severe panic all over the world. The coronavirus (COVID-19) outbreak has already brought massive human suffering and major economic disruption and unfortunately, there is no specific treatment for COVID-19 so far. Herbal medicines and purified natural products can provide a rich resource for novel antiviral drugs. Therefore, in this review, we focused on the sterols and triterpenes as potential candidates derived from natural sources with well-reported in vitro efficacy against numerous types of viruses. Moreover, we compiled from these reviewed compounds a library of 162 sterols and triterpenes that was subjected to a computer-aided virtual screening against the active sites of the recently reported SARS-CoV-2 protein targets. Interestingly, the results suggested some compounds as potential drug candidates for the development of anti-SARS-CoV-2 therapeutics.
Biodegradable Microcapsules Loaded with Nerve Growth Factor Enable Neurite Guidance and Synapse Formation

Neurological disorders and traumas often involve loss of specific neuronal connections, which would require intervention with high spatial precision. We have previously demonstrated the biocompatibility and therapeutic potential of the layer-by-layer (LbL)-fabricated microcapsules aimed at the localized delivery of specific channel blockers to peripheral nerves. Here, we explore the potential of LbL-microcapsules to enable site-specific, directional action of neurotrophins to stimulate neuronal morphogenesis and synaptic circuit formation. We find that nanoengineered biodegradable microcapsules loaded with nerve growth factor (NGF) can guide the morphological development of hippocampal neurons in vitro. The presence of NGF-loaded microcapsules or their clusters increases the neurite outgrowth rate while boosting neurite branching. Microcapsule clusters appear to guide the trajectory of developing individual axons leading to the formation of functional synapses. Our observations highlight the potential of NGF-loaded, biodegradable LbL-microcapsules to help guide axonal development and possibly circuit regeneration in neuropathology.
In Vitro and In Vivo Models of Non-Alcoholic Fatty Liver Disease: A Critical Appraisal

Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), represents the hepatic manifestation of obesity and metabolic syndrome. Due to the spread of the obesity epidemic, NAFLD is becoming the most common chronic liver disease and one of the principal indications for liver transplantation. However, no pharmacological treatment is currently approved to prevent the outbreak of NASH, which leads to fibrosis and cirrhosis. Preclinical research is required to improve our knowledge of NAFLD physiopathology and to identify new therapeutic targets. In the present review, we summarize advances in NAFLD preclinical models from cellular models, including new bioengineered platforms, to in vivo models, with a particular focus on genetic and dietary mouse models. We aim to discuss the advantages and limits of these different models.
Semantic fluency including task switching predicts academic success in medical school

Objectives The future state treaty on the admission of students to German medical schools calls for a variety of selection criteria among which at least two are required to be independent of school leaving grades. Against this background, the present study investigated achievement motivation and executive functions as predictors of academic success in medical school. Material and methods Second year medical students were assessed for executive functioning by using the Tower of London Test (ToL), a German version of the Controlled Oral Word Association Test (COWAT), the Trail Making Test (TMT-A) and for motivation by using the Achievement Motivation Inventory (AMI). Academic success was evaluated twofold, i) whether the first state exam (M1) was passed at the earliest possible, after completion of the second year and ii) via the grades obtained. Results 81 out of 226 students enrolled participated in our study. Passing the M1 was best explained by semantic fluency including task switching. Moreover, academically successful students achieved significantly higher levels in the AMI-facets "compensatory effort" and "engagement". All students scored above average in the TMT-A and average in the ToL. Conclusion Alternating semantic fluency—requiring simultaneously inhibition, updating and task shifting—turned out highly predictive of academic success in medical school. Moreover, higher levels in "compensatory effort" and “engagement” suggested that both, increased energy expenditure as response to fear of failure and elevated readiness to exert effort also impacted positively on success.
Alleviating Molecular-Scale Damages in Silica-Reinforced Natural Rubber Compounds by a Self-Healing Modifier

The property retentions of silica-reinforced natural rubber vulcanizates with various contents of a self-healing modifier called EMZ, which is based on epoxidized natural rubber (ENR) modified with hydrolyzed maleic anhydride (HMA) as an ester crosslinking agent plus zinc acetate dihydrate (ZAD) as a transesterification catalyst, were investigated. To validate its self-healing efficiency, the molecular-scale damages were introduced to vulcanizates using a tensile stress–strain cyclic test following the Mullins effect concept. The processing characteristics, reinforcing indicators, and physicomechanical and viscoelastic properties of the compounds were evaluated to identify the influences of plausible interactions in the system. Overall results demonstrate that the property retentions are significantly enhanced with increasing EMZ content at elevated treatment temperatures, because the EMZ modifier potentially contributes to reversible linkages leading to the intermolecular reparation of rubber network. Furthermore, a thermally annealing treatment of the damaged vulcanizates at a high temperature, e.g., 120 °C, substantially enhances the property recovery degree, most likely due to an impact of the transesterification reaction of the ester crosslinks adjacent to the molecular damages. This reaction can enable bond interchanges of the ester crosslinks, resulting in the feasibly exchanged positions of the ester crosslinks between the broken rubber molecules and, thus, achievable self-reparation of the damages.
Programable Active Fixator System for Systematic In Vivo Investigation of Bone Healing Processes

This manuscript introduces a programable active bone fixator system that enables systematic investigation of bone healing processes in a sheep animal model. In contrast to previous systems, this solution combines the ability to precisely control the mechanical conditions acting within a fracture with continuous monitoring of the healing progression and autonomous operation of the system throughout the experiment. The active fixator system was implemented on a double osteotomy model that shields the experimental fracture from the influence of the animal’s functional loading. A force sensor was integrated into the fixator to continuously measure stiffness of the repair tissue as an indicator for healing progression. A dedicated control unit was developed that allows programing of different loading protocols which are later executed autonomously by the active fixator. To verify the feasibility of the system, it was implanted in two sheep with different loading protocols, mimicking immediate and delayed weight-bearing, respectively. The implanted devices operated according to the programmed protocols and delivered seamless data over the whole course of the experiment. The in vivo trial confirmed the feasibility of the system. Hence, it can be applied in further preclinical studies to better understand the influence of mechanical conditions on fracture healing.
A Bioinformatics Pipeline to Identify a Subset of SNPs for Genomics-Assisted Potato Breeding

Modern potato breeding methods following a genomic-led approach provide means for shortening breeding cycles and increasing breeding efficiency across selection cycles. Acquiring genetic data for large breeding populations remains expensive. We present a pipeline to reduce the number of single nucleotide polymorphisms (SNPs) to lower the cost of genotyping. First, we reduced the number of individuals to be genotyped with a high-throughput method according to the multi-trait variation as defined by principal component analysis of phenotypic characteristics. Next, we reduced the number of SNPs by pruning for linkage disequilibrium. By adjusting the square of the correlation coefficient between two adjacent loci, we obtained reduced subsets of SNPs. We subsequently tested these SNP subsets by two methods; (1) a genome-wide association study (GWAS) for marker identification, and (2) genomic selection (GS) to predict genomic estimated breeding values. The results indicate that both GWAS and GS can be done without loss of information after SNP reduction. The pipeline allows for creating custom SNP subsets to cover all variation found in any particular breeding population. Low-throughput genotyping will reduce the genotyping cost associated with large populations, thereby making genomic breeding methods applicable to large potato breeding populations by reducing genotyping costs.
Assessing Diet Quality of Indigenous Food Systems in Three Geographically Distinct Solomon Islands Sites (Melanesia, Pacific Islands)

Indigenous Solomon Islanders, like many living in Pacific Small Island Developing States (PSIDS), are currently experiencing the global syndemic—the combined threat of obesity, undernutrition, and climate change. This mixed-method study aimed to assess nutrition transitions and diet quality by comparing three geographically unique rural and urban indigenous Solomon Islands populations. Participants in rural areas sourced more energy from wild and cultivated foods; consumed a wider diversity of foods; were more likely to meet WHO recommendations of >400 g of non-starchy fruits and vegetables daily; were more physically active; and had significantly lower body fat, waist circumference, and body mass index (BMI) when compared to urban populations. Urban populations were found to have a reduced ability to self-cultivate agri-food products or collect wild foods, and therefore consumed more ultra-processed foods (classified as NOVA 4) and takeout foods, and overall had less diverse diets compared to rural populations. Clear opportunities to leverage traditional knowledge and improve the cultivation and consumption of underutilized species can assist in building more sustainable and resilient food systems while ensuring that indigenous knowledge and cultural preferences are respected.
The Role of Urine F2-isoprostane Concentration in Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Haemorrhage—A Poor Prognostic Factor

Background: The pathophysiology of delayed cerebral ischemia (DCI) remains unclear. One of the hypotheses suggests that reactive oxygen species play a role in its onset. Thus, we studied F2-isoprostanes (F2-IsoPs)—oxidative stress biomarkers. Our goal was to improve the early diagnosis of DCI in a non-invasive way. Methods: We conducted a prospective single center analysis of 38 aneurysmal subarachnoid hemorrhage patients. We assessed urine F2-IsoP concentration using immunoenzymatic arrays between the first and fifth day after bleeding. A correlation between urine F2-IsoP concentration and DCI occurrence was examined regarding clinical conditions and outcomes. Results: The urine F2-IsoP concentrations were greater than those in the control groups (p < 0.001). The 3rd day urine F2-IsoPs concentrations were correlated with DCI occurrence (p < 0.001) and long term outcomes after 12 months (p < 0.001). Conclusions: High levels of urine F2-IsoPs on day 3 can herald DCI.
Chemical conversion of aged hepatocytes into bipotent liver progenitor cells

In the aging society, understanding the influence of hepatocyte age on hepatocyte donation may inform efforts to expand alternative cell sources to mitigate liver donor shortage. A combination of the molecules Y27632, A‐83‐01, and CHIR99021 has been used to reprogram rodent young hepatocytes into chemically induced liver progenitor (CLiP) cells; however, whether it could also reprogram aged hepatocytes has not yet been elucidated.
Olfactory Choice for Decomposition Stage in the Burying Beetle Nicrophorus vespilloides: Preference or Aversion?

Simple Summary In the burying beetle Nicrophorus vespilloides, mating pairs raise their offspring together on a small carrion resource. We tested whether carcass age affected brood quantity and quality and found that pairs had significantly more offspring on fresher carcasses. To determine whether this reproductive benefit translates to an olfactory preference or aversion for carcass age, we conducted a series of olfactory trials testing adult mated female preferences for carcasses differing in age. Mated females spent more time associating with fresh carcass odors relative to those of an aged one, but also spent more time in empty chambers than those with an aged carcass, suggesting that mated females have a general aversion to those odors. Lastly, we characterized the odor profiles of fresh and aged carcasses to determine which compounds might be driving this olfactory aversion in mated female burying beetles. Abstract Sensory cues predicting resource quality are drivers of key animal behaviors such as preference or aversion. Despite the abundance of behavioral choice studies across the animal kingdom, relatively few studies have tested whether these decisions are driven by preference for one choice or aversion to another. In the burying beetle Nicrophorus vespilloides, adult pairs exhibit parental care to raise their offspring on a small carrion resource. We tested whether carrion decomposition stage affected brood quantity and quality and found that mating pairs had significantly more offspring on fresher carcasses. To determine whether this observed reproductive benefit correlates with maternal preference behavior, we conducted a series of olfactory trials testing mated female preferences for mouse carcasses of differing decomposition stages. When given the option between fresh and older carcasses, females associated significantly more with fresher, 1-day old carcasses. However, this behavior may be driven by aversion, as females that were given a choice between the 7-day old carcass and a blank control spent significantly more time in the control chamber. We characterized volatile organic compound profiles of both carcass types, highlighting unique compounds that may serve as public information (sensu lato) conveying resource quality information to gravid beetles.
Effects of Maternal Fiber Intake on Intestinal Morphology, Bacterial Profile and Proteome of Newborns Using Pig as Model

Dietary fiber intake during pregnancy may improve offspring intestinal development. The aim of this study was to evaluate the effect of maternal high fiber intake during late gestation on intestinal morphology, microbiota, and intestinal proteome of newborn piglets. Sixteen sows were randomly allocated into two groups receiving the control diet (CD) and high-fiber diet (HFD) from day 90 of gestation to farrowing. Newborn piglets were selected from each litter, named as CON and Fiber group, respectively. Maternal high fiber intake did not markedly improve the birth weight, but increased the body length, the ileal crypt depth and colonic acetate level. In addition, maternal high fiber intake increased the α-diversity indices (Observed species, Simpson, and ACE), and the abundance of Acidobacteria and Bacteroidetes at phylum level, significantly increased the abundance of Bradyrhizobium and Phyllobacterium at genus level in the colon of newborn piglets. Moreover, maternal high fiber intake markedly altered the ileal proteome, increasing the abundances of proteins associated with oxidative status, energy metabolism, and immune and inflammatory responses, and decreasing abundances of proteins related to cellular apoptosis, cell structure, and motility. These findings indicated that maternal high fiber intake could alter intestinal morphology, along with the altered intestinal microbiota composition and proteome of offspring.
Shiga Toxin 2a Binds to Complement Components C3b and C5 and Upregulates Their Gene Expression in Human Cell Lines

Enterohemorrhagic Escherichia coli (EHEC) infections can cause EHEC-associated hemolytic uremic syndrome (eHUS) via its main virulent factor, Shiga toxins (Stxs). Complement has been reported to be involved in the progression of eHUS. The aim of this study was to investigate the interactions of the most effective subtype of the toxin, Stx2a, with pivotal complement proteins C3b and C5. The study further examined the effect of Stx2a stimulation on the transcription and synthesis of these complement proteins in human target cell lines. Binding of Stx2a to C3b and C5 was evaluated by ELISA. Kidney and gut cell lines (HK-2 and HCT-8) were stimulated with varied concentrations of Stx2a. Subsequent evaluation of complement gene transcription was studied by real-time PCR (qPCR), and ELISAs and Western blots were performed to examine protein synthesis of C3 and C5 in supernatants and lysates of stimulated HK-2 cells. Stx2a showed a specific binding to C3b and C5. Gene transcription of C3 and C5 was upregulated with increasing concentrations of Stx2a in both cell lines, but protein synthesis was not. This study demonstrates the binding of Stx2a to complement proteins C3b and C5, which could potentially be involved in regulating complement during eHUS infection, supporting further investigations into elucidating the role of complement in eHUS pathogenesis.
In Escherichia coli Ammonia Inhibits Cytochrome bo3 But Activates Cytochrome bd-I

Interaction of two redox enzymes of Escherichia coli, cytochrome bo3 and cytochrome bd-I, with ammonium sulfate/ammonia at pH 7.0 and 8.3 was studied using high-resolution respirometry and absorption spectroscopy. At pH 7.0, the oxygen reductase activity of none of the enzymes is affected by the ligand. At pH 8.3, cytochrome bo3 is inhibited by the ligand, with 40% maximum inhibition at 100 mM (NH4)2SO4. In contrast, the activity of cytochrome bd-I at pH 8.3 increases with increasing the ligand concentration, the largest increase (140%) is observed at 100 mM (NH4)2SO4. In both cases, the effector molecule is apparently not NH4+ but NH3. The ligand induces changes in absorption spectra of both oxidized cytochromes at pH 8.3. The magnitude of these changes increases as ammonia concentration is increased, yielding apparent dissociation constants Kdapp of 24.3 ± 2.7 mM (NH4)2SO4 (4.9 ± 0.5 mM NH3) for the Soret region in cytochrome bo3, and 35.9 ± 7.1 and 24.6 ± 12.4 mM (NH4)2SO4 (7.2 ± 1.4 and 4.9 ± 2.5 mM NH3) for the Soret and visible regions, respectively, in cytochrome bd-I. Consistently, addition of (NH4)2SO4 to cells of the E. coli mutant containing cytochrome bd-I as the only terminal oxidase at pH 8.3 accelerates the O2 consumption rate, the highest one (140%) being at 27 mM (NH4)2SO4. We discuss possible molecular mechanisms and physiological significance of modulation of the enzymatic activities by ammonia present at high concentration in the intestines, a niche occupied by E. coli.