Miracle-dz/UniFAR-FTUs huggingface dataset:
The NEDD8-activating enzyme inhibitor MLN4924 reduces ischemic brain injury in mice

Significance Ischemic stroke is a leading cause of death and disability with limited therapies. Neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8) is a ubiquitin-like protein that is involved in protein neddylation. The first-in-class anticancer agent called MLN4924 plays a crucial role in suppressing tumorigenesis and attenuating inflammatory responses due to specifically inhibiting NEDD8-activating enzyme. Here, we investigated the potential protective role of MLN4924 after experimental stroke. We showed that the neddylation pathway is overactivated in the brain following cerebral ischemia. Inhibition of neddylation by MLN4924 protects the brain against ischemic injury by attenuating neutrophil extravasation and maintaining blood–brain barrier integrity. Our findings provide insights into the promising treatment with neddylation inhibition for ischemic brain injury. Blood–brain barrier (BBB) breakdown and inflammation occurring at the BBB have a key, mainly a deleterious role in the pathophysiology of ischemic stroke. Neddylation is a ubiquitylation-like pathway that is critical in various cellular functions by conjugating neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to target proteins. However, the roles of neddylation pathway in ischemic stroke remain elusive. Here, we report that NEDD8 conjugation increased during acute phase after ischemic stroke and was present in intravascular and intraparenchymal neutrophils. Inhibition of neddylation by MLN4924, also known as pevonedistat, inactivated cullin-RING E3 ligase (CRL), and reduced brain infarction and improved functional outcomes. MLN4924 treatment induced the accumulation of the CRL substrate neurofibromatosis 1 (NF1). By using virus-mediated NF1 silencing, we show that NF1 knockdown abolished MLN4924-dependent inhibition of neutrophil trafficking. These effects were mediated through activation of endothelial P-selectin and intercellular adhesion molecule-1 (ICAM-1), and blocking antibodies against P-selectin or anti–ICAM-1 antibodies reversed NF1 silencing-induced increase in neutrophil infiltration in MLN4924-treated mice. Furthermore, we found that NF1 silencing blocked MLN4924-afforded BBB protection and neuroprotection through activation of protein kinase C δ (PKCδ), myristoylated alanine-rich C-kinase substrate (MARCKS), and myosin light chain (MLC) in cerebral microvessels after ischemic stroke, and treatment of mice with the PKCδ inhibitor rottlerin reduced this increased BBB permeability. Our study demonstrated that increased neddylation promoted neutrophil trafficking and thus exacerbated injury of the BBB and stroke outcomes. We suggest that the neddylation inhibition may be beneficial in ischemic stroke.
Enrichment of Formula in Probiotics or Prebiotics and Risk of Infection and Allergic Diseases up to Age 5.5 years in the Nationwide ELFE Cohort.

BACKGROUND An increasing number of infant and follow-on formulas are enriched with probiotics and/or prebiotics; however, evidence for health effects of such enrichment in early childhood remains inconclusive. OBJECTIVES The present study aimed to assess, whether consumption of formula enriched with probiotics or prebiotics was associated with the risk of infection and allergic diseases in early childhood. METHODS Analyses involved data for 8389 formula-fed children from the Etude Longitudinale Française depuis l'Enfance (ELFE) cohort. Enrichment of the formula with probiotics or prebiotics that was consumed from age 2 to 10 months was identified by the formula ingredient list. Lower respiratory tract infection (LRTI), upper respiratory tract infection (URTI), gastrointestinal infection, wheezing, asthma, food allergy and itchy rash were prospectively reported by parents up to age 5.5 years. Adjusted logistic regression models were used to assess associations between consumption of enriched formula and risk of infection and allergic diseases. RESULTS At age 2 months, more than half of formula-fed infants consumed probiotic-enriched formula and only one in 10 consumed prebiotic-enriched formula. Consumption of Bifidobacterium lactis-enriched formula at 2 months was associated with a lower risk of LRTI (OR[95%CI] = 0.84[0.73-0.96]). Consumption of Bifidobacterium breve-enriched formula up to 6 months was associated with a higher risk of LRTI (OR[95%CI] = 1.75[1.29-2.38]) and asthma (OR[95%CI] = 1.95[1.28-2.97]), while its consumption from 6-10 months was associated with a lower risk of LRTI (OR[95%CI] = 0.64[0.48-0.86]) and asthma (OR[95%CI] = 0.59[0.40-0.88]). Moreover, consumption of Streptococcus thermophilus from 6-10 months was associated with a higher risk of asthma (OR[95%CI] = 1.84[1.29-2.63]). No significant association was found for gastrointestinal infection, food allergy, and itchy rash. Overall, consumption of prebiotic-enriched formula was not significantly associated with infection and allergy risk. CONCLUSIONS Associations between consumption of probiotic-enriched formula and risk of respiratory symptoms differ according to the strain considered and consumption period. Further well-designed studies are needed to confirm these results.
Contrast‐Enhanced Ultrasound Features of Adult Xp11.2 Translocation Renal Cell Carcinoma

To investigate the sonographic features in Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) using both conventional ultrasound (US) and contrast‐enhanced US (CEUS) and evaluate the usefulness of sonographic imaging characteristics to differentiate between Xp11.2 tRCC and the three common RCC subtypes.
Effects of transfusion of stored blood in patients with transfusion-dependent thalassemia.

OBJECTIVES The aim of this study was to investigate the hematological and biochemical effects of stored blood transfusion on patients with transfusion-dependent thalassemia (TDT). METHODS In this quasi-experimental study, 20-patients with TDT were enrolled. Each participant received on first visit, freshly collected red cell concentrate (RCC) (<2-days storage) and 15-days later on second visit, 7-days stored blood. Blood samples were obtained immediately before and 24-hours after each transfusion. Differences in the Complete blood counts, bilirubin, LDH, C-Reactive protein, ferritin, and iron levels in the pre- and post-transfusion samples were compared between the first and second transfusion. RESULTS Fresh blood transfusion resulted in a higher (but non-significant) increase in hemoglobin and other red cell parameters. Notably, a significant increase in white cell counts (WCC) was seen in 7-days stored blood vs fresh blood (1.82×109/l vs 1.01×109/l, P=0.002). No statistically significant difference was found in LDH, direct and indirect bilirubin, creatinine, blood glucose, serum uric acid, serum ferritin, and serum Iron levels. There was a statistically significant rise in C-reactive protein levels in stored (6.43±7.46 mg/dl) versus fresh RCC (1.89±2.38 mg/dl), p-value =0.012. CONCLUSIONS We show that in patients with chronic TDT, an increase in inflammation-associated markers (WCC and CRP) is observed. Further studies to assess the extent and duration of this increase are needed.
Challenges in the hemodynamic management of acute nontraumatic neurological injuries

Purpose of review To appraise the evidence from the literature and suggest an integrated hemodynamic approach of early and delayed phases of acute ischemic stroke (AIS), subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). Recent findings In AIS, the research aims to evaluate the optimal pressure control before, during and after the revascularization, to optimize the perfusion in the ischemic areas, minimizing the risk of hemorrhage or secondary damage to already infarcted areas. In the early phase of SAH, systemic pressure should be controlled to balance the risk of stroke, hypertension-related rebleeding, and maintenance of cerebral perfusion pressure. The late phase aims to minimize the risk of cerebral vasospasm by adapting systemic pressure and volemia to cerebral and systemic physiological hemodynamic targets. In the mild-to-moderate ICH, achieving SAP of less than 140 mmHg and greater than 110 mmHg may be considered as a beneficial target. Caution should be considered in lowering intensively SAP in severe ICH. Summary In nontraumatic brain injuries, the hemodynamic management is strictly related to fluctuating physiology of these diseases, needing a strict control of pressure and flow variable to ensure both cerebral and systemic homeostasis.
Noninvasive Epileptogenic Signal Direction Determination by Effective Connectivity of Resting State Functional MRI - Independent of EEG

The goal of this study was to determine resting state fMRI effective connectivity (RSEC) capacity, agnostic of epileptogenic events, in distinguishing seizure onset zones (SOZ) from propagation zones (pZ). Consecutive patients (2.1-18.2 years old), with epilepsy and hypothalamic hamartoma, pre-operative rs-fMRI-directed surgery, post-operative imaging, and Engel class I outcomes were collected. Cross-spectral dynamic causal modelling (DCM) was used to estimate RSEC between the ablated rs-fMRI-SOZ to its region of highest connectivity outside the HH, defined as the propagation zone (pZ). RSEC between the SOZ and PZ was characterized as positive (excitatory), negative (inhibitory), or null. It was hypothesized that connectivity from the SOZ would be excitatory and connectivity from the pZ would be inhibitory. Sensitivity, accuracy, positive predictive value were determined for node-to-node connections. A Parametric Empirical Bayes (PEB) group analysis was performed to identify effects of Engel class outcome and age. RSEC strength was also evaluated for correlation with percent seizure frequency improvement, sex, and region of interest size. Of the SOZ's RSEC, only 3.6% had no connection of significance to the pZ when patient models were individually reduced. Among remaining, 96% were in expected (excitatory signal found from SOZ[->]pZ and inhibitory signal found from pZ[->]SOZ) versus 3.6% reversed polarities. Both polarity signals were equivalently as expected, with one false signal direction out of 26 each (3.7% total). Sensitivity of 96%, accuracy of 93%, and positive predictive value of 96% in identifying and differentiating the SOZ and pZ. Groupwise PEB analysis confirmed SOZ[->]pZ EC was excitatory, and pZ[->]SOZ EC was inhibitory. Patients with better outcomes (Engel Ia vs. Ib) showed stronger inhibitory signal (pZ[->]SOZ). Age was negatively associated with absolute RSEC bidirectionally, but had no relationship with Directionality SOZ identification performance. This study demonstrates the accuracy of Directionality to identify the origin of excitatory and inhibitory signal between the surgically confirmed SOZ and the region of hypothesized propagation zone in children with DRE due to a HH. Thus, this method validation study in a homogenous DRE population may have potential in narrowing the SOZ-candidates for epileptogenicity in other DRE populations and utility in other neurological disorders.
Predictors of mortality, ICU admission and intubation among hospitalized COVD-19 patients in Jordan.

Abstract Introduction Several studies characterized COVID-19 patients and revealed the factors associated with COVID-19 mortality and severity. However, few studies were conducted in the Middle East, hence we decided to conduct this study to characterize COVID-19 patients, identify the factors associated with COVID-19 mortality and severity and to compare the patients outcomes in the two waves of the pandemic. Method We conducted a retrospective single center cohort study among COVID-19 patients admitted to our hospital. The primary outcomes were COVID-19 related death, ICU admission and invasive intubation. Whereas, the secondary outcome was the length of hospital stay. In addition, the patients were divided into two cohorts to represent the two waves of the pandemic, to compare between them based on the outcomes. Results The total number of COVID-19 patients included in our study was 745. The overall rates of COVID-19 related mortality, ICU admission and invasive intubation were 23.0%, 28.3% and 10.8%, respectively. CKD, troponin, LDH and O2 saturation <90% were significant predictors for mortality. Moreover, the significant predictors for ICU admission were HF and remdesivir use. Whereas, O2 saturation<90% and GI symptoms were the only significant predictors for invasive intubation. Additionally, the second wave had significantly higher rates of ICU admission compared to the first one. Conclusion Our study showed that several factors predicted COVID-19 mortality, ICU admission and invasive intubation. Additionally, our study revealed that the second wave of the pandemic had significantly higher rates of ICU admission but not mortality or invasive intubation compared to the first wave.
The Nicaraguan Pediatric Influenza Cohort Study, 2011-2019: influenza incidence, seasonality, and transmission

Background. Children account for a large portion of global influenza burden and transmission, and a better understanding of influenza in children is needed to improve prevention and control strategies. Methods. To examine the incidence and transmission of influenza we conducted a prospective community-based study of children aged 0-14 years in Managua, Nicaragua between 2011 and 2019. Participants were provided with medical care through study physicians and symptomatic influenza was confirmed by RT-PCR. Wavelet analyses were used to examine seasonality. Generalized growth models (GGMs) were used to estimate effective reproduction numbers. Results. From 2011-2019, 3,016 children participated, with an average of ~1,800 participants per year and median follow-up time of 5 years per child, and 48.3% of the cohort in 2019 had been enrolled their entire lives. The overall incidence rates per 100 person-years were 14.5 symptomatic influenza cases (95%CI: 13.9-15.1) and 1.0 influenza-associated ALRI case (95%CI: 0.8-1.1). Symptomatic influenza incidence peaked at age 9-11 months. Infants born during peak influenza circulation had lower incidence in the first year of their lives. The mean effective reproduction number was 1.2 (range 1.02-1.49), and we observed significant annual patterns for influenza and influenza A, and a 2.5-year period for influenza B. Conclusions. This study provides important information for understanding influenza epidemiology and informing influenza vaccine policy. These results will aid in informing strategies to reduce the burden of influenza.
Brillouin–Raman microspectroscopy for the morpho-mechanical imaging of human lamellar bone

Bone has a sophisticated architecture characterized by a hierarchical organization, starting at the sub-micrometre level. Thus, the analysis of the mechanical and structural properties of bone at this scale is essential to understand the relationship between its physiology, physical properties and chemical composition. Here, we unveil the potential of Brillouin–Raman microspectroscopy (BRaMS), an emerging correlative optical approach that can simultaneously assess bone mechanics and chemistry with micrometric resolution. Correlative hyperspectral imaging, performed on a human diaphyseal ring, reveals a complex microarchitecture that is reflected in extremely rich and informative spectra. An innovative method for mechanical properties analysis is proposed, mapping the intermixing of soft and hard tissue areas and revealing the coexistence of regions involved in remodelling processes, nutrient transportation and structural support. The mineralized regions appear elastically inhomogeneous, resembling the pattern of the osteons' lamellae, while Raman and energy-dispersive X-ray images through scanning electron microscopy show an overall uniform distribution of the mineral content, suggesting that other structural factors are responsible for lamellar micromechanical heterogeneity. These results, besides giving an important insight into cortical bone tissue properties, highlight the potential of BRaMS to access the origin of anisotropic mechanical properties, which are almost ubiquitous in other biological tissues.
Individual snowshoe hares manage risk differently: integrating stoichiometric distribution models and foraging ecology

Herbivores making space use decisions must consider the trade-off between perceived predation risk and forage quality. Herbivores, specifically snowshoe hares (Lepus americanus), must constantly navigate landscapes that vary in predation risk and food quality, providing researchers with the opportunity to explore the factors that govern their foraging decisions. Herein, we tested predictions that intersect the risk allocation hypothesis (RAH) and optimal foraging theory (OFT) in a spatially explicit ecological stoichiometry framework to assess the tradeoff between predation risk and forage quality. We used individual and population estimates of snowshoe hare (n = 29) space use derived from biotelemetry across three summers. We evaluated resource forage quality for lowbush blueberry (Vaccinium angustifolium), a common and readily available forage species within our system, using carbon:nitrogen and carbon:phosphorus ratios. We used habitat complexity to proxy perceived predation risk. We analyzed how forage quality of blueberry, perceived predation risk, and their interaction impact the intensity of herbivore space use. We used generalized mixed effects models, structured to enable us to make inferences at the population and individual home range level. We did not find support for RAH and OFT. However, variation in the individual-level reactions norms in our models showed that individual hares have unique responses to forage quality and perceived predation risk. Our finding of individual-level responses indicates that there is fine-scale decision-making by hares, although we did not identify the mechanism. Our approach illustrates spatially explicit empirical support for individual behavioral responses to the food quality–predation risk trade-off.
Empathic creativity: can trait empathy predict creative concept generation and selection?

Abstract Over the past decade, engineering design research has seen a significant surge of the discussion of empathy. As such, design researchers have been devoted in devising and assessing empathic design activities. While prior research has examined the utility of empathic design experiences on driving creative concept generation, little is known about the role of a designer's empathic tendencies in driving creative concept generation and selection in an engineering design project. Without this knowledge, we cannot be sure if, when, or how empathy influences the design process. Thus, the main goal of this paper was to identify the role of trait empathy in creative concept generation and selection in an engineering design student project. In order to achieve this objective, a study was conducted with 103 first-year engineering students during two design stages of an 8-week design project (concept generation and concept selection). The main findings from this paper highlighted that empathic concern tendencies positively impacted the generation of more ideas while personal distress tendencies negatively impacted the generation of more ideas. During concept selection, perspective-taking tendencies positively impacted participants’ propensity for selecting elegant ideas. This research took the first step in encouraging empirical investigations aimed at understanding the role of trait empathy across different stages of the design process.
Introducing the Replication Studies section

Spatial Economic Analysis is pleased to announce a new section, Replication Studies, devoted to short papers that replicate or extend published empirical results and discuss their sensitivity to relevant changes in the model, estimation method and/or interpretation. Empirical studies are part of the backbone of the social sciences because they help to support theories and form policy recommendations. In recent decades there has been a 50% increase in the share of published empirical studies in comparison with articles focused on economic theory and econometric theory. In addition, empirical papers receive more citations than theoretical papers (Angrist et al., 2017). It is 35 years since Dewald et al. (1986) emphasized the importance of replications in empirical research. Out of a sample of 54 published papers in the Journal ofMoney, Credit and Banking in 1980, they found only eight (15%) were replicable without problems and 14 (26%) were incomplete. More recently, Vilhuber (2020) found that about 30% of replication attempts fail. Still, replication studies are not common. Empirical work from well-published and highly cited articles or top five journals is more likely to be reproduced (Berry et al., 2017; Hamermesh, 2007), but the number of replication studies for even well-published works is small. Berry et al. (2017) find that only 3.5% of the papers that cited empirical works published in the American Economic Review in 2010 are replications. Replications in regional science, spatial economics and economic geography are also scarce and unsatisfactory to our knowledge. By contrast, in experimental economics and financial economics, two subfields within the economics literature, replications are more common (Ingerslev et al., 2021 Maniadis et al., 2017). The literature suggests two reasons for the lack of replication studies (Dewald et al., 1986; Galiani et al., 2017; Vilhuber, 2020):
Iron excess affects release of neutrophil extracellular traps and reactive oxygen species but does not influence other functions of neutrophils

Neutrophils apply several antimicrobial strategies including degranulation, phagocytosis, the generation of reactive oxygen species (ROS) and the release of neutrophil extracellular traps (NETs) to fight pathogens. Iron is considered to be an invaluable constituent of host immune defense and plays a dual role in immunity. It is a well‐known component of antimicrobial proteins and is a necessary microelement for pathogen survival. The aim of this study was to broaden the knowledge regarding the impact of iron on the function of neutrophils. Neutrophils from healthy blood donors and patients with mild iron‐deficiency anemia and HL‐60 cells differentiated toward granulocyte‐like cells were incubated with Fe2+, Fe3+ or holo‐transferrin (holo‐Tf). Moreover, we isolated murine neutrophils of HFE gene knockout (KO) mice and mice fed iron‐deficient, iron‐equivalent and high‐iron diets. We analyzed the release of NETs, phagocytosis, degranulation of azurophilic granules, ROS release, bactericidal activity of granulocytes against Escherichia coli and neutrophil elastase (NE) activity. We show that holo‐Tf inhibits the release of NETs stimulated by phorbol 12‐myristate 13‐acetate by inhibiting NE activity. Studies performed in mice models reveal that iron overload inhibits the release of NETs and ROS production in neutrophils isolated from HFE KO mice and mice fed a high‐iron diet. No impact of a low‐iron diet on neutrophil phagocytosis, ROS production or release of NETs was observed. Our study underscores the physiological significance of iron in neutrophil function, specifically in the release of NETs.