Miracle-dz/UniFAR-FTUs huggingface dataset:
Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and exciting tools to enhance and forward AD research. In particular, these methods are helping advance AD research by contributing multifactorial and multidimensional perspectives, especially considering the crucial role played by lifestyle risk factors in the determination of AD risk. In addition to research techniques, we also consider related pitfalls and flaws in the current research funding system. Conversely, we identify encouraging new trends in research and government policy. In light of these new research directions, we provide recommendations regarding prioritization of research funding. The goal of this document is to stimulate scientific and public discussion on the need to explore new avenues in AD research, considering outcome and ethics as core principles to reliably judge traditional research efforts and eventually undertake new research strategies.
Permeation through the Cell Membrane of a Boron-Based β-Lactamase Inhibitor

Bacteria express beta-lactamases to counteract the beneficial action of antibiotics. Benzo[b]-thiophene-2-boronic acid (BZB) derivatives are β-lactamase inhibitors and, as such, promising compounds to be associated with β-lactam antibacterial therapies. The uncharged form of BZB, in particular, is suggested to diffuse through the outer membrane of Gram negative bacteria. In this study, through the combination of electrophysiological experiments across reconstituted PC/n-decane bilayers and metadynamics-based free energy calculations, we investigate the permeation mechanism of boronic compounds. Our experimental data establish that BZB passes through the membrane, while computer simulations provide hints for the existence of an aqueous, water-filled monomolecular channel. These findings provide new perspectives for the design of boronic acid derivatives with high membrane permeability.
Hypoxia Increases Mouse Satellite Cell Clone Proliferation Maintaining both In Vitro and In Vivo Heterogeneity and Myogenic Potential

Satellite cells (SCs) are essential for postnatal muscle growth and regeneration, however, their expansion potential in vitro is limited. Recently, hypoxia has been used to enhance proliferative abilities in vitro of various primary cultures. Here, by isolating SCs from single mouse hindlimb skeletal myofibers, we were able to distinguish two subpopulations of clonally cultured SCs (Low Proliferative Clones - LPC - and High Proliferative Clones - HPC), which, as shown in rat skeletal muscle, were present at a fixed proportion. In addition, culturing LPC and HPC at a low level of oxygen we observed a two fold increased proliferation both for LPC and HPC. LPC showed higher myogenic regulatory factor (MRF) expression than HPC, particularly under the hypoxic condition. Notably, a different myogenic potential between LPC and HPC was retained in vivo: green fluorescent protein (GFP)+LPC transplantation in cardiotoxin-injured Tibialis Anterior led to a higher number of new GFP+muscle fibers per transplanted cell than GFP+HPC. Interestingly, the in vivo myogenic potential of a single cell from an LPC is similar if cultured both in normoxia and hypoxia. Therefore, starting from a single satellite cell, hypoxia allows a larger expansion of LPC than normal O2 conditions, obtaining a consistent amount of cells for transplantation, but maintaining their myogenic regeneration potential.
Decreased expression of long non-coding RNA MEG3 acts as a potential predictor biomarker in progression and poor prognosis of osteosarcoma.

INTRODUCTION Long non-coding RNA MEG3 (lncRNA MEG3) has been showed to involve in a variety of cancers. However, the association between lncRNA MEG3 expression level and the prognosis of osteosarcoma is still unclear. METHODS The expression levels of lncRNA MEG3 in osteosarcoma tissues and adjacent non-tumor tissues were detected using quantitative real-time PCR (qRT-PCR). Differences in patient survival were determined using the Kaplan-Meier method and a log-rank test. A Cox proportional hazards regression analysis was used for univariate and multivariate analyses of prognostic values. RESULTS Our findings showed that expression of lncRNA MEG3 was clearly lower in osteosarcoma tissues compared with adjacent non-tumor tissues. The expression of lncRNA MEG3 was associated with clinical stage and distant metastasis (P<0.05). Kaplan-Meier analysis showed that patients with low lncRNA MEG3 expression had a shorter overall survival (log-rank test, P<0.05). Furthermore, multivariate analysis revealed that decreased expression of lncRNA MEG3, advanced clinical stage and distant metastasis were all independent predictors to overall survival of osteosarcoma patients. CONCLUSIONS Downregulation of lncRNA MEG3 was associated with poor overall survival of osteosarcoma. LncRNA MEG3 could be a useful biomarker for progression and prognosis of osteosarcoma.
Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout

BACKGROUND Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with those associated with allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and cardiovascular disease. METHODS We conducted a multicenter, double‐blind, noninferiority trial involving patients with gout and cardiovascular disease; patients were randomly assigned to receive febuxostat or allopurinol and were stratified according to kidney function. The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization). RESULTS In total, 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow‐up. In the modified intention‐to‐treat analysis, a primary end‐point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one‐sided 98.5% confidence interval [CI], 1.23; P = 0.002 for noninferiority). All‐cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all‐cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention‐to‐treat analysis. CONCLUSIONS In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. Allcause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035.)
Functionalized PVA–silk blended nanofibrous mats promote diabetic wound healing via regulation of extracellular matrix and tissue remodelling

Chronic cutaneous ulcers, a complex pathophysiological diabetic condition, represent a critical clinical challenge in the current diabetes mellitus pandemic. Consequently, there is a compelling need for bioactive dressings that can trigger healing processes for complete wound repair. Silk fibroin (SF), a natural protein polymer from mulberry and non‐mulberry silkworms, has properties that support accelerated wound healing rate. SF from non‐mulberry variety possesses additional cell‐binding motifs (arginine, glycine, and aspartate), offering cell–material interactions. This study is aimed to investigate wound healing efficacy of dressings made up of various SF varieties blended with poly(vinyl alcohol) biopolymer in alloxan‐induced diabetic rabbit model. The nanofibrous mats have been developed using electrospinning and functionalized with growth factors and LL‐37 antimicrobial peptide for sustained delivery. Following post 14‐day treatment, non‐mulberry SF (NMSF)‐based dressings healed the wounds faster, in comparison with their mulberry Bombyx mori SF, poly(vinyl alcohol), and control counterparts (p < .01). NMSF‐based dressings also supported faster granulation tissue development, angiogenesis, and reepithelialization of wounds. Gene expression study of matrix metalloproteinases and collagen proteins affirmed higher extent of tissue remodelling during the repair process. Furthermore, there was organized extracellular matrix deposition (collagen type I, collagen type III, elastin, and reticulin) and higher wound breaking strength in NMSF compared with other groups after 4 weeks. These results validated the potential of NMSF‐based bioactive dressings to regulate extracellular matrix deposition leading to faster and complete repair of chronic diabetic cutaneous wounds.
Dexmedetomidine versus ketamine combined with midazolam; a comparison of anxiolytic and sedative premedication in children

Background : Preanaesthetic medication plays an important role in the anaesthetic care of children by allaying anxiety, decreasing vagal stimulation and preventing postoperative psychological sequelae. This study was undertaken to evaluate the efficacy of dexmedetomidine when administered orally as a hypnotic and anxiolytic compared to oral combination ketamine/midazolam as preanaesthetic medication in paediatric patients. Methods: Sixty/six children aged 2/6 years posted for elective surgical procedures were randomly allocated to one of two groups ‘Group D’ and ‘Group MK’. Group D received oral dexmedetomidine 3 6g/kg and group MK received 0.25 mg/kg oral midazolam (up to a maximum of 15 mg) mixed with 2.5 mg/kg oral ketamine. Drug acceptance was noted. Heart rate, arterial pressure, respiratory rate, sedation score and anxiolysis score were noted before drug administration and every 5 min for up to 30 min after drug administration. Parental separation score at 30 min and mask acceptance score in addition to parental satisfaction were also noted. Results: premedication with oral MK appeared to be superior to oral dexmedetomidine, in addition to evident haemodynamic stability and higher degree of parental satisfaction (90%), but 97% of children better accepted oral dexmedetomidine. No significant side effects were attributable to either premedication. Emergence from anaesthesia was comparable between groups. Conclusion: premedication with oral midazolam ketamine appeared to be superior to oral dexmedetomidine, with evident haemodynamic stability and a higher degree of parental satisfaction, although oral dexmedetomidine was more accepted by the children.
Effects of Ultraviolet-B Irradiance on Intraspecific Competition and Facilitation of Plants: Self-Thinning, Size Inequality, and Phenotypic Plasticity

(1) The effects of facilitation on the structure and dynamics of plant populations have not been studied so widely as competition. The UV-B radiation, as a typical environmental factor causing stress, may result in direct stress and facilitation. (2) The effects of UV-B radiation on intraspecific competition and facilitation were investigated based on the following three predictions on self-thinning, size inequality, and phenotypic plasticity: i) Self-thinning is the reduction in density that results from the increase in the mean biomass of individuals in crowded populations, and is driven by competition. In this study, the mortality rate of the population is predicted to decrease from UV-B irradiance. ii) The size inequality of a population increases with competition intensity because larger individuals receive a disproportionate share of resources, thereby leaving limited resources for smaller individuals. The second hypothesis assumes that direct stress decreases the size inequality of the population. iii) Phenotypic plasticity is the ability to alter one’s morphology in response to environmental changes. The third hypothesis assumes that certain morphological indices can change among the trade-offs between competition, facilitation, and stress. These predictions were tested by conducting a field pot experiment using mung beans, and were supported by the following results: (3) UV-B radiation increased the survival rate of the population at the end of self-thinning. However, this result was mainly due to direct stress rather than facilitation. (4) Just as competitor, facilitation was also asymmetric. It increased the size inequality of populations during self-thinning, whereas stress decreased the size inequality. (5) Direct stress and facilitation influence plants differently on various scales. Stress inhibited plant growth, whereas facilitation showed the opposite on an individual scale. Stress increased survival rate, whereas facilitation increased individual variability on the population scale. (6) Trade-offs between competitions, facilitation, and direct stress varied in different growing stages.
MicroRNA‐664a‐5p promotes neuronal differentiation of SH‐SY5Y cells

MicroRNAs (miRNAs) belong to a class of small noncoding RNAs that play important roles in the translational regulation of gene expression. A number of miRNAs are known to act as key regulators of diverse processes such as neuronal differentiation. In this study, we have attempted to identify novel miRNAs related to neuronal differentiation via microarray analysis in the human neuronal differentiation model neuroblastoma SH‐SY5Y cells. We identified 15 up‐regulated and eight down‐regulated miRNAs in SH‐SY5Y cells treated with all‐trans retinoic acid to induce differentiation. We further showed that one of the up‐regulated miRNAs, miR‐664a‐5p, promoted neuronal differentiation of SH‐SY5Y cells. These findings enhance our understanding of the miRNAs involved in the process of neurogenesis and, in particular, highlight an important role of miR‐664a‐5p in SH‐SY5Y cell neuronal differentiation. Further studies will be required to confirm the function of miR‐664‐5p in neuronal development and disease and to identify its relevant target genes.
Conformational Temperature-Dependent Behavior of a Histone H2AX: A Coarse-Grained Monte Carlo Approach Via Knowledge-Based Interaction Potentials

Histone proteins are not only important due to their vital role in cellular processes such as DNA compaction, replication and repair but also show intriguing structural properties that might be exploited for bioengineering purposes such as the development of nano-materials. Based on their biological and technological implications, it is interesting to investigate the structural properties of proteins as a function of temperature. In this work, we study the spatial response dynamics of the histone H2AX, consisting of 143 residues, by a coarse-grained bond fluctuating model for a broad range of normalized temperatures. A knowledge-based interaction matrix is used as input for the residue-residue Lennard-Jones potential. We find a variety of equilibrium structures including global globular configurations at low normalized temperature (), combination of segmental globules and elongated chains (), predominantly elongated chains (), as well as universal SAW conformations at high normalized temperature (). The radius of gyration of the protein exhibits a non-monotonic temperature dependence with a maximum at a characteristic temperature () where a crossover occurs from a positive (stretching at ) to negative (contraction at ) thermal response on increasing .
Long-Term Climate Forcing in Loggerhead Sea Turtle Nesting

The long-term variability of marine turtle populations remains poorly understood, limiting science and management. Here we use basin-scale climate indices and regional surface temperatures to estimate loggerhead sea turtle (Caretta caretta) nesting at a variety of spatial and temporal scales. Borrowing from fisheries research, our models investigate how oceanographic processes influence juvenile recruitment and regulate population dynamics. This novel approach finds local populations in the North Pacific and Northwest Atlantic are regionally synchronized and strongly correlated to ocean conditions—such that climate models alone explain up to 88% of the observed changes over the past several decades. In addition to its performance, climate-based modeling also provides mechanistic forecasts of historical and future population changes. Hindcasts in both regions indicate climatic conditions may have been a factor in recent declines, but future forecasts are mixed. Available climatic data suggests the Pacific population will be significantly reduced by 2040, but indicates the Atlantic population may increase substantially. These results do not exonerate anthropogenic impacts, but highlight the significance of bottom-up oceanographic processes to marine organisms. Future studies should consider environmental baselines in assessments of marine turtle population variability and persistence.
Positive emotion in distress as a potentially effective emotion regulation strategy for depression: A preliminary investigation.

OBJECTIVES Emotion regulation utilizing positive emotion during negative emotional states might be one of the effective ways to alleviate depression and anxiety problems among people with emotional disorders. This study examined the psychometric properties and incremental validity of the Positive Emotion In Distress Scale (PEIDS), a newly developed self-report scale, in a sample of university students in Japan. DESIGN AND METHODS To examine the psychometric properties of the PEIDS, the scale was completed by Japanese university students (396 men and 363 women; mean age of 19.92). Participants additionally answered the Emotion Regulation Questionnaire, Rumination and Reflection Questionnaire - Shorter Version, Affective Style Questionnaire, Positive and Negative Affective Schedule, and Hospital Anxiety and Depression Scale. The survey was conducted at two time points separated by 1 month to assess test-retest reliability and validity of the PEIDS. RESULTS Exploratory and confirmatory factor analyses confirmed a one-factor structure. Reliability was confirmed by high internal consistency and test-retest stability; the convergent and discriminant validity was confirmed by correlations with related and unrelated variables. The results of hierarchical regression analyses demonstrated that positive emotion in distress might predict depression above and beyond the effect of baseline depression and other common emotion regulation strategies. CONCLUSIONS The PEIDS showed acceptable reliability and validity within young adults and a non-clinical population in Japan. Further research will be needed to examine the effect of positive emotion among clinical populations. PRACTITIONER POINTS Previous research suggests that positive emotions play a key role in recovery from depression and anxiety problems through some forms of psychotherapy. The Positive Emotion In Distress Scale (PEIDS) measures individual differences regarding the extent to which people can experience positive emotions in negative emotional states. Results suggested that the subjective rating of the ability to experience positive emotions in distress might alleviate depression prospectively but not anxiety problems. The effect of positive emotion in distress demonstrated to have beyond the effects of other emotion regulation strategies.
Human T-Lymphotropic Virus type 1c subtype proviral loads, chronic lung disease and survival in a prospective cohort of Indigenous Australians

Background The Human T-Lymphotropic Virus type 1c subtype (HTLV-1c) is highly endemic to central Australia where the most frequent complication of HTLV-1 infection in Indigenous Australians is bronchiectasis. We carried out a prospective study to quantify the prognosis of HTLV-1c infection and chronic lung disease and the risk of death according to the HTLV-1c proviral load (pVL). Methodology/Principal findings 840 Indigenous adults (discharge diagnosis of bronchiectasis, 154) were recruited to a hospital-based prospective cohort. Baseline HTLV-1c pVL were determined and the results of chest computed tomography and clinical details reviewed. The odds of an association between HTLV-1 infection and bronchiectasis or bronchitis/bronchiolitis were calculated, and the impact of HTLV-1c pVL on the risk of death was measured. Radiologically defined bronchiectasis and bronchitis/bronchiolitis were significantly more common among HTLV-1-infected subjects (adjusted odds ratio = 2.9; 95% CI, 2.0, 4.3). Median HTLV-1c pVL for subjects with airways inflammation was 16-fold higher than that of asymptomatic subjects. There were 151 deaths during 2,140 person-years of follow-up (maximum follow-up 8.13 years). Mortality rates were higher among subjects with HTLV-1c pVL ≥1000 copies per 105 peripheral blood leukocytes (log-rank χ2 (2df) = 6.63, p = 0.036) compared to those with lower HTLV-1c pVL or uninfected subjects. Excess mortality was largely due to bronchiectasis-related deaths (adjusted HR 4.31; 95% CI, 1.78, 10.42 versus uninfected). Conclusion/Significance Higher HTLV-1c pVL was strongly associated with radiologically defined airways inflammation and with death due to complications of bronchiectasis. An increased risk of death due to an HTLV-1 associated inflammatory disease has not been demonstrated previously. Our findings indicate that mortality associated with HTLV-1c infection may be higher than has been previously appreciated. Further prospective studies are needed to determine whether these results can be generalized to other HTLV-1 endemic areas.
Effect of crystallization on microstructure and mechanical properties of poly[(ethylene oxide)-block-(amide-12)]-toughened poly(lactic acid) blend

The effect of crystallization on the microstructure and mechanical properties of a poly[(ethylene oxide)-block-(amide-12)] (PEBA)-toughened poly(lactic acid) (PLA) blend was investigated. Annealing was used to govern the crystallization microstructure and hence the mechanical properties of the blend. Crystallization resulted in the morphology of the PLA component altering from a continuous amorphous phase to continuous crystalline phase. Moreover, as the crystallization of PLA proceeded, the degree of crystallinity, spherulite size and lamellar thickness increased, and the interlamellar and interspherulitic connections became weaker. These led to the large plastic deformation in the matrix during tension being suppressed, and cracks appeared easily under tensile load, which was favorable to fracture for the blend during tension and so a small elongation at break was obtained. However, the elongation at break for all the annealed specimens was higher than that for neat amorphous PLA, suggesting that PEBA still showed a toughening effect for PLA under annealing. (C) 2012 Society of Chemical Industry