Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of a series of 3-(benzo(d)oxazol-2-yl)-5-(1- (piperidin-4-yl)-1H-pyrazol-4-yl) pyridin-2-amines, as a new class of G-protein-coupled receptor kinase 2 and 5 inhibitor

The arising critical implications of G-protein-coupled receptor kinase 2 and 5 (GRK2 and 5) in heart failure have been attracting attention and inhibitors of GRK2 and 5 were considered as a novel therapeutic strategy to prevent and treat heart failure disease. Despite this large therapeutic potential, to date few GRK2 inhibitors have been identified and GRK5 inhibitors in public have been unknown. In our efforts to discover a novel scaffold with potent GRK2 and GRK5 inhibitory activities, we found that a series of 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amines have been identified as a new class of GRK2 and 5 kinase inhibitor. Structural modification of parent benzoxazole scaffolds by introducing substituents on phenyl displayed potent inhibitory activities toward GRK2 and 5. This research highlight discusses the processing and findings of the recent study.
Stereo-microscopy of coccolithophores - modern applications for imaging and morphological analysis.

We present selected stereo-images of living coccospheres to give new insights into the spatial appear- ance of coccolithophores. One picture was made before and one after tilting the scanning electron microscope stage. The images were turned to red and green, respectively, and combined. The complete 3D image can be viewed with red-green glasses. The possibilities of using stereo-microscopy as the basis for 3D mathematical models of coccos- pheres and coccoliths are discussed.
The Reliability and Repeatability of a Lameness Scoring System for Use as an Indicator of Welfare in Dairy Cattle

In 16 dairy herds, a lameness scoring system which was reasonably quick and easy to use was evaluated with regard to reliability and repeatability. The ultimate aim was to include it into an on-farm welfare assessment protocol. Locomotion scores in individual cows (n = 206) were significantly correlated with the heel and sole disorder indices obtained at routine claw trimmings (e.g. index for hind limb lesions: r s = 0.40, p = 0.0001; Spearman Rank Correlation Coefficients). The inclusion of lesions caused by digital dermatitis increased correlation coefficients when hind limbs and all four feet were considered (r s = 0.47/0.50). The inter-observer repeatability of locomotion scores in individual cows was high, and the variation between observers was low when calculated as a percentage of animals within each scoring class. Thus the locomotion scoring system proved to be a useful tool for assessing lameness, and as such a valuable part of on-farm welfare assessment in dairy cattle. It is recommended that scoring be performed at least twice during the housing period.
Metabolic basis and treatment of citrin deficiency

Citrin deficiency is a hereditary disorder caused by SLC25A13 mutations and manifests as neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult‐onset type II citrullinemia (CTLN2). Citrin is a component of the malate‐aspartate nicotinamide adenine dinucleotide hydrogen (NADH) shuttle, an essential shuttle for hepatic glycolysis. Hepatic glycolysis and the coupled lipogenesis are impaired in citrin deficiency. Hepatic lipogenesis plays a significant role in fat supply during growth spurt periods: the fetal period, infancy, and puberty. Growth impairment in these periods is characteristic of citrin deficiency. Hepatocytes with citrin deficiency cannot use glucose and fatty acids as energy sources due to defects in the NADH shuttle and downregulation of peroxisome proliferator‐activated receptor α (PPARα), respectively. An energy deficit in hepatocytes is considered a fundamental pathogenesis of citrin deficiency. Medium‐chain triglyceride (MCT) supplementation with a lactose‐restricted formula and MCT supplementation under a low‐carbohydrate diet are recommended for NICCD and CTLN2, respectively. MCT supplementation therapy can provide energy to hepatocytes, promote lipogenesis, correct the cytosolic NAD+/NADH ratio via the malate‐citrate shuttle and improve ammonia detoxification, and it is a reasonable therapy for citrin deficiency. It is very important to administer MCT at a dose equivalent to the liver's energy requirements in divided doses with meals. MCT supplementation therapy is certainly promising for promoting growth spurts during infancy and adolescence and for preventing CTLN2 onset. Intravenous administration of solutions containing fructose is contraindicated, and persistent hyperglycemia should be avoided due to glucose intoxication for patients receiving hyperalimentation or with complicating diabetes.
Physical and Cognitive Performance During Upper-Extremity Versus Full-Body Exercise Under Dual Tasking Conditions

The purpose of this study was to investigate physical and cognitive performance during dual task conditions of upper-extremity (UE) or full-body (FB) rowing exercise. In a crossover counterbalanced design, college-aged male and female participants completed five conditions: (a) Sitting, (b) Single task UE rowing, (c) Single task FB rowing, (d) Dual task UE rowing, and (e) Dual task FB rowing. For single task UE and FB rowing conditions, participants were asked to row as hard as possible. After sitting and dual-task conditions, we administered the Paced Auditory Serial Addition Test (PASAT) and a word-list memory test. We analyzed participants’ absolute differences (single task – dual task) in power output and their cognitive test scores to compare UE and FB rowing. There were no significant absolute differences from sitting to dual task conditions of UE and FB rowing for either PASAT (p = 0.958) or word list memory (p = 0.899) cognitive scores. Absolute power output loss from single to dual task conditions was significantly higher in FB versus UE for PASAT (p = 0.039; d = 0.54) and word list memory (p = 0.021; d = 0.66) in the dual task condition. These results suggest that, while cognitive performance was preserved regardless of the amount of muscle mass activated during dual task rowing, physical performance suffered more during FB than UE rowing under the dual task condition. These findings have important implications for optimizing cognitive and physical performance in dual task situations.
Warm temperatures increase population growth of a non-native defoliator and inhibit demographic responses by parasitoids.

Changes in thermal regimes that disparately affect hosts and parasitoids could release hosts from biological control. When multiple natural enemy species share a host, shifts in host-parasitoid dynamics could depend on whether natural enemies interact antagonistically versus synergistically. We investigated how biotic and abiotic factors influence the population ecology of larch casebearer (Coleophora laricella), a non-native pest, and two imported parasitoids, Agathis pumila and Chrysocharis laricinellae, by analyzing (i) temporal dynamics in defoliation from 1962-2018 and (ii) historical, branch-level data on densities of larch casebearer and parasitism rates by the two imported natural enemies from 1972-1995. Analyses of defoliation indicated that, prior to the introduction of parasitoids (1962 to ~1980), larch casebearer outbreaks occurred in 2 to 6 year cycles. This pattern was followed by a >15-year period during which populations were at low, apparently stable densities undetectable via aerial surveys, presumably under control from parasitoids. However, since the late 1990s and despite the persistence of both parasitoids, outbreaks exhibiting unstable dynamics have occurred. Analyses of branch-level data indicated that growth of casebearer populations, A. pumila populations, and within-casebearer densities of Ch. laricinellae - a generalist whose population dynamics are likely also influenced by use of alternative hosts - were inhibited by density-dependence, with high intraspecific densities in one year slowing growth into the next. Casebearer population growth was also inhibited by parasitism from A. pumila, but not Ch. laricinellae, and increased with warmer autumnal temperatures. Growth of A. pumila populations and within-casebearer densities of Ch. laricinellae increased with casebearer densities but decreased with warmer annual maximum temperatures. Moreover, parasitism by A. pumila was associated with increased growth of within-casebearer densities of Ch. laricinellae without adverse effects on its own demographics, indicating a synergistic interaction between these parasitoids. Our results indicate that warming can be associated with opposing effects between trophic levels, with deleterious effects of warming on one natural enemy species potentially being exacerbated by similar impacts on another. Coupling of such parasitoid responses with positive responses of hosts to warming might have contributed to the return of casebearer outbreaks to North America.
The clinical correlates of participation levels in people with multiple sclerosis.

BACKGROUND Multiple sclerosis (MS) has a huge impact on patients and affects their ability to participate in meaningful activities. OBJECTIVE To identify motor and non-motor factors that are associated with the participation level in instrumental activities of daily living (IADL), leisure, social and religious activities in people with MS. METHOD This is a cross-sectional study conducted on 110 individuals with MS. The used outcome measures are: Arabic version of the Activity Card Sort, Berg Balance Scale, Modified Fatigue Impact Scale, Nine Hole Peg Test, 6-Minute Walk Test, Brief International Cognitive Assessment for Multiple Sclerosis, Stroop test and Hospital Anxiety and Depression Scale. RESULTS Hand function, balance, gender and cognitive status can predict the participation in IADL (R2 = 0.425, P < 0.0001); depression, age, and cognitive status can predict the participation in leisure activities (R2 = 0.372, P < 0.0001), and fatigue and cognitive status can predict social activities participation (R2 = 0.492, P < 0.000). CONCLUSION Balance, cognition and fatigue affect the level of participation in instrumental activities of daily living, leisure, and religious and social activities.
Biotoxinas marinas: intoxicaciones por el consumo de moluscos bivalvos/Seafood toxins: poisoning by bivalve consumption

Seafood toxins are becoming increasingly important as etiologic agents of foodborne diseases around the world. This is partly because of greater awareness of the potential problems of the paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), diarrheic shellfish poisoning (DSP) and more recently, a new type of seafood toxicity, called amnesic shellfish poisoning (ASP). This review describes the molluskan shellfish and biotoxins implicated, the development of standardized methods for detecting and quantifying these toxins, the importance of the economic loss resulting from their presence and the establishment of regular chemical monitoring for marine toxins.
Religiosity, Spirituality, and Death Anxiety Among Filipino Older Adults: A Correlational Study

The concept of death anxiety is expected of older persons as they age and are nearing their end-of-life. This study examined the relationship between religiosity, spirituality, and death anxiety among Filipino older adults. A convenience sample of 125 Filipino older adults were recruited in the study. Data were collected using the Spirituality Scale, Revised Death Anxiety Scale, and Dimensions of Religiosity Scale. Results of the study revealed that spirituality (r=-0.168, p = 0.061) and religiosity (r=-0.044, p = 0.623) had an inverse relationship with death anxiety. However, even with the inverse relationship, spirituality and religiosity were not significantly correlated with death anxiety, although participants were well aware of the importance of these concepts on their lives. It is suggested that assessing spirituality and religiosity of this age group can inform nurses to engage in quality nursing practice, by affirming the vulnerability, and preserving the personhood of older persons as they near their end-of-life.
Large-scale distribution analysis of Antarctic echinoids using ecological niche modelling

Understanding the factors that determine the distribution of taxa at various spatial scales is a crucial challenge in the context of global climate change. This holds particularly true for polar marine biota that are composed of both highly adapted and vulnerable faunas. We analysed the distribution of 2 Antarctic echinoid species, Sterechinus antarcticus and S. neumayeri, at the scale of the entire Southern Ocean using 2 niche modelling procedures. The performance of distribution models was tested with regard to the known ecology of the species. The respective contributions of environmental parameters are discussed along with the putative roles played by biotic interactions and biogeographic processes. Depth was the parameter that contributed most to both distribution models, whereas sea ice coverage and sea surface temperature had significant contributions for S. neumayeri only. Suitability maps of the 2 species were mostly similar, with a few notable differences. The Campbell Plateau and Tasmania were predicted as suitable areas for S. antarcticus only, while S. neumayeri was restricted to the south of the Ant arctic Polar Front. However, numerous sampling data attest that S. antarcticus is absent from the Campbell Plateau and from Tasmania. Different hypotheses are formulated to explain the mismatch between observed and modelled distribution data. They stress the putative roles played by both oceano- graphic barriers to dispersal (Antarctic Polar Front), biotic factors (species exclusion patterns) and biogeographic processes (ongoing dispersal).
ADVANCED OPTICAL TECHNIQUES TO EXPLORE BRAIN STRUCTURE AND FUNCTION

Understanding brain structure and function, and the complex relationships between them, is one of the grand challenges of contemporary sciences. Thanks to their flexibility, optical techniques could be the key to explore this complex network. In this manuscript, we briefly review recent advancements in optical methods applied to three main issues: anatomy, plasticity and functionality. We describe novel implementations of light-sheet microscopy to resolve neuronal anatomy in whole fixed brains with cellular resolution. Moving to living samples, we show how real-time dynamics of brain rewiring can be visualized through two-photon microscopy with the spatial resolution of single synaptic contacts. The plasticity of the injured brain can also be dissected through cutting-edge optical methods that specifically ablate single neuronal processes. Finally, we report how nonlinear microscopy in combination with novel voltage sensitive dyes allow optical registrations of action potential across a population of neurons opening promising prospective in understanding brain functionality. The knowledge acquired from these complementary optical methods may provide a deeper comprehension of the brain and of its unique features.
The novel β‐secretase inhibitor KMI‐429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild‐type mice

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major component of the plaques, amyloid β peptide (Aβ), is generated from amyloid precursor protein (APP) by β‐ and γ‐secretase‐mediated cleavage. Because β‐secretase/beta‐site APP cleaving enzyme 1 (BACE1) knockout mice produce much less Aβ and grow normally, a β‐secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side‐effects. Here, we report the in vivo inhibitory effects of a novel β‐secretase inhibitor, KMI‐429, a transition‐state mimic, which effectively inhibits β‐secretase activity in cultured cells in a dose‐dependent manner. We injected KMI‐429 into the hippocampus of APP transgenic mice. KMI‐429 significantly reduced Aβ production in vivo in the soluble fraction compared with vehicle, but the level of Aβ in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI‐429 in wild‐type mice remarkably reduced Aβ production in both the soluble and insoluble fractions. Our results indicate that the β‐secretase inhibitor KMI‐429 is a promising candidate for the treatment of AD.
Re-evaluation of total sulphur amino acid requirement and determination of replacement value of cystine for methionine in semi-purified diets of juvenile Nile tilapia, Oreochromis niloticus.

Two feeding experiments were conducted to re-evaluate the total sulphur amino acid (TSAA; methionine and cystine) requirement and determine the replacement value of cystine for methionine of juvenile Nile tilapia (Oreochromis niloticus). Semi-purified diets used in both experiments contained 3510 kcal gross energy and 280 g of protein per kilogram diet from casein, gelatin and crystalline amino acids. The basal diet of the first experiment contained 3.1 g methionine and 0.4 g cystine per kilogram. l-methionine was added to the seven remaining diets at 1.0 g kg⁻¹ increment to produce methionine levels ranging from 3.1 to 10.1 g kg⁻¹ diet. Each diet was fed to four replicate groups of juvenile Nile tilapia (1.28 g mean weight) in a recirculation system for 8 weeks. Broken-line regression analysis of weight gain data indicated that the TSAA requirement of juvenile Nile tilapia was 8.5 g kg⁻¹ of the diet or 30.4 g kg⁻¹ of dietary protein. In the second experiment, TSAA level was set at 95% of the requirement value determined in the first experiment. Seven diets were made with different ratios of l-methionine and l-cystine (20 : 80, 30 : 70, 40 : 60, 50 : 50, 60 : 40, 70 : 30 and 80 : 20, based on an equimolar sulphur basis). Each diet was also fed to four replicate groups of juvenile Nile tilapia (4.14 g mean weight) in a recirculation system for 8 weeks. Regression analysis of weight gain data using broken-line model indicated that cystine (on a molar sulphur basis) could replace up to 49% of methionine requirement in semi-purified diets for juvenile Nile tilapia.
Chloroplast DNA Diversity in Prunus and Its Implication on Genetic Relationships

ADDITIONAL INDEX WORDS. cpDNA haplotypes, PCR-RFLP, restriction enzymes, universal primers ABSTRACT. Chloroplast DNA (cpDNA) in 84 Prunus L. accessions (interspecific hybrids and Prunus species) were analyzed to confirm the maternal origin of the interspecific hybrids of Prunus and to establish genetic relationships among Prunus species. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, which included amplification of cpDNA regions with three universal primer pairs (K1K2, HK, DT) and subsequent digestion with three restriction enzymes (AluI, HinfI, TaqI), revealed 33 haplotypes for the 84 accessions studied. Fourteen from these cpDNA haplotypes were shared by two or more accessions, and 19 were unique. Accessions sharing the same haplotype have maternal relationships among them, which allowed identity confirmation of maternal progenitors of Prunus interspecific hybrids in these cases. Unweighted pair group method average (UPGMA) and minimum-length spanning tree (MST) analyses were performed based on shared common fragments and the number of mutational differences among the 33 haplotypes, respectively. The cpDNA polymorphisms detected made possible the analysis of genetic relationships among the studied Prunus accessions. Most of the recovered relationships are in agreement with current taxonomic hypotheses and artificial crosses.
Infância e política

As atitudes da nossa cultura em relacao as criancas sao ambiguas, o que se observa tambem na relacao entre criancas e politica. O modo protetor a que vem sendo submetidas as criancas nos ultimos dois seculos acaba por afasta-las dos adultos - e dos assuntos serios da economia e da politica. Como resolver esse dilema, que tem como consequencia dificultar um discurso sobre criancas e politica? Este artigo faz algumas reflexoes sobre o tema e sugere que, em principio, quando se trata de politica, pode-se falar de: criancas como sujeitos; criancas/infância como objeto nao visado (em termos do impacto de forcas estruturais); criancas/infância como objetos visados (iniciativas politicas voltadas as criancas) e, finalmente, como objetos instrumentalizados. A grande questao que se coloca em cada caso e saber em que medida as criancas sao beneficiadas e se isso nao ocorre como um efeito colateral dos ganhos para os adultos/sociedade adulta. Sera que haveria investimentos publicos em criancas nas dimensoes que alcancam hoje se nao houvesse expectativas de um retorno lucrativo?
Larger clutch size increases fledging success and offspring quality in a precocial species

1. We tested the hypothesis that the ability of parents to raise viable offspring limits clutch size in the greater snow goose (Anser caerulescens atlanticus L.), a precocial bird. 2. We manipulated clutch size by exchanging complete clutches between pairs of nests to increase or decrease the clutch size by zero (control), one, two or three eggs in 314 nests over 2 years. 3. Pre-fledging survival of goslings increased in enlarged broods and decreased in reduced broods compared to control. Consequently, enlarged broods fledged more offspring and the reverse was true for reduced broods. 4. Size and mass of goslings near fledging was also higher in enlarged broods than in control, which suggests that offspring quality was also enhanced by the manipulation. This is contrary to the common trade-off between offspring numbers and quality. 5. Large families were dominant over smaller ones in feeding sites, which could explain the increased survival and growth of enlarged broods. 6. Our results suggest that the ability to raise young does not limit clutch size in this species and that parents could be more successful (i.e. increase both the number and quality of their offspring) by laying more eggs. However, the time required to lay additional eggs reduces the viability of all offspring and may explain why females do not lay more eggs.
Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases

ABSTRACT Introduction Antisense oligonucleotides (ASOs) represent a class of drugs which can be rationally designed to complement the coding or non-coding regions of target RNA transcripts. They could modulate pre-messenger RNA splicing, induce mRNA knockdown, or block translation of disease-causing genes, thereby slowing disease progression. The pharmacokinetics of intravitreal delivery may enable ASOs to be effective in the treatment of inherited retinal diseases. Areas covered We review the current status of clinical trials of ASO therapies for inherited retinal diseases, which have demonstrated safety, viable durability, and early efficacy. Future applications are discussed in the context of alternative genetic approaches, including gene augmentation and gene editing. Expert opinion Early efficacy data suggest that the splicing-modulating ASO, sepofarsen, is a promising treatment for Leber congenital amaurosis associated with the common c.2991+1655A>G mutation in CEP290. However, potential variability in clinical response to ASO-mediated correction of splicing defect on one allele in patients who are compound heterozygotes needs to be assessed. ASOs hold great therapeutic potential for numerous other inherited retinal diseases with common deep-intronic and dominant gain-of-function mutations. These would complement viral vector-mediated gene augmentation which is generally limited by the size of the transgene and to the treatment of recessive diseases.