Miracle-dz/UniFAR-FTUs huggingface dataset:
In Vivo Phosphorylation of Ser21 and Ser83 during Nutrient-induced Activation of the Yeast Protein Kinase A (PKA) Target Trehalase

Background: Activation of yeast trehalase has been a convenient read-out for nutrient signaling to PKA, but demonstration of phosphorylation in vivo is lacking. Results: Nutrient activation is associated with phosphorylation, but phosphorylation is not enough for activation. Conclusion: Nutrient activation of trehalase is a reliable read-out for nutrient activation of PKA in vivo. Significance: Nutrient-sensing mechanisms can be identified using trehalase activation as a read-out. The readdition of an essential nutrient to starved, fermenting cells of the yeast Saccharomyces cerevisiae triggers rapid activation of the protein kinase A (PKA) pathway. Trehalase is activated 5–10-fold within minutes and has been used as a convenient reporter for rapid activation of PKA in vivo. Although trehalase can be phosphorylated and activated by PKA in vitro, demonstration of phosphorylation during nutrient activation in vivo has been lacking. We now show, using phosphospecific antibodies, that glucose and nitrogen activation of trehalase in vivo is associated with phosphorylation of Ser21 and Ser83. Unexpectedly, mutants with reduced PKA activity show constitutive phosphorylation despite reduced trehalase activation. The same phenotype was observed upon deletion of the catalytic subunits of yeast protein phosphatase 2A, suggesting that lower PKA activity causes reduced trehalase dephosphorylation. Hence, phosphorylation of trehalase in vivo is not sufficient for activation. Deletion of the inhibitor Dcs1 causes constitutive trehalase activation and phosphorylation. It also enhances binding of trehalase to the 14-3-3 proteins Bmh1 and Bmh2, suggesting that Dcs1 inhibits by preventing 14-3-3 binding. Deletion of Bmh1 and Bmh2 eliminates both trehalase activation and phosphorylation. Our results reveal that trehalase activation in vivo is associated with phosphorylation of typical PKA sites and thus establish the enzyme as a reliable read-out for nutrient activation of PKA in vivo.
Genomic variants, genes, and pathways of Alzheimer's disease: An overview

Alzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia. With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets. Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early‐onset forms of AD to the genome‐wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late‐onset AD (LOAD), and which have identified approximately ∼20 genes with common variants contributing to LOAD risk. In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD‐related phenotypes and multi‐variant association studies such as pathway analyses. Finally, we introduce studies of next‐generation sequencing, which have recently helped identify multiple low‐frequency and rare variant contributors to AD, and discuss on‐going efforts with next‐generation sequencing studies to develop statistically well‐ powered and comprehensive genomic studies of AD. Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD. © 2016 Wiley Periodicals, Inc.
TRAUMATIC RETICULO-PERICARDITIS (TRP) IN SHEEP: A REPORT OF 4 CASES IN A HERD

Traumatic reticulo-pericarditis (TRP) was diagnosed in four sheep (one ram and three ewes) during postmortem examination. Gross pathology revealed the penetration of a large needle and three electrical wires through reticular wall into the pericardial sacs, regional artery and myocardium. The prominent findings in the ram were acute cardiac tamponade and hemothorax, whereas pyothorax, enlargement and thickening of the pericardium and peritonitis were the prominent findings in ewes. Disseminated abscesses in spleens, lungs, and livers were also found. During microscopic analysis, fibrosis and inflammation with neutrophilic and lymphocytic infiltrate were observed in the pericardium, epicardium and myocardium. Arcanobacterium pyogenes was isolated from fibrinopurulent exudates and disseminated abscesses of the affected organs.
Meeting the Personnel Needs of Anambra State Industrialists in Nigeria: A Call for Mathematics Education Reforms

The study examined that extent the mathematics education graduates meet the personnel needs of the industrialists in Anambra State. Ninety-four (94) out of 198 managers (employers) from the three private industrial zones in Anambra State, Nigeria were included in the investigation. A descriptive survey instrument was constructed by the researchers based on professional and ICT competencies which incorporated 25 items. Analysis of results showed that: a. Mathematics education graduates posses all the needed professional competencies as identified by Industrialists, b. 41.7% of the needed ICT competencies were acquired by the graduates while 58.3% were not, c. There is a significant difference in the mean ratings of the Industrialists on the expected versus acquired ICT competencies of mathematics education graduates. The findings of the study suggest that Nigeria’s mathematics education program should be revised to reflect the acquisition of ICT skills within the mathematics contents.
Sense of coherence--a determinant of quality of life over time in older female acute myocardial infarction survivors.

AIMS To determine the relationships between different sense of coherence levels and quality of life, and in older female myocardial infarction survivors; to investigate how socio-demographic, clinical characteristics, sense of coherence self-reported symptoms and function affect quality of life; and to determine whether sense of coherence and quality of life are stable during a six-month follow-up. BACKGROUND Myocardial infraction confers new physical and mental challenges. However, research on sense of coherence and other factors involved in maintaining physical, psychosocial and environmental aspects of quality of life in older female myocardial infraction survivors is scant. DESIGN Survey. METHODS A postal survey was conducted of 145 women, aged 62-80 years, three months to five years after myocardial infarction (T1), with a follow-up after six months (T2). Self-reported socio-demographic and clinical data and hospital medical records data were collected. The sense of coherence scale (SOC-29) and the World Health Organization Quality of Life Instrument Abbreviated (WHOQOL-BREF) were used. RESULTS We found a significant difference in quality of life between weak, moderate, and strong sense of coherence groups (p<0.001). Sense of coherence contributed to the level of all quality of life domains (p<0.001). Several clinical characteristics contributed to quality of life: (1) physical domain: comorbidities (p<0.001), previous myocardial infarction (p = 0.013), ejection fraction (p<0.011), length of hospital stay (p = 0.005) symptoms and function (p<0.001); (2) psychological domain: previous myocardial infarction (p = 0.031) and symptoms and function (p<0.001); and (3) environmental domain: education (p = 0.033) and symptoms and function (p = 0.003). On group level, both sense of coherence and quality of life were stable. Experiencing specific health changes (p<0.001), not major life events, influenced quality of life during the six-month follow-up. CONCLUSION Sense of coherence was an important stable determinant of quality of life domains in female myocardial infarction survivors. Although other factors were identified, further research is needed to elucidate additional determinants of quality of life. RELEVANCE TO CLINICAL PRACTICE These specific factors could guide clinicians in making treatment decisions that optimize the quality of life of their patients. Applying a salutogenic perspective through patient education may be important.
Endothelin-converting Enzymes Degrade Intracellular β-Amyloid Produced within the Endosomal/Lysosomal Pathway and Autophagosomes*

Background: Endothelin-converting enzymes (ECEs) degrade β-amyloid (Aβ) peptide. Results: ECE inhibition produces, in addition to extracellular Aβ accumulation, intracellular Aβ accumulation within endosomal/lysosomal and autophagic vesicles. Conclusion: An intracellular pool of Aβ is regulated by ECE activity at the sites of production. Significance: ECE dysfunction may cause intraneuronal Aβ accumulation, which is associated with neurotoxicity early in AD progression. Impairments in Aβ removal are increasingly being considered as a possible cause for the abnormal Aβ build-up typical of Alzheimer disease. Of particular interest is a pool of Aβ that accumulates intraneuronally and may contribute to neuronal toxicity. The mechanism for intraneuronal accumulation, however, is not well understood and is commonly attributed to impaired removal of extracellular Aβ by neurons. Based on the intracellular distribution of the well established Aβ degrading enzymes, ECE-1 and ECE-2, we tested whether impairments in their catalytic activity could lead to intracellular Aβ accumulation. Using SH-SY5Y cells overexpressing wild-type amyloid precursor protein and pharmacological inhibition of endogenous ECE activity, we found that ECEs participate in the degradation of at least two distinct pools of Aβ; one destined for secretion and the other being produced and degraded within the endosomal-autophagic-lysosomal pathways. Although ECE-1 regulates both pools of Aβ, ECE-2 regulates mainly the intracellular pool of the peptide. Consistent with this result, ECE-2 was found to co-localize with markers of the endosomal/lysosomal pathway but not with a trans-Golgi network marker. Furthermore, ECE-2 was detected in autophagic vesicles in cells treated with chloroquine. Under these conditions, ECE inhibition produced significantly higher elevations in intracellular Aβ than chloroquine treatment alone. This study highlights the existence of Aβ clearance mechanisms by ECEs at intracellular sites of production. Alterations in ECE activity may be considered as a cause for increased intraneuronal Aβ in Alzheimer disease.
Antagonistic Function of the RNA-binding Protein HuR and miR-200b in Post-transcriptional Regulation of Vascular Endothelial Growth Factor-A Expression and Angiogenesis*

Background: The role of RNA-binding protein HuR in angiogenesis is not known. Results: In macrophages, HuR and miR-200b antagonistically regulate VEGF-A and angiogenesis. Conclusion: Interplay of HuR and miRNAs in the macrophage regulates tumor angiogenesis in the mouse and embryonic vascular development in zebrafish. Significance: HuR modulation of miRNA function highlights the importance of post-transcriptional gene regulatory mechanisms in biology and disease. HuR, also known as Elavl1, is an RNA-binding protein that regulates embryonic development, progenitor cell survival, and cell stress responses. The role of HuR in angiogenesis is not known. Using a myeloid-specific HuR knock-out mouse model (Elavl1Mø KO), we show that HuR expression in bone marrow-derived macrophages (BMDMs) is needed to maintain the expression of genes enriched in AU-rich elements and U-rich elements in the 3′-UTR. In addition, BMDMs from Elavl1Mø KO mice also showed alterations in expression of several miRNAs. Interestingly, computational analysis suggested that miR-200b, which is up-regulated in Elavl1Mø KO BMDMs, interacts with myeloid mRNAs very close to the HuR binding sites, suggesting competitive regulation of gene expression. One such mRNA encodes vascular endothelial growth factor (VEGF)-A, a major regulator of angiogenesis. Immunoprecipitation of RNA-protein complexes and luciferase reporter assays indicate that HuR antagonizes the suppressive activity of miR-200b, down-regulates miR-200b expression, and promotes VEGF-A expression. Indeed, Vegf-a and other angiogenic regulatory transcripts were down-regulated in Elavl1Mø KO BMDMs. Interestingly, tumor growth, angiogenesis, vascular sprouting, branching, and permeability were significantly attenuated in Elavl1Mø KO mice, suggesting that HuR-regulated myeloid-derived factors modulate tumor angiogenesis in trans. Zebrafish embryos injected with an elavl1 morpholino oligomer or miR-200b mimic showed angiogenesis defects in the subintestinal vein plexus, and elavl1 mRNA rescued the repressive effect of miR-200b. In addition, miR-200b and HuR morpholino oligomer suppressed the activity of a zVEGF 3′-UTR luciferase reporter construct. Together, these studies reveal an evolutionarily conserved post-transcriptional mechanism involving competitive interactions between HuR and miR-200b that controls angiogenesis.
A study on-effect of hematoma and perihematomal edema volume on GCS at the time of admission in patients with spontaneous lobar and basal ganglia hemorrhage

Objective: To know effect of hematoma and perihematomal edema volume on Glasgow Coma Scale (GCS) at the time of admission in patients with spontaneous lobar and basal ganglia hemorrhage. Methods: this cross sectional study was conducted in Neurosurgery department, BSMMU to observe effect of hematoma and perihematomal edema volume on GCS at the time of admission in patients with spontaneous lobar and basal ganglia hemorrhage. The duration of study period was from November 2005 to April 2007. Results: a total 48 patients were included in the study and the variables that were analyzed included site of hematoma, volume of hematoma, perihematomal edema and the initial GCS score. Associations between the hematoma and perihematomal edema, site of hemorrhage and perihematomal edema, hematoma volume and GCS at the time of admission, perihematomal edema volume and GCS at the time of admission were evaluated. Level of consciousness (GCS) at the time of admission is the key factor in predicting outcome and neurological deterioration. In our study we found significant association between- hematoma and perihematomal edema volume, hematoma volume and GCS at the time of admission, perihematomal edema volume and GCS at the time of admission. But there was no significant association found between hemorrhage site and perihematomal edema. Conclusion: more the volume of hematoma more was the volume of perihematomal edema. More the volume of hematoma less was the GCS. More the volume of perihematomal edema less was the GCS. But we found no significant association between site of hemorrhage and perihematomal edema volume. GCS is an established predictor of outcome in patients with SICH (spontaneous intracerebral hemorrhage). Accurate prediction of the outcome in ICH patients is important for several reasons: a reliable prognosis must be given to patient and relatives as soon as possible, realistic rehabilitation goals should be set and resources should be allocated in the most efficient way. Pulse Vol.7 January-December 2014 p.22-28
The Biochemical Mechanism of Auxin Biosynthesis by an Arabidopsis YUCCA Flavin-containing Monooxygenase*

Background: Auxin is essential for plant growth, but its biosynthesis in plants has not been biochemically defined. Results: Key features of the catalytic mechanism for the YUCCA flavoprotein, the rate-limiting enzyme of auxin biosynthesis, are determined. Conclusion: YUCs generate an observable though relatively short lived C4a-(hydro)peroxyflavin intermediate for catalysis in auxin biosynthesis. Significance: This work establishes the previously unknown biochemical mechanism of auxin biosynthesis. Auxin regulates every aspect of plant growth and development. Previous genetic studies demonstrated that YUCCA (YUC) flavin-containing monooxygenases (FMOs) catalyze a rate-limiting step in auxin biosynthesis and that YUCs are essential for many developmental processes. We proposed that YUCs convert indole-3-pyruvate (IPA) to indole-3-acetate (IAA). However, the exact biochemical mechanism of YUCs has remained elusive. Here we present the biochemical characterization of recombinant Arabidopsis YUC6. Expressed in and purified from Escherichia coli, YUC6 contains FAD as a cofactor, which has peaks at 448 nm and 376 nm in the UV-visible spectrum. We show that YUC6 uses NADPH and oxygen to convert IPA to IAA. The first step of the YUC6-catalyzed reaction is the reduction of the FAD cofactor to FADH− by NADPH. Subsequently, FADH− reacts with oxygen to form a flavin-C4a-(hydro)peroxy intermediate, which we show has a maximum absorbance at 381 nm in its UV-visible spectrum. The final chemical step is the reaction of the C4a-intermediate with IPA to produce IAA. Although the sequences of the YUC enzymes are related to those of the mammalian FMOs, which oxygenate nucleophilic substrates, YUC6 oxygenates an electrophilic substrate (IPA). Nevertheless, both classes of enzymes form quasi-stable C4a-(hydro)peroxyl FAD intermediates. The YUC6 intermediate has a half-life of ∼20 s whereas that of some FMOs is >30 min. This work reveals the catalytic mechanism of the first known plant flavin monooxygenase and provides a foundation for further investigating how YUC activities are regulated in plants.
Polygenic risk scores distinguish patients from non‐affected adult relatives and from normal controls in schizophrenia and bipolar disorder multi‐affected kindreds

Recent studies have used results on SNP association with schizophrenia (SZ) and bipolar disorder (BD) to create polygenic risk scores (PRS) discriminating non‐familial unrelated patients from controls. Little is known about the role of PRS in densely affected multigenerational families. We tested PRS differences between affected SZ and BD family members from their non‐affected adult relatives (NAARs) in Eastern Quebec Kindreds and from controls. We examined 1227 subjects: from 17 SZ and BD kindreds, we studied 153 patients (57 SZ, 13 schizoaffective, and 83 BD) and 180 NAARs, and 894 unrelated controls from the Eastern Quebec population. PRS were derived from published case‐control association studies of SZ and BD. We also constructed a combined SZ and BD PRS by using SNPs from both SZ and BD PRS. SZ patients had higher SZ PRS than controls (p = 0.0039, R2 = 0.027) and BD patients had higher BD PRS than controls (p = 0.013, R2 = 0.027). Differences between affected subjects and NAARs and controls were significant with both SZ and BD PRS. Moreover, a combined SZ‐BD PRS was also significantly associated with SZ and BD when compared to NAARs (p = 0.0019, R2 = 0.010) and controls (p = 0.0025, R2 = 0.028), revealing a SZ‐BD commonality effect in PRS at the diagnosis level. The SZ and the BD PRS, however, showed a degree of specificity regarding thought disorder symptoms. Overall, our report would confirm the usefulness of PRS in capturing the contribution of common genetic variants to the risk of SZ and BD in densely affected families.
Teenage and young adult cancer in England : the patient journey and experience

Background: The Improving Outcomes Guidelines recommended treatment of teenage and young adult patients with cancer at designated principle treatment centres. Alongside age appropriate care, site specialist centres exist for several of the diagnostic groups commonly seen in these patients. Objectives: This project aimed to produce a definition of specialist care for teenage and young adult (TYA) patients, describe the variation in care pathways nationally in England and to determine what effect the level of specialist care received has on patient outcomes. Materials and methods: Patients aged between 15 and 24, diagnosed with cancer in England between 2001 and 2006 were identified and cancer registration and hospital episode statistics data were extracted for these cases. Patients were assigned a level of specialist care based on the proportion of their inpatient stay during treatment which was spent at a specialist centre. The variation in access to the specialist centres was assessed for each diagnostic group, as were the demographics of the patients receiving each level of specialist care. Outcomes were measured within the distinct diagnostic groups. Kaplan-Meier curves and Cox regression modelling were used to assess the impact of specialist care on survival. Results: Variation in access to specialist care centres was seen in all diagnostic groups. The proportion of patients in each group who received specialist care also varied, with some diagnostic groups receiving very little care at specialist centres. The level and type of specialist care received was shown to affect survival in all groups. More specialist care was associated with a survival benefit in the case of leukaemia, central nervous system tumours and lymphoma, significantly so in the case of lymphoma. Conclusions: The uptake of specialist care for teenage and young adult patients was variable across England and not all patients were seen to be receiving the care pattern associated with optimum outcomes.
RASopathies are associated with a distinct personality profile

Personality is a complex, yet partially heritable, trait. Although some Mendelian diseases like Williams‐Beuren syndrome are associated with a particular personality profile, studies have failed to assign the personality features to a single gene or pathway. As a family of monogenic disorders caused by mutations in the Ras/MAPK pathway known to influence social behavior, RASopathies are likely to provide insight into the genetic basis of personality. Eighty subjects diagnosed with cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, and Noonan syndrome were assessed using a parent‐report BFQ‐C (Big Five Questionnaire for Children) evaluating agreeableness, extraversion, conscientiousness, intellect/openness, and neuroticism, along with 55 unaffected sibling controls. A short questionnaire was added to assess sense of humor. RASopathy subjects and sibling controls were compared for individual components of personality, multidimensional personality profiles, and individual questions using Student tests, analysis of variance, and principal component analysis. RASopathy subjects were given lower scores on average compared to sibling controls in agreeableness, extraversion, conscientiousness, openness, and sense of humor, and similar scores in neuroticism. When comparing the multidimensional personality profile between groups, RASopathies showed a distinct profile from unaffected siblings, but no difference in this global profile was found within RASopathies, revealing a common profile for the Ras/MAPK‐related disorders. In addition, several syndrome‐specific strengths or weaknesses were observed in individual domains. We describe for the first time an association between a single pathway and a specific personality profile, providing a better understanding of the genetics underlying personality, and new tools for tailoring educational and behavioral approaches for individuals with RASopathies.