Miracle-dz/UniFAR-FTUs huggingface dataset:
α-Synuclein Negatively Regulates Nurr1 Expression Through NF-κB-Related Mechanism

The nuclear receptor-related 1 protein (Nurr1) is critical for the development and survival of midbrain dopamine neurons that are predominantly affected and progressively degenerated in Parkinson’s disease (PD). The expression level of Nurr1 has been proposed to be modulated by α-synuclein (α-SYN), an important pathological hallmark of PD. However, the underlying molecular mechanisms of α-SYN-Nurr1 interaction are still rarely explored. In this study, we investigated the effect and mechanism of α-SYN on the transcription level of Nurr1. Our results showed that overexpression of α-SYN (WT or A53T) reduced Nurr1 and its downstream gene expressions. α-SYN neither affected the mRNA stability nor bound with the promoter of Nurr1, but modulated the transcription activity of Nurr1 promoter region ranging from −605 bp to −418 bp, which contains the binding site of nuclear factor-kappa B (NF-κB). Moreover, overexpression of α-SYN (WT or A53T) down-regulated NF-κB expression level, thereby inhibiting the transcription factor activity of NF-κB and decreasing the binding quantity of NF-κB with Nurr1 promoter. These findings may give us new insights to better understand the molecular mechanisms underlying the α-SYN-regulated Nurr1 function, which may fascinate the investigation of dopamine neuron degeneration in PD pathogenesis.
Metabolomic Analysis Identifies Glycometabolism Pathways as Potential Targets of Qianggan Extract in Hyperglycemia Rats

Qianggan formula, a designed prescription according to the Traditional Chinese Medicine (TCM) theory, is widely used in treating chronic liver diseases, and indicated to prevent blood glucose increase in patients via unknown mechanisms. To unravel the effects and underlying mechanisms of Qianggan formula on hyperglycemia, we administrated Qianggan extract to high fat and high sucrose (HFHS) diet rats. Results showed that four-week Qianggan extract intervention significantly decreased serum fasting blood glucose, hemoglobin A1c, and liver glycogen levels. Gas chromatography-mass spectrometry (GC-MS) approach was employed to explore metabolomic profiles in liver and fecal samples. By multivariate and univariate statistical analysis (variable importance of projection value > 1 and p value < 0.05), 44 metabolites (18 in liver and 30 in feces) were identified as significantly different. Hierarchical cluster analysis revealed that most differential metabolites had opposite patterns between pair-wise groups. Qianggan extract restored the diet induced metabolite perturbations. Metabolite sets enrichment and pathway enrichment analysis revealed that the affected metabolites were mainly enriched in glycometabolism pathways such as glycolysis/gluconeogenesis, pentose phosphate pathway, fructose, and mannose metabolism. By compound-reaction-enzyme-gene network analysis, batches of genes (e.g. Hk1, Gck, Rpia, etc) or enzymes (e.g. hexokinase and glucokinase) related to metabolites in enriched pathways were obtained. Our findings demonstrated that Qianggan extract alleviated hyperglycemia, and the effects might be partially due to the regulation of glycometabolism related pathways.
Reduced Post-ischemic Brain Injury in Transient Receptor Potential Vanilloid 4 Knockout Mice

Background and Purpose In the acute phase of ischemia-reperfusion, hypoperfusion associated with ischemia and reperfusion in microvascular regions and disruption of the blood–brain barrier (BBB) contribute to post-ischemic brain injury. We aimed to clarify whether brain injury following transient middle cerebral artery occlusion (tMCAO) is ameliorated in Transient receptor potential vanilloid 4 knockout (Trpv4–/–) mice. Methods tMCAO was induced in wild-type (WT) and Trpv4–/– mice aged 8–10 weeks. Ischemia-induced lesion volume was evaluated by 2,3,5-triphenyltetrazolium chloride staining at 24 h post-tMCAO. Tissue water content and Evans blue leakage in the ipsilateral hemisphere and a neurological score were evaluated at 48 h post-tMCAO. Transmission electron microscopy (TEM) was performed to assess the morphological changes in microvasculature in the ischemic lesions at 6 h post-tMCAO. Results Compared with WT mice, Trpv4–/– mice showed reduced ischemia-induced lesion volume and reduced water content and Evans blue leakage in the ipsilateral hemisphere alongside milder neurological symptoms. The loss of zonula occludens-1 and occludin proteins in the ipsilateral hemisphere was attenuated in Trpv4–/– mice. TEM revealed that parenchymal microvessels in the ischemic lesion were compressed and narrowed by the swollen endfeet of astrocytes in WT mice, but these effects were markedly ameliorated in Trpv4–/– mice. Conclusion The present results demonstrate that TRPV4 contributes to post-ischemic brain injury. The preserved microcirculation and BBB function shortly after reperfusion are the key neuroprotective roles of TRPV4 inhibition, which represents a promising target for the treatment of acute ischemic stroke.
Biochemical Predictors of Response to Neoadjuvant Therapy in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is becoming increasingly more common. Treatment for PDAC is dependent not only on stage at diagnosis, but complex anatomical relationships. Recently, the therapeutic approach to this disease has shifted from upfront surgery for technically resectable lesions to a neoadjuvant therapy first approach. Selecting an appropriate regimen and determining treatment response is crucial for optimal oncologic outcome, especially since radiographic imaging has proven unreliable in this setting. Tumor biomarkers have the potential to play a key role in treatment planning, treatment monitoring, and surveillance as an adjunct laboratory test. In this review, we will discuss common chemotherapeutic options, mechanisms of resistance, and potential biomarkers for PDAC. The aim of this paper is to present currently available biomarkers for PDAC and to discuss how these markers may be affected by neoadjuvant chemotherapy treatment. Understanding current chemotherapy regiments and mechanism of resistance can help us understand which markers may be most affected and why; therefore, determining to what ability we can use them as a marker for treatment progression, prognosis, or potential relapse.
'Haying-off', the negative grain yield response of dryland wheat to nitrogen fertiliser II.Carbohydrate and protein dynamics

Changes in carbohydrate and protein in stems, leaves, spikes, and grain between anthesis and maturity were measured in 3 dryland wheat crops whose responses to applied nitrogen (N) ranged from increases in grain yield through to decreases in grain yield. This decrease in grain yield, known as haying-off, was described in Paper I in this series. Measurements reported there showed that apparent retranslocation, defined as the decrease in weight of vegetative organs during grain filling, was generally greater for crops of high-N status than for those of low-N status. Retranslocation in this context is the process of moving compounds assimilated before anthesis to the grain. The largest source of assimilates available for retranslocation in all crops at anthesis was water-soluble carbohydrates (WSC) contained in the stems and spikes, and represented a potential contribution of 34-50% to yield for the most severely hayed-off crops. The absolute amount of WSC present in high-N crops was less than that in low-N crops, despite a greater biomass. The lack of this form of assimilate available for retranslocation was the greatest single contributor to the yield reduction of the crops of high-N status. The quantity of protein retranslocated increased with crop N status, but the amounts involved were smaller than the quantity of WSC. Virtually all of the WSC reserves were utilised in all crops, in contrast to the protein reserves which were poorly retranslocated in the hayed-off crops. Most of the WSC was contained in the stems and most of the protein in the leaves. The potential contribution of retranslocated WSC and protein from leaves was more difficult to estimate because of an apparent loss of 40-50% of leaf tissue after anthesis. The nature of the loss was estimated from the amounts of acid detergent fibre (ADF; fibre not solubilised by hot acid detergent) present at anthesis and maturity. Since ADF comprises cellulose and lignin which decompose slowly, the loss of 30-37% of ADF was applied as a correction factor in calculating potential retranslocation from leaves. There was no loss of stem ADF. Using the correction, the potential retranslocation of leaf protein and leaf WSC was equivalent to 6-15% of yield. The export of all WSC and protein failed to account for the total decrease in leaf biomass, even after correction of leaf losses. We identified hemicellulose as an additional and previously unsuspected source of carbohydrate for retranslocation. Unlike WSC, the amount of leaf and stem hemicellulose at anthesis increased with crop N status, and the increase in hemicellulose between anthesis and maturity was equal to 10-17% of yield.
Body Weight Variability Increases Dementia Risk Among Older Adults: A Nationwide Population-Based Cohort Study

Background: Recent growing evidences suggest that body weight (Bwt) variability, a repeated loss and regain of weight within a specific period, causes metabolic disturbances and can be a marker for poor homeostasis. Although there have been many studies about the association between Bwt variability and various health status, its association with the incidence of dementia among elderly people has not been examined. Methods: We performed a retrospective elderly cohort study from 19,987 participants with mean age 73 years old in the Korean National Health Insurance Service. We examined the risk of incident dementia, including Alzheimer's dementia and vascular dementia, according to the quartile of Bwt variability, represented as coefficient of variation (Bwt-CV), SD (Bwt-SD), and variability independent of the mean (Bwt-VIM). Results: In fully adjusted model, the group with the highest Bwt variability (Bwt-VIM Q4) showed an increased risk of all-cause dementia (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.206–1.603) and Alzheimer's dementia (HR 1.46, CI 1.240–1.724) compared to the lowest quartile (Bwt-VIM Q1). We also found that subjects with the highest Bwt variability (Q4) and underweight BMI had a significantly increased risk of developing dementia (HR 1.994, 95% CI 1.302–3.054), while subjects with low Bwt variability (Q1 and Q2) and obese BMI had decreased risk of dementia (HR 0.664, 95% CI 0.505–0.872 and HR 0.648, 95% CI 0.493–0.852, respectively) compared to reference group (lowest Bwt variability (Q1) with normal baseline BMI). The effect of Bwt variability on the incidence of dementia was more prominent in subjects <75 years old and abnormal BMI groups (P for interaction < 0.05). Conclusion: The present study revealed that high Bwt variability was associated with an increased risk of dementia in the elderly.
Effect of Exposure to Seminal Plasma Through Natural Mating in Cattle on Conceptus Length and Gene Expression

A growing body of evidence suggests that paternal factors have an impact on offspring development. These studies have been mainly carried out in mice, where seminal plasma (SP) has been shown to regulate endometrial gene expression and impact embryo development and subsequent offspring health. In cattle, infusion of SP into the uterus also induces changes in endometrial gene expression, however, evidence for an effect of SP on early embryo development is lacking. In addition, during natural mating, the bull ejaculates in the vagina; hence, it is not clear whether any SP reaches the uterus in this species. Thus, the aim of the present study was to determine whether SP exposure leads to improved early embryo survival and developmental rates in cattle. To this end, Day 7 in vitro produced blastocysts were transferred to heifers (12–15 per heifer) previously mated to vasectomized bulls (n = 13 heifers) or left unmated (n = 12 heifers; control). At Day 14, heifers were slaughtered, and conceptuses were recovered to assess size, morphology and expression of candidate genes involved in different developmental pathways. Additionally, CL volume at Day 7, and weight and volume of CL at Day 14 were recorded. No effect of SP on CL volume and weight not on conceptus recovery rate was observed. However, filamentous conceptuses recovered from SP-exposed heifers were longer in comparison to the control group and differed in expression of CALM1, CITED1, DLD, HNRNPDL, PTGS2, and TGFB3. In conclusion, data indicate that female exposure to SP during natural mating can affect conceptus development in cattle. This is probably achieved through modulation of the female reproductive environment at the time of mating.
Public Attitudes Toward Precision Medicine: A Nationwide Survey on Developing a National Cohort Program for Citizen Participation in the Republic of Korea

This nation-wide survey was conducted among Korean adults to examine the public interest in and attitudes toward establishing a citizen participation cohort model and to collect data to support and determine the future policy and research directions of the Resource Collection Project for Precision Medicine Research (RCP-PMR) before the project proceeds. The demographic framework of the survey population was established based on the statistical standards of the Ministry of the Interior and Safety. An online survey was carried out using web panels between 14 May 2018 and 23 May 2018. Sampling was performed using a simple proportional allocation method considering region, gender, and age. From this survey, the RCP-PMR received very high support (94.5%) and the intention to participate was as high as 83.5%. Respondents had a very positive attitude toward providing their samples and information to the study (84.5–89.9%). In terms of incentives to participate, respondents wanted to receive health information (80.2%), monetary compensation (51.4%), and smart devices (41.3%). Most participants responded that it was appropriate to carry out the project at governmental research institutes (66.9%). Respondents also had a positive attitude toward sharing their information and samples as long as it was only shared with the governmental researchers who run the project (88.0%). However, the survey participants expressed concerns about the study being time consuming or a hassle (38.1%), privacy breaches (33.6%), and the lack of returning benefits of participation (25.1%). Participants had a negative attitude toward sharing their data with researchers who are not directly involved in the RCP-PMR. Considering the future use of the database derived from this project, it will be important to communicate with the lay public as well as the RCP-PMR participants to understand their needs in participating in the forthcoming study and to improve their understanding of the goals of the project, and how data sharing can contribute to disease research and prevention. The RCP-PMR should consider building an efficient citizen-participation program and privacy protection for the research participants.
THE ACTIVE TRANSPORT OF WATER IN LIVING SYSTEMS

I . Introduction. 11. The fluid compartments of the mammalian body . ( I ) The existence of subcompartments . (2) Measurement of the volumes of the compartments (3) Osmotic equilibria within the body . (4) Dynamic aspects of osmotic equilibria . ( I ) General . (2) Unicellular organisms. IF‘. Active transport of water in plants . V. The mechanism of water transport . VI. Conclusion . VII. Summary . VI I I. References . IX. Addendum . 111. Osmoregulation in aquatic animals PAGE . 158 . I59 . I59 . 162 . 165 . 169 ’ 174 . 174 . I77 . I79 . 182 . 186 . 186 . 187 . I93
Demonstration of Binding Induced Structural Plasticity in a SH2 Domain

SH2 domains are common protein interaction domains able to recognize short aminoacidic sequences presenting a phosphorylated tyrosine (pY). In spite of their fundamental importance for cell physiology there is a lack of information about the mechanism by which these domains recognize and bind their natural ligands. The N-terminal SH2 (N-SH2) domain of PI3K mediates the interaction with different scaffolding proteins and is known to recognize a specific pY-X-X-M consensus sequence. These interactions are at the cross roads of different molecular pathways and play a key role for cell development and division. By combining mutagenesis, chemical kinetics and NMR, here we provide a complete characterization of the interaction between N-SH2 and a peptide mimicking the scaffolding protein Gab2. Our results highlight that N-SH2 is characterized by a remarkable structural plasticity, with the binding reaction being mediated by a diffused structural region and not solely by the residues located in the binding pocket. Furthermore, the analysis of kinetic data allow us to pinpoint an allosteric network involving residues far from the binding pocket involved in specificity. Results are discussed on the light of previous works on the binding properties of SH2 domains.
Primary Immunodeficiencies in a Mesoregion of São Paulo, Brazil: Epidemiologic, Clinical, and Geospatial Approach

Background: Primary immunodeficiencies (PIDs) are rare genetic disorders leading to immunologic abnormalities that can affect different organs and systems. We determined the epidemiology, clinical, and geospatial characteristics of PID disorders among patients diagnosed over a 5 year period in a reference hospital covering a mesoregion in São Paulo, Brazil. Methods: A retrospective analysis of 39 patients with recognizable PIDs according to the criteria of the European Society of Primary Immunodeficiencies were enrolled. Thirty-four patients came from outpatient immunodeficiency clinics and five patients from active search. Demographic, clinical, and immunologic data were collected, and maps were constructed using a geographic information system. Results: The ratio of females to males was 1.4:1, and 48.7% of patients were younger than 17 years of age. The mean age at the onset of symptoms in children was 2.0 years [standard error of the mean (SEM), 1.7 years] and the diagnosis lag was 5.1 years (SEM, 3.1 years); the mean age at diagnosis in adults was 16.3 years (SEM, 11.8 years) and the lag was 10.8 years (SEM, 10.9 years). Antibody deficiency and common variable immunodeficiencies were the most common categories and phenotypes, respectively. The need for intravenous antibiotics and respiratory tract infections were the most prevalent warning signs, with an overall mortality rate of 15.3%. Autoimmune diseases were diagnosed in 56.4% and visceral leishmaniasis in 5.1% of patients. In the active search, 29 patients were investigated and 17.2% were diagnosed; early diagnosis, the involvement of multidisciplinary professionals, and dissemination of knowledge achieved milestone benefits. The distribution of PID networks in Brazil shows great asymmetry between regions and at a regional level; it was shown that the patients lived mainly in Presidente Prudente municipality. Conclusions: The implementation of an immunodeficiency outpatient clinic in a referral hospital covering a mesoregion with a large population has led to the generation of policies and practices to improve the diagnosis, quality of life, and care of patients with PIDs and their families. Furthermore, the search for hospitalized patients with warning signs for PIDs showed great benefits. Inequality in the distribution of PID network centers in Brazil was demonstrated.
Outcome Measures for Evaluating the Effect of a Multidisciplinary Intervention on Axial Symptoms of Parkinson's Disease

Introduction: The satisfactory symptomatic control of the axial symptoms of Parkinson's disease (PD) remains challenging. As these symptoms are an important cause of disability, new therapeutic strategies should be developed and evaluated. To do this, it is necessary to select the outcomes to be measured and reported in a clinical trial. In this study, we sought to identify the most responsive outcome measures for assessing the efficacy of a multidisciplinary intervention on the axial symptoms of PD. Methods: An exploratory prospective clinical study was conducted. PD patients engaged in a pre-defined multidisciplinary intervention program for parkinsonian patients were assessed at admission and discharge by a multidisciplinary team. The responsiveness to intervention was evaluated and the smallest sample size needed to enable statistically significant results for an expected 30% change from baseline for each outcome was calculated. Results: Twenty-two patients were included in the study. The effect size detected varied between 0.04 and 0.83. The Movement Disorder Society—Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score and each subsection, the N-FOG questionnaire, the 10-m walk test, and Frenchay Dysarthria Assessment-2 Edition (FDA-2) showed a medium to large effect size. Sample size calculations for 90% power and assuming 30% change from baseline ranged from eight to 180 participants. The outcome measures that require a small number of participants to enable statistically significant results were the FDA-2 rating scale (n = 4 participants), the MDS-UPDRS total score (n = 9), the 10-m walk test (n = 9), and the MDS-UPDRS motor examination (n = 10). Conclusions: The MDS-UPDRS part III and total score and the 10-m walk test were the outcomes with the best responsiveness to a multidisciplinary intervention and required a small number of participants to enable statistically significant results. Further studies are needed to clarify the suitability of the Timed Up and Go test.
Bone status and aortic calcifications in chondrocalcinosis patients

Abstract Aim: We aimed to examine the association between several circulating bone turnover markers [ osteocalcin (OC), osteoprotegerin (OPG), beta-CrossLaps (β-CTx)], hip and spine bone mineral density (BMD) and abdominal aortic calcification (AAC) in patients with chondrocalcinosis (CC). Methods: Thirty-six patients with CC and thirty-seven controls were consecutively enrolled in this pilot case-control, cross-sectional study. The following parameters were assessed: serum levels of OC, OPG and β-CTx by enzyme-linked immunosorbent assay (ELISA); hip and spine BMD by dual-energy X-ray absorptiometry and AAC score by lateral radiography. Results: Patients with CC had higher levels of serum bone turnover markers and AAC score than the control group: OC [6.5 (3.5-9.9) vs 4.5 (2.6-7.2) ng/ml; p=0.05], OPG [(7.7 (6.2-9.4) vs 6.5 (5.5-8.12) pmol/ml; p=0.02], β-CTx [6078 (5870-6171) vs 5851 (5465-6109) pg/ml; p=0.02] and AAC score (3.6±6.2 vs 0.5±2; p=0.006). Conversely, even if statistical significance was not reached, hip and spine BMD was lower in patients with CC. Additionally, we found a positive correlation between OPG and AAC, but also between OPG and osteoporosis in patients with CC. Conclusion: Patients with CC are characterized by higher circulating OC, OPG and β-CTx. The presence of AAC was more common in patients with CC, being only associated with serum OPG.