Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of the ATP‐driven proton pump in RPE lysosomes by the major lipofuscin fluorophore A2‐E may contribute to the pathogenesis of age‐related macular degeneration

Lipofuscin accumulation in the retinal pigment epithelium (RPE) is associated with various blinding retinal diseases, including age‐related macular degeneration (AMD). The major lipofuscin fluorophor A2‐E is thought to play an important pathogenetic role. In previous studies A2‐E was shown to severely impair lysosomal function of RPE cells. However, the underlying molecular mechanism remained obscure. Using purified lysosomes from RPE cells we now demonstrate that A2‐E is a potent inhibitor of the ATP‐driven proton pump located in the lysosomal membrane. Such inhibition of proton transport to the lysosomal lumen results in an increase of the lysosomal pH with subsequent inhibition of lysosomal hydrolases. An essential task of the lysosomal apparatus of postmitotic RPE for normal photoreceptor function is phagocytosis and degradation of membranous discs shed from photoreceptor outer segments (POS) and of biomolecules from autophagy. When the lysosomes of cultured RPE cells were experimentally loaded with A2‐E, we observed intracellular accumulation of exogenously added POS with subsequent congestion of the phagocytic process. Moreover, the autophagic sequestration of cytoplasmic material was also markedly reduced after A2‐E loading. These data support the hypothesis that A2‐E‐induced lysosomal dysfunction contributes to the pathogenesis of AMD and other retinal diseases associated with excessive lipofuscin accumulation.
Discovering multifactorial associations with the development of age-related cataract using contrast mining

Cataract is a cloudiness of eye lens and studies have reported many risk factors for the development of cataract. However, the cumulative effect of multiple factors along with clinical and systemic disease conditions have not been adequately tested due to a limitation in methodology. The collection of a large volume of Electronic Health Records (EHR) offers an opportunity to apply computational tools for knowledge discovery in databases (KDD) process which enable to discover and extract hidden patterns and relationships among a large number of variables. This approach is possible because of the computational friendly EHR database such as the Cerner Health Facts Database. The main goal of this paper is to investigate the factors which are associated with the development of age-related cataracts using EHR data. This study demonstrates the potential of applying data mining tools for risk assessments using large-scale EHR data.
Evidence for the presence of cannabinoid CB1 receptors in mouse urinary bladder

1 CP 55,244, (−)−11‐hydroxy‐dimethylheptyl‐Δ8‐tetrahydrocannabinol, WIN 55,212‐2, Δ9‐tetrahydro‐cannabinol, nabilone and anandamide each inhibited electrically‐evoked contractions of the mouse isolated urinary bladder in a concentration‐related manner, their EC50 values being respectively 15.9, 18.27, 27.23, 1327.6, 1341.5 and 4950.3 nM. (+)‐11‐hydroxy‐dimethylheptyl‐Δ8‐tetrahydrocannabinol was inactive at the highest concentration used (10 μm). 2 SR141716A (31.62 or 100 nM) produced parallel rightward shifts in the log concentration‐response curves of CP 55,244, (−)−11‐hydroxy‐dimethylheptyl‐Δ8‐tetrahydrocannabinol, WIN 55,212‐2, Δ9‐tetrahydrocannabinol and anandamide for inhibition of electrically‐evoked bladder contractions. The effect of the antagonist on the log concentration‐response curve of CP 55,244 was shown to depend on the concentration of SR141716A used (31.62 to 1000 nM). 3 The amplitudes of contractions evoked by acetylcholine or β, γ‐methylene‐L‐ATP were not decreased by 316.2 nM CP 55,244 or 3162 nM Δ9‐tetrahydrocannabinol. Electrically‐evoked contractions were almost completely abolished by 200 nM tetrodotoxin. 4 The above results support the hypothesis that mouse urinary bladder contains prejunctional CB1 cannabinoid receptors which can mediate inhibition of electrically‐evoked contractions, probably by reducing contractile transmitter release. 5 AM 630 which behaves as a cannabinoid receptor antagonist in the mouse isolated vas deferens did not antagonize the ability of CP 55,244 or Δ9‐tetrahydrocannabinol to inhibit electrically‐evoked contractions of the mouse bladder. 6 SR141716A produced small but significant increases in the amplitude of electrically‐evoked contractions of the bladder suggesting that this tissue may release an endogenous cannabinoid receptor agonist or that some cannabinoid receptors in this tissue are precoupled to the effector system.
Assessing the solvent-dependent surface area of unfolded proteins using an ensemble model

We present a physically rigorous method to calculate solvent-dependent accessible surface areas (ASAs) of amino acid residues in unfolded proteins. ASA values will be larger in a good solvent, where solute–solvent interactions dominate and promote chain extension. Conversely, they will be smaller in a poor solvent, where solute–solute interactions dominate and promote chain collapse. In the method described here, these solvent-dependent effects are modeled by Boltzmann-weighting a simulated ensemble for solvent quality—good or poor. Solvent quality is parameterized as intramolecular hydrogen bond strength, using a “hydrogen bond dial” that can be varied from “off” to “high” (i.e., from 0 to −6 kcal/mol per hydrogen bond). When plotted as a function of hydrogen bond strength, the Boltzmann-weighted distribution of conformers describes a sigmoidal curve, with a transition midpoint near 1.5 kcal/mol per hydrogen bond. ASA tables for the 20 residues are provided under good solvent conditions and at this transition midpoint. For the backbone, these midpoint ASA values are found to be in good agreement with the earlier estimate of unfolded state ASA given by the mean of Creamer's upper and lower bounds [Creamer TP, et al. (1997) Biochemistry 36:2832–2835], a gratifying result in that cosolvents of experimental interest, such as urea (good solvent) and trimethylamine N-oxide (poor solvent), are known to affect the backbone predominantly. Unanticipated results from our simulations predict that a significant population of three-residue, hydrogen-bonded turns (inverse γ-turns) will be detectable in blocked polyalanyl heptamers in poor solvent—an experimentally verifiable conjecture.
A Fission Yeast Gene,him1+/dfp1+, Encoding a Regulatory Subunit for Hsk1 Kinase, Plays Essential Roles in S-Phase Initiation as Well as in S-Phase Checkpoint Control and Recovery from DNA Damage

ABSTRACT Saccharomyces cerevisiae CDC7 encodes a serine/threonine kinase required for G1/S transition, and its related kinases are present in fission yeast as well as in higher eukaryotes, including humans. Kinase activity of Cdc7 protein depends on the regulatory subunit, Dbf4, which also interacts with replication origins. We have identified him1+ from two-hybrid screening with Hsk1, a fission yeast homologue of Cdc7 kinase, and showed that it encodes a regulatory subunit of Hsk1. Him1, identical to Dfp1, previously identified as an associated molecule of Hsk1, binds to Hsk1 and stimulates its kinase activity, which phosphorylates both catalytic and regulatory subunits as well as recombinant MCM2 protein in vitro. him1+ is essential for DNA replication in fission yeast cells, and its transcription is cell cycle regulated, increasing at middle M to late G1. The protein level is low at START in G1, increases at the G1/S boundary, and is maintained at a high level throughout S phase. Him1 protein is hyperphosphorylated at G1/S through S during the cell cycle as well as in response to early S-phase arrest induced by nucleotide deprivation. Deletion of one of the motifs conserved in regulatory subunits for Cdc7-related kinases as well as alanine substitution of three serine and threonine residues present in the same motif resulted in a defect in checkpoint regulation normally induced by hydroxyurea treatment. The alanine mutant also showed growth retardation after UV irradiation and the addition of methylmethane sulfonate. In keeping with this result, a database search indicates that him1+ is identical to rad35+ . Our results reveal a novel function of the Cdc7/Dbf4-related kinase complex in S-phase checkpoint control as well as in growth recovery from DNA damage in addition to its predicted essential function in S-phase initiation.
A comparative clinical survey of the prevalence of refractive errors and eye diseases in urban and rural school children.

OBJECTIVE To assess the prevalence of refractive error and common ocular diseases in school-aged children in urban and rural populations in and around Hyderabad, India. DESIGN Population-based, cross-sectional study. PARTICIPANTS A total of 3314 school children, 1789 from urban areas and 1525 from rural areas. METHODS The examination included visual acuity measurements, retinoscopy and autorefraction under cycloplegia, examination of the anterior segment and external eye, and ocular motility evaluation. RESULTS In the urban group the prevalence of uncorrected presenting and best-corrected visual impairment (< or = 20/40 in the better eye) was 9.8%, which dropped to 7.1% with presenting vision and was further reduced to 1.1% with best-corrected visual acuity. Uncorrected visual acuity in the rural group was 6.6%, which dropped to 3.3% with presenting vision and was further reduced to 2.5% with best-corrected visual acuity. The prevalence of refractive error was greater (25.2%) in the urban than the rural group (8%). Myopia measured with autorefraction was observed in 51.4% of urban children and 16.7% in rural children. Increased literacy rate, duration of study hours, and older age of the child were found to have contributed more to the prevalence of myopia in the urban group. Hyperopia with autorefraction was found to be 3.3% in the urban and 3.1% in the rural group. Hyperopia was associated with younger age in the study group. Trachoma was the leading cause of ocular morbidity in the rural group (3.5%) compared with the urban group (0.16%). Night blindness was reported in 3.2% of children in the rural group and 0.33% in the urban group. Vitamin A deficiency, low socio-economic status, and poor personal and environmental hygienic practice were found to have a positive correlation with ocular morbidity among rural group children. CONCLUSIONS Provision of health education, periodic visual screening programs, and primary eye care by trained health care personnel in the elementary schools will prevent the prevalence of refractive errors and common ocular diseases in school children.
Use of the Journal Impact Factor in academic review, promotion, and tenure evaluations

We analyzed how often and in what ways the Journal Impact Factor (JIF) is currently used in review, promotion, and tenure (RPT) documents of a representative sample of universities from the United States and Canada. 40% of research-intensive institutions and 18% of master’s institutions mentioned the JIF, or closely related terms. Of the institutions that mentioned the JIF, 87% supported its use in at least one of their RPT documents, 13% expressed caution about its use, and none heavily criticized it or prohibited its use. Furthermore, 63% of institutions that mentioned the JIF associated the metric with quality, 40% with impact, importance, or significance, and 20% with prestige, reputation, or status. We conclude that use of the JIF is encouraged in RPT evaluations, especially at research-intensive universities, and that there is work to be done to avoid the potential misuse of metrics like the JIF.
The Novel Role of Interleukin-1 Receptor-Associated Kinase 1 in the Signaling Process Controlling Innate Immunity and Inflammation

Obesity-induced chronic inflammation plays a key role in the pathogenesis of insulin resistance and the metabolic syndrome. Proinflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signaling transduction. Interleukin-1 receptor-associated kinase-1 (IRAK-1) is a serine/threonine kinase functioning in Toll-like Receptor signaling pathways, and plays an important role in inflammation and immune response. In our studies, we demonstrated that IRAK-1 is involved with the negative regulation of PI3K-Akt dependent signaling pathway induced by insulin and TLR 2&4 agonists. Out data also indicate that IRAK-1 can interact with IRS-1 protein both in vivo and in vitro. The binding sites for the IRAK1-IRS1 biochemical interaction are IRS-1’s PH domain and IRAK-1’s proline-rich LWPPPP motif. Our studies also indicate that IRAK-1 is involved with the negative regulation of glycogen synthesis through inhibiting PI3K-Akt signaling pathway and thus releasing GSK3β’s inhibitory effect on glycogen synthase. Moreover, our studies also suggest that IRAK-1 is involved in the activation of transcription factors CREB and ATF-1 by stimulating CREB-Ser133 and ATF-1 phosphorylation. CREB transcription factor family induces genes involved in cellular metabolism, gene transcription, cell cycle regulation, cell survival, as well as growth factor and cytokine genes. That may partially explain our finding that IRAK-1 may be also involved with cell proliferation and survival pathway.
Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo

Embryonic stem (ES) cells can be derived and propagated from multiple strains of mouse and rat through application of small-molecule inhibitors of the fibroblast growth factor (FGF)/Erk pathway and of glycogen synthase kinase 3. These conditions shield pluripotent cells from differentiation-inducing stimuli. We investigate the effect of these inhibitors on the development of pluripotent epiblast in intact pre-implantation embryos. We find that blockade of Erk signalling from the 8-cell stage does not impede blastocyst formation but suppresses development of the hypoblast. The size of the inner cell mass (ICM) compartment is not reduced, however. Throughout the ICM, the epiblast-specific marker Nanog is expressed, and in XX embryos epigenetic silencing of the paternal X chromosome is erased. Epiblast identity and pluripotency were confirmed by contribution to chimaeras with germline transmission. These observations indicate that segregation of hypoblast from the bipotent ICM is dependent on FGF/Erk signalling and that in the absence of this signal, the entire ICM can acquire pluripotency. Furthermore, the epiblast does not require paracrine support from the hypoblast. Thus, naïve epiblast and ES cells are in a similar ground state, with an autonomous capacity for survival and replication, and high vulnerability to Erk signalling. We probed directly the relationship between naïve epiblast and ES cells. Dissociated ICM cells from freshly harvested late blastocysts gave rise to up to 12 ES cell clones per embryo when plated in the presence of inhibitors. We propose that ES cells are not a tissue culture creation, but are essentially identical to pre-implantation epiblast cells.
Baseline Smoking Status and the Long-Term Risk of Death or Nonfatal Vascular Event in People with Stroke: A 10-Year Survival Analysis

Background and Purpose— Smoking may exacerbate the risk of death or further vascular events in those with stroke, but data are limited. Methods— 1589 cases of first-ever and recurrent stroke were recruited between 1996 and 1999 from a defined geographical region in North East Melbourne. Both hospital and nonhospital cases were included. Over a 10-year period, all deaths, recurrent stroke events, and acute myocardial infarctions that were reported at follow-up interviews were validated using medical records. Cox proportional hazards regression was used to assess the association between baseline smoking status (never, ex, and current) and outcome (death, acute myocardial infarction, or recurrent stroke). Results— Patients who were current smokers (Hazard Ratio [HR], 1.30; 95% Confidence Interval [CI], 1.06–1.60; P=0.012) at the time of their stroke had poorer outcome when compared with those who had never smoked. Among those who survived the first 28 days of stroke, current smokers (HR, 1.42; 95% CI, 1.13–1.78; P<0.003) and ex-smokers (HR, 1.18; 95% CI, 1.01–1.39; P=0.039) at baseline had poorer outcome than those who had never smoked. Current smokers also had a greater risk of recurrent events than past smokers (HR, 1.23; 95% CI, 1.00–1.50; P=0.050). Conclusions— Patients who smoked at the time of their stroke or had smoked before their stroke had greater risk of death or recurrent vascular events when compared with patients who were never smokers. There are benefits of smoking cessation, with ex-smokers appearing to have a lesser risk of recurrent vascular events than current smokers.
Effect of potassium on the action of the KATP modulators cromakalim, pinacidil, or glibenclamide on arrhythmias in isolated perfused rat heart subjected to regional ischaemia.

OBJECTIVE The ATP sensitive potassium channel openers cromakalim (n = 10) and pinacidil (n = 10), and a blocker of this channel, glibenclamide (n = 10), were studied in isolated perfused rat hearts subjected to regional ischaemia at varying concentrations (2 to 8 mM) of external potassium ([K+]o). METHODS Hearts were isolated and perfused on a Langendorff apparatus. Vehicle (0.1% DMSO), cromakalim (10 microM), pinacidil (10 microM), or glibenclamide (10 microM) were given 10 min before ischaemia. The left coronary artery was then occluded for 15 min and reperfused for 5 min. RESULTS No agent caused more than a 10% change in heart rate. Both cromakalim and pinacidil increased (30%), and glibenclamide decreased (30%) coronary flow at 4 and 6 mM [K+]o. In the vehicle group, increases in [K+]o produced concentration dependent reductions in arrhythmia scores by decreasing ventricular fibrillation. No concentration dependent effects of [K+]o on ischaemic ventricular tachycardia was observed. Under ischaemic conditions, potassium channel openers and glibenclamide more markedly reduced ischaemic ventricular tachycardia and fibrillation relative to the effects of increased [K+]o. CONCLUSIONS Ischaemic ventricular fibrillation was inversely related to changes in [K+]o, whereas effects on ventricular tachycardia were all-or-none. Neither potassium channel openers nor glibenclamide elicited significant proarrhythmic activity despite variations in [K+]o. These data suggest that both potassium channel openers and glibenclamide display potential antiarrhythmic activity through their ability to abolish two distinct arrhythmogenic mechanisms during ischaemia. It is also suggested that the underlying mechanisms of ventricular tachycardia and fibrillation are coupled during ischaemia in the rat.
Oesophageal motor and sensitivity abnormalities in non-obstructive dysphagia

Objectives To evaluate oesophageal sensitivity to balloon distension in patients with non-obstructive dysphagia (NOD), and to determine its relationship with the motility pattern in response to food ingestion. Patients and methods Twenty-one healthy volunteers and 19 consecutive patients complaining of NOD with normal standard manometry were included. An oesophageal sensitivity test was carried out before the manometry study with liquid and solid swallows. Results The median threshold to distension was 9 ml in control subjects and 5 ml in patients (P < 0.002). Dysphagia or odynophagia were reproduced in 15/19 (78.9%) patients during manometry with solid swallows only. The percentage of swallows with abnormal motility patterns was higher in patients than control subjects (P < 0.001). Compared with control values, sensitivity abnormality was defined by a distension threshold of < 6 ml. Motor abnormality was defined by > 19% of swallows occurring with one or more abnormal motor profiles. A total of 8/19 (42%) patients presented with the association of an abnormal sensitivity threshold and an abnormal motor pattern; 5/19 (26%) presented with isolated motor abnormalities; 4/19 (21%) patients presented with isolated abnormal sensitivity thresholds; and 2/19 (11%) patients presented without any abnormality. Conclusion Manometry with solid swallows and oesophageal balloon distension are useful in characterizing NOD.
US Presidential election effects on Mexican ADRs: a two-year analysis

ABSTRACT Examinations of the impact of Brexit on UK ADRs show the ADR and Great British Pound (GBP) values decreased immediately after the vote results were known. Within a year, the ADRs recovered but the GBP did not. This study examines the one- and two-year changes in Mexican ADR and Peso values following the 2016 US Presidential election vote to determine whether a similar reaction and overreaction resulted. Because of the President’s campaign platform, including the renegotiation of trade agreements like NAFTA, uncertainty about profitability of firms headquartered in Mexico increased. Within two months of the vote, Mexican ADRs lost about 7 percent of their value (mostly due to the depreciation of the Peso). The ADRs underperformed the Peso by 3 percent after 1 year and 10 percent after 2 years. However, the ADRs underperformed the S&P 500 by 19 percent after 1 year and 41 percent after 2 years indicating the initial reaction was not overreaction based on the sustained losses years later (unlike the Brexit results on UK ADRs).
Comparison between vaginal tampon and cervicovaginal lavage specimen collection for detection of human papillomavirus DNA by the polymerase chain reaction

The aim of the study was to compare the accuracy of self‐administered vaginal tampon (VT) specimens for the detection of human papillomaviruses (HPVs) with that of cervicovaginal lavage specimens (CVL). Two hundred seventy‐four paired VT and CVL specimens were collected prospectively from women at risk of sexually transmitted diseases. Specimens were treated and amplified with the polymerase chain reaction (PCR). Each woman served as her own control. One hundred and forty‐four of 272 (52.9%) CVLs and 159 of 271 (58.7%) VTs contained HPV DNA sequences (correlation of 88%). The sensitivity and specificity of vaginal tampons reached 93.9% (138/147) and 80.5% (99/123), respectively. HPV typing results were concordant for 99 negative paired samples and 114 paired samples positive for the same type(s) (correlation of 78.9%). It is concluded that these sampling methods collect cells from different areas of the genital epithelium, highlighting the importance of further assessment of the comparative predictive value of HPV detection in each sample. J Med Virol 51: 42–47, 1997. © 1997 Wiley‐Liss, Inc.