Miracle-dz/UniFAR-FTUs huggingface dataset:
FLASH Is Required for the Endonucleolytic Cleavage of Histone Pre-mRNAs but Is Dispensable for the 5′ Exonucleolytic Degradation of the Downstream Cleavage Product

ABSTRACT 3′-end cleavage of histone pre-mRNAs is catalyzed by CPSF-73 and requires the interaction of two U7 snRNP-associated proteins, FLASH and Lsm11. Here, by using scanning mutagenesis we identify critical residues in human FLASH and Lsm11 that are involved in the interaction between these two proteins. We also demonstrate that mutations in the region of FLASH located between amino acids 50 and 99 do not affect binding of Lsm11. Interestingly, these mutations convert FLASH into an inhibitory protein that reduces in vitro processing efficiency of highly active nuclear extracts. Our results suggest that this region in FLASH in conjunction with Lsm11 is involved in recruiting a yet-unknown processing factor(s) to histone pre-mRNA. Following endonucleolytic cleavage of histone pre-mRNA, the downstream cleavage product (DCP) is degraded by the 5′–3′ exonuclease activity of CPSF-73, which also depends on Lsm11. Strikingly, while cleavage of histone pre-mRNA is stimulated by FLASH and inhibited by both dominant negative mutants of FLASH and anti-FLASH antibodies, the 5′–3′ degradation of the DCP is not affected. Thus, the recruitment of FLASH to the processing complex plays a critical role in activating the endonuclease mode of CPSF-73 but is dispensable for its 5′–3′ exonuclease activity. These results suggest that CPSF-73, the catalytic component in both reactions, can be recruited to histone pre-mRNA largely in a manner independent of FLASH, possibly by a separate domain in Lsm11.
Optical Detector Array Design for Navigational Feedback Between Unmanned Underwater Vehicles (UUVs)

Designs for an optical sensor detector array for use in autonomous control of unmanned underwater vehicles (UUVs), or between UUVs and docking station, are studied in this paper. Here, various optical detector arrays are designed for the purpose of determining and distinguishing relative 5 degrees-of-freedom (DOF) motion between UUVs: 3-DOF translation and 2-DOF rotation (pitch and yaw). In this paper, a numerically based simulator is developed to evaluate varying detector array designs. The simulator includes a single light source as a guiding beacon for a variety of UUV motion types. The output images of the light field intersecting the detector array are calculated based on detector hardware characteristics, the optical properties of water, and expected noise sources. Using the simulator, the performance of planar and curved detector array designs (of varying size arrays) are analytically compared and evaluated. Output images are validated using empirical in situ measurements conducted in underwater facilities at the University of New Hampshire, Durham, NH, USA. Results of this study show that the optical detector array is able to distinguish relative 5-DOF motion with respect to the simulator light source. Furthermore, tests confirm that the proposed detector array design is able to distinguish positional changes of 0.2 m and rotational changes of 10 ° within 4-8 m range in x-axis based on given output images.
Etoricoxib Attenuates Effect of Antihypertensives in a Rodent Model of DOCA-Salt Induced Hypertension

While it is known that non-steroidal anti-inflammatory drugs including selective cyclooxygenase-2 (COX-2) inhibitors influence BP, the exact relationship and underlying mechanisms are still unclear. We investigated the effect of etoricoxib, a selective COX-2 inhibitor on the antihypertensive efficacy of atenolol; beta-blocker, ramipril; angiotensin converting enzyme inhibitor and telmisartan; angiotensin receptor blocker in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, a mineralocorticoid volume expansion model. Etoricoxib attenuated the antihypertensive-induced reduction of systolic (atenolol; P < .001, ramipril; P = .011, telmisartan; P = .003) and mean arterial pressure (atenolol; P < .001, ramipril; P = .032, telmisartan; P = .023). These results demonstrate that COX-2 dependent mechanisms play a significant role in blood pressure regulation, and etoricoxib-induced COX-2 inhibition blunts the therapeutic effect of different classes of antihypertensives in this mineralocorticoid volume expansion model of hypertension.
Extracranial Carotid Plaque Length and Parent Vessel Diameter Significantly Affect Baseline Ipsilateral Intracranial Blood Flow

BACKGROUND:The degree of carotid artery stenosis has traditionally been used as a marker of hemodynamic compromise and increased stroke risk. However, the hemodynamic effect of carotid atherosclerotic plaque length on cerebral blood flow has not previously been studied. OBJECTIVE:To determine whether carotid plaque length, in addition to degree of stenosis, significantly affects carotid blood flow in patients with >65% carotid stenosis. METHODS:Consecutively treated surgical patients with unilateral >65% carotid stenosis at a single institution were analyzed. Quantitative measurements of plaque length, internal carotid artery (ICA) vessel diameter, and degree of stenosis were made from magnetic resonance angiography images. Quantitative phase-contrast magnetic resonance angiography flow maps were generated to estimate ICA flow compromise by calculating a ratio of the ipsilateral/contralateral ICA flow rates. RESULTS:Of 38 eligible patients, 23 had full anatomic and ICA flow data sets available for analysis. Univariate regression analysis demonstrated that longer carotid plaques and increasing percentage carotid stenosis were associated with a significant decline in ipsilateral ICA flow (P = .008 and P = .02, respectively). A multivariate regression identified both plaque length and vessel diameter as independent predictors of ICA flow (P = .001 and P = .002, respectively). CONCLUSION:Carotid plaque length and vessel diameter appear to be significant variables, in addition to degree of stenosis, in predicting ipsilateral carotid blood flow compromise in patients undergoing carotid revascularization.
Mutant NG108‐15 cells (NG‐CR72) deficient in GM1 synthase respond aberrantly to axonogenic stimuli and are vulnerable to calcium‐induced apoptosis: they are rescued with LIGA‐20

The neuroblastoma × glioma NG108‐15 hybrid cell line, a widely used model for the study of neuronal differentiation, contains a variety of gangliosides including GM1 and its sialosylated derivative, GD1a. To investigate the role of these a‐series gangliotetraose gangliosides in neuritogenesis, we have obtained a mutated subclone of NG108‐15 that is deficient in that family of gangliosides. NG108‐15 cells were grown in the presence of cholera toxin, which killed the large majority of cells, and from the cholera‐resistant survivors we isolated a clone, NG‐CR72, that lacks GM1 and GD1a in the plasma and nuclear membranes. GM2 concentration was significantly higher in the plasma membrane. Enzyme assay indicated deficiency of UDP‐Gal:GM2 galactosyltransferase (GM1 synthase), which was confirmed by incorporation studies with [3H]sphingosine. These cells resembled wild‐type NG108‐15 in extending dendritic processes in response to dendritogenic agents (retinoic acid, dibutyryl cAMP) but responded aberrantly to axonogenic stimuli (KCl, ionomycin) by extending unstable neurites that showed the cytoskeletal staining characteristic of dendrites. Moreover, mutant cells treated with the Ca2+‐elevating axonogenic agents underwent apoptosis over time, attributed to dysfunction of Ca2+ regulatory mechanisms normally mediated by GM1. Such agents caused dramatic and sustained elevation of intracellular Ca2+ in mutant cells, in contrast to modest and temporary elevation in wild‐type cells. Exogenous GM1, inserted into the plasma membrane, had no discernable protective effect on NG‐CR72 cells whereas LIGA‐20, a membrane‐permeant derivative of GM1 that entered both plasma and nuclear membranes, blocked apoptosis, permitted extension of stable neurites, and attenuated the abnormal elevation of intracellular Ca2+.
Parathyroid hormone, aldosterone-to-renin ratio and fibroblast growth factor-23 as determinants of nocturnal blood pressure in primary hyperparathyroidism: the eplerenone in primary hyperparathyroidism trial

Objectives: The high prevalence of arterial hypertension in primary hyperparathyroidism (pHPT) is largely unexplained. Apart from parathyroid hormone (PTH), the mineral hormones fibroblast growth factor (FGF)-23 and aldosterone-to-renin ratio (ARR) are upregulated in pHPT. We aimed to determine whether nocturnal blood pressure (BP) is related with PTH, FGF-23 or ARR in a relatively large sample of pHPT patients. Methods: Cross-sectional data of the single-center “Eplerenone in Primary Hyperparathyroidism” trial were used. All patients with a biochemical diagnosis of pHPT who had both available 24-h ambulatory BP monitoring and valid laboratory data were included. Results: Full data were available in 136 patients (mean age 67 ± 10 years, 78% women). Median PTH was 99 (interquartile range: 82–124) pg/ml and mean calcium was 2.63 ± 0.15 mmol/l. ARR, but not PTH or FGF-23, was significantly and directly related with nocturnal SBP (Pearson's r = 0.241, P < 0.01) and DBP (r = 0.328, P < 0.01). In multivariate regression analyses, with adjustment for age, sex, PTH, FGF-23, traditional cardiovascular risk factors, antihypertensive medication and parameters of calcium metabolism ARR remained significantly and directly related with nocturnal BP (SBP: adjusted &bgr;-coefficient = 0.289, P < 0.01; DBP: &bgr; = 0.399, P < 0.01). The relationship between ARR and nocturnal SBP was exclusively present in patients with PTH levels above the median of 99 pg/ml. Conclusion: ARR, but not FGF-23 or PTH, was independently and directly related with nocturnal BP parameters in patients with pHPT, and this relationship was dependent on pHPT disease severity. Inappropriately, elevated aldosterone may partially explain the high prevalence of arterial hypertension in pHPT.
Matteo Ricci: A Jesuit in the Ming Court

Prologue Chapter 1: The Jesuit and Mathematics Chapter 2: In the East Chapter 3: The Difficulty of Learning Chinese Chapter 4: The Man from the West Chapter 5: The Pride of Li Madou Chapter 6: The Meeting of Confucius and Euclid Chapter 7: Metamorphosis into Mandarins Chapter 8: The Strength of Friendship Chapter 9: To Beijing! Chapter 10: Heated Disputes and Science Lessons Chapter 11: Prisoner of the Eunuch Chapter 12: In the Heart of the Empire Chapter 13: The Empty Throne Chapter 14: The Lord of Heaven Chapter 15: Doctor Paul Chapter 16: Euclid Becomes Chinese Chapter 17: The Open Door Chapter 18: After Matteo Ricci: The Scientific Legacy, Triumph, and Persecution Chronology Chinese Dynasties Glossary Bibliography
Predictors of cumulative length of psychiatric inpatient stay over one year: a national case register study.

BACKGROUND Prior studies have shown inconsistent results regarding predictors of length of stay (LOS) and of readmission in psychiatric hospitals. “Cumulative LOS” over a given period, which reflects both LOS and readmission, has not been examined so far in a systematic way. The Israel Psychiatric Case Register in Israel made it possible to examine predictors of Cumulative LOS in a nationwide, representative sample. METHOD All hospitalization admissions during a six-month period in Israel were recorded and followed-up for one year. The variables predicting Cumulative LOS over one year were identified through a Cox regression. RESULTS The median Cumulative LOS during one year was 43.0 days, and only 1.7% of the patients remained hospitalized for more than one year after admission. The variables significantly predicting longer Cumulative LOS were: Jewish ethnicity, a diagnosis of schizophrenia or other functional psychosis, prior hospitalization, compulsory admission and Northern and Jerusalem districts of hospitalization (which have a lower admission rate). LIMITATIONS Lack of information on severity of pathology and type of treatment. CONCLUSION Cumulative LOS, which reflects both the length of each inpatient episode and the rate of readmission, is affected not only by clinical factors,but also by the cultural background of the patient population and by administrative factors such as bed pressure.
Effect of Papillotoxic Agents on Expression of Cyclooxygenase Isoforms in the Rat Kidney

Inhibition of renal vasodilatory prostaglandins (PGs) and secondary ischemia due to inhibition of cyclooxygenase (COX) activity has been suggested as a possible mechanism for development of analgesic-related renal papillary necrosis (RPN) in rats. Recently, it has been shown that COX exists in two related but unique isoforms, COX-1 and COX-2. It is unclear what potential roles these isoforms play in the maintenance of blood flow in the renal papilla or genesis of RPN. We evaluated the effect of 2 papillotoxic agents, including a nonsteroidal anti-inflammatory drug, indomethacin, and a chemical agent, 2-bromoethanamine hydrobromide (2-BEA), on COX-1 and COX-2 in the renal papilla as a means of assessing what changes occur in the expression of these isoforms during the development of RPN. Female Wistar rats ≃10–17 wk old were treated with either indomethacin (75 mg/kg, single dose, or 10 mg/kg/day for 5 days) or 2-BEA (100 mg/kg/day for 4 days) to create lesions of RPN. In this study, a single 75-mg/kg dose of indomethacin did not cause light microscopic changes of RPN. However, RPN was observed in animals administered indomethacin at 10 mg/kg/day for 1 wk or 2-BEA for 5 days. The immunohistochemical analyses of kidneys showed that both COX-1 and COX-2 were present in the renal papilla of control rats. In animals treated with indomethacin (75 mg/kg), a slight to moderate decrease in both isoforms was observed in essentially normal renal papillary cells within 2 hr, that was followed by an increase in COX-2 immunoreactivity in the renal papilla, macula densa, and thick ascending limbs (both 10-and 75-mg/kg animals). This COX-2 immunoreactivity was greatest in animals with concomitant indomethacin-induced gastrointestinal injury, suggesting a possible role of inflammatory cytokines in COX-2 induction. No changes in the expression of COX isoforms in the intact papilla occurred as a result of 2-BEA; however, cells undergoing degeneration and necrosis lost immunoreactivity to both COX isoforms. The possible mechanism that leads to an initial decrease in COX immunoreactivity in indomethacin-treated animals is not known; however, a reversible ultrastructural change in the papillary cells cannot be ruled out. This decrease in COX isoforms in the renal papilla may contribute to the development of RPN through the loss of vasodilatory PGs.
Executive function deficits in children with attention-deficit/hyperactivity disorder and improvement with lisdexamfetamine dimesylate in an open-label study.

OBJECTIVE To assess the effects of lisdexamfetamine dimesylate (LDX) on executive function (EF) behaviors in children with attention-deficit/hyperactivity disorder (ADHD). METHODS This observational, open-label, 7-week, dose-optimization study of LDX (20-70 mg/day) in children with ADHD evaluated efficacy with the ADHD Rating Scale IV; safety measures included adverse events (AEs). EF was assessed with the Behavior Rating Inventory of Executive Function (BRIEF). Post hoc analyses examined BRIEF scores by sex, ADHD subtype, comorbid psychiatric symptoms, and common treatment-emergent AEs (TEAEs). ADHD Rating Scale IV scores were assessed in subjects categorized by baseline BRIEF global executive composite T scores with clinically significant (≥65) or not clinically significant (<65) impairment in EF. RESULTS Mean (standard deviation) change from baseline to endpoint for BRIEF of -17.9 (12.5) for Global Executive Composite, -15.4 (12.6) for Behavioral Regulation Index, and -17.6 (12.3) for Metacognition Index demonstrated improvement with LDX (pooled doses; p < 0.0001 for all). Improvements in BRIEF scores were seen regardless of sex, ADHD subtype, comorbid psychiatric symptoms, common TEAEs, or baseline EF impairment category. TEAEs included decreased appetite, decreased weight, irritability, insomnia, headache, upper abdominal pain, and initial insomnia. CONCLUSIONS Improvements were demonstrated in EF behaviors and ADHD symptoms with LDX. LDX safety profile was consistent with long-acting stimulant use.
The pregnane X receptor locus is associated with susceptibility to inflammatory bowel disease.

BACKGROUND & AIMS The pregnane X receptor (PXR) regulates an array of genes involved in the response to xenobiotics. Evidence from several studies suggests that xenobiotic metabolism may play a role in inflammatory bowel disease (IBD) and that low levels of PXR may be associated with disease expression. The aim of this study was to investigate the association of functional polymorphisms of the PXR encoding gene (NR1I2) with disease in IBD populations. METHODS This was a case-control study examining 8 NR1I2 single nucleotide polymorphisms (SNPs) previously associated with altered activity of PXR-regulated genes in an Irish cohort including 422 patients with IBD and 350 ethnically matched controls. RESULTS We showed significant associations of NR1I2 with IBD, Crohn's disease (CD), and ulcerative colitis (UC) groups compared with a control population for SNPs -23585 (IBD: P = .000008; odds ratio [OR], 1.62; 95% confidence interval [CI], 1.31-2.00) and -24381 (IBD: P = .0002; OR, 1.50; 95% CI, 1.21-1.84). SNPs 7635 (P = .0008) and 8055 (P = .007) were found to be associated with IBD and CD but not UC. Risk of IBD is strongly correlated to genotype at these sites, especially for the -25385CC genotype (P = .00001; OR, 2.92; 95% CI, 1.87-4.66). We also show specific correlations of IBD phenotype with genotypes and haplotypes in the patient group. CONCLUSIONS These results show that genetic variation in the PXR encoding gene, which has been associated with altered activity of PXR, is strongly associated with susceptibility to IBD, CD, and UC.
Pharmacists' patterns of use, knowledge, and attitudes toward complementary and alternative medicine.

OBJECTIVES To determine the patterns of use, knowledge, and attitudes toward complementary and alternative medicine (CAM) among pharmacists. DESIGN Anonymous self-administered survey. SETTINGS 61st International Congress of International Pharmaceutical Federation (FIP), Singapore Traditional Chinese Medicine (TCM) Research Symposium, and retail and hospital pharmacies in Singapore. SUBJECTS Pharmacists attending the FIP Congress, TCM Symposium, and pharmacists working in retail and hospital pharmacies. OUTCOME MEASURES Frequency of use of different types of CAM by demographic attributes, knowledge scores, and attitudinal scores. RESULTS Of the 430 surveys received, 420 fit the criteria for inclusion. Of the pharmacists, 84.3% reported use of some form of CAM in their lifetime. CAM was used for chronic and acute conditions. There was no difference in use of CAM based on gender and income. The mean score on the knowledge test was 7.23 of 10. Of the pharmacists, 72.6% were moderately satisfied with CAM and 79.4% indicated they would recommend CAM to family and friends. They received information on CAM from books/magazines (64%), friends/family (35.7%), and the Internet (31.4%). Eighty-one percent (81%) of pharmacists felt they had inadequate skills and knowledge to counsel patients on herbal medicine and 90.5% felt the professional curricula should have more components on CAM. CONCLUSIONS The use of CAM among pharmacists is widespread and prevalent. The increased use of CAM necessitates the need for more education. Pharmacists acknowledge that CAM may have a place in health care and accept their role as information providers. There is also a need for reliable sources of information on CAM.
The Wisdom to Know the Difference

The ability to regulate emotions is central to well-being, but healthy emotion regulation may not merely be about using the “right” strategies. According to the strategy-situation-fit hypothesis, emotion-regulation strategies are conducive to well-being only when used in appropriate contexts. This study is the first to test the strategy-situation-fit hypothesis using ecological momentary assessment of cognitive reappraisal—a putatively adaptive strategy. We expected people who used reappraisal more in uncontrollable situations and less in controllable situations to have greater well-being than people with the opposite pattern of reappraisal use. Healthy participants (n = 74) completed measures of well-being in the lab and used a smartphone app to report their use of reappraisal and perceived controllability of their environment 10 times a day for 1 week. Results supported the strategy-situation-fit hypothesis. Participants with relatively high well-being used reappraisal more in situations they perceived as lower in controllability and less in situations they perceived as higher in controllability. In contrast, we found little evidence for an association between greater well-being and greater mean use of reappraisal across situations.
Early growth response gene 1 (EGR1) is deleted in estrogen receptor‐negative human breast carcinoma

Patients with estrogen receptor (ER)‐positive and ER‐negative breast carcinomas differ in terms of disease progression, treatment regimens, and prognosis. The mechanism underlying the biologic differences of the two groups is understood poorly. Array comparative genome hybridization (CGH) on breast carcinoma subtypes demonstrated a consistent association between loss in regions of chromosome 5q and ER‐negative tumors. It was shown previously that early growth response gene 1 (EGR1) on 5q acts like a tumor‐suppressor gene, with its expression repressed in breast carcinomas.
Transcranial Sonographic Alterations of Substantia Nigra and Third Ventricle in Parkinson's Disease with or without Dementia

Background: Numerous studies have demonstrated that patients with Parkinson's disease (PD) have a higher prevalence of substantia nigra (SN) hyperechogenicity compared with controls. Our aim was to explore the neuroimaging characteristics of transcranial sonography (TCS) of patients with PD and those with PD with dementia (PDD). The correlation between the echogenicity of the SN and clinical symptoms in Chinese patients with PDD was also assessed. Methods: The ratios of SN hyperechogenicity (SN+), maximum sizes of SN+, and widths of third ventricle (TV) were measured using TCS for all the recruited patients. Data were analyzed using one-way analysis of variance, rank-sum test, Chi-square test, and receiver-operating characteristic (ROC) curve analysis. Results: The final statistical analysis included 46 PDD patients, 52 PD patients, and 40 controls. There were no significant differences in ratios of SN+ and maximum sizes of SN+ between PDD and PD groups (P > 0.05). TV widths were significantly larger in PDD group (7.1 ± 1.9 mm) than in PD group (6.0 ± 2.0 mm) and controls (5.9 ± 1.5 mm, P < 0.05); however, the ratios of enlarged TV did not differ among the three groups (P = 0.059). When cutoff value was set at 6.8 mm, the TV width had a relatively high sensitivity and specificity in discriminating between PDD and PD groups (P = 0.030) and between PDD group and controls (P = 0.003), based on ROC curve analysis. In PDD patients, SN+ was more frequently detected in akinetic-rigid subgroup, and patients with SN+ showed significantly higher Hoehn and Yahr stage and Nonmotor Symptoms Questionnaire scores (P < 0.05). Conclusions: Compared to Chinese patients with PD, patients with PDD had a wider TV, altered SN sonographic features, and more severe clinical symptoms. Our findings suggest that TCS can be used to assess brain atrophy in PD and may be useful in discriminating between PD with and without dementia.