Miracle-dz/UniFAR-FTUs huggingface dataset:
An Evolutionarily Conserved Function of Proliferating Cell Nuclear Antigen for Cdt1 Degradation by the Cul4-Ddb1 Ubiquitin Ligase in Response to DNA Damage*

The DNA replication licensing factor Cdt1 is degraded by the ubiquitin-proteasome pathway during S phase of the cell cycle, to ensure one round of DNA replication during each cell division and in response to DNA damage to halt DNA replication. Constitutive expression of Cdt1 causes DNA re-replication and is associated with the development of a subset of human non-small cell-lung carcinomas. In mammalian cells, DNA damage-induced Cdt1 degradation is catalyzed by the Cul4-Ddb1-Roc1 E3 ubiquitin ligase. We report here that overexpression of the proliferating cell nuclear antigen (PCNA) inhibitory domain from the CDK inhibitors p21 and p57, but not the CDK-cyclin inhibitory domain, blocked Cdt1 degradation in cultured mammalian cells after UV irradiation. In vivo soluble Cdt1 and PCNA co-elute by gel filtration and associate with each other physically. Silencing PCNA in cultured mammalian cells or repression of pcn1 expression in fission yeast blocked Cdt1 degradation in response to DNA damage. Unexpectedly, deletion of Ddb1 in fission yeast cells also accumulated Cdt1 in the absence of DNA damage. We suggest that the Cul4-Ddb1 ligase evolved to ubiquitinate Cdt1 during normal cell growth as well as in response to DNA damage and a separate E3 ligase, possibly SCFSkp2, evolved to either share or take over the function of Cdt1 ubiquitination during normal cell growth and that PCNA is involved in mediating Cdt1 degradation by the Cul4-Ddb1 ligase in response to DNA damage.
Platelet function and fibrinolytic activity during rest and exercise in borderline hypertensive patients

Abstract. In this study we examined whether the reduced fibrionolysis and increased platelet activity that are known to occur in hypertension are already present in borderline hypertension. Twelve patients with ‘borderline’ hypertension (diastolic blood pressure 90–95 mmHg) were found to have substantially reduced fibrinolytic activity, both at rest and during exercise, compared with 12 normotensive controls. Euglobulin clot lysis time (ECLT) was significantly higher in hypertensive subjects (218 min vs. 145 min; P < 0.05), and this difference persisted during exercise. Resting tissue plasminogen activator activity (t‐PA) did not differ in the two groups, but the brisk increase in t‐PA in controls during exercise (0.64 rising to 1.4IU mL‐1; P < 0.01) did not occur to the same extent in the borderline hypertensive subjects. Levels of the fast‐acting t‐PA inhibitor, normally referred to as PAI‐1, were considerably higher in hypertensives (9.22 vs. 4.41 IU mL‐1; P < 0.02), and this difference persisted in the upright posture, indicating a decrease in fibrinolytic activity. Platelet aggregability induced by ADP in vitro was not significantly higher in the hypertensive subjects, but indices of platelet activity in vivo (B‐TG and PF‐4 levels) revealed enhanced platelet function in the hypertensives. These results indicate that the indicators of altered haemostatic function known to occur in hypertension, namely diminished fibrinolytic activity and increased platelet function, are already detectable during the very earliest stage of the disease.
Evaluation of human immunodeficiency virus (HIV) type 1 RNA levels in cerebrospinal fluid and viral resistance to zidovudine in children with HIV encephalopathy.

The amount of human immunodeficiency virus (HIV) type 1 RNA and the presence of a codon 215 mutation indicative of zidovudine resistance were evaluated in cerebrospinal fluid (CSF) and plasma obtained from HIV-1-infected children. The level of HIV-1 RNA in CSF was highest in children with severe encephalopathy (n = 25; median, 430 copies/mL; range, 0-2.2 x 10(5) copies/mL) followed by the moderately encephalopathic (n = 7; median, 330; range, 0-1130) and nonencephalopathic groups (n = 9; median, 0; range, 0-566) (P = .007). There was no correlation between CSF and plasma HIV-1 RNA levels. Five of 7 children with the codon 215 mutation in CSF had a progression of encephalopathy, while all 8 children with wild type codon 215 had improved or stable disease during zidovudine treatment (P = .007). These findings suggest that increased viral replication and emergence of drug-resistant HIV-1 variants within the central nervous system may play a role in progression of HIV encephalopathy.
Two pathways for RNase E action in Escherichia coli in vivo and bypass of its essentiality in mutants defective for Rho‐dependent transcription termination

The endonuclease RNase E of Escherichia coli is essential for viability, but deletion of its C‐terminal half (CTH) is not lethal. RNase E preferentially acts on 5′‐monophosphorylated RNA whose generation from primary transcripts is catalysed by RppH, but ΔRppH strains are viable. Here we show that the RNase E‐ΔCTH ΔRppH combination is lethal, and that the lethality is suppressed by rho or nusG mutations impairing Rho‐dependent transcription termination. Lethality was correlated with defects in bulk mRNA decay and tRNA processing, which were reversed by the rho suppressor. Lethality suppression was dependent on RNase H1 or the helicase UvsW of phage T4, both of which act to remove RNA–DNA hybrids (R‐loops). The rho and nusG mutations also rescued inviability of a double alteration R169Q (that abolishes 5′‐sensing) with ΔCTH in RNase E, as also that of conditional RNase E deficiency. We suggest that the ΔCTH alteration leads to loss of a second 5′‐end‐independent pathway of RNase E action. We further propose that an increased abundance of R‐loops in the rho and nusG mutants, although ordinarily inimical to growth, contributes to rescue the lethality associated with loss of the two RNase E cleavage pathways by providing an alternative means of RNA degradation.
Pharmacogenetics in perioperative medicine

Purpose of review This review will discuss the most recent developments in pharmacogenetics of commonly used perioperative medications, new collaboration networks in the field of personalized medicine, and future clinical implications of pharmacogenetics. Recent findings Evidence now suggests that pharmacogenetics has a role in the effects of analgesic, sedative, beta-blocker, local anesthetic, antiemetic, and obstetric medications. Variants in the &mgr; opioid receptor gene change the analgesic effects of morphine. Additional opioids recently studied include remifentanil, methadone, tramadol, and codeine. Ibuprofen's clearance varies with CYP2C9*3 genotype. Midazolam is primarily metabolized by the CYP3A4/CYP3A5 enzymes. Enzyme induction was found to be about 50% greater with CYP3A5*3 homozygous genotype. Variations in minimum alveolar concentrations of volatile anesthetics and subcutaneous lidocaine efficacy have been attributed in part to melanocortin-1 receptor variants. Metoprolol achieved different effects in patients with CYP2D6 and beta1-receptor polymorphisms. Genetic background of the beta2-receptor contributes to susceptibility for experiencing preterm labor. The Pharmacogenomics Research Network and the Clinical Pharmacogenetics Implementation Consortium are partnerships of researchers who are dedicated to elucidating how the genome contributes to an individual patient's medication responses. Summary In the near future, pharmacogenetic approaches may facilitate personalized perioperative intervention trials.
Family residency and psychosomatic problems among adolescents in Sweden: The impact of child-parent relations

Aims: Profound changes in family structure took place in many countries, during the second part of the previous century. The purpose of this paper is to analyse the association between the type of family residency and psychosomatic problems in younger and older adolescents, particularly focusing on alternate residency, and to examine the impact of child-parent relations. Methods: We used data collected in 2009 by Statistics Sweden among 172,298 Swedish students in Grade 6 and Grade 9 (approximate ages 12 and 15 years old); comprising 80% and 86%, respectively, of the entire population of students in those grades. We collected the data with a questionnaire, completed anonymously in school: We used the Psychosomatic Problems (PSP) scale as the outcome measure. Results: The type of family residency showed a weaker association with psychosomatic problems than the child-parent relationships did. Living in non-intact families increased the probability of adolescent psychosomatic problems by 0–0.05, compared to intact families. In Grade 9, there were no differences in psychosomatic problems between the students in alternate residency and those living with their two parents; and in Grade 6, these differences were relatively small. In comparison, a worse relationship with parents increased the probability of psychosomatic problems by 0.11–0.17, depending on the school grade and type of family residency. Conclusions: The structure of the family, as well as the child-parent relationships needs to be taken into account, to properly estimate the magnitude of the family situation as a determinant of adolescent psychosomatic problems. Our results justify universal intervention at the policy level.
Pyrrolidine dithiocarbamate augments IL-10, inhibits TNF-alpha, MIP-1alpha, IL-12, and nitric oxide production and protects from the lethal effect of endotoxin.

During endotoxemia, immune cells activated by lipopolysaccharide (LPS) produce various inflammatory mediators, including cytokines and nitric oxide (NO). The genes of several mediators are activated in part by the rapid binding of the transcription factor nuclear factor-kappa B (NF-kappaB) to its promoter. The induction of this transcription factor can be blocked by a wide range of antioxidants, including pyrrolidine dithiocarbamate (PDTC). Here we investigated in mice the effect of this compound on the plasma tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), macrophage inflammatory protein-1alpha (MIP-1alpha), and nitric oxide (NO) response to intraperitoneal (i.p.) injection of LPS. Pretreatment of animals with PDTC (10-100 mg/kg) 30 min prior to LPS challenge (4 mg/kg, i.p.) decreased plasma TNF-alpha, IL-12, MIP-1alpha, and nitrite/nitrate (breakdown products of NO) concentrations, but enhanced plasma levels of IL-10. Moreover, pretreatment of mice with PDTC (10-100 mg/kg, i.p.) did not alter LPS-induced (4 mg/kg) production of IL-1alpha, IL-6, and IFN-gamma. Finally, PDTC (100 mg/kg) protected the mice against LPS (100 mg/kg)-induced lethality. These results indicate that blockade of the NF-kappaB pathway by PDTC has potent anti-inflammatory action in systemic inflammatory processes.
The association of hypertension with asymptomatic cardiovascular organ damage in rheumatoid arthritis

Abstract Background: The association of hypertension with asymptomatic cardiovascular organ damage in patients with rheumatoid arthritis (RA) has been little studied by echocardiography. Methods: Echocardiography was done in 134 RA patients and 102 healthy controls. Left ventricular (LV) geometry was considered abnormal if LV mass index or relative wall thickness was increased. LV diastolic dysfunction was considered present if septal early diastolic tissue velocity <8 cm/s. Systemic arterial compliance (SAC) was assessed from stroke volume index/pulse pressure ratio. Results: The hypertensive RA patients (n = 72) had higher inflammatory activity, older age and more diabetes than the normotensive RA patients (n = 62) (all p < 0.05). Rates of abnormal LV geometry, LV diastolic dysfunction and lower SAC were higher among the hypertensive RA patients (p < 0.05), but similar between normotensive RA patients and controls. Hypertension was associated with a 3-fold higher prevalence both for abnormal LV geometry (odds ratio 2.89 [95% confidence interval 1.09–7.63], p = 0.03) and for diastolic LV dysfunction (odds ratio 2.92 [95% confidence interval 1.14–7.46], p = 0.03) as well as lower SAC (β = 0.31, p = 0.001) independent of age, gender, diabetes and inflammatory activity measured by erythrocyte sedimentation rate. Conclusion: The presence of asymptomatic cardiovascular organ damage in RA patients is closely associated with hypertension independent of inflammatory activity.
Brain SPECT findings in long-term inhalant abuse

This study evaluates brain perfusion in long-term inhalant abusers of toluene, acetone, benzene and derivatives. Ten patients in the age range 16-18 years (mean, 17.3±0.67 years), who had been inhalant dependent for a mean period of 48.3±6.2 months, but who had stopped using inhalants for 1-11 months (mean, 5.4±2.1 months), and ten controls (mean age, 17.3±0.67 years) were included in the study. Psychiatric tests, biochemical tests and Tc-99m-hexamethylpropyleneamine oxime (Tc-99m-HMPAO) brain single photon emission computed tomography (SPECT) were performed on all patients. Brain SPECT images were evaluated qualitatively and quantitatively. The mean IQ level was found to be 84 (by psychological tests). Brain SPECT showed non-homogeneous Tc-99m-HMPAO uptake and hypoperfusion areas in all patients (five left temporal, one right temporal, two left temporal plus bilateral parietooccipital, one biparietal and one left temporoparietal). Seven patients had hyperperfused foci (unifocal in five patients and multifocal in two patients). Six hyperperfused foci were in a parietal and one in a temporoparietal location. This study suggests that inhalant dependents exhibit serious abnormalities in brain SPECT images, including hypo-hyperperfusion foci and non-homogeneous uptake of the radiopharmaceutical. A further study with a larger number of patients and long-term follow-up may help to reach a more specific conclusion.
TEM studies of plasma nitrided austenitic stainless steel

Cross‐sectional transmission electron microscopy and X‐ray phase analysis were used to study the structure of a layer formed during nitriding the AISI 316L stainless steel at temperature 440°C. It was found that the applied treatment led to the formation of 6‐μm‐thick layer of the S‐phase. There is no evidence of CrN precipitation. The X‐ray diffraction experiments proved that the occurred austenite lattice expansion – due to nitrogen atoms – depended on the crystallographic direction. The cross‐sectional transmission electron microscopy studies showed that the layer consisted of a single cubic phase that contained a lot of defects such as dislocations, stacking faults, slip bands and twins. The high‐resolution electron microscopy observations were applied to study the defect formation due to the nitriding process. It was shown that the presence of great number of stacking faults leads to formation of nanotwins. Weak, forbidden {100} reflections were still another characteristic feature of the S‐phase. These were not detected in the X‐ray spectra of the phase. Basing on the high‐resolution electron microscopy studies it can be suggested that the short‐range ordering of the nitrogen atoms in the octahedral sites inside the f.c. c. matrix lattice takes place and gives rise to appearance of these spots. It is suggested that the cubic lattice undergoes not only expansion but also slight rombohedral distortion that explains differences in the lattice expansion for different crystallographic directions.
Towards understanding the origin of threshold voltage instability of AlGaN/GaN MIS-HEMTs

GaN-power HEMTs with insulated gate structure suffer from threshold voltage drifts (ΔVth) under forward gate bias stress. We present a systematical approach to characterize the phenomenon and understand the dominant physical mechanisms causing this effect. We found out that ΔVth is caused by traps with a broad distribution of trapping and emission time constants. This distribution is analyzed using so called Capture Emission Time (CET) maps known from the study of bias temperature instability (BTI) in CMOS devices. Physical models, which could explain the broad distribution of time constants, are discussed.
Heterotopic expression of B-class floral homeotic genes PISTILLATA/GLOBOSA supports a modified model for crocus (Crocus sativus L.) flower formation

For uncovering and understanding the molecular mechanisms controlling flower development in cultivated Crocus sativus and particularly the transformation of sepals in outer whorl (whorl 1) tepals, we have cloned and characterized the expression of a family of five PISTILLATA/GLOBOSA-like (PI/GLO-like) MADS-box genes expressed in the C. sativus flower. The deduced amino acid sequences of the coded proteins indicated high homology with members of the MADS-box family of transcription factors, and particularly with other members of the PI/GLO family of MADS-box proteins that control floral organ identity. PI/GLO expression studies in cultivated C. sativus uncover the presence of PI/GLO transcripts not only in the second and third whorls of flower organs as expected, but also in the outer whorl tepals that are the sepals in most typical flowers. This heterotopic expression of both B-class genes: PI/GLO and AP3/DEF, known to form heterodimers for stamens and petals (petaloid inner whor l–whorl 2-tepals in C. sativus), explains the homeotic transformation of sepals into outer whorl tepals in this species. Analysis of PI/GLO sequences from C. sativus for putative targets to known micro-RNAs (miRNAs) showed that the target site for ath-miRNA167 found in Arabidopsis thaliana PI is not present in C. sativus, however, the PI/GLO sequences may be regulated by an ath-miRNA163.
US nurse labor market dynamics are key to global nurse sufficiency.

OBJECTIVES To review estimates of U.S. nurse supply and demand, document trends in nurse immigration to the United States and their impact on nursing shortage, and consider strategies for resolving the shortage of nurses in the United States without adversely affecting health care in lower-income countries. PRINCIPAL FINDINGS Production capacity of nursing schools is lagging current and estimated future needs, suggesting a worsening shortage and creating a demand for foreign-educated nurses. About 8 percent of U.S. registered nurses (RNs), numbering around 219,000, are estimated to be foreign educated. Eighty percent are from lower-income countries. The Philippines is the major source country, accounting for more than 30 percent of U.S. foreign-educated nurses. Nurse immigration to the United States has tripled since 1994, to close to 15,000 entrants annually. Foreign-educated nurses are located primarily in urban areas, most likely to be employed by hospitals, and somewhat more likely to have a baccalaureate degree than native-born nurses. There is little evidence that foreign-educated nurses locate in areas of medical need in any greater proportion than native-born nurses. Although foreign-educated nurses are ethnically more diverse than native-born nurses, relatively small proportions are black or Hispanic. Job growth for RNs in the United States is producing mounting pressure by commercial recruiters and employers to ease restrictions on nurse immigration at the same time that American nursing schools are turning away large numbers of native applicants because of capacity limitations. CONCLUSIONS Increased reliance on immigration may adversely affect health care in lower-income countries without solving the U.S. shortage. The current focus on facilitating nurse immigration detracts from the need for the United States to move toward greater self-sufficiency in its nurse workforce. Expanding nursing school capacity to accommodate qualified native applicants and implementing evidence-based initiatives to improve nurse retention and productivity could prevent future nurse shortages.
Correlation of Body Mass Index and Physical Activity Among 7- to 11-Year Children at Zahedan, Iran

Background: Childhood obesity is currently one of the major concerns in pediatric field. In recent literature, correlation of obesity with some behavioral factors such as physical activity (PA) received attention. Objective: The purpose of this study was to determine the relationship between body mass index (BMI) and PA. Materials and Methods: This cross-sectional study was carried out in 2012 on 548 randomly selected 7- to 11-year schoolchildren from Zahedan, Iran. The underweight, normal weight, overweight, and obesity status were all based on BMI percentiles for age and sex. Moderate to vigorous PA during the previous 7 days was assessed by a modified version of the Physical Activity Questionnaire for Children. Results: The prevalence of underweight, normal weight, overweight, and obesity among the participants was 18.3%, 47.9%, 11.8%, and 22.1%, respectively. Overweight and obesity were significantly higher among girls than boys. Mean PA score in participants was 2.4 ± 0.5. The results showed the PA score was significantly higher among boys than girls. The PA score had a significant association with BMI (P = .018), and it was greater in normal participants than in obese participants. Conclusion: On the basis of observed data and due to the impact of PA on BMI as an indicator of nutritional status and health, teaching children to have better nutrition and lifestyle changes is very important. Therefore, more studies should focus on childhood obesity prevention programs to prevent nonoverweight children from becoming overweight or obese in the future.
Environmental lead exposure during early childhood.

OBJECTIVE To determine the relative contribution of residential lead hazards to children's blood lead concentrations during early childhood. METHODS We enrolled children 6 months of age and followed them until 24 months of age. Blood and samples of dust, soil, water and paint were analyzed for lead at 6-month intervals, and interviews were conducted to estimate nutritional, behavioral, and demographic factors linked with lead exposure. RESULTS Of the 276 children enrolled, 249 (90%) were followed until 24 months of age. The geometric mean blood lead concentration of children at 6 months of age was 2.9 microg/dL (95% CI, 2.7-3.1). At 24 months of age, children's mean blood lead was 7.5 microg/dL; 82 (33%) had a blood lead level of > or = 10 microg/dL. In adjusted analyses, lead-contaminated floor dust, soil, and water contributed to children's lead intake throughout the first 2 years of life (P < .05). Lead-contaminated dust from window troughs was a source of lead exposure, especially in the second year of life. Dietary iron intake, but not calcium intake, was inversely associated with blood lead levels (P < .05). Blood lead concentration was over 50% higher in black than in white children (P = .0001). CONCLUSION Lead-contaminated house dust is the major source of lead intake during early childhood. Black children remain at increased risk for higher blood lead concentration after adjusting for environmental lead exposures and dietary intake.