Miracle-dz/UniFAR-FTUs huggingface dataset:
cAMP-dependent protein kinase, but not the cGMP-dependent enzyme, rapidly phosphorylates delta-CREB, and a synthetic delta-CREB peptide.

Phosphorylation of the cAMP response element binding protein (CREB) by the catalytic subunit of cAMP-dependent protein kinase (cAK) has been implicated in the cAMP-dependent stimulation of gene transcription. delta-CREB, a spliced variant of CREB, and CREBtide (KRREILSRRPSYR), a synthetic peptide based on the phosphorylation sequence in delta-CREB, were tested as substrates of cAK. Phosphorylation of delta-CREB (0.17 microM) was stoichiometric within 30 s when using a concentration of cAK which approximated the intracellular level (0.2 microM). The rate of phosphorylation of delta-CREB was comparable to the rates of the best physiological substrates of cAK tested. The rate of CREBtide phosphorylation was at least as great as that of delta-CREB, indicating that the peptide retained the determinants of delta-CREB which were responsible for substrate efficacy. The apparent Km of CREBtide phosphorylation by cAK was 3.9 microM, which is 10-fold lower than that of kemptide (Km = 39 microM), the synthetic peptide substrate most often employed for cAK measurement. The Vmax values were 12.4 mumol/(min.mg) for CREBtide and 9.8 mumol/(min.mg) for kemptide. The apparent Km of CREBtide phosphorylation by cGMP-dependent protein kinase (cGK) was 2.9 microM and the Vmax value was 3.2 mumol/(min.mg). Both delta-CREB and CREBtide were phosphorylated at a much slower rate by cGK as compared with cAK, implying that the high cAK/cGK specificity exhibited by delta-CREB was retained by the peptide. Taken together, the results indicated that delta-CREB and CREBtide are among the best substrates tested for cAK and suggested that phosphorylation of CREB by this enzyme could occur in intact cells. (ABSTRACT TRUNCATED AT 250 WORDS)
Structural basis for pH-insensitive inhibition of immunoglobulin G recycling by an anti-neonatal Fc receptor antibody

The neonatal Fc receptor FcRn plays a critical role in the trafficking of IgGs across tissue barriers and in retaining high circulating concentrations of both IgG and albumin. Although generally beneficial from an immunological perspective in maintaining IgG populations, FcRn can contribute to the pathogenesis of autoimmune disorders when an abnormal immune response targets normal biological components. We previously described a monoclonal antibody (DX-2507) that binds to FcRn with high affinity at both neutral and acidic pH, prevents the simultaneous binding of IgG, and reduces circulating IgG levels in preclinical animal models. Here, we report a 2.5 Å resolution X-ray crystal structure of an FcRn–DX-2507 Fab complex, revealing a nearly complete overlap of the IgG–Fc binding site in FcRn by complementarity-determining regions in DX-2507. This overlap explains how DX-2507 blocks IgG binding to FcRn and thereby shortens IgG half-life by preventing IgGs from recycling back into circulation. Moreover, the complex structure explains how the DX-2507 interaction is pH-insensitive unlike normal Fc interactions and how serum albumin levels are unaffected by DX-2507 binding. These structural studies could inform antibody-based therapeutic approaches for limiting the effects of IgG-mediated autoimmune disease.
The 70-kDa Heat Shock Proteins Associate with Glandular Intermediate Filaments in an ATP-dependent Manner (*)

Keratin polypeptides 8 and 18 (K8/18) are intermediate filament proteins expressed preferentially in glandular epithelia. We describe the identification, by co-immunoprecipitation from normal human colonic tissues and cultured cell lines, of the 70-kDa heat shock protein (hsp) and its related heat shock cognate protein as K8/18-associated proteins (hsp/c). The association is significant but sub-stoichiometric and occurs preferentially with the soluble rather than the cytoskeletal K8/18 fractions. Heat stress increases the level of soluble K8/18 in association with an increase in hsp70 levels and an increase in the stoichiometry of K8/18-hsp70 association. Identity of the associated proteins was confirmed by microsequencing of a tryptic digest of the purified associated protein and by using anti-hsp/c70-specific antibodies. The K8/18-hsp/c70 complex can be dissociated in a Mg-ATP-dependent manner that requires ATP hydrolysis. Binding of hsp to K8/18 can be reconstituted using purified bovine hsp70 and human K8/18 immunoprecipitates that have been depleted of bound hsp/c70 and increases slightly in the presence of ATP. The reconstituted K8/18-hsp70 complex can be again released in the presence of Mg-ATP. In addition, hsp70 binds to K8/18 without having a significant effect on in vitro filament assembly when added during or after assembly. Using an overlay assay, hsp70 binds exclusively to K8 in the presence of ATP. Our results show direct association of the hsp/c70 proteins with K8/18. This interaction may serve, at least in part, to regulate the function of these two abundant protein groups.
Low-dose flunarizine does not affect short-term fetal circulatory responses to acute asphyxia in sheep near term.

Asphyxia is one of the major causes of perinatal brain damage and neuronal cell loss, which may result in psychomotor deficits during later development. It has been shown previously that the immature brain can be protected from ischemic injury by flunarizine, a class IV calcium antagonist. However, cardiovascular side-effects of flunarizine, when applied at the dosages used in those studies, have been reported. Recently, the present authors were able to demonstrate that even by injecting flunarizine at a far lower dosage (1 mg kg-1 estimated bodyweight) neuronal cell damage, caused by occlusion of both carotid arteries for 30 min, can be reduced in fetal sheep near term. The aim of the present study was, therefore, to examine whether low-dose flunarizine affects fetal cardiovascular responses to acute asphyxia in sheep near term. Ten fetal sheep were chronically instrumented at a mean gestational age of 132 +/- 1 days (term is at 147 days). Fetuses from the study group received a bolus injection of flunarizine (1 mg kg-1 estimated fetal weight) 60 min before asphyxia, whereas the solvent was administered to the fetuses from the control group. Organ blood flows, physiological variables and plasma concentrations of catecholamines were measured before, during and after a single occlusion of uterine blood flow for 2 min (i.e. at 0, 1, 2, 3, 4, and 30 min). Before asphyxia, the distribution of combined ventricular output and physiological variables, as well as concentrations of catecholamines, in fetuses from the control group were in the normal range for chronically prepared fetal sheep near term. During acute asphyxia there was a redistribution of cardiac output towards the central organs accompanied by a pronounced bradycardia and a rapid increase in arterial blood pressure. After asphyxia circulatory centralization did not resolve quite as rapidly as it developed, but was almost completely recovered at 30 min after the insult. There were nearly no differences in the time course of physiological and cardiovascular variables measured before, during and after acute intrauterine asphyxia between the control and study groups. From the present study it was concluded that low-dose flunarizine does not affect short-term fetal circulatory responses to acute asphyxia in sheep near term.
Can we prevent sudden cardiac death in dialysis patients?

End-stage renal disease (ESRD) patients are at high risk for mortality. The annual death rate for prevalent US dialysis patients in 2004 was 230 deaths per 1000 patient-years (1). Cardiac disease is the largest single cause of death for both hemodialysis and peritoneal dialysis patients, accounting for 43% of all-cause mortality (1). In the United States Renal Data System (USRDS) database, arrhythmic mechanisms account for 58% of cardiac deaths (25% of all deaths) among peritoneal dialysis patients, and 64% of cardiac deaths (27% of all deaths) among hemodialysis patients (1). In the Hemodialysis (HEMO) (2) and Die Deutsche Diabetes-Dialyse Study (4D) (3) trials, sudden death accounted for 25 to 26% of the observed total mortality. The USRDS Cardiovascular Special Studies Center estimated a sudden cardiac death rate among 2002 prevalent US dialysis patients of approximately 7% per year (1). ESRD patients are particularly vulnerable to sudden cardiac death. Myocardial ischemia in the setting of obstructive coronary artery disease is likely an important contributor, but if it were the major contributor we would expect dialysis patients undergoing surgical coronary artery revascularization to be at low long-term risk for subsequent arrhythmic death. To the contrary, the annual mortality of dialysis patients ascribed to arrhythmic mechanisms after coronary artery bypass surgery was 7% per year, similar to the entire prevalent dialysis population, which implies that primary reliance on amelioration of myocardial ischemia may be an inadequate clinical strategy (4). Left ventricular hypertrophy (present in at least 75% of dialysis patients), rapid …
Does maternal depression predict young children's executive function? - a 4-year longitudinal study.

BACKGROUND Building on reports that parental maltreatment and neglect adversely affect young children's executive function (EF), this longitudinal study examined whether exposure to a more common risk factor, mothers' depressive symptoms, predicted individual differences in EF at school-age. METHODS We followed up at age 6 a socially diverse sample of 126 children (78 boys, 48 girls) for whom direct observations of mother-child interactions have been shown to predict gains in EF between the ages of 2 and 4. We used an EF latent factor based on scores from three tasks (Beads, Day/Night, Tower of London) that tapped working memory, inhibitory control and planning, as well as a latent growth model of mothers' Beck Depression Inventory factor scores at four time-points, and included age 6 verbal ability as a covariate in all analyses. RESULTS The intercept and slope for mothers' depressive symptoms each predicted unique variance in EF at age 6; these predictive effects remained significant when we also included: (a) age 2 working memory, (b) maternal education and (c) direct observations of maternal positive control at ages 2 and 6. CONCLUSION Our findings suggest that early exposure to mothers' depressive symptoms adversely affects children's developing EF, and that the chronicity of this exposure may matter.
Potential of an Injectable Polymer to Prevent Hyperacute Rejection of Ex Vivo Perfused Porcine Lungs

Background. Removal of xenoreactive antibodies in pig-to-human lung transplantation by columns or organ perfusions proofed to be unsatisfactory and associated with adverse effects. In an ex-vivo lung perfusion model, we evaluated the potential of a soluble trisaccharide polymer (GAS914) to bind α-Gal antibodies and to protect a pulmonary xenograft from hyperacute rejection (HAR) and pulmonary xenograft dysfunction. Methods. Porcine lungs were perfused with fresh human blood for 240 min. In the GAS914 treated group (n=6) the polymer was applied in three different concentrations. The control group (n=6) received no GAS914. Survival and function of perfused xenografts were monitored, and α-Gal antibodies as well as cytolytic anti-porcine antibodies analyzed. Results. In the GAS-treated group survival of lungs was significantly prolonged, pulmonary vascular resistance reduced, pulmonary edema prevented, and oxygenation improved. On histopathological evaluation application of GAS resulted in minimal graft injury and significantly less deposition of the terminal complement complex C5b-9. Following application of GAS914, up to 89.8% of IgG α-Gal, 79.5% of IgM and 73.6% of anti-porcine antibodies in the human blood were bound by the polymer. Subsequent perfusion of porcine lungs resulted in absorption of only 3% of the baseline IgG α-Gal antibodies in the GAS914 group, compared to 87% in the controls. Conclusions. In this ex-vivo lung perfusion model, a trisaccharide polymer prevented immediate HAR, due to effective removal of α-Gal antibodies. In combination with additional strategies GAS914 may be a valuable tool in overcoming HAR and dysfunction of pulmonary xenografts.
Evaluating the Effects of Metformin Use on Height in Children and Adolescents: A Meta-analysis of Randomized Clinical Trials.

IMPORTANCE Metformin hydrochloride use is increasing in children and adolescents. Previous meta-analyses have identified a large variability in the effects of metformin use on body mass index changes but have not considered height changes as a confounder, to our knowledge. OBJECTIVE To conduct a systematic review and meta-analysis of the effects of metformin use on height in children and adolescents. DATA SOURCES Computerized databases, including MEDLINE and EMBASE, were searched up to September 9, 2014, for terms related to metformin and childhood or adolescence. STUDY SELECTION Randomized clinical trials examining the effects of metformin use on height of participants younger than 19 years were considered eligible. Trials with cointerventions other than lifestyle changes were excluded. DATA EXTRACTION AND SYNTHESIS Height, weight, body mass index, age, sex, metformin dosage, and study duration were independently extracted by 2 reviewers. The weighted mean differences for changes in height, weight, and body mass index were compared between the metformin and control groups using random-effects models. MAIN OUTCOME AND MEASURE Height changes. RESULTS Ten studies were included, with a total of 562 participants, 330 (58.7%) of whom were female. The mean age within the studies ranged from 7.9 to 16.1 years, with a high variability in most studies. The duration of metformin interventions lasted from 3 to 48 months. Overall, height changes were not significantly different between the metformin and control groups. However, stratified analyses according to the cumulative metformin dose (in milligrams per day times the number of days of treatment) showed a greater increase in height with metformin use in the 5 studies providing the largest cumulative metformin doses (weighted mean difference, 1.0; 95% CI, 0.0 to 2.0 cm) but not in the 5 studies providing the lowest doses (weighted mean difference, -0.1; 95% CI, -0.7 to 1.0 cm) compared with the control group. CONCLUSIONS AND RELEVANCE Preliminary evidence suggests a dose-response relationship between metformin use and increases in height in children and adolescents compared with a control group. While an approximate 1-cm increase in height may appear small, it is likely underestimated given that many studies were of short duration and included older adolescents, potentially after epiphyseal growth plate closure.
Glycemic index, glycemic load and insulinemic index of Chinese starchy foods.

AIM To determine the glycemic index (GI), glycemic load (GL) and insulinemic index (II) of five starchy foods that are commonly used in Chinese diets. METHODS Ten healthy subjects aged between 20-30 years were recruited. Each subject was asked to consume 50 g of available carbohydrate portions of test foods and reference food. Finger capillary blood samples were collected at the start of eating and 15, 30, 45, 60, 90 and 120 min after consumption. The GI and II of foods were calculated from the ratio of incremental area under the glucose/insulin response curves of test and reference foods. The GL for each test food was determined from its GI value and carbohydrate content. RESULTS The results showed that brown rice elicited the highest postprandial glucose and insulin responses, followed by taro, adlay, yam and mung bean noodles, which produced the lowest. Among the five starchy foods, brown rice evoked the highest GI and GL at 82 ± 0.2 and 18 ± 0.2, followed by taro (69 ± 0.4, 12 ± 0.2), adlay (55 ± 0.4, 10 ± 0.2), yam (52 ± 0.3, 9 ± 0.0) and mung bean noodles (28 ± 0.5, 7 ± 0.2), respectively. The II values of the test foods corresponded with GI values. Similarly, brown rice gave the highest II at 81 ± 0.1, followed by taro (73 ± 0.3), adlay (67 ± 0.3), yam (64 ± 0.5) and mung bean noodles (38 ± 0.3). All five starchy foods had lower GI, GL and II than reference bread (P < 0.05). CONCLUSION The GI, GL and II values of starchy foods provide important information for the public to manage their diet and could be useful for the prevention of lifestyle-related diseases such as diabetes mellitus.
Ovarian follicular dynamics in heifers during early pregnancy.

Daily ultrasonic monitoring of individual follicles was used to compare follicular wave characteristics of nonbred (n = 6) and pregnant heifers (n = 6). The dominant follicle of the first wave (Wave 1) did not differ significantly between reproductive statuses for any endpoint. The dominant follicle of Wave 2 was the ovulatory follicle in all nonbred heifers. The maximum diameter of the dominant follicle of Wave 2 was greater (p less than 0.05) for the nonbred heifers (14.8 mm) than for the pregnant heifers (13.0 mm). The dominant follicle of Wave 3 was detected later (p less than 0.003; Day 19.7 vs. Day 17.3) and reached a greater diameter (p less than 0.05; 16.6 mm vs. 12.0 mm) in the nonbred than in the pregnant heifers. On the mean day of onset of luteolysis (Day 15.2) in the nonbred heifers, the dominant follicle was similar in diameter for the two groups. Within a few days, the follicle began to regress in the pregnant heifers but maintained or increased in diameter in the nonbred heifers so that a greater maximum diameter was attained. During Days 0 70 of pregnancy, the interval from emergence of a wave to the emergence of the next wave was constant (not significantly different; mean intervals, 8.5 9.8 days). The mean maximum diameter attained by the dominant follicles differed significantly among the first 6 follicular waves; diameter was greatest for Wave 1 (15.7 mm), smallest for Waves 2 (13.1 mm) and 3 (12.6 mm), and intermediate for Waves 4 (14.0 mm), 5 (13.7 mm), and 6 (14.5 mm). (ABSTRACT TRUNCATED AT 250 WORDS)
Size and Charge Selectivity of the Glomerular Filter in Patients with Insulin-Dependent Diabetes mellitus: Urinary Immunoglobulins and Glycosaminoglycans

Background: In diabetic nephropathy, a reduction in negative membrane charge in the glomerular filter, i.e., the number of sulphated groups of glycosaminoglycans, has been argued to lead to increases in excretion of negatively charged molecules, such as albumin and IgG4. However, albuminuria and an increased excretion rate of IgG may also be caused by an increase in radius or number of glomerular large pores. Methods: Timed urinary excretion rates of sulphated glycosaminoglycans, albumin, and IgG2, IgG4, and IgM were analyzed in 94 patients with insulin-dependent diabetes mellitus with different degrees of nephropathy and compared with the excretion rates in 26 control subjects. Sulphated glycosaminoglycans were measured spectrophotometrically after addition of 1,9-dimethylmethylene blue. Albumin and immunoglobulins were measured by immunoassays. Results: With increases in the albumin excretion rate the excretion of IgG2, IgG4, and IgM also increased, in contrast to a decrease in glycosaminoglycans and the ratio between IgG2 and IgG4 (selectivity index). This index decreased from 6.2 to 0.7 (median; p < 0.01). However, with linear regression analysis the excretion rates of albumin and immunoglobulins were not associated with those of glycosaminoglycans. Conclusion: In diabetic nephropathy changes in both large-pore number and in charge selectivity may be pathogenic mechanisms for albuminuria.
Methylation of the phosphatase‐transcription activator EYA1 by protein arginine methyltransferase 1: mechanistic, functional, and structural studies

The eyes absent (EYA) family proteins are conserved transcriptional coactivators with intrinsic protein phosphatase activity. They play an essential role in the development of various organs in metazoans. These functions are associated with a unique combination of phosphatase and transactivation activities. However, it remains poorly understood how these activities and the consequent biologic functions of EYA are regulated. Here, we demonstrate that 2 conserved arginine residues, R304 and R306, of EYA1 are essential for its in vitro phosphatase activity and in vivo function during Drosophila eye development. EYA1 physically interacts with protein arginine methyltransferase 1, which methylates EYA1 at these residues both in vitro and in cultured mammalian and insect cells. Moreover, we show that wild‐type, but not methylation‐defective, EYA1 associates with γ‐H2A.X in response to ionizing radiation. Taken together, our results identify the conserved arginine residues of EYA1 that play an important role for its activity, thus implicating arginine methylation as a novel regulatory mechanism of EYA function. —Li, X. , Eberhardt, A. , Hansen, J. N. , Bohmann, D. , Li, H. , Schor, N. F. Methylation of the phosphatase‐transcription activator EYA1 by protein arginine methyltransferase 1: mechanistic, functional, and structural studies. FASEB J. 31, 2327–2339 (2017). www.fasebj. org
Which Distribution Distances are Sublinearly Testable?

Given samples from an unknown distribution $p$ and a description of a distribution $q$, are $p$ and $q$ close or far? This question of "identity testing" has received significant attention in the case of testing whether $p$ and $q$ are equal or far in total variation distance. However, in recent work, the following questions have been been critical to solving problems at the frontiers of distribution testing: -Alternative Distances: Can we test whether $p$ and $q$ are far in other distances, say Hellinger? -Tolerance: Can we test when $p$ and $q$ are close, rather than equal? And if so, close in which distances? Motivated by these questions, we characterize the complexity of distribution testing under a variety of distances, including total variation, $\ell_2$, Hellinger, Kullback-Leibler, and $\chi^2$. For each pair of distances $d_1$ and $d_2$, we study the complexity of testing if $p$ and $q$ are close in $d_1$ versus far in $d_2$, with a focus on identifying which problems allow strongly sublinear testers (i.e., those with complexity $O(n^{1 - \gamma})$ for some $\gamma > 0$ where $n$ is the size of the support of the distributions $p$ and $q$). We provide matching upper and lower bounds for each case. We also study these questions in the case where we only have samples from $q$ (equivalence testing), showing qualitative differences from identity testing in terms of when tolerance can be achieved. Our algorithms fall into the classical paradigm of $\chi^2$-statistics, but require crucial changes to handle the challenges introduced by each distance we consider. Finally, we survey other recent results in an attempt to serve as a reference for the complexity of various distribution testing problems.