Miracle-dz/UniFAR-FTUs huggingface dataset:
Histidine‐stimulated divalent metal uptake in human erythrocytes and in the erythroleukaemic cell line HEL.92.1.7

The uptake of 65Zn by human erythrocytes was investigated in the presence of high (40 mm) and low (5 mm) concentrations of histidine and 0–500 μm cobalt, nickel, manganese and zinc. Varying concentrations of metal mono‐ and bis‐histidine complexes will be formed and the inhibition of 65Zn uptake could be correlated with the calculated complex concentrations to investigate competition between metals. For each metal, the calculated concentrations of bis‐histidine complex giving 50% inhibition of 65Zn uptake were similar at both 5 mm and 40 mm histidine. Manganese–bis‐histidine appeared to have a much higher affinity for the binding site than the other metal–bis‐histidine complexes, which had similar affinities to each other. Studies of the inhibition of histidine‐stimulated 54Mn uptake by the addition of manganese confirmed that manganese–bis‐histidine does act as a substrate for the transporter in a similar fashion to the other metals studied. In addition, human erythroleukaemic cells (HEL cells) were used as a model for erythroid precursor cells. l‐histidine, but not d‐histidine, stimulated 65Zn uptake in a saturable fashion. The other metals competed with zinc in a similar manner to that seen in erythrocytes, and the affinity for manganese–bis‐histidine was much greater than for the bis‐histidine complexes of the other three metals. Both the capacity for metal transport per cell, and the affinity of the transporter for the metal–bis‐histidine complexes, were much greater in the HEL cells than in the erythrocyte. It is suggested that histidine‐stimulated metal transport may play a role in the supply of metals to maturing erythroid cells.
Positive Transcription Elongation Factor b Activity in Compensatory Myocardial Hypertrophy is Regulated by Cardiac Lineage Protein-1

Emerging evidence illustrates the importance of the positive transcription elongation factor (P-TEF)b in control of global RNA synthesis, which constitutes a major feature of the compensatory response to diverse hypertrophic stimuli in cardiomyocytes. P-TEFb complex, composed of cyclin T and cdk9, is critical for elongation of nascent RNA chains via phosphorylation of the carboxyl-terminal domain of RNA polymerase (Pol) II. We and others have shown that the activity of P-TEFb is inhibited by its association with cardiac lineage protein (CLP)-1, the mouse homolog of human HEXIM1, in various physiological and pathological conditions. To investigate the mechanism of control of P-TEFb activity by CLP-1 in cardiac hypertrophy, we used a transgenic mouse model of hypertrophy caused by overexpression of calcineurin in the heart. We observed that the level of CLP-1 associated with P-TEFb was reduced markedly in hypertrophic hearts. We also generated bigenic mice (MHC–cyclin T1/CLP-1+/−) by crossing MHC–cyclin T1 transgenic mice with CLP-1 heterozygote. The bigenic mice exhibit enhanced susceptibility to hypertrophy that is accompanied with an increase in cdk9 activity via an increase in serine 2 phosphorylation of carboxyl-terminal domain and an increase in GLUT1/GLUT4 ratio. These mice have compensated systolic function without evidence of fibrosis and reduced lifespan. These data suggest that the reduced level of CLP-1 introduced in the background of elevated levels of cyclin T1 elevates derepression of P-TEFb activity and emphasizes the importance of the role of CLP-1 in the mechanism governing compensatory hypertrophy in cardiomyocytes.
Are Nonlinear Methods Necessary at the Zero Lower Bound?

This paper examines the importance of the zero lower bound (ZLB) constraint on the nominal interest rate by estimating three variants of a small-scale New Keynesian model: (1) a nonlinear model with an occassionally binding ZLB constraint; (2) a constrained linear model, which imposes the constraint in the filter but not the solution; and (3) an unconstrained linear model, which never imposes the constraint. The posterior distributions are similar, but important differences arise in their predictions at the ZLB. The nonlinear model fits the data better at the ZLB and primarily attributes the ZLB to a reduction in household demand due to discount factor shocks. In the linear models, the ZLB is due to large contractionary monetary policy shocks, which is at odds with the Fed’s expansionary policy during the Great Recession. Posterior predictive analysis shows the nonlinear model is partially able to account for the increase in output volatility and the negative skewness in output and inflation that occurred during the ZLB period, whereas the linear models predict almost no changes in those statistics. We also compare the results from our nonlinear model to the quasi-linear solution based on OccBin. The quasi-linear model fits the data better than the linear models, but it still generate too little volatility at the ZLB and predicts that a large policy shock caused the ZLB to bind in 2008Q4.
Genetic Diversity and Prevalence of Porcine Circovirus Type 2 in China During 2000-2019

As the major pathogen for porcine circovirus-associated disease (PCVAD), porcine circovirus type 2 (PCV2) is no longer treated as an emerging virus anymore. The wide distribution of PCV2 infection in China causes huge economic losses in the swine industry. Currently, it is generally believed that PCV2 has eight genotypes (PCV2a to PCV2h), with PCV2a, PCV2b, and PCV2d being widely distributed. To comprehensively explore the genetic diversity and prevalence of PCV2 in China, PCV-2 sequences submitted from China in the GenBank database were retrieved. With a total of 714 PCV2 strains were retrieved, we found that early-submitted PCV2 sequences were mainly collected from coastal provinces in the southeast part of China, which may indicate PCV2 was initially circulating in those regions. From 2002 to 2008, PCV2b was the dominant prevalent genotype in those retrieved sequences. From 2009, PCV2d became the dominant genotype in those sequences, dropping a hint that a potential shift of PCV2b to PCV2d might occur in 2009, which is similar to the patterns at the global level. In addition to the PCV2a, PCV2b, and PCV2d genotypes, novel strains were also characterized. We further revealed that the amino acid sequences consistency of PCV2a Cap is higher than those in other genotypes. Together, this study provided clues for the possible prevalent genotypes and dynamics of genetic diversity in China from 2000 to 2019.
Microarray and pathway analysis highlight Nrf2/ARE-mediated expression profiling by polyphenolic myricetin.

SCOPE Myricetin is a dietary flavonol and widely distributed in many edible plants. It has been reported to have many bioactivities and considered as a promising chemopreventive compound. The present study aimed to investigate the influences of myricetin on gene expressions in genome-wide and underlying mechanisms. METHODS AND RESULTS Among total 44K gene probes, myricetin treatment upregulated the signals of 143 gene probes (0.33% of total probes) and downregulated signals of 476 gene probes (1.08% of total probes) by greater than or equal to twofold in HepG2 cells. The network pathway analysis revealed that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated antioxidant response element (ARE) activation is involved in myricetin-induced genes expressions. Molecular data revealed that myricetin activated Nrf2-ARE pathway by inhibiting Nrf2 ubiquitination and protein turnover, stimulating Nrf2 expression and kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 modification. All of these events finally increased nuclear Nrf2 accumulation and ARE-binding activity to enhance ARE-mediated genes expressions. Additionally, treatment with Nrf2 small interfering RNA attenuated the myricetin-induced ARE activity and gene expression. CONCLUSION An Nrf2-mediated ARE activation is involved in myricetin-induced expression profiling in hepatic cells.
Empirical evaluation of very large treatment effects of medical interventions.

CONTEXT Most medical interventions have modest effects, but occasionally some clinical trials may find very large effects for benefits or harms. OBJECTIVE To evaluate the frequency and features of very large effects in medicine. DATA SOURCES Cochrane Database of Systematic Reviews (CDSR, 2010, issue 7). STUDY SELECTION We separated all binary-outcome CDSR forest plots with comparisons of interventions according to whether the first published trial, a subsequent trial (not the first), or no trial had a nominally statistically significant (P < .05) very large effect (odds ratio [OR], ≥5). We also sampled randomly 250 topics from each group for further in-depth evaluation. DATA EXTRACTION We assessed the types of treatments and outcomes in trials with very large effects, examined how often large-effect trials were followed up by other trials on the same topic, and how these effects compared against the effects of the respective meta-analyses. RESULTS Among 85,002 forest plots (from 3082 reviews), 8239 (9.7%) had a significant very large effect in the first published trial, 5158 (6.1%) only after the first published trial, and 71,605 (84.2%) had no trials with significant very large effects. Nominally significant very large effects typically appeared in small trials with median number of events: 18 in first trials and 15 in subsequent trials. Topics with very large effects were less likely than other topics to address mortality (3.6% in first trials, 3.2% in subsequent trials, and 11.6% in no trials with significant very large effects) and were more likely to address laboratory-defined efficacy (10% in first trials,10.8% in subsequent, and 3.2% in no trials with significant very large effects). First trials with very large effects were as likely as trials with no very large effects to have subsequent published trials. Ninety percent and 98% of the very large effects observed in first and subsequently published trials, respectively, became smaller in meta-analyses that included other trials; the median odds ratio decreased from 11.88 to 4.20 for first trials, and from 10.02 to 2.60 for subsequent trials. For 46 of the 500 selected topics (9.2%; first and subsequent trials) with a very large-effect trial, the meta-analysis maintained very large effects with P < . 001 when additional trials were included, but none pertained to mortality-related outcomes. Across the whole CDSR, there was only 1 intervention with large beneficial effects on mortality, P < . 001, and no major concerns about the quality of the evidence (for a trial on extracorporeal oxygenation for severe respiratory failure in newborns). CONCLUSIONS Most large treatment effects emerge from small studies, and when additional trials are performed, the effect sizes become typically much smaller. Well-validated large effects are uncommon and pertain to nonfatal outcomes.
How do memory and attention change with pregnancy and childbirth? A controlled longitudinal examination of neuropsychological functioning in pregnant and postpartum women

Current literature on cognitive functioning in pregnancy and postpartum is mixed, with most research showing deficits in memory and attention during pregnancy or no difference between pregnant participants and controls with little emphasis on the postpartum period. In the current study, we used a longitudinal controlled design and 42 primarily not depressed participants to compare pregnant women in the third trimester and approximately three months postpartum with matched controls over the same time period on neuropsychological domains including memory, attention, learning, visuospatial, and executive functioning. We also evaluated the role of mood and quality of life as potential moderators of cognitive functioning in pregnancy/postpartum. Results indicated no differences between controls and pregnant/postpartum women on neuropsychological measures at any time points. Self-reported memory difficulties, however, were higher in the pregnant/postpartum women. Pregnant and postpartum women had worse self-reported mood and quality of life than controls. Mood and quality of life slightly moderated specific measures of attention and verbal fluency; however, neither mood nor quality of life moderated overall neuropsychological functioning in either group. Number of previous pregnancies had no effect on the study findings. Results suggest differences in subjective memory complaints, but no differences in objective neuropsychological test results between controls and pregnant/postpartum women who are primarily not diagnosed with depression.
Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells

Lung cancer, with its most prevalent form non-small-cell lung carcinoma (NSCLC), is one of the leading causes of cancer-related deaths worldwide, and is commonly treated with chemotherapeutic drugs such as cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (EPO). However, studies have indicated that EPO not only promotes erythropoiesis in hematopoietic cells, but may also enhance survival of NSCLC cells. Here, we verified that the NSCLC cell line H838 expresses functional erythropoietin receptors (EPOR) and that treatment with EPO reduces cisplatin-induced apoptosis. To pinpoint differences in EPO-induced survival signaling in erythroid progenitor cells (CFU-E, colony forming unit-erythroid) and H838 cells, we combined mathematical modeling with a method for feature selection, the L1 regularization. Utilizing an example model and simulated data, we demonstrated that this approach enables the accurate identification and quantification of cell type-specific parameters. We applied our strategy to quantitative time-resolved data of EPO-induced JAK/STAT signaling generated by quantitative immunoblotting, mass spectrometry and quantitative real-time PCR (qRT-PCR) in CFU-E and H838 cells as well as H838 cells overexpressing human EPOR (H838-HA-hEPOR). The established parsimonious mathematical model was able to simultaneously describe the data sets of CFU-E, H838 and H838-HA-hEPOR cells. Seven cell type-specific parameters were identified that included for example parameters for nuclear translocation of STAT5 and target gene induction. Cell type-specific differences in target gene induction were experimentally validated by qRT-PCR experiments. The systematic identification of pathway differences and sensitivities of EPOR signaling in CFU-E and H838 cells revealed potential targets for intervention to selectively inhibit EPO-induced signaling in the tumor cells but leave the responses in erythroid progenitor cells unaffected. Thus, the proposed modeling strategy can be employed as a general procedure to identify cell type-specific parameters and to recommend treatment strategies for the selective targeting of specific cell types.
Clinical Comparison of Intraarticular Anterior Cruciate Ligament Reconstruction Using Autogenous Semitendinosus and Gracilis Tendons in Men versus Women *

Reconstruction of the anterior cruciate ligament using a hamstring tendon autograft has often been recommended for female athletes. We compared the results of acute, isolated, intraarticular anterior cruciate ligament reconstructions using quadruple-looped hamstring autografts in 39 female and 26 male patients. All reconstructions were performed by the same surgeon using a similar surgical technique and the same postoperative management. In each case, patients had Endobutton femoral fixation and either post or button fixation for the tibial side. The average follow-up was 40.9 months for women and 39.0 months for men. Objective analysis of results included examination for the presence of effusion and crepitus, Lachman and pivot shift testing, and KT-1000 arthrometer testing for side-to-side differences. Subjective analysis consisted of a 15-item visual analog scale completed by patients postoperatively, and pre- and postoperative Tegner and Lysholm scores. The clinical failure rate was 23% (9 of 39) for the female patients and 4% (1 of 26) for the male patients, which was statistically significant. There was also a trend toward increased laxity in female patients. Subjectively, the women also reported a higher frequency and intensity of pain. Based on Tegner activity levels, more of the men returned to their preinjury level of activity than did the women. When compared with the male patients, female patients had a significantly higher failure rate after reconstruction.
Beam-Blocked Channel Estimation for FDD Massive MIMO With Compressed Feedback

To fully exploit both multiplexing gain and array gain of massive multiple-input–multiple-output (MIMO), the channel state information must be obtained accurately at transmitter side (CSIT). However, conventional channel estimation solutions are not suitable for frequency-division duplexing (FDD) multiuser massive MIMO because of overwhelming pilot and feedback overhead. To reduce the pilot and feedback overhead of channel estimation in FDD systems, we propose a compressive channel estimation scheme for FDD massive MIMO systems in this paper, where the beam-blocked sparsity of massive MIMO channels in beamspace is leveraged. Particularly, we first propose a beam-blocked compressive channel estimation scheme, which can reduce the overhead for downlink training. Then, an optimal block orthogonal matching pursuit algorithm at the BS is proposed to acquire reliable CSIT from the limited number of pilots. Furthermore, an efficient algorithm for channel matrix recovery from separately quantized amplitude and phase of received signals is developed to efficiently decrease feedback load. Simulation results demonstrate that our proposed scheme outperforms conventional solutions.
Readmissions After Unauthorized Discharges in the Cardiovascular Setting

Background:Patients who left against medical advice (AMA) may be at higher risk for a hospital readmission if the unauthorized discharge was premature. The objective of this study is to examine the relationship between discharges AMA from nonfederal acute care hospitals and cardiovascular disease (CVD) hospital readmissions while addressing bias due to potential confounding, selection, and hospital-level clustering. Methods:This cross-sectional study used hospital discharge data covering the period between 2000 and 2005. The outcome variables captured readmissions for a CVD-related condition following an index CVD-related discharge. The covariate of interest was an indicator for a discharge AMA in the index hospitalization. The relationship between discharges AMA and 7-day, 31-day, and 180-day readmissions was examined using multivariate models with adjustment for clustering and selection bias. Results:The sample included 348,572 patients, of which 7001 (2%), 19,779 (6%), and 48,855 (14%) were readmitted within 7, 31, and 180 days, respectively. The percentage of patients who were readmitted (7 days; 31 days; 180 days) was higher among the AMA group versus the non-AMA group (2.2% vs. 1%, P < 0.002; 1.3% vs. 1%, P < 0.001; 1.2% vs. 1%, P = 0.02). The adjusted odds of a CVD-related readmission to the same hospital within 7 days, 31 days, and 180 days were 154% (P < 0.001), 51% (P < 0.001), and 19% (P = 0.004) higher, respectively, for patients who left AMA. Results were robust in examining readmissions to any hospital as well as corrections for observable selection bias through propensity score analysis. Conclusions:A discharge AMA among patients with a discharge diagnosis for CVD during the index hospitalization was predictive of CVD-related readmissions. The strength of the association between a discharge AMA and readmission was greatest within the first week after discharge.
Retrospective review of CT‐guided intervertebral disc biopsies performed at a tertiary referral centre for suspected osteodiscitis

Patients with osteodiscitis are often prescribed antibiotics prior to biopsy. There is controversy in the literature about whether antibiotic pre‐treatment prior to CT‐guided biopsy decreases the microbiological culture yield. Conclusions from previous studies are influenced by sample size error and selection bias. Our study, conducted in a large number of patients over a 10‐year period, clarifies this issue so that best clinical practice is assured.
Identifying and Engineering Ion Pairs in Adenylate Kinases

Molecular dynamics simulations were performed to study thermal stabilization of proteins via electrostatic interactions of ion pairs. Dynamic motions of four ion pairs previously proposed to be important in thermal stability of adenylate kinase from the thermophile Bacillus stearothermophilus were monitored during the simulation. One of the four ion pairs identified in the crystal structure, Lys180-Asp114, was not maintained in close contact suggesting that the ion pair does not contribute to thermal stability. Among the other three ion pairs, the ion pair Arg116-Glu198 was proposed to be the most important for stability. To predict behaviors of the ion pairs when engineered into a mesophilic homologue to increase stability, in silico mutants of adenylate kinase from the mesophile Bacillus subtilis were generated, and their molecular dynamics simulations were carried out. The ion pairs in the mutant simulations displayed similar behaviors to those in the simulation of the thermophilic protein. To validate the results of the simulations experimentally, the same mutants were produced in vitro and their thermal stabilities were measured using differential scanning calorimetry. In agreement with the simulations, the Lys180-Asp114 did not result in any increase in stability by itself or additive effect with other ion pairs, whereas a mutant with the Arg116-Glu198 exhibited the highest stability among the mutants having one of the four ion pairs. These results provide specific knowledge about stability in adenylate kinases and more generally suggest that molecular dynamics simulations can provide valuable information for identifying and engineering ion pairs.
Pharmacogenetic and case–control study on potassium channel related gene variants and genetic generalized epilepsy

Abstract Potassium channels are the targets of antiepileptic drugs (AEDs), which play important roles in the etiology of epilepsy. KCNA1 and KCNA2 encode mammalian Kv1.1 and Kv1.2 channels, which are essential roles in the initiation and shaping of action potentials. KCNV2 encodes Kv8.2, which is a regional overlap with Kv2 subunits as functional heterotetramers. In our study, we aim to investigate whether variants of KCNA1, KCNA2, and KCNV2 genes influence susceptibility to genetic generalized epilepsies (GGEs) and the efficacy of AEDs. Seven hundred sixty-seven subjects (284 healthy controls, 279 drug-responsive, and 204 drug-resistant GGE patients) were enrolled in our study. Eight variants of KCNA1, KCNA2, and KCNV2 were assessed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method. Results showed that there were no statistically significant correlations between the 8 variants of KCNA1, KCNA2, and KCNV2 and the risk/drug resistance of GGEs. In conclusion, our study suggests that KCNA1, KCNA2, and KCNV2 variants may not be involved in the risk/drug resistance of GGEs. Further multicenter, multiethnic, and large sample size pharmacogenetic and case–control studies are warranted to confirm our negative results.