Miracle-dz/UniFAR-FTUs huggingface dataset:
Nonadditivity of mutational effects at the folate binding site of Escherichia coli dihydrofolate reductase.

The function of the hydrophobic residues Leu28, Phe31, Ile50, and Leu54 at the folate binding site in Escherichia coli dihydrofolate reductase (5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 1.5.1.3) has been studied by a combination of site-specific mutagenesis and reaction kinetics. Studies suggest that the overall protein structure and kinetic sequence for the reaction did not change for the mutant proteins compared to the wild-type enzyme. Two sets of mutated reductases have been constructed. The first set, in which the side chains of the targeted amino acids are spatially well separated (approximately 8 A), includes two single mutants (L28Y and L54F) and a double mutant (L28Y-L54F). This set features residues that increased the side chain surface area and the potential for substrate interactions. Unexpectedly, nonadditivity in the free energy changes for the thermodynamics of ligand binding and in the rates of hydride transfer and product release is observed. The progressive increase in dihydrofolate binding is reversed for the sterically more crowded double mutant, with delta delta G ca. 3 kcal mol-1 less favorable than anticipated. On the other hand, the decrease in the rate constant for hydride transfer noted with the single mutants relative to the wild-type enzyme is reversed for the double mutant, so that delta delta G not equal to is ca. 2 kcal mol-1 more favorable. The second set of mutant proteins includes two double mutants (L28A-F31A and I50A-L54G) in which the selected amino acids are separated by three to four intervening amino acids and a quadruple mutant (L28A-F31A-I50A-L54G) in which the two sets L28A-F31A and I50A-L54G are spatially distinct. This set deleted the side chain surface area to lower the opportunity for substrate interactions. Nonadditivity in the free energy changes associated with key kinetic and thermodynamic parameters is again observed. The decrease in dihydrofolate binding found with the two double mutants is not observed with the quadruple mutant, which binds the substrate with delta delta G ca. 6.5 kcal mol-1 more favorable than expected. Similarly, the quadruple mutant has a larger rate constant for hydride transfer (-delta delta G not equal to congruent to 1.7 kcal mol-1) than predicted. One interpretation for the nonadditivity is that these residues interact through binding of the folate substrate, which serves to link molecularly remote side chain moieties within the active site. (ABSTRACT TRUNCATED AT 400 WORDS)
CGP 3466 increases survival of cultured fetal dopaminergic neurons.

PURPOSE To analyze the effects of CGP 3466, a compound structurally related to deprenyl, on survival and function of fetal ventral mesencephalic dopaminergic neurons. METHODS Free-floating roller tube (FFRT) cultures of rat (E14) ventral mesencephalon were treated with CGP 3466 [10-8 M] for 7 days. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) immunocytochemistry was performed to allow analysis of dopaminergic neurons and astroglial cells, respectively. Lactate dehydrogenase activity in the culture medium served as a measure of cell death. Control and CGP 3466 treated cultures were grafted into 6-hydroxydopamine-lesioned rats, and graft survival and function evaluated 9 weeks posttransplantation. RESULTS FFRT cultures treated with CGP 3466 contained significantly more (two fold) surviving TH-immunoreactive (-ir) neurons and decreased lactate dehydrogenase activity in the culture medium compared to controls. The actions of CGP 3466 seem not to be mediated by astroglial cells, since GFAP-ir cell numbers and GFAP protein levels did not differ between the groups. CGP 3466 pretreatment of donor cultures did not improve TH-ir cell survival in the grafts nor did it alter functional recovery as compared to controls. CONCLUSIONS CGP 3466 is an effective survival factor for cultured midbrain dopaminergic neurons. However, CGP 3466 pretreatment does not ameliorate survival and function of the dopaminergic neurons after grafting into a rat model of Parkinson's disease.
High-dimensional regression adjustments in randomized experiments

Significance As datasets get larger and more complex, there is a growing interest in using machine-learning methods to enhance scientific analysis. In many settings, considerable work is required to make standard machine-learning methods useful for specific scientific applications. We find, however, that in the case of treatment effect estimation with randomized experiments, regression adjustments via machine-learning methods designed to minimize test set error directly induce efficient estimates of the average treatment effect. Thus, machine-learning methods can be used out of the box for this task, without any special-case adjustments. We study the problem of treatment effect estimation in randomized experiments with high-dimensional covariate information and show that essentially any risk-consistent regression adjustment can be used to obtain efficient estimates of the average treatment effect. Our results considerably extend the range of settings where high-dimensional regression adjustments are guaranteed to provide valid inference about the population average treatment effect. We then propose cross-estimation, a simple method for obtaining finite-sample–unbiased treatment effect estimates that leverages high-dimensional regression adjustments. Our method can be used when the regression model is estimated using the lasso, the elastic net, subset selection, etc. Finally, we extend our analysis to allow for adaptive specification search via cross-validation and flexible nonparametric regression adjustments with machine-learning methods such as random forests or neural networks.
Validating the Inventory of School Motivation with Mainland Chinese Students

The purpose of this study was to validate the Inventory of School Motivation (Mainland China), which was developed specifically for use with Mainland Chinese students. Development of the instrument was grounded in Personal Investment theory and built on the Inventory of School Motivation instrument, which has been shown to accurately tap the achievement goal constructs hypothesized by the theory. Our data analysis indicated that the subscales in our instrument do represent dimensions associated with achievement goals: task, effort, competition, social power, affiliation, social concern, praise, and token. Participants were 458 undergraduates from five universities in eastern China. A series of nested confirmatory factor analyses supported a multidimensional school motivation structure. The results indicated both convergent and concurrent validity for the instrument with Mainland students. Relationships were found between Inventory of School Motivation goal constructs and global motivation goals, family-oriented goals, self-concepts, and learning approaches. Our findings support that Mainland Chinese students’ achievement goal orientation is consistent with that found in other cultures, suggesting that the instrument and the theory that informs it may further cross-cultural research in this area. At the same time, though, our findings show that Mainland students endorse some goal orientations differently from other groups, suggesting an inventory instrument specific to Mainland China is both important and necessary.
Cholecystectomy Alleviates Acalculous Biliary Pain in Patients With a Reduced Gallbladder Ejection Fraction

Background. We sought to determine whether a reduced gallbladder ejection fraction, (GBEF) ascertained by cholecystokinin-cholescintigraphy (CCK-CS), predicts symptomatic improvement after cholecystectomy. Methods. Medical records of patients who had had CCK-CS as well as negative results of gallbladder ultrasonography were reviewed, and patients were contacted by telephone to determine whether they had benefited from cholecystectomy. Results. There were 35 patients (33 female, 2 male) who had a decreased GBEF. Cholecystectomy was done in 30, of whom 20 (67%) had resolution of pain, 8 (27%) had partial improvement, and 2 (7%) had no change. The 5 who declined cholecystectomy included none (0%) who were pain free, 2 (40%) who had partial improvement, and 3 (60%) who had no change. The clinical outcome of the two groups was significantly different. There were 14 patients (10 female, 4 male) with a normal GBEF. The 2 patients who had cholecystectomy were asymptomatic. Of the 12 patients who did not have cholecystectomy, 9 (75%) were asymptomatic, 1 (8%) had some improvement, and 2 (17%) had no change. Conclusions. Cholecystectomy is indicated for patients with acalculous biliary pain and reduced GBEF, since symptoms will likely resolve with surgery and will persist without it. Cholecystectomy for patients with a normal GBEF should be considered only after failure of a nonoperative trial, since improvement usually occurs over time.
Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways

Inbreeding is a known risk factor for recessive Mendelian diseases and previous studies have suggested that it could also play a role in complex disorders, such as psychiatric diseases. Recent inbreeding results in the presence of long runs of homozygosity (ROHs) along the genome, which are also defined as autozygosity regions. Genetic variants in these regions have two alleles that are identical by descent, thus increasing the odds of bearing rare recessive deleterious mutations due to a homozygous state. A recent study showed a suggestive enrichment of long ROHs in schizophrenic patients, suggesting that recent inbreeding could play a role in the disease. To better understand the impact of autozygosity on schizophrenia risk, we selected, from a cohort of 180 Italian patients, seven subjects with extremely high numbers of large ROHs that were likely due to recent inbreeding and characterized the mutational landscape within their ROHs using Whole Exome Sequencing and, gene set enrichment analysis. We identified a significant overlap (17%; empirical p-value = 0.0171) between genes inside ROHs affected by low frequency functional homozygous variants (107 genes) and the group of most promising candidate genes mutated in schizophrenia. Moreover, in four patients, we identified novel and extremely rare damaging mutations in the genes involved in neurodevelopment (MEGF8) and in GABA/glutamatergic synaptic transmission (GAD1, FMN1, ANO2). These results provide insights into the contribution of rare recessive mutations and inbreeding as risk factors for schizophrenia. ROHs that are likely due to recent inbreeding harbor a combination of predisposing low-frequency variants and extremely rare variants that have a high impact on pivotal biological pathways implicated in the disease. In addition, this study confirms that focusing on patients with high levels of homozygosity could be a useful prioritization strategy for discovering new high-impact mutations in genetically complex disorders.
Turbo decoding in impulsive noise environment

Power line channels often suffer from impulsive interference generated by electrical appliances. Therefore, power line communication (PLC) degrades due to such impulsive interference. Middleton's class A noise model is frequently utilized for the modeling of such impulsive noise environments. We deal with turbo decoding for turbo codes over an additive white class A noise (AWAN) channel. We propose a turbo decoding which is suitable for AWAN channels. In addition, we show the BER (bit error rate) performance of the proposed turbo decoding in a class A noise environment by computer simulation.
Attitudes of schizophrenia outpatients toward psychiatric medications: relationship to clinical variables and insight.

BACKGROUND Attitude toward medications is important for medication adherence. A patient's drug attitude probably reflects a weighing of benefits against experienced or anticipated side effects or risks associated with the medication. We predicted (1) that drug attitudes would be more positive among schizophrenia patients taking second-generation compared to first-generation antipsychotics because of their greater tolerability and efficacy; and (2) that greater insight into illness, fewer extrapyramidal symptoms, and better social functioning would be associated with better attitudes toward psychiatric medication. METHOD In a cross-sectional study of 81 DSM-IV-diagnosed schizophrenia outpatients, we used multivariate analysis to determine clinical and demographic predictors of drug attitude. Drug attitude was assessed with the 10-item Drug Attitude Inventory (DAI). The relationship between the DAI and psychopathology, insight, extrapyramidal symptoms, level of functioning, and type of antipsychotic (first-generation versus second-generation versus clozapine) was examined. RESULTS Less awareness of current symptoms, presence of deficit symptoms, and employment predicted a negative attitude toward psychiatric medications. Extrapyramidal symptoms did not predict drug attitude. Drug attitudes were no different between patients taking first- or second-generation antipsychotics or clozapine. CONCLUSION Patients may not favor second-generation over first-generation antipsychotics, and extrapyramidal symptoms may not be a primary factor determining attitudes. While attitudes may be more positive in patients who recognize therapeutic drug effects, patients who work may view medications particularly negatively, possibly due to a sense of stigma. Because drug attitudes may reflect compliance and are difficult to predict, clinicians should inquire directly.
Clinical Response to Methylphenidate in Children Diagnosed with Attention-Deficit Hyperactivity Disorder and Comorbid Psychiatric Disorders

Objective: To determine to what extent the clinical response to methylphenidate (MPH) is affected by psychiatric comorbidities in children diagnosed with attention-deficit hyperactivity disorder (ADHD). Methods: Children (n = 267) aged 6 to 12 years diagnosed with ADHD participated in a double-blind, placebo-controlled, 2-week medication trial of MPH. Children were assessed using parent and teacher ratings and laboratory measures. Clinical response to MPH was determined by integrating all obtained measures. Results: Meeting criteria for conduct disorder (CD) was 27.7% of children, 40.8% for oppositional defiant (ODD), 47.2% for anxiety, and 7.9% for depressive disorders. The presence of CD or ODD was associated with good response to MPH. In contrast, children diagnosed with only comorbid anxiety were more likely to receive poor response rating independent of age, sex, or socioeconomic status. Low family income was found to be predictive of good response to MPH. Conclusions: The response to MPH in children with ADHD may be dependent on the type of comorbid disorder present. Clinical Trial Registration Number: NCT00483106
Arterial Compliance in Elderly Men with Chronic Kidney Disease

Background/Aim: Chronic kidney disease (CKD) is associated with decreased arterial compliance (AC). The stage of development of impaired arterial function in CKD in relation to loss of glomerular filtration rate (GFR) is not known. This study’s aim was to evaluate the relationship between GFR and AC in patients with CKD. Methods: We recruited 91 men aged ≧60 years with GFR 15–89 ml/min (mean 47 ± 21) to evaluate the relationship between GFR and AC in a cross-sectional study. We measured AC at the brachial artery with an oscillometric device (brachial artery distensibility; BAD). Results: There was no correlation between GFR and BAD (r = 0.08, p = 0.44). When stratified according to CKD stages, all groups showed decreased BAD compared with reference values, and there were no differences among them (one-way ANOVA). Bivariate analyses showed statistically significant correlations between BAD and age (r = –0.23, p = 0.03), antihypertensive drug number (r = 0.27, p = 0.009) and serum hemoglobin (r = 0.24, p = 0.02), but only age and antihypertensive drug number remained significant markers of BAD in a multiple regression model. Conclusion: Older men with CKD have impaired arterial function, but GFR and CKD stage have no relationship to the degree of decrease in brachial artery distensibility.
Using calcium chloride injection to improve tenderness of beef from mature cows.

The objective of this investigation was to determine the effect of calcium chloride (CaCl2) injection on Warner-Bratzler shear force (WBS), sensory panel ratings, and collagen traits of mature cow beef. Within 30 min of exsanguination, subprimals (top round, TR; top sirloin, TS; strip loin, SL) from alternate sides of the carcass were injected with a . 3 M CaCl2 solution (10% of the subprimal weight) and aged for 1, 7, or 14 d. The corresponding cold-boned cuts of the other side served as a control. Injecting CaCl2 eliminated the requirement for extended postmortem storage, as indicated by d 1 WBS. During the 14-d aging period, WBS of noninjected cuts decreased by 2.59 kg, whereas WBS of CaCl2-injected samples decreased by only . 35 kg. Compared with control cuts, CaCl2 injection improved (P less than .05) d-14 WBS of steaks from SL, TS, and TR by 41.1, 40.1, and 15.3%, respectively. Additionally, CaCl2-injected subprimals exhibited higher (P less than .05) sensory panel tenderness ratings, lower (P less than .05) amounts of detectable connective tissue, and shorter (P less than .05) sarcomere lengths. No differences (P greater than .05) were observed in any quantitative collagen traits between CaCl2-injected and control cuts. These results indicate that CaCl2 injection improved ultimate tenderness and sensory ratings of meat from mature cow cuts.
Interplay between electron–phonon and Coulomb interactions in cuprates

Evidence for strong electron–phonon coupling in high-Tc cuprates is reviewed, with emphasis on the electron and phonon spectral functions. Effects due to the interplay between the Coulomb and electron–phonon interactions are studied. For weakly doped cuprates, the phonon self-energy is strongly reduced due to correlation effects, while there is no corresponding strong reduction for the electron self-energy. Polaron formation is studied, focusing on effects of Coulomb interaction and antiferromagnetic correlations. It is argued that experimental indications of polaron formation in undoped cuprates are due to a strong electron–phonon interaction for these systems.
Motor plasticity in a juggling task in older adults-a developmental study.

OBJECTIVE to examine the plasticity of motor performance in old age. Older adults were instructed and trained in a juggling task and their performances were compared, first, within the group of older adults and, second, with the performances of children, youths and younger adults. SUBJECTS older adults, children, youths and younger adults (n = 1,206, range 6-89 years). METHODS participants were asked to learn a juggling task. Performance was tested before semantic instruction (pre-test 1), after semantic instruction (pre-test 2) and after 6 days of juggling practice (post-test). None of the participants had prior experiences in juggling. Results were analysed using repeated measure analysis of variance (ANOVA). RESULTS older adults showed a clear improvement in juggling performance after instruction and after six training sessions. On average, they reached performances comparable with those of children aged between 10 and 14 years, and with those of younger adults aged between 30 and 59 years. Only youths and younger adults aged between 15 and 29 years showed significantly higher performances at baseline, after instruction and after training. CONCLUSIONS older adults exhibit high reserve capacity, that is, a potential for learning 'new' motor skills.
Diagnostic Imaging of Diabetic Foot Disorders

The International Diabetes Federation estimates that 415 million people worldwide have diabetes mellitus. This number has more than doubled since 2000 and is projected to affect nearly 642 million people—10% of the global population—by 2040. In the National Health Service (NHS), the cost of treatment for diabetes accounts for 5% of the overall NHS budget, and half of this is spent on treating complications of the disease. Between 20% and 40% of health care resources spent on diabetes are spent on treating diabetic feet. Diabetes patients develop foot problems as a consequence of the combination of neurologic and vascular pathology. Sensory neuropathy causes loss of protective sensation and neuroarthropathy. Autonomic disturbance leads to stiff, dry, and scaly skin that is prone to cracking and less resistant to infection. Motor neuropathy leads to clawing of the toes due to imbalance of the intrinsic and extrinsic muscles, giving a clinical picture of an intrinsic minus foot. Diabetes patients can also develop an acquired gastrocnemius contracture with associated equinus deformity. Vascular pathology is both macroand micro-vascular, with diffuse sclerotic disease of the media and intima affecting vessels distal to the popliteal trifurcation. In addition, small vessel and capillary abnormalities lead to abnormal tissue perfusion. Disease of the vasa nervorum is likely to cause a significant part of the neuropathy. The altered immune response seen in diabetes patients combined with these pathologies can lead to infection of the diabetic foot, a potentially limband lifethreatening complication. Diabetic foot disorders comprise a broad spectrum of pathology. The range of the spectrum in those presenting can extend from a foot problem secondary to a complication of diabetes such as neuroarthropathy, ulceration, or infection to those with a diagnosis of diabetes who have routine foot pathology such as metatarsalgia or fracture. There may be a combination of pathologies. In diabetes patients, accurate and timely diagnosis of complications is essential to a successful outcome. Diabetic foot pathologies often present with occult signs that are easily overlooked unless a high degree of suspicion and vigilance is maintained. The differential diagnosis for acute pain or swelling in a diabetic foot includes infection, neuroarthropathy, vascular disease, acute inflammatory arthropathy, gout, acute thrombosis, and trauma. Appropriate radiologic investigations may help in determining the diagnosis; however, imaging of the diabetic foot often produces nonspecific findings that require careful interpretation. This review summarizes the current evidence on relevant radiologic evaluation.
Laboratory models of regional chemotherapy

Development of new treatment strategies and agents is a difficult and costly matter in oncology. Routinely drugs are tested in vitro on tumor cells which, however, may have limited predictive value for their activity in patients. Also, the pharmacokinetic behavior, intratumoral distribution, as well as toxic side effects, binding to other compounds and stability of an agent are very important in determining activity in the patient. More so, development and evaluation of surgical delivery methods, i.e. regional treatment strategies, cannot be tested in cell systems. Therefore animal models are crucial for the development of regional chemotherapy methodologies. To allow translation of the animal data to patients it is important that the animal model closely mimics the clinical setting as for instance is achieved with isolated limb perfusion. However, animal models remain limited in their use, as eventually the efficacy of the approach may be different in animals compared to patients. Here we describe the use of animal models for regional treatment of solid tumors.