Miracle-dz/UniFAR-FTUs huggingface dataset:
Interleukins-12 and -23 Do Not Alter Expression or Activity of Multiple Cytochrome P450 Enzymes in Cryopreserved Human Hepatocytes

Psoriasis is a T-cell-mediated autoimmune disease involving the skin. Two cytokines, interleukin-12 (IL-12) and IL-23 have been shown to play a pivotal role in the pathogenesis of the disease. Ustekinumab (Stelara) is a therapeutic monoclonal antibody (mAb) targeted against the p40 shared subunit of IL-12 and IL-23. Recently the ability of therapeutic proteins (TP) including mAbs that target either cytokines directly (e.g., Pegasys; peginterferon α-2a) or their respective cell surface receptors [e.g., tocilizumab (Actemra); anti IL-6R] to desuppress cytochrome P450 (P450) enzymes in vitro and in the clinic, has been demonstrated. In the present study the ability of IL-12 and IL-23 to suppress multiple P450 enzymes was investigated in vitro using six separate lots of cultured human hepatocytes. Following exposure of 10 ng/ml IL-12 and IL-23 for 48 hours, either alone or in combination, no change in CYP2B6, 2C9, 2C19, or 3A4 gene expression or functional activity was observed. None of the untreated hepatocyte donors showed appreciable expression of the IL-12 or IL-23 receptors. Similar results were seen with whole human liver samples. Exposure of hepatocytes to IL-12 and/or IL-23, known P450 suppressors (IL-6 and tumor necrosis factor-α) or known P450 inducers (β-naphthoflavone, phenobarbital, and rifampicin) did not appreciably alter the expression of the IL-12 and IL-23 receptors either. Finally, in contrast to the positive control IL-6, expression of the acute phase C-reactive protein was unaltered following IL-12 and/or IL-23 treatment. Together, these data suggest a negligible propensity for IL-12 or IL-23 to directly alter P450 enzymes in human hepatocytes.
Gray matter structural networks are associated with cardiovascular risk factors in healthy older adults

While recent ‘big data' analyses discovered structural brain networks that alter with age and relate to cognitive decline, identifying modifiable factors that prevent these changes remains a major challenge. We therefore aimed to determine the effects of common cardiovascular risk factors on vulnerable gray matter (GM) networks in a large and well-characterized population-based cohort. In 616 healthy elderly (258 women, 60–80 years) of the LIFE-Adult-Study, we assessed the effects of obesity, smoking, blood pressure, markers of glucose and lipid metabolism as well as physical activity on major GM-networks derived using linked independent component analysis. Age, sex, hypertension, diabetes, white matter hyperintensities, education and depression were considered as confounders. Results showed that smoking, higher blood pressure, and higher glycated hemoglobin (HbA1c) were independently associated with lower GM volume and thickness in GM-networks that covered most areas of the neocortex. Higher waist-to-hip ratio was independently associated with lower GM volume in a network of multimodal regions that correlated negatively with age and memory performance. In this large cross-sectional study, we found selective negative associations of smoking, higher blood pressure, higher glucose, and visceral obesity with structural covariance networks, suggesting that reducing these factors could help to delay late-life trajectories of GM aging.
The Alzheimer’s disease metabolic brain pattern in mild cognitive impairment

We investigated the expression of the Alzheimer’s disease-related metabolic brain pattern (ADRP) in 18F-FDG-PET scans of 44 controls, 27 patients with mild cognitive impairment (MCI) who did not convert to Alzheimer’s disease (AD) after five or more years of clinical follow-up, 95 MCI patients who did develop AD dementia on clinical follow-up, and 55 patients with mild-to-moderate AD. The ADRP showed good sensitivity (84%) and specificity (86%) for MCI-converters when compared to controls, but limited specificity when compared to MCI non-converters (66%). Assessment of 18F-FDG-PET scans on a case-by-case basis using the ADRP may be useful for quantifying disease progression.
Local oxygen homeostasis during various neuronal network activity states in the mouse hippocampus

Cortical information processing comprises various activity states emerging from timed synaptic excitation and inhibition. However, the underlying energy metabolism is widely unknown. We determined the cerebral metabolic rate of oxygen (CMRO2) along a tissue depth of <0.3 mm in the hippocampal CA3 region during various network activities, including gamma oscillations and sharp wave-ripples that occur during wakefulness and sleep. These physiological states associate with sensory perception and memory formation, and critically depend on perisomatic GABA inhibition. Moreover, we modelled vascular oxygen delivery based on quantitative microvasculature analysis. (1) Local CMRO2 was highest during gamma oscillations (3.4 mM/min), medium during sharp wave-ripples, asynchronous activity and isoflurane application (2.0–1.6 mM/min), and lowest during tetrodotoxin application (1.4 mM/min). (2) Energy expenditure of axonal and synaptic signaling accounted for >50% during gamma oscillations. (3) CMRO2 positively correlated with number and synchronisation of activated synapses, and neural multi-unit activity. (4) The median capillary distance was 44 µm. (5) The vascular oxygen partial pressure of 33 mmHg was needed to sustain oxidative phosphorylation during gamma oscillations. We conclude that gamma oscillations featuring high energetics require a hemodynamic response to match oxygen consumption of respiring mitochondria, and that perisomatic inhibition significantly contributes to the brain energy budget.
The Trouble With Blame: Victims, Perpetrators, and Responsibility

In recent years, the public has been treated to a regular diet of sensational sexual abuse cases that have found their way into the courts. The Menendez brothers, who killed their parents, sought exculpation by claiming that extreme fear after years of psychological and sexual abuse propelled their crime. Lorena Bobbitt, who lopped off her husband's penis, mounted a successful insanity defense based on the battered wife syndrome. The legal defense of victimization has come to be called pejoratively the "abuse excuse. " The law is all or nothing—you either win or you lose. Society in general and many health care professionals in particular also hold extreme black-andwhite views concerning victims and perpetrators of abuse. Dr Lamb, an assistant professor of psychology at Bryn Mawr College, attempts to bring balance to this emotionally overwrought subject. In a clearly written, well-reasoned book, the author announces her main premise early: "In this book
Expression Variability of Absorption, Distribution, Metabolism, Excretion–Related MicroRNAs in Human Liver: Influence of Nongenetic Factors and Association with Gene Expression

Genes that are important for the detoxification of drugs and other xenobiotics show a high degree of interindividual variation attributable to regulation by diverse genetic, nongenetic, and epigenetic mechanisms including microRNAs (miRNAs). We selected a set of 56 miRNAs predicted to target the 3′-untranslated region of absorption, distribution, metabolism, excretion (ADME) genes to assess their hepatic expression levels and interindividual variability in a well-documented human liver tissue cohort (n = 92), together with the well-known hepatic miRNAs miR-122, miR-21, miR-27b, and miR-148a. Quantification by stem-loop real-time reverse-transcription polymerase chain reaction confirmed high expression for these microRNAs and revealed particularly strong variability of expression (>1000-fold) for miR-539, miR-200c, miR-31, miR-15a, and miR-22. Association analysis revealed a high degree of correlation among various miRNAs, suggesting coregulation. Statistical analysis considering liver donor meta-data including correction for multiple testing revealed strongly elevated levels of miR-21, miR-34a, miR-130b, and miR-132 in cholestatic liver and of miR-21 and miR-130b during inflammation, as indicated by elevated C-reactive protein levels in serum. Although none of the miRNAs was strongly associated with sex, several miRNAs, including miR-34a and miR-200a/b, were positively correlated with age. Association analysis with ADME gene expression profiles and with cytochrome P450 gene expression phenotypes (mRNA, protein, enzymatic activity) revealed numerous significant correlations. Negatively affected protein and/or activity levels were observed for CYP1A1 (e.g., miR-132, miR-142-3p, miR-21), CYP2A6 (miR-142-3p, miR-21), CYP2C19 (e.g., miR-130b, miR-185, miR-34a), and CYP2E1 (miR-10a, let-7g, miR-200c). These data should be useful to further elucidate regulatory functions of miRNAs in liver pathophysiology and regulation of ADME gene expression.
Social Support Seeking and Early Adolescent Depression and Anxiety Symptoms

This study examined how social support seeking and rumination interacted to predict depression and anxiety symptoms 6 months later in early adolescents (N = 118; 11-14 years at baseline). We expected social support seeking would be more helpful for adolescents engaging in low rather than high levels of rumination. Adolescents self-reported on all measures at baseline, and on depression and anxiety symptoms 6 months later. Social support seeking predicted fewer symptoms of depression and anxiety at low rumination levels but was not associated with benefits as rumination increased. For depression symptoms, social support seeking predicted more symptoms at high rumination levels. Results were stronger for emotion-focused than problem-focused support seeking and for depression compared with anxiety symptoms. These findings suggest that cognitive risk factors like rumination may explain some inconsistencies in previous social support literature, and highlight the importance of a nuanced approach to studying social support seeking.
Colossal, Scattered, and Chaotic (Planning with a Large Distributed Team)

If planning for a large co-located 30-plus development team is not enough to make you want to pull your hair out then try a 30-plus development team located across several time zones, in places with different cultures and languages. Now, youpsilave reached a level in the Agile planning game that would send most product owners running home to their mommies. Planning in Agile Projects requires enabling the team to have a continuous conversation with the customer. How can you have meaningful, continuous conversation and feedback when your team is scattered across several time zones, cultures and languages? This paper describes our experience of how one of our largest teams in Sabre Airline Solutions was able to make changes that allowed the continuous conversations to take place. The paper is written from the perspective of both development locations the main office in Dallas, Texas and the "remote" office in Krakow, Poland. The team successfully overcame many obstacles while rapidly growing a small co-located development team into a large globally distributed team that was able to efficiently deliver customer valued, quality code and customer satisfaction with each one-week iteration. It attributed this success to three main Agile areas: evolving the Agile Customer Role, making our meetings valuable and efficient for everyone involved, and good coordination across the sub teams.
Risk Factors for Development of Cholestatic Drug-Induced Liver Injury: Inhibition of Hepatic Basolateral Bile Acid Transporters Multidrug Resistance-Associated Proteins 3 and 4

Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potential of drugs. The inhibitory effect of 88 drugs (100 μM) on MRP3- and MRP4-mediated substrate transport was measured in membrane vesicles. Drugs selected for investigation included 50 BSEP non-inhibitors (24 non-cholestatic; 26 cholestatic) and 38 BSEP inhibitors (16 non-cholestatic; 22 cholestatic). MRP4 inhibition was associated with an increased risk of cholestatic potential among BSEP non-inhibitors. In this group, for each 1% increase in MRP4 inhibition, the odds of the drug being cholestatic increased by 3.1%. Using an inhibition cutoff of 21%, which predicted a 50% chance of cholestasis, 62% of cholestatic drugs inhibited MRP4 (P < 0.05); in contrast, only 17% of non-cholestatic drugs were MRP4 inhibitors. Among BSEP inhibitors, MRP4 inhibition did not provide additional predictive value of cholestatic potential; almost all BSEP inhibitors were also MRP4 inhibitors. Inclusion of pharmacokinetic predictor variables (e.g., maximal unbound concentration in plasma) in addition to percent MRP4 inhibition in logistic regression models did not improve cholestasis prediction. Association of cholestasis with percent MRP3 inhibition was not statistically significant, regardless of BSEP-inhibition status. Inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI.
Factors Influencing Contraceptive Use in Sub-Saharan Africa: A Systematic Review

The purpose of this study was to systematically review the literature regarding factors influencing contraceptive use in sub-Saharan Africa between 2005 and 2015. A total of 58 studies from twelve Sub-Saharan African countries were reviewed. Keywords were grouped using the PEN-3 cultural model. Negative factors prohibiting or reducing contraceptive use were women’s misconceptions of contraceptive side–effects, male partner disapproval, and social/cultural norms surrounding fertility. Positive factors included education, employment, and communication with male partner. Increasing modern contraceptive use in Sub-Saharan Africa is a multi-faceted problem that will require community and systems wide interventions that aim to counteract negative perceptions and misinformation.
The Relationship Between Perceptions of Emergency Preparedness, Disaster Experience, Health-Care Provider Education, and Emergency Preparedness Levels

Objective The purpose of this study was to assess the self-reported level of individual emergency preparedness, the dependent variable, of people who attended a community health-related fair. The study’s independent variables included demographic characteristics, perceptions of preparedness, previous disaster experience, and the presence of a medical condition and were used to examine the variability in self-reported emergency preparedness levels. Methods Data came from attendees at two community health-related fairs. Multivariate analysis on 188 participants was performed. A model predicting preparedness levels with demographic variables was constructed; successive models were built adding perceptions of preparedness, personal experiences with disasters, and presence of a medical condition. Results Preparedness levels varied little across sociodemographic dimensions explaining virtually no variance in overall preparedness. Subsequent models adding perceptions of preparedness and personal experiences significantly increased the explained variance to 40%. Of participants who reported a medical condition, the model including discussions about emergency preparedness with health-care providers explained 67% of the variance in overall preparedness levels. Conclusion The strong, positive relationship between the health-care provider and preparedness levels indicates a pathway for effecting change in preparedness levels and ultimately community health after an emergency. The inclusion of such education at community events should be considered. Research agendas should include providing evidence for the contents of disaster supply kits.
The Effect of Graphical and Numerical Presentation of Hypothetical Prenatal Diagnosis Results on Risk Perception

Objective. To evaluate various formats for the communication of prenatal test results. Design. In study 1 (N=400), female students completed a questionnaire assessing risk perception, affect, and perceived usefulness of prenatal test results. A randomized, 2 (risk level; low, high) × 4 (format; ratio with numerator 1, ratio with denominator 1000, Paling Perspective Scale, pictograms) design was used. Study 2 (N=200) employed a 2 (risk level; low, high) × 2 (format; Paling Perspective Scale, risk comparisons in numerical format) design. Results. In study 1, the Paling Perspective Scale resulted in a higher level of perceived risk across different risk levels compared with the other formats. Furthermore, participants in the low-risk group perceived the test results as less risky compared with participants in the high-risk group (P < 0.001) when the Paling Perspective Scale was used. No significant differences between low and high risks were observed for the other 3 formats. In study 2, the Paling Perspective Scale evoked higher levels of perceived risks relative to the numerical presentation of risk comparisons. For both formats, we found that participants confronted with a high risk perceived test results as more risky compared with participants confronted with a low risk. Conclusion. The Paling Perspective Scale resulted in a higher level of perceived risk compared with the other formats. This effect must be taken into account when choosing a graphical or numerical format for risk communication.
The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases.
Time-Tradeoff Utilities for Identifying and Evaluating a Minimum Data Set for Time-Critical Biosurveillance

Background. Researchers and policy makers are interested in identifying, implementing, and evaluating a national minimum data set for biosurveillance. However, work remains to be done to establish methods for measuring the value of such data. Purpose. The purpose of this article is to establish and evaluate a method for measuring the utility of biosurveillance data. Method. The authors derive an expected utility model in which the value of data may be determined by trading data relevance for time delay in receiving data. In a sample of 23 disease surveillance practitioners, the authors test if such tradeoffs are sensitive to the types of data elements involved (chief complaint v. emergency department [ED] log of visit) and proportional changes to the time horizon needed for receiving data (24 v. 48 h). In addition, they evaluate the logical error rate: the proportion of responses that scored less relevant data as having higher utility. Results. Utilities of chief complaints were significantly higher than ED log of visit, F(1, 21)= 5.60, P < 0.05, suggesting the method is sensitive. Further utilities did not depend on time horizon used in the exercise, F(1, 21) = 0.00, P = ns. Of 92 time tradeoffs elicited, there were 5 logical errors (i.e., 5% logical error rate). Conclusions. In this article, the authors establish a time-tradeoff exercise for valuing biosurveillance data. Empirically, the method shows initial promise for evaluating a minimum data set for biosurveillance. Future applications of this approach may prove useful in disease surveillance planning and evaluation.
Oxidative Metabolic Pathway of Lenvatinib Mediated by Aldehyde Oxidase

Lenvatinib is a multityrosine kinase inhibitor that inhibits vascular endothelial growth factor receptors, and is being developed as an anticancer drug. P450s are involved in one of the elimination pathways of lenvatinib, and mono-oxidized metabolites, such as N-oxide (M3) and desmethylated metabolite (M2), form in rats, dogs, monkeys, and humans. Meanwhile, two other oxidative metabolites are produced only in monkey and human liver S9 fractions, and their structures have been identified using high-resolution mass spectrometry as a quinolinone form of lenvatinib (M3′) and a quinolinone form of desmethylated lenvatinib (M2′). The formation of M3′ from lenvatinib occurred independently of NADPH and was effectively inhibited by typical inhibitors of aldehyde oxidase, indicating the involvement of aldehyde oxidase, but not P450s, in this pathway. M2′ was a dioxidized metabolite arising from a combination of mono-oxidation and desmethylation and could only be produced from M2 in a NADPH-independent manner; M2′ could not be generated from M3 or M3′. These results suggested that M2′ is formed from lenvatinib by a unique two-step pathway through M2. Although both lenvatinib and M2 were substrates for aldehyde oxidase, an enzyme kinetic study indicated that M2 was a much more favorable substrate than lenvatinib. No inhibitory activities of lenvatinib, M2′, or M3′ and no significant inhibitory activities of M2 or M3 on aldehyde oxidase were observed, suggesting a low possibility of drug-drug interactions in combination therapy with substrates of aldehyde oxidase.