Miracle-dz/UniFAR-FTUs huggingface dataset:
Analysis and minimization of cellular RNA editing by DNA adenine base editors

We report cellular RNA editing by adenine base editors and new ABE variants with reduced RNA editing activity. Adenine base editors (ABEs) enable precise and efficient conversion of target A•T base pairs to G•C base pairs in genomic DNA with a minimum of by-products. While ABEs have been reported to exhibit minimal off-target DNA editing, off-target editing of cellular RNA by ABEs has not been examined in depth. Here, we demonstrate that a current ABE generates low but detectable levels of widespread adenosine-to-inosine editing in cellular RNAs. Using structure-guided principles to design mutations in both deaminase domains, we developed new ABE variants that retain their ability to edit DNA efficiently but show greatly reduced RNA editing activity, as well as lower off-target DNA editing activity and reduced indel by-product formation, in three mammalian cell lines. By decoupling DNA and RNA editing activities, these ABE variants increase the precision of adenine base editing by minimizing both RNA and DNA off-target editing activity.
Real estate as a hedge against inflation: learning from the Swiss case

Tests the inflation‐hedging ability of Swiss real estate over the 1943‐1991 period and, for comparison purposes, that of stocks. Results show that in the long run real estate seems to provide a better hedge against inflation than common stocks. When the inflation rate is broken down into its expected and unexpected components, all coefficients are negative for stocks, whereas some coefficients are positive for real estate. This is particularly true for unexpected inflation. These results are interesting in that the proxy used for real estate (i.e. data pertaining to real estate mutual funds) should be a much better indicator of changes in the underlying real estate than indices which have been used so far. Moreover, the data exists for a very long time period, which makes it possible to test the long‐term ability of real estate to hedge against changes in the purchasing power.
Embedding new entrepreneurship programmes in UK higher education institutions: Challenges and considerations

Purpose – The purpose of this paper is to develop the understanding of the challenges and considerations of how new and innovative entrepreneurship education programmes may be inculcated into UK higher education institutions (HEIs). Design/methodology/approach – The paper employs an action research approach to provide insights into entrepreneurship education andragogy in the first instance and in the second instance evaluate the success of such a programme then discuss the challenges of embedding it within universities.Findings – The paper provides substantial evidence for the effectiveness of innovative programmes and concludes that it would be difficult to embed such a programme within HEIs in the UK due to: resource limitations; lack of training in synergistic methods; keeping the freshness alive; finding suitable entrepreneurs to take part in the programme; finding the right space in academic timetable and curriculum.Research limitations/implications – In this paper the evidence for the success of the .
Realizing the demographic dividend: Is Africa any different?

The demographic transition creates a window of opportunity during which economies may benefit from a temporary increase in the working age share of the population. While many economies have already enjoyed these benefits, they remain a promising opportunity for much of Sub-Saharan Africa. We show in this paper that Sub-Saharan Africa adheres to the same principles as the rest of the world with respect to the determinants of economic growth, including particularly the effects of demographic change. Assuming a policy and institutional context that is conducive to economic growth, most Sub-Saharan countries have the potential to reap a sizable demographic dividend.
The Influence of Synthetic Cannabinoid UR-144 on Human Psychomotor Performance—A Case Report Demonstrating Road Traffic Risks

Objective: UR-144 [(1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)-methanone] is a synthetic cannabinoid, which has been detected in many “legal highs” seized from the global drug market since the beginning of 2012. It gained popularity as a “legal” alternative to classic cannabis in countries where it was not controlled. The popularity of UR-144 means that this substance is also abused by individuals driving motor vehicles. This article describes a case of driving under the influence (DUI) of UR-144. The aim of the undertaken case analysis and presenting description of pharmacological similarity of THC and UR-144 is to answer the question whether UR-144 can produce effects incompatible with safe driving. Methods: Blood from the driver was obtained by a physician approximately 2 h after the collision and 4.5 h after self-reported dosing. Police from the crash site provided behavioral observations, and the physician performed medical examination. Blood was analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/MS). The developed method was described in detail. The method was linear in the range of 0.5–50 ng/mL; the precision and accuracy values obtained were less than 15%. The symptoms observed by police and physician who collected the blood sample were described. Results: In the blood sample collected from the driver, UR-144 and its major pyrolysis product [1-(1-pentyl-1H-indol-3-yl)-3-methyl-2-(propan-2-yl)but-3-en-1-one] were detected. Whole-blood concentration of UR-144 was 14.6 ng/mL. The result of blood analysis and observed symptoms clearly indicated that the driver was under the influence of UR-144. Conclusions: UR-144 produces effects and impairment similar to or even more dangerous than delta-9-tetrahydrocannabinol (Δ9-THC), making it unsafe for driving. Therefore, UR-144 should be treated as a potentially dangerous substance in traffic safety.
Narrowing the Gap in Treatment of Depression

Objective: Although effective treatments for depression exist, under or non-treatment of depression is common. Efforts were made in the early 1990s to improve recognition and treatment of depression, with many of those efforts targeted at groups most vulnerable to under-treatment. The purpose of this study is to assess treatment rates in 1993–1994 and 1996–1997. Method: Using nationally representative surveys of office-based practice covering the years 1993, 1994, 1996, and 1997, we obtained estimates of visits by adults in which depression was diagnosed and a prescription for antidepressant medication and/or psychotherapy was provided or ordered. Results: The proportion of physician office visits in which a depression diagnosis was recorded did not change from 1993–1994 (3.48 percent) to 1996–1997 (3.40 percent). However, the rate of antidepressant prescription or psychotherapy rose from 74.2 percent of visits with a depression diagnosis in 1993–1994 to 82.3 percent of these visits in 1996–1997. Significantly lower rates of treatment for depression during office visits made by African American patients, elderly patients, and patients on Medicaid occurred in 1993–1994, but were not evident in 1996–1997, reflecting improved rates of depression treatment in these populations. Conclusions: Although rates of diagnosis of depression during office visits have not increased, treatment rates for depression are improving among those who are diagnosed, including groups of people who historically were less likely to be offered treatment. Additional efforts to improve recognition and diagnosis of depression in ambulatory medical practice and to improve dissemination of treatment are needed.
Combining and sequencing medication and cognitive-behaviour therapy for childhood anxiety disorders

Despite the absence of data on the efficacy of combination therapy (i.e., psychosocial and medication) for the treatment of anxiety disorders in youths, clinicians in clinical practice often utilize this treatment approach. This paper discusses issues related to sequencing, combining, and integrating cognitive behavioural and pharmacological interventions for anxiety disorders in children and adolescents. We briefly summarize the empirical evidence for mono and combination therapy and raise a variety of issues that should be considered when making treatment decisions. Finally, we present an integrated treatment model to facilitate the delivery of a comprehensive treatment approach across care providers. These suggestions are geared toward optimizing clinical outcomes for anxious youths.
Sex‐specific, reciprocal regulation of ERα and miR‐22 controls muscle lipid metabolism in male mice

Control of energy homeostasis and metabolism is achieved by integrating numerous pathways, and miRNAs are involved in this process by regulating expression of multiple target genes. However, relatively little is known about the posttranscriptional processing of miRNAs and a potential role for the precursors they derive from. Here, we demonstrate that mature miRNA‐22 is more abundant in muscle from male mice relative to females and that this enables sex‐specific regulation of muscular lipid metabolism and body weight by repressing estrogen receptor alpha (ERα) expression. We found that the ERα adjusts its own activity by preventing processing of miR‐22 via direct binding to a conserved ERα‐binding element within the primary miR‐22 precursor. Mutation of the ERα binding site within the pri‐miR‐22 in vivo eliminates sex‐specific differences in miR‐22 expression. We reason that the resulting tissue selective negative feedback regulation is essential to establish sex‐specific differences in muscle metabolism and body weight development.
“Teaching Online Made Me a Better Teacher”

Abstract Anecdotal accounts from teachers have long suggested the possibility that virtual teaching experiences have a positive impact on face-to-face teaching practices, a so-called “reverse impact” phenomenon. Survey and focus group data collected as part of a statewide evaluation of a virtual school offered an opportunity to explore this impact. Findings from a study of teacher perceptions indicate that three quarters of teachers who teach in both virtual and traditional environments felt that virtual experiences improved their practice in face-to-face classrooms. The authors discuss three types of impact reflected in teacher comments and discuss tentative implications for teacher preparation programs and for bolstering the rationale for using technology in education.
A Probabilistic Model for Cushing's Syndrome Screening in At-Risk Populations: A Prospective Multicenter Study.

CONTEXT Cushing's syndrome (CS) is challenging to diagnose. Increased prevalence of CS in specific patient populations has been reported, but routine screening for CS remains questionable. To decrease the diagnostic delay and improve disease outcomes, simple new screening methods for CS in at-risk populations are needed. OBJECTIVE To develop and validate a simple scoring system to predict CS based on clinical signs and an easy-to-use biochemical test. DESIGN Observational, prospective, multicenter. SETTING Referral hospital. PATIENTS A cohort of 353 patients attending endocrinology units for outpatient visits. INTERVENTIONS All patients were evaluated with late-night salivary cortisol (LNSC) and a low-dose dexamethasone suppression test for CS. MAIN OUTCOME MEASURES Diagnosis or exclusion of CS. RESULTS Twenty-six cases of CS were diagnosed in the cohort. A risk scoring system was developed by logistic regression analysis, and cutoff values were derived from a receiver operating characteristic curve. This risk score included clinical signs and symptoms (muscular atrophy, osteoporosis, and dorsocervical fat pad) and LNSC levels. The estimated area under the receiver operating characteristic curve was 0.93, with a sensitivity of 96.2% and specificity of 82.9%. CONCLUSIONS We developed a risk score to predict CS in an at-risk population. This score may help to identify at-risk patients in non-endocrinological settings such as primary care, but external validation is warranted.
Cystatin C versus creatinine for kidney function-based risk.

n engl j med 369;25 nejm.org december 19, 2013 2457 The Authors Reply: Birzniece postulates that the decreased secretion of growth hormone was associated with an increase in fat mass in our participants with hypogonadism. As she notes, both estrogen deficiency and estrogen blockade reduce growth hormone secretion. Our study was not designed to examine mechanisms whereby estrogen deficiency increases body fat; however, we agree that diminished growth hormone secretion is a potential mechanism. Schooling et al. state that we implied that “boosting estrogen levels . may decrease cardiovascular risk. ” We wrote that “the marked increase in intraabdominal fat with aromatase inhibition could portend an increase in cardiovascular disease with long-term estrogen deficiency,” not that estrogen administration would reduce such risk. Moreover, the studies they cited as evidence that estrogen administration increases the risk of cardiovascular disease among men1,2 used doses far higher than those needed for physiologic replacement. Schellhammer cites personal experience, published urologic literature, and our article as evidence that estrogen therapy is beneficial in men with prostate cancer who are receiving ADT. As noted above, we did not study the effects of estrogen administration in men receiving ADT. Nevertheless, the finding that estrogen deficiency is responsible for several of the undesirable consequences of ADT raises the possibility that the administration of low-dose estradiol might benefit men with prostate cancer who are receiving ADT. Randomized, controlled trials are needed to determine whether estradiol administration is effective and safe in such patients. Finally, Malnick et al. question the ethics of using a gonadotropin-releasing hormone agonist to investigate reproductive physiology. We3 and others4 have used this approach in studies for many years, and no safety issues have been observed. Our study was specifically designed to be sufficiently brief so that clinically important bone loss, as assessed by means of dual-energy x-ray absorptiometry (DXA), would not occur. We measured bone mineral density (BMD) by means of DXA at baseline and study completion. As predicted, changes in the BMD of the spine and hip were 1% or less, and there were no significant differences between the hypogonadal group and the eugonadal (control) group. The major side effects of ADT, hot flashes and decreased sexual function, resolve with medication discontinuation and have no known residual effect on health. Moreover, because most of the men in our study received some testosterone, most participants did not report such ADT-related side effects. Participants were informed that if they had troubling side effects, they could withdraw from the study and receive testosterone replacement until the ADT wore off. Finally, ethical concerns were not raised by our institutional review board, our data and safety monitoring board, or the National Institutes of Health.
New Human Immunodeficiency Virus Diagnosis Independently Associated With Rectal Gonorrhea and Chlamydia in Men Who Have Sex With Men

Background Rectal sexually transmitted infections (STI) have been associated with human immunodeficiency virus (HIV) diagnosis, but inferring a causal association requires disentangling them from receptive anal intercourse (RAI). Methods We conducted a stratified case-control study by frequency matching 4 controls to each case within year using clinical data from men who have sex with men (MSM) attending the Seattle STD Clinic 2001 to 2014. Cases were MSM with a new HIV diagnosis and negative HIV test at 12 months or less. Controls were HIV-negative MSM. All included men had rectal STI testing, tested negative for syphilis, and had complete sexual behavior data. We categorized men by RAI: (1) none; (2) condoms for all RAI; (3) condomless RAI only with HIV-negative partners; and (4) condomless RAI with HIV-positive or unknown-status partners. We created 3 logistic regression models: (1) 3 univariate models of concurrent rectal gonorrhea, rectal chlamydia, and rectal STI in 12 months or less with new HIV diagnosis; (2) those 3 infections, plus age, race, year, number of sexual partners in 2 months or less, and methamphetamine use; and (3) model 2 with RAI categories. We calculated the population attributable risk of rectal STI on HIV diagnoses. Results Among 176 cases and 704 controls, rectal gonorrhea, chlamydia and rectal STI in 12 months or less were associated with HIV diagnosis. The magnitude of these associations attenuated in the second model, but persisted in model 3 (gonorrhea: adjusted odds ratio [aOR], 2.3; 95% confidence interval [CI], 1.3–3.8; chlamydia: aOR, 2.5; 95% CI, 1.5–4.3; prior STI: aOR, 3.0; 95% CI, 1.5–6.2). One in 7 HIV diagnoses can be attributed to rectal STI. Conclusions Rectal STI are independently associated with HIV acquisition. These findings support the hypothesis that rectal STI play a biologically mediated causal role in HIV acquisition and support screening/treatment of STI for HIV prevention.
Prostaglandin E2-induced IL-23p19 Subunit Is Regulated by cAMP-responsive Element-binding Protein and C/AATT Enhancer-binding Protein β in Bone Marrow-derived Dendritic Cells*

Background: The molecular mechanisms involved in IL-23 up-regulation by PGE2 are not elucidated. Results: PGE2 induces IL-23p19 through the EP4 cAMP-PKA/EPAC-CREB/C/EBPβ signaling pathway. Conclusion: PGE2 synergizes with TLR ligands and with proinflammatory cytokines such as TNFα to up-regulate Il23a gene expression. Significance: Understanding is gained of one of the major functions of PGE2 leading to activation of pathogenic Th17 cells. We reported previously that prostaglandin E2 (PGE2) up-regulates IL-23 in vitro in bone marrow-derived dendritic cells and in vivo in models of collagen-induced arthritis and inflammatory bowel disease, leading to preferential Th17 development and activity. There is very little information on the molecular mechanisms involved in the PGE2-induced up-regulation of Il23a gene expression. In this study we investigated the signaling pathways and transcription factors involved in the stimulatory effect of PGE2. Although PGE2 does not induce IL-23p19 expression by itself, it synergizes with both extra- and intracellular Toll-like receptor ligands and with inflammatory cytokines such as TNFα. We established that the effect of PGE2 in conjunction with either LPS or TNFα is mediated through the EP4 receptor and the cAMP-dependent activation of both protein kinase A (PKA) and exchange protein activated by cAMP (EPAC). Using the EP4 agonist PGE1OH in conjunction with TNFα, we found that PKA-induced phosphorylation of cAMP-response element-binding protein (PCREB) and EPAC-induced phosphorylation of C/AATT enhancer-binding protein β (PC/EBPβ) mediate the stimulatory effect of PGE2 on IL-23p19 expression. This is the first report of CREB and C/EBPβ involvement in Il23a promoter activation. Mutation within the putative CREB and C/EBP sites combined with in vivo DNA binding (ChIP) assays identified the distal CREB site (−1125) and the two proximal C/EBP sites (−274 and −232) as essential for PKA-activated CREB and EPAC-activated C/EBPβ-induced IL-23p19 expression.
Demand for Money in India: 1953-2003

The demand for money, especially in the developing countries, is an important relationship for formulating appropriate monetary policy and targeting monetary variables. In this paper we estimate the demand for narrow money in India and evaluate its robustness. It is found that there is a stable demand for money for almost half a century from 1953 to 2003. There is no evidence for any significant effects of the $1991$ financial reforms.
The development and pilot testing of the marijuana retail surveillance tool (MRST): assessing marketing and point-of-sale practices among recreational marijuana retailers

As recreational marijuana expands, it is critical to develop standardized surveillance measures to study the retail environment. To this end, our research team developed and piloted a tool assessing recreational marijuana retailers in a convenience sample of 20 Denver retailers in 2016. The tool assesses: (i) compliance and security (e.g. age-of-sale signage, ID checks, security cameras); (ii) marketing (i.e. promotions, product availability and price) and (iii) contextual and neighborhood features (i.e. retailer type, facilities nearby). Most shops (90.0%) indicated the minimum age requirement, all verified age. All shops posted interior ads (M = 2.6/retailer, SD = 3.4), primarily to promote edibles and other non-smoked products. Price promotions were common in shops (73.7%), 57.9% used social media promotions and 31.6% had take-away materials (e.g. menus, party promotions). Nearly half of the shops (42.1%) advertised health claims. All shops offered bud, joints, honey oil, tinctures, kief, beverages, edibles and topicals; fewer sold clones and seeds. Six shops (31.6%) sold shop-branded apparel and/or paraphernalia. Prices for bud varied within and between stores ($20-$45/'eighth', ∼3.5 g). Twelve were recreational only, and eight were both recreational and medicinal. Liquor stores were commonly proximal. Reliability assessments with larger, representative samples are needed to create a standardized marijuana retail surveillance tool.
Are farmers in low-rainfall cropping regions under-fertilizing? An Australian case-study

Cropping in low-rainfall regions can be risky business. Farms are often characterized by high climatic and spatial variability, while input prices, particularly nitrogen (N) fertilisers, are rising steadily relative to grain prices. Consequently, in anticipation of having a poor season, farmers minimize downside-risk, which is perceived as far more likely than upside gain in such risky environments, by applying fixed low rates of N to their cereal crops. However, farmers might benefit from using higher fertiliser rates and adjusting the rate of N fertiliser applied during the growing season, because if seasons are favourable the crop demands more nutrients. Using a combination of crop simulation, probability theory, profit function and finance techniques to quantify the trade-offs between magnitude and variability in net returns, we found that the use of higher N rates (relative to the region’s average) can reduce risk in a highly variable dryland environment like the Mallee region in south-eastern Australia. Overall, typically risk-averse Mallee farmers with low starting N seem likely to benefit from increasing their N rates to up to 60 kg N ha-1 from the 15 kg N ha-1 currently applied, with less risk-averse farmers being likely do this by adopting a more tactical approach to N fertilisation.