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Abstract Lin28 is a key regulator of cancer stem cell gene network that promotes therapy-resistant tumor progression in various tumors. However, no Lin28 inhibitor has been approved to treat cancer patients, urging exploration of novel compounds as candidates to be tested for clinical trials. In this contribution, we applied computer-aided drug design (CADD) in combination with quantitative biochemical and biological assays. These efforts led to the discovery of Ln268 as a drug candidate that can block Lin28 from binding to its RNA substrates and inhibit Lin28 activities. Ln268 suppressed Lin28-mediated cancer cell proliferation and spheroid growth. Results from nuclear magnetic resonance spectroscopy confirmed that Ln268 perturbs the conformation of the zinc knuckle domain of Lin28, validating the rational drug design by CADD. The inhibitory effects of Ln268 are dependent on Lin28 protein expression in cancer cells, highlighting limited off-target effects of Ln268. Moreover, Ln268 synergizes with several chemotherapy drugs to suppress tumor cell growth. In summary, Ln268 is a promising candidate for further development to target Lin28 as a cancer therapy.

IntroductionThis study reports on the effectiveness and efficiency from the program funder’s perspective of the Suraj Social Franchise (SSF) voucher program in which private health-care providers in remote rural areas were identified, trained, upgraded, and certified to deliver family planning services to underserved women of reproductive age in 29 districts of Sindh and 3 districts of Punjab province, Pakistan between October 2013 and June 2016.MethodA decision tree compared the cost of implementing SSF to the program funder and its effects of providing additional couple years of protection (CYPs) to targeted women, compared to business-as-usual. Costs included vouchers given to women to receive a free contraceptive method of their choice from the SSF provider. The vouchers were then reimbursed to the SSF provider by the program.ResultsA total of 168,206 married women of reproductive age (MWRA) received SSF vouchers between October 2013 and June 2016, costing $3,278,000 ($19.50/recipient). The average effectiveness of the program per voucher recipient was an additional 1.66 CYPs, giving an incremental cost-effectiveness of the program of $4.28 per CYP compared to not having the program (95% CI: $3.62–5.31).ConclusionThe result compares favorably to other interventions with similar objectives and appears affordable for the Pakistan national health-care system. It is therefore recommended to help address the unmet need for contraception among MWRA in these areas of Pakistan and is worthy of trial implementation in the country more widely.

We present Voice2Face: a Deep Learning model that generates face and tongue animations directly from recorded speech. Our approach consists of two steps: a conditional Variational Autoencoder generates mesh animations from speech, while a separate module maps the animations to rig controller space. Our contributions include an automated method for speech style control, a method to train a model with data from multiple quality levels, and a method for animating the tongue. Unlike previous works, our model generates animations without speaker‐dependent characteristics while allowing speech style control. We demonstrate through a user study that Voice2Face significantly outperforms a comparative state‐of‐the‐art model in terms of perceived animation quality, and our quantitative evaluation suggests that Voice2Face yields more accurate lip closure in speech with bilabials through our speech style optimization. Both evaluations also show that our data quality conditioning scheme outperforms both an unconditioned model and a model trained with a smaller high‐quality dataset. Finally, the user study shows a preference for animations including tongue. Results from our model can be seen at https://go.ea.com/voice2face. [ABSTRACT FROM AUTHOR]

The article poses a dual research question: What are the determining factors of the type of audit opinion in a stressed economic environment and do these factors differ between family and nonfamily firms? Our results show that auditor tenure and return on assets (ROA) raise the probability of receiving a favorable opinion. On the contrary, losses during the previous year, high financial leverage, and hiring a “Big 4” firm increase the probability of receiving an unfavorable opinion. Although the sign and the statistical significance are similar, the size of such effects differs between family and nonfamily firms. Finally, the probability of receiving a report with a favorable opinion increases as the economic situation improves.