AFLOW-ML: A RESTful API for machine-learning predictions of materials properties

Machine learning approaches, enabled by the emergence of comprehensive databases of materials properties, are becoming a fruitful direction for materials analysis. As a result, a plethora of models have been constructed and trained on existing data to predict properties of new systems. These powerful methods allow researchers to target studies only at interesting materials \unicode{x2014} neglecting the non-synthesizable systems and those without the desired properties \unicode{x2014} thus reducing the amount of resources spent on expensive computations and/or time-consuming experimental synthesis. However, using these predictive models is not always straightforward. Often, they require a panoply of technical expertise, creating barriers for general users. AFLOW-ML (AFLOW $\underline{\mathrm{M}}$achine $\underline{\mathrm{L}}$earning) overcomes the problem by streamlining the use of the machine learning methods developed within the AFLOW consortium. The framework provides an open RESTful API to directly access the continuously updated algorithms, which can be transparently integrated into any workflow to retrieve predictions of electronic, thermal and mechanical properties. These types of interconnected cloud-based applications are envisioned to be capable of further accelerating the adoption of machine learning methods into materials development.Comment: 10 pages, 2 figure

Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

<p>Abstract</p> <p>Background</p> <p>Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor.</p> <p>Methods</p> <p>The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry.</p> <p>Results</p> <p>Treatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm³vs. 1195 ± 84 mm³, p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg.</p> <p>Conclusions</p> <p>CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis.</p

Aligned electrospun nanofibers specify the direction of dorsal root ganglia neurite growth

Nerve injury, a significant cause of disability, may be treated more effectively using nerve guidance channels containing longitudinally aligned fibers. Aligned, electrospun nanofibers direct the neurite growth of immortalized neural stem cells, demonstrating potential for directing regenerating neurites. However, no study of neurite guidance on these fibers has yet been performed with primary neurons. Here, we examined neurites from dorsal root ganglia explants on electrospun poly- L -lactate nanofibers of high, intermediate, and random alignment. On aligned fibers, neurites grew radially outward from the ganglia and turned to follow the fibers upon contact. Neurite guidance was robust, with neurites never leaving the fibers to grow on the surrounding cover slip. To compare the alignment of neurites to that of the nanofiber substrates, Fourier methods were used to quantify the alignment. Neurite alignment, however striking, was inferior to fiber alignment on all but the randomly aligned fibers. Neurites on highly aligned substrates were 20 and 16% longer than neurites on random and intermediate fibers, respectively. Schwann cells on fibers assumed a very narrow morphology compared to those on the surrounding coverslip. The robust neurite guidance demonstrated here is a significant step toward the use of aligned, electrospun nanofibers for nerve regeneration. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res, 2007Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57401/1/31285_ftp.pd

Esterase mutation is a mechanism of resistance to antimalarial compounds

Pepstatin is a potent peptidyl inhibitor of various malarial aspartic proteases, and also has parasiticidal activity. Activity of pepstatin against cultured Plasmodium falciparum is highly variable depending on the commercial source. Here we identify a minor contaminant (pepstatin butyl ester) as the active anti-parasitic principle. We synthesize a series of derivatives and characterize an analogue (pepstatin hexyl ester) with low nanomolar activity. By selecting resistant parasite mutants, we find that a parasite esterase, PfPARE (P. falciparum Prodrug Activation and Resistance Esterase) is required for activation of esterified pepstatin. Parasites with esterase mutations are resistant to pepstatin esters and to an open source antimalarial compound, MMV011438. Recombinant PfPARE hydrolyses pepstatin esters and de-esterifies MMV011438. We conclude that (1) pepstatin is a potent but poorly bioavailable antimalarial; (2) PfPARE is a functional esterase that is capable of activating prodrugs; (3) Mutations in PfPARE constitute a mechanism of antimalarial resistance

Concert recording 2015-12-06

[Track 01]. Lachen und Weinen / Franz Schubert -- Zitronenfalter im April / Hugo Wolf -- [Track 02]. Ganymed / Franz Schubert -- [Track 03]. Gesang Weylas / Hugo Wolf -- [Track 04]. An Silvia / Franz Schubert -- [Track 05]. Der Gärtner / Hugo Wolf -- [Track 06]. Gott im Frühling / Franz Schubert -- [Track 07]. Elfenlied / Hugo Wolf -- [Track 08]. Schäfers Klagelied / Franz Schubert -- [Track 09]. Verborgenheit / Hugo Wolf -- [Track 10]. Gretchens Bitte / Franz Schubert -- [Track 11]. Die Zigeunerin / Hugo Wolf -- [Track 12]. Liebesbotschaft / Franz Schubert -- [Track 13]. In dem Schatten meiner Locken / Hugo Wolf -- [Track 14]. Die junge Nonne / Franz Schubert -- [Track 15]. Nimmersatte Liebe / Hugo Wolf -- [Track 16]. Liebe schwärmt auf allen Wegen / Franz Schubert -- [Track 17]. Er ist\u27s / Hugo Wolf -- [Track 18]. Der Musensohn / Franz Schubert -- [Track 19]. Storchenbotschaft / Hugo Wolf

Plexin D1 emerges as a novel target in the development of neural lineage plasticity in treatment-resistant prostate cancer

Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 was highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression was associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibited neural lineage pathways, thereby suppressing NEPC cell proliferation, patient derived xenograft (PDX) tumor organoid viability, and xenograft tumor growth. Mechanistically, the heat shock protein 70 (HSP70) regulated PLXND1 protein stability through degradation, and inhibition of HSP70 decreased PLXND1 expression and NEPC organoid growth. In summary, our findings indicate that PLXND1 could serve as a promising therapeutic target and molecular marker for NEPC

Subtype and Site Specific-Induced Metabolic Vulnerabilities in Prostate Cancer

Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer [androgen receptor-expressing prostate cancer (ARPC) and aggressive variant prostate cancer (AVPC)]. Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared with AVPC. Unbiased screening of metabolic signaling pathways in patient-derived xenograft models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared with AVPC, and a skewing toward glycolysis by AVPC. In vitro, ARPC C4-2B cells depended on aerobic respiration, while AVPC PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacologic interference using IACS-10759, a clinical-grade inhibitor of OXPHOS. In vivo studies confirmed IACS-10759\u27s inhibitory effects in subcutaneous and bone-localized C4-2B tumors, and no effect in subcutaneous PC3 tumors. Unexpectedly, IACS-10759 inhibited PC3 tumor growth in bone, indicating microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies, which can further undergo metabolic reprogramming in bone

Supraphysiologic Testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions

Since Huggins defined the androgen-sensitive nature of prostate cancer (PCa), suppression of systemic testosterone (T) has remained the most effective initial therapy for advanced disease although progression inevitably occurs. From the inception of clinical efforts to suppress androgen receptor (AR) signaling by reducing AR ligands, it was also recognized that administration of T in men with castration-resistant prostate cancer (CRPC) could result in substantial clinical responses. Data from preclinical models have reproducibly shown biphasic responses to T administration, with proliferation at low androgen concentrations and growth inhibition at supraphysiological T concentrations. Many questions regarding the biphasic response of PCa to androgen treatment remain, primarily regarding the mechanisms driving these responses and how best to exploit the biphasic phenomenon clinically. Here we review the preclinical and clinical data on high dose androgen growth repression and discuss cellular pathways and mechanisms likely to be involved in mediating this response. Although meaningful clinical responses have now been observed in men with PCa treated with high dose T, not all men respond, leading to questions regarding which tumor characteristics promote response or resistance, and highlighting the need for studies designed to determine the molecular mechanism(s) driving these responses and identify predictive biomarkers

The Prostate Low Dose, Alternating Electric Current Inhibits Growth of Prostate Cancer

BACKGROUND. A number of minimally invasive technologies exist for the treatment of prostate cancer (CaP), each with their associated morbidities. We sought to test the efficacy of low dose alternating electric current (LDAEC) to inhibit CaP growth in a preclinical setting and determine its effect on normal tissue. METHODS. In the first study, two power settings, 15 or 25 mA of current, and two treatment times, 15 or 60 min, were evaluated in C4-2B CaP xenografts. In the second study, power was regulated to maintain an intra-tumoral temperature of 458C in C4-2B and LuCaP 35 tumors. In both studies, tumor volume, serum PSA levels, survival and histology were analyzed. In a third study, LDAEC was applied to mice hamstrings with evaluation of gait and histology. RESULTS. The most effective tumor volume reduction in the first study was seen with tumors treated with 25 mA for 15 min (62 AE 9.4% decrease, P ¼ 0.001). Longer treatment time did not enhance treatment effect. Using 458C to govern delivery of LDAEC resulted in a near 100% reduction in tumor volume in 8/10 mice with C4-2B tumors (P &lt; 0.001) with similar inhibition of LuCaP 35 tumors (P ¼ 0.01). This treatment, although resulting in skeletal muscle necrosis, did not affect nerves, smooth muscle and blood vessels. CONCLUSION. LDAEC demonstrates efficacy against C4-2B and LuCaP 35 CaP xenografts while causing no harm to nerves and blood vessels. These results warrant further investigations into the use of LDAEC as a treatment for CaP. Prostate

Fiabilidad y validez de la Escala del Contínuum de Salud Mental (MHC–SF) en el contexto ecuatoriano

The present study aims to study the factor structure, reliability and validity of the Mental Health Continuum (MHC-SF) of Keyes (2009) in the Ecuadorian context. The scale was applied to two samples, one of 100 people that worked as a pilot and another of 550 people resident in the city of Cuenca-Ecuador, who also were applied an adaptation of the PERMA Profile of Butler and Kern (2016) to verify the convergent and discriminant validity. It was observed that the application in this population presents adequate levels of adjustment and high internal consistency (α=.91) and an adequate general adjustment of the structure of three factors: psychological well-being, social welfare and emotional well-being proposed by the author whose main fit values are RMSEA= .045, CFI= .996, χ2(52)= 109.048 (p= .000), GFI= .997 y TLI= 0.993. The bifactor model presents good values as well: RMSEA=.042, CFI= .996, χ2(52) = 103.040 (p= .000), GFI= .997, TLI= 0.993. We conclude that the Spanish version of MHC-SF (Keyes, 2009) and the bifactor model are appropriate tools to measure mental health in the Ecuadorian context. &nbsp;El presente estudio tiene como objetivo estudiar la estructura factorial, fiabilidad y validez del Contínuum de Salud Mental (MHC–SF) de Keyes (2009) en el contexto ecuatoriano. La escala fue aplicada a dos muestras, una de 100 personas que funcionó como piloto y otra de 550 personas residentes en la ciudad de Cuenca- Ecuador, a quienes también se aplicó una adaptación del Perfil PERMA de Butler y Kern (2016) para comprobar la validez convergente y discriminante. Se observó que la aplicación en esta población presenta adecuados niveles de ajuste y alta consistencia interna (α= .91) y un ajuste general adecuado de la estructura de tres factores: bienestar psicológico, bienestar social, bienestar emocional propuestos por el autor, dando valores de RMSEA= .045, CFI= .996, χ2(52)= 109.048 (p= .000), GFI= .997 y TLI= 0.993. El modelo bifactorial presenta valores de RMSEA= .042, CFI= .996, χ2 (52)= 103.040 (p= .000), GFI= .997, TLI= 0.993. Se concluye que la versión en español de MHC-SF (Keyes, 2009) y la versión bifactorial son herramientas apropiadas para medir la salud mental en el contexto ecuatoriano. &nbsp