Virtual Fragment Screening Identification of a Quinoline‐5,8‐dicarboxylic Acid Derivative as a Selective JMJD3 Inhibitor

The quinoline‐5,8 dicarboxylic acid scaffold has been identified by a fragment‐based approach as new potential lead compound for the development of JMJD3 inhibitors. Among them, 3‐(2,4‐dimethoxypyrimidin‐5‐yl)quinoline‐5,8‐dicarboxylic acid (compound 3 ) shows low micromolar inhibitory activity against Jumonji domain‐containing protein 3 (JMJD3). The experimental evaluation of inhibitory activity against seven related isoforms of JMJD3 highlighted an unprecedented selectivity toward the biological target of interest.     

Chemically Controlled Reversible and Irreversible Extraction Barriers Via Stable Interface Modification of Zinc Oxide Electron Collection Layer in Polycarbazole‐based Organic Solar Cells

A spin‐cast method is presented for the formation of phosphonic acid functionalized small molecule layers on solution‐processed ZnO substrates for use as electron collecting interlayers in organic photovoltaics. Phosphonic acid interlayers modify the ZnO work function and the charge carrier injection barrier at its interface, resulting in systematic control of V _OC in inverted bulk heterojunction solar cells. Surface modification is shown to moderate the need for UV light‐soaking of the ZnO contact layers. Lifetime studies (30 days) indicate stable and improved OPV performance over the unmodified ZnO contact, which show significant increases in charge extraction barriers and series resistance. Results suggest that enhanced stability using small molecule modifiers is due to partial passivation of the oxide surface to molecular oxygen adsorption. Surface passivation while maintaining work function control of a selective interlayer can be employed to improve net efficiency and lifetime of organic photovoltaic devices. The modified cathode work function modulates V _OC via static energetic barriers and modulates contact conductivity by creating reversible and irreversible S‐shape current‐voltage characteristics as a result of kinetic barriers to charge transport.     

Evaluation and characterization of estrus alerts and behavioral parameters generated by an ear-attached accelerometer-based system for automated detection of estrus

Our objectives were to evaluate the performance of an ear-attached automated estrus detection (AED) system (Smartbow; Zoetis) that monitored physical activity and rumination time, and to characterize AED system estrus alert features (i.e., timing and duration). Lactating Holstein cows (n = 216) commenced a protocol for the synchronization of estrus at 50 ± 3 DIM or 18 ± 3 d after artificial insemination. For 7 d after induction of luteolysis with PGF_2α (d 0), we used visual observation of estrous behavior (30 min, 2 times per day) and data from an automated mounting behavior monitoring system based on a pressure-activated tail-head sensor (HeatWatch; Cowchips LLC) as a reference test (RTE) to detect behavioral estrus. Concomitantly, estrus alerts and their features were collected from the AED system. Progesterone levels confirmed luteal regression, and transrectal ultrasonography confirmed the occurrence and timing of ovulation. Performance metrics for the AED system were estimated with PROC FREQ in SAS, using the RTE or ovulation only as a reference. Performance was also estimated after the removal of cows with a discrepancy between the RTE and ovulation. Continuous outcomes with or without repeated measurements were evaluated by ANOVA using PROC MIXED in SAS. Based on the RTE, 86.6% (n = 187) of the cows presented estrus and ovulated; 1.4% (n = 3) presented estrus and did not ovulate; 6.4% (n = 14) did not present estrus but ovulated; and 5.6% (n = 12) did not present estrus or ovulation. We found no difference in the proportion of cows detected in estrus and with ovulation for the AED system (83.4%) and the RTE (86.6%). Compared with estrus events as detected by the RTE, sensitivity for the AED was 91.6% (95% CI: 87.6–95.5) and specificity was 69.2% (95% CI: 51.5–87.0). Using ovulation as reference, sensitivity was 89.6% (95% CI: 85.3–93.8) and specificity was 86.7% (95% CI 69.5–100). For all cows with agreement between the RTE and ovulation, sensitivity was 92.5% (95% CI: 88.7–96.3) and specificity was 91.7% (95% CI: 76.0–100). The mean (±SD) interval from induction of luteolysis to estrus alerts, estrus alert duration, and the onset of estrus alerts to ovulation interval were 72.2 ± 18.1, 13.5 ± 3.8, and 23.8 ± 7.1 h, respectively. We concluded that an ear-attached AED system that monitored physical activity and rumination time was effective at detecting cows in estrus and generated few false positive alerts when accounting for ovulation, cow physiological limitations, and the limitations of the RTE.     

The Néel IRAM KID Arrays (NIKA)

We are developing an instrument based on Kinetic Inductance Detectors (KID) known as the Néel IRAM KID Array (NIKA). Leveraging the experience gained from the first generation NIKA in 2009, an improved, dual-band (150?GHz and 240?GHz) instrument has been designed and tested at the Institut of RadioAstronomie Millimetrique (IRAM) 30-meter telescope in October 2010. The performances, in terms of sensitivity on-the-sky at 150?GHz, are already comparable to existing state-of-the-art bolometer-based instruments. NIKA represents thus the first real proof that KID are a viable technology for ground-based Astronomy. We will describe the instrument, the most recent results and the future plans for building a large resident mm-wave camera.     

Genetics and Pathogenetic Role of Inflammasomes in Philadelphia Negative Chronic Myeloproliferative Neoplasms: A Narrative Review

The last decade has been very important for the quantity of preclinical information obtained regarding chronic myeloproliferative neoplasms (MPNs) and the following will be dedicated to the translational implications of the new biological acquisitions. The overcoming of the mechanistic model of clonal evolution and the entry of chronic inflammation and dysimmunity into the new model are the elements on which to base a part of future therapeutic strategies. The innate immune system plays a major role in this context. Protagonists of the initiation and regulation of many pathological aspects, from cytokine storms to fibrosis, the NLRP3 and AIM2 inflammasomes guide and condition the natural history of the disease. For this reason, MPNs share many biological and clinical aspects with non-neoplastic diseases, such as autoimmune disorders. Finally, cardiovascular risk and disturbances in iron metabolism and myelopoiesis are also closely linked to the role of inflammasomes. Although targeted therapies are already being tested, an increase in knowledge on the subject is desirable and potentially translates into better care for patients with MPNs.     

A case study on the application of destructive and non-destructive methods for evaluating jet-grouting column integrity for bridge-pier scour protection (Cuneo,NW Italy)

Bulletin of Engineering Geology and the Environment - A case study on the use of direct and indirect investigations for the effectiveness evaluation of jet-grouting interventions for bridge scour...     

Economic performance of lactating dairy cows submitted for first service timed artificial insemination after a voluntary waiting period of 60 or 88 days

The objective of this study was to evaluate the economic performance of dairy cows managed with a voluntary waiting period (VWP) of 60 or 88 d. A secondary objective was estimating variation in cash flow under different input pricing scenarios through stochastic Monte Carlo simulations. Lactating Holstein cows from 3 commercial farms were blocked by parity group and total milk yield in their previous lactation and then randomly assigned to a VWP of 60 (VWP60; n = 1,352) or 88 d (VWP88; n = 1,359). All cows received timed-artificial insemination (TAI) for first service after synchronization of ovulation with the Double-Ovsynch protocol. For second and greater services, cows received artificial insemination (AI) after detection of estrus or the Ovsynch protocol initiated 32 ± 3 d after AI. Two analyses were performed: (1) cash flow per cow for the calving interval of the experimental lactation and (2) cash flow per slot occupied by each cow enrolled in the experiment for an 18-mo period after calving in the experimental lactation. Extending the VWP from 60 to 88 d delayed time to pregnancy during lactation (～20 d) and increased the risk of leaving the herd for multiparous cows (hazard ratio = 1.21). As a result, a smaller proportion of multiparous cows calved again and had a subsequent lactation (?6%). The shift in time to pregnancy combined with the herd exit dynamics resulted in longer lactation length for primiparous (22 d) but not multiparous cows. Longer lactations led to greater milk income over feed cost and a tendency for greater cash flow during the experimental lactation for primiparous but not multiparous cows in the VWP88 group. On the other hand, profitability per slot for the 18-mo period was numerically greater ($68 slot/18 mo) for primiparous cows but numerically reduced (?$85 slot/18 mo) for multiparous cows in the VWP88 treatment. For primiparous cows most of the difference in cash flow was explained by replacement cost, whereas for multiparous cows it was mostly explained by differences in replacement cost and income over feed cost. Under variable input pricing conditions generated through stochastic simulations, the longer VWP treatment always increased cash flow per 18 mo for primiparous and reduced cash flow for multiparous cows. In conclusion, extending the duration of the VWP from 60 to 88 d numerically increased profitability of primiparous cows and reduced profitability of multiparous cows. Such an effect depended mostly on the herd replacement dynamics and milk production efficiency.     

Profitability of dairy cows submitted to the first service with the Presynch-Ovsynch or Double-Ovsynch protocol and different duration of the voluntary waiting period

The objective of this study was to compare cash flow and parameters of economic performance for dairy cows submitted to the first service using a combination of insemination at detected estrus and timed AI (TAI) in cows synchronized with the Presynch-Ovsynch (PSOv) protocol versus all TAI after synchronization of ovulation with the Double-Ovsynch (DO) protocol with different durations of the voluntary waiting period. A secondary objective was to calculate the variation in cash flow under different input pricing scenarios through stochastic Monte Carlo simulation. Lactating Holstein cows from a commercial dairy farm were randomly assigned to 3 first-service management programs. Cows in the PSOv treatment (n = 450) received first service through a combination of insemination at detected estrus after a voluntary waiting period of 50 d in milk (DIM; i.e., after second PGF_2α treatment of the protocol) and TAI at 72 ± 3 DIM. Cows in the DO60 (n = 458) and DO88 (n = 462) treatments received first service by TAI at 60 ± 3 and 88 ± 3 DIM, respectively. Individual cow cash flow was calculated for the calving interval after enrollment and for an 18-mo period after calving. Cash flow was the aggregation of daily income over feed cost, replacement cost, calf value, recombinant bovine somatotropin treatment cost, reproductive cost, and other operating expenses. All analyses were conducted separately for primiparous and multiparous cows. Continuous, binomial, and time to event outcomes were analyzed using ANOVA, logistic regression, and Cox's proportional hazard regression in SAS (SAS Institute Inc., Cary, NC). Treatments affected the dynamics of pregnancy creation, which affected time to pregnancy during lactation. As a result, we observed differences in the proportion of nonpregnant cows at the end of lactation, herd exit dynamics, lactation length, calving interval, and proportion of cows that calved again. Some of these effects varied by parity, affecting the direction and magnitude of treatment differences within parity group. For primiparous cows, maximum cash flow differences per slot for the 18-mo period were in the range of $26 (PSOv > DO60) to $29 (DO88 > DO60) but did not differ statistically. For multiparous cows, maximum cash flow differences per slot for the 18-mo period were in the range of $122 (PSOv > DO88) to $155 (DO60 > DO88) but did not differ statistically. Despite the substantial differences in cash flow (in particular for multiparous cows) caused by the effect of treatments on reproductive performance, herd exit dynamics, and calving interval, large variability in overall cash flow among individual cows and compensation between multiple outcomes resulted in lack of statistical differences in cash flow. Outcomes from the stochastic analysis indicated that similar trends for differences between treatments would be observed under varying scenarios for economic input values. In conclusion, we did not detect statistically significant cash flow differences between the PSOv, DO60, and DO88 treatments, but numerical trends and stochastic simulation indicated that the DO88 and PSOv treatments were more economically favorable than the DO60 treatment for primiparous cows. For multiparous cows, the DO60 and PSOv treatments were more economically favorable than the DO88 treatment.