Effects of Dry Matter Content and Microbial Additive on Tifton 85 \u3ci\u3e(Cynodon dactylon ssp.)\u3c/i\u3e Wilted Silage Fermentation Parameters

The objective of this study was to evaluate the wilting and the addition of a bacterial-enzymatic additive effects on the fermentation parameters of Tifton 85 (Cynodon dactylon spp.) silage. Forage was stored as 326 kg bales wrapped with a plastic film. Treatments consisted of 5 forage dry matter levels (20-30%, 30-40%, 40-50%, 50 -60% e 60 a 70%) without additive and 3 dry matter levels (20-30%, 40-50%, e 60-70%) with additive. Buffered propionic acid solution was sprayed onto 60-70% dry matter bales, prior to wrapping, determining an additional treatment. Core samples were taken at 0, 6, 12 hours and 1, 2, 4, 8, 16, and 32 days after wrapping to establish silage pH and temperature trends. Field dry matter losses during the baling process were also evaluated. Bale weight with no additive decreased (364 kg to 254 kg) with increased forage DM content, which in turn resulted in lower bale bulk density (310 to 216 kg/m3 ). Lower field DM losses (281 to 177 kg/ha) were associated with higher forage DM content. Final silage pH and temperature peaks were increased at higher DM content, whereas the presence of microbial additive prevented temperature surge

Ellipsoidal configurations in the de Sitter spacetime

The cosmological constant $\Lambda$ modifies certain properties of large astrophysical rotating configurations with ellipsoidal geometries, provided the objects are not too compact. Assuming an equilibrium configuration and so using the tensor virial equation with $\Lambda$ we explore several equilibrium properties of homogeneous rotating ellipsoids. One shows that the bifurcation point, which in the oblate case distinguishes the Maclaurin ellipsoid from the Jacobi ellipsoid, is sensitive to the cosmological constant. Adding to that, the cosmological constant allows triaxial configurations of equilibrium rotating the minor axis as solutions of the virial equations. The significance of the result lies in the fact that minor axis rotation is indeed found in nature. Being impossible for the oblate case, it is permissible for prolate geometries, with $\Lambda$ zero and positive. For the triaxial case, however, an equilibrium solution is found only for non-zero positive $\Lambda$. Finally, we solve the tensor virial equation for the angular velocity and display special effects of the cosmological constant there.Comment: 15 pages, 11 figures, published in Class. Quant. Grav. References adde

Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma

Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911-17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC

uPA is upregulated by high dose celecoxib in women at increased risk of developing breast cancer

<p>Abstract</p> <p>Background</p> <p>While increased urokinase-type plasminogen activator (uPA) expression in breast cancer tissue is directly associated with poor prognosis, recent evidence suggests that uPA overexpression may suppress tumor growth and prolong survival. Celecoxib has been shown to have antiangiogenic and antiproliferative properties. We sought to determine if uPA, PA inhibitor (PAI)-1 and prostaglandin (PG)E₂expression in nipple aspirate fluid (NAF) and uPA and PGE₂expression in plasma were altered by celecoxib dose and concentration in women at increased breast cancer risk.</p> <p>Methods</p> <p>NAF and plasma samples were collected in women at increased breast cancer risk before and 2 weeks after taking celecoxib 200 or 400 mg twice daily (bid). uPA, PAI-1 and PGE₂were measured before and after intervention.</p> <p>Results</p> <p>Celecoxib concentrations trended higher in women taking 400 mg (median 1025.0 ng/mL) compared to 200 mg bid (median 227.3 ng/mL), and in post- (534.6 ng/mL) compared to premenopausal (227.3 ng/mL) women. In postmenopausal women treated with the higher (400 mg bid) celecoxib dose, uPA concentrations increased, while PAI-1 and PGE₂decreased. In women taking the higher dose, both PAI-1 (r = -.97, p = .0048) and PGE₂(r = -.69, p = .019) in NAF and uPA in plasma (r = .45, p = .023) were correlated with celecoxib concentrations.</p> <p>Conclusion</p> <p>Celecoxib concentrations after treatment correlate inversely with the change in PAI-1 and PGE₂in the breast and directly with the change in uPA in the circulation. uPA upregulation, in concert with PAI-1 and PGE₂downregulation, may have a cancer preventive effect.</p

FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury

The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreERt2 knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing of dedifferentiated cells while measuring the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones coexpressed KIM1, VIMENTIN, SOX9, and KI67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells, rather than fixed tubular progenitor cells, account for repair. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor Foxm1 was induced early in injury, was required for epithelial proliferation in vitro, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair, and we reveal an EGFR/FOXM1-dependent signaling pathway that drives proliferative repair after injury

Proteomic fingerprint identification of Neotropical hard tick species (Acari: Ixodidae) using a self-curated mass spectra reference library

Matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry is an analytical method that detects macromolecules that can be used as biomarkers for taxonomic identification in arthropods. The conventional MALDI approach uses fresh laboratory-reared arthropod specimens to build a reference mass spectra library with high-quality standards required to achieve reliable identification. However, this may not be possible to accomplish in some arthropod groups that are difficult to rear under laboratory conditions, or for which only alcohol preserved samples are available. Here, we generated MALDI mass spectra of highly abundant proteins from the legs of 18 Neotropical species of adult field-collected hard ticks, several of which had not been analyzed by mass spectrometry before. We then used their mass spectra as fingerprints to identify each tick species by applying machine learning and pattern recognition algorithms that combined unsupervised and supervised clustering approaches. Both principal component analysis (PCA) and linear discriminant analysis (LDA) classification algorithms were able to identify spectra from different tick species, with LDA achieving the best performance when applied to field-collected specimens that did have an existing entry in a reference library of arthropod protein spectra. These findings contribute to the growing literature that ascertains mass spectrometry as a rapid and effective method for taxonomic identification of disease vectors, which is the first step to predict and manage arthropod-borne pathogens. Author Summary Hard ticks (Ixodidae) are external parasites that feed on the blood of almost every species of terrestrial vertebrate on earth, including humans. Due to a complete dependency on blood, both sexes and even immature stages, are capable of transmitting disease agents to their hosts, causing distress and sometimes death. Despite the public health significance of ixodid ticks, accurate species identification remains problematic. Vector species identification is core to developing effective vector control schemes. Herein, we provide the first report of MALDI identification of several species of field-collected Neotropical tick specimens preserved in ethanol for up to four years. Our methodology shows that identification does not depend on a commercial reference library of lab-reared samples, but with the help of machine learning it can rely on a self-curated reference library. In addition, our approach offers greater accuracy and lower cost per sample than conventional and modern identification approaches such as morphology and molecular barcoding.Matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry is an analytical method that detects macromolecules that can be used as biomarkers for taxonomic identification in arthropods. The conventional MALDI approach uses fresh laboratory-reared arthropod specimens to build a reference mass spectra library with high-quality standards required to achieve reliable identification. However, this may not be possible to accomplish in some arthropod groups that are difficult to rear under laboratory conditions, or for which only alcohol preserved samples are available. Here, we generated MALDI mass spectra of highly abundant proteins from the legs of 18 Neotropical species of adult field-collected hard ticks, several of which had not been analyzed by mass spectrometry before. We then used their mass spectra as fingerprints to identify each tick species by applying machine learning and pattern recognition algorithms that combined unsupervised and supervised clustering approaches. Both principal component analysis (PCA) and linear discriminant analysis (LDA) classification algorithms were able to identify spectra from different tick species, with LDA achieving the best performance when applied to field-collected specimens that did have an existing entry in a reference library of arthropod protein spectra. These findings contribute to the growing literature that ascertains mass spectrometry as a rapid and effective method for taxonomic identification of disease vectors, which is the first step to predict and manage arthropod-borne pathogens. Author Summary Hard ticks (Ixodidae) are external parasites that feed on the blood of almost every species of terrestrial vertebrate on earth, including humans. Due to a complete dependency on blood, both sexes and even immature stages, are capable of transmitting disease agents to their hosts, causing distress and sometimes death. Despite the public health significance of ixodid ticks, accurate species identification remains problematic. Vector species identification is core to developing effective vector control schemes. Herein, we provide the first report of MALDI identification of several species of field-collected Neotropical tick specimens preserved in ethanol for up to four years. Our methodology shows that identification does not depend on a commercial reference library of lab-reared samples, but with the help of machine learning it can rely on a self-curated reference library. In addition, our approach offers greater accuracy and lower cost per sample than conventional and modern identification approaches such as morphology and molecular barcoding

Discovery and Cross-Section Measurement of Neutron-Rich Isotopes in the Element Range from Neodymium to Platinum at the FRS

With a new detector setup and the high-resolution performance of the fragment separator FRS at GSI we discovered 57 new isotopes in the atomic number range of 60$\leq Z \leq 78$: \nuc{159-161}{Nb}, \nuc{160-163}{Pm}, \nuc{163-166}Sm, \nuc{167-168}{Eu}, \nuc{167-171}{Gd}, \nuc{169-171}{Tb}, \nuc{171-174}{Dy}, \nuc{173-176}{Ho}, \nuc{176-178}{Er}, \nuc{178-181}{Tm}, \nuc{183-185}{Yb}, \nuc{187-188}{Lu}, \nuc{191}{Hf}, \nuc{193-194}{Ta}, \nuc{196-197}{W}, \nuc{199-200}{Re}, \nuc{201-203}{Os}, \nuc{204-205}{Ir} and \nuc{206-209}{Pt}. The new isotopes have been unambiguously identified in reactions with a $^{238}$U beam impinging on a Be target at 1 GeV/u. The isotopic production cross-section for the new isotopes have been measured and compared with predictions of different model calculations. In general, the ABRABLA and COFRA models agree better than a factor of two with the new data, whereas the semiempirical EPAX model deviates much more. Projectile fragmentation is the dominant reaction creating the new isotopes, whereas fission contributes significantly only up to about the element holmium.Comment: 9 pages, 4 figure

Характеристики и методы лечения основных нежелательных явлений у пациентов с распространенным почечно-клеточным раком, получающих терапию комбинацией ленватиниба с пембролизумабом на основании результатов исследования CLEAR

.Введение. Комбинация ленватиниба с пембролизумабом продемонстрировала значительное улучшение показателей выживаемости без прогрессирования и общей выживаемости у пациентов с распространенным почечно-клеточным раком по сравнению с сунитинибом в исследовании CLEAR (Clinicaltrials.gov: NCT02811861).Цель исследования – на основании данных исследования CLEAR охарактеризовать основные нежелательные явления (НЯ) (предпочтительные термины сгруппированы в соответствии с обзором регулирующего органа), ассоциированные с использованием комбинации ленватиниба с пембролизумабом, и привести стратегии их преодоления.Материалы и методы. Проанализирована безопасность комбинации ленватиниба с пембролизумабом у 352 пациентов, включенных в исследование CLEAR. Наиболее важные НЯ были выбраны на основании частоты их встречаемости (≥30 %). Оценено время до появления НЯ и описаны подходы к их лечению.Результаты. Наиболее частыми НЯ были повышенная утомляемость (63,1 %), диарея (61,9 %), скелетно-мышечные боли (58,0 %), гипотиреоз (56,8 %) и гипертония (56,3 %). НЯ ≥III степени тяжести, зафиксированные у ≥5 % пациентов, включали гипертонию (28,7 %), диарею (9,9 %), повышенную утомляемость (9,4 %), снижение массы тела (8,0 %) и протеинурию (7,7 %). Медиана времени до появления первых симптомов основных НЯ составила приблизительно 5 мес (около 20 нед) с момента начала лечения. Стратегии эффективного преодоления НЯ включали мониторинг исходных показателей, изменение дозы препарата и/или назначение сопутствующих медикаментозных препаратов.Заключение. Профиль безопасности комбинации ленватиниба с пембролизумабом соответствовал известному профилю каждого из 2 препаратов, применяемых в монорежиме. НЯ рассматривались как преодолимые с помощью таких подходов, как мониторинг, изменение доз и поддерживающая терапия. Активное и своевременное выявление НЯ и их лечение важны для безопасности пациента и продолжения лечения.Идентификатор исследования на Clinicaltrials.gov: NCT0281186

In-situ formation of solidified hydrogen thin-membrane targets using a pulse tube cryocooler

An account is given of the Central Laser Facility's work to produce a cryogenic hydrogen targetry system using a pulse tube cryocooler. Due to the increasing demand for low Z thin laser targets, CLF (in collaboration with TUD) have been developing a system which allows the production of solid hydrogen membranes by engineering a design which can achieve this remotely; enabling the gas injection, condensation and solidification of hydrogen without compromising the vacuum of the target chamber. A dynamic sealing mechanism was integrated which allows targets to be grown and then remotely exposed to open vacuum for laser interaction. Further research was conducted on the survivability of the cryogenic targets which concluded that a warm gas effect causes temperature spiking when exposing the solidified hydrogen to the outer vacuum. This effect was shown to be mitigated by improving the pumping capacity of the environment and reducing the minimum temperature obtainable on the target mount. This was achieved by developing a two-stage radiation shield encased with superinsulating blanketing; reducing the base temperature from 14 0.5 K to 7.2 0.2 K about the coldhead as well as improving temperature control stability following the installation of a high-performance temperature controller and sensor apparatus. The system was delivered experimentally and in July 2014 the first laser shots were taken upon hydrogen targets in the Vulcan TAP facility.</p