Cинтез технологий обогащения руд

Мета. Розробка методики аналітичного синтезу технології збагачення з виділенням в кожній із стадій переробки концентрату, відходів і промпродукту. Завданням є ознайомлення науково-технічних працівників з методикою аналітичного синтезу технологічної лінії збагачення. Методи і апаратура. Теоретичний аналіз і розрахунок. Результати. Цінний мінерал зосереджений в руді у вигляді вкраплення. Розкриття цінного мінералу відбувається при подрібненні руди за певною закономірністю з утворенням в кожній із стадій подрібнення відкритих рудних, нерудних частинок, багатих і бідних зро-стків. При заданих значеннях якості концентрату і граничного вмісту цінного мінералу в відходах визначається точка перегину сепараційної характеристики і її вигляд. Формується технологічний блок, який виділяє три продукти: концентрат; промпродукт і відходи. Вико-нується оцінка виходу проміжного продукту для досягнення заданої якості концентрату, при необхідності промпродукт направляється на подальшу стадію розкриття (подрібнен-ня), і алгоритм повторюється. Наукова цінність статті полягає в розробці загальної методики синтезу технологіч-ної лінії збагачення руд, що мають вкраплену структуру цінного мінералу, яка дозволяє ви-значити кількість стадій подрібнення, операцій збагачення, очікувані показники розділення на основі розміру вкраплення цінного мінералу, його вмісту та подрібнюваності руди, зада-ної якості концентрату і допустимих втрат з відходами переробки. Практичне значення. Запропонована загальна методика розрахунку ґрунтується на єдиному алгоритмі розрахунку для всіх стадій збагачення. Ключові слова: збагачення, сепараційна характеристика, граничний вміст цінного мі-нералу, вихід продуктів розділення, технологічний блок. Цель. Разработка методики аналитического синтеза технологии обогащения с выде-лением в каждой из стадий переработки концентрата, отходов и промпродукта. Задачей является ознакомление научно-технических работников с методикой анали-тического синтеза технологической линии обогащения. Методы и аппаратура. Теоретический анализ и расчет. Результаты. Ценный минерал сосредоточен в руде в виде вкраплений. Раскрытие цен-ного минерала происходит при измельчении руды по определенной закономерности с образо-ванием в каждой из стадий измельчения открытых рудных, нерудных частиц, богатых и бедных сростков. При заданных значениях качества концентрата и предельного содержа-ния ценного минерала в отходах определяется точка перегиба сепарационной характери-стики и ее вид. Формируется технологический блок, который выделяет три продукта: кон-центрат; промпродукт и отходы. Выполняется оценка выхода промежуточного продукта для достижения заданного качества концентрата, при необходимости промпродукт направляется на последующую стадию раскрытия (измельчения), и алгоритм повторяется. Научная ценность статьи состоит в разработке общей методики синтеза техноло-гической линии обогащения руд с вкрапленной структурой ценного минерала, которая позво-ляет определить количество стадий измельчения, операций обогащения, ожидаемые пока-затели разделения, исходя из размера вкрапленности ценного минерала, его содержания и измельчаемости руды, заданного качества концентрата и допустимых потерь с отходами переработки. Практичне значення. Предложенная общая методика расчета основана на едином алгоритме расчета для всех стадий обогащения. Ключевые слова: обогащение, сепарационная характеристика, предельное содержание ценного минерала, выход продуктов разделения, технологический блок. Purpose. Development of a methodology for analytical synthesis of enrichment technology with obtaining concentrate, waste and middling product in each of the stages of preparation. The problem is to familiarize scientific and technical workers with the methodology of analyt-ical synthesis of the processing line. Methodology. Theoretical analysis and calculation. Findings. A valuable mineral is concentrated in ore in the form of inclusions. The disclosure of a valuable mineral occurs during ore grinding according to a certain regularity with the for-mation in each of the grinding stages of released ore grains, nonmetallic particles, rich and poor aggregates. For given values of the quality of the concentrate and the limiting content of valuable mineral in the waste, the inflection point of the separation characteristic and its type are deter-mined. A technological unit is formed to obtain three products: concentrate; middling product and waste. The yield of the middling product is estimated to achieve the specified quality of the concen-trate, if necessary, the middling product is sent to the subsequent stage of disclosure (grinding), and the algorithm is repeated. The scientific value of the article lies in the development of a general synthesis methodology for the ore dressing line with disseminated structure of a valuable mineral, which allows one to de-termine the number of grinding stages, concentration operations, expected separation indicators based on the size of the disseminated valuable mineral, its content and ore grindability, the speci-fied quality of concentrate and acceptable losses with processing waste. Practical implication. The proposed general calculation procedure is based on a single cal-culation algorithm for all stages of enrichment. Keywords: preparation, separation characteristic, limiting content of valuable mineral, yield of separation products, technological unit

Systemic Toxicity Reported for CDK8/19 Inhibitors CCT251921 and MSC2530818 Is Not Due to Target Inhibition

CDK8/19 kinases, which mediate transcriptional reprogramming, have become an active target for cancer drug discovery. Several small-molecule CDK8/19 inhibitors showed in vivo efficacy and two have entered clinical trials, with no significant toxicities reported. However, Clarke et al. (eLife 2016; 5; e20722) found severe systemic toxicity associated with two potent CDK8/19 inhibitors, Cmpd3 (CCT251921) and Cmpd4 (MSC2530818), and suggested that their toxicity was due to on-target effects. Here, we compared five CDK8/19 inhibitors: Cmpd3, Cmpd4, Senexin B, 16-didehydro-cortistatin A (dCA) and 15w, in different assays. Only Cmpd4 showed striking toxicity in developing zebrafish. In cell-based assays for CDK8 and CDK19 inhibition, Cmpd3, Cmpd4, dCA and 15w showed similar low-nanomolar potency and efficacy against CDK8 and CDK19, while Senexin B was less potent. Only dCA produced sustained inhibition of CDK8/19-dependent gene expression. While toxicity of different compounds did not correlate with their effects on CDK8 and CDK19, kinome profiling identified several off-target kinases for both Cmpd3 and Cmpd4, which could be responsible for their toxicity. Off-target activities could have been achieved in the study of Clarke et al. due to high in vivo doses of Cmpd3 and Cmpd4, chosen for the ability to inhibit STAT1 S727 phosphorylation in tumor xenografts. We show here that STAT1 S727 phosphorylation is induced by various cytokines and stress stimuli in CDK8/19-independent manner, indicating that it is not a reliable pharmacodynamic marker of CDK8/19 activity. These results illustrate the need for careful off-target analysis and dose selection in the development of CDK8/19 inhibitors

Murine Pancreatic Adenocarcinoma Reduces Ikaros Expression and Disrupts T Cell Homeostasis

Background Maintenance of T cell immune homeostasis is critical for adequate anti-tumor immunity. The transcription factor Ikaros is essential for lymphocyte development including T cells. Alterations in Ikaros expression occur in blood malignancies in humans and mice. In this study, we investigated the role of Ikaros in regulating T cell immune balance in pancreatic cancer mouse models. Methodology and Principal Findings Using our Panc02 tumor-bearing (TB) mouse model, western blot analysis revealed a reduction in Ikaros proteins while qRT-PCR showed no differences in Ikaros mRNA levels in TB splenocytes compared to control. Treatment of naïve splenocytes with the proteasomal inhibitor, MG132, stabilized Ikaros expression and prevented Ikaros downregulation by Panc02 cells, in vitro. Western blot analyses showed a reduction in protein phosphatase 1 (PP1) and protein kinase CK2 expression in TB splenocytes while CK2 activity was increased. Immunofluorescence microscopy revealed altered punctate staining of Ikaros in TB splenocytes. Flow cytometry revealed a significant decrease in effector CD4+ and CD8+ T cell percentages but increased CD4+CD25+ regulatory T cells in TB splenocytes. Similar alterations in T cell percentages, as well as reduced Ikaros and CK2 but not PP1 expression, were observed in a transgenic, triple mutant (TrM) pancreatic cancer model. Ikaros expression was also reduced in enriched TB CD3+ T cells. MG132 treatment of naïve CD3+ T cells stabilized Ikaros expression in the presence of Panc02 cells. Western blots showed reduced PP1 and CK2 expression in TB CD3+ T cells. Conclusions/Significance The results of this study suggest that the pancreatic tumor microenvironment may cause proteasomal degradation of Ikaros, possibly via dysregulation of PP1 and CK2 expression and activity, respectively. This loss of Ikaros expression may contribute to an imbalance in T cell percentages. Ikaros may potentially be a therapeutic target to restore T cell homeostasis in pancreatic cancer hosts, which may be critical for effective anti-tumor immunity

Biomechanical comparison of screw-based zoning of PHILOS and Fx proximal humerus plates

Background Treatment of proximal humerus fractures with locking plates is associated with complications. We aimed to compare the biomechanical effects of removing screws and blade of a fixed angle locking plate and hybrid blade plate, on a two-part fracture model. Methods Forty-five synthetic humeri were divided into nine groups where four were implanted with a hybrid blade plate and the remaining with locking plate, to treat a two-part surgical neck fracture. Plates’ head screws and blades were divided into zones based on their distance from fracture site. Two groups acted as a control for each plate and the remaining seven had either a vacant zone or blade swapped with screws. For elastic cantilever bending, humeral head was fixed and the shaft was displaced 5 mm in extension, flexion, valgus and varus direction. Specimens were further loaded in varus direction to investigate their plastic behaviour. Results In both plates, removal of inferomedial screws or blade led to a significantly larger drop in varus construct stiffness than other zones. In blade plate, insertion of screws in place of blade significantly increased the mean extension, flexion valgus and varus bending stiffness (24.458%/16.623%/19.493%/14.137%). In locking plate, removal of screw zones proximal to the inferomedial screws reduced extension and flexion bending stiffness by 26–33%. Conclusions Although medial support improved varus stability, two inferomedial screws were more effective than blade. Proximal screws are important for extension and flexion. Mechanical consequences of screw removal should be considered when deciding the number and choice of screws and blade in clinic

CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development

Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying protein 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) complex but is also suggested to localize to the nuclear matrix and regulate chromatin structure. Here, we show that loss-of-function mutations in human CHMP1A cause reduced cerebellar size (pontocerebellar hypoplasia) and reduced cerebral cortical size (microcephaly). CHMP1A-mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation. Chromatin immunoprecipitation suggests loss of the normal INK4A repression by BMI in these cells. Morpholino-based knockdown of zebrafish chmp1a resulted in brain defects resembling those seen after bmi1a and bmi1b knockdown, which were partially rescued by INK4A ortholog knockdown, further supporting links between CHMP1A and BMI1-mediated regulation of INK4A. Our results suggest that CHMP1A serves as a critical link between cytoplasmic signals and BMI1-mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells

The transcriptional landscape of hematopoietic stem cell ontogeny

Transcriptome analysis of adult hematopoietic stem cells (HSCs) and their progeny has revealed mechanisms of blood differentiation and leukemogenesis, but a similar analysis of HSC development is lacking. Here, we acquired the transcriptomes of developing HSCs purified from >2,500 murine embryos and adult mice. We found that embryonic hematopoietic elements clustered into three distinct transcriptional states characteristic of the definitive yolk sac, HSCs undergoing specification, and definitive HSCs. We applied a network-biology-based analysis to reconstruct the gene regulatory networks of sequential stages of HSC development and functionally validated candidate transcriptional regulators of HSC ontogeny by morpholino-mediated knockdown in zebrafish embryos. Moreover, we found that HSCs from in vitro differentiated embryonic stem cells closely resemble definitive HSCs, yet lack a Notch-signaling signature, likely accounting for their defective lymphopoiesis. Our analysis and web resource will enhance efforts to identify regulators of HSC ontogeny and facilitate the engineering of hematopoietic specification

A network of epigenetic regulators guides developmental haematopoiesis in vivo

The initiation of cellular programs is orchestrated by key transcription factors and chromatin regulators that activate or inhibit target gene expression. To generate a compendium of chromatin factors that establish the epigenetic code during developmental haematopoiesis, a large-scale reverse genetic screen was conducted targeting orthologues of 425 human chromatin factors in zebrafish. A set of chromatin regulators was identified that target different stages of primitive and definitive blood formation, including factors not previously implicated in haematopoiesis. We identified 15 factors that regulate development of primitive erythroid progenitors and 29 factors that regulate development of definitive haematopoietic stem and progenitor cells. These chromatin factors are associated with SWI/SNF and ISWI chromatin remodelling, SET1 methyltransferase, CBP-p300-HBO1-NuA4 acetyltransferase, HDAC-NuRD deacetylase, and Polycomb repressive complexes. Our work provides a comprehensive view of how specific chromatin factors and their associated complexes play a major role in the establishment of haematopoietic cells in vivo