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Induction Motor (IM) speed control is an area of research that has been in prominence for some time now. In this paper, a nonlinear controller is presented for IM drives. The nonlinear controller is designed based on input-output feedback linearization control technique, combined with sliding mode control (SMC) to obtain a robust, fast and precise control of IM speed. The input-output feedback linearization control decouples the flux control from the speed control and makes the synthesis of linear controllers possible. To validate the performances of the proposed control scheme, we provided a series of simulation results and a comparative study between the performances of the proposed control strategy and those of the feedback linearization control (FLC) schemes. Simulation results show that the proposed control strategy scheme shows better performance than the FLC strategy in the face of system parameters variation

Control of Induction Motor (IM) is well known to be difficult owing to the fact the models of IM are highly nonlinear and time variant. In this paper, to achieve accurate control performance of rotor position control of IM, a new method is proposed by using adaptive inverse control (AIC) technique. In recent years, AIC is a very vivid field because of its advantages. It is quite different from the traditional control. AIC is actually an open loop control scheme and so in the AIC the instability problem cased by feedback control is avoided and the better dynamic performances can also be achieved. The model of IM is identified using adaptive filter as well as the inverse model of the IM, which was used as a controller. The significant of using the inverse of the IM dynamic as a controller is to makes the IM output response to converge to the reference input signal. To validate the performances of the proposed new control scheme, we provided a series of simulation results.

Induction Motors have been used as the workhorse in the industry for a long time due to its easy build, high robustness, and generally satisfactory efficiency. However, they are significantly more difficult to control than DC motors. One of the problems which might cause unsuccessful attempts for designing a proper controller would be the time varying nature of parameters and variables which might be changed while working with the motion systems. One of the best suggested solutions to solve this problem would be the use of Sliding Mode Control (SMC). This paper presents the design of a new controller for a vector control induction motor drive that employs an outer loop speed controller using SMC. Several tests were performed to evaluate the performance of the new controller method, and two other sliding mode controller techniques. From the comparative simulation results, one can conclude that the new controller law provides high performance dynamic characteristics and is robust with regard to plant parameter variations.

The discovery of well-preserved fossil Vitis L. seeds from the Gelasian stage in Italy has provided a unique opportunity to investigate the systematics of fossilized Vitis species. Through seed image analyses and elliptical Fourier transforms of fossil Vitis seeds from the sites Buronzo−Gifflenga and Castelletto Cervo II, we pointed out a strong relationship to the group of extant Eurasian Vitis species. However, classification analyses highlighted challenges in accurately assigning the fossil grape seeds to specific modern species. Morphological comparisons with modern Vitis species revealed striking similarities between the fossil seeds and V. vinifera subsp. sylvestris, as well as several other wild species from Asia. This close morphological resemblance suggests the existence of a population of V. vinifera sensu lato in Northen Italy during the Gelasian. These findings contributed to our understanding of the evolution and the complex interplay between ancient and modern Vitis species.

ABSTRACT Physiological dormancy of Vitis vinifera seeds jeopardises breeding programs and biodiversity evolution. To increase the knowledge on dormancy breaking, seeds of white and black Sardinian grape cultivars (cvs) were exposed to different pre-germination treatments. To shed light on the physiological and structural factors involved in seed dormancy, the contents of oil, abscisic acid, gibberellic acid, 3-indolacetic acid, condensed tannins, and total polyphenols were determined. In addition, sectioned seeds were observed by SEM to determine the morphological and anatomical characteristics. Dormancy break in white, but not in black grape seeds, occurred under almost all imposed pre-germination treatments. Among red cvs, only seeds from ‘Cagnulari’ germinated when kept at 25 °C. Chilling seeds of the white cvs ‘Malvasia sarda’ and ‘Vernaccia di Oristano’ for 30 d resulted in the most effective treatment. Compared to white cvs, seeds of red ones owned 7 times higher levels of abscisic acid however, gibberellic acid content resulted 4 times less. Concerning the coat characteristics, red cv seeds had a thicker cuticle (6-10 µm) than white (4-6 µm) ones, however the most significant diversities were found for the inner integument, where in addition to size variances, palisade cell wall were structurally different.

Candida auris has become a major concern in critical care medicine due to the increasing number of immunocompromised patients and candidiasis is the most frequent cause of fungal infections. C. auris and other fungal pathogens are responsible for at least 13 million infections and 1.5 million deaths globally per year. In immunocompromised patients, infections can quickly become severe, causing wound infections, otitis and candidemia, resulting in high morbidity and mortality. The clinical presentation of C. auris is often non-specific and similar to other types of systemic infections; in addition, it is harder to identify from cultures than other, more common types of Candida spp. Some infections are particularly difficult to treat due to multi-resistance to several antifungal agents, including fluconazole (and other azoles), amphotericin B and echinocandins. This entails treatment with more drugs and at higher doses. Even after treatment for invasive infections, patients generally remain colonized for long periods, so all infection control measures must be followed during and after treatment of the C. auris infection. Screening patients for C. auris colonization enables facilities to identify individuals with C. auris colonization and to implement infection prevention and control measures. This pathogenic fungus shows an innate resilience, enabling survival and persistence in healthcare environment and the ability to rapidly colonize the patient’s skin and be easily transmitted within the healthcare setting, thus leading to a serious and prolonged outbreak.

Higher plants are the source of a wide array of bioactive compounds that support skin integrity and health. Hibiscus syriacus, family Malvaceae, is a plant of Chinese origin known for its antipyretic, anthelmintic, and antifungal properties. The aim of this study was to assess the healing and hydration properties of H. syriacus ethanolic extract (HSEE). We established a cell culture from Hibiscus syriacus leaves and obtained an ethanol soluble extract from cultured cells. The properties of the extract were tested by gene expression and functional analyses on human fibroblast, keratinocytes, and skin explants. HSEE treatment increased the healing potential of fibroblasts and keratinocytes. Specifically, HSEE significantly stimulated fibronectin and collagen synthesis by 16 and 60%, respectively, while fibroblasts contractility was enhanced by 30%. These results were confirmed on skin explants, where HSEE accelerated the wound healing activity in terms of epithelium formation and fibronectin production. Moreover, HSEE increased the expression of genes involved in skin hydration and homeostasis. Specifically, aquaporin 3 and filaggrin genes were enhanced by 20 and 58%, respectively. Our data show that HSEE contains compounds capable of stimulating expression of biomarkers relevant to skin regeneration and hydration thereby counteracting molecular pathways leading to skin damage and aging. [ABSTRACT FROM AUTHOR]

Induction Motor (IM) speed control is an area of research that has been in prominence for some time now. In this paper, a nonlinear controller is presented for IM drives. The nonlinear controller is designed based on input-output feedback linearization control technique, combined with sliding mode control (SMC) to obtain a robust, fast and precise control of IM speed. The input-output feedback linearization control decouples the flux control from the speed control and makes the synthesis of linear controllers possible. To validate the performances of the proposed control scheme, we provided a series of simulation results and a comparative study between the performances of the proposed control strategy and those of the feedback linearization control (FLC) schemes. Simulation results show that the proposed control strategy scheme shows better performance than the FLC strategy in the face of system parameters variation. [ABSTRACT FROM AUTHOR]

Induction Motors have been used as the workhorse in the industry for a long time due to its easy build, high robustness, and generally satisfactory efficiency. However, they are significantly more difficult to control than DC motors. One of the problems which might cause unsuccessful attempts for designing a proper controller would be the time varying nature of parameters and variables which might be changed while working with the motion systems. One of the best suggested solutions to solve this problem would be the use of Sliding Mode Control (SMC). This paper presents the design of a new controller for a vector control induction motor drive that employs an outer loop speed controller using SMC. Several tests were performed to evaluate the performance of the new controller method, and two other sliding mode controller techniques. From the comparative simulation results, one can conclude that the new controller law provides high performance dynamic characteristics and is robust with regard to plant parameter variations. [ABSTRACT FROM AUTHOR]

Control of Induction Motor (IM) is well known to be difficult owing to the fact the models of IM are highly nonlinear and time variant. In this paper, to achieve accurate control performance of rotor position control of IM, a new method is proposed by using adaptive inverse control (AIC) technique. In recent years, AIC is a very vivid field because of its advantages. It is quite different from the traditional control. AIC is actually an open loop control scheme and so in the AIC the instability problem cased by feedback control is avoided and the better dynamic performances can also be achieved. The model of IM is identified using adaptive filter as well as the inverse model of the IM, which was used as a controller. The significant of using the inverse of the IM dynamic as a controller is to makes the IM output response to converge to the reference input signal. To validate the performances of the proposed new control scheme, we provided a series of simulation results. [ABSTRACT FROM AUTHOR]

BACKGROUND: A recent report by the UK Drugs Policy Commission has highlighted the high levels of drug use in Britain and this has been interpreted as indicative of ineffective drug polices. However, the interpretation was based on sporadic self-report data and indirect extrapolation. This paper assesses trends in the prevalence and incidence of drug misuse in the UK from 1998 to 2005 as recorded in general practice. METHODS: The study was a retrospective analysis of the General Practice Research Database. The study cohort comprised approximately 900,000 patients each year from 183 general practices. RESULTS: Among the Government's key target age group (16-24 years), there was a marked decrease in both prevalence and incidence of illicit drug misuse from 1998 to 2002 (P < 0.01). In older adults (25-59 years), the pattern was more variable during the first part of this period, but incidence remained stable from 2002 to 2005. CONCLUSIONS: These data indicate that the problematic drug use in the UK may be declining and that the policies may be more effective than has been previously thought. General Practice data are nonetheless only part of the picture in terms of understanding the prevalence of problematic drug use. [ABSTRACT FROM AUTHOR]

In this work, the seed morpho-colorimetric differentiation of the Sardinian endemic species of Anchusa (Boraginaceae) was evaluated. In Sardinia, the Anchusa genus includes the following seven taxa: A. capellii, A. crispa ssp. crispa, A. crispa ssp. maritima, A. formosa, A. littorea, A. montelinasana, and A. sardoa. Seed images were acquired using a flatbed scanner and analyzed using the free software package ImageJ. A total of 74 seed morpho-colorimetric features of 2692 seed lots of seven taxa of Anchusa belonging to 17 populations were extrapolated and used to build a database of seed size, shape, and color features. The data were statistically elaborated by the stepwise linear discriminant analysis (LDA) to compare and discriminate each accession and taxon. In addition, the seed morpho-colorimetric differences among coastal and mountainous taxa were evaluated. Considering the ecological conditions, the LDA was able to discriminate among the Anchusa taxa with a correct identification of 87.4% and 90.8% of specimens for mountainous and coastal plants, respectively. Moreover, the LDA of the 17 populations of Anchusa showed a low separation among species and populations within the coastal group, highlighting how the long-distance dispersal by flotation on the sea water surface and the pollination network may influence the similarity patterns observed. In addition, a misattribution was observed for A. crispa ssp. crispa, which was misclassified as A. crispa ssp. maritima in 14.1% of cases, while A. crispa ssp. maritima was misidentified as A. crispa ssp. crispa in 21.1% of cases, highlighting a close phenotypic relationship between these two taxa. The statistical results obtained through the seed image analysis showed that the morpho-colorimetric features of the seeds provide important information about the adaptation and evolution of Anchusa taxa in Sardinia.

The identification of archaeological charred grape seeds is a difficult task due to the alteration of the morphological seeds shape. In archaeobotanical studies, for the correct discrimination between Vitis vinifera subsp. sylvestris and Vitis vinifera subsp. vinifera grape seeds it is very important to understand the history and origin of the domesticated grapevine. In this work, different carbonisation experiments were carried out using a hearth to reproduce the same burning conditions that occurred in archaeological contexts. In addition, several carbonisation trials on modern wild and cultivated grape seeds were performed using a muffle furnace. For comparison with archaeological materials, modern grape seed samples were obtained using seven different temperatures of carbonisation ranging between 180 and 340ºC for 120 min. Analysing the grape seed size and shape by computer vision techniques, and applying the stepwise linear discriminant analysis (LDA) method, discrimination of the wild from the cultivated charred grape seeds was possible. An overall correct classification of 93.3% was achieved. Applying the same statistical procedure to compare modern charred with archaeological grape seeds, found in Sardinia and dating back to the Early Bronze Age (2017-1751 2σ cal. BC), allowed 75.0% of the cases to be identified as wild grape. The proposed method proved to be a useful and effective procedure in identifying, with high accuracy, the charred grape seeds found in archaeological sites. Moreover, it may be considered valid support for advances in the knowledge and comprehension of viticulture adoption and the grape domestication process. The same methodology may also be successful when applied to other plant remains, and provide important information about the history of domesticated plants.

Se estudió la infección por T. cruzi en mujeres embarazadas en la localidad de General Güemes, provincia de Salta. La misma fue del 12,3 %. El 8,8% de los recién nacidos estudiados tuvieron diagnóstico de Enfermedad de Chagas utilizando la técnica directa (microhematocrito). Todos fueron tratados con benznidazol a razón de 5mg/kg/día durante 30 dias. Todos presentaron anemia, que fue interpretada como reacción adversa medicamentosa. Se estima que la técnica directa representa la mejor opción para llevar a cabo el diagnóstico de esta enfermedad en el recién nacido. Se ha propuesto un flujograma para el seguimiento de la infección por T. cruzi en el recién nacido.

Se presenta el caso de un paciente oriundo y procedente del Paraguay, de 40 años de edad, portador de una ulceración crónica en cara externa del pie izquierdo, de 2 meses de evolución, debida a una hialohifomicosis por Fusarium oxysporum. Se destacan las características clínicas, métodos de diagnóstico y terapeútica de esta micosis, además de las diferentes etiologías a considerar en el diagnóstico diferencial de una úlcera en personas procedentes del área tropical o subtropical.

The role of polyunsaturated fatty acid (PUFA) biosynthesis in acute myeloid leukemia (AML) remains largely undefined. A comparative expression analysis of 35 genes encoding fatty acid biosynthesis enzymes showed that fatty acid desaturase 1 (FADS1) was highly expressed across multiple AML subtypes relative to healthy controls and that elevated FADS1 expression correlates with worse overall AML patient survival. Functionally, shRNA-mediated inhibition of FADS1 reduced AML cell growth in vitro and significantly delayed leukemia onset in an AML mouse model. AML cell lines depleted of FADS1 arrested in the G1/S-phase of the cell cycle, acquired characteristics of myeloid maturation and subsequently died. To understand the molecular consequences of FADS1 inhibition, a combination of mass spectrometry-based analysis of complex lipids and gene expression analysis (RNA-seq) was performed. FADS1 inhibition caused AML cells to exhibit significant lipidomic remodeling, including depletion of PUFAs from the phospholipids, phosphatidylserine, and phosphatidylethanolamine. These lipidomic alterations were accompanied by an increase induction of inflammatory and stimulator of interferon genes (STING)-mediated type-1 interferon signaling. Remarkably, genetic deletion of STING largely prevented the AML cell maturation and death phenotypes mediated by FADS1 inhibition. Highlighting the therapeutic implications of these findings, pharmacological blockade of PUFA biosynthesis reduced patient-derived AML cell numbers ex vivo but not that of healthy donor cells. Similarly, STING agonism attenuated patient-derived-AML survival; however, STING activation also reduced healthy granulocyte numbers. Collectively, these data unveil a previously unrecognized importance of PUFA biosynthesis in leukemogenesis and that imbalances in PUFA metabolism can drive STING-mediated AML maturation and death., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene ( 1 ). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC 50 as well as IC 50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1 . While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1 .

RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in murine KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a constitutively active variant capable of inducing maturation and loss of their proliferative phenotype. RXRA DT448/9PP was associated with ligand-independent activity in reporter assays, with enhanced co-activator interactions, reduced engraftment in vivo, and activation of myeloid maturation transcriptional signatures that overlapped with those of cells treated with the potent RXRA agonist bexarotene, suggestive of constitutive activity that leads to leukemic maturation. Phenotypes of RXRA DT448/9PP appear to differ from those of two other RXRA mutations with forms of constitutive activity (F318A and S427F), in that DT448/9PP activity was resistant to mutations at critical ligand-interacting amino acids (R316A/L326A) and was resistant to pharmacological antagonists, suggesting it may be ligand-independent. These data provide further evidence that activated retinoid X receptors can regulate myeloid maturation and provide a novel constitutively active variant that may be germane for broader studies of retinoid X receptors in other settings.

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid-or NEt-4IB-in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene ( 1 ), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC 50 and IC 50 values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1 .

The orphan nuclear receptor Nur77 is an immediate-early response gene that based on tissue and cell context is implicated in a plethora of cellular processes, including proliferation, differentiation, apoptosis, metabolism, and inflammation. Nur77 has a ligand-binding pocket that is obstructed by hydrophobic side groups. Naturally occurring, cell-endogenous ligands have not been identified, and Nur77 transcriptional activity is thought to be regulated through posttranslational modification and modulation of protein levels. To determine whether Nur77 is transcriptionally active in hematopoietic cells in vivo, we used an upstream activating sequence (UAS)-GFP transgenic reporter. We found that Nur77 is transcriptionally inactive in vivo in hematopoietic cells under basal conditions, but that activation occurs following cytokine exposure by G-CSF or IL-3. We also identified a series of serine residues required for cytokine-dependent transactivation of Nur77. Moreover, a kinase inhibitor library screen and proximity labeling-based mass spectrometry identified overlapping kinase pathways that physically interacted with Nur77 and whose inhibition abrogated cytokine-induced activation of Nur77. We determined that transcriptional activation of Nur77 by G-CSF or IL-3 requires functional JAK and mTor signaling since their inhibition leads to Nur77 transcriptional inactivation. Thus, intracellular cytokine signaling networks appear to regulate Nur77 transcriptional activity in mouse hematopoietic cells., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting RXR ligands (e.g. bexarotene) and RARA ligands (e.g. all-trans retinoic acid, ATRA), which induced either leukemic maturation or apoptosis depending on cell culture conditions. Co-repressor release from the RARA:RXRA heterodimer occurred with RARA activation, but not RXRA activation, providing an explanation for the combination synergy. Combination synergy could be replicated in additional, but not all, AML cell lines and primary samples, and was associated with improved survival in vivo, although tolerability of bexarotene administration in mice remained an issue. These data provide insight into the basal presence of natural retinoids in leukemias in vivo and a potential strategy for clinical retinoid combination regimens in leukemias beyond acute promyelocytic leukemia.

Objectives: A population-based physical activity (PA) programme was implemented to increase PA levels and encourage individuals to join the local council leisure facility., Study Design: This is a cross-sectional design., Methods: The 6-week programme Summer of Sport (SOS) involved a total of 487 individuals registered for PA sessions. The sessions were held at three local council leisure facilities included badminton, swimming, table tennis, squash and group cycle. The programme was assessed using a survey based on the Theory of Planned Behaviour. Individuals were asked for their current fitness levels, whether the programme encouraged them to be more active and for their intentions to join the leisure centre after the programme., Results: Of the 487 who originally registered for the programme, there were 161 users of SOS, with 112 not already members of the leisure facility. After the programme, 83% considered themselves already being active, with 78% stating that they partook in at least 30 min of exercise, 3 times per week. Although a large proportion of individuals were already physically active, 78% stated that taking part encouraged them to become more active. More than half suggested that they would not join the leisure facility, 30% said that they had joined after the programme and 17% stated their intention to join. Many individuals highlighted that the programme provided an opportunity to be active with their family., Conclusions: Public health teams should work with partner organisations to embed robust processes for measuring outcomes that impact on population health., (Copyright © 2019 The Royal Society for Public Health. All rights reserved.)

Up until the first half of the 20th century, silver found significant employment in medical applications, particularly in the healing of open wounds, thanks to its antibacterial and antifungal properties. Wound repair is a complex and dynamic biological process regulated by several pathways that cooperate to restore tissue integrity and homeostasis. To facilitate healing, injuries need to be promptly treated. Recently, the interest in alternatives to antibiotics has been raised given the widespread phenomenon of antibiotic resistance. Among these alternatives, the use of silver appears to be a valid option, so a resurgence in its use has been recently observed. In particular, in contrast to ionic silver, colloidal silver, a suspension of metallic silver particles, shows antibacterial activity displaying less or no toxicity. However, the human health risks associated with exposure to silver nanoparticles (NP) appear to be conflicted, and some studies have suggested that it could be toxic in different cellular contexts. These potentially harmful effects of silver NP depend on various parameters including NP size, which commonly range from 1 to 100 nm. In this study, we analyzed the effect of a colloidal silver preparation composed of very small and homogeneous nanoparticles of 0.62 nm size, smaller than those previously tested. We found no adverse effect on the cell proliferation of HaCaT cells, even at high NP concentration. Time-lapse microscopy and indirect immunofluorescence experiments demonstrated that this preparation of colloidal silver strongly increased cell migration, re-modeled the cytoskeleton, and caused recruitment of E-cadherin at cell-cell junctions of human cultured keratinocytes.

SMC3 encodes a subunit of the cohesin complex that has canonical roles in regulating sister chromatids segregation during mitosis and meiosis. Recurrent heterozygous mutations in SMC3 have been reported in acute myeloid leukemia (AML) and other myeloid malignancies. In this study, we investigated whether the missense mutations in SMC3 might have dominant-negative effects or phenocopy loss-of-function effects by comparing the consequences of Smc3-deficient and -haploinsufficient mouse models. We found that homozygous deletion of Smc3 during embryogenesis or in adult mice led to hematopoietic failure, suggesting that SMC3 missense mutations are unlikely to be associated with simple dominant-negative phenotypes. In contrast, haploinsufficiency was tolerated during embryonic and adult hematopoiesis. Under steady-state conditions, Smc3 haploinsufficiency did not alter colony forming in methylcellulose, only modestly decreased mature myeloid cell populations, and led to limited expression changes and chromatin alteration in Lin - cKit + bone marrow cells. However, following transplantation, engraftment, and subsequent deletion, we observed a hematopoietic competitive disadvantage across myeloid and lymphoid lineages and within the stem/progenitor compartments. This disadvantage was not affected by hematopoietic stresses, but was partially abrogated by concurrent Dnmt3a haploinsufficiency, suggesting that antecedent mutations may be required to optimize the leukemogenic potential of Smc3 mutations., (Published by Elsevier Inc.)

The retinoid X receptor α (RXRA) has been implicated in diverse hematological processes. To identify natural ligands of RXRA that are present in hematopoietic cells, we adapted an upstream activation sequence-green fluorescent protein (UAS-GFP) reporter mouse to detect natural RXRA ligands in vivo. We observed reporter activity in diverse types of hematopoietic cells in vivo. Reporter activity increased during granulocyte colony-stimulating factor (G-CSF)-induced granulopoiesis and after phenylhydrazine (PHZ)-induced anemia, suggesting the presence of dynamically regulated natural RXRA ligands in hematopoietic cells. Mouse plasma activated Gal4-UAS reporter cells in vitro, and plasma from mice treated with G-CSF or PHZ recapitulated the patterns of reporter activation that we observed in vivo. Plasma from mice with dietary vitamin A deficiency only mildly reduced RXRA reporter activity, whereas plasma from mice on a fatty acid restriction diet reduced reporter activity, implicating fatty acids as plasma RXRA ligands. Through differential extraction coupled with mass spectrometry, we identified the long-chain fatty acid C24:5 as a natural RXRA ligand that was greatly increased in abundance in response to hematopoietic stress. Together, these data suggest that natural RXRA ligands are present and dynamically increased in abundance in mouse hematopoietic cells in vivo., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Correct spatial and temporal control of cell proliferation is of fundamental importance for tissue homeostasis. Its deregulation has been associated with several pathological conditions. In common with almost every aspect of plant and animal biology, cell proliferation is dominated by day-night rhythms generated by the circadian clock. However, our understanding of the crosstalk between the core clock and cell cycle control mechanisms remains incomplete. In this study, using zebrafish as a vertebrate model system, we show that the nuclear localization of the Y-box binding protein 1 (YB-1), a regulator of cyclin expression and a hallmark of certain cancers, is robustly regulated by the circadian clock. We implicate clock-controlled changes in YB-1 SUMOylation as one of the mechanisms regulating its periodic nuclear entry at the beginning of the light phase. Furthermore, we demonstrate that YB-1 nuclear protein is able to downregulate cyclin A2 mRNA expression in zebrafish via its direct interaction with the cyclin A2 promoter. Thus, by acting as a direct target of cyclic posttranslational regulatory mechanisms, YB-1 serves as one bridge between the circadian clock and its cell cycle control.