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Lessons learned from women in leadership positions.

Abstract: Eileen Elias has decades of experience in leadership positions within government and nongovernmental organizations. As the first female Commissioner for Mental Health in the Commonwealth of Massachusetts and the US in the early 1990s, Elias gained experience on navigating gender-based challenges to attain recognized performance outcomes.From lessons learned from women leaders, educate young women entering their careers on attaining leadership positions.Comprehensive research of literature from 2012 through 2017 and interviews with women leaders representing non-Fortune 500 companies including academia, research, non-profit, for-profit, and primary and secondary education. Interviewees included:1.Gail Bassin, Co-Chief Executive Officer and Treasurer, JBS International Inc.2.Jeri Epstein, Executive Director, The Ambit Foundation3.Valerie Fletcher, Executive Director, Institute for Human Centered Design4.Christine James-Brown, President and CEO, Child Welfare League of America5.Daria Mochly-Rosen, PhD, Professor and Fellow, Chemical and Systems Biology, Stanford University School of Medicine6.Eileen O'Keefe, MD, MPH, Clinical Associate Professor and Director, Boston University Health Sciences7.Jeri Shaw, President and Co-Chief Executive Officer, JBS International Inc.A comprehensive understanding of key women leaders' lessons learned and recommendations targeting young women as they assess leadership opportunities in the public or private sectors.

Pub.: 23 Jan '18, Pinned: 23 Jan '18

Improved non-destructive 2D and 3D X-ray imaging of leaf venation

Abstract: Leaf venation traits are important for many research fields such as systematics and evolutionary biology, plant physiology, climate change, and paleoecology. In spite of an increasing demand for vein trait data, studies are often still data-limited because the development of methods that allow rapid generation of large sets of vein data has lagged behind. Recently, non-destructive X-ray technology has proven useful as an alternative to traditional slow and destructive chemical-based methods. Non-destructive techniques more readily allow the use of herbarium specimens, which provide an invaluable but underexploited resource of vein data and related environmental information. The utility of 2D X-ray technology and microfocus X-ray computed tomography, however, has been compromised by insufficient image resolution. Here, we advanced X-ray technology by increasing image resolution and throughput without the application of contrast agents.For 2D contact microradiography, we developed a method which allowed us to achieve image resolutions of up to 7 µm, i.e. a 3.6-fold increase compared to the industrial standard (25 µm resolution). Vein tracing was further optimized with our image processing standards that were specifically adjusted for different types of leaf structure and the needs of higher imaging throughput. Based on a test dataset, in 91% of the samples the 7 µm approach led to a significant improvement in estimations of minor vein density compared to the industrial standard. Using microfocus X-ray computed tomography, very high-resolution images were obtained from a virtual 3D–2D transformation process, which was superior to that of 3D images.Our 2D X-ray method with a significantly improved resolution advances rapid non-destructive bulk scanning at a quality that in many cases is sufficient to determine key venation traits. Together with our high-resolution microfocus X-ray computed tomography method, both non-destructive approaches will help in vein trait data mining from museum collections, which provide an underexploited resource of historical and recent data on environmental and evolutionary change. In spite of the significant increase in effective image resolution, a combination of high-throughput and full visibility of the vein network (including the smallest veins and their connectivity) remains challenging, however.

Pub.: 19 Jan '18, Pinned: 23 Jan '18

Enzymatic scarification of Anacamptis morio (Orchidaceae) seed facilitates lignin degradation, water uptake and germination.

Abstract: The seed coat of many species contains hydrophobic lignins, and in soil the action of microbial ligninases may contribute to release from dormancy. Laboratory use of ligninases to stimulate germination is promising because of the specific action on the seed coat, whereas chemical scarification agents may also corrode the embryo. We hypothesized that exposure of Anacamptis morio (Orchidaceae) seeds to fungal laccase stimulates germination, and that the mechanism involves lignin degradation and increased imbibition. Germination capacity in vitro was quantified with 1U of filter-sterilized laccase added to agar medium following autoclaving, compared to a 10% bleach solution (a standard bleach surface sterilization/scarification method used in orchid seed sowing). Lignin degradation was quantified using an optical method (phloroglucinol-HCl staining) combined with image analysis, following experimental pre-treatments involving immersion in laccase solution, distilled water (negative control) or bleach (positive control). Water uptake after experimental treatments was quantified as the proportion of seeds exhibiting visible uptake of an aqueous fluorochrome under UV excitation. Laccase stimulated a doubling of germination in vitro with respect to bleach surface sterilization/scarification alone, from 23.7 to 49.8% (p=0.007). Laccase and bleach methods both significantly decreased the optical signal of phloroglucinol (for laccase, to 79.9 ±1.3% of controls; ANOVA: F=10.333, p=0.002). Laccase resulted in a modest but highly significant (p<0.0001) increase in water uptake with respect to the control (11.7%; c.f. 99.4% for bleach). Laccase scarification can stimulate germination of A. morio by a mechanism of targeted seed coat degradation. The results demonstrate the potential of this relatively non-invasive enzymatic scarification technique. This article is protected by copyright. All rights reserved.

Pub.: 20 Jan '18, Pinned: 23 Jan '18

Mulberry leaves and their potential effects against cardiometabolic risks: a review of chemical compositions, biological properties and clinical efficacy.

Abstract: Cardiometabolic risks are regarded as the crucial factors associated with type 2 diabetes (T2DM) and cardiovascular diseases (CVD). Regarding an increased attention to medicinal plants in the current healthcare system, the effects of mulberry (Morus spp., Moraceae) leaves on cardiometabolic risks have been consecutively considered in scientific research.The present review compiles and summarizes the chemical compositions, biological properties and clinical efficacy of mulberry leaves that are related to the amelioration of cardiometabolic risks.Published English literature from the PubMed, Science Direct and Google Scholar databases was searched by using 'mulberry leaves' 'Morus spp.', 'hyperglycemia', 'hyperlipidemia', 'obesity', 'hypertension', 'oxidative stress', 'atherosclerosis' and 'cardiovascular diseases' as the keywords. The relevant articles published over the past two decades were identified and reviewed.Mulberry leaves contain numerous chemical constituents. 1-Deoxynojirimycin (DNJ), phenolics and flavonoids are the prominent functional compounds. Preclinical and clinical studies showed that mulberry leaves possessed various beneficial effects against cardiometabolic risks, including antihyperglycaemic, antihyperlipidaemic, antiobesity, antihypertensive, antioxidative, anti-inflammatory, anti-atherosclerotic and cardioprotective effects.Mulberry leaves could be a promising therapeutic option for modulating cardiometabolic risks. However, further investigations should be performed to substantiate the potential of mulberry leaves in practical uses.

Pub.: 20 Jan '18, Pinned: 23 Jan '18

HAfTs are novel lncRNA transcripts from aflatoxin exposure.

Abstract: The transcriptome can reveal insights into precancer biology. We recently conducted RNA-Seq analysis on liver RNA from male rats exposed to the carcinogen, aflatoxin B1 (AFB1), for 90 days prior to liver tumor onset. Among >1,000 differentially expressed transcripts, several novel, unannotated Cufflinks-assembled transcripts, or HAfTs (Hepatic Aflatoxin Transcripts) were found. We hypothesized PCR-cloning and RACE (rapid amplification of cDNA ends) could further HAfT identification. Sanger data was obtained for 6 transcripts by PCR and 16 transcripts by 5'- and 3'-RACE. BLAST alignments showed, with two exceptions, HAfT transcripts were lncRNAs, >200nt without apparent long open reading frames. Six rat HAfT transcripts were classified as 'novel' without RefSeq annotation. Sequence alignment and genomic synteny showed each rat lncRNA had a homologous locus in the mouse genome and over half had homologous loci in the human genome, including at least two loci (and possibly three others) that were previously unannotated. While HAfT functions are not yet clear, coregulatory roles may be possible from their adjacent orientation to known coding genes with altered expression that include 8 HAfT-gene pairs. For example, a unique rat HAfT, homologous to Pvt1, was adjacent to known genes controlling cell proliferation. Additionally, PCR and RACE Sanger sequencing showed many alternative splice variants and refinements of exon sequences compared to Cufflinks assembled transcripts and gene prediction algorithms. Presence of multiple splice variants and short tandem repeats found in some HAfTs may be consequential for secondary structure, transcriptional regulation, and function. In summary, we report novel, differentially expressed lncRNAs after exposure to the genotoxicant, AFB1, prior to neoplastic lesions. Complete cloning and sequencing of such transcripts could pave the way for a new set of sensitive and early prediction markers for chemical hepatocarcinogens.

Pub.: 20 Jan '18, Pinned: 23 Jan '18

Discovery of novel diarylpyrimidines as potent HIV-1 NNRTIs by investigating the chemical space of a less explored "hydrophobic channel".

Abstract: A new series of diarylpyrimidines (DAPYs) were designed, synthesized and evaluated as novel HIV-1 NNRTIs to further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), guided by the comprehensive analysis of X-ray structural biology data of HIV-1 RT/NNRTI complexes and molecular modeling. Encouragingly, most of the synthesized DAPYs were found to be active against the HIV-1 wild-type (WT) strain with EC50 values ranging from 3 nM to 63 nM, and displayed significantly reduced cytotoxicity compared with etravirine (ETV) and rilpivirine (RPV). Among them, two most promising compounds Z10 (EC50 = 3 nM) and Z13 (EC50 = 3 nM) showed equivalent potency against the HIV-1 WT strain to the reference drugs efavirenz (EFV, EC50 = 3 nM) and ETV (EC50 = 3 nM). Notably, Z13 also showed the most potent activity against HIV-1 mutant strains including K103N (EC50 = 10 nM), E138K (EC50 = 22 nM) and RES056 (EC50 = 0.935 μM). Against mutant strains Y181C, Y188L and F227L + V106A, Z17 showed double-digit nanomolar inhibitory activity with EC50 values 27 nM, 98 nM and 30 nM, respectively. The structure-activity relationships (SARs) and molecular docking studies provided important clues for further molecular elaboration. Collectively, this study provides useful information to guide lead optimization and drug discovery via the exploration of this seldom investigated region.

Pub.: 20 Jan '18, Pinned: 23 Jan '18

Identification of potential inhibitors against nuclear Dam1 complex subunit Ask1 of Candida albicans using virtual screening and MD simulations.

Abstract: Identification of hit compounds against specific target form the starting point for a drug discovery program. A consistent decline of new chemical entities (NCEs) in recent years prompted a challenge to explore newer approaches to discover potential hit compounds that in turn can be converted into leads, and ultimately drug with desired therapeutic efficacy. The vast amount of omics and activity data available in public databases offers an opportunity to identify novel targets and their potential inhibitors. State of the art in silico methods viz., clustering of compounds, virtual screening, molecular docking, MD simulations and MMPBSA calculations were employed in a pipeline to identify potential 'hits' against those targets as well whose structures, as of now, could only predict through threading approaches. In the present work, we have started from scratch, amino acid sequence of target and compounds retrieved from PubChem compound database, modeled it in such a way that led to the identification of possible inhibitors of Dam1 complex subunit Ask1 of Candida albicans. We also propose a ligand based binding site determination approach. We have identified potential inhibitors of Ask1 subunit of a Dam1 complex of C. albicans, which is required to prevent precocious spindle elongation in pre-mitotic phases. The proposed scheme may aid to find virtually potential inhibitors of other unique targets against candida.

Pub.: 19 Jan '18, Pinned: 23 Jan '18

Remarkable Similarity in Plasmodium falciparum and Plasmodium vivax Geranylgeranyl Diphosphate Synthase (GGPPS) Dynamics and its Implication for Anti-Malarial Drug Design.

Abstract: Malaria, mainly caused by Plasmodium falciparum and Plasmodium vivax, has been a growing cause of morbidity and mortality. P. falciparum is more lethal than is P. vivax, but there is a vital need for effective drugs against both species. Geranylgeranyl diphosphate synthase (GGPPS) is an enzyme involved in the biosynthesis of quinones and in protein prenylation, and has been proposed to be a malaria drug target. However, the structure of P. falciparum GGPPS (PfGGPPS) has not been determined, due to difficulties in crystallization. Here, we created a PfGGPPS model using the homologous P.vivax GGPPS X-ray structure as a template. We simulated the modeled PfGGPPS as well as PvGGPPS using conventional and Gaussian accelerated molecular dynamics in both apo- and GGPP -bound states. The MD simulations revealed a striking similarity in the dynamics of both enzymes with loop 9-10 controlling access to the active site. We also found that GGPP stabilizes PfGGPPS and PvGGPPS into closed conformations and via similar mechanisms. Shape-based analysis of the binding sites throughout the simulations suggest that the two enzymes will be readily targeted by the same inhibitors. Finally, we produced three MD-validated conformations of PfGGPPS to be used in future virtual screenings for potential new anti-malarial drugs acting on both PvGGPPS and PfGGPPS. This article is protected by copyright. All rights reserved.

Pub.: 19 Jan '18, Pinned: 23 Jan '18

Calcium-dependent protein kinases in cotton: insights into early plant responses to salt stress

Abstract: Soil salinization is one of the major environmental constraints to plant growth and agricultural production worldwide. Signaling components involving calcium (Ca2+) and the downstream calcium-dependent protein kinases (CPKs) play key roles in the perception and transduction of stress signals. However, the study of CPKs in cotton and their functions in response to salt stress remain unexplored.A total of 98 predicted CPKs were identified from upland cotton (Gossypium hirsutum L. ‘TM-1’), and phylogenetic analyses classified them into four groups. Gene family distribution studies have revealed the substantial impacts of the genome duplication events to the total number of GhCPKs. Transcriptome analyses showed a wide distribution of CPKs’ expression among different organs. A total of 19 CPKs were selected for their rapid responses to salt stress at the transcriptional level, most of which were also incduced by the thylene-releasing chemical ethephon, suggesting a partal overlap of the salinity and ethylene responses. Silencing of 4 of the 19 CPKs (GhCPK8, GhCPK38, GhCPK54, and GhCPK55) severely compromised the basal cotton resistance to salt stress.Our genome-wide expression analysis of CPK genes from up-land cotton suggests that CPKs are involved in multiple developmental responses as well as the response to different abiotic stresses. A cluster of the cotton CPKs was shown to participate in the early signaling events in cotton responses to salt stress. Our results provide significant insights on functional analysis of CPKs in cotton, especially in the context of cotton adaptions to salt stress.

Pub.: 17 Jan '18, Pinned: 23 Jan '18

Dawning of a new era in TRP channel structural biology by cryo-electron microscopy

Abstract: Cryo-electron microscopy (cryo-EM) permits the determination of atomic protein structures by averaging large numbers of individual projection images recorded at cryogenic temperatures—a method termed single-particle analysis. The cryo-preservation traps proteins within a thin glass-like ice layer, making literally a freeze image of proteins in solution. Projections of randomly adopted orientations are merged to reconstruct a 3D density map. While atomic resolution for highly symmetric viruses was achieved already in 2009, the development of new sensitive and fast electron detectors has enabled cryo-EM for smaller and asymmetrical proteins including fragile membrane proteins. As one of the most important structural biology methods at present, cryo-EM was awarded in October 2017 with the Nobel Prize in Chemistry. The molecular understanding of Transient-Receptor-Potential (TRP) channels has been boosted tremendously by cryo-EM single-particle analysis. Several near-atomic and atomic structures gave important mechanistic insights, e.g., into ion permeation and selectivity, gating, as well as into the activation of this enigmatic and medically important membrane protein family by various chemical and physical stimuli. Lastly, these structures have set the starting point for the rational design of TRP channel-targeted therapeutics to counteract life-threatening channelopathies. Here, we attempt a brief introduction to the method, review the latest advances in cryo-EM structure determination of TRP channels, and discuss molecular insights into the channel function based on the wealth of TRP channel cryo-EM structures.

Pub.: 17 Jan '18, Pinned: 23 Jan '18

MRI in the Study of Animal Models of Stroke.

Abstract: Stroke consists of the loss of cerebral functions resulting from the interruption of blood supply to a region of the brain, and represents the second cause of death and the leading cause of major disability in adults in Europe. Stroke is a very active field of research at preclinical and clinical levels, and Magnetic Resonance Imaging (MRI) is one of the most powerful tools that scientist and clinicians have for the study of the onset, evolution and consequences of this devastating disease, as well as for the monitoring of the success of available treatments, or for the development of novel therapeutic strategies.MRI can tackle the study of stroke from different points of view, and at scales ranging from subcellular to systems biology level. Magnetic resonance spectroscopy (MRS) allows the noninvasive measurement of the levels of principal metabolites in the brain, and how they change during the course of the disease, or in response to therapy. Glutamate, in particular, is very important in the field of stroke. Several anatomical MR techniques allow the characterization of the lesion volumes, the formation of cytotoxic and vasogenic edema, changes in cerebral blood flow and volume, structural changes in gray and white matter, the obtaining of the vascular architecture and status, etc. At functional level, diverse modalities of functional MRI (fMRI) allow the assessment of the alteration in the function and organization of neuronal networks of the subject under study, as a consequence of the disease or in response to treatment. Finally, emerging imaging modalities that include temperature and pH mapping of the brain, imaging by chemical exchange saturation transfer effect (CEST), all of them closely related to tissue status, or the use of contrast agents for the targeting of tissue in theranostic approaches or for cell tracking studies in cell-based therapies, etc., are only a few examples of the power and versatility of MRI as a definitive tool for the study of stroke.In this work we will set our focus on preclinical imaging of stroke models, emphasizing the most commonly used imaging modalities in a stroke-dedicated research laboratory. However, advanced techniques will be briefly discussed, providing references to specialized literature for more advanced readers. Thus, the aim of this chapter consist in the description of a simple imaging protocol for the study of the most important and common aspects of stroke in a research laboratory.

Pub.: 18 Jan '18, Pinned: 23 Jan '18