306 research outputs found
Single Protein Encapsulated Doxorubicin as an Efficacious Anticancer Therapeutic
Smallâmolecule chemotherapeutics are potent and effective against a variety of malignancies, but common and severe side effects restrict their clinical applications. Nanomedicine approaches represent a major focus for improving chemotherapy, but have met limited success. To overcome the limitations of chemotherapy drugs, a novel single protein encapsulation (SPE)âbased drug formulation and delivery platform is developed and its utility in improving doxorubicin (DOX) treatment is tested. Using this methodology, a series of SPEDOX complexes are generated by encapsulating various numbers of DOX molecules into a single human serum albumin (HSA) molecule. UV/fluorescence spectroscopy, membrane dialysis, and dynamic light scattering techniques show that SPEDOXs are stable and uniform as monomeric HSA and display unique properties distinct from those of DOX and DOXâHSA mixture. Furthermore, detailed procedures to precisely monitor and control both DOX payload and binding strength to HSA are established. Breast cancer xenograft tumor studies reveal that SPEDOXâ6 treatment displays improved pharmacokinetic profiles, higher antitumor efficacy, and lower DOX accumulation in the heart tissue compared with unformulated DOX. This SPE technology, which does not involve nanoparticle assembly and modifications to either smallâmolecule drugs or HSA, may open up a new avenue for developing new drug delivery systems to improve anticancer therapeutics
New tunnel diode for zero-bias direct detection for millimeter-wave imagers
High-resolution passive millimeter wave imaging cameras require per pixel detector circuitry that is simple, has high sensitivity, low noise, and low power. Detector diodes that do not require bias or local oscillator input, and have high cutoff frequencies are strongly preferred. In addition, they must be manufacturable in large quantities with reasonable uniformity and reproducibility. Such diodes have not been obtainable for W-band and above. We are developing zero-bias square-law detector diodes based on InAs/Alsb/GaAlSb heterostructures which for the first time offer a cost-effective solution for large array formats. The diodes have a high frequency response and are relatively insensitive to growth and process variables. The large zero- bias non-linearity in current floor necessary for detection arises from interband tunneling between the InAs and the GaAlSb layers. Video resistance can be controlled by varying an Alsb tunnel barrier layer thickness. Our analysis shows that capacitance can be further decreased and sensitivity increased by shrinking the diode area, as the diode can have very high current density. DC and RF characterization of these devices and an estimate of their ultimate frequency performance in comparison with commercially available diodes are presented
A neurogenetic model for the study of schizophrenia spectrum disorders: The International 22q11.2 Deletion Syndrome Brain Behavior Consortium
Rare copy number variants contribute significantly to the risk for schizophrenia, with the
22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome
(22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders,
compared to individuals in the general population. The International 22q11DS Brain Behavior
Consortium is examining this highly informative neurogenetic syndrome phenotypically and
genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and
neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and
subthreshold expression of psychosis. The genomic approach includes a combination of whole
genome sequencing and genome-wide microarray technologies, allowing the investigation of all
possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic
expression. A phenotypically rich data set provides a psychiatrically well-characterized sample
of unprecedented size (n=1,616) that informs the neurobehavioral developmental course of
22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to
elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders
New tunnel diode for zero-bias direct detection for millimeter-wave imagers
High-resolution passive millimeter wave imaging cameras require per pixel detector circuitry that is simple, has high sensitivity, low noise, and low power. Detector diodes that do not require bias or local oscillator input, and have high cutoff frequencies are strongly preferred. In addition, they must be manufacturable in large quantities with reasonable uniformity and reproducibility. Such diodes have not been obtainable for W-band and above. We are developing zero-bias square-law detector diodes based on InAs/Alsb/GaAlSb heterostructures which for the first time offer a cost-effective solution for large array formats. The diodes have a high frequency response and are relatively insensitive to growth and process variables. The large zero- bias non-linearity in current floor necessary for detection arises from interband tunneling between the InAs and the GaAlSb layers. Video resistance can be controlled by varying an Alsb tunnel barrier layer thickness. Our analysis shows that capacitance can be further decreased and sensitivity increased by shrinking the diode area, as the diode can have very high current density. DC and RF characterization of these devices and an estimate of their ultimate frequency performance in comparison with commercially available diodes are presented
The dynamics of expertise acquisition in sport : the role of affective learning design
Objectives: The aim of this position paper is to discuss the role of affect in designing learning experiences to enhance expertise acquisition in sport. The design of learning environments and athlete development programmes are predicated on the successful sampling and simulation of competitive performance conditions during practice. This premise is captured by the concept of representative learning design, founded on an ecological dynamics approach to developing skill in sport, and based on the individual-environment relationship. In this paper we discuss how the effective development of expertise in sport could be enhanced by the consideration of affective constraints in the representative design of learning experiences. Conclusions: Based on previous theoretical modelling and practical examples we delineate two key principles of Affective Learning Design: (i) the design of emotion-laden learning experiences that effectively simulate the constraints of performance environments in sport; (ii) recognising individualised emotional and coordination tendencies that are associated with different periods of learning. Considering the role of affect in learning environments has clear implications for how sport psychologists, athletes and coaches might collaborate to enhance the acquisition of expertise in sport.</p
LSST: from Science Drivers to Reference Design and Anticipated Data Products
(Abridged) We describe here the most ambitious survey currently planned in
the optical, the Large Synoptic Survey Telescope (LSST). A vast array of
science will be enabled by a single wide-deep-fast sky survey, and LSST will
have unique survey capability in the faint time domain. The LSST design is
driven by four main science themes: probing dark energy and dark matter, taking
an inventory of the Solar System, exploring the transient optical sky, and
mapping the Milky Way. LSST will be a wide-field ground-based system sited at
Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m
effective) primary mirror, a 9.6 deg field of view, and a 3.2 Gigapixel
camera. The standard observing sequence will consist of pairs of 15-second
exposures in a given field, with two such visits in each pointing in a given
night. With these repeats, the LSST system is capable of imaging about 10,000
square degrees of sky in a single filter in three nights. The typical 5
point-source depth in a single visit in will be (AB). The
project is in the construction phase and will begin regular survey operations
by 2022. The survey area will be contained within 30,000 deg with
, and will be imaged multiple times in six bands, ,
covering the wavelength range 320--1050 nm. About 90\% of the observing time
will be devoted to a deep-wide-fast survey mode which will uniformly observe a
18,000 deg region about 800 times (summed over all six bands) during the
anticipated 10 years of operations, and yield a coadded map to . The
remaining 10\% of the observing time will be allocated to projects such as a
Very Deep and Fast time domain survey. The goal is to make LSST data products,
including a relational database of about 32 trillion observations of 40 billion
objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures
available from https://www.lsst.org/overvie
A neurogenetic model for the study of schizophrenia spectrum disorders: The International 22q11.2 Deletion Syndrome Brain Behavior Consortium
Rare copy number variants contribute significantly to the risk for schizophrenia, with the
22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome
(22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders,
compared to individuals in the general population. The International 22q11DS Brain Behavior
Consortium is examining this highly informative neurogenetic syndrome phenotypically and
genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and
neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and
subthreshold expression of psychosis. The genomic approach includes a combination of whole
genome sequencing and genome-wide microarray technologies, allowing the investigation of all
possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic
expression. A phenotypically rich data set provides a psychiatrically well-characterized sample
of unprecedented size (n=1,616) that informs the neurobehavioral developmental course of
22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to
elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders
Evaluation of HIV protease and nucleoside reverse transcriptase inhibitors on proliferation, necrosis, apoptosis in intestinal epithelial cells and electrolyte and water transport and epithelial barrier function in mice
<p>Abstract</p> <p>Background</p> <p>Protease inhibitors (PI's) and reverse transcriptase drugs are important components of highly active antiretroviral therapy (HAART) for treating human acquired immunodeficiency syndrome (AIDS). Long-term clinical therapeutic efficacy and treatment compliance of these agents have been limited by undesirable side-effects, such as diarrhea. This study aims to investigate the effects of selected antiretroviral agents on intestinal histopathology and function <it>in vivo </it>and on cell proliferation and death <it>in vitro</it>.</p> <p>Methods</p> <p>Selected antiretroviral drugs were given orally over 7 days, to Swiss mice, as follows: 100 mg/kg of nelfinavir (NFV), indinavir (IDV), didanosine (DDI) or 50 mg/kg of zidovudine (AZT). Intestinal permeability measured by lactulose and mannitol assays; net water and electrolyte transport, in perfused intestinal segments; and small intestinal morphology and cell apoptosis were assessed in treated and control mice. <it>In vitro </it>cell proliferation was evaluated using the WST-1 reagent and apoptosis and necrosis by flow cytometry analysis.</p> <p>Results</p> <p>NFV, IDV, AZT and DDI caused significant reductions in duodenal and in jejunal villus length (p < 0.05). IDV and AZT increased crypt depth in the duodenum and AZT increased crypt depth in the jejunum. NFV, AZT and DDI significantly decreased ileal crypt depth. All selected antiretroviral drugs significantly increased net water secretion and electrolyte secretion, except for DDI, which did not alter water or chloride secretion. Additionally, only NFV significantly increased mannitol and lactulose absorption. NFV and IDV caused a significant reduction in cell proliferation <it>in vitro </it>at both 24 h and 48 h. DDI and AZT did not alter cell proliferation. There was a significant increase in apoptosis rates in IEC-6 cells after 24 h with 70 ug/mL of NFV (control: 4.7% vs NFV: 22%) while IDV, AZT and DDI did not show any significant changes in apoptosis compared to the control group. In jejunal sections, IDV and NFV significantly increased the number of TUNEL positive cells.</p> <p>Conclusion</p> <p>The PI's, NFV and IDV, increased cell apoptosis <it>in vivo</it>, water and electrolyte secretion and intestinal permeability and decreased villus length and cell proliferation. NFV was the only drug tested that increased cell apoptosis <it>in vitro</it>. The nucleoside reverse transcriptase inhibitors, AZT and DDI, did not affect cell apoptosis or proliferation. These findings may partly explain the intestinal side-effects associated with PI's.</p
A New Chicken Genome Assembly Provides Insight into Avian Genome Structure
The importance of the Gallus gallus (chicken) as a model organism and agricultural animal merits a continuation of sequence assembly improvement efforts. We present a new version of the chicken genome assembly (Gallus_gallus-5.0; GCA_000002315.3), built from combined long single molecule sequencing technology, finished BACs, and improved physical maps. In overall assembled bases, we see a gain of 183 Mb, including 16.4 Mb in placed chromosomes with a corresponding gain in the percentage of intact repeat elements characterized. Of the 1.21 Gb genome, we include three previously missing autosomes, GGA30, 31, and 33, and improve sequence contig length 10-fold over the previous Gallus_gallus-4.0. Despite the significant base representation improvements made, 138 Mb of sequence is not yet located to chromosomes. When annotated for gene content, Gallus_gallus-5.0 shows an increase of 4679 annotated genes (2768 noncoding and 1911 protein-coding) over those in Gallus_gallus-4.0. We also revisited the question of what genes are missing in the avian lineage, as assessed by the highest quality avian genome assembly to date, and found that a large fraction of the original set of missing genes are still absent in sequenced bird species. Finally, our new data support a detailed map of MHC-B, encompassing two segments: one with a highly stable gene copy number and another in which the gene copy number is highly variable. The chicken model has been a critical resource for many other fields of study, and this new reference assembly will substantially further these efforts
Dentifrices, mouthwashes, and remineralization/caries arrestment strategies
While our knowledge of the dental caries process and its prevention has greatly advanced over the past fifty years, it is fair to state that the management of this disease at the level of the individual patient remains largely empirical. Recommendations for fluoride use by patients at different levels of caries risk are mainly based on the adage that more is better. There is a general understanding that the fluoride compound, concentration, frequency of use, duration of exposure, and method of delivery can influence fluoride efficacy. Two important factors are (1) the initial interaction of relatively high concentrations of fluoride with the tooth surface and plaque during application and (2) the retention of fluoride in oral fluids after application
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