ResearchPad - 36 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Initial Results from Mobile Low‐Dose Computerized Tomographic Lung Cancer Screening Unit: Improved Outcomes for Underserved Populations]]> https://www.researchpad.co/article/elastic_article_8331 The BodyTom CT is the first mobile screening unit in the U.S., designed to improve access to lung cancer screening for underserved patient groups. This article reports results of the initial pilot study using this first‐of‐its‐kind mobile low‐dose whole body CT screening unit. Twelve cases of lung cancer were found in 550 smokers (including 6 early stage).

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<![CDATA[Automated analysis of scanning electron microscopic images for assessment of hair surface damage]]> https://www.researchpad.co/article/N363bee0f-dcd6-4cb7-88b4-8137645b53d8

Mechanical damage of hair can serve as an indicator of health status and its assessment relies on the measurement of morphological features via microscopic analysis, yet few studies have categorized the extent of damage sustained, and instead have depended on qualitative profiling based on the presence or absence of specific features. We describe the development and application of a novel quantitative measure for scoring hair surface damage in scanning electron microscopic (SEM) images without predefined features, and automation of image analysis for characterization of morphological hair damage after exposure to an explosive blast. Application of an automated normalization procedure for SEM images revealed features indicative of contact with materials in an explosive device and characteristic of heat damage, though many were similar to features from physical and chemical weathering. Assessment of hair damage with tailing factor, a measure of asymmetry in pixel brightness histograms and proxy for surface roughness, yielded 81% classification accuracy to an existing damage classification system, indicating good agreement between the two metrics. Further ability of the tailing factor to score features of hair damage reflecting explosion conditions demonstrates the broad applicability of the metric to assess damage to hairs containing a diverse set of morphological features.

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<![CDATA[Cognition at age 70]]> https://www.researchpad.co/article/Nd27d6813-5240-40fa-aebc-105afba68a90

Objective

To investigate predictors of performance on a range of cognitive measures including the Preclinical Alzheimer Cognitive Composite (PACC) and test for associations between cognition and dementia biomarkers in Insight 46, a substudy of the Medical Research Council National Survey of Health and Development.

Methods

A total of 502 individuals born in the same week in 1946 underwent cognitive assessment at age 69–71 years, including an adapted version of the PACC and a test of nonverbal reasoning. Performance was characterized with respect to sex, childhood cognitive ability, education, and socioeconomic position (SEP). In a subsample of 406 cognitively normal participants, associations were investigated between cognition and β-amyloid (Aβ) positivity (determined from Aβ-PET imaging), whole brain volumes, white matter hyperintensity volumes (WMHV), and APOE ε4.

Results

Childhood cognitive ability was strongly associated with cognitive scores including the PACC more than 60 years later, and there were independent effects of education and SEP. Sex differences were observed on every PACC subtest. In cognitively normal participants, Aβ positivity and WMHV were independently associated with lower PACC scores, and Aβ positivity was associated with poorer nonverbal reasoning. Aβ positivity and WMHV were not associated with sex, childhood cognitive ability, education, or SEP. Normative data for 339 cognitively normal Aβ-negative participants are provided.

Conclusions

This study adds to emerging evidence that subtle cognitive differences associated with Aβ deposition are detectable in older adults, at an age when dementia prevalence is very low. The independent associations of childhood cognitive ability, education, and SEP with cognitive performance at age 70 have implications for interpretation of cognitive data in later life.

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<![CDATA[Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle]]> https://www.researchpad.co/article/Nd7e69f02-f8ed-4a9e-ab82-7155b6484ccc

Xia et al. show that constricted migration causes DNA damage and a cell cycle block that is rescued by antioxidant plus myosin II inhibition or overexpressed repair factors. Cell cycle progression exhibits a threshold in the mechanically induced DNA damage.

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<![CDATA[Filamin A mediates isotropic distribution of applied force across the actin network]]> https://www.researchpad.co/article/N0962f5d9-4c12-43d3-9009-2da42517958f

In this work, Kumar et al. use their previously developed talin tension sensor to study the immediate response of cells to uniaxial stretch. Tension measurements together with high-resolution electron microscopy reveal a novel role for the actin cross-linking protein filamin A in mediating tensional symmetry within the F-actin network.

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<![CDATA[Yorkie controls tube length and apical barrier integrity during airway development]]> https://www.researchpad.co/article/N8510fe64-1ef6-4de2-b892-e6d4e824e187

Skouloudaki et al. identify an alternative role of the transcriptional coactivator Yorkie (Yki) in controlling water impermeability and tube size of developing Drosophila airways. Tracheal impermeability is triggered by Yki-mediated transcriptional regulation of δ-aminolevulinate synthase (Alas), whereas tube elongation is controlled by binding of Yki to the actin-severing factor Twinstar.

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<![CDATA[Beyond proteases: Basement membrane mechanics and cancer invasion]]> https://www.researchpad.co/article/N63e701df-c906-4411-81fa-7d0382f224c2

Chang and Chaudhuri discuss basement membrane mechanics and how cells use both proteolytic and physical mechanisms to invade basement membranes during cancer progression.

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<![CDATA[Nonulosonic acids contribute to the pathogenicity of the oral bacterium Tannerella forsythia]]> https://www.researchpad.co/article/5c94e7d6d5eed0c484654ab6

Periodontitis is a polymicrobial, biofilm-caused, inflammatory disease affecting the tooth-supporting tissues. It is not only the leading cause of tooth loss worldwide, but can also impact systemic health. The development of effective treatment strategies is hampered by the complicated disease pathogenesis which is best described by a polymicrobial synergy and dysbiosis model. This model classifies the Gram-negative anaerobe Tannerella forsythia as a periodontal pathogen, making it a prime candidate for interference with the disease. Tannerella forsythia employs a protein O-glycosylation system that enables high-density display of nonulosonic acids via the bacterium's two-dimensional crystalline cell surface layer. Nonulosonic acids are sialic acid-like sugars which are well known for their pivotal biological roles. This review summarizes the current knowledge of T. forsythia's unique cell envelope with a focus on composition, biosynthesis and functional implications of the cell surface O-glycan. We have obtained evidence that glycobiology affects the bacterium's immunogenicity and capability to establish itself in the polymicrobial oral biofilm. Analysis of the genomes of different T. forsythia isolates revealed that complex protein O-glycosylation involving nonulosonic acids is a hallmark of pathogenic T. forsythia strains and, thus, constitutes a valuable target for the design of novel anti-infective strategies to combat periodontitis.

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<![CDATA[Cell type and receptor identity regulate cholera toxin subunit B (CTB) internalization]]> https://www.researchpad.co/article/5c94e7d4d5eed0c484654aa8

Cholera toxin (CT) is a secreted bacterial toxin that binds to glycoconjugate receptors on the surface of mammalian cells, enters mammalian cells through endocytic mechanisms and intoxicates mammalian cells by activating cytosolic adenylate cyclase. CT recognizes cell surface receptors through its B subunit (CTB). While the ganglioside GM1 has been historically described as the sole receptor, CTB is also capable of binding to fucosylated glycoconjugates, and fucosylated molecules have been shown to play a functional role in host cell intoxication by CT. Here, we use colonic epithelial and respiratory epithelial cell lines to examine how two types of CT receptors—gangliosides and fucosylated glycoconjugates—contribute to CTB internalization. We show that fucosylated glycoconjugates contribute to CTB binding to and internalization into host cells, even when the ganglioside GM1 is present. The contributions of the two classes of receptors to CTB internalization depend on cell type. Additionally, in a cell line that harbours both classes of receptors, gangliosides dictate the efficiency of CTB internalization. Together, the results lend support to the idea that fucosylated glycoconjugates play a functional role in CTB internalization, and suggest that CT internalization depends on both receptor identity and cell type.

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<![CDATA[Rapid and high efficiency transformation of Chlamydomonas reinhardtii by square-wave electroporation]]> https://www.researchpad.co/article/5c4b93f4d5eed0c48487d680

Chlamydomonas reinhardtii, the unicellular green algae, is the model organism for studies in various physiological processes and for bioindustrial applications. To explore the molecular mechanisms underlying physiological processes or to establish engineered cell lines, the exogenous DNA needs to be integrated into the genome for the insertional mutagenesis or transgene expression. However, the amount of selected marker DNA is not seriously considered in the existing electroporation methods for mutants library construction. Here, we reported a rapid-and-high-efficiency transformation technique for cell-walled strains using square-wave electroporation system. The final yield with this electroporation method was 2–6 × 103 transformants per μg exogenous DNA for cell-walled strains in a strain-dependent manner. In general, this electroporation technique was the easy and applicable way to build a mutant library for screening phenotypes of interest.

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<![CDATA[Immediate and persistent antidepressant-like effects of Chaihu-jia-Longgu-Muli-tang are associated with instantly up-regulated BDNF in the hippocampus of mice]]> https://www.researchpad.co/article/5c4b93f6d5eed0c48487d6e1

Conventional antidepressants have a disadvantage in delayed onset of efficacy. Here, we aimed to evaluate the immediate and persistent antidepressant-like action of a classic herbal medicine Chaihu-jia-Longgu-Muli decoction (CLM) as well as the action of CLM on hippocampal brain-derived neurotrophic factor (BDNF) over time. CLM consists of Xiaochaihu decoction (XchD), Longgu-Muli (LM) and several other herbs. The contribution of constituent herbal formula XchD and other parts of CLM was also assessed. Following a single dose of CLM, tail suspension test (TST), forced swim test (FST), and novelty-suppressed feeding test (NSF) were performed. The antidepressant activity of XchD, its interaction with LM or remaining parts of CLM was also examined after a single administration. BDNF expression in the hippocampus was examined at 30 min and 24 hr post a single CLM. A single administration of half of clinical dose of CLM elicited antidepressant effects at TST 30 min post administration, and lasted for 72 hr. Furthermore, CLM also reduced the latency to eat in NSF test. A single proportional dose of XchD induced antidepressant effects at 30 min and lasted for 48 hr, whereas the effect lasted for 72 hr when combined with either LM or the remaining parts of CLM. BDNF expression increased at 30 min and persisted at least for 24 hr after a single dose of CLM. The results support that Chaihu-jia-Longgu-Muli decoction was capable to immediately and enduringly elicit antidepressant activity via enhancement of hippocampal BDNF expression, in which the constituent Xiaochaihu decoction played the primary role.

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<![CDATA[QRREM method for the isolation of high-quality RNA from the complex matrices of coconut]]> https://www.researchpad.co/article/5c4b93ebd5eed0c48487d4af

Complex plant tissues vary in hardness, i.e. some are succulent, while others are complex to break. Besides, plant metabolites, such as polysaccharides, proteins, polyphenols and lipids, can greatly interfere with the RNA extraction. So, in order to obtain a high-quality RNA from the complex tissues (like coconut endosperm, coconut apple and coconut leaf bud) rich in secondary metabolites, a robust method is demanded. Several methods (MRIP, CTAB and TRIZOL) have been used previously for the isolation of quality RNA from the coconut tissues, but without any success. The present study will provide with the details of a new method (Quick and Reliable RNA Extraction Method or QRREM), which have efficiently isolated the intact RNA form the complex tissues of coconut compared with CTAB, Trizol and RNA plant. The method has been validated for the isolation of high-quality intact RNA from the other available plant species (Areca/betel nut, mint and spring onion). The method has various advantages over the other methods in terms of time and cost effectiveness. Furthermore, the resulted RNA from various tissues of coconut performed well in the downstream experiments, i.e. reverse transcription and PCR for the production and amplification of cDNA.

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<![CDATA[CRISPR base editors: genome editing without double-stranded breaks]]> https://www.researchpad.co/article/5c035ec2d5eed0c484540d6b

The CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 adaptive immunity system has been harnessed for genome editing applications across eukaryotic species, but major drawbacks, such as the inefficiency of precise base editing and off-target activities, remain. A catalytically inactive Cas9 variant (dead Cas9, dCas9) has been fused to diverse functional domains for targeting genetic and epigenetic modifications, including base editing, to specific DNA sequences. As base editing does not require the generation of double-strand breaks, dCas9 and Cas9 nickase have been used to target deaminase domains to edit specific loci. Adenine and cytidine deaminases convert their respective nucleotides into other DNA bases, thereby offering many possibilities for DNA editing. Such base-editing enzymes hold great promise for applications in basic biology, trait development in crops, and treatment of genetic diseases. Here, we discuss recent advances in precise gene editing using different platforms as well as their potential applications in basic biology and biotechnology.

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<![CDATA[Pulses and waves of contractility]]> https://www.researchpad.co/article/5c01f927d5eed0c4842c04b7

Wu discusses a study by Graessl et al. that describes a Rho GTPase signaling network that combines positive and negative feedback to regulate subcellular contraction patterns.

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<![CDATA[Translating the biology of aging into novel therapeutics for Alzheimer disease]]> https://www.researchpad.co/article/5c5f19e0d5eed0c484699df0

Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer disease (AD), a progressive neurodegenerative disease with currently no therapies that prevent, slow, or halt disease progression. Like other chronic diseases of old age, the progressive pathology of AD begins decades before the onset of symptoms. Many decades of research in biological gerontology have revealed common processes that are relevant to understanding why the aging brain is vulnerable to AD. In this review, we frame the development of novel therapeutics for AD in the context of biological gerontology. The many therapies currently in development based on biological gerontology principles provide promise for the development of a new generation of therapeutics to prevent and treat AD.

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<![CDATA[Probing the mechanisms for the selectivity and promiscuity of methyl parathion hydrolase]]> https://www.researchpad.co/article/5bd1081440307c3ab68b0b74

Diverse organophosphate hydrolases have convergently evolved the ability to hydrolyse man-made organophosphates. Thus, these enzymes are attractive model systems for studying the factors shaping enzyme functional evolution. Methyl parathion hydrolase (MPH) is an enzyme from the metallo-β-lactamase superfamily, which hydrolyses a wide range of organophosphate, aryl ester and lactone substrates. In addition, MPH demonstrates metal-ion-dependent selectivity patterns. The origins of this remain unclear, but are linked to open questions about the more general role of metal ions in functional evolution and divergence within enzyme superfamilies. Here, we present detailed mechanistic studies of the paraoxonase and arylesterase activities of MPH complexed with five different transition metal ions, and demonstrate that the hydrolysis reactions proceed via similar pathways and transition states. However, while it is possible to discern a clear structural origin for the selectivity between different substrates, the selectivity between different metal ions appears to lie instead in the distinct electrostatic properties of the metal ions themselves, which causes subtle changes in transition state geometries and metal–metal distances at the transition state rather than significant structural changes in the active site. While subtle, these differences can be significant for shaping the metal-ion-dependent activity patterns observed for this enzyme.

This article is part of the themed issue ‘Multiscale modelling at the physics–chemistry–biology interface’.

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<![CDATA[Regional amyloid accumulation and cognitive decline in initially amyloid-negative adults]]> https://www.researchpad.co/article/5c19b0ded5eed0c484c4b1a1

Objective

To assess whether global or regional changes in amyloid burden over 4 years predict early declines in episodic memory in initially amyloid-negative adults.

Methods

One hundred twenty-six initially amyloid-negative, cognitively normal participants (age 30–89 years) were included from the Dallas Lifespan Brain Study who completed florbetapir PET and a cognitive battery at baseline and 4-year follow-up. Standardized uptake value ratio (SUVR) change was computed across 8 bilateral regions of interest. Using general linear models, we examined the relationship between change in global and regional SUVR and change in episodic memory, controlling for baseline SUVR, baseline memory, age, sex, education, and APOE status.

Results

In initially amyloid-negative adults, we detected a regionally specific relationship between declining episodic memory and increasing amyloid accumulation across multiple posterior cortical regions. In addition, these amyloid-related changes in memory persisted when we focused on middle-aged adults only and after controlling for atrophy in global cortical, hippocampal, and Alzheimer disease signature cortical volume.

Conclusion

Our results indicate that assessing regional changes in amyloid, particularly in posterior cortical regions, can aid in the early detection of subclinical amyloid-related decline in episodic memory as early as middle age. Future research incorporating tau and other markers of neurodegeneration is needed to clarify the sequence of events that lead to this early, subclinical memory decline.

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<![CDATA[Systematic polypharmacology and drug repurposing via an integrated L1000-based Connectivity Map database mining]]> https://www.researchpad.co/article/5c22c693d5eed0c484aa085b

Drug repurposing aims to find novel indications of clinically used or experimental drugs. Because drug data already exist, drug repurposing may save time and cost, and bypass safety concerns. Polypharmacology, one drug with multiple targets, serves as a basis for drug repurposing. Large-scale databases have been accumulated in recent years, and utilization and integration of these databases would be highly helpful for polypharmacology and drug repurposing. The Connectivity Map (CMap) is a database collecting gene-expression profiles of drug-treated human cancer cells, which has been widely used for investigation of polypharmacology and drug repurposing. In this study, we integrated the next-generation L1000-based CMap and an analytic Web tool, the L1000FWD, for systematic analyses of polypharmacology and drug repurposing. Two different types of anti-cancer drugs were used as proof-of-concept examples, including histone deacetylase (HDAC) inhibitors and topoisomerase inhibitors. We identified KM-00927 and BRD-K75081836 as novel HDAC inhibitors and mitomycin C as a topoisomerase IIB inhibitor. Our study provides a prime example of utilization and integration of the freely available public resources for systematic polypharmacology analysis and drug repurposing.

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<![CDATA[Microbial oil production from solid-state fermentation by a newly isolated oleaginous fungus, Mucor circinelloides Q531 from mulberry branches]]> https://www.researchpad.co/article/5c22c6aed5eed0c484aa1326

In this study, a newly isolated oleaginous fungus, Mucor circinelloides (M. circinelloides) Q531, was able to convert mulberry branches into lipids. The highest yield and the maximum lipid content produced by the fungal cells were 42.43 ± 4.01 mg per gram dry substrate (gds) and 28.8 ± 2.85%, respectively. The main components of lignocellulosic biomass were gradually reduced during solid-state fermentation (SSF). Cellulose, hemicellulose and lignin were decreased from 45.11, 31.39 and 17.36% to 41.48, 28.71, and 15.1%, respectively. Gas chromatography analysis showed that the major compositions of the fermented products were palmitic acid (C16:0, 18.42%), palmitoleic acid (C16:1, 5.56%), stearic acid (C18:0, 5.87%), oleic acid (C18:1, 33.89%), linoleic acid (C18:2, 14.45%) and γ-linolenic acid (C18:3 n6, 22.53%) after 2 days of SSF. The fatty acid methyl esters contained unsaturated fatty acids with a ratio of 75.95%. The composition and content obtained in this study are more advantageous than those of many other biomass lipids. Meanwhile, the oleaginous fungus had a high cellulase activity of 1.39 ± 0.09 FPU gds−1. The results indicate that the enzyme activity of the isolated fungus was capable of converting the cellulose and hemicelluloses to available sugar monomers which are beneficial for the production of lipids.

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