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In vitro Evaluation of ASCs and HUVECs Co-cultures in 3D Biodegradable Hydrogels on Neurite Outgrowth and Vascular Organization.

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In vitro Evaluation of ASCs and HUVECs Co-cultures in 3D Biodegradable Hydrogels on Neurite Outgrowth and Vascular Organization.

Front Cell Dev Biol. 2020;8:489

Authors: Rocha LA, Gomes ED, Afonso JL, Granja S, Baltazar F, Silva NA, Shoichet MS, Sousa RA, Learmonth DA, Salgado AJ

Abstract
Vascular disruption following spinal cord injury (SCI) decisively contributes to the poor functional recovery prognosis facing patients with the condition. Using a previously developed gellan gum hydrogel to which the adhesion motif GRGDS was grafted (GG-GRGDS), this work aimed to understand the ability of adipose-derived stem cells (ASCs) to impact vascular organization of human umbilical vein endothelial cells (HUVECs), and how this in turn affects neurite outgrowth of dorsal root ganglia (DRG) explants. Our data shows that culturing these cells together lead to a synergistic effect as showed by increased stimulation of neuritogenesis on DRG. Importantly, HUVECs were only able to assemble into vascular-like structures when cultured in the presence of ASCs, which shows the capacity of these cells in reorganizing the vascular milieu. Analysis of selected neuroregulatory molecules showed that the co-culture upregulated the secretion of several neurotrophic factors. On the other hand, ASCs, and ASCs + HUVECs presented a similar profile regarding the presence of angiotrophic molecules herein analyzed. Finally, the implantation of GG-GRGDS hydrogels encapsulating ASCs in the chick chorioallantoic membrane (CAM) lead to increases in vascular recruitment toward the hydrogels in comparison to GG-GRGDS alone. This indicates that the combination of ASCs with GG-GRGDS hydrogels could promote re-vascularization in trauma-related injuries in the central nervous system and thus control disease progression and induce functional recovery.

PMID: 32612997 [PubMed]




Understanding the association between osteoarthritis and social participation: a CLSA population-based study.

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Understanding the association between osteoarthritis and social participation: a CLSA population-based study.

Arthritis Care Res (Hoboken). 2020 Jun 29;:

Authors: Perruccio AV, Yip C, Power JD, Canizares M, Gignac MA, Badley EM

Abstract
OBJECTIVE: The focus on disability in osteoarthritis (OA) has largely been on performing specific activities, neglecting wider implications for social participation (SP). We investigated the association between OA and SP considering activity limitations (AL) and instrumental supports (IS) as intervening variables in the association.
METHODS: Data were from 21,214 respondents aged 45-85 from cycle 1, Canadian Longitudinal Study on Aging. The questionnaire elicited: self-reported doctor-diagnosed OA; difficulty with 14 activities; perceived availability and receipt of IS; and 17 SP activities. Structural equation modeling was used.
PRIMARY OUTCOME: SP; Primary predictor: OA; Intervening variables: AL, received IS, perceived IS. Latent variables were developed for intervening and SP variables. Covariates: age, sex, body mass index, income, education, smoking, comorbidity count.
RESULTS: Mean age was 63 years, 51% were female, and 26.5% reported OA. Two distinct SP indicators were identified, SP-Diversity and SP-Intensity. Without considering intervening variables, minimal/no association was found between OA and SP. When considered, unique pathways linking OA and SP were found. The overall negative association between AL and SP was, in part, direct and, in part, buffered by both receipt and perceived availability of IS. Absent AL, OA was associated with greater SP.
CONCLUSIONS: Enhanced SP in people with OA without AL may reflect proactive steps taken by those with mild OA to maintain activity and social engagement. For those with AL, findings highlight the need for interventions to mitigate limitations and draw particular attention to the importance of both provision and awareness of available IS in maintaining SP.

PMID: 32598513 [PubMed - as supplied by publisher]




Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins.

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Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins.

Cell. 2020 Jun 23;:

Authors: Lee H, Beilhartz GL, Kucharska I, Raman S, Cui H, Lam MHY, Liang H, Rubinstein JL, Schramek D, Julien JP, Melnyk RA, Taipale M

Abstract
Pathogenic clostridial species secrete potent toxins that induce severe host tissue damage. Paeniclostridium sordellii lethal toxin (TcsL) causes an almost invariably lethal toxic shock syndrome associated with gynecological infections. TcsL is 87% similar to C. difficile TcdB, which enters host cells via Frizzled receptors in colon epithelium. However, P. sordellii infections target vascular endothelium, suggesting that TcsL exploits another receptor. Here, using CRISPR/Cas9 screening, we establish semaphorins SEMA6A and SEMA6B as TcsL receptors. We demonstrate that recombinant SEMA6A can protect mice from TcsL-induced edema. A 3.3 Å cryo-EM structure shows that TcsL binds SEMA6A with the same region that in TcdB binds structurally unrelated Frizzled. Remarkably, 15 mutations in this evolutionarily divergent surface are sufficient to switch binding specificity of TcsL to that of TcdB. Our findings establish semaphorins as physiologically relevant receptors for TcsL and reveal the molecular basis for the difference in tissue targeting and disease pathogenesis between highly related toxins.

PMID: 32589945 [PubMed - as supplied by publisher]




Occurrence and partitioning of brominated flame retardants (BFRs) in indoor air and dust: a 15-month case study in a test home.

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Occurrence and partitioning of brominated flame retardants (BFRs) in indoor air and dust: a 15-month case study in a test home.

Environ Sci Pollut Res Int. 2020 Jun 25;:

Authors: Guo JQ, Li YF, Liu LY, Huo CY, Sun Y, Ma WL, Zhang ZF, Li YF

Abstract
Ten polybrominated diphenyl ethers (PBDEs) and 16 novel brominated flame retardants (NBFRs) were measured in air and dust samples collected in a test home in Harbin, China, from January 2017 to June 2018. The PBDE and NBFR concentrations in indoor air were in the ranges of 0.598-14.5 pg m-3 and 9.28-686 pg m-3, respectively. The ranges of the PBDE and NBFR concentrations in indoor dust were 221-1060 ng g-1 and 71.9-1160 ng g-1, respectively. Brominated flame retardant (BFR) concentrations in indoor air were affected by the temperature, relative humidity (RH), and ventilation. The BFR concentrations in indoor dust did not show temperature dependence. All dust samples were sieved into 6 size fractions (F1-F6: 1000-2000 μm, 500-1000 μm, 250-500 μm, 125-250 μm, 63-125 μm, and < 63 μm). The mass percentage of BFRs in F6 was the highest. The BFR concentrations did not increase constantly with a particle size decrease, and the concentrations in F2 were higher than those in F3. The partitioning behavior of BFRs illustrates that the dust-air partitioning coefficient approximately approached equilibrium within F5, F6, and the total dust fraction (FA) in the test home when logKOA was between 9.1 and 11.32. Air-dust fugacity fractions were calculated, and the results suggested that most of the BFRs were mainly transferred from air to dust in the indoor environment for F1-F6.

PMID: 32588303 [PubMed - as supplied by publisher]




Exploring whole-genome duplicate gene retention with complex genetic interaction analysis.

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Exploring whole-genome duplicate gene retention with complex genetic interaction analysis.

Science. 2020 06 26;368(6498):

Authors: Kuzmin E, VanderSluis B, Nguyen Ba AN, Wang W, Koch EN, Usaj M, Khmelinskii A, Usaj MM, van Leeuwen J, Kraus O, Tresenrider A, Pryszlak M, Hu MC, Varriano B, Costanzo M, Knop M, Moses A, Myers CL, Andrews BJ, Boone C

Abstract
Whole-genome duplication has played a central role in the genome evolution of many organisms, including the human genome. Most duplicated genes are eliminated, and factors that influence the retention of persisting duplicates remain poorly understood. We describe a systematic complex genetic interaction analysis with yeast paralogs derived from the whole-genome duplication event. Mapping of digenic interactions for a deletion mutant of each paralog, and of trigenic interactions for the double mutant, provides insight into their roles and a quantitative measure of their functional redundancy. Trigenic interaction analysis distinguishes two classes of paralogs: a more functionally divergent subset and another that retained more functional overlap. Gene feature analysis and modeling suggest that evolutionary trajectories of duplicated genes are dictated by combined functional and structural entanglement factors.

PMID: 32586993 [PubMed - in process]




14-3-3ζ-c-Src-integrin-β3 complex is vital for platelet activation.

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14-3-3ζ-c-Src-integrin-β3 complex is vital for platelet activation.

Blood. 2020 Jun 25;:

Authors: Shen C, Liu M, Xu R, Wang G, Li J, Chen P, Ma W, Mwangi J, Lu Q, Duan Z, Zhang Z, Dahmani FZ, Mackeigan D, Ni H, Lai R

Abstract
Several adaptor molecules bind to cytoplasmic tails of β-integrins and facilitate bidirectional signaling, which is critical in thrombosis and hemostasis. Interfering with integrin-adaptor interactions spatially or temporally to inhibit thrombosis without affecting hemostasis is an attractive strategy for the development of safe anti-thrombotics. Here we show for the first time that 14-3-3ζ-c-Src-integrin-β3 complex is formed during platelet activation. 14-3-3ζ-c-Src interaction is mediated by -pirlglalnfsvfyye- fragment (PE16) on 14-3-3ζ and SH2-domain on c-Src, while 14-3-3ζ-integrin β3 interaction is mediated by -eskvfylkmkgdyyrYL- fragment (EL17) on 14-3-3ζ and -keatstf- fragment (KF7) on β3 integrin cytoplasmic tail. EL17-motif inhibitor or KF7 peptide interferes with the formation of 14-3-3ζ-c-Src-integrin-β3 complex and selectively inhibits β3 outside-in signaling without affecting the integrin-fibrinogen interaction, which suppresses thrombosis without causing significant bleeding. This study characterizes a previously unidentified 14-3-3ζ-c-Src-integrin-β3 complex in platelets and provides a novel strategy for the development of safe and effective anti-thrombotic therapies.

PMID: 32584951 [PubMed - as supplied by publisher]




GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib.

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GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib.

Front Mol Neurosci. 2020;13:81

Authors: Li J, Ma S, Chen J, Hu K, Li Y, Zhang Z, Su Z, Woodgett JR, Li M, Huang Q

Abstract
Glycogen synthase kinase-3 (GSK-3) dysregulation has been implicated in nigral dopaminergic neurodegeneration, one of the main pathological features of Parkinson's disease (PD). The two isoforms, GSK-3α and GSK-3β, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3β on PD pathogenesis, while the role of GSK-3α has been largely overlooked. Here, we report in situ observations that both GSK-3α and GSK-3β are dephosphorylated at a negatively acting regulatory serine, indicating kinase activation, selectively in nigral dopaminergic neurons following exposure of mice to 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP). To identify whether GSK-3α and GSK-3β display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3a null (Gsk3a ΔDat ) and Gsk3b null (Gsk3b ΔDat ) mice, respectively. We found that Gsk3b ΔDat , but not Gsk3a ΔDat , showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3α and GSK-3β in PD pathogenesis. In addition, we tested the neuroprotective effect of tideglusib, the most clinically advanced inhibitor of GSK-3, in the MPTP model of PD. Administration of higher doses (200 mg/kg and 500 mg/kg) of tideglusib exhibited significant neuroprotection, whereas 50 mg/kg tideglusib failed to prevent dopaminergic neurodegeneration from MPTP toxicity. Administration of 200 mg/kg tideglusib improved motor symptoms of MPTP-treated mice. Together, these data demonstrate GSK-3β and not GSK-3α is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3β acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy.

PMID: 32581704 [PubMed]




Is returning to work during the COVID-19 pandemic stressful? A study on immediate mental health status and psychoneuroimmunity prevention measures of Chinese workforce.

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Is returning to work during the COVID-19 pandemic stressful? A study on immediate mental health status and psychoneuroimmunity prevention measures of Chinese workforce.

Brain Behav Immun. 2020 07;87:84-92

Authors: Tan W, Hao F, McIntyre RS, Jiang L, Jiang X, Zhang L, Zhao X, Zou Y, Hu Y, Luo X, Zhang Z, Lai A, Ho R, Tran B, Ho C, Tam W

Abstract
This study aimed to quantify the immediate psychological effects and psychoneuroimmunity prevention measures of a workforce returning to work during the COVID-19 epidemic. Workforce returning to work was invited to complete an online questionnaire regarding their attitude toward the COVID-19 epidemic and return-to-work along with psychological parameters including the Impact of Event Scale-Revised, Depression, Anxiety, Stress Scale- 21 (DASS-21) and Insomnia Severity Index (ISI). Psychoneuroimmunity prevention measures include precautions at personal and organization levels. From 673 valid questionnaires, we found that 10.8% of respondents met the diagnosis of post-traumatic stress disorder (PTSD) after returning to work. The respondents reported a low prevalence of anxiety (3.8%), depression (3.7%), stress (1.5%) and insomnia (2.3%). There were no significant differences in the severity of psychiatric symptoms between workers/technicians and executives/managers. >95% reported psychoneuroimmunity prevention measures including good ventilation in the workplace and wore a face mask as protective. Factors that were associated with the severity of psychiatric symptoms in the workforce were marital status, presence of physical symptom, poor physical health and viewing return to work as a health hazard (p < 0.05). In contrast, personal psychoneuroimmunity prevention measures including hand hygiene and wearing face masks as well as organizational measures including significant improvement of workplace hygiene and concerns from the company were associated with less severe psychiatric symptoms (p < 0.05). Contrary to expectations, returning to work had not caused a high level of psychiatric symptoms in the workforce. The low prevalence of psychiatric symptoms could be due to confidence instilled by psychoneuroimmunity prevention measures before the resumption of work. Our findings would provide information for other countries during the COVID-19 pandemic.

PMID: 32335200 [PubMed - indexed for MEDLINE]




Long Noncoding RNAs and Repetitive Elements: Junk or Intimate Evolutionary Partners?

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Long Noncoding RNAs and Repetitive Elements: Junk or Intimate Evolutionary Partners?

Trends Genet. 2019 12;35(12):892-902

Authors: Lee H, Zhang Z, Krause HM

Abstract
Our recent ability to sequence entire genomes, along with all of their transcribed RNAs, has led to the surprising finding that only ∼1% of the human genome is used to encode proteins. This finding has led to vigorous debate over the functional importance of the transcribed but untranslated portions of the genome. Currently, scientists tend to assume coding genes are functional until proven not to be, while the opposite is true for noncoding genes. This review takes a new look at the evidence for and against widespread noncoding gene functionality. We focus in particular on long noncoding RNA (noncoding RNAs longer than 200 nucleotides) genes and their 'junk' associates, transposable elements, and satellite repeats. Taken together, the suggestion put forward is that more of this junk DNA may be functional than nonfunctional and that noncoding RNAs and transposable elements act symbiotically to drive evolution.

PMID: 31662190 [PubMed - indexed for MEDLINE]




Pooled CRISPR-Based Genetic Screens in Mammalian Cells.

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Pooled CRISPR-Based Genetic Screens in Mammalian Cells.

J Vis Exp. 2019 09 04;(151):

Authors: Chan K, Tong AHY, Brown KR, Mero P, Moffat J

Abstract
Genome editing using the CRISPR-Cas system has vastly advanced the ability to precisely edit the genomes of various organisms. In the context of mammalian cells, this technology represents a novel means to perform genome-wide genetic screens for functional genomics studies. Libraries of guide RNAs (sgRNA) targeting all open reading frames permit the facile generation of thousands of genetic perturbations in a single pool of cells that can be screened for specific phenotypes to implicate gene function and cellular processes in an unbiased and systematic way. CRISPR-Cas screens provide researchers with a simple, efficient, and inexpensive method to uncover the genetic blueprints for cellular phenotypes. Furthermore, differential analysis of screens performed in various cell lines and from different cancer types can identify genes that are contextually essential in tumor cells, revealing potential targets for specific anticancer therapies. Performing genome-wide screens in human cells can be daunting, as this involves the handling of tens of millions of cells and requires analysis of large sets of data. The details of these screens, such as cell line characterization, CRISPR library considerations, and understanding the limitations and capabilities of CRISPR technology during analysis, are often overlooked. Provided here is a detailed protocol for the successful performance of pooled genome-wide CRISPR-Cas9 based screens.

PMID: 31545321 [PubMed - indexed for MEDLINE]




Examining the fundamental biology of a novel population of directly reprogrammed human neural precursor cells.

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Examining the fundamental biology of a novel population of directly reprogrammed human neural precursor cells.

Stem Cell Res Ther. 2019 06 13;10(1):166

Authors: Ahlfors JE, Azimi A, El-Ayoubi R, Velumian A, Vonderwalde I, Boscher C, Mihai O, Mani S, Samoilova M, Khazaei M, Fehlings MG, Morshead CM

Abstract
BACKGROUND: Cell reprogramming is a promising avenue for cell-based therapies as it allows for the generation of multipotent, unipotent, or mature somatic cells without going through a pluripotent state. While the use of autologous cells is considered ideal, key challenges for their clinical translation include the ability to reproducibly generate sufficient quantities of cells within a therapeutically relevant time window.
METHODS: We performed transfection of three distinct human somatic starting populations of cells with a non-integrating synthetic plasmid expressing Musashi 1 (MSI1), Neurogenin 2 (NGN2), and Methyl-CpG-Binding Domain 2 (MBD2). The resulting directly reprogrammed neural precursor cells (drNPCs) were examined in vitro using RT-qPCR, karyotype analysis, immunohistochemistry, and FACS at early and late time post-transfection. Electrophysiology (patch clamp) was performed on drNPC-derived neurons to determine their capacity to generate action potentials. In vivo characterization was performed following transplantation of drNPCs into two animal models (Shiverer and SCID/Beige mice), and the numbers, location, and differentiation profile of the transplanted cells were examined using immunohistochemistry.
RESULTS: Human somatic cells can be directly reprogrammed within two weeks to neural precursor cells (drNPCs) by transient exposure to Msi1, Ngn2, and MBD2 using non-viral constructs. The drNPCs generate all three neural cell types (astrocytes, oligodendrocytes, and neurons) and can be passaged in vitro to generate large numbers of cells within four weeks. drNPCs can respond to in vivo differentiation and migration cues as demonstrated by their migration to the olfactory bulb and contribution to neurogenesis in vivo. Differentiation profiles of transplanted cells onto the corpus callosum of myelin-deficient mice reveal the production of oligodendrocytes and astrocytes.
CONCLUSIONS: Human drNPCs can be efficiently and rapidly produced from donor somatic cells and possess all the important characteristics of native neural multipotent cells including differentiation into neurons, astrocytes, and oligodendrocytes, and in vivo neurogenesis and myelination.

PMID: 31196173 [PubMed - indexed for MEDLINE]




Impact of immigration status on health behaviors and perceptions in cancer survivors.

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Impact of immigration status on health behaviors and perceptions in cancer survivors.

Cancer Med. 2019 05;8(5):2623-2635

Authors: Liu SY, Lu L, Pringle D, Mahler M, Niu C, Charow R, Tiessen K, Lam C, Halytskyy O, Naik H, Hon H, Irwin M, Pat V, Gonos C, Chan CWT, Villeneuve J, Shani RM, Chaudhry M, Brown MC, Selby P, Howell D, Xu W, Alibhai SMH, Jones JM, Liu G, Eng L

Abstract
BACKGROUND: Health behaviors including smoking cessation, physical activity (PA), and alcohol moderation are key aspects of cancer survivorship. Immigrants may have unique survivorship needs. We evaluated whether immigrant cancer survivors had health behaviors and perceptions that were distinct from native-born cancer survivors.
METHODS: Adult cancer patients from Princess Margaret Cancer Centre were surveyed on their smoking, PA, and alcohol habits and perceptions of the effects of these behaviors on quality of life (QoL), 5-year survival, and fatigue. Multivariable models evaluated the association of immigration status and region-of-origin on behaviors and perceptions.
RESULTS: Of the 784 patients, 39% self-identified as immigrants. Median time of survey was 24 months after histological diagnosis. At baseline, immigrants had trends toward not meeting Canadian PA guidelines or being ever-drinkers; patients from non-Western countries were less likely to smoke (aORcurrent  = 0.46, aORex-smoker  = 0.47, P = 0.02), drink alcohol (aORcurrent  = 0.22, aORex-drinker  = 0.52, P < 0.001), or meet PA guidelines (aOR = 0.44, P = 0.006). Among immigrants, remote immigrants (migrated ≥40 years ago) were more likely to be consuming alcohol at diagnosis (aOR = 5.70, P < 0.001) compared to recent immigrants. Compared to nonimmigrants, immigrants were less likely to perceive smoking as harmful on QoL (aOR = 0.58, P = 0.008) and survival (aOR = 0.56, P = 0.002), and less likely to perceive that PA improved fatigue (aOR = 0.62, P = 0.04) and survival (aOR = 0.64, P = 0.08).
CONCLUSIONS: Immigrants had different patterns of health behaviors than nonimmigrants. Immigrants were less likely to perceive continued smoking as harmful and were less likely to be aware of PA benefits. Culturally tailored counselling may be required for immigrants who smoke or are physically sedentary at diagnosis.

PMID: 30897287 [PubMed - indexed for MEDLINE]




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