Global Medical Discovery features paper: Need pain relief. Think Synovia capsules by Bioparanta

Arthritis is group of conditions  which can cause pain stiffness and swelling in the joints. Arthritis can involve almost any part of the body, most often affecting the hip, spine, knee or other weight-bearing joints, but also found in the fingers and other non-weight-bearing joints. Some forms of arthritis can also affect other parts of the body. As a result of arthritis people sometime can be disabled, socially isolated and in sometimes even depress.

SYNOVIA By BioParanta which comes in an easy to swallow capsules is a unique blend of natural ingredients designed to treat wide range of conditions that is related to inflammation. Such as Arthritis, Carpal tunnel syndrome, Tendonitis, and tennis elbow. As we use our joint the cartilage mussels and tends undergo damage, with increase physical activates, sport and age, our bodies abilities to repair can’t keep up  with the damage process, this result in jointly generation giving us pain, stiffness and weakness in the joints. SYNOVIA gets to the root cause of the problem and pain which is inflammation. The active ingredient in its formula are design to reduce the inflammation of  nerves, muscles, tendons, and ligaments. SYNOVIA By BioParanta helps to strengthen the fundamental of the body while feeding the bones, ligaments and tendon specific nutrition, to create strength and mobility from the inside out.  In addition studies showed blood circulation will also be improved as well as nerve functions.

SYNOVIA By BioParanta has all natural ingredients made up of unique blend  of totally natural ingredient. The ingredients work powerfully together as a team to  reduce the inflammation, stimulate the regrowth of the cartilage tissue ,  stop the degeneration process, and bring it back healing. All the ingredients were carefully chosen for maximum effectiveness to increase absorption and utilization in a unique formulation that gives Synovia the superiority over any arthritis pain relief pill. While insuring long term safety as well as being free of side effects (it does not contain non-steroidal anti-inflammatory drugs, NSIADs).

SYNOVIA by BioParanta has natural anti- inflammatory compounds have also been added to target pain centers and restrict the inflammation that has been caused by on-going deterioration. This is a key attribute of the formula of SYNOVIA so that it supports the recovery of joints while keeping a protective response relating to ongoing wear and tear.

This innovative formula targets the trigger points to tackle the underlying cause of the pain thereby providing pain relief.Over all SYNOVIA by BioParanta is powerful, all natural trusted and highly effective formula to reduce pain and inflammation.

 

The post Need pain relief. Think Synovia capsules by Bioparanta appeared first on Global Medical Discovery.

Global Medical Discovery features paper: DNA binding activity of Ku during chemotherapeutic agent-induced early apoptosis

Significance Statement

This study analyzed the expression of the Ku protein and its DNA-binding activity during early apoptosis. In the study, Ku was neither cleaved nor degraded during early apoptosis induced by etoposide treatment. In addition, Ku was found to bind cleaved chromosomal DNA and/or nucleosomes in apoptotic cells.

The DNA-binding properties of Ku were assessed by two methods, each of which is based on electrophoresis mobility shift assay (EMSA). One commonly applied method, EMSA with 15-bp ³²P-labeled DNA probe (RI-EMSA), employs radiolabeled DNA probes. The other method, EMSA combined with western blot (WB-EMSA), employs unlabeled DNA probes followed by western blot and detection using anti-Ku antiserum. This study showed that both WB-EMSA and RI-EMSA are useful for evaluating Ku-DNA binding activity.

The significance of this work lies in its contribution to the understanding of the mechanism of interaction of Ku with DNA during apoptosis.

Figure legends:

1. RI-EMSA: Protein extract obtained from cells treated with etoposide for the duration indicated was incubated with ³²P-labeled, 15-bp dsDNA probes in the presence of closed circular DNA.
2. Western blot: Protein extract obtained from either control or etoposide-treated cells was run on a 10% SDS polyacrylamide gel under reducing conditions. Ku70 and Ku80 were detected using human polyclonal antiserum.
3. WB-EMSA: Extracts from etoposide-treated HL-60 cells were separated by 6% native PAGE, and then analyzed by western blot with polyclonal antiserum raised against Ku (lane 1). Extracts from untreated HL-60 cells were incubated with 160-bp DNA, followed by western blot (lane 2). Extracts from untreated or etoposide treated HL-60 cells were incubated with 15-bp DNA, followed by western blot (lanes 3–6).
4. Comparison of WB-EMSA to conventional RI-EMSA. The diagram of RI-EMSA is a part of Figure A, and the figure of WB-EMSA is a part of Figure C.

About The Author

Katsuya Iuchi is currently an assistant professor at the Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School. His research focuses on the mechanism of cell death and lipid peroxidation of biomembranes. Prior to joining Nippon Medical School, he was a postdoctoral fellow in the Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology Agency. He received his Ph.D. in chemistry from Kwansei Gakuin University, Japan in 2009.  

Journal Reference

Exp Cell Res. 2016;342(2):135-44.

Iuchi K¹, Yagura T².

Show Affiliations

1. Department of Bioscience, Faculty of Science and Technology, Kwansei Gakuin University, 2-1 Gakuin, Sanda-shi, Hyogo-ken 669-1337, Japan. Electronic address: iuchi@nms.ac.jp.
2. Department of Bioscience, Faculty of Science and Technology, Kwansei Gakuin University, 2-1 Gakuin, Sanda-shi, Hyogo-ken 669-1337, Japan.

Abstract

Ku-protein is a heterodimer composed of two subunits, and is capable of both sequence-independent and sequence-specific DNA binding. The former mode of DNA binding plays a crucial role in DNA repair. The biological role of Ku-protein during apoptosis remains unclear. Here, we show characterization of Ku-protein during apoptosis. In order to study the DNA binding properties of Ku, we used two methods for the electrophoresis mobility shift assay (EMSA). One method, RI-EMSA, which is commonly used, employed radiolabeled DNA probes. The other method, WB-EMSA, employed unlabeled DNA followed by western blot and detection with anti-Ku antiserum. In this study, Ku-DNA probe binding activity was found to dramatically decrease upon etoposide treatment, when examined by the RI-EMSA method. In addition, pre-treatment with apoptotic cell extracts inhibited Ku-DNA probe binding activity in the non-treated cell extract. The inhibitory effect of the apoptotic cell extract was reduced by DNase I treatment. WB-EMSA showed that the Ku in the apoptotic cell extract bound to fragmented endogenous DNA. Interestingly, Ku in the apoptotic cell extract purified by the Resource Q column bound 15-bp DNA in both RI-EMSA and WB-EMSA, whereas Ku in unpurified apoptotic cell extracts did not bind additional DNA. These results suggest that Ku binds cleaved chromosomal DNA and/or nucleosomes in apoptotic cells. In conclusion,Ku is intact and retains DNA binding activity in early apoptotic cells.

Copyright © 2016 Elsevier Inc. All rights reserved.

Go To Exp Cell Res.

 

Global Medical Discovery features paper: Identification of Palmitoylated Transitional Endoplasmic Reticulum ATPase by Proteomic Technique and Pan Antipalmitoylation Antibody

J Proteome Res. 2016 Mar 4;15(3):956-62. doi: 10.1021/acs.jproteome.5b00979.

Caiyun Fang,^† Xiaoqin Zhang,^† Lei Zhang, Xing Gao, Pengyuan Yang, and Haojie Lu^*

Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China

 

Abstract

Protein palmitoylation plays a significant role in a wide range of biological processes such as cell signal transduction, metabolism, apoptosis, and carcinogenesis. For high-throughput analysis of protein palmitoylation, approaches based on the acyl-biotin exchange or metabolic labeling of azide/alkynyl-palmitate analogs are commonly used. No palmitoylation antibody has been reported. Here, the palmitoylated proteome of human colon cancer cell lines SW480 was analyzed via a TS-6B-based method. In total, 151 putative palmitoylated sites on 92 proteins, including 100 novel sites, were identified. Except for 3 known palmitoylated transmembrane proteins, ATP1A1, ZDHHC5, and PLP2, some important proteins including kinases, ion channels, receptors, and cytoskeletal proteins were also identified, such as CLIC1, PGK1, PPIA, FKBP4, exportin-2, etc. More importantly, the pan antipalmitoylation antibody was developed and verified for the first time. Our homemade pan antipalmitoylation antiserum could differentiate well protein palmitoylation from mouse brain membrane fraction and SW480 cells, which affords a new technique for analyzing protein palmitoylation by detecting the palmitic acid moiety directly. Furthermore, the candidate protein transitional endoplasmic reticulum ATPase (VCP) identified in SW480 cells was validated to be palmitoylated by Western blotting with anti-VCP antibody and the homemade pan antipalmitoylation antibody.

Go To Proteome Research 

Global Medical Discovery features paper: Synthesis, antimicrobial activity of Schiff base compounds of cinnamaldehyde and amino acids

Significance Statement

Microorganism infection is a continue threat to human health. About the control the infection, using antimicrobial agent is one of the effective options. Now, natural antimicrobial agents are focused extensively because they are low-toxic and safe. Cinnamaldehyde is a natural antimicrobial substance, which is extracted from bark of  Cinnamomum genus trees. Cinnamaldehyde possesses good bioactivity and could inhibit the growing of many kinds of fungi and bacteria. Cinnamaldehyde is categorized as Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration. However, Cinnamaldehyde has several drawbacks, such as its strong odor, high volatility and water insolubility, which limited its application.

In our research, cinnamaldehyde was modified by amino acids to synthesize a new class of Schiff base compounds. Bioactivity results indicated that the Schiff base compounds remarkably inhibited the growth of the tested bacteria and fungi, and they have broad-spectrum antimicrobial activity. Compared with control compounds, i.e. Ciprofloxacin and Fluconazole, most of the Schiff base compounds exhibited better bioactivity than the two control compounds.

The key finding of this study is that, the new class of cinnamaldehyde Schiff base compounds, which could be easily synthesized, have great bioactivity, low-toxicity, low odor and good water solubility. Therefore, cinnamaldehyde Schiff base compounds were potential to be antibacterial agents or food preservatives.

Moreover, the further analysis on antimicrobial activity and chemical structure were conducted in our research. Results from the structure-activity relationship suggest that both p-Cl of benzene ring from cinnamaldehyde and the number of –COOK from amino acid salts significantly contributed to their antimicrobial activity.

Our research results provided an alternative option for exploring of new antimicrobial agents. 

About The Author

Prof. Shujun Li received her Bachelor Degree in Forest Products Chemical Processing from Northeast Forestry University, China in 1995. She received her Master Degree in 1998, also in the same major, and received her Ph. D in 2001, majored in wood science and technology.

Currently, she serves as a full Professor of Forest Products Chemical Processing Department at Northeast Forestry University, Harbin, China. Her research interests include biomass conversion and application in a high-value way. 

 

About The Author

Miss Hui Wang received her bachelor degree in 2013 from Lanzhou University of Technology, Lanzhou, China. She is now a doctoral candidate at Northeast Forestry University, and her current research is synthesis of cinnamaldehyde derivatives and its bioactivity. 

Journal Reference

Bioorg Med Chem Lett. 2016 Feb 1;26(3):809-13.

Wang H¹, Yuan H¹, Li S², Li Z¹, Jiang M¹. 

Show Affiliations

1. Key Laboratory of Bio-Based Material Science and Technology of the Ministry of Education, Northeast Forestry University, Harbin 150040, China.
2. Key Laboratory of Bio-Based Material Science and Technology of the Ministry of Education, Northeast Forestry University, Harbin 150040, China. Electronic address: lishujun@nefu.edu.cn.

Abstract

The purpose of this study was to synthesize hydrophilic cinnamaldehyde Schiff base compounds and investigate those bioactivity. A total of 24Schiff base compounds were synthesized using a simple approach with 3 cinnamaldehyde derivates and 8 amino acids as raw materials. The structures of synthesized compounds were confirmed using FTIR, (1)HNMR, HRMS purity and melting point. The antimicrobial activities of newcompounds were evaluated with fluconazole and ciprofloxacin as the control against Aspergillus niger, Penicillium citrinum, Escherichia coli and Staphylococcus aureus.

Findings show that major compounds exhibited significant bioactivity. Results from the structure-activity relationship suggest that both -p-Cl on benzene ring of cinnamaldehyde and the number of -COOK of amino acid salts significantly contributed to antimicrobialactivity.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Go To Bioorg Med Chem Lett

 

 

 

Global Medical Discovery features paper: Impact of patient characteristics on the clinical efficacy of mongersen (GED-0301), an oral Smad7 antisenseoligonucleotide, in active Crohn’s disease

Significance Statement

Crohn’s disease (CD) is a chronic condition characterized by segmental, transmural inflammation, which, although most common in the terminal ileum and right colon, can affect any part of the alimentary tract. In addition to the commonly observed signs and symptoms of Crohn’s disease, local complications as well as manifestations outside the digestive tract can also occur as a result of Crohn’s disease -associated inflammation, underscoring the importance of effective treatment options.

Subgroup analyses from prospective, randomised, controlled trials in patients with active Crohn’s disease have shown that patient demographics and disease characteristics such as disease duration and treatment history can impact clinical outcomes. Our retrospective study further evaluated the impact of patient baseline clinical and disease characteristics on the efficacy of mongersen, an oral, locally active Smad7 antisense oligonucleotide that targets Smad7 in the ileum and colon. In addition to the impact of human serum C-reactive protein (hsCRP) values, disease duration, and disease activity at baseline on mongersen over 10 weeks, our analysis also looked at how sex, body mass index, smoking status, history of Crohn’s disease-related intestinal resection, steroid status, and immunosuppressant use at baseline impacted treatment efficacy.

Our results showed that patients with Crohn’s Disease Activity Index (CDAI) scores ≤260 at baseline had significantly higher clinical remission rates (defined as a CDAI <150) with mongersen 40 mg/day and 160 mg/day treatment, whereas patients with CDAI scores >260 at baseline achieved clinical remission most frequently with the highest mongersen dose (160 mg/day), suggesting that greater disease activity can impact clinical benefit. Baseline disease characteristics such as hsCRP (<3 mg/L or ≥3 mg/L) and disease duration (<5 or ≥5 years) did not appear to significantly impact efficacy of mongersen treatment in our study.

About The Author

Giovanni Monteleone received his medical degree from the University Magna Graecia of Catanzaro (Italy) and completed his internship, residency, and a fellowship in gastroenterology at the same university. He joined the faculty at the University of Rome Tor Vergata in 2003, becoming an Assistant Professor of Gastroenterology, then Professor of Gastroenterology. He is the Head of Gastroenterology Unit at the Policlinico Tor Vergata in Rome. Dr. Monteleone’s basic research is mostly focused on mechanisms involved in the control of mucosal immune homeostasis and inflammatory signals that sustain and amplify pathological processes in the gastrointestinal tract. In particular, he is interested in understanding how immune cells and non-immune cells cross-talk in the gastrointestinal mucosa and which molecules mediate such an interplay. So far, these studies have contributed to delineate novel pathways of intestinal mucosal damage and paved the way for the development of anti-inflammatory compounds, which are now ready to move into the clinic. Dr. Monteleone is also interested in the immune-inflammatory networks involved in the colitis-associated colon carcinogenesis. He is author of >300 peer-reviewed articles, books, and book chapters, and serves as an editorial board member or a reviewer for several journals.

 

Journal Reference

Aliment Pharmacol Ther. 2016 ;43(6):717-24.

Monteleone G¹, Di Sabatino A², Ardizzone S³, Pallone F¹, Usiskin K⁴, Zhan X⁴, Rossiter G⁴, Neurath MF⁵. 

Show Affiliations

1. Department of Systems Medicine, University of Tor Vergata, Rome, Italy.
2. First Department of Internal Medicine, St. Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
3. Department of Surgery, “L. Sacco” University Hospital, Milan, Italy.
4. Celgene Corporation, Warren, NJ, USA.
5. Department of Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.

Abstract

BACKGROUND:

In a phase 2 study, mongersen, an oral antisense oligonucleotide targeting Smad7, was effective in inducing clinical remission in approximately 60% of patients with active Crohn’s disease (CD).

AIM:

In a post hoc analysis to evaluate those patient disease characteristics that may have influenced the efficacy and safety of mongersen therapy.

METHODS:

Patients with steroid-dependent/resistant, active Crohn’s disease were randomised to mongersen 10, 40 or 160 mg/day or placebo for 2 weeks; patients were followed for 10 weeks. Clinical remission [Crohn’s Disease Activity Index (CDAI) score <150] and clinical response (CDAI score reduction ≥100 points) were assessed at weeks 2, 4 and 12 for these subgroups: disease duration <5/≥5 years, human serum C-reactive protein (hsCRP) <3/≥3 mg/L, and CDAI at baseline ≤260/>260. Additional patient baseline and disease characteristics were explored.

RESULTS:

Clinical remission and response rates were significantly higher in patients receiving mongersen 40 and 160 mg/day but not 10 mg/day vs. placebo and independent of disease duration and hsCRP. Patients with baseline CDAI ≤260 had significantly higher remission rates with 40 and 160 mg/day. In patients with baseline CDAI >260, remission rates were statistically greater with 160 mg/day and numerically better with 40 mg/day vs. placebo. Adverse event rates were similar across treatment groups. Mongersen was safe and well tolerated.

CONCLUSIONS:

Patients with higher CDAI scores achieved clinical remission most frequently with the highest mongersen dose. Disease duration and baseline human serum C-reactive protein did not appear to significantly impact efficacy of mongersen in this study (EudraCT Number: 2011-002640-27.).

© 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Go To Aliment Pharmacol Ther

 

Global Medical Discovery features paper: Low-density lipoprotein transport through an arterial wall under hyperthermia and hypertension conditions–An analytical solution

About The Author

Professor Kambiz Vafai received his B.S. in Mechanical Engineering from the University of Minnesota at Minneapolis in 1975. He received his M.S. degree in Mechanical Engineering from the University of California at Berkeley in 1977 and his Ph.D. degree in Mechanical Engineering also from the University of California, Berkeley in 1980. He is currently serves as Distinguished Professor of Mechanical Engineering at the University of California, Riverside, USA.

Professor Vafai holds 12 US patents associated with electronic cooling and medical applications. His research interests include transport through porous media, multiphase transport, aircraft brakes, biomedical applications, microcantilever-based biosensors, biofilms, electronic cooling, macromolecule transport through arteries, cooling enhancement investigations, modeling of tissue and organs, natural convection in complex configurations, analysis of porous insulations, heat flux applications, free surface flows, flat-shaped heat pipes, thermal design and modeling, and feasibility, optimization, and parametric studies for various engineering applications and power electronics. He is one of the highest cited in his fields of research.

He is currently Editor in Chief- Journal of Porous Media and Editor in Chief- Special Topics & Reviews in Porous Media

Journal Reference

J Biomech. 2016;49(2):193-204.

Iasiello M¹, Vafai K², Andreozzi A³, Bianco N³.

Show Affiliations

1. Department of Mechanical Engineering, University of California, Riverside, CA 92521, USA; Dipartimento di Ingegneria Industriale, Università degli Studi di Napoli Federico II, P.le Tecchio, 80, Napoli 80125, Italy.
2. Department of Mechanical Engineering, University of California, Riverside, CA 92521, USA. Electronic address: vafai@engr.ucr.edu.
3. Dipartimento di Ingegneria Industriale, Università degli Studi di Napoli Federico II, P.le Tecchio, 80, Napoli 80125, Italy. 

Abstract

An analytical solution for Low-Density Lipoprotein transport through an  arterial wall  under hyperthermia conditions is established in this work. A four-layer model is used to characterize the arterial wall. Transport governing equations are obtained as a combination between Staverman-Kedem-Katchalsky membrane equations and volume-averaged porous media equations. Temperature and solute transport fields are coupled by means of Ludwig-Soret effect.

Results are in excellent agreement with numerical and analytical literature data  under  isothermal conditions, and with numerical literature data for the hyperthermia case. Effects of hypertension  combined with hyperthermia, are also analyzed in this work.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Go To J Biomech

 

Global Medical Discovery features paper: Effect of collagen-glycosaminoglycan scaffold pore size on matrix mineralization and cellular behavior in different cell types

Significance Statement

Bone tissue engineering has emerged as one of the leading fields in tissue engineering and regenerative medicine. Its success relies on understanding the interplay between progenitor cells, regulatory signals, and the biomaterials/scaffolds used to deliver them. Subtle changes in scaffold architecture can have significant effects on cellular activity. Optimising the design of bioactive scaffolds is guided by an understanding of the behaviour and responses of cells to their surrounding environment. Pore size is an essential architectural consideration in construct development; therefore, it is crucial to identify the optimal pore size for augmented tissue formation.

Using a series of collagen-glycosaminoglycan (CG) scaffolds with a homogenous mean pore size ranging from 85 µm up to 325 µm, we identified key differences in osteoblast and mesenchymal stem cell (MSC) behaviour in response to pore size. Scaffolds with the largest pore size (325 µm) facilitated superior osteoblast attachment, migration, scaffold infiltration and matrix deposition. MSC response was similar to osteoblasts but cell motility, proliferation, and scaffold infiltration was reduced. This was associated with differences in the profile of integrin subunits (α2) and collagen receptors (CD44), indicating that osteoblasts have a stronger affinity for collagen-glycosaminoglycan scaffolds compared to MSCs.

This study, for the first time within the literature, compares two very different cell types head to head to investigate individual cell behaviour in response to a single parameter. The findings elucidate fundamental mechanisms underlying the differences between the two cell types and highlight the importance of tailoring scaffold micro-architecture and cell type for cell-specific applications.

About The Author

Dr. Ciara Murphy received her PhD in area of bone tissue engineering from the Royal College of Surgeons in Ireland (RCSI) in 2010. Subsequently, she joined the Orthopaedic & Biotechnology Research (ORB) Group in the Children’s Hospital at Westmead, Sydney, Australia, where she focused her post-doctoral research on developing biologic delivery systems that utilised tissue engineering technologies, including collagen-based scaffolds, as novel therapies for bone healing.

In 2014, she was awarded the New Investigator Recognition Award (NIRA) at the International Orthopaedic Research Society (ORS) for her postdoctoral work. She returned to Ireland in 2015 joining University College Dublin (UCD) as an Assistant Professor in the School of Medicine and a Principal Investigator in the UCD Centre for Biomedical Engineering. Her research focuses on developing advanced biomaterials as innovative platforms for targeted therapeutic delivery, disease model systems and 3-D studies of cell-matrix interactions. 

 

About The Author

A/Prof Garry Duffy leads a multidisciplinary team of biomaterials, stem cell and drug delivery scientists within the Tissue Engineering Research Group (TERG), based in the Royal College of Surgeons in Ireland, with a large focus on chronic diseases. The long-term goal of his lab is to develop advanced biomaterials to facilitate targeted delivery and future clinical translation of cell based therapeutics.  As well as the DRIVE project, Garry also leads the Advanced Materials for Cardiac Regeneration (AMCARE) project, an €8.6 million FP7-funded research programme with the goal of using smart biomaterials and minimally-invasive surgical devices for targeted delivery of stem cells to treat the infarcted myocardium.

About The Author

A/Prof Aaron Schindeler is a Senior Research Scientist at The Children’s Hospital at Westmead and the Director of Basic Research in the Centre for Children’s Bone & Musculoskeletal Health (CCBMH). He joined the orthopaedic research department in 2003 and since then has tackled a range of research questions looking at traumatic bone injuries and genetic diseases affecting. Aaron leads a multidisciplinary team of scientists, engineers, and medical and allied health professionals. Key research areas for him include reducing the risk and impact of fracture and implant infection, cell and genetic therapies for brittle bone disease, studying the metabolic muscle weakness associated with neurofibromatosis type 1, and bone tissue engineering using novel biomaterials and 3D printing. 

About The Author

Prof Fergal O’Brien is a leading innovator in the development of advanced biomaterials for drug delivery and tissue repair. He is Professor of Bioengineering & Regenerative Medicine, Deputy Director for Research and heads the Tissue Engineering Research Group based in the Royal College of Surgeons in Ireland. He is also a PI and Deputy Director of the €58 million SFI-funded Advanced Materials and Bioengineering Research (AMBER) Centre. He is currently a member of the World Council of Biomechanics, Biomaterials Topic Chair for the Orthopaedic Research Society and President of the Section of Bioengineering of the Royal Academy of Medicine in Ireland.

Since his faculty appointment in 2003, he has published over 150 journal articles in leading peer-reviewed international journals and supervised 30 doctoral candidates to completion. He has a current h-index of 47.  Accolades include a Fulbright Scholarship (2001), New Investigator Recognition Award by the Orthopaedic Research Society (2002), Science Foundation Ireland, President of Ireland Young Researcher Award (€1.1. million, 2004), Engineers Ireland Chartered Engineer of the Year (2005), European Research Council (ERC) Investigator Award (€2 million, 2009),  Anatomical Society New Fellow of the Year (2014) and Fellowship of Engineers Ireland (2013) and the European Alliance for Medical & Biological Engineering Science (2016).

 

Journal Reference

J Biomed Mater Res A. 2016;104(1):291-304. 

Murphy CM^1,2,3, Duffy GP^2,3,4, Schindeler A^5,6, O’brien FJ^2,3,4.

Show Affiliations

1. School of Medicine & Medical Science, University College Dublin, Dublin, Ireland.
2. Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
3. Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin, Ireland.
4. Advanced Materials and Bioengineering Research Centre (AMBER) RCSI & TCD, Dublin, Ireland.
5. Orthopaedic Research & Biotechnology Unit the Children’s Hospital at Westmead.
6. Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia.

Abstract

We have previously examined osteoblast behavior on porous collagen-glycosaminoglycan (CG) scaffolds with a range of mean pore sizes demonstrating superior cell attachment and migration in scaffolds with the largest pores (325 μm). Scaffolds provide a framework for construct development; therefore, it is crucial to identify the optimal pore size for augmented tissue formation. Utilizing the same range of scaffolds (85 μm – 325 μm), this study aimed to examine the effects of mean pore size on subsequent osteoblast differentiation and matrix mineralization, and to understand the mechanism by which pore size influences behavior of different cell types. Consequently, primary mesenchymal stem cells (MSCs) were assessed and their behavior compared to osteoblasts.

Results demonstrated that scaffolds with the largest pore size (325 μm) facilitated improved osteoblast infiltration, earlier expression of mature bone markers osteopontin (OPN) and osteocalcin (OCN), and increased mineralization. MSCs responded similarly to osteoblasts whereby cell attachment and scaffold infiltration improved with increasing pore size. However, MSCs showed reduced cell motility, proliferation, and scaffold infiltration compared to osteoblasts. This was associated with differences in the profile of integrin subunits (α2) and collagen receptors (CD44), indicating that osteoblasts have a stronger affinity for collagen-glycosaminoglycan scaffolds compared to MSCs.

In summary, these results reveal how larger pores promote improved cell infiltration, essential for construct development, however the optimal scaffold pore size can be cell type specific. As such, this study highlights a necessity to tailor both scaffold micro-architecture and cell-type when designing constructs for successful bone tissue engineering applications.

© 2015 Wiley Periodicals, Inc.

Go To J Biomed Mater Res A.

 

Global Medical Discovery features paper: Kir3 channels undergo arrestin-dependant internalization following delta opioid receptor activation

Significance Statement

Protein-protein interactions are of great importance for virtually all biological processes and whether transient or stable, they support the formation of multimeric complexes. Monitoring such interactions may help us characterize signaling and trafficking behaviours of these complexes and sometimes allows us to elucidate new signaling pathways for a known protein. A better and detailed knowledge of these different aspects of complex function is essential not only to understand the majority of physiological processes but also for the development of new therapeutic ligands.

In this article, we characterized protein-protein interactions within a complex involved in opioid analgesia which is formed by delta opioid receptors (DORs), heterotrimeric G protein (Gαoβ1γ2) and their effector, the G protein-gated inwardly rectifying potassium channel (GIRK/Kir3). It is well established that sustained DOR stimulation by an agonist triggers a series of adaptive changes that reduce receptor ability to signal and this desensitization may contribute to analgesic tolerance. Although there is considerable information of how desensitization reduces receptor ability to interact and activate the G protein, much less is known on how desensitization modifies the channel standing in the complex. We therefore focused on how interactions between the channel and other complex components were modified by sustained receptor activation.

Our results show that DORs, G protein and Kir3 channels form a constitutive complex at the plasma membrane. This complex undergoes rapid conformational rearrangements upon acute DOR stimulation and maintains its integrity over more prolonged periods of receptor activation. During this time, the DOR/G protein/Kir3 complex undergoes additional conformational changes imposed by βarrestin 2 (βarr2) recruitment and association with receptors and channels. This interaction not only induces DOR removal from the membrane but also that of the channel. Both signaling partners are concomitantly internalized via a clathrin and dynamin-dependent mechanism.

Conclusion: Taken together, these data show that DORs and Kir3 channels form a constitutive complex which is recognized and internalized as a signaling unit by βarr2.

Contribution to the advancement of knowledge: Kir3 channels removal from the membrane represents an additional level of regulation of opioid receptor signaling that had not been previously described. Moreover, given active Kir3 channels participation in opioid analgesia, their removal from the membrane may constitute an additional and powerful mechanism of tolerance. Thus, it is reasonable to expect that development of DOR ligands that activate the channel but could prevent complex interaction with βarr2 could lead to the production of opioid analgesics that preserve their therapeutic efficacy.

Highlights

– Kir3.1/3.2 channels, G proteins and DORs form a complex.

– The complex maintains its integrity over prolonged periods of receptor stimulation.

– βarr2 is recruited to DORs and channels mediating their internalization as a unit.

– DOR-Kir3 channel internalization is clathrin/dynamin dependent.

Figure Legend. Mechanism of analgesia induced by Kir3 channels at the synaptic cleft.

When released into the synaptic cleft, neurotransmitters such as endogenous opioids (pink) activate the DOR receptor (red) of the postsynaptic neuron, which in turn activate the Kir3 channel (green). Activation of Kir3 channels produces hyperpolarization at the postsynaptic membrane thereby reducing the transmission of nociceptive impulses.

About The Author

Dr. Karim Nagi received his Bachelor’s degree in Biology from the Lebanese University, Tripoli, Lebanon (2005-2008). He then moved to Canada where he completed one year in basic research in Molecular Cardiology and Genetics at Sacré-Cœur Hospital’s Research Center, Montreal, Canada. In 2010, he entered the MSc program at the Department of Pharmacology, University of Montreal under the supervision of Prof. Pineyro at Sainte-Justine Hospital Research Center. By the end of his first year, he was offered accelerated switch to the PhD program which he completed in 2015. During this time Dr Nagi applied a variety of approaches in biochemistry and neuroscience to investigate the network properties of GPCR signaling with particular focus in the analgesic actions of opioid receptor ligands and their potential to induce tolerance.

Dr. Nagi has authored 7 publications in peer-reviewed journals and 50+ presentations. In addition, he received eight awards for the best oral and poster presentations in scientific conferences, two travel awards to international congresses and his studies were supported by a number of fellowship awards including CHU Sainte-Justine and Foundation of Stars fellowship, fellowship from the Department of Pharmacology and a fellowship from the Faculty of Graduate and Postdoctoral Studies, University of Montreal. He was also granted a Recognition Award for the Best Scientific Contribution of the year (2014-2015) among students in the Department of Pharmacology.

After completing graduate studies, Dr. Nagi continued his training as a postdoctoral fellow in the Department of Cellular Biology, Duke University, Durham, USA under the supervision of Prof. Marc G. Caron. His current research focuses on characterizing different biased receptors signaling and regulation.

Working at these different institutions with a world-renowned reputation in pharmacological research, Dr. Nagi has developed expertise in GPCRs pharmacology, BRET-based biosensor development for drug screening, molecular biology and biased signaling.

About The Author

Graciela Pineyro, MD, Ph.D. 

Prof. Graciela Pineyro is a Full Professor at the Department of Psychiatry, University of Montreal, Montreal, Canada. In 1991, she received her medical degree with specialty in Pharmacology from the Faculty of Medicine, National University, Uruguay. She then moved to Canada where she obtained a Ph.D. in Neurosciences from McGill University, Montreal, Canada (1997) followed by postdoctoral training in molecular pharmacology in the Department of Biochemistry, University of Montréal (1997-2001). During her career she was supported by different fellowships and awards including McGill Major Fellowships (Canada), Fogarty-NIH International Fellowship (USA) and Postdoctoral Fellowships from Medical Research Council of Canada and Heart and Stroke Foundation of Canada.

Today, she is head of a pharmacology laboratory with research focus on molecular determinants of analgesic efficacy of opioids, as well as cellular and molecular bases of analgesic tolerance. She has substantially contributed to the notion of biased signaling showing that delta opioid receptors adopt ligand-specific conformations with distinct signaling and trafficking properties. Insights from her research have provided the basis for the rational development of novel opioid analgesics with a reduced side effects profile.

Prof. Pineyro has authored 37 peer-reviewed publications, 7 book chapters and 100+ presentations, and holds 2 licensed patents.

As an independent investigator, she has received the New Investigator Award from Fond de Recherche en Santé du Québec and her research has been continuously funded by Canadian Institutes of Health Research and Natural Sciences and Engineering Research Council of Canada.

About The Author

Iness Charfi, MSc 

Iness Charfi received her Bachelor in Pharmacy in 2008 at Monastir University (Tunisia). In 2009, she joined Prof. Graciela Pineyro’s Lab as an MSc student in Neuropsychopharmacology at the Sainte-Justine Hospital Research Center, through the Department of Pharmacology, University of Montreal (Canada). After graduating in 2012, she started a PhD in the same laboratory. Throughout her training, she focused on the mechanistic understanding of the molecular basis of delta opioid receptor post-endocytic trafficking, in order to better understand the development of analgesic tolerance to opioids. Iness has been awarded a number of prizes and fellowships, including two presentation awards for best oral and poster presentations at scientific meetings. Her fellowship awards include a CHU Sainte-Justine and Fondation of Stars fellowship, a recruitment fellowship from the Department of Pharmacology, University of Montreal and a fellowship award from the FRSQ.

 

Journal Reference

Cell Mol Life Sci. 2015 Sep;72(18):3543-57.

Karim Nagi^1,2, Iness Charfi^1,2 and Graciela Pineyro^1,2,3

Show Affiliations

1. Sainte-Justine Hospital Research Center, Montreal, Quebec, H3T 1C5, Canada.
2. Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, H3T 1J4, Canada.
3. Department of Psychiatry, Faculty of Medicine, University of Montreal, Montreal, Quebec, H3T 1J4, Canada.

Abstract 

Kir3 channels control excitability in the nervous system and the heart. Their surface expression is strictly regulated but mechanisms responsible for channel removal from the membrane remain incompletely understood. Using transfected cells, we show that Kir3.1/3.2 channels and delta opioid receptors (DORs) associate in a complex which persists during receptor activation, behaving as a scaffold that allows beta-arrestin (βarr) to interact with both signaling partners. This organization favored co-internalization of DORs and Kir3 channels in a βarr-dependent manner via a clathrin/dynamin-mediated endocytic path. Taken together, these findings identify a new way of modulating Kir3 channel availability at the membrane and assign a putatively novel role for βarrs in regulating canonical effectors for G protein-coupled receptors.

Go To Cell Mol Life Sci

 

Global Medical Discovery features paper: RASGRF2 controls nuclear migration in postnatal retinal cone photoreceptors

Journal Reference

J Cell Sci. 2016 Feb 15;129(4):729-42. doi: 10.1242/jcs.180919. Epub 2016 Jan 7.

Jimeno D¹, Gómez C¹, Calzada N¹, de la Villa P², Lillo C³, Santos E⁴.

Show Affiliations

1. Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer (CSIC – Universidad de Salamanca), Salamanca 37007, Spain.
2. Departamento de Fisiología, Universidad Alcalá, Alcalá de Henares 28871, Spain, Spain.
3. INCYL, IBSAL (Universidad de Salamanca), Salamanca 37006, Spain.
4. Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer (CSIC – Universidad de Salamanca), Salamanca 37007, Spain esantos@usal.es. 

Abstract

Detailed immunocytochemical analyses comparing wild-type (WT), GRF1-knockout (KO), GRF2-KO and GRF1/2 double-knockout (DKO) mouse retinas uncovered the specific accumulation of misplaced, ‘ectopic’ cone photoreceptor nuclei in the photoreceptor segment (PS) area of retinas from GRF2-KO and GRF1/2-DKO, but not of WT or GRF1-KO mice. Localization of ectopic nuclei in the PS area of GRF2-depleted retinas occurred postnatally and peaked between postnatal day (P)11 and P15. Mechanistically, the generation of this phenotype involved disruption of the outer limiting membrane and intrusion into the PS layer by cone nuclei displaying significant perinuclear accumulation of signaling molecules known to participate in nuclear migration and cytoskeletal reorganization, such as PAR3, PAR6 and activated, phosphorylated forms of PAK, MLC2 and VASP. Electroretinographic recordings showed specific impairment of cone-mediated retinal function in GRF2-KO and GRF1/2-DKO retinas compared with WT controls. These data identify defective cone nuclear migration as a novel phenotype in mouse retinas lacking GRF2 and support a crucial role of GRF2 in control of the nuclear migration processes required for proper postnatal development and function of retinal cone photoreceptors.

© 2016. Published by The Company of Biologists Ltd.

Go To J Cell Sci

Global Medical Discovery features paper: Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells

Significance Statement

The mammalian olfactory bulb (OB), the first center of synaptic integration in the olfactory systems, receives massive cholinergic inputs from the basal forebrain and dense noradrenergic innervations from the locus coeruleus, both of which have profound effects on odor processing as well as olfactory learning and memory.  However, the effects of acetylcholine (ACh) and norepinephrine (NE) have not been clearly distinguished.  Given the important roles of cholinergic and noradrenergic modulation in the olfactory bulb, achieving clear functional dissociation among the roles of these two modulators is not trivial and is required for a mechanistic and integrated understanding of olfactory information processing in the brain.  Using detailed biophysical simulations of granule cells, the major interneurons in the olfactory bulb, both alone and embedded in a microcircuit with mitral cells (MCs), the principal output neurons of olfactory bulb, we demonstrated computationally for the first time that the effects of ACh and NE on olfactory bulb function are both distinct and functionally complementary to one another.  While ACh increases MC spike synchronization and sharpens MC firing rate representation, NE mainly modulates the neuronal signal-to-noise ratio (S/N) and can regulate cholinergic function.  Co-application of ACh and NE sharpens MC tuning, improves the S/N ratio and enhances spike synchronization among mitral cells.  Our main conclusions are that ACh is particularly important for odor discrimination and sensory information encoding via a spike-timing code, while NE is more important for odor detection.  Therefore, this work is significant in understanding the cholinergic and noradrenergic function in the olfactory bulb and offers important specific and testable hypotheses for future work.

Figure Legend: The effects of acetylcholine (ACh) and norepinephrine (NE) in the olfactory bulb are both distinct and complementary to each other.  ACh modulation increases mitral cell (MC) spike synchronization and sharpens odor representation by suppressing the weakly activated MCs.  By comparison, NE modulation increases the signal-to-noise (S/N) ratio by suppressing MC spontaneous activities.  Simultaneous activation of ACh and NE leads to highly synchronized MCs, large S/N ratio and highly tuned MC responses with little overlap between different odors.

 

About The Author

Dr. Guoshi Li is currently a postdoctoral research associate in the Department of Psychiatry at University of North Carolina at Chapel Hill.  His primary focus is to perform cutting edge computational neuroscience research.  He is currently working on two research projects: (1) Developing biophysically realistic models of the thalamocortical network to understand the cellular and circuit mechanisms underlying distinct states of oscillatory activities and how brain stimulation impacts the thalamocortical network dynamics; and (2) Extending an existing olfactory bulb network model (Li and Cleland, 2013) he developed previously to examine the dynamical mechanisms of external tufted cells in olfactory information processing.  His research in olfaction is funded by a NIH/NIDCD R03 grant.

Prior to joining the Frohlich lab at UNC, Dr. Li was a postdoctoral research associate in the Computational Physiology Lab at Cornell University directed by Dr. Thomas Cleland and Dr. Christiane Linster.  His postdoc research at Cornell focused on olfactory information processing in the olfactory bulb with a particular interest in cholinergic and noradrenergic neuromodulation and gamma oscillations.

Dr. Li obtained his PhD in Electrical Engineering from University of Missouri – Columbia in 2009 and MS in Mechanical Engineering from State University of New York at Buffalo in 2003.  His PhD research concentrated on understanding the neural mechanisms of fear learning and extinction using a computational modeling approach.  

About The Author

Dr. Christiane Linster is a professor in the Department of Neurobiology and Behavior at Cornell University.  Her research focuses on the neural basis of sensory information processing, using olfaction as a model system. She is primarily interested in the relationship between perceptual qualities, as measured by behavioral experiments, and neural activity patterns, as observed electrophysiologically.  Her present work concerns how the central nervous system neuromodulators acetylcholine and noradrenaline, both of which have been implicated in memory deficits such as those symptomatic of Alzheimer’s disease, influence the representation and storage of olfactory information.  This approach necessitates coordinated behavioral and electrophysiological experiments based on predictive theories.

About The Author

Dr. Thomas Cleland is an associate professor in the Department of Psychology at Cornell University.  His research concerns how complex cognitive and perceptual phenomena can arise from, and be regulated by, cellular and neural circuit properties. Primarily using the sense of smell (olfaction), Dr. Cleland investigates how learning, memory, expectation, and like processes shape the transformations performed on sensory inputs by relatively peripheral (i.e., experimentally accessible) cortical circuitry, and how these different transformations in turn influence behavior and subsequent learning.  He and his colleagues triangulate on these questions using a range of techniques including electrophysiology, pharmacology, behavior and behavior genetics, and biophysically constrained computational modeling.  In collaboration with colleagues in the College of Engineering, he also implemented circuit models of olfactory processing in neuromorphic digital chips.

Journal Reference

J Neurophysiol. 2015 Dec;114(6):3177-200.

Li G¹, Linster C², Cleland TA³. 

Show Affiliations

1. Department of Psychology, Cornell University, Ithaca, New York; guoshi_li@med.unc.edu.
2. Department of Neurobiology and Behavior, Cornell University, Ithaca, New York.
3. Department of Psychology, Cornell University, Ithaca, New York; 

Abstract

Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed  biophysical  simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function.  Cholinergic  and  noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. We report that the effects of ACh and NE on granule cell physiology are distinct and functionally complementary to one another. ACh strongly regulates granule cell firing rates and after potentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of after depolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication of ACh and NE both functionally improved the signal-to-noise ratio and enhanced spike synchronization among mitral cells. In summary, our computational results support distinct and complementary roles for ACh and NE in modulating olfactory bulb circuitry and suggest that NE may play a role in the regulation of cholinergic function.

Copyright © 2015 the American Physiological Society.

Go To J Neurophysiol.

 

Global Medical Discovery features paper: Surface nitridation improves bone cell response to melt-derived bioactive silicate/borosilicate glass composite scaffolds

Significance Statement

Biomaterials have long been used in the orthopaedic surgery to guide and assist bone repair. Nowadays, they also have the potential of being used as substrates for bone tissue engineering. Bioglasses like 45S5 present optimal bioactivity, but when sinterized into 3D monoliths they crystallize and partly loose their properties, mainly in vivo absorb ability. We have developed a novel bioglass, called ICIE16/BSG-NITRI, that not only overcomes this limitation but also displays improved reactivity and biocompatibility due to surface nitridation. ICIE16/SBG-NITRI was synthesized from a mixture of two melt-derived glasses through combined gel casting and foam replication techniques, followed by nitridation. It is highly porous but mechanically stable and mimics the architecture of bone tissue. Nitridation confers it improved reactivity and bioactivity facilitating its resorption and deposition of apatite (bone-like mineral) at its surface. The nitrided surface also improved its interaction with bone cells, which were found to attach better to ICIE16/SBG-NITRI and to differentiate earlier on its surface.

Figure legend: bone on the left and our ICIE16/BSG-Nitru bioglass on the right (in both cases bar is 500 µm).

Figure legend: merge of visible and fluorescent-blue channels to show cell distribution on the bioglass surface. The hoechst-stained nuclei can be seen as blue dots.

About The Author

Felipe Orgaz, Ph. D.

Felipe Orgaz is a tenured researcher at the Glass and Ceramic Research Institute (Madrid, Spain). He obtained his Ph. D. from the University of Madrid on strengthening glasses by ion exchange, and then conducted his post-doctoral studies at Sheffield University (UK) on sol-gel process. He joined the Spanish company Explosivos Río Tinto, and then Encros as Head of the Department of Ceramic Technology, conducting projects on structural ceramics for aerospace applications. He has also worked for the Spanish Ministry of Science and Technology evaluating technology transfer activities. He has conducted research on glasses and coatings from sol-gel process, nano-structured materials, dynamic fracture of advanced materials, transparent ceramics for armors, mechanical behavior of silicon nitride structural ceramics, TiO2 catalysts, and ion-densified ceramic foams and materials. His current research is focused on surface nitridation and its effects on the interface of the materials with living tissues, including protein adsorption and cell response. He has authored 10 international patents and more than 55 articles, in national and international journals and conference proceedings. He has also been part of several technical committees of the International Commission on Glass (ICG). He has been member of the steering committee of Fundación Círculo para la Defensa y la Seguridad, he has been member of the editorial board of the Bulletin of the Spanish Society of Ceramics and Glass, and of the Journal of Sol-Gel Science and Technology. He is currently the president of the Education and Innovation Area of the Spanish Society of Glass and Ceramic.

About The Author

Leonor Santos-Ruiz, Ph. D.

Leonor Santos-Ruiz is a Senior Researcher at the Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN, Spain), and part-time associate professor at the Faculty of Sciences of the University of Málaga (Spain). She earned her PhD degree in Regenerative Biology in 2001, from the University of Málaga, and completed her post-doctoral fellowship at the Advanced Biotechnology Centre (Genoa, Italy) and the Institute for Child Health (ICH-UCL; London, UK). Her research is focused on bone repair and seeks the application of regenerative biology principles to develop tissue engineering products that stimulate bone regeneration, particularly in individuals where bone endogenous natural repair is hampered due to age or disease. She is interested in conditions like osteoporosis, osteonecrosis and skeletal dysplasias, particularly craniosynostosis, and her work includes the use of adult and perinatal stem cells for stem cell therapy, and the development and evaluation of novel biomaterials to be used as cell carriers and/or drug deliverers. She is the author of 2 international patents and more than thirty articles in international journals and conference proceedings.

Journal Reference

Acta Biomater. 2016;29:424-34.

Orgaz F¹, Dzika A¹, Szycht O¹, Amat D^2,3, Barba F¹, Becerra J^3,4,5, Santos-Ruiz L^3,4,5.

Show Affiliations

¹ Instituto de Cerámica y Vidrio, Consejo Superior de Investigaciones Científicas (ICV-CSIC), c/ Kelsen n° 5, 28049 Madrid, Spain

² Universidad de Málaga, Departamento de Anatomía y Medicina Legal, Facultad de Medicina, Campus de Teatinos, 29071 Málaga, Spain

³ Centro de Investigación Biomédica en Red. Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, c/ Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029 Madrid, Spain

⁴ Universidad de Málaga & IBIMA, Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Campus de Teatinos, 29071 Málaga, Spain

⁵ BIONAND-Universidad de Málaga, c/ Severo Ochoa 35, Campanillas, 29590 Málaga, Spain 

Abstract

Novel bioactive amorphous glass-glass composite scaffolds (ICIE16/BSG) with interconnected porosity have been developed. Hierarchically interconnected porous glass scaffolds were prepared from a mixture of two melt-derived glasses: a ICIE16 bioactive glass that was previously developed by Wu et al. (2011) to prevent crystallization, and a borosilicate glass of composition 73.48 SiO2-11.35 B2O3-15.15 Na2O (wt%). The resulting melt derived glass-glass composite scaffolds (ICIE16/BSG) were subject to surface functionalization to further improve its interaction with biological systems. Surface  functionalization was performed by a nitridation process with hot gas N2/ammonia at 550°C for 2h, obtaining the ICIE16/BSG-NITRI. Evaluation of the degradation rate and the conversion to hydroxyapatite after immersion in simulated body fluid predicted a good biological activity of all the scaffolds, but particularly of the nitrided ones. In vitro evaluation of osteoblastic cells cultured onto the nitrided and non-nitrided scaffolds showed cell attachment, proliferation and differentiation on all scaffolds, but both proliferation and differentiation were improved in the nitrided ICIE16/BSG-NITRI.

STATEMENT OF SIGNIFICANCE:

Biomaterials are often required in the clinic to stimulate bone repair. We have developed a novel bioglass (ICIE16/SBG-NITRI) that can be sintered into highly porous 3D scaffolds, and we have further improved its bioactivity by nitridation. ICIE16/SBG-NITRI was synthesized from a mixture of two melt-derived glasses through combined gel casting and foam replication techniques, followed by nitridation. To mimic bone, it presents high-interconnected porosity while being mechanically stable.  Nitridation improved its reactivity and bioactivity facilitating its resorption and the deposition of apatite (bone-like mineral) on its surface and increasing its degradation rate. The nitrided surface also improved the bioglass’ interaction with bone cells, which were found to attach better to ICIE16/SBG-NITRI and to differentiate earlier on its surface.

Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Go To Acta Biomater

 

Global Medical Discovery features paper: Controlling the mechanical behavior of dual-material 3D printed meta-materials for patient-specific tissue-mimicking phantoms

Significance Statement

Mimicking the dynamic mechanical properties of the human aorta in 3D printed models is challenging because of the inherent difference between mechanical behaviors of polymeric materials and human tissues (Fig. A). We sought to print the aortic root using materials which achieved the strain-stiffening behavior of the human aortic tissues using commercial polymer printing materials. The mechanical behavior of aortic tissue is mimicked by a 3D printed meta-material, in which sinusoidal wave-shaped stiff fibers were embedded in a soft polymeric matrix (Fig. B). The wavelength, amplitude, and fiber diameter of the embedded sinusoidal fiber were tuned to study the meta-material’s stress-strain relationship. Then, fibers of ideal configurations were embedded in a 3D printed aortic root phantom (Fig. D). The designed meta-material demonstrated strain-stiffening behavior similar to the human aortic tissues. The stress-strain curve of the meta-materials was controlled by the design of the embedded fibers (Fig. C). As a follow-up to the study in this paper, a CoreValve prosthesis was deployed to simulate TAVR. The model was connected to a flow loop, and CMR images were acquired to visualize the in-vitro anatomy, and characterize and quantify the flow velocity field (Fig. E). 3D printed tissue-mimicking aortic root may enable predictions of post-TAVR root strain and distribution and aortic flow pattern, for pre-TAVR planning.

About The Author

Kan Wang received the B.S. degree in Theoretical and Applied Mechanics from Peking University, Beijing, China, in 2005, the M.S. degree in Aircraft Design from Beihang University, Beijing, China, in 2007, and the Ph.D. degree in Industrial and Manufacturing Engineering from Florida State University, Tallahassee, USA in 2013. Currently, he is a post-doctoral fellow at the H. Milton Stewart School of Industrial and Systems Engineering and Georgia Tech Manufacturing Institute, Georgia Institute of Technology, Atlanta, USA. His research interest include nanomanufacturing, additive manufacturing, printed electronics technologies and their applications in smart materials and biomedical devices.

Journal Reference

Materials & Design, Volume 90, 15 January 2016, Pages 704–712.

Kan Wang^1,2 , Yuanshuo Zhao¹ , Yung-Hang Chang^1,2, ,Zhen Qian⁴, Chuck Zhang^1,2 , Ben Wang^1,2,3, Mani A. Vannan⁴, Mao-Jiun Wang⁵

Show Affiliations

1. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
2. Georgia Tech Manufacturing Institute, Georgia Institute of Technology, Atlanta, GA 30332, USA
3. School of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
4. Department of Cardiovascular Imaging, Piedmont Heart Institute, 95 Collier Road, Atlanta, GA 30309, USA
5. Department of Industrial Engineering and Engineering Management, National Tsing-Hua University, Hsinchu, Taiwan

Abstract

Patient-specific tissue-mimicking phantoms are becoming available with the advent of additive manufacturing. Phantoms currently in use are focused on the geometrical accuracy and mechanical properties under small deformation. Mimicking the mechanical properties at large deformation is challenging because of the inherent difference between the mechanical behaviors of polymeric materials and that of human tissues. In this study, the mechanical behavior of soft tissues under a uniaxial tension is mimicked by dual-material 3D printed meta-materials with stiff micro-structured fibers embedded in a soft polymeric matrix. Although the two base materials are strain-softening polymers, some of the designed meta-materials demonstrate certain degree of strain-stiffening behavior. Further investigation shows how the stress–strain curve of the meta-materials can be controlled by the design parameters. Sensitivity analysis is used to study the effects of each parameter. General design guidelines are proposed based on the results of the experiments. Dual-material 3D printed meta-materials have great potential in fabricating patient-specific phantoms with accurate mechanical properties that are associated with the gender, age, ethnicity, and other physiological/pathological characteristics. Mechanically accurate phantoms can play an important role in a variety of biomedical applications, including validation of computational models, testing of medical devices, surgery planning, medical education and training, and doctor-patient interaction.

Go To Materials & Design

 

Global Medical Discovery features paper: Establishment and characterization of a novel VEGF-producing HHV-8-unrelated PEL-like lymphoma cell line, OGU1

Significance Statement

Under immunocompromised conditions such as human immunodeficiency virus (HIV) infection, human herpesvirus-8 (HHV-8) is associated with the development extracavitary large B-cell lymphoma, a condition known as primary effusion lymphoma (PEL). Recently, body cavity-based lymphomas have emerged that resemble PEL, but are not associated with HHV-8 and develop in the absence of HIV infection; these have been termed HHV-8-unrelated PEL-like lymphoma. HHV-8-unrelated PEL-like lymphomas show distinct features from PEL, including expression of pan-B cell markers, frequent occurrence in elderly patients, and a more favorable response to therapy. However, this type of lymphoma also shows some heterogeneity with respect to its clinical manifestation, and its pathophysiology is largely unknown. To elucidate the oncogenetic mechanism of this type of lymphoma, we established and characterized a novel cell line, named OGU1, from a patient with HHV-8-unrelated PEL-like lymphoma with ascites development.

OGU1 cells expressed CD20 and CD19 pan-B cell markers and revealed a rearrangement of the immunoglobulin heavy chain gene identical to the parental tumor cells. HHV-8 mRNA and its encoded product LANA-1 were not detected in either OGU1 cells or the parental tumors, which is compatible with the typical features of HHV-8-unrelated PEL-like lymphoma. Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of a variety of tumors, including hematologic malignancies, and has been reported as a useful marker for predicting the prognosis of non-Hodgkin’s lymphomas. We found that the OGU1 cells produced abundant VEGF and expressed VEGF receptor-1 at both the mRNA and protein levels. Intriguingly, monoclonal antibodies against VEGF or inhibitors for the VEGF receptor caused growth retardation of the cells, indicating that VEGF, at least in part, promotes the proliferation or survival of OGU1 cells thorough an autocrine mechanism. Furthermore, we found activation of tyrosine kinases (Src and Lyn), PKCa, and S6K1 signaling molecules, and high expression levels of miRNAs such as the miR-17-92 cluster, suggesting a role of these molecules in the lymphomagenesis of the cells. OGU1 cells may be a useful model for investigating the tumor biology of this unique type of lymphoma.  

FigureLegend: OGU1 cells were negative for HHV-8 (immunostaining with anti-HHV-8 antibody, left panel).

VEGF mRNA expression in OGU1 cell line was detected by RT-PCR (right panel). Arrow indicates VEGF mRNA. S; sample (OGU1), PC; positive control, NC; normal control, MQ; Milli-Q, M; size marker.

About The Author

Kiyotaka Kawauchi completed his residency in internal medicine at Tokyo Women’s Medical University Daini Hospital, and then proceeded to a specialty in hematology and oncology. He received a Ph.D in medicine from Tokyo Women’s Medical University in 1988, in which he studied the mechanism of interferon-induced human natural killer cell activation. He also conducted research on B-cell antigen receptor signaling at the Best Institute of the University of Toronto in Canada from 1991 to 1994 as a postdoctoral fellow. He obtained the position of Associate professor at Tokyo Women’s Medical University Medical Center East in 1999. He is now a director of the Nishiogu Clinic. He also serves as a councilor of the Japanese Society of Hematology and is a member of the editorial board of Case Reports in Hematology.  

Journal Reference

Eur J Haematol. 2016 Feb;96(2):144-51.

Kawauchi K^1,2, Ogasawara T¹, Aiba M³, Fujibayashi M³, Sanaka T⁴, Sakura H¹, Shibuya M^5,6.

Show Affiliations

1. Medical Center East, Department of Medicine, Tokyo Women’s Medical University, Tokyo, Japan.
2. Nishiogu Clinic, Tokyo, Japan.
3. Medical Center East, Department of Surgical Pathology, Tokyo Women’s Medical University, Tokyo, Japan.
4. Center of CKD and Lifestyle Related Diseases, Edogawa Hospital, Ichikawa city, Japan.
5. Institute of Physiology and Medicine, Jobu University, Takasaki, Japan.
6. Institute of Medical Science, University of Tokyo, Tokyo, Japan. 

Abstract

Primary effusion lymphoma (PEL) is a rare B-cell lymphoma subtype that is characterized by lymphomatous effusion without the presence of masses, and it typically occurs in human immunodeficiency virus (HIV)-infected individuals. Lymphoma cells are universally positive for human herpesvirus 8 (HHV-8). Recently, a cavity-based effusion lymphoma that is similar to PEL without HHV-8 infection, called HHV-8-unrelated PEL-like lymphoma, has been reported in non-HIV-infected individuals. However, the pathophysiology of this lymphoma is largely undefined. We established a novel B-cell line OGU1 derived from a patient with HHV-8-unrelated PEL-like lymphoma. Notably, OGU1 cells produced vascular endothelial growth factor (VEGF) and expressed VEGF receptor 1, whose inhibitors retarded cell growth. Because VEGF acts as a vascular permeability and growth factor, it could play a role, at least in part, in the pathogenesis of this unique lymphoma. Thus, the OGU1 cell line is useful for the investigation of HHV-8-unrelated PEL-like lymphoma.

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Go To Eur J Haematol