Improving Deep Brain Stimulation Electrode Performance in vivo Through Use of Conductive Hydrogel Coatings

Active implantable neurological devices like deep brain stimulators have been used over the past few decades to treat movement disorders such as those in people with Parkinson’s disease and more recently, in psychiatric conditions like obsessive compulsive disorder. Electrode-tissue interfaces that support safe and effective targeting of specific brain regions are critical to success of these devices. Development of directional electrodes that activate smaller volumes of brain tissue requires electrodes to operate safely with higher charge densities. Coatings such as conductive hydrogels (CHs) provide lower impedances and higher charge injection limits (CILs) than standard platinum electrodes and support safer application of smaller electrode sizes. The aim of this study was to examine the chronic in vivo performance of a new low swelling CH coating that supports higher safe charge densities than traditional platinum electrodes. A range of hydrogel blends were engineered and their swelling and electrical performance compared. Electrochemical performance and stability of high and low swelling formulations were compared during insertion into a model brain in vitro and the formulation with lower swelling characteristics was chosen for the in vivo study. CH-coated or uncoated Pt electrode arrays were implanted into the brains of 14 rats, and their electrochemical performance was tested weekly for 8 weeks. Tissue response and neural survival was assessed histologically following electrode array removal. CH coating resulted in significantly lower voltage transient impedance, higher CIL, lower electrochemical impedance spectroscopy, and higher charge storage capacity compared to uncoated Pt electrodes in vivo, and this advantage was maintained over the 8-week implantation. There was no significant difference in evoked potential thresholds, signal-to-noise ratio, tissue response or neural survival between CH-coated and uncoated Pt groups. The significant electrochemical advantage and stability of CH coating in the brain supports the suitability of this coating technology for future development of smaller, higher fidelity electrode arrays with higher charge density requirement

Superconductivity in a new layered triangular-lattice system Li2IrSi2

We report on the crystal structure and superconducting properties of a novel iridium-silicide, namely Li2IrSi2. It has a Ag2NiO2-type structure (space group R-3m) with the lattice parameters a = 4.028 30(6) Å and c = 13.161 80(15) Å. The crystal structure comprises IrSi2 and double Li layers stacked alternately along the c-axis. The IrSi2 layer includes a two-dimensional Ir equilateral-triangular lattice. Electrical resistivity and static magnetic measurements revealed that Li2IrSi2 is a type-II superconductor with critical temperature (Tc) of 3.3 K. We estimated the following superconducting parameters: lower critical field Hc1(0) ~ 42 Oe, upper critical field Hc2(0) ~ 1.7 kOe, penetration depth λ0 ~ 265 nm, coherence length ξ0 ~ 44 nm, and Ginzburg–Landau parameter κGL ~ 6.02. The specific-heat data suggested that superconductivity in Li2IrSi2 could be attributed to weak-coupling Cooper pairs

Anti-inflammatory Effects of Abdominal Vagus Nerve Stimulation on Experimental Intestinal Inflammation

Electrical stimulation of the cervical vagus nerve is an emerging treatment for inflammatory bowel disease (IBD). However, side effects from cervical vagal nerve stimulation (VNS) are often reported by patients. Here we hypothesized that stimulating the vagus nerve closer to the end organ will have fewer off-target effects and will effectively reduce intestinal inflammation. Specifically, we aimed to: (i) compare off-target effects during abdominal and cervical VNS; (ii) verify that VNS levels were suprathreshold; and (iii) determine whether abdominal VNS reduces chemically-induced intestinal inflammation in rats. An electrode array was developed in-house to stimulate and record vagal neural responses. In a non-recovery experiment, stimulation-induced off-target effects were measured by implanting the cervical and abdominal vagus nerves of anaesthetized rats (n = 5) and recording changes to heart rate, respiration and blood pressure during stimulation (10 Hz; symmetric biphasic current pulse; 320 nC per phase). In a chronic experiment, the efficacy of VNS treatment was assessed by implanting an electrode array onto the abdominal vagus nerve and recording in vivo electrically-evoked neural responses during the implantation period. After 14 days, the intestine was inflamed with TNBS (2.5% 2,4,6-trinitrobenzene sulphonic acid) and rats received therapeutic VNS (n = 7; 10 Hz; 320 nC per phase; 3 h/day) or no stimulation (n = 8) for 4.5 days. Stool quality, plasma C-reactive protein and histology of the inflamed intestine were assessed. Data show that abdominal VNS had no effect (two-way RM-ANOVA: P ≥ 0.05) on cardiac, respiratory and blood pressure parameters. However, during cervical VNS heart rate decreased by 31 ± 9 beats/minute (P ≥ 0.05), respiration was inhibited and blood pressure decreased. Data addressing efficacy of VNS treatment show that electrically-evoked neural response thresholds remained stable (one-way RM ANOVA: P ≥ 0.05) and therapeutic stimulation remained above threshold. Chronically stimulated rats, compared to unstimulated rats, had improved stool quality (two-way RM ANOVA: P < 0.0001), no blood in feces (P < 0.0001), reduced plasma C-reactive protein (two-way RM ANOVA: P < 0.05) and a reduction in resident inflammatory cell populations within the intestine (Kruskal–Wallis: P < 0.05). In conclusion, abdominal VNS did not evoke off-target effects, is an effective treatment of TNBS-induced inflammation, and may be an effective treatment of IBD in humans

Innervation of peripheral and central auditory tissues by human embryonic stem cell-derived neurons in vitro

© 2017 Dr Tomoko HyakumuraThe loss of auditory neurons that occurs with profound hearing loss is irreversible in humans. Stem cell therapy for auditory neuron replacement thereby offers potential for hearing restoration in patients with profound deafness. This project aims to investigate and quantify the formation of new synapses between human embryonic stem cell-derived neurons and target peripheral and central auditory tissues in vitro. Sensory neuron-like cells were generated from human embryonic stem cells over 21 days in vitro and then co-cultured with developing sensory hair cells or cochlear nucleus slices for a further 2 weeks. Synapse formation was examined using four-channel immunofluorescence and confocal microscopy, and analysed using ImageJ software. Sites of apparent contact between stem cell-derived neurons and target auditory tissues were compared to synapses in the developing mammalian peripheral and central auditory tissues. Stem cell-derived neurons expressed synapsin 1 and vesicular glutamate transporter-1 at sites of innervation with both hair cells and cochlear nucleus neurons. This observation is consistent with results obtained from control co-cultures using early postnatal auditory neurons and auditory tissues. Significantly more synaptic contacts were observed in stem cell co-cultures in comparison to control co-cultures (P <0.05). Moreover, potential synapses from stem cell-derived neurons corresponded anatomically with early synaptogenesis in the developing mammalian auditory system in vivo. This assay describes the characterisation, timing and quantification of potential synaptic connections both by stem cell-derived neurons in vitro and in the developing mammalian auditory system

Assessment of the immunogenicity of biochemically modified hepatitis B virus-like particles and their ability to deliver a medically relevant HIV-1 antigenic sequence

The hepatitis B virus (HBV) is one of the most significant human viruses. Approximately 2 billion people worldwide have been infected with HBV and more than 240 million people are chronically infected (WHO, 2016a). The current preventative HBV vaccine consists of virus-like particles (VLPs) assembled from the small HBV surface antigen (HBsAg-S) embedded in a phospholipid membrane. Approximately 10% of the population are non-responsive to the HBV vaccine, and the development of a HBV vaccine with enhanced immunogenicity for the non-responsive population is needed. Also, for the development of immunogens suitable for therapeutic applications, VLPs with enhanced immunogenicity are required.<br> <br> The ability of the VLPs to serve as potent immunogens against not only the parent virus but also against inserted foreign antigenic sequences has allowed the development of HBsAg-S VLP platforms capable of inducing immune responses against the malaria parasite, bacterial pathogens, and other viruses. Approximately 37 million people worldwide are infected with HIV-1 (WHO, 2016b), which results in the acquired immunodeficiency syndrome (AIDS) if infection is not treated. Where antiviral drug treatment is available and affordable, infection with HIV-1 is now considered to be a chronic but manageable condition. However, this is no substitute for prevention, and treatment remains inaccessible to many people in developing countries. The use of vaccines remains the most effective strategy to eliminate infectious diseases.<br> <br>The membrane-proximal external region (MPER) of the HIV-1 envelope protein gp41 is targeted by broadly neutralising antibodies. However, the development of an efficient vaccine to induce neutralising anti-MPER antibodies has not yet been accomplished due in part to the requirement that the MPER epitope be presented in close proximity to a phospholipid membrane. As such, HBsAg-S VLPs may represent a suitable scaffold for the presentation of the MPER in a phospholipid membrane-proximal context for the generation of anti-HIV antibodies. <br><br> In order to enhance the immunogenicity of HBV VLPs, the glycan abundance was modulated and enhanced to promote interactions with immune competent cells. Antigenic profiling of hypo- and hyperglycosylated HBsAg-S VLPs revealed that inducing significant differences in the abundance of N-glycans was not detrimental to the formation and structure of HBsAg-S VLPs. Hyperglycosylated VLPs were found to enhance the humoral immune response in an animal model, with an HBsAg-S T116N mutant inducing a significantly earlier and longer lasting antibody response.<br><br> To create VLPs capable of stimulating an anti-HIV antibody response, chimeric HBsAg- S VLPs with an inserted HIV-1 MPER sequence were constructed. To enhance VLP immunogenicity, the glycosylation patterns and disulphide bonds within the chimeric HBsAg-S-MPER subunits were modulated. Analysis of HBsAg-S-MPER VLP antigenicity using anti-HBsAg-S and anti-MPER antibodies revealed that inserting the MPER in a membrane-proximal location possibly allowed its presentation in a closer-to-native conformation compared to MPER peptides.<br> <br> Immunisations in animal models revealed that HBsAg-S-MPER VLPs are capable of inducing MPER-specific antibodies. Changing the disulfide bonding or glycosylation status did not modify MPER exposure, but hyperglycosylation improved the humoral immune response generated by HBsAg-S-MPER VLPs. Importantly, the presence of a glycan at the N3 position adjacent to the inserted MPER sequence was found to both improve the overall immunogenicity of the VLPs and was critical for the stimulation of an effective anti-MPER antibody response. These antibodies were capable of binding to HIV-1 envelope protein complexes expressed on cellular surfaces, but neutralisation of HIV-1 entry was not observed, most likely as a result of an insufficiently raised anti- MPER antibody titre (approximately 1:1,000).<br> <br> These results demonstrate that HBsAg-S VLPs are a suitable platform for the insertion of the HIV-1 MPER epitope and that biochemical modifications can impact on the immunogenicity of VLPs and their inserted sequences. The finding that hyperglycosylation can both enhance the overall immunogenicity of HBsAg-S VLPs and facilitate the development of humoral immune responses directed toward specific epitopes has significant implications for the development of a more effective HBV vaccine and for the general use of HBsAg-S VLPs as a platform for foreign epitopes.<br> <br> The chimeric VLPs developed in this study demonstrate that biochemical modifications such as glycosylation alter immunogenicity. This represents an important step toward the design of immunogens with a potentially therapeutic capability. These outcomes demonstrate that HBsAg-S VLPs can be produced with a MPER-specific immunogenicity while presenting the MPER sequence in proximity to a lipid environment. Further assessments of different HBsAg-S-MPER VLP formulations in the presence of adjuvant will be required for the development of a preventative HIV-1 vaccine

Forestland Concession, Land Rights, and Livelihood Changes of Ethnic Minorities: The Case of the Madhupur Sal Forest, Bangladesh

Forestland concession has been the dominant governance tool for the acquisition of natural state-owned forest resources in many tropical countries, including Bangladesh. Moreover, the forestland concession process confers the holder a bundle of rights. The Sal forests of Bangladesh are treated as some of the greatest concession forests, as a number of ethnic minorities use these forests for their daily living. Therefore, the objectives of the study were to assess the impacts of Sal forestland concession and land rights on the livelihood development of the ethnic minorities living in the Madhupur Sal Forest (MSF) area of Bangladesh. Using both qualitative and quantitative data collection techniques, the study found out that about two thirds of the original Sal forestland was grabbed by the state and non-state actors. As a result, the ethnic minority inhabitants have lost their traditional land and free access rights to the Sal forests. The process of losing ethnic minorities&#8217; land and forest access rights has been enhanced by the institutional arrangements of the state, which had also created severe conflicts between the Forest Department and the ethnic communities. The study also revealed that the forestland concession has negatively affected the five livelihood capitals development of the ethnic minorities, consequently, their forest-based livelihood has shifted to non-securing jobs or poor income sources, like daily wage labor and subsistence agriculture. Despite this, the development drivers have emphasized the Sal forests and biodiversity conservation, while the livelihood development of the ethnic minorities has been ignored from every level. Therefore, this study would recommend establishing a legitimate process in order to settle the issue of traditional land and the forest rights of ethnic minorities, which could also attain the conservation and development goals of the Sal forests

Forestland Grabbing by the Foreigners in Hokkaido, Japan: Is It a Big Concern for Sustainable Forest Development?

A world-wide demand in large-scale land acquisition over the past decade has been discussed as a land grab for access to natural resources. Forestland grab is the dynamics of land use changes by the foreign or national entities that can enable forests and biodiversity transformations on a wider scale. In recent times, forestland grabbing performed by foreigners in the Hokkaido Island of Japan has been increasing and causing a lot of debate. Therefore, this study analyzed the social, economic, and ecological impacts of forestland grabbing by the foreigners in the Hokkaido Island of Japan, and also analyzed the land ownership rules and regulations of Japan that have an impact on the land-grabbing process. This study is formed by an analysis of public and forestry agency documents, grey and academic literatures, interview with questionnaire and practical observation in central Hokkaido, Japan. The study found out that the forestland grabs have been taking place on the Hokkaido Island using the existing Japanese policy and legal arrangements. However, some people and print media have disagreed with the treatment of forestlands as a commodity because the land and water resources are limited and also essential for the national sovereignty and local culture. On the other hand, the small-scale forestland grabbing and development activities by foreigners were totally in the grip of the local government and no significant forest and biodiversity losses have been identified so far. The study also revealed that the entry of foreign companies has augmented the local economy and tourism industries and also provided jobs for the local people. Therefore, the foreigners-based land grabs and investments have caused an immense debate, and the study would recommend the proper execution of conservation regulations at every level instead of blocking the entry of foreign entities through law

Agroforestry, Livelihood and Biodiversity Nexus: The Case of Madhupur Tract, Bangladesh

Agroforestry has long been considered one of the most important land-use practices for conserving species while also meeting the fundamental requirements of millions of poor people in developing countries. Thus, the objective of the study was to determine the impacts of agroforestry practices on the livelihood development of rural farmers and biodiversity conservation potency in the Madhupur tract, Bangladesh. The study was conducted in the Madhupur tract, a famous agroforestry region in Bangladesh, using a mix-method approach to data collection, such as face-to-face interviews of 100 agroforestry farmers for livelihood analysis and using sampling techniques across 50 quadrats (20 m × 20 m) for measuring biodiversity. The results showed that the agroforestry practices significantly increased farm income and provided more benefits to rural farmers. Agroforestry farmers were able to build a social platform while simultaneously increasing their capability through training programs. As a result, the development of agroforestry farmers’ livelihood capital was significant. At the same time, the agroforestry practices introduced 34 plant species into the bare forestland and, therefore, provided higher-quality habitats for biodiversity conservation. The fast-growing tree species, mainly Acacia (diversity index of 0.366), in association with partial shade-loving crops such as pineapple, turmeric, and ginger, were the most dominant species in the agroforestry practices of the Madhupur tract. The study also revealed that agroforestry serves as a wildlife corridor and attracts birds for feeding and breeding. Finally, the agroforestry of the Madhupur tract is a viable land-use practice for biodiversity conservation and livelihood development of rural farmers in Bangladesh, and it is highly suggested that it be strengthened and disseminated