Antimicrobial Resistance (AMR) and Multidrug Resistance (MDR): Overview of Current Approaches, Consortia and Intellectual Property Issues

The supply of new diagnostics and treatments is insufficient to keep up with the increase in antimicrobial resistance (AMR) and multidrug resistance (MDR) as older medicines are used more widely and microbes develop resistance to them. At the same time, significant quantities of antibiotics are used on patients and animals that do not need them, while others who do need them lack access. Effective responses to AMR/MDR require effort by both the public and private sectors to develop and disseminate new diagnostics, vaccines and treatments on a global scale, as well as to adapt them to local needs. This calls for good governance to identify priorities, raise awareness and ensure effective stewardship at global, regional and national levels to minimize the development of resistance. Failure to act appropriately in one country will adversely impact all countries as resistance travels fast. Based on a review of recent literature, this WIPO Global Challenges Report includes a broad overview of current approaches and consortia designed to meet the challenge of research and development (R&D) investment for new treatments. It also examines patent applications by both the public and the private sectors as an indicator of innovative activity. This report finds that there is a need to address the unique market challenges and specific uncertainties associated with the development of new diagnostics and treatments, where current approaches are not optimal. An effective global framework that achieves the necessary political support while ensuring effective local implementation is crucial. There is an opportunity to complement this work by formulating mechanisms that drive innovation for results to incentivize success, while feeding expertise and experience into stewardship and access efforts. Intellectual property (IP) could be used in a constructive manner as one element in any reward or prize system for AMR/MDR R&D – both in terms of providing an incentive and governance

Terguride stimulates locomotor activity at 2 months but not 10 months after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets

The mixed dopamine (DA) agonist/antagonist terguride acts as a DA antagonist on normosensitive receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinson's disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmosets with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Terguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced behavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguride has anti-akinetic efficacy in this primate model of Parkinson's disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species

The percutaneous absorption of soman in a damaged skin porcine model and the evaluation of WoundStat™ as a topical decontaminant

PURPOSE: The aim of this study was to evaluate a candidate haemostat (WoundStat™), down-selected from previous in vitro studies, for efficacy as a potential skin decontaminant against the chemical warfare agent pinacoyl methylfluorophosphonate (Soman, GD) using an in vivo pig model. MATERIALS AND METHODS: An area of approximately 3 cm2 was dermatomed from the dorsal ear skin to a nominal depth of 100 µm. A discrete droplet of 14C-GD (300 µg kg-1) was applied directly onto the surface of the damaged skin at the centre of the dosing site. Animals assigned to the treatment group were given a 2 g application of WoundStat™ 30 s after GD challenge. The decontamination efficacy of WoundStat™ against GD was measured by the direct quantification of the distribution of 14C-GD, as well as routine determination of whole blood cholinesterase and physiological measurements. RESULTS: WoundStat™ sequestered approximately 70% of the applied 14C-GD. Internal radiolabel recovery from treated animals was approximately 1% of the initially applied dose. Whole blood cholinesterase levels decreased to less than 10% of the original value by 15 min post WoundStat™ treatment and gradually decreased until the onset of apnoea or until euthanasia. All treated animals showed signs of GD intoxication that could be grouped into early (mastication, fasciculations and tremor), intermediate (miosis, salivation and nasal secretions) and late onset (lacrimation, body spasm and apnoea) effects. Two of the six WoundStat™ treated animals survived the study duration. CONCLUSIONS: The current study has shown that the use of WoundStat™ as a decontaminant on damaged pig ear skin was unable to fully protect against GD toxicity. Importantly, the findings indicate that the use of WoundStat™ in GD contaminated wounds would not exacerbate GD toxicity. These data suggest that absorbent haemostatic products may offer some limited functionality as wound decontaminants.Peer reviewedFinal Accepted Versio

Altered muscarinic and nicotinic receptor densities in cortical and subcortical brain regions in Parkinson's disease

Muscarinic and nicotinic cholinergic receptors and choline acetyltransferase activity were studied in postmortem brain tissue from patients with histopathologically confirmed Parkinson's disease and matched control subjects. Using washed membrane homogenates from the frontal cortex, hippocampus, caudate nucleus, and putamen, saturation analysis of specific receptor binding was performed for the total number of muscarinic receptors with [3H]quinuclidinyl benzilate, for muscarinic M1 receptors with [3H]pirenzepine, for muscarinic M2 receptors with [3H]oxotremorine-M, and for nicotinic receptors with (-)-[3H]nicotine. In comparison with control tissues, choline acetyl-transferase activity was reduced in the frontal cortex and hippocampus and unchanged in the caudate nucleus and putamen of parkinsonian patients. In Parkinson's disease the maximal binding site density for [3H]quinuclidinyl benzilate was increased in the frontal cortex and unaltered in the hippocampus, caudate nucleus, and putamen. Specific [3H]pirenzepine binding was increased in the frontal cortex, unaltered in the hippocampus, and decreased in the caudate nucleus and putamen. In parkinsonian patients Bmax values for specific [3H]oxotremorine-M binding were reduced in the cortex and unchanged in the hippocampus and striatum compared with controls. Maximal (-)-[3H]nicotine binding was reduced in both the cortex and hippocampus and unaltered in both the caudate nucleus and putamen. Alterations of the equilibrium dissociation constant were not observed for any ligand in any of the brain areas examined. The present results suggest that both the innominatocortical and the septohippocampal cholinergic systems degenerate in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS

Brain muscarinic cholinergic receptors in Huntington's disease

Muscarinic cholinergic receptors and choline acetyltransferase (ChAT) activity were studied in postmortem brain tissue from patients with Huntington's disease and matched control subjects. In comparison with controls, reductions in ChAT activity were found in the hippocampus, but not in the temporal cortex in Huntington's disease. Patients with Huntington's disease showed reduced densities of the total number of muscarinic receptors and of M-2 receptors in the hippocampus while the density of M-1 receptors was unaltered. Muscarinic receptor binding was unchanged in the temporal cortex. These results indicate a degeneration in Huntington's disease of the septo-hippocampal cholinergic pathway, but no impairment of the innominato-cortical cholinergic system

Binge-watching: Video-on-demand, quality TV and mainstreaming fandom

This article explores the concept of the binge as viewing protocol associated with fan practices, industry practice and linked to ‘cult’ and ‘quality’ serialised content. Viewing binge-watching as an intersection of discourses of industry, audience and text, the concept is analysed here as shaped by a range of issues that dominate the contemporary media landscape. In this, factors like technological developments, fan discourses and practices being adopted as ‘mainstream’ media practice, changes in the discursive construction of ‘television’ and an emerging Video-on-Demand industry contribute to the construction of binge-watching as deliberate, self-scheduled alternative to ‘watching TV’

Heme ligation and redox chemistry in two bacterial thiosulfate dehydrogenase (TsdA) enzyme

Thiosulfate dehydrogenases (TsdA) are bidirectional bacterial di-heme enzymes that catalyze the interconversion of tetrathionate and thiosulfate at measurable rates in both directions. In contrast to our knowledge of TsdA activities, information on the redox properties in the absence of substrates is rather scant. To address this deficit, we combined magnetic circular dichroism (MCD) spectroscopy and protein film electrochemistry (PFE) in a study to resolve heme ligation and redox chemistry in two representative TsdAs. We examined the TsdAs from Campylobacter jejuni, a micro-aerobe human pathogen, and from the purple sulfur bacterium Allochromatium vinosum. In these organisms, the enzyme functions as a tetrathionate reductase and a thiosulfate oxidase respectively. The active site Heme 1 in both enzymes has His/Cys− ligation in the ferric and ferrous states and the midpoint potentials (Em) of the corresponding redox transformations are similar, −185 mV versus standard hydrogen electrode (SHE). However, fundamental differences are observed in the properties of the second, electron transferring, Heme 2. In C. jejuni TsdA Heme 2 has His/Met ligation and an Em of +172 mV. In A. vinosum TsdA, Heme 2 reduction triggers a switch from His/Lys ligation (Em, −129 mV) to His/Met (Em,+266 mV) but the rates of interconversion are such that His/Lys ligation would be retained during turnover. In summary, our findings have unambiguously assigned Em values to defined axial ligand sets in TsdAs, specified the rates of Heme 2 ligand exchange in the A. vinosum enzyme, and provided information relevant to describing their catalytic mechanism(s)

Річард Смоллі і знамениті «десять вересневих днів»

У вересні цього року виповнюється 27 років, як було відкрито фулерен — нову сфероподібну форму вуглецю. Ця подія буквально приголомшила вчених, які на той час вважали, що про елементарний вуглець їм відомо практично все. Історія відкриття цієї речовини досить незвичайна. Ще в 1971 р. можливість існування молекули фулерену була передбачена японським ученим Е. Осавою (E. Osawa), за два роки радянські хіміки-теоретики Д.А. Бочвар і О.Г. Гальперн квантово-хімічними розрахунками підтвердили стабільність молекули С60, і лише у 1985 р. Р. Смоллі, Р. Керл та Г. Крото експериментально отримали кластери із 60 атомів вуглецю в стійкій формі, яку вони пояснили структурою молекули у вигляді футбольного м’яча. Натхненнику цього відкриття, видатному вченому, нобелівському лауреату, активному популяризатору нанотехнологій Річарду Смоллі присвячено цей матеріал.В сентябре этого года исполняется 27 лет с момента открытия фуллерена — новой сферообразной формы углерода. Это событие буквально потрясло ученых, которые в то время считали, что об элементарном углероде им известно практически все. История открытия этого вещества довольно необычна. Еще в 1971 г. возможность су ществования молекулы фуллерена была предсказана японским ученым Е. Осавой (E. Osawa), через два года советские химики-теоретики Д.А. Бочвар и Е.Г. Гальперн с помощью квантово-химических расчетов подтвердили стабильность молекулы С60, и только в 1985 г. Р. Смолли, Р. Керл и Г. Крото экспериментально получили кластеры из 60 атомов углерода в устойчивой форме, которую они объяснили структурой молекулы в виде футбольного мяча. Вдохновителю этого открытия, выдающемуся ученому, нобелевскому лауреату, активному популяризатору нанотехнологий Ричарду Смолли посвящен этот материал.27 years since the discovery of fullerene, the new form of carbon, is observed in September of this year. This event has literally shocked scientists, who believed at that time that they know almost everything about the elementary carbon. History of this discovery is rather unusual. Long ago, in 1971 the possibility of the existence of a fullerene molecule was predicted by an young Japanese scientist E. Osawa. Then two Soviet chemists and theorists D.A. Bochvar and E.G. Hal pern confirm the stability of the C60 molecule using quantum chemical calculations, and in 1985 at last R. Smalley, R. Curl and H. Kroto experimentally obtained clusters of 60 carbon atoms in a sustainable form. They explained the structure of this molecule as the structure of a soccer ball. This material is devoted to the inspirer of this discovery, an outstanding scientist, Nobel laureate, active popularizer of nanotechnology — Richard Smalley

The role of culture and society in the development of plot in tanushree podders escape from harem and gita mehtas a river sutra: a feminist reading

Culture and Society are often the main gist of most novels. These two factors often influence and control the characters, thus helping in the development of the plot. A plot, as defined by Egan (1978), is used to indicate an outline of events and serves as a skeleton in a literary piece. In other words, it is a tool in making sure the main incidents or scenarios are presented in a particular order to establish a clear understanding of what is being written. Culture and society plays the essence in a novel as it constructs these main ideas in engaging the interest of a reader and also extends the intended message of the particular writer. This paper looks into how culture and society helps in developing the plots of the selected novels using the feminist approach. Tanushree Podder’s, Escape from Harem (2013) and Gita Mehta’s A River Sutra (1993) amazingly are both set in India. Podder and Mehta have inserted the perception society had over women and how male supremacy was glorified in many aspects. The essence of feminist approach was very much present in these two novels. According to Tyson (2006), feminism concerns the ways in which literature undermines the economic, political, social and psychological oppression on women. Though the setting of both novels fall in different eras but the theme of female oppression remains the same. The patriarchal society uses culture and religion as a tool to control women and oppress them. Both authors have shown how the women in the 17th century and in the 20th century face the same kind of judgment from the society and men in general

The impacts of environmental warming on Odonata: a review

Climate change brings with it unprecedented rates of increase in environmental temperature, which will have major consequences for the earth's flora and fauna. The Odonata represent a taxon that has many strong links to this abiotic factor due to its tropical evolutionary history and adaptations to temperate climates. Temperature is known to affect odonate physiology including life-history traits such as developmental rate, phenology and seasonal regulation as well as immune function and the production of pigment for thermoregulation. A range of behaviours are likely to be affected which will, in turn, influence other parts of the aquatic ecosystem, primarily through trophic interactions. Temperature may influence changes in geographical distributions, through a shifting of species' fundamental niches, changes in the distribution of suitable habitat and variation in the dispersal ability of species. Finally, such a rapid change in the environment results in a strong selective pressure towards adaptation to cope and the inevitable loss of some populations and, potentially, species. Where data are lacking for odonates, studies on other invertebrate groups will be considered. Finally, directions for research are suggested, particularly laboratory studies that investigate underlying causes of climate-driven macroecological patterns