Synthesis and elaboration of N-methylpyrrolidone as an acetamide fragment substitute in bromodomain inhibition

N-Methylpyrrolidone is a solvent molecule which has been shown to compete with acetyl-lysine-containing peptides for binding to bromodomains. From crystallographic studies, it has also been shown to closely mimic the acetamide binding motif in several bromodomains, but has not yet been directly pursued as a fragment in bromodomain inhibition. In this paper, we report the elaboration of N-methylpyrrolidone as a potential lead in fragment-based drug design. Firstly, N-methylpyrrolidone was functionalised to provide points for chemical elaboration. Then, the moiety was incorporated into analogues of the reported bromodomain inhibitor, Olinone. X-ray crystallography revealed that the modified analogues showed comparable binding affinity and structural mimicry to Olinone in the bromodomain binding site.     

Sonic hedgehog in the pharyngeal endoderm controls arch pattern via regulation of Fgf8 in head ectoderm

Fgf8 signalling is known to play an important role during patterning of the first pharyngeal arch, setting up the oral region of the head and then defining the rostral and proximal domains of the arch. The mechanisms that regulate the restricted expression of Fgf8 in the ectoderm of the developing first arch, however, are not well understood. It has become apparent that pharyngeal endoderm plays an important role in regulating craniofacial morphogenesis. Endoderm ablation in the developing chick embryo results in a loss of Fgf8 expression in presumptive first pharyngeal arch ectoderm. Shh is locally expressed in pharyngeal endoderm, adjacent to the Fgf8-expressing ectoderm, and is thus a candidate signal regulating ectodermal Fgf8 expression. We show that in cultured explants of presumptive first pharyngeal arch, loss of Shh signalling results in loss of Fgf8 expression, both at early stages before formation of the first arch, and during arch formation. Moreover, following removal of the endoderm, Shh protein can replace this tissue and restore Fgf8 expression. Overexpression of Shh in the non-oral ectoderm leads to an expansion of Fgf8, affecting the rostral-caudal axis of the developing first arch, and resulting in the formation of ectopic cartilage. Shh from the pharyngeal endoderm thus regulates Fgf8 in the ectoderm and the role of the endoderm in pharyngeal arch patterning may thus be indirectly mediated by the ectoderm.     

The first description of the potentially toxic dinoflagellate, Alexandrium minutum in Hunts Bay, Kingston Harbour, Jamaica

The occurrence and morphology of the potentially toxic dinoflagellate species Alexandrium minutum found for the first time in Jamaica, were examined and described by light and scanning electron microscopy. Classical morphological examinations of whole cells, the thecal plate pattern of intact cells and more importantly the structure of individual thecal plates of squashed cells, were conducted in an attempt to positively identify the species. Characteristics such as a tear-drop shaped apical pore plate with a comma-shaped apical pore and no anterior attachment pore; a narrow sixth precingular plate; a narrow anterior sulcal plate longer than or approximately as long as it is wide; and a posterior sulcal plate wider than long, confirmed the Jamaican species as A. minutum. This dinoflagellate which produces potent neurotoxins responsible for paralytic shellfish poisoning (PSP) in humans in many parts of the World, as well as mass mortality of various marine flora and fauna, was identified in water samples collected during an extensive bloom of the species in the brackish to saline water body of Hunts Bay, an estuarine arm of Kingston Harbour, Jamaica in August 1994. The highest cell concentration was 4.6 × 10⁵ cells l⁻¹, a concentration which far exceeds acceptable concentrations (<10³ cells l⁻¹) of PSP-toxin producing A. minutum in several countries including: Spain and Denmark. No PSP human symptoms were reported during the bloom; however it was accompanied by a large kill of small pelagic fish extending across a third of the bay. Since then, smaller blooms of A. minutum have occurred with the most recent in February and April 2004. Hunts Bay is an important fishing, shrimping and to some extent oyster/mussel collection area and provides an important source of livelihood and food for many fishermen in nearby fishing communities as well as an important source of food for members of other communities. Although there are no known records of human illness due to PSP in Jamaica, the occurrence and blooming in Jamaican waters of this potentially toxic dinoflagellate, is great cause for concern.     

湖北兴山发现霍氏缺齿鼩

2016年12月,在湖北省兴山县采集到1只食虫类标本。其体型较小(头体长75.00 mm),通体呈棕褐色,尾较长(82.00 mm),眼细小。头骨扁平,较为坚固,齿尖具有浅红棕色色斑。通过测定其线粒体Cyt b基因序列,并结合缺齿鼩属6个物种的同源区序列,构建其系统发生关系,发现该标本与基因库中霍氏缺齿鼩(Chodsigoa hoffmanni)序列聚为具较高支持度的一支。综合形态学与系统发育学证据,将该标本鉴定为霍氏缺齿鼩。此次发现是湖北省境内该物种的首次记录,也是其在我国云南省及越南分布区外的又一发现,拓展了对该物种在我国分布范围的认识。     

中国土壤原生动物新纪录种·肉鞭虫门

报道了首次在中国土壤中鉴定到隶属于肉鞭虫门的１１种原生动物。这些种类是蚁固滴虫、唇缝口虫、斜缝口虫、喜盐匣壳虫、束拟砂壳虫、尖足法帽虫、长匣壳虫、森林地壳虫、佩氏三足虫、花瓶梨壳虫和鬃鳞壳虫。     

The incidence of Helicobacter pylori acquisition in children of a Canadian First Nations community and the potential for parent-to-child transmission

BACKGROUND AND AIMS: We have previously reported that Wasagamack, a Canadian First Nations community has a seroprevalence rate of Helicobacter pylori of 95% and a prevalence rate among children aged 0-12 years as measured by stool antigen testing of 56%. We aimed to determine the rate of infection acquisition and possible modes of transmission of childhood Helicobacter pylori infection in this Canadian First Nations community. METHODS: Children who were previously negative for H. pylori by stool antigen testing in August 1999 were eligible for enrollment in August 2000; 50 (77%) eligible children underwent stool collection. H. pylori stool antigen status was tested using the Premier Platinum HpSA test. Drinking water samples, maternal saliva, breast milk, local berries and flies were tested by three complementary H. pylori-specific PCR assays. Soothers or bottle nipples, collected from 16 children whose H. pylori stool antigen status was determined, were bathed in sterile water and this water was tested by PCR. RESULTS: Stool was positive for H. pylori in 16% (8/ 50) of children retested. Five had no other siblings infected and three had infected siblings. The mothers of all children infected were positive for H. pylori. The median age of newly infected children was 6 years (range 1-13 years). By PCR, 78% (18/23) mothers' saliva samples, 69% (11/16) soother water samples and 9% (1/11) water samples from infected homes tested positive. All of 24 sequenced PCR-produced DNA fragments from samples showed 99% homology with that from ATCC type strain H. pylori. CONCLUSIONS: The rate of childhood H. pylori acquisition was 16% over 1 year, and was not dependent on number of siblings infected. The finding of homologous H. pylori DNA in saliva and in soother water suggests the possibility of human to human transmission, particularly via an oral-oral route. Thus, there is the potential for further investigations in this population and other endemic communities that are directed at prevention of infection transmission via this modality.     

Leech responses to tissue transplantation

The aim of the present work is to describe histologically, histochemically and immunocytochemically, the sequence of events that lead to first and second set rejection of allo- or xenograft in leeches. Graft responses of leeches are comparable and are described following specific steps: inflammatory phase, rejection phase and granulation tissue formation (including re-epithelialisation, angiogenesis and fibroplasia).The responses to first and second graft in first set graft rejection as well as to the first transplant in second set graft experiments are identical and in the time span of a week all grafts are destroyed and disappear. In the second set graft rejection experiments the responses against the second transplant are markedly accelerated. The second graft shows massive structural alterations and it is rapidly rejected, within 3-4 days.Our results permit to highlight that in leeches there is a specific responsiveness of immune system similar to those described in highly divergent phyla.     

Aid for aggregating the impacts in Life Cycle assessment

Background and Objectives  Multiple Criteria Decision Aid (MCDA) methods may be employed in a great number of fields. Life Cycle Assessment (LCA) is a specific method among the MCDA Methods. A stage of MCDA methods to be respected in LCA is the comparative evaluation of the environmental impacts. This stage is the most difficult to implement because it is a question of estimating the global environmental impact of the life cycles studied. To achieve this purpose, it is necessary to model the environmental impacts and to apply a Multicriteria Analysis (MCA) method. The problem is to choose the most suitable among the available MCA methods. The objective of this paper is to help the LCA practitioner to make this choice. Methodology  The MCA methods are compared according to their non-compensatory degree, their sensitivity to thresholds, their practicability and their workability. Results and Conclusion  The protocol presented in this paper allows to choose the most appropriate MCA method for a given LCA according to the four previous criteria. This choice will depend on the priorities of the decision maker with concern to the comparison criteria.     

以中枢神经系统症状为首发表现的干燥综合征1例并文献复习

目的:探讨干燥综合征累及中枢神经病变的临床表现及诊断、鉴别诊断、治疗。方法:报告中国人民解放军第175医院1例累及中枢神经病变的干燥综合征患者的临床资料并复习相关文献,对其临床表现、诊断、容易混淆的鉴别诊断及治疗进行分析。结果:1例累及中枢神经病变的干燥综合征患者经治疗病情好转出院。结论:累及中枢神经病变的干燥综合征,尤其以中枢神经系统症状为首发表现者,极易误诊为多发性硬化,遇可疑病例应及时完善检查,避免因忽视其它系统症状而导致漏诊和误诊,影响患者的预后。