Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival

Tissue-type plasminogen activator (tPA) plays roles in the development and the plasticity of the nervous system. Here, we demonstrate in neurons, that by opposition to the single chain form (sc-tPA), the two-chains form of tPA (tc-tPA) activates the MET receptor, leading to the recruitment of N-Methyl-D-Aspartate receptors (NMDARs) and to the endocytosis and proteasome-dependent degradation of NMDARs containing the GluN2B subunit. Accordingly, tc-tPA down-regulated GluN2B-NMDAR-driven signalling, a process prevented by blockers of HGFR/MET and mimicked by its agonists, leading to a modulation of neuronal death. Thus, our present study unmasks a new mechanism of action of tPA, with its two-chains form mediating a crosstalk between MET and the GluN2B subunit of NMDARs to control neuronal survival.

Regioselective Dehydration of Sugar Thioacetals under Mild Conditions

Pentose and hexose sugars are abundant constituents of waste biomass, making them sustainable, chiral building blocks for organic synthesis. The demand for chiral saturated heterocyclic rings from the pharmaceutical industry is increasing as they provide well-defined three-dimensional frameworks that show increased metabolic resistance. Through the formation of thioacetals, sugars may be manipulated in their straight-chain form and dehydrated selectively under basic conditions at C-2. This approach was applied to an array of sugars and extended to the production of useful chiral THFs via further selective dehydration reactions.

Regioselective Dehydration of Sugar Thioacetals under Mild Conditions

Pentose and hexose sugars are abundant constituents of waste biomass, making them sustainable, chiral building blocks for organic synthesis. The demand for chiral saturated heterocyclic rings from the pharmaceutical industry is increasing as they provide well-defined three-dimensional frameworks that show increased metabolic resistance. Through the formation of thioacetals, sugars may be manipulated in their straight-chain form and dehydrated selectively under basic conditions at C-2. This approach was applied to an array of sugars and extended to the production of useful chiral THFs via further selective dehydration reactions.

Four new species of Amynthas earthworms in southeastern Vietnam (Annelida, Oligochaeta, Megascolecidae)

Four new earthworm species of the genus Amynthas Kinberg, 1867 are described from southeastern Vietnam, named A. longiprostaticus sp. nov., A. dorsomorrioides sp. nov., A. minhdam sp. nov., and A. ocularius sp. nov. A. longiprostaticus sp. nov. belongs to the A. minimus group of species, characterized by spermathecal pores in 5/6. It is distinguished by small body size with length 5–7 cm, and by elongate prostate glands, which extend over more than 10 segments. A. dorsomorrioides sp. nov. belongs to the A. morrisi group, characterized by holandry and spermathecal pores in 5/6/7. It is distinguished by a dorsal location of these pores, by one pair of large genital markings presetal in xvii, and by the absence of genital markings in the spermathecal region. A. minhdam sp. nov. also belongs to the A. morrisi group, and is distinguished by a pair of genital markings located medially in xviii and by the spermathecal diverticula, which have a small seminal chamber sub-divided by constrictions into 4 or 5 parts, in chain-form. A. ocularius sp. nov. belongs to the A. gracilis group by virtue of holandry and spermathecal pores in 5/6/7/8. It is distinguished by numerous small genital markings in the male region, postsetal in xviii and presetal in xix, and arranged in a peculiar fashion reminiscent of eyeglasses connected by a bridge. With these descriptions, there are now 119 species of Amynthas known in Vietnam.

Anemia Falciforme e o Comprometimento da Aprendizagem em Crianças e Jovens no Período Escolar

A doença falciforme - DF é uma hemoglobinopatia que afeta a cadeia da hemoglobina presente nas hemácias. Os indivíduos portadores apresentam a forma homozigótica da cadeia S da hemoglobina denominada de HbSS. A DF é considerada um problema de saúde pública no Brasil por ser uma doença frequente, grave e associada à elevada taxa de letalidade, especialmente, entre os jovens durante a idade escolar. Este trabalho teve como objetivo avaliar o impacto da DF em crianças e adolescentes de 5 a 18 anos acompanhados no Hemocentro de Cuiabá-MT, no período escolar. Para a execução deste estudo foram selecionados 55 pacientes de ambos os sexos, diagnosticados com Anemia Falciforme - AF e usuários de hidroxiureia por um período mínimo de seis meses. A qualidade de vida relacionada à saúde e a aprendizagem escolar dos pacientes foi avaliada através da aplicação do questionário “PedsQL”, específico para pacientes na faixa etária pediátrica. Os resultados demonstraram uma piora na qualidade de vida de pacientes com AF associada à demora do início do tratamento, principalmente, quando o mesmo se inicia após os oito anos de idade. A qualidade de vida é maior em pacientes mais novos (5 a 7 anos) por não apresentarem, ainda, os efeitos mais danosos da doença. O domínio escolar apresentou o pior score de qualidade de vida, demonstrando que quanto mais tarde a criança inicia o tratamento, pior será seu escore de qualidade de vida e maiores serão as dificuldades de aprendizagem, devido aos comprometimentos relacionados à doença. Este estudo mostrou que a AF afeta o desempenho de criança em período escolar e permitiu uma melhor compreensão de variáveis preditoras para elaboração de práticas pedagógicas socioeducacionais especializadas e adaptadas para doentes com AF.Palavras-chave: Anemia Falciforme. Qualidade de Vida. Escolaridade.AbstractSickle cell disease - DF is a hemoglobinopathy that affects the hemoglobin chain present in red blood cells. Carrier individuals exhibit the homozygous S-chain form of hemoglobin called HbSS. FD is considered a public health problem in Brazil because it is a frequent disease, severe and associated with a high lethality rate especially among young people during school age. The objective of this study was to evaluate the FD impact on children and adolescents aged 5 to 18 accompanied at the Blood Center of Cuiabá-MT, in the school period. For the execution of this study 55 patients of both sexes were selected, diagnosed with AF and users of hydroxyurea for a minimum period of six months. Quality of life related to patients' health was assessed through the application of the "PedsQL" questionnaire, specific for patients in the pediatric age group. The results demonstrated a worsening in the patients’ quality of life with AF associated with delayed onset of treatment, especially when it starts after eight years of age. Quality of life is higher in younger patients (5 to 7 years) because they do not present, still , the most harmful effects of the disease. This study showed that FA affects the children’s performance during the school period and allowed a better understanding of predictive variables for the elaboration of specialized pedagogical educational practices and adapted for FA patients.Keywords: Sickle Cell Anemia. Quality of Life. Education

Identifying combinatorially symmetric Hidden Markov Models

A sufficient criterion for the unique parameter identification of combinatorially symmetric Hidden Markov Models, based on the structure of their transition matrix, is provided. If the observed states of the chain form a zero forcing set of the graph of the Markov model, then it is uniquely identifiable and an explicit reconstruction method is given.

MULTIPLICATIVELY CLOSED MARKOV MODELS MUST FORM LIE ALGEBRAS

We prove that the probability substitution matrices obtained from a continuous-time Markov chain form a multiplicatively closed set if and only if the rate matrices associated with the chain form a linear space spanning a Lie algebra. The key original contribution we make is to overcome an obstruction, due to the presence of inequalities that are unavoidable in the probabilistic application, which prevents free manipulation of terms in the Baker–Campbell–Haursdorff formula.

An essential role of high-molecular-weight kininogen in endotoxemia

In this study, we show that mice lacking high-molecular-weight kininogen (HK) were resistant to lipopolysaccharide (LPS)-induced mortality and had significantly reduced circulating LPS levels. Replenishment of HK-deficient mice with human HK recovered the LPS levels and rendered the mice susceptible to LPS-induced mortality. Binding of HK to LPS occurred through the O-polysaccharide/core oligosaccharide, consistent with the ability to bind LPS from K. pneumoniae, P. aeruginosa, S. minnesota, and different E. coli strains. Binding of LPS induced plasma HK cleavage to the two-chain form (HKa, containing a heavy chain [HC] and a light chain [LC]) and bradykinin. Both HKa and the LC, but not the HC, could disaggregate LPS. The light chain bound LPS with high affinity (Kd = 1.52 × 10−9 M) through a binding site in domain 5 (DHG15). A monoclonal antibody against D5 significantly reduced LPS-induced mortality and circulating LPS levels in wild-type mice. Thus, HK, as a major LPS carrier in circulation, plays an essential role in endotoxemia.

Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation

Key PointsThe single-chain form of FXII, a component of the plasma contact system, has proteolytic activity. Single-chain FXII activity suggests a mechanism of contact activation initiation when blood is exposed to physiologic/artificial surfaces.