Molecular mechanism of SHP2 activation by PD-1 stimulation.

In cancer, the programmed death-1 (PD-1) pathway suppresses T cell stimulation and mediates immune escape. Upon stimulation, PD-1 becomes phosphorylated at its immune receptor tyrosine-based inhibitory motif (ITIM) and immune receptor tyrosine-based switch motif (ITSM), which then bind the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2), initiating T cell inactivation. The SHP2-PD-1 complex structure and the exact functions of the two SH2 domains and phosphorylated motifs remain unknown. Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation. We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2. This binding event requires the formation of a new inter-domain interface, offering opportunities for the development of novel immunotherapeutic approaches.

Characterization of lake minnow Eupallasella percnurus semen in relation to sperm morphology, regulation of sperm motility and interpopulation diversity.

Sperm morphology and regulation of sperm motility of lake minnow Eupallasella percnurus, an endangered cyprinid, were investigated. Milt characteristics from two isolated populations of E. percnurus were compared to characterize the interpopulation diversity. Electron microscopic studies revealed that E. percnurus spermatozoa comprise simple, uniflagellate, anacrosomal aquasperm with species-specific features as an eccentrically located implantation of nuclear fossa and eccentric insertion of flagellum. Sperm motility was significantly inhibited by relatively low ion concentrations (150, 150 and 8 mM for NaCl, KCl and CaCl2 , respectively). Sperm maintained a high motility rate over a wide pH range (5.5-10.5), which may reflect adaptation to a highly variable environment. The two E. percnurus populations were markedly different in milt volume, sperm concentration, seminal plasma pH, sperm motility and beat cross frequency, which may result from genetic differences and environmental conditions.

Alpha-ketoglutarate stabilizes redox homeostasis and improves arterial elasticity in aged mice.

The objective of this study was to evaluate the effect of α-ketoglutarate on redox state parameters and arterial elasticity in elderly mice. Mice in the control group were fed with standard diet, while the experimental animals received the diet supplemented either with calcium (Ca-AKG) or sodium salt of α-ketoglutarate (Na-AKG). The experimental animals were divided into 4 groups with 10 individuals in each: control I (12 months old), control II (2 months old), experimental group I fed with Ca-AKG (12 months old) and experimental group II fed with Na-AKG (12 months old). Mice treated with Ca-AKG as well as the control II animals demonstrated significantly higher level of total antioxidant status (TAS), comparing to the control I animals and those treated with Ca-AKG. Thiobarbituric acid reactive substances (TBARS) level in blood plasma was found significantly lower in young and Ca-AKG treated mice. TBARS liver concentration was significantly different in each examined group. The study also demonstrates the decrease in TBARS level in Ca-AKG treated animals. Treatment with Na-AKG significantly increased glutathione peroxidase activity and decreased the activity of superoxide dismutase. The presented results suggest that Ca-AKG protects the organism against the free radicals related elderly processes. The study presents also the effect of Ca-AKG treatment on arterial elastic characteristics in elderly mice. The beneficial effect of Ca-AKG on ageing organisms was confirmed via redox state stabilization and blood vessel elasticity improvement.

Cranial MRI in the Nijmegen breakage syndrome.

We present the results paragraph signof MRI examinations in ten patients with documented Nijmegen paragraph signbreakage syndrome (NBS), aged 1.75-19 years. T1-, Proton-Density- and T2-weighted spin-echo sequences were performed in three planes. All patients showed microcephaly with decreased size of the frontal lobes and narrow frontal horns. In four patients agenesis of the posterior part of the corpus callosum was found, with colpocephaly and temporal horns dilatation. In one patient callosal hypoplasia was accompanied by abnormal cerebrospinal fluid spaces and wide cerebral cortex, suspicious of pachygyria. Sinusitis was present in all ten patients, as a result of primary immunodeficiency. As in ataxia teleangiectasia and other breakage syndromes, patients with NBS show an inherited susceptibility to malignancy and hypersensitivity to X- and gamma-radiation. CT is therefore contraindicated in these patients and MRI should be the method of choice for diagnostic imaging.

[Report from the conference on "safe and hygienic learning conditions as indispensable elements of elementary schools' functioning"]. / Sprawozdanie z konferencji pt. "bezpieczne i higieniczne warunki nauczania niezbednym elementem funkcjonowania szkól podstawowych".

The conference was organized in Warsaw on the 14th of November 1997, by the Main Section of School Hygiene of the Polish Society of Hygiene. 202 people took part in the conference. They represented following institutions: a sanitary inspection, a health care service, academy institutes, pedagogical institutions, community councils. The purpose of the meeting was to point out and widespread local initiatives and ideas, appearing in various regions of Poland, that concern the following topics: 1: improvement of health conditions in schools, 2) improvement of conditions and realization's methods of increased number of physical training lessons in schools (a gradual increase from 3 hours a week at the present time to 5 in the year 2000), 3) providing actions to minimize the number of accidents among children and adolescents. There were panel discussions concerning the problems mentioned above. Many conclusions were formulated as the result of the discussion, out of which the most important are: ad 1) Maintaining the conditions of proper education demands cooperation between schools' headquarters and community councils and an initiative in seeking allies and sponsors. Examples of the activities of community councils to maintain proper safe and hygienic conditions in education should be propagated. These examples can be applied in another areas. ad 2) There is a dramatic shortage of facilities. Schools try to fulfil the increased requirements by: utilizing elements of natural environment, profiting from the spontaneous activity of children and parents, extending a traditional curriculum offered by new elements of physical culture. Increasing the number of physical training classes gives a chance to create social attitudes during these classes and health behaviour. ad 3) Accident risk in schools should be eliminated by carrying out a systematic many-sided and preventive activity. The coordination of actions should exist on all levels of local and national administration. In schools decisions concerning organizational solutions should be taken up, with the active involvement of headquarters, teachers, administrative workers and parents.

[Growth and maturation of children of normal short stature in the light of selected auxological determinants]. / Wzrastanie i dojrzewanie dzieci z prostym niedoborem wysokosci ciala w swietle wybranych determinantów auksologicznych.

In longitudinal complex auxological studies of healthy short stature children in the first decade of life the authors analyse the dynamics of height velocity and growth rate of 11 somatic patterns with skeletal maturation of the hand and wrist as well as the influence of some genetic, paragenetic and biological determinants (morbidity). They find that the degree of stature deficit is on the same level during the period of observation (5-10 years) with slow growth rate in some of the analysed anthropological parameters. The delay of skeletal maturation typical for children under study is coexistent with a number of minor anomalies of hands and wrists which are more frequent than in healthy normal children. These minor anomalies are more frequent in boys than in girls. The analysed paragenetic determinants seem not to be significant, however there exists a strong association between the short stature of mothers and children under study. Moreover a higher morbidity of respiratory tracts is observed in short stature children than in general population.

[Level and characteristics of the psychosomatic development of children from nurseries]. / Poziom i trendy rozwoju psychosomatycznego dzieci wychowywanych w zlobkach.

The authors describe the results of longitudinal complex investigations carried out in the years 1976-80 for estimating the psychomotor development, somatic development and health status of 370 children aged 12-36 month in Warsaw's cr eches . The level of psychomotor development exept language was good in children under study and depended on the psycho-educational level of personnel. The analysis of anthropological traits showed the higher value of children under study as compared with standard values (secular trend). High morbidity were also found in children from cr eches .

[Auxological analysis of children with normal short stature]. / Analiza auksologiczna dzieci z zespolem prostego niedoboru wysokosci ciala.

Auxological investigations involved 123 children aged 5 and 7 years, who were observed for the period of two years. They included pediatric, anthropometric and social examinations. The authors concluded that socio-economic conditions were not so different, so that they could influence the level of development of children under study. The tendency for increasing deficit of stature with age and for changes in type of body built were also observed.

[Use of the RWT method for predicting final adult body height in boys of short stature]. / Zastosowanie metody RWT do przewidywania ostatecznej wysokosci ciala chlopców z prostym niedoborem wzrostu.

On the empirical data of body height of 75 healthy short stature boys, the comparison using Roche, Weiner and Thiessen (RWT) method for predicting adult stature was conducted. There are no significant differences between real and predicted body height, since body height of normal short boys aged 18-19 years was in agreement with the stature predicted retrospectively in the age 10-15 years. American RWT method for predicting final adult stature may be used for Polish boys with hypostatura simplex.

[Sexual dimorphism of somatic characteristics of children of short stature]. / Charakterystyka dymorfizmu plciowego cech somatycznych u dzieci z prostym niedoborem wysokosci ciala.

The material of normal 199 Warsaw children with hypostatura previously elaborated from the point of view of morphological traits and biological maturity are analysed at present from the point of view of sexual dimorphism. Dimorphic values of the following traits were tested: body height, trunk length, lower extremity length, biacromial diameter, biiliac diameter, chest breadth, chest depth, distal femoral epiph., chest circumference, thigh circumference, arm circumference, subscapular skinfold and body weight. For a more detailed analysis sexual dimorphic index was evaluated. The following conclusions were drawn from this analysis: 1. Sex dimorphism in children with hypostatura is less distinctly expressed than in normal children. 2. The biggest dimorphic differences among analysed anthropologic traits in both age groups concerned the width of distal femoral epiph. 3. Sex dimorphic index of analysed somatic features is in parallel direction with the control group and is of higher value among 7 year old children with hypostatura. 4. Basing on the results, slower biological maturity was confirmed among children under study.