Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically

Is Mn-Bound Substrate Water Protonated in the S2 State of Photosystem II?

In spite of great progress in resolving the geometric structure of the water-splitting Mn4OxCa cluster in photosystem II, the binding sites and modes of the two substrate water molecules are still insufficiently characterized. While time-resolved membrane-inlet mass spectrometry measurements indicate that both substrate water molecules are bound to the oxygen-evolving complex (OEC) in the S2 and S3 states (Hendry and Wydrzynski in Biochemistry 41:13328–13334, 2002), it is not known (1) if they are both Mn-bound, (2) if they are terminal or bridging ligands, and (3) in what protonation state they are bound in the different oxidation states Si (i = 0, 1, 2, 3, 4) of the OEC. By employing 17O hyperfine sublevel correlation (HYSCORE) spectroscopy we recently demonstrated that in the S2 state there is only one (type of) Mn-bound oxygen that is water exchangeable. We therefore tentatively identified this oxygen as one substrate ‘water’ molecule, and on the basis of the finding that it has a hyperfine interaction of about 10 MHz with the electron spin of the Mn4OxCa cluster, we suggest that it is bound as a Mn–O–Mn bridge within a bis-μ2 oxo-bridged unit (Su et al. in J Am Chem Soc 130:786–787, 2008). Employing pulse electron paramagnetic resonance, 1H/2H Mims electron-nuclear double resonance and 2H-HYSCORE spectroscopies together with 1H/2H-exchange here, we test this hypothesis by probing the protonation state of this exchangeable oxygen. We conclude that this oxygen is fully deprotonated. This result is discussed in the light of earlier reports in the literature

STXBP2-R190C Variant in a Patient With Neonatal Hemophagocytic Lymphohistiocytosis (HLH) and G6PD Deficiency Reveals a Critical Role of STXBP2 Domain 2 on Granule Exocytosis

Neonatal hemophagocytic lymphohistiocytosis (HLH) is a medical emergency that can be associated with significant morbidity and mortality. Often these patients present with familial HLH (f-HLH), which is caused by gene mutations interfering with the cytolytic pathway of cytotoxic T-lymphocytes (CTLs) and natural killer cells. Here we describe a male newborn who met the HLH diagnostic criteria, presented with profound cholestasis, and carried a maternally inherited heterozygous mutation in syntaxin-binding protein-2 [STXBP2, c.568C\u3eT (p.Arg190Cys)] in addition to a severe pathogenic variant in glucose 6-phosphate dehydrogenase [G6PD, hemizygous c.1153T\u3eC (Cys385Arg)]. Although mutations in STXBP2 gene are associated with f-HLH type 5, the clinical and biological relevance of the p.Arg190Cys mutation identified in this patient was uncertain. To assess its role in disease pathogenesis, we performed functional assays and biochemical and microscopic studies. We found that p.Arg190Cys mutation did not alter the expression or subcellular localization of STXBP2 or STX11, neither impaired the STXBP2/STX11 interaction. In contrast, forced expression of the mutated protein into normal CTLs strongly inhibited degranulation and reduced the cytolytic activity outcompeting the effect of endogenous wild-type STXBP2. Interestingly, arginine 190 is located in a structurally conserved region of STXBP2 where other f-HLH-5 mutations have been identified. Collectively, data strongly suggest that STXBP2-R190C is a deleterious variant that may act in a dominant-negative manner by probably stabilizing non-productive interactions between STXBP2/STX11 complex and other still unknown factors such as the membrane surface or Munc13-4 protein and thus impairing the release of cytolytic granules. In addition to the contribution of STXBP2-R190C to f-HLH, the accompanied G6PD mutation may have compounded the clinical symptoms; however, the extent by which G6PD deficiency has contributed to HLH in our patient remains unclear

A guided tour of asynchronous cellular automata

Research on asynchronous cellular automata has received a great amount of attention these last years and has turned to a thriving field. We survey the recent research that has been carried out on this topic and present a wide state of the art where computing and modelling issues are both represented.Comment: To appear in the Journal of Cellular Automat

Species Used for Drug Testing Reveal Different Inhibition Susceptibility for 17beta-Hydroxysteroid Dehydrogenase Type 1

Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (17β-HSD 1) for the treatment of breast cancer or endometriosis, novel substances based on 15-substituted estrone were validated. We checked the specificity for different 17β-HSD types and species. Compounds were tested for specificity in vitro not only towards recombinant human 17β-HSD types 1, 2, 4, 5 and 7 but also against 17β-HSD 1 of several other species including marmoset, pig, mouse, and rat. The latter are used in the processes of pharmacophore screening. We present the quantification of inhibitor preferences between human and animal models. Profound differences in the susceptibility to inhibition of steroid conversion among all 17β-HSDs analyzed were observed. Especially, the rodent 17β-HSDs 1 were significantly less sensitive to inhibition compared to the human ortholog, while the most similar inhibition pattern to the human 17β-HSD 1 was obtained with the marmoset enzyme. Molecular docking experiments predicted estrone as the most potent inhibitor. The best performing compound in enzymatic assays was also highly ranked by docking scoring for the human enzyme. However, species-specific prediction of inhibitor performance by molecular docking was not possible. We show that experiments with good candidate compounds would out-select them in the rodent model during preclinical optimization steps. Potentially active human-relevant drugs, therefore, would no longer be further developed. Activity and efficacy screens in heterologous species systems must be evaluated with caution

Cultural facial expressions dynamically convey emotion category and intensity information

Communicating emotional intensity plays a vital ecological role because it provides valuable information about the nature and likelihood of the sender’s behavior.1,2,3 For example, attack often follows signals of intense aggression if receivers fail to retreat.4,5 Humans regularly use facial expressions to communicate such information.6,7,8,9,10,11 Yet how this complex signaling task is achieved remains unknown. We addressed this question using a perception-based, data-driven method to mathematically model the specific facial movements that receivers use to classify the six basic emotions—"happy,” “surprise,” “fear,” “disgust,” “anger,” and “sad”—and judge their intensity in two distinct cultures (East Asian, Western European; total n = 120). In both cultures, receivers expected facial expressions to dynamically represent emotion category and intensity information over time, using a multi-component compositional signaling structure. Specifically, emotion intensifiers peaked earlier or later than emotion classifiers and represented intensity using amplitude variations. Emotion intensifiers are also more similar across emotions than classifiers are, suggesting a latent broad-plus-specific signaling structure. Cross-cultural analysis further revealed similarities and differences in expectations that could impact cross-cultural communication. Specifically, East Asian and Western European receivers have similar expectations about which facial movements represent high intensity for threat-related emotions, such as “anger,” “disgust,” and “fear,” but differ on those that represent low threat emotions, such as happiness and sadness. Together, our results provide new insights into the intricate processes by which facial expressions can achieve complex dynamic signaling tasks by revealing the rich information embedded in facial expressions

On-line mass spectrometry: membrane inlet sampling

Significant insights into plant photosynthesis and respiration have been achieved using membrane inlet mass spectrometry (MIMS) for the analysis of stable isotope distribution of gases. The MIMS approach is based on using a gas permeable membrane to enable the entry of gas molecules into the mass spectrometer source. This is a simple yet durable approach for the analysis of volatile gases, particularly atmospheric gases. The MIMS technique strongly lends itself to the study of reaction flux where isotopic labeling is employed to differentiate two competing processes; i.e., O2 evolution versus O2 uptake reactions from PSII or terminal oxidase/rubisco reactions. Such investigations have been used for in vitro studies of whole leaves and isolated cells. The MIMS approach is also able to follow rates of isotopic exchange, which is useful for obtaining chemical exchange rates. These types of measurements have been employed for oxygen ligand exchange in PSII and to discern reaction rates of the carbonic anhydrase reactions. Recent developments have also engaged MIMS for online isotopic fractionation and for the study of reactions in inorganic systems that are capable of water splitting or H2 generation. The simplicity of the sampling approach coupled to the high sensitivity of modern instrumentation is a reason for the growing applicability of this technique for a range of problems in plant photosynthesis and respiration. This review offers some insights into the sampling approaches and the experiments that have been conducted with MIMS

Testing the “Learning Journey” of MSW Students in a Rural Program

Using a quasi-experimental one-group, pretest–posttest design with non-random convenience sampling, the researchers assessed 61 advanced standing MSW students who matriculated at a rural intermountain Northwest school of social work. Changes in students\u27 knowledge and attitudes toward lesbian, gay, and bisexual (LGB) people were measured using subscales of the LGB-KASH scale and include knowledge of LGB history, religious conflict, internalized affirmation of LGB people and issues, hatred and violence toward LGB people, and knowledge and attitudes toward extension and exclusion of civil rights for LGB people. Completion of required, highly experiential bridge course content regarding LGB history and experience appears to be significant in reducing religious conflict, increasing knowledge of LGB issues, and enhancing internalized affirmation of LGB individuals

Electron Transfer from Cyt b559 and Tyrosine-D to the S2 and S3 states of the water oxidizing complex in Photosystem II at Cryogenic Temperatures

The Mn4CaO5 cluster of photosystem II (PSII) catalyzes the oxidation of water to molecular oxygen through the light-driven redox S-cycle. The water oxidizing complex (WOC) forms a triad with Tyrosine(Z) and P-680, which mediates electrons from water towards the acceptor side of PSII. Under certain conditions two other redox-active components, Tyrosine(D) (Y-D) and Cytochrome b (559) (Cyt b (559)) can also interact with the S-states. In the present work we investigate the electron transfer from Cyt b (559) and Y-D to the S-2 and S-3 states at 195 K. First, Y-D (aEuro cent) and Cyt b (559) were chemically reduced. The S-2 and S-3 states were then achieved by application of one or two laser flashes, respectively, on samples stabilized in the S-1 state. EPR signals of the WOC (the S-2-state multiline signal, ML-S-2), Y-D (aEuro cent) and oxidized Cyt b (559) were simultaneously detected during a prolonged dark incubation at 195 K. During 163 days of incubation a large fraction of the S-2 population decayed to S-1 in the S-2 samples by following a single exponential decay. Differently, S-3 samples showed an initial increase in the ML-S-2 intensity (due to S-3 to S-2 conversion) and a subsequent slow decay due to S-2 to S-1 conversion. In both cases, only a minor oxidation of Y-D was observed. In contrast, the signal intensity of the oxidized Cyt b (559) showed a two-fold increase in both the S-2 and S-3 samples. The electron donation from Cyt b (559) was much more efficient to the S-2 state than to the S-3 state

Sex Differences in Social Attention in Infants at Risk for Autism

We studied visual attention to emotional faces in 10-month-old infant siblings of children with ASD (ASD-sibs; N = 70) and a siblings of typically developing children (N = 29) using static stimuli. Contrary to our predictions, we found no evidence for atypical gaze behavior in ASD-sibs when boys and girls were analyzed together. However, a sex difference was found in ASD-sibs' visual attention to the mouth. Male ASD-sibs looked more at the mouth across emotions compared to male controls and female ASD-sibs. In contrast, female ASD-sibs looked less at the mouth compared to female controls. These findings suggest that some aspects of early emerging atypical social attention in ASD-sibs may be sex specific