Strong-Isospin-Breaking Correction to the Muon Anomalous Magnetic Moment from Lattice QCD at the Physical Point.

All lattice-QCD calculations of the hadronic-vacuum-polarization contribution to the muon's anomalous magnetic moment to date have been performed with degenerate up- and down-quark masses. Here we calculate directly the strong-isospin-breaking correction to a_{µ}^{HVP} for the first time with physical values of m_{u} and m_{d} and dynamical u, d, s, and c quarks, thereby removing this important source of systematic uncertainty. We obtain a relative shift to be applied to lattice-QCD results obtained with degenerate light-quark masses of δa_{µ}^{HVP,m_{u}≠m_{d}}=+1.5(7)%, in agreement with estimates from phenomenology.

N-terminal or signal peptide sequence engineering prevents truncation of human monoclonal antibody light chains.

Monoclonal antibodies (mAbs) contain short N-terminal signal peptides on each individual polypeptide that comprises the mature antibody, targeting them for export from the cell in which they are produced. The signal peptide is cleaved from each heavy chain (Hc) and light chain (Lc) polypeptide after translocation to the ER and prior to secretion. This process is generally highly efficient, producing a high proportion of correctly cleaved Hc and Lc polypeptides. However, mis-cleavage of the signal peptide can occur, resulting in truncation or elongation at the N-terminus of the Hc or Lc. This is undesirable for antibody manufacturing as it can impact efficacy and can result in product heterogeneity. Here, we describe a truncated variant of the Lc that was detected during a routine developability assessment of the recombinant human IgG1 MEDI8490 in Chinese hamster ovary cells. We found that the truncation of the Lc was caused due to the use of the murine Hc signal peptide together with a lambda Lc containing an SYE amino acid motif at the N-terminus. This truncation was not caused by mis-processing of the mRNA encoding the Lc and was not dependent on expression platform (transient or stable), the scale of the fed-batch culture or clonal lineage. We further show that using alternative signal peptides or engineering the Lc SYE N-terminal motif prevented the truncation and that this strategy will improve Lc homogeneity of other SYE lambda Lc-containing mAbs. Biotechnol. Bioeng. 2017;114: 1970-1977. © 2017 Wiley Periodicals, Inc.

The emergence and stability of attention deficit hyperactivity disorder in boys with fragile X syndrome.

BACKGROUND: Children with fragile X syndrome (FXS) are at high risk for developing a range of behavioural disorders, including attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). However, very few studies have investigated the comorbid profile of FXS and ADHD and the possible dissociation from the FXS and ASD profile. The present study examined the relationship of childhood temperament characteristics of the Surgency facet (activity level, impulsivity, approach, shyness, and smiling and laughter) and the severity of ADHD and ASD features at two measurement time points in childhood, preschool (ages 3-4) and at school entry (ages 5-6). METHODS: The study consisted of males with FXS measured at each time point (preschool and school entry), as well as comparison of typically developing (TD) boys at the preschool measurement time point. Parent reported measures of temperament and behavioural symptoms were collected at each time point. Multiple regression analyses were used to analyse obtained data. RESULTS: Elevated activity level scores are associated with ADHD scores at preschool age and elevated shyness and decreased smiling and laughter are strongly associated with ADHD scores upon school entry. Impulsivity emerges as a strong indicator of elevated ADHD scores around school age, but even preschool impulsivity scores demonstrate some predictive value for higher ADHD scores later in school. Finally, no Surgency characteristic was significantly related to ASD scores at any age. CONCLUSIONS: Impulsivity serves as an indicator of elevated ADHD symptoms across development periods in boys with FXS, while activity level is just indicative of higher ADHD scores at the preschool age. The Surgency facet of temperament at either age does not predict strong relationships of comorbid pathologies of ADHD and ASD in FXS. However, Surgency characteristics may serve as informative discriminative factors when studying behavioural outcomes in boys with FXS.

Working memory subsystems and task complexity in young boys with Fragile X syndrome.

BACKGROUND: Working memory problems have been targeted as core deficits in individuals with Fragile X syndrome (FXS); however, there have been few studies that have examined working memory in young boys with FXS, and even fewer studies that have studied the working memory performance of young boys with FXS across different degrees of complexity. The purpose of this study was to investigate the phonological loop and visual-spatial working memory in young boys with FXS, in comparison to mental age-matched typical boys, and to examine the impact of complexity of the working memory tasks on performance. METHODS: The performance of young boys (7 to 13-years-old) with FXS (n = 40) was compared with that of mental age and race matched typically developing boys (n = 40) on measures designed to test the phonological loop and the visuospatial sketchpad across low, moderate and high degrees of complexity. Multivariate analyses were used to examine group differences across the specific working memory systems and degrees of complexity. RESULTS: Results suggested that boys with FXS showed deficits in phonological loop and visual-spatial working memory tasks when compared with typically developing mental age-matched boys. For the boys with FXS, the phonological loop was significantly lower than the visual-spatial sketchpad; however, there was no significant difference in performance across the low, moderate and high degrees of complexity in the working memory tasks. Reverse tasks from both the phonological loop and visual-spatial sketchpad appeared to be the most challenging for both groups, but particularly for the boys with FXS. CONCLUSIONS: These findings implicate a generalised deficit in working memory in young boys with FXS, with a specific disproportionate impairment in the phonological loop. Given the lack of differentiation on the low versus high complexity tasks, simple span tasks may provide an adequate estimate of working memory until greater involvement of the central executive is achieved.

Distinguishing features of autism in boys with fragile X syndrome.

BACKGROUND: Males with fragile X syndrome and autism (FXS/autism) represent a distinct subgroup of males with FXS at risk for markedly poorer outcomes. Early identification and intervention can improve outcomes for males with autism spectrum disorder. METHOD: To advance the development of a specialised autism screening tool for young males with FXS that could assist in early identification, backward regression was used to identify the combination of parent-report questionnaire items that best predicted autism symptoms in a sample of 60 males with FXS, ages 4-18 years old. RESULTS: Both social and repetitive behaviours distinguished males with FXS/autism, with repetitive behaviours playing a more prominent role than previously documented in the literature. CONCLUSIONS: Healthcare workers and early interventionists may be able to interview parents about a few key behaviours to determine if young child with FXS should be formally evaluated for autism. Evidence-based practices identified for children with autism spectrum disorder can be implemented as early as possible.

Maternal responses to child frustration and requests for help in dyads with fragile X syndrome.

BACKGROUND: Variability in behaviour displayed by children with fragile X syndrome (FXS) may be partially attributable to environmental factors such as maternal responsivity. The purpose of this study was to explore variables associated with maternal behaviour during a task designed to elicit frustration in their children with FXS. METHODS: Forty-six mother-child dyads, in which the child had full-mutation FXS, were observed in their homes during a task designed to elicit frustration in the child. Each child was given a wrong set of keys and asked to open a box to retrieve a desired toy. Mothers were provided with the correct set of keys and instructed to intervene when they perceived their child was getting too frustrated. Child-expressed frustration and requests for help and maternal behaviours (comforting, negative control, and encouraging/directing) were observed and coded. Maternal variables (e.g. depression, stress, education levels), child variables (e.g. autistic behaviours, age, medication use) and child behaviours (frustration, requests for help) were explored as predictors of maternal behaviour. RESULTS: Almost all mothers intervened to help their children and most used encouraging/directing behaviours, whereas very few used comforting or negative control. Child age and child behaviours during the frustrating event were significant predictors of encouraging/directing behaviours in the mothers. Children whose mothers reported higher depressive symptomology used fewer requests for help, and mothers of children with more autistic behaviours used more negative control. CONCLUSIONS: The results of this study suggest that child age and immediate behaviours are more strongly related to maternal responsivity than maternal traits such as depression and stress.

Fed-batch operation of an industrial cell culture process in shaken microwells.

Recently we have demonstrated batch suspension culture of mammalian cells in microwell plates. Here we describe a method for fed-batch culture of an industrially relevant GS-CHO (Glutamine Synthetase-Chinese Hamster Ovary) cell line in shaken 24-standard round well (24-SRW) plates. Use of a commercially available 'sandwich lid' and appropriate dilution of the bolus feeds counteracted liquid evaporation from the wells resulting in similar cell growth and antibody formation kinetics in both 24-SRW plates (800 mul) and shaken flasks (50 ml). Peak viable cell densities obtained were 8 +/- 0.5 x 10(6) and 9 +/- 1.3 x 10(6) ml(-1), respectively, while comparable final titres of a whole IgG of approximately 1.5 g l(-1) were recorded. Use of microwells provides at least a 50-fold reduction in medium requirements compared to shake-flask and other culture devices currently used in early stage cell culture process development. The ability to run multiple wells in parallel and to automate culture operation also offers considerable enhancements in experimental throughput.

Early temperament and negative reactivity in boys with fragile X syndrome.

BACKGROUND: The phenotype of children and adults with fragile X syndrome (FXS) includes a number of problem behaviours such as inattention, social anxiety and aggressive outbursts. However, very little work has been conducted with young children with FXS less than 5 years of age to examine the developmental pathway of problem behaviours in this population and to determine if later occurring problem behaviours may be rooted in early appearing temperament profiles. METHODS: Parent ratings and laboratory-based behavioural observations of negative reactivity were examined in 25 3-year-old boys with FXS and compared with 64 typically developing boys matched on age. RESULTS: Compared with the typically developing group, boys with FXS were rated by their parents as exhibiting less anger and sadness on the Child Behaviour Questionnaire (CBQ), and they showed less facial sadness on the Laboratory Temperament Assessment Battery (Lab-TAB). No group differences were found on the Lab-TAB measures of distress vocalisations, bodily struggle, and facial anger; and anger peaked in the middle of the arm restraint episode for both groups. For boys with FXS, mental age was moderately positively correlated, and autistic behaviour was moderately negatively correlated, with sadness scores from the CBQ. CONCLUSIONS: Our results show different behavioural profiles in very young children with FXS than reported in older-aged children with FXS which implies that temperamental differences and elevated problem behaviours reported in older-aged children with FXS may not be rooted in early temperament. This information is important to develop the phenotype of early development in FXS to facilitate early identification and treatment.

Missed antenatal depression among high risk women: a secondary analysis.

Psychiatrically high-risk women were recruited for a postpartum depression prevention trial. Participants were screened at entry (20-26 weeks gestation) by a psychiatrist prior to receiving randomized treatment. Of the 31 patients who did not complete the study, 10 (33%) were dropped because of diagnosed depression. Only two women developed major depression in the postpartum period. Our data suggests, among high-risk women, obstetric care providers may be overlooking up to one fifth of women with current major depression.

Blink rate in boys with fragile X syndrome: preliminary evidence for altered dopamine function.

BACKGROUND: Dopamine, a neurotransmitter involved in motor and cognitive functioning, can be non-invasively measured via observation of spontaneous blink rates. Blink rates have been studied in a number of clinical conditions including schizophrenia, autism, Parkinsons, and attention deficit/hyperactivity disorder with results implicating either hyper or hypo dopaminergic states. METHODS: This study examined spontaneous blink rate in boys with fragile X syndrome (FXS). Blink rates of boys (4-8 years old) with FXS (n = 6) were compared with those of age-matched typically developing boys (n = 6) during active and passive tasks. Blink rates (blinks per minute) for each task were compared between the two groups. Then, the relation between blink measures and core FXS-related features [problem behaviours, arousal, fmr 1 protein (FMRP)] were examined within the group of boys with FXS. RESULTS: Blink rate in boys with FXS was significantly higher than typically developing boys during passive tasks. Within the FXS group, there were significant correlations between blink rate and problem behaviours and physiological arousal (i.e. heart activity) but not with FMRP. CONCLUSIONS: Observed differences in spontaneous blink rate between boys with and without FXS and the relation between blink rate and physiological and behavioural measures in boys with FXS suggests that further work examining dopamine dysfunction as a factor in the pathophysiology of FXS may be warranted.

Matrix-metalloproteinases in Hodgkin lymphoma.

BACKGROUND: Classical Hodgkin lymphomas are characterized by relatively few tumour cells and prominent proliferation of plasma cells, histiocytes, lymphocytes and eosinophils. In addition there is a varying degree of sclerosis, which is especially prominent in nodular sclerosis. These morphological peculiarities led to the idea that the interaction between tumour cells and bystander cells as well as the extracellular matrix may be important in Hodgkin lymphomas. MATERIALS AND METHODS: Thirty-four classical Hodgkin lymphomas (CHL) were analysed regarding the expression of EMMPRIN, MMP-2, -7, -9, -10 and-11 using immunohistochemistry. RESULTS: The tumour cells were positive for EMMPRIN in 100% of the cases. In 82% of CHL the Hodgkin and Reed-Sternberg cells (HRS) were negative for MMP-2. In contrast the surrounding non-neoplastic cells were MMP-2-positive in 71% of the cases. The HRS cells stained positive for MMP-7 in 68% of CHL, whereas only a few surrounding cells were positive for this marker. In all but one case (97%) the HRS cells were negative for MMP-9. However, the surrounding cells stained positive in 32%, thus resembling the staining pattern for MMP-2. Only scattered cells of both populations, HRS cells as well as bystander cells, stained for MMP-10 and -11, and no specific staining pattern was observed. CONCLUSION: Our data indicate a complex interaction between tumour cells and bystander cells with regard to metalloproteinases. The expression of EMMPRIN in the tumour cells may induce the expression of MMP-2 in the surrounding non-neoplastic cells. MMP-2 can be activated by MMP-7, which is expressed in the tumour cells. It is tempting to speculate that an interruption of this cycle could be of therapeutic benefit.

Mirror domain structures induced by interlayer magnetic wall coupling.

We have found that during giant magnetoresistance measurements in approximately 10 x 10 mm(2) NiFe/Cu/Co continuous film spin-valve structures, the resistance value suddenly drops to its absolute minimum during the NiFe reversal. The results reveal that the alignment of all magnetic domains in the NiFe film follow exactly that of corresponding domains in the Co film for an appropriate applied field strength. This phenomenon is caused by trapping of the NiFe domain walls through the magnetostatic interaction with the Co domain-wall stray fields. Consequently, the interlayer domain-wall coupling induces a mirror domain structure in the magnetic trilayer.

Cardiovascular indices of physiological arousal in boys with fragile X syndrome.

In this study, the relationship between physiological arousal, as indexed by heart rate variability, was examined in boys with fragile X syndrome (FXS) and typically developing boys matched on chronological age. In addition, the relationship of heart activity to clinical and molecular factors in the group of boys with FXS was examined. Results suggest that boys with FXS have higher levels of heart activity during the passive phases, as reflected in shorter heart periods. This high level of heart activity appears to be due to increased sympathetic activity and reduced parasympathetic activity. Boys with FXS did not display the expected patterns of heart activity in response to phases of increasing challenge, and sympathetic and parasympathetic systems did not appear coordinated in these boys with FXS. Clinical factors may be related to neural regulation of heart activity while molecular factors do not appear to be.

Homeless women's access to health services: a study of social networks and managed care in the US.

Homeless women experience more severe physical and mental health problems than women in the general population. Under-utilization of health services complicates these health conditions. The study reported here explored how homeless women access health services within the context of shelter living and emerging managed care systems. Informed by grounded theory and dimensional analysis, the investigator conducted in-depth interviews with 19 homeless women, 6 staff from agencies serving homeless women, and 2 community health nurses. Findings revealed that homeless women usually had circuitous rather than direct routes to health services. First, they typically found a social network opportunity structure where brokers could assist them into the health care system. The first tiers of access included a domestic violence shelter, a shelter for single homeless women, and a cafe offering low-cost meals to an inner city homeless population. Even after locating this opportunity structure, the conditions of managed care, with its mechanisms of referral and unfamiliarity with the needs of impoverished women, complicated access. Thus, access requires policies that address not only the availability of health professionals, but also tiers of access that include a social network opportunity structure where women can interact with advocates who broker their entry into the health care system.

Autistic behavior, FMR1 protein, and developmental trajectories in young males with fragile X syndrome.

In the context of a longitudinal study, we assessed the relationship between ratings of autistic behavior, FMR1 protein expression (FMRP), and the developmental trajectories of 55 young males with fragile X syndrome. Autistic behavior, as measured by the Childhood Autism Rating Scale, was not related to FMRP expression. However, autistic behavior was a significant predictor of both developmental status and developmental change. Boys with both autistic behavior and fragile X syndrome functioned at significantly lower levels of development and grew at significantly slower rates than those without autistic behavior. FMRP expression accounted for less variance in developmental level than did autistic behavior, and was not significantly related to slope (developmental change over time). No autistic behavior x FMRP interaction was found.

Homeless women and children's access to health care: a paradox.

Homeless women and children who reside in shelters experience many health-related problems. The aim of the qualitative study reported here was to (a) explore how shelter staffs manage health problems among their residents and assist them in accessing health services, and (b) identify clinical strategies for community health nurses working with this population. Findings demonstrate a paradox whereby homeless shelter staffs try to gain access to care for their residents through a system that is designed to keep them out. In addition, findings indicate a need for increased community health nursing services in homeless shelters. Strategies for resolving this paradox include providing assessment, policy development, and assurance of health care for homeless women and children.

Variability in FMRP and early development in males with fragile X syndrome.

To test the hypothesis that variability in development in fragile X syndrome is related to FMRP (the protein deficient in this syndrome expression), we studied 53 males between 23 and 98 months of age. For the entire group, which included males with either mosaism, partially methylated full mutation, and fully methylated full mutation, FMRP expression ranged from 1% to 40% and accounted for a small but significant amount of variance in level, but not rate, of total development as well as motor, social, adaptive, cognitive, and language development. For males with a fully methylated full mutation, the association was in the hypothesized direction, but not statistically significant. Findings support the hypothesized relationship between FMRP and individual capabilities but suggest that other factors also play a major role.

Family experiences and factors associated with the diagnosis of fragile X syndrome.

The authors interviewed 41 mothers of young boys with fragile X syndrome to determine the process by which they learned their child had fragile X syndrome. The average family had concerns about the child's development at 9 months of age. Developmental delay was determined at an average age of 24 months, and fragile X syndrome was diagnosed at a mean age of 35 months. Considerable variability was found in age of first concern, determination of delay, and diagnosis of fragile X syndrome. Three child variables (severity of delay, autistic behavior, temperament style) and four family variables (mother's age, mother's education, sibling status, social support) did not account for this variability, although birth year did (children born more recently were somewhat more likely to be identified earlier). Families often encountered physicians who initially discounted concerns or said that it was too early to determine whether a problem did indeed exist. Given current knowledge and practice, improving the early identification (under 3 years of age) of children with fragile X syndrome is likely to remain difficult if based solely on behavioral and clinical observations.