Frontolimbic neural circuitry at 6 months predicts individual differences in joint attention at 9 months

Elucidating the neural basis of joint attention in infancy promises to yield important insights into the development of language and social cognition, and directly informs developmental models of autism. We describe a new method for evaluating responding to joint attention performance in infancy that highlights the 9- to 10-month period as a time interval of maximal individual differences. We then demonstrate that fractional anisotropy in the right uncinate fasciculus, a white matter fiber bundle connecting the amygdala to the ventral-medial prefrontal cortex and anterior temporal pole, measured in 6-month-olds predicts individual differences in responding to joint attention at 9 months of age. The white matter microstructure of the right uncinate was not related to receptive language ability at 9 months. These findings suggest that the development of core nonverbal social communication skills in infancy is largely supported by preceding developments within right lateralized frontotemporal brain systems

Cross-Sectional Associations Bet ween Abdominal and Thoracic Adipose Tissue Compartments and Adiponectin and Resistin in the Framingham Heart Study

OBJECTIVE: To test the association of regional fat depots with circulating adiponectin and resistin concentrations and to assess the potential mediating effect of adipokines on associations between abdominal fat depots and cardiometabolic risk factors. RESEARCH DESIGN AND METHODS: Participants from the Framingham Heart Study offspring cohort (n = 916, 55% women; mean age 59 years) free of cardiovascular disease underwent computed tomography measurement of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), pericardial fat, and intrathoracic fat volumes and assays of circulating adiponectin and resistin. RESULTS: VAT, SAT, pericardial fat, and intrathoracic fat were negatively correlated with adiponectin (r = −0.19 to −0.34, P < 0.001 [women]; r = −0.15 to −0.26, P < 0.01 [men] except SAT) and positively correlated with resistin (r = 0.16–0.21, P < 0.001 [women]; r = 0.11–0.14, P < 0.05 [men] except VAT). VAT increased the multivariable model R2 for adiponectin from 2–4% to 10–13% and for resistin from 3–4% to 3–6%. Adjustment for adipokines did not fully attenuate associations between VAT, SAT, and cardiometabolic risk factors. CONCLUSIONS: Adiponectin and resistin are correlated with fat depots cross-sectionally, but none of the adipokines can serve as surrogates for the fat depots. Relations between VAT, SAT, and cardiometabolic risk factors were not fully explained by adiponectin or resistin concentrations.National Insitute's of Health National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195); the National Institutes of Health; National Center for Research Resources; General Clinical Research Centers Program (M01-RR-01066); Career Development Award from the American Diabetes Association; National Institute of Diabetes and Digestive and Kidney Diseases (K24 DK080140, RO1 DK080739); National Heart, Lung, and Blood Institute, National Institutes of Health (2K24HL04334

Star formation in 30 Doradus

Using observations obtained with the Wide Field Camera 3 (WFC3) on board the Hubble Space Telescope (HST), we have studied the properties of the stellar populations in the central regions of 30 Dor, in the Large Magellanic Cloud. The observations clearly reveal the presence of considerable differential extinction across the field. We characterise and quantify this effect using young massive main sequence stars to derive a statistical reddening correction for most objects in the field. We then search for pre-main sequence (PMS) stars by looking for objects with a strong (> 4 sigma) Halpha excess emission and find about 1150 of them over the entire field. Comparison of their location in the Hertzsprung-Russell diagram with theoretical PMS evolutionary tracks for the appropriate metallicity reveals that about one third of these objects are younger than ~4Myr, compatible with the age of the massive stars in the central ionising cluster R136, whereas the rest have ages up to ~30Myr, with a median age of ~12Myr. This indicates that star formation has proceeded over an extended period of time, although we cannot discriminate between an extended episode and a series of short and frequent bursts that are not resolved in time. While the younger PMS population preferentially occupies the central regions of the cluster, older PMS objects are more uniformly distributed across the field and are remarkably few at the very centre of the cluster. We attribute this latter effect to photoevaporation of the older circumstellar discs caused by the massive ionising members of R136.Comment: 15 pages, 12 figures. Accepted for publication in The Astrophysical Journa

Mapping the processivity determinants of the kinesin-3 motor domain

Kinesin superfamily members play important roles in many diverse cellular processes, including cell motility, cell division, intracellular transport, and regulation of the microtubule cytoskeleton. How the properties of the family-defining motor domain of distinct kinesins are tailored to their different cellular roles remains largely unknown. Here, we employed molecular-dynamics simulations coupled with energetic calculations to infer the family-specific interactions of kinesin-1 and kinesin-3 motor domains with microtubules in different nucleotide states. We then used experimental mutagenesis and single-molecule motility assays to further assess the predicted residue-wise determinants of distinct kinesin-microtubule binding properties. Collectively, our results identify residues in the L8, L11, and α6 regions that contribute to family-specific microtubule interactions and whose mutation affects motor-microtubule complex stability and processive motility (the ability of an individual motor to take multiple steps along its microtubule filament). In particular, substitutions of prominent kinesin-3 residues with those found in kinesin-1, namely, R167S/H171D, K266D, and R346M, were found to decrease kinesin-3 processivity 10-fold and thus approach kinesin-1 levels

Development of white matter circuitry in infants with fragile x syndrome

IMPORTANCE Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy. OBJECTIVE To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls. DESIGN, SETTING, AND PARTICIPANTS Longitudinal behavioral and brain imaging datawere collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second-degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder. MAIN OUTCOMES AND MEASURES Nineteen major white matter pathwayswere defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development. RESULTS There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age × group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate, F = 10.06; false discovery rate-corrected P = .03; right uncinate, F = 21.8; P = .004). CONCLUSIONS AND RELEVANCE The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age

Lifespan extension and the doctrine of double effect

Recent developments in biogerontology—the study of the biology of ageing—suggest that it may eventually be possible to intervene in the human ageing process. This, in turn, offers the prospect of significantly postponing the onset of age-related diseases. The biogerontological project, however, has met with strong resistance, especially by deontologists. They consider the act of intervening in the ageing process impermissible on the grounds that it would (most probably) bring about an extended maximum lifespan—a state of affairs that they deem intrinsically bad. In a bid to convince their deontological opponents of the permissibility of this act, proponents of biogerontology invoke an argument which is grounded in the doctrine of double effect. Surprisingly, their argument, which we refer to as the ‘double effect argument’, has gone unnoticed. This article exposes and critically evaluates this ‘double effect argument’. To this end, we first review a series of excerpts from the ethical debate on biogerontology in order to substantiate the presence of double effect reasoning. Next, we attempt to determine the role that the ‘double effect argument’ is meant to fulfil within this debate. Finally, we assess whether the act of intervening in ageing actually can be justified using double effect reasoning

The Large Zinc Finger Protein ZAS3 Is a Critical Modulator of Osteoclastogenesis

Mice deficient in the large zinc finger protein, ZAS3, show postnatal increase in bone mass suggesting that ZAS3 is critical in the regulation of bone homeostasis. Although ZAS3 has been shown to inhibit osteoblast differentiation, its role on osteoclastogenesis has not been determined. In this report we demonstrated the role of ZAS3 in bone resorption by examining the signaling mechanisms involved in osteoclastogenesis.Comparison of adult wild-type and ZAS3 knockout (ZAS3-/-) mice showed that ZAS3 deficiency led to thicker bones that are more resistant to mechanical fracture. Additionally, ZAS3-/- bones showed fewer osteoclasts and inefficient M-CSF/sRANKL-mediated osteoclastogenesis ex vivo. Utilizing RAW 264.7 pre-osteoclasts, we demonstrated that overexpression of ZAS3 promoted osteoclastogenesis and the expression of crucial osteoclastic molecules, including phospho-p38, c-Jun, NFATc1, TRAP and CTSK. Contrarily, ZAS3 silencing by siRNA inhibited osteoclastogenesis. Co-immunoprecipitation experiments demonstrated that ZAS3 associated with TRAF6, the major receptor associated molecule in RANK signaling. Furthermore, EMSA suggested that nuclear ZAS3 could regulate transcription by binding to gene regulatory elements.Collectively, the data suggested a novel role of ZAS3 as a positive regulator of osteoclast differentiation. ZAS3 deficiency caused increased bone mass, at least in part due to decreased osteoclast formation and bone resorption. These functions of ZAS3 were mediated via activation of multiple intracellular targets. In the cytoplasmic compartment, ZAS3 associated with TRAF6 to control NF-kB and MAP kinase signaling cascades. Nuclear ZAS3 acted as a transcriptional regulator for osteoclast-associated genes. Additionally, ZAS3 activated NFATc1 required for the integration of RANK signaling in the terminal differentiation of osteoclasts. Thus, ZAS3 was a crucial molecule in osteoclast differentiation, which might potentially serve as a target in the design of therapeutic interventions for the treatment of bone diseases related to increased osteoclast activity such as postmenopausal osteoporosis, Paget's disease, and rheumatoid arthritis

Progressive star formation in the young galactic super star cluster NGC 3603

Early release science observations of the cluster NGC3603 with the WFC3 on the refurbished HST allow us to study its recent star formation history. Our analysis focuses on stars with Halpha excess emission, a robust indicator of their pre-main sequence (PMS) accreting status. The comparison with theoretical PMS isochrones shows that 2/3 of the objects with Halpha excess emission have ages from 1 to 10 Myr, with a median value of 3 Myr, while a surprising 1/3 of them are older than 10 Myr. The study of the spatial distribution of these PMS stars allows us to confirm their cluster membership and to statistically separate them from field stars. This result establishes unambiguously for the first time that star formation in and around the cluster has been ongoing for at least 10-20 Myr, at an apparently increasing rate.Comment: 10 pages, 8 figures, accepted for publication in The Astrophysical Journa

Illness Labels and Social Distance

The authors examine a key proposition in the modified labeling theory—that a psychiatric label increases vulnerability to negative evaluation and social rejection—using an experimental design wherein female participants interact with a female teammate over a computer. The authors also evaluate a hypothesis derived from the disease-avoidance account of disgust by examining this same process for a nonpsychiatric illness: food poisoning. In addition, they introduce a composite measure of social distance behavior that is easy to implement in a laboratory experiment. The authors find, as predicted, that women seek greater social distance from teammates with a history of psychiatric or food poisoning hospitalization than they do from teammates with no hospitalization history. But, contrary to predictions, a teammate’s hospitalization history does not affect participants’ ratings of her likability. The results also do not vary significantly by psychiatric diagnosis (depression vs. schizophrenia), suggesting that the stigma of depression may be just as strong as the stigma of schizophrenia when information about symptoms is not available. The authors discuss the implications of these findings for the modified labeling theory of mental illness and for the literature on disgust and stigma. They also outline avenues for future research.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline