Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders

BACKGROUND:Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood. METHODS:Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. RESULTS:Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain. CONCLUSIONS:These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.Siddharth Srivastava, Tejasvi Niranjan, Melanie M. May, Patrick Tarpey, William Allen ... Jozef Gecz ... et al

New fossil remains of Homo naledi from the Lesedi Chamber, South Africa

The Rising Star cave system has produced abundant fossil hominin remains within the Dinaledi Chamber, representing a minimum of 15 individuals attributed to Homo naledi. Further exploration led to the discovery of hominin material, now comprising 131 hominin specimens, within a second chamber, the Lesedi Chamber. The Lesedi Chamber is far separated from the Dinaledi Chamber within the Rising Star cave system, and represents a second depositional context for hominin remains. In each of three collection areas within the Lesedi Chamber, diagnostic skeletal material allows a clear attribution to H. naledi. Both adult and immature material is present. The hominin remains represent at least three individuals based upon duplication of elements, but more individuals are likely present based upon the spatial context. The most significant specimen is the near-complete cranium of a large individual, designated LES1, with an endocranial volume of approximately 610 ml and associated postcranial remains. The Lesedi Chamber skeletal sample extends our knowledge of the morphology and variation of H. naledi, and evidence of H. naledi from both recovery localities shows a consistent pattern of differentiation from other hominin species.SP201

Fertility preservation for male patients with childhood, adolescent, and young adult cancer:recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group

Item does not contain fulltextMale patients with childhood, adolescent, and young adult cancer are at an increased risk for infertility if their treatment adversely affects reproductive organ function. Future fertility is a primary concern of patients and their families. Variations in clinical practice are barriers to the timely implementation of interventions that preserve fertility. As part of the PanCareLIFE Consortium, in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in male patients who are diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. Recognising the need for global consensus, this clinical practice guideline used existing evidence and international expertise to rigorously develop transparent recommendations that are easy to use to facilitate the care of male patients with childhood, adolescent, and young adult cancer who are at high risk of fertility impairment and to enhance their quality of life

Homo naledi, a new species of the genus Homo from the Dinaledi Chamber, South Africa.

Homo naledi is a previously-unknown species of extinct hominin discovered within the Dinaledi Chamber of the Rising Star cave system, Cradle of Humankind, South Africa. This species is characterized by body mass and stature similar to small-bodied human populations but a small endocranial volume similar to australopiths. Cranial morphology of H. naledi is unique, but most similar to early Homo species including Homo erectus, Homo habilis or Homo rudolfensis. While primitive, the dentition is generally small and simple in occlusal morphology. H. naledi has humanlike manipulatory adaptations of the hand and wrist. It also exhibits a humanlike foot and lower limb. These humanlike aspects are contrasted in the postcrania with a more primitive or australopith-like trunk, shoulder, pelvis and proximal femur. Representing at least 15 individuals with most skeletal elements repeated multiple times, this is the largest assemblage of a single species of hominins yet discovered in Africa

The construction of identity through visual intertextuality in a Bohemian early modern travelogue

Cultural historians have long been concerned with visual sources. Their research has centred on ways of reading images and how they can most accurately be interpreted. This article focuses on an alternative aspect of these visual sources: on how images were made and used. It analyses how the identity of a Bohemian Catholic, Bed?ich z Donín, is constructed by his use of images in a travelogue based on his pilgrimage in the early 17th century. Highlighting the process of ‘visual intertextuality’, it claims that the ways in which Donín adopts and adapts visual images reveals his association with various affinity groups. The distinction between ‘actual’ and ‘habitual’ intertextuality is applied to the analysis of this historical source and shows how competing voices are present in the images. This article is an example of how historians can use the methodologies of semioticians to benefit their research

Indigenous women managing pregnancy complications in rural Ecuador

Previous research has explored the potential use of digital health to support maternal health in the Global South highlighting the importance of understanding the socio-cultural context to inform system design. However, the experiences of indigenous women managing pregnancy complications in Latin America remain underexplored in HCI. We present a qualitative study with 25 indigenous pregnant women in an Ecuadorian rural community looking at their experiences during complications, their antenatal care visits and their access and use of technologies. Our findings highlight key barriers that hinder the use of antenatal care services and influence women's experiences managing complications. Based on the findings, we present opportunities for digital health centered on indigenous women to enhance antenatal care in rural Ecuador

Application and validation of the Feeding Infants: Behaviour and Facial Expression Coding System (FIBFECS) to assess liking and wanting in infants at the time of complementary feeding

Introduction: The aim of this study was to validate a novel tool developed to measure liking and wanting in infants during the weaning period. The Feeding Infants: Behaviour and Facial Expression Coding System (FIBFECS; Hetherington et al., in press) is an evidence based video coding tool, consisting of 13 items. There are 6 measures of avoidance/approach behaviours (turns head away, arches back, pushes spoon away, crying/fussy, leaning forward and rate of acceptance) to assess wanting and 7 facial expressions (brow lowered, inner brow raised, squinting, nose wrinkling, lip corners down, upper lip raised and gaping) to assess liking. Lower scores on the total scale indicated greater wanting and/or liking. The tool was applied to a recent randomized control trial (Hetherington et al., 2015). Method: 36 mother-infant dyads took part in the study and were randomised to the intervention or the control group. Infants were filmed on two occasions whilst eating a generally liked vegetable (carrots) and less preferred vegetable (green bean). 72 video extracts were coded by 4 trained researchers with adequate certification scores, each video was coded by at least two coders. Items and scales were tested for discrimination ((1) intervention vs control; (2) liked vs disliked vegetable) and construct validity (correlation with intake and liking assessed by mother and researcher). Results: Very good discrimination (p < 0.001) was obtained for carrots vs green bean for the total score and total negative facial expressions and rejection behaviours (p=0.003). Discrimination for the intervention vs control groups was only obtained for the total rejections and the rate of acceptance (p < 05). The FIBFECS subscales had good construct validity as these were significantly correlated with intake and liking ratings (p < 0.01). Items such as crying/fussy and leaning forward were removed from the scale as well as inner brow raised, squinting and lip corners down, as these do not correlate with other variables. Their removal did not affect the integrity of the scale. The rate of acceptance parameter was found to have potential as a short method to measure wanting in infants. Conclusion: The present study has demonstrated that the FIBFECS can be used to identify liking and wanting independent of subjective ratings from mothers and researchers, therefore, this tool can be used widely in the study of infant responses to novel foods at the time of weaning. There is potential to develop the tool for infants beyond the period of complementary feeding and to assist in identifying fussy eating in the early stages of development

The performance of the jet trigger for the ATLAS detector during 2011 data taking

The performance of the jet trigger for the ATLAS detector at the LHC during the 2011 data taking period is described. During 2011 the LHC provided proton–proton collisions with a centre-of-mass energy of 7 TeV and heavy ion collisions with a 2.76 TeV per nucleon–nucleon collision energy. The ATLAS trigger is a three level system designed to reduce the rate of events from the 40 MHz nominal maximum bunch crossing rate to the approximate 400 Hz which can be written to offline storage. The ATLAS jet trigger is the primary means for the online selection of events containing jets. Events are accepted by the trigger if they contain one or more jets above some transverse energy threshold. During 2011 data taking the jet trigger was fully efficient for jets with transverse energy above 25 GeV for triggers seeded randomly at Level 1. For triggers which require a jet to be identified at each of the three trigger levels, full efficiency is reached for offline jets with transverse energy above 60 GeV. Jets reconstructed in the final trigger level and corresponding to offline jets with transverse energy greater than 60 GeV, are reconstructed with a resolution in transverse energy with respect to offline jets, of better than 4 % in the central region and better than 2.5 % in the forward direction