Experimental and Theoretical Evidence for Nitrogen-Fluorine Halogen Bonding in Silver-Initiated Radical Fluorinations

We report experimental and computational evidence for nitrogen–fluorine halogen bonding in Ag­(I)-initiated radical C–H fluorinations. Simple pyridines form [N–F–N]+ halogen bonds with Selectfluor to facilitate single-electron reduction by catalytic Ag­(I). Pyridine electronics affect the extent of halogen bonding, leading to significant differences in selectivity between mono- and difluorinated products. Electronic structure calculations show that halogen bonding to various pyridines alters the single-electron reduction potential of Selectfluor, which is consistent with experimental electrochemical analysis. Multinuclear correlation NMR also provides spectroscopic evidence for pyridine halogen bonding to Selectfluor under ambient conditions

Strontium is required for statolith development and thus normal swimming behaviour of hatchling cephalopods

When cephalopod eggs were incubated in artificial sea water it was found that they sometimes resulted in hatchlings with defects of the statocyst suprastructure, leading to the severe behavioural defect of uncontrolled swimming. Experiments in defined media (seven basic salts mixed in deionized water) with seven species of cephalopods demonstrated clearly that there is 100% normal development of the aragonite statoliths when strontium levels were 8 mg l-1. Conversely, statoliths did not develop when strontium was absent. In cuttlefish, the growth of the cuttlebone was also affected adversely when strontium was absent. In mariculture production tanks, supplementing commercial artificial sea water with strontium to normal levels of 8 mg l-1 almost eliminated the occurrence of abnormal hatchlings. Circumstantial evidence indicates that there is a critical window in development during which strontium is required for normal development. The role of strontium in biomineralization during embryogenesis is unknown, but it appears to be important in the Mollusca

Material Characterization and Real-Time Wear Evaluation of Pistons and Cylinder Liners of the Tiger 131 Military Tank

Material characterisation and wear evaluation of the original and replacement pistons and cylinder-liners of Tiger 131 is reported. Original piston and cylinder-liner were operative in the Tigers’ engine during WWII. The replacement piston and cylinder-liner were used as substitutes and were obtained after failure in two hours of operation in the actual engine. Material characterisation revealed that the original piston was aluminium silicon hypereutectic alloy whereas the replacement piston was aluminium copper alloy with very low silicon content. Both original and replacement cylinder-liners consisted of mostly iron which is indicative of cast iron, a common material for this application. The replacement piston average surface roughness was found to be 9.09 μm while for replacement cylinder-liner it was 5.78 μm

Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression

The unfolded protein response (UPR) maintains protein homeostasis by governing the processing capacity of the endoplasmic reticulum (ER) to manage ER client loads; however, key regulators within the UPR remain to be identified. Activation of the UPR sensor PERK (EIFAK3/PEK) results in the phosphorylation of the α subunit of eIF2 (eIF2α-P), which represses translation initiation and reduces influx of newly synthesized proteins into the overloaded ER. As part of this adaptive response, eIF2α-P also induces a feedback mechanism through enhanced transcriptional and translational expression of Gadd34 (Ppp1r15A),which targets type 1 protein phosphatase for dephosphorylation of eIF2α-P to restore protein synthesis. Here we describe a novel mechanism by which Gadd34 expression is regulated through the activity of the zinc finger transcription factor NMP4 (ZNF384, CIZ). NMP4 functions to suppress bone anabolism, and we suggest that this occurs due to decreased protein synthesis of factors involved in bone formation through NMP4-mediated dampening of Gadd34 and c-Myc expression. Loss of Nmp4 resulted in an increase in c-Myc and Gadd34 expression that facilitated enhanced ribosome biogenesis and global protein synthesis. Importantly, protein synthesis was sustained during pharmacological induction of the UPR through a mechanism suggested to involve GADD34-mediated dephosphorylation of eIF2α-P. Sustained protein synthesis sensitized cells to pharmacological induction of the UPR, and the observed decrease in cell viability was restored upon inhibition of GADD34 activity. We conclude that NMP4 is a key regulator of ribosome biogenesis and the UPR, which together play a central role in determining cell viability during endoplasmic reticulum stress

Walking and the social life of solar charging in rural Africa

We consider practices that sustain social and physical environments beyond those dominating sustainable HCI discourse. We describe links between walking, sociality, and using resources in a case study of community-based, solar, cellphone charging in villages in South Africa’s Eastern Cape. Like 360 million rural Africans, inhabitants of these villages are poor and, like 25% and 92% of the world, respectively, do not have domestic electricity or own motor vehicles. We describe nine practices in using the charging stations we deployed. We recorded 700 people using the stations, over a year, some regularly. We suggest that the way we frame practices limits insights about them, and consider various routines in using and sharing local resources to discover relations that might also feature in charging. Specifically, walking interconnects routines in using, storing, sharing and sustaining resources, and contributes to knowing, feeling, wanting and avoiding as well as to different aspects of sociality, social order and perspectives on sustainability. Along the way, bodies acquire literacies that make certain relationalities legible. Our study shows we cannot assert what sustainable practice means a priori and, further, that detaching practices from bodies and their paths limits solutions, at least in rural Africa. Thus, we advocate a more “alongly” integrated approach to data about practices.Web of Scienc

Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality

A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor Nuclear Matrix Protein 4 (Nmp4, Zfp384, Ciz, ZNF384) respond to several classes of osteoporosis drugs with enhanced bone formation compared to wild type (WT) animals. Nmp4-/- mesenchymal stem/progenitor cells (MSPCs) exhibit an accelerated and enhanced mineralization during osteoblast differentiation. To address the mechanisms underlying this hyper-anabolic phenotype, we carried out RNA-sequencing and molecular and cellular analyses of WT and Nmp4-/- MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that Nmp4 has a broad impact on the transcriptome during osteogenic differentiation, contributing to the expression of over 5,000 genes. Phenotypic anchoring of transcriptional data was performed for the hypothesis-testing arm through analysis of cell metabolism, protein synthesis and secretion, and bone material properties. Mechanistic studies confirmed that Nmp4-/- MSPCs exhibited an enhanced capacity for glycolytic conversion- a key step in bone anabolism. Nmp4-/- cells showed elevated collagen translation and secretion. Expression of matrix genes that contribute to bone material-level mechanical properties were elevated in Nmp4-/- cells, an observation that was supported by biomechanical testing of bone samples from Nmp4-/- and WT mice. We conclude that loss of Nmp4 increases the magnitude of glycolysis upon the metabolic switch, which fuels the conversion of the osteoblast into a super-secretor of matrix resulting in more bone with improvements in intrinsic quality

DSM-IV defined conduct disorder and oppositional defiant disorder: An investigation of shared liability in female twins

BACKGROUND: DSM-IV specifies a hierarchal diagnostic structure such that an ODD diagnosis is applied only if criteria are not met for CD. Genetic studies of ODD and CD support a combination of shared genetic and environmental influences, but largely ignore the imposed diagnostic structure. METHODS: We examined whether ODD and CD share an underlying etiology while accounting for DSM-IV diagnostic specifications. Data from 1446 female twin pairs, aged 11–19, were fitted to two-stage models adhering to the DSM-IV diagnostic hierarchy. RESULTS: Models suggested that DSM-IV ODD-CD covariation is attributed largely to shared genetic influences. CONCLUSIONS: This is the first study, to our knowledge, to examine genetic and environmental overlap among these disorders while maintaining DSM-IV hierarchical structure. Findings reflect primarily shared genetic influences and specific (i.e., uncorrelated) shared/familial environmental effects on these DSM-IV defined behaviors. These results have implications for how best to define CD and ODD for future genetically-informed analyses

Exploring clinicians' perspectives on the 'Obstetric Anal Sphincter Injury Care Bundle' national quality improvement programme: a qualitative study.

INTRODUCTION: Obstetric anal sphincter injuries (OASI) can have severe debilitating consequences to women and health systems. The OASI Care Bundle quality improvement programme was introduced in 16 maternity units across England, Scotland and Wales (January 2017 to March 2018) to address increasing OASI rates. OBJECTIVES: To explore clinicians' (midwives' and obstetricians') perspectives of the OASI Care Bundle with respect to (1) acceptability, (2) feasibility, and (3) sustainability. DESIGN: A qualitative exploratory study using focus groups methodology. SETTING: A total of 16 focus groups were conducted in 16 maternity units in England, Scotland and Wales where the OASI Care Bundle was implemented. Focus groups took place approximately 3 months following initial implementation of the care bundle in each unit. PARTICIPANTS: A total of 101 clinicians participated, with an average of six per focus group. Participants volunteered to take part and compromised of 37 obstetricians and 64 midwives (including eight students). The majority were female and the mean age was 36.5 years. RESULTS: Four main themes emerged: 'Implementation strategies', 'Opportunities to use the OASI Care Bundle', 'Does current practice need to change?' and 'Perceptions of what women want'. Midwives were more likely than obstetricians to report themes alluding to 'what women want' and variations in intrapartum perineal protection techniques. Both professional groups reported similar views of other themes, in particular regarding the supporting clinical evidence. Gaps were identified in clinicians' knowledge and experience of intrapartum perineal management. CONCLUSIONS: Adoption of the OASI Care Bundle was associated with a number of cognitive and interpersonal factors, such as personal values, interprofessional working and how the intervention was launched; which both facilitated and impeded adoption. The 'what women want' theme has implications for maternal autonomy and needs further exploration. Our findings can be used by similar initiatives to reduce perineal trauma both nationally and internationally. TRIAL REGISTRATION NUMBER: ISCTRN 12143325; https://doi.org/10.1186/ISRCTN12143325

Nuclear matrix proteins distinguish normal diploid osteoblasts from osteosarcoma cells

Interrelationships between nuclear architecture and gene expression were examined by comparing the representation of nuclear matrix proteins in ROS 17/2.8 rat and MG-63 human osteosarcoma cells with those in normal diploid osteoblasts. The tumor-derived cells coexpress genes which are expressed in a sequential and mutually exclusive manner during the progressive stages of osteoblast differentiation. In osteosarcoma cells two-dimensional electrophoretic analysis indicates a composite representation of nuclear matrix proteins characteristic of both the proliferative and postproliferative periods of osteoblast phenotype development. In addition, nuclear matrix proteins unique to the tumor cells and the absence of nuclear matrix proteins found only in normal diploid osteoblasts are observed. Tumor-specific nuclear matrix proteins include those expressed in a proliferation-dependent and independent manner. There is a parallel relationship between nuclear matrix proteins and the expression of cell growth and tissue-specific genes during osteoblast differentiation and in osteosarcoma cells where the developmental sequence of gene expression has been abrogated. Nuclear matrix proteins therefore provide markers reflecting defined periods of bone cell differentiation and phenotypic characteristics of an osteosarcoma

Nmp4/CIZ suppresses the response of bone to anabolic parathyroid hormone by regulating both osteoblasts and osteoclasts

How parathyroid hormone (PTH) increases bone mass is unclear, but understanding this phenomenon is significant to the improvement of osteoporosis therapy. Nmp4/CIZ is a nucleocytoplasmic shuttling transcriptional repressor that suppresses PTH-induced osteoblast gene expression and hormone-stimulated gains in murine femoral trabecular bone. To further characterize Nmp4/CIZ suppression of hormone-mediated bone growth, we treated 10-week-old Nmp4-knockout (KO) and wild-type (WT) mice with intermittent human PTH(1–34) at 30 μg/kg daily or vehicle, 7 days/week, for 2, 3, or 7 weeks. Null mice treated with hormone (7 weeks) gained more vertebral and tibial cancellous bone than WT animals, paralleling the exaggerated response in the femur. Interestingly, Nmp4/CIZ suppression of this hormone-stimulated bone formation was not apparent during the first 2 weeks of treatment. Consistent with the null mice enhanced PTH-stimulated addition of trabecular bone, these animals exhibited an augmented hormone-induced increase in serum osteocalcin 3 weeks into treatment. Unexpectedly, the Nmp4-KO mice displayed an osteoclast phenotype. Serum C-terminal telopeptide, a marker for bone resorption, was elevated in the null mice, irrespective of treatment. Nmp4-KO bone marrow cultures produced more osteoclasts, which exhibited elevated resorbing activity, compared to WT cultures. The expression of several genes critical to the development of both osteoblasts and osteoclasts was elevated in Nmp4-KO mice at 2 weeks, but not 3 weeks, of hormone exposure. We propose that Nmp4/CIZ dampens PTH-induced improvement of trabecular bone throughout the skeleton by transiently suppressing hormone-stimulated increases in the expression of proteins key to the required enhanced activity and number of both osteoblasts and osteoclasts