The level of BMP4 signaling is critical for the regulation of distinct T-box gene expression domains and growth along the dorso-ventral axis of the optic cup

BACKGROUND: Polarised gene expression is thought to lead to the graded distribution of signaling molecules providing a patterning mechanism across the embryonic eye. Bone morphogenetic protein 4 (Bmp4) is expressed in the dorsal optic vesicle as it transforms into the optic cup. Bmp4 deletions in human and mouse result in failure of eye development, but little attempt has been made to investigate mammalian targets of BMP4 signaling. In chick, retroviral gene overexpression studies indicate that Bmp4 activates the dorsally expressed Tbx5 gene, which represses ventrally expressed cVax. It is not known whether the Tbx5 related genes, Tbx2 and Tbx3, are BMP4 targets in the mammalian retina and whether BMP4 acts at a distance from its site of expression. Although it is established that Drosophila Dpp (homologue of vertebrate Bmp4) acts as a morphogen, there is little evidence that BMP4 gradients are interpreted to create domains of BMP4 target gene expression in the mouse. RESULTS: Our data show that the level of BMP4 signaling is critical for the regulation of distinct Tbx2, Tbx3, Tbx5 and Vax2 gene expression domains along the dorso-ventral axis of the mouse optic cup. BMP4 signaling gradients were manipulated in whole mouse embryo cultures during optic cup development, by implantation of beads soaked in BMP4, or the BMP antagonist Noggin, to provide a local signaling source. Tbx2, Tbx3 and Tbx5, showed a differential response to alterations in the level of BMP4 along the entire dorso-ventral axis of the optic cup, suggesting that BMP4 acts across a distance. Increased levels of BMP4 caused expansion of Tbx2 and Tbx3, but not Tbx5, into the ventral retina and repression of the ventral marker Vax2. Conversely, Noggin abolished Tbx5 expression but only shifted Tbx2 expression dorsally. Increased levels of BMP4 signaling caused decreased proliferation, reduced retinal volume and altered the shape of the optic cup. CONCLUSION: Our findings suggest the existence of a dorsal-high, ventral-low BMP4 signaling gradient across which distinct domains of Tbx2, Tbx3, Tbx5 and Vax2 transcription factor gene expression are set up. Furthermore we show that the correct level of BMP4 signaling is critical for normal growth of the mammalian embryonic eye

"A hard day’s night?" The effects of Compressed Working Week interventions on the health and work-life balance of shift workers: a systematic review

Objective: To systematically review studies of the effects of the Compressed Working Week on the health and work-life balance of shift workers, and to identify any differential impacts by socio-economic group. Methods: Systematic review. Following QUORUM guidelines, published or unpublished experimental and quasi-experimental studies were identified. Data were sourced from 27 electronic databases, websites, bibliographies, and expert contacts. Results: Forty observational studies were found. The majority of studies only measured self-reported outcomes and the methodological quality of the included studies was not very high. Interventions did not always improve the health of shift workers, but in the five prospective studies with a control group, there were no detrimental effects on self-reported health. However, work-life balance was generally improved. No studies reported differential impacts by socio-economic group; however, most of the studies were conducted on homogeneous populations. Conclusion: This review suggests that the Compressed Working Week can improve work-life balance, and that it may do so with a low risk of adverse health or organisational effects. However, better designed studies that measure objective health outcomes are needed

Metabolic regulation of ApoB mRNA editing is associated with phosphorylation of APOBEC-1 complementation factor

Apolipoprotein B (apoB) mRNA editing is a nuclear event that minimally requires the RNA substrate, APOBEC-1 and APOBEC-1 Complementation Factor (ACF). The co-localization of these macro-molecules within the nucleus and the modulation of hepatic apoB mRNA editing activity have been described following a variety of metabolic perturbations, but the mechanism that regulates editosome assembly is unknown. APOBEC-1 was effectively co-immunoprecipitated with ACF from nuclear, but not cytoplasmic extracts. Moreover, alkaline phosphatase treatment of nuclear extracts reduced the amount of APOBEC-1 co-immunoprecipitated with ACF and inhibited in vitro editing activity. Ethanol stimulated apoB mRNA editing was associated with a 2- to 3-fold increase in ACF phosphorylation relative to that in control primary hepatocytes. Significantly, phosphorylated ACF was restricted to nuclear extracts where it co-sedimented with 27S editing competent complexes. Two-dimensional phosphoamino acid analysis of ACF immunopurified from hepatocyte nuclear extracts demonstrated phosphorylation of serine residues that was increased by ethanol treatment. Inhibition of protein phosphatase I, but not PPIIA or IIB, stimulated apoB mRNA editing activity coincident with enhanced ACF phosphorylation in vivo. These data demonstrate that ACF is a metabolically regulated phosphoprotein and suggest that this post-translational modification increases hepatic apoB mRNA editing activity by enhancing ACF nuclear localization/retention, facilitating the interaction of ACF with APOBEC-1 and thereby increasing the probability of editosome assembly and activity

Multiple GF-1 binding sites flank the erythroid specific transcription unit of the human carbonic anhydrase I gene

AbstractSix potential GF-1 sites which bind an erythroid factor are present in the 5' and 3' regions flanking the erythroid-speciflc transcription unit of the human carbonic anhydrase 1 (HCAI) gene. When two of these sites are placed upstream of a minimal eukaryotic promoter they confer upregulated expression in erythroid over non-erythroid cells. The presence of the erythroid factor in TPA-treated HEL cells in which the level of HCAI transcript has greatly decreased and in non-HCAI-expressing K562 cells suggests that in these cases the presence of the factor is not sufficient for HCAI expression

Spectrum of Mutations in NDP Resulting in Ocular Disease; a Systematic Review

Aims and Rationale: The inner retina is supplied by three intraretinal capillary plexi whereas the outer retina is supplied by the choroidal circulation: NDP is essential for normal intraretinal vascularisation. Pathogenic variants in NDP (Xp11.3) may result in either a severe retinal phenotype associated with hearing loss (Norrie Disease) or a moderate retinal phenotype (Familial Exudative Vitreoretinopathy, FEVR). However, little is known about whether the nature or location of the NDP variant is predictive of severity. In this systematic review we summarise all reported NDP variants and draw conclusions about whether the nature of the NDP variant is predictive of the severity of the resulting ocular pathology and associated hearing loss and intellectual disability. Findings: 201 different variants in the NDP gene have been reported as disease-causing. The pathological phenotype that may result from a disease-causing NDP variant is quite diverse but generally comprises a consistent cluster of features (retinal hypovascularisation, exudation, persistent foetal vasculature, tractional/exudative retinal detachment, intellectual disability and hearing loss) that vary predictably with severity. Previous reviews have found no clear pattern in the nature of NDP mutations that cause either FEVR or Norrie disease, with the exception that mutations affecting cysteine residues have been associated with Norrie Disease and that visual loss amongst patients with Norrie disease tends to be more severe if the NDP mutation results in an early termination of translation as opposed to a missense related amino acid change. A key limitation of previous reviews has been variability in the case definition of Norrie disease and FEVR amongst authors. We thus reclassified patients into two groups based only on the severity of their retinal disease. Of the reported pathogenic variants that have been described in more than one patient, we found that any given variant caused an equivalent severity of retinopathy each time it was reported with very few exceptions. We therefore conclude that specific NDP mutations generally result in a consistent retinal phenotype each time they arise. Reports by different authors of the same variant causing either FEVR or Norrie disease conflict primarily due to variability in the authors' respective case definitions rather than true differences in disease severity

What helps to support people affected by Adverse Childhood Experiences? A review of evidence

Adverse Childhood Experiences (ACEs) include physical, sexual or emotional abuse; neglect; domestic violence in the home; homelessness or living in care; parental mental health problems or substance abuse; and parents who are absent through imprisonment, separation or death. We sought to understand how people affected by ACEs can best be supported by conducting a review of evidence. The review involved three components: a qualitative synthesis of UK views studies; a systematic review of reviews which measured the effectiveness of interventions to support people affected by ACEs; and a stakeholder workshop with young people with lived experience of ACEs. The review was commissioned by the Department of Health and Social Care

Molecular pathology of Usher 1B patient-derived retinal organoids at single cell resolution

Usher syndrome-associated retinitis pigmentosa (RP) causes progressive retinal degeneration, which has no cure. The pathomechanism of Usher type 1B (USH1B)-RP caused by MYO7A mutation remains elusive because of the lack of faithful animal models and limited knowledge of MYO7A function. Here, we analyzed 3D retinal organoids generated from USH1B patient-derived induced pluripotent stem cells. Increased differential gene expression occurred over time without excessive photoreceptor cell death in USH1B organoids compared with controls. Dysregulated genes were enriched first for mitochondrial functions and then proteasomal ubiquitin-dependent protein catabolic processes and RNA splicing. Single-cell RNA sequencing revealed MYO7A expression in rod photoreceptor and Müller glial cells corresponding to upregulation of stress responses in NRL+ rods and apoptotic signaling pathways in VIM+ Müller cells, pointing to the defensive mechanisms that mitigate photoreceptor cell death. This first human model for USH1B-RP provides a representation of patient retina in vivo relevant for development of therapeutic strategies

Effects of Pacing When Using Material Handling Manipulators

Common manipulator-assisted materials handling tasks were performed in a laboratory simulation at self-selected and faster (paced) speeds. The effects of pacing on peak hand forces, torso kinematics, spine moments and forces, and muscle antagonism were determined, along with any influences of several task variables on these effects. The faster trials were performed 20% more rapidly than the self-paced trials. It was found that (a) achieving this level of performance required 10% higher hand forces and 5%-10% higher torso moments, (b) consistent torso postures and motions were used for both speed conditions, and (c) the faster trials resulted in 10% higher spine forces and 15% higher levels of lumbar muscle antagonism. On whole, these results suggest a higher risk of musculoskeletal injury associated with performance of object transfers at faster than self-selected speeds with and without a manipulator. Further analysis provided evidence that the use of manipulators involves higher levels of motor coordination than do manual tasks. Several implications regarding the use of material handling manipulators in paced operations are discussed. Results from this investigation can be used in the design, evaluation, and selection of material handling manipulators.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67067/2/10.1518_001872099779591240.pd