Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b

Pseudohypoparathyroidism (PHP) is caused by reduced expression of genes within the GNAS cluster, resulting in parathormone resistance. The cluster contains multiple imprinted transcripts, including the stimulatory G protein α subunit (Gs-α) and NESP55 transcript preferentially expressed from the maternal allele, and the paternally expressed XLas, A/B and antisense transcripts. PHP1b can be caused by loss of imprinting affecting GNAS A/B alone (associated with STX16 deletion), or the entire GNAS cluster (associated with deletions of NESP55 in a minority of cases). We performed targeted genomic next-generation sequencing (NGS) of the GNAS cluster to seek variants and indels underlying PHP1b. Seven patients were sequenced by hybridisation-based capture and fourteen more by long-range PCR and transposon-mediated insertion and sequencing. A bioinformatic pipeline was developed for variant and indel detection. In one family with two affected siblings, and in a second family with a single affected individual, we detected maternally inherited deletions of 40 and 33 bp, respectively, within the deletion previously reported in rare families with PHP1b. All three affected individuals presented with atypically severe PHP1b; interestingly, the unaffected mother in one family had the detected deletion on her maternally inherited allele. Targeted NGS can reveal sequence changes undetectable by current diagnostic methods. Identification of genetic mutations underlying epigenetic changes can facilitate accurate diagnosis and counselling, and potentially highlight genetic elements critical for normal imprint settin

Expression of Human Papillomavirus Type 16 E7 Is Sufficient To Significantly Increase Expression of Angiogenic Factors But Is Not Sufficient To Induce Endothelial Cell Migration

Indiana University-Purdue University Indianapolis (IUPUI)Human papillomavirus 16 (HPV 16) causes cancer. Two viral oncoproteins of HPV 16, E6 and E7, are consistently expressed in these cancers. HPV 16 E6 and E7 proteins target p53 and Rb family members, respectively, for degradation thus inactivating the functiond of these tumor suppressor proteins. Tumor development requires the acquisition of a blood supply, a process known as angiogenesis. Tumor suppressors negatively regulate angigogenesis. Expression of HPV 16 E6 and E7 together in human foreskin keratinocytes (HFKs) increases the level of angiogenic inducers vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Further, conditioned media from such cells are sufficient to alter endothelial cell behavior both in vitro and in vivo. To determine the individual contributions of HPV E6 and E7 to angiogenesis, translational termination linkers (TTLs) were inserted into the coding region of E6 or E7. Following retroviral transduction of the mutated cassette into HFKs, the ability of E7 in the context of the E6TTL mutation (E6TTLE7) and E6 in the context of the E7TTL mutation (E6E7TTL) to induce VEGF and IL-8 was compared to the LXSN control retrovirus. E7 and, to a lesser extent E6, increased the expression of VEGF and IL-8. Migration of human microvascular endothelial cells was not induced using conditioned media from either E6 or E7 expressing cells. Since the increased levels of VEGF and IL-8 induced by HPV 16E6ETTLE7 were not sufficient to alter endothelial cell behavior, immunological depletion experiments were used to determine whether either angiogenic factor was required for HPV 16E6 and E7 together to induce HMVEC migration. Only VEGF was required. Preliminary data suggest that the ability of HPV 16 E7 to induce angiogenic factors is dependent upon degradation of a specific Rb family member

How do healthy individuals adapt to reversed vision generated when using mirror specs? An investigation into mirror devices, adaptation to body schema and imagery ability in healthy participants

Introduction: This study investigates a new form of Mirror Therapy (MT), the Mirror Specs. Evidence suggests that MT is a non-invasive, cost effective method of reducing pain and increasing functioning in some chronic pain conditions. There is no clear explanation for the underlying mechanisms of MT, however, a plausible hypothesis suggests that adaptation to the Body Schema is an integral component. Aims and Hypotheses: The current study examined Body Schema adaptation in healthy participants when performing a Finger Tapping Task with both Mirror Specs and a Mirror Box. It was hypothesised that adaptation would be indicated by increases in Reaction Times (RTs) and Error Rates when comparing unimanual phases of a Finger Tapping Task, following a bimanual „adaptation‟ phase. It was hypothesised that there would be no difference between participants‟ ability to adapt to each device. Finally, the study proposed that there would be a relationship between the adaptation observed on the Finger Tapping Task and participants individual imagery abilities. Method: Participants performed 4 phases of a Finger Tapping Task with alternate bimanual and unimanual phases when using both the Mirror Specs and Mirror Box. Imagery abilities were measured using self-report questionnaires and a Motor Imagery computer task. Results and Discussion: Repeated Measures ANOVAs revealed reductions in RTs and Error Rates in Phase 3 compared to Phase 1 on the Finger Tapping Task. There were no differences between RTs and Error Rates when using the Mirror Specs and Mirror Box. These findings suggest that healthy participants were able to use each Mirror Device effectively and this provide impetus for the proposal that Mirror Specs could provide a practical, cost effective addition to rehabilitation services. Finally, there were no clinically significant relationships between use of the Mirror Devices and imagery abilities, thereby indicating imagery abilities did not influence how participants adapted to using the Mirror Devices

Emon: an R-package to support the design of marine ecological and environmental studies, surveys and monitoring programmes

1. Marine systems and their biota are always changing, in response to environmental and human pressures such as climate variation and change, eutrophication, fisheries exploitation, litter, noise and accidental releases or regular discharges of contaminants, radioactivity and hazardous substances. Studies, surveys and monitoring help to describe and understand system responses to these pressures, and provide evidence to assess the needs for, and effects of, management interventions. Studies, surveys and monitoring are often costly, especially offshore, so small investments in preliminary data collection and systematic planning of these activities can help to make best use of resources and inform trade-offs between budgets and expectations. 2. To meet recognised needs for accessible tools to plan some aspects of studies, surveys and monitoring, we developed the R package emon. Emon includes routines for study design through power analysis (assuming independence of observations) and feature detection; which are the focus of this paper. 3. We hope that access to the functions in emon, many drawing on work which was previously published but without code for implementation, will raise awareness of what marine studies, surveys and monitoring can achieve, thus encouraging cost-effective, needs- and evidence-based designs

A Systematic Review: The Impact of Social Support Programs on Caregiver Burnout for Caregivers of Children with Cancer

Title: A Systematic Review: The Impact of Social Support Programs on Caregiver Burnout for Caregivers of Children with Cancer Background: In addition to children diagnosed with cancer, their caregivers may also experience hardship. While caregivers handle their own personal responsibilities, they also provide emotional, physical, and financial support to their children. In addition to the likely stress that occurs from caring for a child with a long-term illness, lack of social support, educational resources, or support programs may lead to caregiver burnout. Objective: The purpose of the systematic review was to review published research focused on caregiver burnout for caregivers of children diagnosed with cancer and the impact of social support programs on caregiver burnout. Methods: A systematic literature review was conducted using PubMed and CINAHL databases to search for peer-reviewed journal articles that were published between 2011 and 2021. Inclusion and exclusion criteria were used to screen studies using specific keywords such as “caregiver”, “burnout”, “children with cancer”, “childhood cancer”, “social support program”, and “therapy”. Relevant articles were assessed and evaluated for the highest quality to include in the final review. Results: Eight articles were chosen and assessed from the initial search. Interventions such as family therapy, internet-based self-help, acceptance and commitment therapy (ACT), promoting resilience in stress management for parents (PRISM-P), and religious participation demonstrated improvement in decreasing caregiver burnout for caregivers of children with cancer. Conclusion: Social support, educational resources, and support programs may decrease the level of burnout for caregivers as they care for their children compared to caregivers with a lack of support. Keywords: Childhood cancer, caregiver burden, social suppor

Dredging and Shipping Impacts on Southeast Florida Coral Reefs

Many coastal regions have experienced extensive population growth during the last century. Commonly, this growth has led to port development and expansion as well as increased vessel activity which can have detrimental effects on coral reef ecosystems. In southeast Florida, three major ports built in the late 1920’s along 112 km of coastline occur in close proximity to a shallow coral reef ecosystem. Recent habitat mapping data were analyzed in GIS to quantify the type and area of coral reef habitats impacted by port and shipping activities. Impact areas were adjusted by impact severity: 100% of dredge and burial areas, 75% of grounding and anchoring areas, and 15% of areas in present anchorage. Estimates of recent local stony coral density and cover data were used to quantify affected corals and live cover. After adjusting for impact severity, 312.5 hectares (ha) of impacted coral reef habitats were identified. Burial by dredge material accounted for 175.8 ha. Dredging of port inlet channels accounted for 84.5 ha of reef removal. And 47.6 ha were impacted from a large ship anchorage. Although the full extent of all ship groundings and anchor drags associated with the ports is unknown, the measured extents of these events totaled 6 ha. Based on the adjusted impact areas, over 8.1million corals covering over 11.7 ha of live cover were impacted. Burial impacts were the greatest. The planned expansion of two of the ports would remove an additional approximate 9.95 ha of coral reef habitat. Ongoing marine spatial planning efforts are evaluating the placement of large ship anchorages in an effort reduce future impacts from ship anchoring. However, increasing populations and shipping needs will likely continue to be prioritized over protection of these valuable natural resources

Does repetitive task training improve functional activity after stroke? A Cochrane systematic review and meta-analysis.

Repetitive task training resulted in modest improvement across a range of lower limb outcome measures, but not upper limb outcome measures. Training may be sufficient to have a small impact on activities of daily living. Interventions involving elements of repetition and task training are diverse and difficult to classify: the results presented are specific to trials where both elements are clearly present in the intervention, without major confounding by other potential mechanisms of action

Influence of Fault System Geometry and Slip Rates on the Relative Role of Coseismic and Interseismic Stresses on Earthquake Triggering and Recurrence Variability

We model Coulomb stress transfer (CST) due to 30 strong earthquakes occurring on normal faults since 1509 CE in Calabria, Italy, including the influence of interseismic loading, and compare the results to existing studies of stress interaction from the Central and Southern Apennines, Italy. The three normal fault systems have different geometries and long‐term slip‐rates. We investigate the extent to which stress transfer can influence the occurrence of future earthquakes and what factors may govern the variability in earthquake recurrence in different fault systems. The Calabrian, Central Apennines, and Southern Apennines fault systems have 91%, 73%, and 70% of faults with mean positive cumulative CST in the time considered; this is due to fewer faults across strike, more across strike stress reductions, and greater along‐strike spacing in the three regions respectively. In regions with close along strike spacing or few faults across strike, such as Calabria and Southern Apennines, the stress loading history is mostly dominated by interseismic loading and most faults are positively stressed before an earthquake occur on them (96% of all faults that ruptured in Calabria; 94% of faults in Southern Apennines), and some of the strongest earthquakes occur on faults with the highest mean cumulative stress of all faults prior to the earthquake. In the Central Apennines, where across strike interactions are the predominant process, 79% of earthquakes occur on faults positively stressed. The results highlight that fault system geometry plays a central role in characterizing the stress evolution associated with earthquake recurrence

Mapping of ESE-1 subdomains required to initiate mammary epithelial cell transformation via a cytoplasmic mechanism

<p>Abstract</p> <p>Background</p> <p>The ETS family transcription factor ESE-1 is often overexpressed in human breast cancer. ESE-1 initiates transformation of MCF-12A cells via a non-transcriptional, cytoplasmic process that is mediated by a unique 40-amino acid serine and aspartic acid rich (SAR) subdomain, whereas, ESE-1's nuclear transcriptional property is required to maintain the transformed phenotype of MCF7, ZR-75-1 and T47D breast cancer cells.</p> <p>Results</p> <p>To map the minimal functional nuclear localization (NLS) and nuclear export (NES) signals, we fused in-frame putative NLS and NES motifs between GFP and the SAR domain. Using these GFP constructs as reporters of subcellular localization, we mapped a single NLS to six basic amino acids (²⁴²HGKRRR²⁴⁷) in the AT-hook and two CRM1-dependent NES motifs, one to the pointed domain (NES1: ¹⁰²LCNCALEELRL¹¹²) and another to the DNA binding domain (DBD), (NES2: ²⁷⁵LWEFIRDILI²⁸⁴). Moreover, analysis of a putative NLS located in the DBD (³¹⁶GQKKKNSN³²³) by a similar GFP-SAR reporter or by internal deletion of the DBD, revealed this sequence to lack NLS activity. To assess the role of NES2 in regulating ESE-1 subcellular localization and subsequent transformation potency, we site-specifically mutagenized NES2, within full-length GFP-ESE-1 and GFP-NES2-SAR reporter constructs. These studies show that site-specific mutation of NES2 completely abrogates ESE-1 transforming activity. Furthermore, we show that exclusive cytoplasmic targeting of the SAR domain is sufficient to initiate transformation, and we report that an intact SAR domain is required, since block mutagenesis reveals that an intact SAR domain is necessary to maintain its full transforming potency. Finally, using a monoclonal antibody targeting the SAR domain, we demonstrate that the SAR domain contains a region accessible for protein - protein interactions.</p> <p>Conclusions</p> <p>These data highlight that ESE-1 contains NLS and NES signals that play a critical role in regulating its subcellular localization and function, and that an intact SAR domain mediates MEC transformation exclusively in the cytoplasm, via a novel nontranscriptional mechanism, whereby the SAR motif is accessible for ligand and/or protein interactions. These findings are significant, since they provide novel molecular insights into the functions of ETS transcription factors in mammary cell transformation.</p