Abstract Background Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with ...significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit. Report Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G > A p.(Arg1914His); c.3010C > T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G > A p.(Arg1914His); c.2032C > T p.(Glu678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency. Discussion Homozygous missense NBAS variants cause SOPH syndrome (short stature; optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from ‘Classical’ OI. Conclusions Here we report on variants in NBAS , as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS . We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients.
The multifunctional protein, splicing factor, proline- and glutamine-rich (SFPQ) has been implicated in numerous cancers often due to interaction with coding and non-coding RNAs, however, its role in ...melanoma remains unclear. We report that knockdown of SFPQ expression in melanoma cells decelerates several cancer-associated cell phenotypes, including cell growth, migration, epithelial to mesenchymal transition, apoptosis, and glycolysis. RIP-seq analysis revealed that the SFPQ-RNA interactome is reprogrammed in melanoma cells and specifically enriched with key melanoma-associated coding and long non-coding transcripts, including SOX10, AMIGO2 and LINC00511 and in most cases SFPQ is required for the efficient expression of these genes. Functional analysis of two SFPQ-enriched lncRNA, LINC00511 and LINC01234, demonstrated that these genes independently contribute to the melanoma phenotype and a more detailed analysis of LINC00511 indicated that this occurs in part via modulation of the miR-625-5p/PKM2 axis. Importantly, analysis of a large clinical cohort revealed that elevated expression of SFPQ in primary melanoma tumours may have utility as a prognostic biomarker. Together, these data suggest that SFPQ is an important driver of melanoma, likely due to SFPQ-RNA interactions promoting the expression of numerous oncogenic transcripts.
Increased anthropogenic CO₂ emissions in the last two centuries have lead to rising sea surface temperature and falling ocean pH, and it is predicted that current global trends will worsen over the ...next few decades. There is limited understanding of how genetic variation among individuals will influence the responses of populations and species to these changes. A microcosm system was set up to study the effects of predicted temperature and CO₂ levels on the bryozoan Celleporella hyalina. In this marine species, colonies grow by the addition of male, female and feeding modular individuals (zooids) and can be physically subdivided to produce a clone of genetically identical colonies. We studied colony growth rate (the addition of zooids), reproductive investment (the ratio of sexual to feeding zooids) and sex ratio (male to female zooids) in four genetically distinct clonal lines. There was a significant effect of clone on growth rate, reproductive investment and sex ratio, with clones showing contrasting responses to the various temperature and pH combinations. Overall, decreasing pH and increasing temperature caused reduction of growth, and eventual cessation of growth was often observed at the highest temperature, especially during the latter half of the 15-day trials. Reproductive investment increased with increasing temperature and decreasing pH, varying more widely with temperature at the lowest pH. The increased production of males, a general stress response of the bryozoan, was seen upon exposure to reduced pH, but was not expressed at the highest temperature tested, presumably due to the frequent cessation of growth. Further to the significant effect of pH on the measured whole-colony parameters, observation by scanning electron microscopy revealed surface pitting of the calcified exoskeleton in colonies that were exposed to increased acidity. Studying ecologically relevant processes of growth and reproduction, we demonstrate the existence of relevant levels of variation among genetic individuals which may enable future adaptation via non-mutational natural selection to falling pH and rising temperature.
•Alcohol consumption patterns and attitudes towards drink-driving were examined in a large sample of drivers (N=2994).•Drivers with more risky alcohol consumption patterns were more likely to drink ...and drive when they could get away with it.•Drivers with more risky alcohol consumption patterns were less likely to perceive the crash risk associated with drink-driving.•Drivers who reported drink-driving were also more likely to have friends and family who frequently engage in the behaviour.
Alcohol contributes to approximately 30% of all serious crashes. While the majority of drivers acknowledge the risks associated with drink-driving, a significant proportion of the population continue to engage in this behaviour. Attitudes towards drink-driving as well as personal alcohol consumption patterns are likely to underpin a driver’s decision to drink-drive. These associations were explored in the current study.
A large (N=2994) cross-sectional online survey of a representative sample of drivers in Australia was conducted. Participants provided information about their own alcohol consumption patterns, drink-driving behaviour as well as attitudes towards drink-driving (own and others) and enforcement strategies.
Alcohol consumption patterns differed according to age, gender and work status. Drivers who reported drink-driving behaviour and had high risk alcohol consumption patterns were less likely to agree that drink-driving leads to increased crash risk and more likely to agree they drink and drive when they believed they could get away with it. In contrast, drivers who did not report drink-driving and had low risk consumption patterns were more likely to report that the enforcement strategies are too lenient. Binary logistic regression showed that high risk alcohol consumption patterns and agreement from drivers that they drink and drive when they believe they can get away with it had the strongest associations with drink-driving. These findings highlight the relationships between one’s drinking patterns, drink-drive behaviour and attitudes towards drink-driving and drink-driving enforcement
The patterns of associations that emerged suggest that drink-driving is the expression of a broader health issue for the most “at-risk” cohort of drinkers. The decision to drink and drive may result from a need borne from an alcohol dependent lifestyle exacerbated by a social acceptability of the behaviour and positive attitudes towards one’s ability to drink-drive with few adverse consequences. Therefore, the broader alcohol consumption patterns of drink-drivers needs to be considered when targeting drink-drive reductions.
Knowledge about supportive care needs in patients with cutaneous invasive melanoma is scarce. We examined the unmet needs of melanoma patients treated with surgery and factors associated with these ...needs to assist health professionals identify areas needing clinical attention.
Cross-sectional multisite survey of UK patients ascertained 3 months to 5 years after complete resection of stage I–III cutaneous melanoma. Participants completed the following validated questionnaires: Supportive Care Needs Survey (SCNS-SF34 with melanoma module), Hospital Anxiety and Depression Scale and 51-item Functional Assessment of Cancer Therapy-Melanoma quality-of-life scale.
A total of 472 participants were recruited 319 (67%) clinical stage I–II). Mean age was 60 years (standard deviation = 14) and 255 (54%) were female. One hundred and twenty-three (27%) participants reported at least one unmet need (mostly ‘low’ level). The most frequently reported unmet needs were fears of cancer returning (n = 138, 29%), uncertainty about the future (n = 119, 25%), lack of information about risk of recurrence (n = 112, 24%) and about possible outcomes if melanoma were to spread (n = 91, 20%). One hundred and thirty-eight (29%) participants reported anxiety and 51 (11%) depression at clinical or subclinical levels. Patients with nodal disease had a significantly higher level of unmet supportive care needs (P < 0.001) as did patients with anxiety or depression (P < 0.001). Key correlates of the total SCNS-SF34 score for unmet supportive care needs were younger age (odds ratio, OR = 2.23, P < 0.001) and leaving school early (OR = 4.85, P < 0.001), while better emotional (OR = 0.89, P < 0.001) and social well-being (OR = 0.91, P < 0.001) were linked with fewer unmet needs. Neither patients' sex nor tumour thickness was associated with unmet needs.
Around a quarter of melanoma patients may have unmet support needs in the mid to long term after primary treatment. In particular, patients who are younger, less educated, distressed or socially isolated could benefit from more support.
Yes-associated protein (YAP) has been shown to positively regulate p53 family members and to be negatively regulated by the AKT proto-oncogene product in promoting apoptosis. On the basis of this ...function and its location at 11q22.2, a site of frequent loss of heterozygosity (LOH) in breast cancer, we investigated whether YAP is a tumor suppressor in breast. Examination of tumors by immunohistochemistry demonstrated significant loss of YAP protein. LOH analysis revealed that protein loss correlates with specific deletion of the YAP gene locus. Functionally, short hairpin RNA knockdown of YAP in breast cell lines suppressed anoikis, increased migration and invasiveness, inhibited the response to taxol and enhanced tumor growth in nude mice. This is the first report indicating YAP as a tumor suppressor, revealing its decreased expression in breast cancer as well as demonstrating the functional implications of YAP loss in several aspects of cancer signaling.
Regular exercise-induced acute inflammatory responses are suggested to improve the inflammatory profile and insulin sensitivity. As body temperature elevations partly mediate this response, passive ...heating might be a viable tool to improve the inflammatory profile. This study investigated the acute and chronic effects of hot water immersion on inflammatory and metabolic markers. Ten sedentary, overweight men body mass index (BMI): 31.0 ± 4.2 kg/m
, mean ± SD were immersed in water set at 39°C for 1 h (HWI) or rested for 1 h at ambient temperature (AMB). Venous blood was obtained before the session, immediately postsession, and 2 h postsession for assessment of monocyte intracellular heat shock protein-72 (iHsp72) and plasma concentrations of extracellular Hsp72 (eHsp72), interleukin-6 (IL-6), fasting glucose, insulin, and nitrite. Thereafter, participants underwent a 2-wk intervention period, consisting of 10 hot water immersion sessions (INT). Eight BMI-matched participants (BMI: 30.0 ± 2.5 kg/m
) were included as control (CON). Plasma IL-6 and nitrite concentrations were higher immediately following HWI compared with AMB (IL-6 P < 0.001, HWI: 1.37 ± 0.94 to 2.51 ± 1.49 pg/ml; nitrite P = 0.04, HWI: 271 ± 52 to 391 ± 72 nM), whereas iHsp72 expression was unchanged ( P = 0.57). In contrast to resting iHsp72 expression ( P = 0.59), fasting glucose ( P = 0.04; INT: 4.44 ± 0.93 to 3.98 ± 0.98 mmol/l), insulin ( P = 0.04; INT: 68.1 ± 44.6 to 55.0 ± 29.9 pmol/l), and eHsp72 ( P = 0.03; INT: 17 ± 41% reduction) concentrations were lowered after INT compared with CON. HWI induced an acute inflammatory response and increased nitric oxide bioavailability. The reductions in fasting glucose and insulin concentrations following the chronic intervention suggest that hot water immersion may serve as a tool to improve glucose metabolism. NEW & NOTEWORTHY A single hot water immersion (HWI) session induces an acute increase in plasma interleukin-6 and nitrite concentrations but does not acutely elevate heat shock protein-72 expression in monocytes intracellular Hsp72 (iHsp72). A chronic HWI intervention reduces fasting glucose and insulin concentrations in the absence of changes in resting iHsp72. Therefore, HWI shows potential as a strategy to combat chronic low-grade inflammation and improve glucose metabolism in individuals without the physical capacity to do so using exercise.
The bryozoan
Schizoporella japonica
Ortmann (1890) was first recorded in European waters in 2010 and has since been reported from further locations in Great Britain (GB) and Norway. This paper ...provides a new earliest European record for the species from 2009, a first record from Ireland and presence and absence records from a total of 231 marinas and harbours across GB, Ireland, the Isle of Man, France and Portugal. This species is typically associated with human activity, including commercial and recreational vessels, aquaculture equipment, and both wave and tidal energy devices. It has also been observed in the natural environment, fouling rocks and boulders. The species has an extensive but widely discontinuous distribution in GB and Ireland. Although found frequently in marinas and harbours in Scotland, it inhabits only a few sites in England, Wales and Ireland, interspersed with wide gaps that are well documented as genuine absences. This appears to be a rare example of a southward-spreading invasion in GB and Ireland. The species has been reported from the Isle of Man and Norway but has not been found in France or Portugal. In the future we expect
S. japonica
to spread into suitable sections of the English, Welsh and Irish coasts, and further within Europe. The species’ capability for long-distance saltatory spread and potential for negative impact on native ecosystems and economic activity suggests that
S. japonica
should now be considered invasive in GB and Ireland. As such, it is recommended that biosecurity procedures alongside effective surveillance and monitoring should be prioritised for regions outside the species’ current distribution.
Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen ...levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Biochemical and haematological testing is recommended in the United Kingdom when inflicted injury is suspected. We examined the associations of test results with radiologically-confirmed ...fracture(s), and between test results, in a large retrospective observational cohort. Methods: Infants up to age two years presenting with suspected inflicted injury, without clinically or radiologically apparent bone disease, and where a skeletal survey was undertaken during the period 1st August 2013 to 31st December 2020, were included. Biochemical parameters: corrected calcium (cCa); phosphate (P); alkaline phosphatase (ALP); parathyroid hormone (PTH); 25-hydroxyvitamin D (25D); and haematological parameters: haemoglobin (Hb); mean corpuscular haemoglobin (MCH); mean corpuscular haemoglobin content (MCHC); mean corpuscular volume (MCV); platelet count were collated together with the results of the radiological assessments. Findings: Of 332 eligible infants (190 male), 142 (84 male) had fracture(s) and/or intracranial injury. Mean PTH in the non-fracture group (n measured 50/190) was 27.3 ng/l; in those with intracranial injury alone (n measured 9/23) was 39.4 ng/l; in those with fracture alone (n measured 62/84) was 45.0 ng/l; and in those with fracture and intracranial injury (n measured 20/35) 51.8 ng/l. F-test of multiple means = 0.0369. There was no difference in 25D between the groups. Interpretation: PTH was raised in infants who had fracture(s), intracranial injury or both. A single raised PTH may not necessarily be an indicator of prior disturbed skeletal health in these circumstances. The relevance of vitamin D status and interpretation of data from biochemical testing should be informed by the overall presentation in suspected inflicted injury cases. A single raised PTH may be a consequence of the child's injuries rather than prior disturbed bone health.
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