Systematic study of constitutive cyclo-oxygenase-2 expression: role of NFκB and NFAT transcriptional pathways

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system

Microbial micropatches within microbial hotspots

© 2018 Dann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The spatial distributions of organism abundance and diversity are often heterogeneous. This includes the sub-centimetre distributions of microbes, which have ‘hotspots’ of high abundance, and ‘coldspots’ of low abundance. Previously we showed that 300 μl abundance hotspots, coldspots and background regions were distinct at all taxonomic levels. Here we build on these results by showing taxonomic micropatches within these 300 μl microscale hotspots, coldspots and background regions at the 1 μl scale. This heterogeneity among 1 μl subsamples was driven by heightened abundance of specific genera. The micropatches were most pronounced within hotspots. Micropatches were dominated by Pseudomonas, Bacteroides, Parasporobacterium and Lachnospiraceae incertae sedis, with Pseudomonas and Bacteroides being responsible for a shift in the most dominant genera in individual hotspot subsamples, representing up to 80.6% and 47.3% average abundance, respectively. The presence of these micropatches implies the ability these groups have to create, establish themselves in, or exploit heterogeneous microenvironments. These genera are often particle-associated, from which we infer that these micropatches are evidence for sub-millimetre aggregates and the aquatic polymer matrix. These findings support the emerging paradigm that the microscale distributions of planktonic microbes are numerically and taxonomically heterogeneous at scales of millimetres and less. We show that microscale microbial hotspots have internal structure within which specific local nutrient exchanges and cellular interactions might occur

The vertical profile of recent tropical temperature trends: Persistent model biases in the context of internal variability

This is the final version. Available on open access from IOP Publishing via the DOI in this recordData Availability: The data that support the findings of this study are openly available at https://esgf-index1.ceda.ac.uk/projects/cmip6-ceda/. ERA5 data are available from ECMWF. Radiosonde data are available from Leopold Haimberger. Our code is freely available at https://github.com/BrisClim/.Tropospheric and stratospheric tropical temperature trends in recent decades have been notoriously hard to simulate using climate models, particularly in the upper troposphere. Aside from the warming trend itself, this has broader implications, e.g. atmospheric circulation trends depend on latitudinal temperature gradients. In this study, tropical temperature trends in the CMIP6 models are examined, from 1979 to 2014, and contrasted with trends from the RICH/RAOBCORE radiosondes, and the ERA5/5.1 reanalysis. As in earlier studies, we find considerable warming biases in the CMIP6 modeled trends, and we show that these biases are linked to biases in surface temperature. We also uncover previously undocumented biases in the lower-middle stratosphere: the CMIP6 models appear unable to capture the time evolution of stratospheric cooling, which is non-monotonic owing to the Montreal Protocol. Finally, using models with large ensembles, we show that their standard deviation in tropospheric temperature trends, which is due to internal variability alone, explains ∼ 50% (± 20%) of that from the CMIP6 models.Natural Environment Research Council (NERC)University of BristolUS National Science Foundatio

Maternal sleep practices and stillbirth: Findings from an international case‐control study

Background: Late stillbirth, which occurs ≥28 weeks’ gestation, affects 1.3‐8.8 per 1000 births in high‐income countries. Of concern, most occur in women without established risk factors. Identification of potentially modifiable risk factors that relate to maternal behaviors remains a priority in stillbirth prevention research. This study aimed to investigate, in an international cohort, whether maternal sleep practices are related to late stillbirth. Methods: An Internet‐based case‐control study of women who had a stillbirth ≥28 weeks’ gestation within 30 days before completing the survey (n = 153) and women with an ongoing third‐trimester pregnancy or who had delivered a live born child within 30 days (n = 480). Bivariate and multivariate logistic regressions were used to determine unadjusted and adjusted odds ratios (OR and aOR, respectively) with 95% confidence intervals (95% CIs) for stillbirth. Results: Sleeping >9 hours per night in the previous month was associated with stillbirth (aOR 1.75 [95% CI 1.10‐2.79]), as was waking on the right side (2.27 [1.31‐3.92]). Nonrestless sleep in the last month was also found to be associated with stillbirth (1.73 [1.03‐2.99]), with good sleep quality in the last month approaching significance (1.64 [0.98‐2.75]). On the last night of pregnancy, not waking more than one time was associated with stillbirth (2.03 [1.24‐3.34]). No relationship was found with going to sleep position during pregnancy, although very few women reported settling in the supine position (2.4%). Conclusions: Long periods of undisturbed sleep are associated with late stillbirth. Physiological studies of how the neuroendocrine and autonomic system pathways are regulated during sleep in the context of late pregnancy are warranted

Medical students who decompress during the M-1 year outperform those who fail and repeat it: A study of M-1 students at the University of Illinois College of Medicine at Urbana-Champaign 1988–2000

BACKGROUND: All medical schools must counsel poor-performing students, address their problems and assist them in developing into competent physicians. The objective of this study was to determine whether students with academic deficiencies in their M-1 year graduate more often, spend less time to complete the curriculum, and need fewer attempts at passing USMLE Step 1 and Step 2 by entering the Decompressed Program prior to failure of the M-1 year than those students who fail the M-1 year and then repeat it. METHOD: The authors reviewed the performance of M-1 students in the Decompressed Program and compared their outcomes to M-1 students who failed and fully repeated the M-1 year. To compare the groups upon admission, t-Tests comparing the Cognitive Index of students and MCAT scores from both groups were performed. Performance of the two groups after matriculation was also analyzed. RESULTS: Decompressed students were 2.1 times more likely to graduate. Decompressed students were 2.5 times more likely to pass USMLE Step 1 on the first attempt than the repeat students. In addition, 46% of those in the decompressed group completed the program in five years compared to 18% of the repeat group. CONCLUSION: Medical students who decompress their M-1 year prior to M-1 year failure outperform those who fail their first year and then repeat it. These findings indicate the need for careful monitoring of M-1 student performance and early intervention and counseling of struggling students

An international internet survey of the experiences of 1,714 mothers with a late stillbirth: The STARS cohort study

Background: Stillbirth occurring after 28 weeks gestation affects between 1.5-4.5 per 1,000 births in high-income countries. The majority of stillbirths in this setting occur in women without risk factors. In addition, many established risk factors such as nulliparity and maternal age are not amenable to modification during pregnancy. Identification of other risk factors which could be amenable to change in pregnancy should be a priority in stillbirth prevention research. Therefore, this study aimed to utilise an online survey asking women who had a stillbirth about their pregnancy in order to identify any common symptoms and experiences. Methods: A web-based survey. Results: A total of 1,714 women who had experienced a stillbirth >3 weeks prior to enrolment completed the survey. Common experiences identified were: perception of changes in fetal movement (63 % of respondents), reports of a "gut instinct" that something was wrong (68 %), and perceived time of death occurring overnight (56 %). A quarter of participants believed that their baby's death was due to a cord issue and another 18 % indicated that they did not know the reason why their baby died. In many cases (55 %) the mother believed the cause of death was different to that told by clinicians. Conclusions: This study confirms the association between altered fetal movements and stillbirth and highlights novel associations that merit closer scrutiny including a maternal gut instinct that something was wrong. The potential importance of maternal sleep is highlighted by the finding of more than half the mothers believing their baby died during the night. This study supports the importance of listening to mothers' concerns and symptoms during pregnancy and highlights the need for thorough investigation of stillbirth and appropriate explanation being given to parents

Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Ramified rectilinear polygons: coordinatization by dendrons

Simple rectilinear polygons (i.e. rectilinear polygons without holes or cutpoints) can be regarded as finite rectangular cell complexes coordinatized by two finite dendrons. The intrinsic $l_1$-metric is thus inherited from the product of the two finite dendrons via an isometric embedding. The rectangular cell complexes that share this same embedding property are called ramified rectilinear polygons. The links of vertices in these cell complexes may be arbitrary bipartite graphs, in contrast to simple rectilinear polygons where the links of points are either 4-cycles or paths of length at most 3. Ramified rectilinear polygons are particular instances of rectangular complexes obtained from cube-free median graphs, or equivalently simply connected rectangular complexes with triangle-free links. The underlying graphs of finite ramified rectilinear polygons can be recognized among graphs in linear time by a Lexicographic Breadth-First-Search. Whereas the symmetry of a simple rectilinear polygon is very restricted (with automorphism group being a subgroup of the dihedral group $D_4$), ramified rectilinear polygons are universal: every finite group is the automorphism group of some ramified rectilinear polygon.Comment: 27 pages, 6 figure