Plasma Bmil mRNA as a potential prognostic biomarker for distant metastasis in colorectal cancer patients

published_or_final_versio

Lower cerebrospinal fluid/plasma fibroblast growth factor 21 (FGF21) ratios and placental FGF21 production in gestational diabetes

Objectives: Circulating Fibroblast Growth Factor 21 (FGF21) levels are increased in insulin resistant states such as obesity, type 2 diabetes mellitus and gestational diabetes mellitus (GDM). In addition, GDM is associated with serious maternal and fetal complications. We sought to study human cerebrospinal fluid (CSF) and corresponding circulating FGF21 levels in women with gestational diabetes mellitus (GDM) and in age and BMI matched control subjects. We also assessed FGF21 secretion from GDM and control human placental explants. Design: CSF and corresponding plasma FGF21 levels of 24 women were measured by ELISA [12 GDM (age: 26–47 years, BMI: 24.3–36.3 kg/m2) and 12 controls (age: 22–40 years, BMI: 30.1–37.0 kg/m2)]. FGF21 levels in conditioned media were secretion from GDM and control human placental explants were also measured by ELISA. Results: Glucose, HOMA-IR and circulating NEFA levels were significantly higher in women with GDM compared to control subjects. Plasma FGF21 levels were significantly higher in women with GDM compared to control subjects [234.3 (150.2–352.7) vs. 115.5 (60.5–188.7) pg/ml; P<0.05]. However, there was no significant difference in CSF FGF21 levels in women with GDM compared to control subjects. Interestingly, CSF/Plasma FGF21 ratio was significantly lower in women with GDM compared to control subjects [0.4 (0.3–0.6) vs. 0.8 (0.5–1.6); P<0.05]. FGF21 secretion into conditioned media was significantly lower in human placental explants from women with GDM compared to control subjects (P<0.05). Conclusions: The central actions of FGF21 in GDM subjects maybe pivotal in the pathogenesis of insulin resistance in GDM subjects. The significance of FGF21 produced by the placenta remains uncharted and maybe crucial in our understanding of the patho-physiology of GDM and its associated maternal and fetal complications. Future research should seek to elucidate these points

Brownian bridges to submanifolds

We introduce and study Brownian bridges to submanifolds. Our method involves proving a general formula for the integral over a submanifold of the minimal heat kernel on a complete Riemannian manifold. We use the formula to derive lower bounds, an asymptotic relation and derivative estimates. We also see a connection to hypersurface local time. This work is motivated by the desire to extend the analysis of path and loop spaces to measures on paths which terminate on a submanifold

State of the California current 2012-13: No such thing as an “average” year

This report reviews the state of the California Current System (CCS) between winter 2012 and spring 2013, and includes observations from Washington State to Baja California. During 2012, large-scale climate modes indicated the CCS remained in a cool, productive phase present since 2007. The upwelling season was delayed north of 42°N, but regions to the south, especially 33° to 36°N, experienced average to above average upwelling that persisted throughout the summer. Contrary to the indication of high production suggested by the climate indices, chlorophyll observed from surveys and remote sensing was below average along much of the coast. As well, some members of the forage assemblages along the coast experienced low abundances in 2012 surveys. Specifically, the concentrations of all lifestages observed directly or from egg densities of Pacific sardine, Sardinops sagax, and northern anchovy, Engraulis mordax, were less than previous years’ survey estimates. However, 2013 surveys and observations indicate an increase in abundance of northern anchovy. During winter 2011/2012, the increased presence of northern copepod species off northern California was consistent with stronger southward transport. Krill and small-fraction zooplankton abundances, where examined, were generally above average. North of 42°N, salps returned to typical abundances in 2012 after greater observed concentrations in 2010 and 2011. In contrast, salp abundance off central and southern California increased after a period of southward transport during winter 2011/2012. Reproductive success of piscivorous Brandt’s cormorant, Phalacrocorax penicillatus, was reduced while planktivorous Cassin’s auklet, Ptychoramphus aleuticus was elevated. Differences between the productivity of these two seabirds may be related to the available forage assemblage observed in the surveys. California sea lion pups from San Miguel Island were undernourished resulting in a pup mortality event perhaps in response to changes in forage availability. Limited biological data were available for spring 2013, but strong winter upwelling coastwide indicated an early spring transition, with the strong upwelling persisting into early summer

Comparison of non-laser and laser transvenous lead extraction: a systematic review and meta-analysis.

BACKGROUND: Transvenous lead extraction (TLE) is performed using non-laser and laser techniques with overall high efficacy and safety. Variation in outcomes between the two approaches does exist with limited comparative evidence in the literature. AIM: We sought to compare non-laser and laser TLE in a meta-analysis. METHODS: We searched Medline, Embase, Scopus, ClinicalTrials.gov and CENTRAL databases for TLE studies published between 1991-2021. From the included 68 studies, safety and efficacy data was carefully evaluated and extracted. Aggregated cases of outcomes were used to calculate odds ratio (OR) and pooled rates were synthesised from eligible studies, to compare non-laser and laser techniques. Subgroup comparison of rotational tool and laser extraction was also performed. RESULTS: Non-laser in comparison to laser had lower procedural mortality (pooled rate 0% vs 0.1%, p < 0.01), major complications (pooled rate 0.7% vs 1.7%, p < 0.01) and superior vena cava (SVC) injury (pooled rate 0% vs 0.5%, p < 0.001), with higher complete success (pooled rate 96.5% vs 93.8%, p < 0.01). Non-laser comparatively to laser was more likely to achieve clinical (OR 2.16 [1.77-2.63], p < 0.01) and complete (OR 1.87 [1.69-2.08], p < 0.01) success, with a lower procedural mortality risk (OR 1.6 [1.02-2.5], p < 0.05). In the subgroup analysis, rotational tool compared to laser achieved greater complete success (pooled rate 97.4% vs 95%, p < 0.01) with lower SVC injury (pooled rate 0% vs 0.7%, p < 0.01). CONCLUSION: Non-laser TLE is associated with a better safety and efficacy profile when compared to laser methods. There is a greater risk of SVC injury associated with laser sheath extraction

Lineage Divergence and Historical Gene Flow in the Chinese Horseshoe Bat (Rhinolophus sinicus)

PMCID: PMC3581519This 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

Assisted evolution enables HIV-1 to overcome a high trim5α-imposed genetic barrier to rhesus macaque tropism

Diversification of antiretroviral factors during host evolution has erected formidable barriers to cross-species retrovirus transmission. This phenomenon likely protects humans from infection by many modern retroviruses, but it has also impaired the development of primate models of HIV-1 infection. Indeed, rhesus macaques are resistant to HIV-1, in part due to restriction imposed by the TRIM5α protein (rhTRIM5α). Initially, we attempted to derive rhTRIM5α-resistant HIV-1 strains using two strategies. First, HIV-1 was passaged in engineered human cells expressing rhTRIM5α. Second, a library of randomly mutagenized capsid protein (CA) sequences was screened for mutations that reduced rhTRIM5α sensitivity. Both approaches identified several individual mutations in CA that reduced rhTRIM5α sensitivity. However, neither approach yielded mutants that were fully resistant, perhaps because the locations of the mutations suggested that TRIM5α recognizes multiple determinants on the capsid surface. Moreover, even though additive effects of various CA mutations on HIV-1 resistance to rhTRIM5α were observed, combinations that gave full resistance were highly detrimental to fitness. Therefore, we employed an 'assisted evolution' approach in which individual CA mutations that reduced rhTRIM5α sensitivity without fitness penalties were randomly assorted in a library of viral clones containing synthetic CA sequences. Subsequent passage of the viral library in rhTRIM5α-expressing cells resulted in the selection of individual viral species that were fully fit and resistant to rhTRIM5α. These viruses encoded combinations of five mutations in CA that conferred complete or near complete resistance to the disruptive effects of rhTRIM5α on incoming viral cores, by abolishing recognition of the viral capsid. Importantly, HIV-1 variants encoding these CA substitutions and SIVmac239 Vif replicated efficiently in primary rhesus macaque lymphocytes. These findings demonstrate that rhTRIM5α is difficult to but not impossible to evade, and doing so should facilitate the development of primate models of HIV-1 infection

Specificity quantification of biomolecular recognition and its implication for drug discovery

Highly efficient and specific biomolecular recognition requires both affinity and specificity. Previous quantitative descriptions of biomolecular recognition were mostly driven by improving the affinity prediction, but lack of quantification of specificity. We developed a novel method SPA (SPecificity and Affinity) based on our funneled energy landscape theory. The strategy is to simultaneously optimize the quantified specificity of the “native” protein-ligand complex discriminating against “non-native” binding modes and the affinity prediction. The benchmark testing of SPA shows the best performance against 16 other popular scoring functions in industry and academia on both prediction of binding affinity and “native” binding pose. For the target COX-2 of nonsteroidal anti-inflammatory drugs, SPA successfully discriminates the drugs from the diversity set, and the selective drugs from non-selective drugs. The remarkable performance demonstrates that SPA has significant potential applications in identifying lead compounds for drug discovery

Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-\u3b1 and lipopolysaccaride (LPS). TNF-\u3b1 time-dependently increased Saa1 (but not Saa3) mRNA expression in purified microglia, enriched astrocytes, and OPCs (as did LPS for microglia and astrocytes). Astrocytes depleted of microglia were markedly less responsive to TNF-\u3b1 and LPS, even after re-addition of microglia. Microglia and enriched astrocytes showed complementary Saa1 expression profiles following TNF-\u3b1 or LPS challenge, being higher in microglia with TNF-\u3b1 and higher in astrocytes with LPS. Recombinant human apo-SAA stimulated production of both inflammatory mediators and its own mRNA in microglia and enriched, but not microglia-depleted astrocytes. Co-ultramicronized palmitoylethanolamide/luteolin, an established anti-inflammatory/neuroprotective agent, reduced Saa1 expression in OPCs subjected to TNF-\u3b1 treatment. These last data, together with past findings suggest that co-ultramicronized palmitoylethanolamide/luteolin may be a novel approach in the treatment of inflammatory demyelinating disorders like MS