Functional determinants for general Sturm-Liouville problems

Simple and analytically tractable expressions for functional determinants are known to exist for many cases of interest. We extend the range of situations for which these hold to cover systems of self-adjoint operators of the Sturm-Liouville type with arbitrary linear boundary conditions. The results hold whether or not the operators have negative eigenvalues. The physically important case of functional determinants of operators with a zero mode, but where that mode has been extracted, is studied in detail for the same range of situations as when no zero mode exists. The method of proof uses the properties of generalised zeta-functions. The general form of the final results are the same for the entire range of problems considered.Comment: 28 pages, LaTe

Associations of cord blood metabolites with early childhood obesity risk

Background/Objective Rapid postnatal weight gain is a potentially modifiable risk factor for obesity and metabolic syndrome. To identify markers of rapid infancy weight gain and childhood obesity, we analyzed the metabolome in cord blood from infants differing in their postnatal weight trajectories. Methods: We performed a nested case-control study within Project Viva, a longitudinal cohort of mothers and children. We selected cases (n=26) based on top quartile of change in weight-for-age 0-6 mo and BMI >85th percentile in mid-childhood (median 7.7 years). Controls (n=26) were age- and sex-matched, had normal postnatal weight gain (2nd or 3rd quartile of change in weight-for-age 0-6 mo) and normal mid-childhood weight (BMI 25th-75th percentile). Cord blood metabolites were measured using untargeted LC/MS; individual metabolites and pathways differing between cases vs. controls were compared in categorical analyses. We adjusted metabolites for maternal age, maternal BMI, and breastfeeding duration (linear regression), and assessed whether metabolites improved the ability to predict case-control status (logistic regression). Results: Of 415 detected metabolites, 16 were altered in cases vs. controls (T-test, nominal P<0.05). 3 metabolites were related to tryptophan: serotonin, tryptophan betaine, and tryptophyl leucine (46%, 48% and 26% lower in cases, respectively, P<0.05). Mean levels of 2 methyl donors, dimethylglycine and N-acetylmethionine, were also lower in cases (18% and 16% respectively, P=0.01). Moreover, the glutamine:glutamate ratio was reduced by 33% (P<0.05) in cases. Levels of serotonin, tryptophyl leucine, and N-acetylmethionine remained significantly different after adjustment for maternal BMI, age, and breastfeeding. Adding metabolite levels to logistic regression models including only clinical covariates improved the ability to predict case vs. control status. Conclusions: Several cord blood metabolites are associated with rapid postnatal weight gain. Whether these patterns are causally linked to childhood obesity is not clear from this cross-sectional analysis, but will require further study

The IgG1/G2 subclass shift – a sensitive, tissue non-specific marker for malignancy. Diagnostic performance with squamous cell carcinoma of the head and neck

A significant decrease in %IgG1 accompanied by an increase in %IgG2 in total serum IgG has been previously reported as a highly sensitive marker for detecting early stages of carcinomas of various localizations. Here we investigated the question as to whether this phenomenon is also observed in sera of patients with squamous cell carcinoma of the head–neck region (SCC-HN), and to evaluate its diagnostic performance in the post-operative monitoring. Using quantitative affinity chromatography, serum concentrations of IgG1, IgG2 and total IgG were determined in 81 patients with different stages of primary and untreated SCC-HN, in 51 SCC-HN patients in post-therapeutical follow up, and in 33 patients with organ matched benign diseases. The data were compared with a total of 174 healthy controls. It was found that (i) 105 SCC-HN patients exhibited a mean value of 56.0 ± 0.7% IgG1, which likewise differed from healthy controls (63.2 ± 0.5) and benign diseases (61.5 ± 1.0) with P < 0.0005, (ii) sensitivities and specificities for discriminating primary malignancies from healthy controls were 70 and 74% respectively, and from benign diseases 65 and 76%, (iii) highest sensitivities and specificities were observed with post-therapeutic cases suffering from tumour recurrence (88% and 75%) or patients with distant metastases (87% and 86%), (iv) apparently tumour-free post-therapeutic patients showed a mean %IgG1 not different from the normal value. The decrease in %IgG1 accompanied by increased %IgG2 is an efficient, sensitive and early marker of SCC-HN, which appears particularly useful for the post-therapeutic monitoring. © 1999 Cancer Research Campaig

Functional determinants for general self-adjoint extensions of Laplace-type operators resulting from the generalized cone

In this article we consider the zeta regularized determinant of Laplace-type operators on the generalized cone. For {\it arbitrary} self-adjoint extensions of a matrix of singular ordinary differential operators modelled on the generalized cone, a closed expression for the determinant is given. The result involves a determinant of an endomorphism of a finite-dimensional vector space, the endomorphism encoding the self-adjoint extension chosen. For particular examples, like the Friedrich's extension, the answer is easily extracted from the general result. In combination with \cite{BKD}, a closed expression for the determinant of an arbitrary self-adjoint extension of the full Laplace-type operator on the generalized cone can be obtained.Comment: 27 pages, 2 figures; to appear in Manuscripta Mathematic

Versatility of MicroRNA Biogenesis

MicroRNAs (miRNAs) are short single-stranded RNA molecules that regulate gene expression. MiRNAs originate from large primary (pri) and precursor (pre) transcripts that undergo various processing steps along their biogenesis pathway till they reach their mature and functional form. It is not clear, however, whether all miRNAs are processed similarly. Here we show that the ratio between pre-miRNA and mature miRNA forms varies between different miRNAs. Moreover, over-expression of several factors involved in miRNA biogenesis, including Exportin-5, Drosha, NF90a, NF45 and KSRP, displayed bidirectional effects on pre/mature miRNA ratios, suggesting their intricate biogenesis sensitivity. In an attempt to identify additional factors that might explain the versatility in miRNA biogenesis we have analyzed the contribution of two hnRNP family members, hnRNPH1 and hnRNPR. Knock-down or over-expression of these genes suggested that hnRNPR inhibits, whereas hnRNPH1 facilitates, miRNA processing. Overall, our results emphasize that miRNA biogenesis is versatile

High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling

Thoracic costotransverse joint pain patterns: a study in normal volunteers

<p>Abstract</p> <p>Background</p> <p>Pain referral patterns of asymptomatic costotransverse joints have not been established. The objective of this study was to determine the pain referral patterns of asymptomatic costotransverse joints via provocative intra-articular injection.</p> <p>Methods</p> <p>Eight asymptomatic male volunteers received a combined total of 21 intra-articular costotransverse joint injections. Fluoroscopic imaging was used to identify and isolate each costotransverse joint and guide placement of a 25 gauge, 2.5 inch spinal needle into the costotransverse joint. Following contrast medium injection, the quality, intensity, and distribution of the resultant pain produced were recorded.</p> <p>Results</p> <p>Of the 21 costotransverse joint injections, 16 (76%) were classified as being intra-articular via arthrograms taken at the time of injection, and 14 of these injections produced a pain sensation distinctly different from that of needle placement. Average pain produced was 3.3/10 on a 0–10 verbal pain scale. Pain was described generally as a deep, dull ache, and pressure sensation. Pain patterns were located superficial to the injected joint, with only the right T2 injections showing referred pain 2 segments cranially and caudally. No chest wall, upper extremity or pseudovisceral pains were reported.</p> <p>Conclusion</p> <p>This study provides preliminary data of the pain referral patterns of costotransverse joints. Further research is needed to compare these findings with those elicited from symptomatic subjects.</p

Gene processing control loops suggested by sequencing, splicing, and RNA folding

Abstract Background Small RNAs are known to regulate diverse gene expression processes including translation, transcription, and splicing. Among small RNAs, the microRNAs (miRNAs) of 17 to 27 nucleotides (nts) undergo biogeneses including primary transcription, RNA excision and folding, nuclear export, cytoplasmic processing, and then bioactivity as regulatory agents. We propose that analogous hairpins from RNA molecules that function as part of the spliceosome might also be the source of small, regulatory RNAs (somewhat smaller than miRNAs). Results Deep sequencing technology has enabled discovery of a novel 16-nt RNA sequence in total RNA from human brain that we propose is derived from RNU1, an RNA component of spliceosome assembly. Bioinformatic alignments compel inquiring whether the novel 16-nt sequence or its precursor have a regulatory function as well as determining aspects of how processing intersects with the miRNA biogenesis pathway. Specifically, our preliminary in silico investigations reveal the sequence could regulate splicing factor Arg/Ser rich 1 (SFRS1), a gene coding an essential protein component of the spliceosome. All 16-base source sequences in the UCSC Human Genome Browser are within the 14 instances of RNU1 genes listed in wgEncodeGencodeAutoV3. Furthermore, 10 of the 14 instances of the sequence are also within a common 28-nt hairpin-forming subsequence of RNU1. Conclusions An abundant 16-nt RNA sequence is sourced from a spliceosomal RNA, lies in a stem of a predicted RNA hairpin, and includes reverse complements of subsequences of the 3'UTR of a gene coding for a spliceosome protein. Thus RNU1 could function both as a component of spliceosome assembly and as inhibitor of production of the essential, spliceosome protein coded by SFRS1. Beyond this example, a general procedure is needed for systematic discovery of multiple alignments of sequencing, splicing, and RNA folding data