Association between weight gain and knee osteoarthritis: a systematic review.

OBJECTIVE: Although weight loss is recommended to manage knee osteoarthritis (KOA), adults tend to gain weight with age which may affect KOA symptoms and progression. We conducted a systematic review and data synthesis to investigate the association between weight gain and KOA, defined by clinical features, structural progression, and total knee replacement (TKR). DESIGN: MEDLINE and EMBASE were systematically searched for controlled trials and cohort studies of participants with (or at risk of) KOA examining the relationship between weight gain and KOA clinical features (pain, function, quality of life), structural progression, and TKR. Risk of bias was assessed using the ROBINS-I tool. Results were organised by outcome, with meta-analyses performed where appropriate. RESULTS: Twenty-three studies were included. Results showed significant detrimental effects of weight gain on pain (4 of 7 studies), stiffness (2 of 2 studies), function (5 of 6 studies), and the single studies examining quality of life, and clinical and radiographic KOA. Weight gain adversely affected cartilage (6 of 9 studies), bone marrow lesions (1 of 4 studies), meniscal damage (1 of 3 studies) and effusion/synovitis (1 of 1 study). Weight gain significantly increased TKR (3 of 6 studies): meta-analysis of 2 with available data demonstrated significant increases in TKR/5 kg weight gain in women, HR 1.34 (95% CI 1.18-1.51), and in men, HR 1.25 (95% CI 1.16-1.34). CONCLUSIONS: Weight gain in adults is associated with increased clinical and structural KOA and TKR. Prevention of weight gain should be considered to improve outcomes in KOA.

What is the evidence for interactions between filaggrin null mutations and environmental exposures in the aetiology of atopic dermatitis? A systematic review.

BACKGROUND: Epidemiological studies indicate that gene-environment interactions play a role in atopic dermatitis (AD). OBJECTIVES: To review the evidence for gene-environment interactions in AD aetiology, focusing on filaggrin (FLG) loss-of-function mutations. METHODS: A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS-I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta-analysis. RESULTS: Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG-environment interactions in six of the studies (P-value for interaction ≤ 0·05), including early-life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss-of-function mutations and exposure to specific environmental factors, and variation in exposure definitions. CONCLUSIONS: Evidence on FLG-environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411.

CommWalker: correctly evaluating modules in molecular networks in light of annotation bias.

Motivation: Detecting novel functional modules in molecular networks is an important step in biological research. In the absence of gold standard functional modules, functional annotations are often used to verify whether detected modules/communities have biological meaning. However, as we show, the uneven distribution of functional annotations means that such evaluation methods favor communities of well-studied proteins. Results: We propose a novel framework for the evaluation of communities as functional modules. Our proposed framework, CommWalker, takes communities as inputs and evaluates them in their local network environment by performing short random walks. We test CommWalker's ability to overcome annotation bias using input communities from four community detection methods on two protein interaction networks. We find that modules accepted by CommWalker are similarly co-expressed as those accepted by current methods. Crucially, CommWalker performs well not only in well-annotated regions, but also in regions otherwise obscured by poor annotation. CommWalker community prioritization both faithfully captures well-validated communities and identifies functional modules that may correspond to more novel biology. Availability and implementation: The CommWalker algorithm is freely available at opig.stats.ox.ac.uk/resources or as a docker image on the Docker Hub at hub.docker.com/r/lueckenmd/commwalker/. Contact: deane@stats.ox.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.

The rapid assembly of an elliptical galaxy of 400 billion solar masses at a redshift of 2.3.

Stellar archaeology shows that massive elliptical galaxies formed rapidly about ten billion years ago with star-formation rates of above several hundred solar masses per year. Their progenitors are probably the submillimetre bright galaxies at redshifts z greater than 2. Although the mean molecular gas mass (5 × 10(10) solar masses) of the submillimetre bright galaxies can explain the formation of typical elliptical galaxies, it is inadequate to form elliptical galaxies that already have stellar masses above 2 × 10(11) solar masses at z ≈ 2. Here we report multi-wavelength high-resolution observations of a rare merger of two massive submillimetre bright galaxies at z = 2.3. The system is seen to be forming stars at a rate of 2,000 solar masses per year. The star-formation efficiency is an order of magnitude greater than that of normal galaxies, so the gas reservoir will be exhausted and star formation will be quenched in only around 200 million years. At a projected separation of 19 kiloparsecs, the two massive starbursts are about to merge and form a passive elliptical galaxy with a stellar mass of about 4 × 10(11) solar masses. We conclude that gas-rich major galaxy mergers with intense star formation can form the most massive elliptical galaxies by z ≈ 1.5.

The suppression of star formation by powerful active galactic nuclei.

The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight correlation between the mass of the black hole and the mass of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming galaxies are usually dust-obscured and are brightest at infrared and submillimetre wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expelling the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.

Submillimetre galaxies reside in dark matter haloes with masses greater than 3 × 10(11) solar masses.

The extragalactic background light at far-infrared wavelengths comes from optically faint, dusty, star-forming galaxies in the Universe with star formation rates of a few hundred solar masses per year. These faint, submillimetre galaxies are challenging to study individually because of the relatively poor spatial resolution of far-infrared telescopes. Instead, their average properties can be studied using statistics such as the angular power spectrum of the background intensity variations. A previous attempt at measuring this power spectrum resulted in the suggestion that the clustering amplitude is below the level computed with a simple ansatz based on a halo model. Here we report excess clustering over the linear prediction at arcminute angular scales in the power spectrum of brightness fluctuations at 250, 350 and 500 µm. From this excess, we find that submillimetre galaxies are located in dark matter haloes with a minimum mass, M(min), such that log(10)[M(min)/M(⊙)] = 11.5(+0.7)(-0.2) at 350 µm, where M(⊙) is the solar mass. This minimum dark matter halo mass corresponds to the most efficient mass scale for star formation in the Universe, and is lower than that predicted by semi-analytical models for galaxy formation.

An extremely luminous X-ray outburst at the birth of a supernova.

Massive stars end their short lives in spectacular explosions--supernovae--that synthesize new elements and drive galaxy evolution. Historically, supernovae were discovered mainly through their 'delayed' optical light (some days after the burst of neutrinos that marks the actual event), preventing observations in the first moments following the explosion. As a result, the progenitors of some supernovae and the events leading up to their violent demise remain intensely debated. Here we report the serendipitous discovery of a supernova at the time of the explosion, marked by an extremely luminous X-ray outburst. We attribute the outburst to the 'break-out' of the supernova shock wave from the progenitor star, and show that the inferred rate of such events agrees with that of all core-collapse supernovae. We predict that future wide-field X-ray surveys will catch each year hundreds of supernovae in the act of exploding.

Serine peptidases: classification, structure and function.

Serine peptidases play key roles in human health and disease and their biochemical properties shaped the molecular evolution of these processes. Of known proteolytic enzymes, the serine peptidase family is the major cornerstone of the vertebrate degradome. We describe the known diversity of serine peptidases with respect to structure and function. Particular emphasis is placed on the S1 peptidase family, the trypsins, which underwent the most predominant genetic expansion yielding the enzymes responsible for vital processes in man such as digestion, blood coagulation, fibrinolysis, development, fertilization, apoptosis and immunity.

Determinants of specificity in coagulation proteases.

Proteases play diverse roles in a variety of essential biological processes, both as non-specific catalysts of protein degradation and as highly specific agents that control physiologic events. Here, we review the mechanisms of substrate specificity employed by serine proteases and focus our discussion on coagulation proteases. We dissect the interplay between active site and exosite specificity and how substrate recognition is regulated allosterically by Na+ binding. We also draw attention to a functional polarity that exists in the serine protease fold, which sheds light on the structural linkages between the active site and exosites.

Submillimeter evidence for the coeval growth of massive black holes and galaxy bulges.

The correlation, found in nearby galaxies, between black hole mass and stellar bulge mass implies that the formation of these two components must be related. Here we report submillimeter photometry of eight x-ray-absorbed active galactic nuclei that have luminosities and redshifts characteristic of the sources that produce the bulk of the accretion luminosity in the universe. The four sources with the highest redshifts are detected at 850 micrometers, with flux densities between 5.9 and 10.1 millijanskies, and hence are ultraluminous infrared galaxies. If the emission is from dust heated by starbursts, then the majority of stars in spheroids were formed at the same time as their central black holes built up most of their mass by accretion. This would account for the observed demography of massive black holes in the local universe. The skewed rate of submillimeter detection with redshift is consistent with a high redshift epoch of star formation in radio-quiet active galactic nuclei, similar to that seen in radio galaxies.

Isolation and characterization of the new purine 1,3, 7-trimethylisoguanine from the New Zealand ascidian Pseudodistoma cereum.

The new purine 1,3,7-trimethylisoguanine (1) has been isolated from the ascidian Pseudodistoma cereum. The structure of 1 was elucidated by analysis of NMR spectroscopic and mass spectrometric data and by comparison with the regioisomeric purine 1,3,7-trimethylguanine (2).

Cd1d-restricted cellular lysis by peripheral blood lymphocytes: relevance to the inflammatory bowel diseases.

The CD1d molecule has been implicated to play a role in inflammatory bowel diseases (IBD), possibly through its presentation of an intestinal antigen trigger. To understand the role of the CD1d class I-like protein in IBD, we investigated the molecule's expression in diseased intestinal tissue and determined its potential to undergo specific recognition by intraepithelial and peripheral blood lymphocytes (PBLs) derived from IBD patients. We have observed an increase in precipitable CD1d in inflamed tissues, which suggests CD1d up-regulation in IBD; this was not accompanied by the occurrence of CD1d-specific cytotoxicity by lymphocytes isolated from the same tissue sites. In contrast, we have observed CD1d-specific cytotoxicity by PBLs from both patients and normal controls mediated by a possibly unique type of lymphocytic cell. These observations support a model in which intestinal inflammation may be initiated by circulating PBLs following the tissue-specific upregulation of CD1d. These activated PBLs may then be the source of the extraintestinal manifestations observed with IBD. We therefore propose that the cells responsible for this activity may play a role in regulating immune responses through the specific recognition of CD1d-specific antigen(s).

Absence of GNAI2 codon 179 oncogene mutations in inflammatory bowel disease.

The human GNAI2 gene coding for G protein, Galphai2, is located on chromosome 3p21 in proximity to the region where an inflammatory bowel disease (IBD) locus has been suggested. Galphai2-deficient mice develop a lethal diffuse colitis that resembles human ulcerative colitis (UC) and frequently progresses to colon adenocarcinoma. Furthermore, the human GNAI2 gene is subject to point mutations at certain positions, including three at codon 179, all of which have been reported in human endocrine tumors. In order to evaluate the possible involvement of this gene in IBD pathogenesis, we have examined GNAI2 codon 179 sequences in 28 familial IBD patients, including 13 UC, 15 Crohn's disease (CD), and 7 patients with colon cancer/dysplasia, from 12 multiplex IBD families. The wildtype codon 179, CGC for arginine, plus the first G of the codon 180 engender a sequence recognizable by the enzyme BstUI. Mutations, therefore, can result in the abrogation of BstUI digestion of polymerase chain reaction (PCR) products containing the codon 179. Using the PCR-restriction fragment length polymorphism technique, all 28 IBD patients, including those with colon cancer, and 14 non-IBD family members show a BstUI-cleavable PCR-banding pattern indicating the presence of wildtype codon 179. We conclude that, in the familial IBD and colon cancer/dysplasia patients studied, there is no detectable mutation in the codon 179 of the GNAI2 gene.

Mycalamide D, a new cytotoxic amide from the New Zealand marine sponge Mycale species.

A new mycalamide, mycalamide D (3), has been isolated from the New Zealand marine sponge Mycale sp. This new metabolite, in which the C13-O-methyl group of mycalamide A (1) is replaced by a hydrogen atom, was found to be cytotoxic to a range of mammalian cell lines, with a potency approximately 20-fold less than that of 1.

Increased gelsolin expression and retarded collagen lattice contraction with smooth muscle cells from Crohn's diseased intestine.

Intestinal smooth muscle cells (SMC) produce the fibrotic tissue, strictures, that characterize Crohn's disease. These SMC change their phenotype from a contractile muscle form to an inflammation-responsive form that migrates and synthesizes a collagen matrix. It is postulated that the inflammatory responsive SMC form associates differently with its surrounding collagen matrix compared to the normal SMC form. SMC derived from Crohn's diseased and uninvolved bowel were sustained in cell culture. Cultured SMC incorporated in collagen lattices have the capacity to reduce the size of that lattice, referred to as lattice contraction. At day 2, Crohn's SMC-populated collagen lattices were reduced to 21% of their initial area, while non-Crohn's SMC collagen lattices were reduced to 8%. Crohn's SMC demonstrate retarded lattice contraction compared to non-Crohn's SMC. When grown in monolayer culture, Crohn's-derived SMC cover 30% more area than non-Crohn's SMC. By Western blot analysis Crohn's SMC express more gelsolin, an actin-binding protein found elevated in cells exhibiting increased cell motility. Was the increased expression of gelsolin related to retarded collagen lattice contraction? Intracellular levels of gelsolin were elevated by the electroporation of plasma gelsolin protein into suspended non-Crohn's SMC. When incorporated in collagen lattices, gelsolin loaded cells showed retarded lattice contraction compared to SMC loaded with albumin. Crohn's SMC show increased expression of gelsolin, which may be associated with a diminished capacity to reorganize collagen fiber bundles. It is suggested that increased concentrations of gelsolin in Crohn's SMC is consistent with enhanced cell migration as a consequence of the inflammatory state of Crohn's diseased intestine.

Proteomic definition of normal human luminal and myoepithelial breast cells purified from reduction mammoplasties.

Normal human luminal and myoepithelial breast cells separately purified from a set of 10 reduction mammoplasties by using a double antibody magnetic affinity cell sorting and Dynabead immunomagnetic technique were used in two-dimensional gel proteome studies. A total of 43,302 proteins were detected across the 20 samples, and a master image for each cell type comprising a total of 1,738 unique proteins was derived. Differential analysis identified 170 proteins that were elevated 2-fold or more between the two breast cell types, and 51 of these were annotated by tandem mass spectrometry. Muscle-specific enzyme isoforms and contractile intermediate filaments including tropomyosin and smooth muscle (SM22) alpha protein were detected in the myoepithelial cells, and a large number of cytokeratin subclasses and isoforms characteristic of luminal cells were detected in this cell type. A further 134 nondifferentially regulated proteins were also annotated from the two breast cell types, making this the most extensive study to date of the protein expression map of the normal human breast and the basis for future studies of purified breast cancer cells.

Gamma delta intraepithelial lymphocytes drive tumor necrosis factor-alpha responsiveness to intestinal iron challenge: relevance to hemochromatosis.

The dependence of intestinal epithelial cell (IEC) growth and differentiation on intraepithelial lymphocytes (IELs) expressing the gamma/delta (gamma delta) T-cell receptor (TCR), suggested a potential role for gamma delta + IELs in the regulation of iron absorption. We therefore examined the levels of hepatic iron and the IEL cytokine responses in C57BL/6J control and class I and TCR knockout lines (placed on a C57BL/6J genetic background) following the administration of supplemental dietary iron. The highest level of liver iron was found in the beta 2-microglobulin knockout (beta 2m-/-) mice followed by the TCR-delta knockout (TCR delta-/-) animals. TCR-alpha knockout (TCR alpha-/-) and control animals did not differ in their iron levels. Liver iron loading correlated inversely with the ability of the mice to generate an IEL tumor necrosis factor (TNF)-alpha response. These observations suggest a model in which IEC iron loading is communicated to IELs via the HFE class I protein. The result of this communication is the initiation of TNF-alpha release by gamma delta + IELs (sustained by macrophages and dendritic cells) contributing to the upregulation of ferritin expression and possibly to the normal maintenance of the IEC apoptotic pathway.

A novel, orally administered nucleoside analogue, OGT 719, inhibits the liver invasive growth of a human colorectal tumor, C170HM2.

OGT 719 is a novel p.o. bioavailable nucleoside analogue in which galactose is incorporated onto the fluoropyrimidine moiety of the cytotoxic agent 5-fluorouracil (5-FU). OGT 719 has been designed to reduce the systemic toxicity normally associated with 5-FU while retaining activity against disease localized in the liver, in which it may be preferentially localized through the asialoglycoprotein receptor (ASGP-R). We report studies confirming the activity of OGT 719 in inhibiting growth of metastatic human colorectal tumors in the liver of nude mice. The human colorectal cancer cell line C170HM2 readily forms liver metastases in vivo. Oral administration of 1500 mg/kg/day OGT 719 inhibited liver tumor burden by 95% compared with vehicle control, without any observable signs of toxicity. When the tumor burden was increased and the same OGT 719 treatment was compared with a standard clinical dose regimen of 25 mg/kg/day 5-FU/leucovorin given i.v., both treatments were equally efficacious, although 5-FU/leucovorin treatment started 7 days earlier. In contrast to 5-FU, OGT 719 is p.o. bioavailable and has a plasma half-life between 1.5 and 3 h. Several colorectal cancer cell lines express the asialoglycoprotein receptor, although no significant levels can be detected in C170HM2 cells, consistent with the observation that OGT 719 is approximately 3 log orders of magnitude less potent in vitro than 5-FU. Flux through thymidylate synthase, as measured by 3H release from [3H]dUrd, was inhibited by OGT 719 at 4 h. The notable difference in the potency of OGT 719 efficacy on C170HM2 cells in vitro and in vivo supports our model of liver-specific activation of OGT 719. As our data suggest, OGT 719 may significantly inhibit growth of metastatic colorectal tumors in the liver in vivo. This hypothesis is presently being explored in clinical trials for primary hepatocellular carcinoma and colorectal liver metastases.

New model of ErbB-2 over-expression in human mammary luminal epithelial cells.

The ErbB-2 receptor has been strongly implicated in the development of breast cancer. To establish a new model system to investigate the role of erbB-2 in tumorigenesis of the breast, the conditionally immortalised human mammary luminal epithelial cell line HB4a was transfected with erbB-2 cDNA. Biological and biochemical characterisation of the resulting cell lines demonstrated that high levels of ErbB-2 expression were sufficient to cause transformation in vitro but did not cause tumours in vivo. Transformation by overexpression of ErbB-2 correlated with ligand-independent tyrosine phosphorylation of ErbB-2 and the adaptor protein Shc. Over-expression of ErbB-2 also resulted in the ligand-independent constitutive association between Shc and another adaptor protein, Grb2, indicating that receptor activation was sufficient to activate downstream signalling pathways. Using the model described, it was found that elevation of ErbB-2 expression levels caused marked quantitative and qualitative alterations in responses to the ligands epidermal growth factor and heregulin. Data indicate a central role for ErbB-2 in mediating the responses induced by these ligands and suggest that these altered ligand-dependent responses play an important role in tumorigenesis in vivo.