Nadeem Akhter, Ajit Wilson, Hossein Arefanian
et al.
Obesity and metabolic syndrome involve chronic low-grade inflammation called metabolic inflammation as well as metabolic derangements from increased endotoxin and free fatty acids. It is debated whether the endoplasmic reticulum (ER) stress in monocytic cells can contribute to amplify metabolic inflammation; if so, by which mechanism(s). To test this, metabolic stress was induced in THP-1 cells and primary human monocytes by treatments with lipopolysaccharide (LPS), palmitic acid (PA), or oleic acid (OA), in the presence or absence of the ER stressor thapsigargin (TG). Gene expression of tumor necrosis factor (TNF)-α and markers of ER/oxidative stress were determined by qRT-PCR, TNF-α protein by ELISA, reactive oxygen species (ROS) by DCFH-DA assay, hypoxia-inducible factor 1-alpha (HIF-1α), p38, extracellular signal-regulated kinase (ERK)-1,2, and nuclear factor kappa B (NF-κB) phosphorylation by immunoblotting, and insulin sensitivity by glucose-uptake assay. Regarding clinical analyses, adipose TNF-α was assessed using qRT-PCR/IHC and plasma TNF-α, high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and oxidized low-density lipoprotein (OX-LDL) via ELISA. We found that the cooperative interaction between metabolic and ER stresses promoted TNF-α, ROS, CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF2) expression (p ≤ 0.0183),. However, glucose uptake was not impaired. TNF-α amplification was dependent on HIF-1α stabilization and p38 MAPK/p65 NF-κB phosphorylation, while the MAPK/NF-κB pathway inhibitors and antioxidants/ROS scavengers such as curcumin, allopurinol, and apocynin attenuated the TNF-α production (p ≤ 0.05). Individuals with obesity displayed increased adipose TNF-α gene/protein expression as well as elevated plasma levels of TNF-α, CRP, MDA, and OX-LDL (p ≤ 0.05). Our findings support a metabolic–ER stress cooperativity model, favoring inflammation by triggering TNF-α production via the ROS/CHOP/HIF-1α and MAPK/NF-κB dependent mechanisms. This study also highlights the therapeutic potential of antioxidants in inflammatory conditions involving metabolic/ER stresses.
Jeffrey A. Johnson, Ademola Itiola, Shakib Rahman
et al.
Abstract Background Decision aids can help patients set realistic expectations. In this study, we explored alternative presentations to visualise patient-reported outcomes (EQ-5D-5L) data within an online, individualized patient decision aid for total knee arthroplasty (TKA) that, in part, generates individualized comparisons based on age, sex and body mass index, to enhance usability prior to implementation into routine clinical practice. Methods We used data visualization techniques to modify the presentation of EQ-5D-5L outcomes data within the decision aid. The EQ-5D-5L data was divided into two parts allowing patients to compare themselves to similar individuals (1) pre-surgery and (2) 1-year post-surgery. We created 2 versions for each part and sought patient feedback on comprehension, usefulness, and visual appeal. Patients from an urban orthopedic clinic were recruited and their ratings and comments were recorded using a researcher-administered checklist. Data were managed using Microsoft Excel, R version 3.6.1 and ATLAS.ti V8 and analyzed using descriptive statistics and directed content analysis. Results A total of 24 and 25 patients participated in Parts 1 and 2, respectively. Overall, there was a slight preference for Version 1 in Part 1 (58.3%) and Version 2 in Part 2 (64%). Most participants demonstrated adequate comprehension for all versions (range 50–72%) and commented that the instructions were clear. While 50–60% of participants rated the content as useful, including knowing the possible outcomes of surgery, some participants found the information interesting only, were unsure how to use the information, or did not find it useful because they had already decided on a treatment. Participants rated visual appeal for all versions favorably but suggested improvements for readability, mainly larger font and image sizes and enhanced contrast between elements. Conclusions Based on the results, we will produce an enhanced presentation of EQ-5D-5L data within the decision aid. These improvements, along with further usability testing of the entire decision aid, will be made before implementation of the decision aid in routine clinical practice. Our results on patients’ perspectives on the presentation of EQ-5D-5L data to support decision making for TKA treatments contributes to the knowledge on EQ-5D-5L applications within healthcare systems for clinical care.
Sina Kavalakatt, Abdelkrim Khadir, Dhanya Madhu
et al.
AbstractThe neuropeptide urocortin 3 (UCN3) has a beneficial effect on metabolic disorders, such as obesity, diabetes, and cardiovascular disease. It has been reported that UCN3 regulates insulin secretion and is dysregulated with increasing severity of obesity and diabetes. However, its function in the adipose tissue is unclear. We investigated the overexpression of UCN3 in 3T3-L1 preadipocytes and differentiated adipocytes and its effects on heat shock response, ER stress, inflammatory markers, and glucose uptake in the presence of stress-inducing concentrations of palmitic acid (PA). UCN3 overexpression significantly downregulated heat shock proteins (HSP60, HSP72 and HSP90) and ER stress response markers (GRP78, PERK, ATF6, and IRE1α) and attenuated inflammation (TNFα) and apoptosis (CHOP). Moreover, enhanced glucose uptake was observed in both preadipocytes and mature adipocytes, which is associated with upregulated phosphorylation of AKT and ERK but reduced p-JNK. Moderate effects of UCN3 overexpression were also observed in the presence of 400 μM of PA, and macrophage conditioned medium dramatically decreased the UCN3 mRNA levels in differentiated 3T3-L1 cells. In conclusion, the beneficial effects of UCN3 in adipocytes are reflected, at least partially, by the improvement in cellular stress response and glucose uptake and attenuation of inflammation and apoptosis.
AbstractWe show that an RA loop has a torsion-free normal complement in the loop of normalized units of its integral loop ring. We also investigate whether an RA loop can be normal in its unit loop. Over fields, this can never happen.
We prove (the excellent case of) Schreyer's conjecture that a local ring with countable Cohen--Macaulay type has at most a one-dimensional singular locus. Furthermore we prove that the localization of a Cohen-Macaulay local ring of countable CM type is again of countable CM type.
We show that the F-signature of a local ring of characteristic p, defined by Huneke and Leuschke, is positive if and only if the ring is strongly F-regular.
We study a certain truncation of the ring of arithmetical functions with unitary convolution, consisting of functions vanishing on arguments >n. The truncations are artinian monomial quotients of a polynomial ring in finitely many indeterminates, and are isomorphic to the ``artinified'' Stanley-Reisner rings of certain simplicial complexes.
We examine some recent work of Phillip Griffith on étale covers and fibered products from the point of view of tight closure theory. While it is known that cyclic covers of Gorenstein rings with rational singularities are Cohen-Macaulay, we show this is not true in general in the absence of the Gorenstein hypothesis. Specifically, we show that the canonical cover of a $\mathbb Q$-Gorenstein ring with rational singularities need not be Cohen-Macaulay.
In his paper "Residues of a Pfaff system relative to an invariant subscheme" in Trans. Amer. Math. Soc. 352, 2000, 4019-4035, F. Sancho de Salas defines the universal Koszul complex of a module $M$ over a sheaf of rings $\mathcal{O}$ as ${\rm Kos}(M)=Λ(M)\otimes_{\mathcal{O}}S(M)$, where $Λ(M)$ and $S(M)$ stand for the exterior and symmetric algebras of $M$, endowed with the usual differential, and he conjectures (Conjecture 2.3.) that ${\rm Kos}(M)$ is always acyclic. We give here an example of a non acyclic Koszul complex ${\rm Kos}(M)$.
The main result of the paper states that for a graded ideal I in a polynomial ring R over a field of characteristic 0, the Hilbert functions of the local cohomology modules of R/I and of R/Gin(I) coincide if and only if R/I is sequentially Cohen-Macaulay.
We show that the h-vector of a ladder determinantal ring cogenerated by M=[u_1|v_1] is log-concave. Thus we prove an instance of a conjecture of Stanley, resp. Conca and Herzog
We present short and elementary proofs of two theorems of Huckaba and Marley, while generalizing them at the same time to the case of a module. The theorems concern a characterization of the depth of the associated graded ring of a Cohen-Macaulay module, with respect to a Hilbert filtration, in terms of the Hilbert coefficient e_1. As an application, we derive bounds on the higher Hilbert coefficient e_i in terms of e_0.
We give a canonical construction of a balanced big Cohen-Macaulay algebra for a domain of finite type over $\mathbb C$ by taking ultraproducts of absolute integral closures in positive characteristic. This yields a new tight closure characterization of rational singularities in characteristic zero.
Let $k$ be a perfect field of characteristic $p>0$, $k(t)_{per}$ the perfect closure of $k(t)$ and $A$ a $k$-algebra. We characterize whether the ring $A\otimes_k k(t)_{per}$ is noetherian or not. As a consequence, we prove that the ring $A\otimes_k k(t)_{per}$ is noetherian when $A$ is the ring of formal power series in $n$ indeterminates over $k$.
Let G be a finite group acting by automorphism on a lattice A, and hence on the group algebra S=k[A]. The algebra of G-invariants in S is called an algebra of multiplicative invariants. We investigate when algebras of multiplicative invariants are semigroup algebras. In particular, we present an explicit version of a result of Farkas stating that multiplicative invariants of finite reflection groups are indeed semigroup algebras. On the other hand, multiplicative invariants arising from fixed point free actions are shown to never be semigroup algebras. In particular, this holds whenever G has odd prime order.
Let $R=k[x_1, ..., x_n]/(x_1^d + ... + x_n^d)$, where $k$ is a field of characteristic $p$, $p$ does not divide $d$ and $n \geq 3$. We describe a method for computing the test ideal for these diagonal hypersurface rings. This method involves using a characterization of test ideals in Gorenstein rings as well as developing a way to compute tight closures of certain ideals despite the lack of a general algorithm. In addition, we compute examples of test ideals in diagonal hypersurface rings of small characteristic (relative to $d$) including several that are not integrally closed. These examples provide a negative answer to Smith's (2000, Comm. in Alg.) question of whether the test id eal in general is always integrally closed.