Disrupted degradative sorting of TLR7 is associated with human lupus.

Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations in TLR7 were identified as a monogenic cause of human lupus. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes.

Facts to Consider in Developing Materials That Emulate the Upper Jawbone: A Microarchitecture Study Showing Unique Characteristics at Four Different Sites.

The maxilla is generally acknowledged as being more trabecular than the mandible. Allograft currently available for use in the maxillofacial region is harvested from the hip and long bones, irrespective of their local characteristics, and grafted onto the jawbones. Other alternative are autograft or commercially available bone substitutes.

Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease.

Thymic selection and peripheral activation of conventional T (Tconv) and regulatory T (Treg) cells depend on TCR signaling, whose anomalies are causative of autoimmunity. Here, we expressed in normal mice mutated ZAP-70 molecules with different affinities for the CD3 chains, or wild type ZAP-70 at graded expression levels under tetracycline-inducible control. Both manipulations reduced TCR signaling intensity to various extents and thereby rendered those normally deleted self-reactive thymocytes to become positively selected and form a highly autoimmune TCR repertoire.

Control of foreign Ag-specific Ab responses by Treg and Tfr.

Regulatory T cells (Tregs) expressing the transcription factor Foxp3 play a critical role in the control of immune homeostasis including the regulation of humoral immunity. Recently, it has become clear that a specialized subset of Tregs, T-follicular regulatory cells (Tfr), have a particular role in the control of T-follicular helper (Tfh) cell-driven germinal center (GC) responses. Following similar differentiation signals as received by Tfh, Tfr gain expression of characteristic chemokine receptors and transcription factors such as CXCR5 and BCL6 allowing them to travel to the B-cell follicle and deliver in situ suppression.

Phosphoinositide 3-kinase δ is a regulatory T-cell target in cancer immunotherapy.

Tumour infiltration by regulatory T (Treg) cells contributes to suppression of the anti-tumour immune response, which limits the efficacy of immune-mediated cancer therapies. The phosphoinositide 3-kinase (PI3K) pathway has key roles in mediating the function of many immune cell subsets, including Treg cells. Treg function is context-dependent and depends on input from different cell surface receptors, many of which can activate the PI3K pathway.

Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy.

Redundancy and compensation provide robustness to biological systems but may contribute to therapy resistance. Both tumor-associated macrophages (TAMs) and Foxp3+ regulatory T (Treg) cells promote tumor progression by limiting antitumor immunity. Here we show that genetic ablation of CSF1 in colorectal cancer cells reduces the influx of immunosuppressive CSF1R+ TAMs within tumors.

Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors.

Multiple modes of immunosuppression restrain immune function within tumors. We previously reported that phosphoinositide 3-kinase δ (PI3Kδ) inactivation in mice confers resistance to a range of tumor models by disrupting immunosuppression mediated by regulatory T cells (Tregs). The PI3Kδ inhibitor idelalisib has proven highly effective in the clinical treatment of chronic lymphocytic leukemia and the potential to extend the use of PI3Kδ inhibitors to nonhematological cancers is being evaluated.

Amplification of 12 OAM Modes in an air-core erbium doped fiber.

We theoretically propose an air-core erbium doped fiber amplifier capable of providing relatively uniform gain for 12 orbital angular momentum (OAM) modes (|L| = 5, 6 and 7, where |L| is the OAM mode order) over the C-band. Amplifier performance under core pumping conditions for a uniformly doped core for each of the supported pump modes (110 in total) was separately assessed. The differential modal gain (DMG) was found to vary significantly depending on the pump mode used, and the minimum DMG was found to be 0.

Adaptation to NaCl Reduces the Susceptibility of Enterococcus faecalis to Melaleuca alternifolia (Tea Tree) Oil.

This study investigated the hypothesis that the salt adaptation response of Enterococcus faecalis alters susceptibility to tea tree oil (TTO). Six E. faecalis isolates were adapted to 6.

Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias.

The oncomir microRNA-125b (miR-125b) is upregulated in a variety of human neoplastic blood disorders and constitutive upregulation of miR-125b in mice can promote myeloid and B-cell leukemia. We found that miR-125b promotes myeloid and B-cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors.

Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer.

Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours.

Evaluation of in vitro cytochrome P450 induction and inhibition activity of deoxyelephantopin, a sesquiterpene lactone from Elephantopus scaber L.

Drug metabolism involving cytochrome P450 (CYP) enzymes is a key determinant of significant drug interactions. Deoxyelephantopin was evaluated for its effects on the expression of mRNAs encoding CYP1A2, CYP2D6 and CYP3A4, and protein expression and resultant enzymatic activity. The mRNA and protein expression of cytochrome isoforms were carried out using an optimized multiplex qRT-PCR assay and Western blot analysis, respectively.

In vitro evaluation of cytochrome P450 induction and the inhibition potential of mitragynine, a stimulant alkaloid.

CYP450 enzymes are key determinants in drug toxicities, reduced pharmacological effect and adverse drug reactions. Mitragynine, an euphoric compound was evaluated for its effects on the expression of mRNAs encoding CYP1A2, CYP2D6 and CYP3A4 and protein expression and resultant enzymatic activity. The mRNA and protein expression of CYP450 isoforms were carried out using an optimized multiplex qRT-PCR assay and Western blot analysis.

GWASdb: a database for human genetic variants identified by genome-wide association studies.

Recent advances in genome-wide association studies (GWAS) have enabled us to identify thousands of genetic variants (GVs) that are associated with human diseases. As next-generation sequencing technologies become less expensive, more GVs will be discovered in the near future. Existing databases, such as NHGRI GWAS Catalog, collect GVs with only genome-wide level significance.

Effects of raising muscle glycogen synthesis rate on skeletal muscle ATP turnover rate in type 2 diabetes.

Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. We hypothesized that any impairment in insulin-stimulated muscle ATP production could merely reflect the lower rates of muscle glucose uptake and glycogen synthesis, rather than cause it. If this is correct, muscle ATP turnover rates in type 2 diabetes could be increased if glycogen synthesis rates were normalized by the mass-action effect of hyperglycemia.

Inhibition of lipolysis in Type 2 diabetes normalizes glucose disposal without change in muscle glycogen synthesis rates.

Suppression of lipolysis by acipimox is known to improve insulin-stimulated glucose disposal, and this is an important phenomenon. The mechanism has been assumed to be an enhancement of glucose storage as glycogen, but no direct measurement has tested this concept or its possible relationship to the reported impairment in insulin-stimulated muscle ATP production. Isoglycaemic-hyperinsulinaemic clamps with [13C]glucose infusion were performed on Type 2 diabetic subjects and matched controls with measurement of glycogen synthesis by 13C MRS (magnetic resonance spectroscopy) of muscle.

Associations between adipokines and obesity-related cancer.

There is increasing evidence that obesity may have pathophysiological effects that extend beyond its well-known co-morbidities; in particular its role in cancer has received considerable epidemiological support. As adipose tissue becomes strongly established as an endocrine organ, two of its most abundant and most investigated adipokines, leptin and adiponectin, are also taken beyond their traditional roles in energy homeostasis, and are implicated as mediators of the effects of obesity on cancer development. This review examines these adipokines in relation to the prostate, breast, colorectal, thyroid, renal, pancreatic, endometrial and oesophageal cancers, and how they may orchestrate the influence of obesity on the development of these malignancies.

Measuring the acute effect of insulin infusion on ATP turnover rate in human skeletal muscle using phosphorus-31 magnetic resonance saturation transfer spectroscopy.

Mitochondrial dysfunction has been proposed to underlie the insulin resistance of type 2 diabetes. However, the relative time course of insulin action in stimulating ATP turnover rate and glucose uptake in skeletal muscle has not been examined. These two parameters were measured in young healthy subjects using the (31)P MRS saturation transfer method in conjunction with the euglycaemic hyperinsulinaemic clamp technique respectively.

Increased daily walking improves lipid oxidation without changes in mitochondrial function in type 2 diabetes.

Objective: To determine whether increased daily physical activity improves mitochondrial function and/or lipid oxidation in type 2 diabetes.

Research Design And Methods: Volunteers with (n = 10) and without (n = 10) type 2 diabetes were matched for habitual physical activity, age, sex, and weight. Basal and maximal mitochondrial activity, physical activity, and resting substrate oxidation were measured at baseline and after 2 and 8 weeks of increased physical activity.