Dissecting interferon-induced transcriptional programs in human peripheral blood cells

Interferons are key modulators of the immune system, and are central to the control of many diseases. The response of immune cells to stimuli in complex populations is the product of direct and indirect effects, and of homotypic and heterotypic cell interactions. Dissecting the global transcriptional profiles of immune cell populations may provide insights into this regulatory interplay. The host transcriptional response may also be useful in discriminating between disease states, and in understanding pathophysiology. The transcriptional programs of cell populations in health therefore provide a paradigm for deconvoluting disease-associated gene expression profiles.We used human cDNA microarrays to (1) compare the gene expression programs in human peripheral blood mononuclear cells (PBMCs) elicited by 6 major mediators of the immune response: interferons alpha, beta, omega and gamma, IL12 and TNFalpha; and (2) characterize the transcriptional responses of purified immune cell populations (CD4+ and CD8+ T cells, B cells, NK cells and monocytes) to IFNgamma stimulation. We defined a highly stereotyped response to type I interferons, while responses to IFNgamma and IL12 were largely restricted to a subset of type I interferon-inducible genes. TNFalpha stimulation resulted in a distinct pattern of gene expression. Cell type-specific transcriptional programs were identified, highlighting the pronounced response of monocytes to IFNgamma, and emergent properties associated with IFN-mediated activation of mixed cell populations. This information provides a detailed view of cellular activation by immune mediators, and contributes an interpretive framework for the definition of host immune responses in a variety of disease settings

Plasma Glucose and Lipid Profiles Following High-Fat Diet and Acute Aerobic Exercise

PURPOSE: To examine the effects of a 3-week high-fat (HF) diet on plasma glucose, lipids, and lipoproteins following an acute bout of aerobic exercise in middle-aged men. METHODS: Physically active (non-elite, competitive marathon runners), male participants (N=8, age=39.5±9.9 years) volunteered for the study. Participants maintained their habitual high-carbohydrate (HC) diet (60-70% caloric intake from carbohydrate) prior to switching to the HF diet (70% caloric intake from fat, not exceeding 50g of carbohydrates) for 3 weeks. At the end of each diet trial, participants performed an acute bout of aerobic exercise, which consisted of running at varying paces (personal race paces) on a treadmill for 50 minutes (split into 5, 10-minute periods with 2 minutes of rest in between). Following a 20-minute recovery from the treadmill exercise, participants additionally ran a 5-km time trial (average run time = 23.69±2.41 minutes) on an outdoor road course. Overnight fasting blood samples were collected before and 24 hours after exercise for the HC and HF diet trial to analyze glucose, triglyceride (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), lipoprotein(a), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein-cholesterol (LDL-C). The data were analyzed using a two-way ANOVA [2 (diet: HC and HF) X 2 (time: pre and post-exercise)]. Any significant interactions were further analyzed using a Tukey’s post-hoc test. A p-value was set at \u3c 0.05. RESULTS: A glucose level was higher (p=0.046) in the HC diet (96.81±2.45 mg/dL) than the HF diet (89.6±2.45 mg/dL). As compared with the HC diet, the HF diet showed a higher level of TC (142.58±4.75 vs. 171.71±4.75 mg/dL, p=0.001), HDL-C (49.26±3.01 vs. 58.58±3.01 mg/dL, p=0.037), and LDL-C (91.51±4.91 vs. 111.20±4.91 mg/dL, p=0.008), respectively. TG significantly decreased (p=0.03) from 65.68±5.93 to 38.46±5.93 mg/dL at 24 hours of post-exercise. CONCLUSION: The 3-weeks of HF diet modestly increased plasma lipids and lipoproteins within the desirable range. Implementing a relatively short-term HF diet does not appear to significantly elicit negative cardiovascular disease risk markers in non-elite, healthy middle-aged male runners. However, it is strongly recommended for future studies to investigate the safety and beneficial effects of a long-term HF diet on cardiovascular disease risk factors in a variety of population including the untrained

Experiences of living with chronic back pain: The physical disabilities

Purpose. Back-related functional limitations are largely assessed using lists of activities, each scored on a yes/no basis and the scores then summed. This provides little information about how chronic back pain (CBP) patients live with their condition. This study describes the consequences of living day-to-day with CBP and documents the 'insider' accounts of its impact on daily life. Method. Unstructured interviews, using the 'Framework' approach with topic guide, were recorded and transcribed verbatim. Subjects were sampled for age, sex, ethnicity and occupation from new referrals with back pain to a rheumatology outpatient clinic. Eleven subjects (5 male, 6 female) were interviewed either in English (n = 9) or their preferred language (n = 2). Interviews were read in-depth twice to identify the topics. Data were extracted in phrases and sentences using thematic content analysis. Results. Four themes emerged: sleep/rest, mobility, independence and leisure. All subjects reported issues about sleep and rest, nine about mobility, seven about independence and six on leisure. Most descriptions concerned loss and limitation in daily life. Strategies for coping with sleep disruption and physical limitations were described. Conclusions. Subjects provided graphic 'in-depth' descriptions of experiences living with CBP every day; expressed regret at the loss of capabilities and distress at the functional consequences of those losses. Facilitating 'adjustment' to 'loss' may be more helpful than inferring the potential for a life free of pain as a result of therapeutic endeavours

Compilation of extended recursion in call-by-value functional languages

This paper formalizes and proves correct a compilation scheme for mutually-recursive definitions in call-by-value functional languages. This scheme supports a wider range of recursive definitions than previous methods. We formalize our technique as a translation scheme to a lambda-calculus featuring in-place update of memory blocks, and prove the translation to be correct.Comment: 62 pages, uses pi

Bis{μ-2-[(pyridin-2-yl)imino­meth­yl]phenolato}bis­[(2-formyl­phenolato)copper(II)]

The asymmetric unit of the title compound, [Cu2(C12H9N2O)2(C7H5O2)2], contains two independent (2-formyl­phen­olato){2-[(pyridin-2-yl)imino­meth­yl]phenolato}copper(II) mol­ecules that form pseudocentrosymmetric dimers via inter­actions between the Cu and pyridyl N atoms of independent monomers. The square-planar geometry of the Cu atoms in the monomer thus becomes square-based pyramidal in the dimer. The crystal studied was an inversion twin, with unequal populations of 0.353 (17) and 0.647 (17)

Biomimetic oyster shell–replicated topography alters the behaviour of human skeletal stem cells

The regenerative potential of skeletal stem cells provides an attractive prospect to generate bone tissue needed for musculoskeletal reparation. A central issue remains efficacious, controlled cell differentiation strategies to aid progression of cell therapies to the clinic. The nacre surface from Pinctada maxima shells is known to enhance bone formation. However, to date, there is a paucity of information on the role of the topography of P. maxima surfaces, nacre and prism. To investigate this, nacre and prism topographical features were replicated onto polycaprolactone and skeletal stem cell behaviour on the surfaces studied. Skeletal stem cells on nacre surfaces exhibited an increase in cell area, increase in expression of osteogenic markers ALP (p

Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-offunction mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n¼40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC