Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses

Natural killer T (NKT) cells play a critical role in the host's innate immune response. CD1d-mediated presentation of glycolipid antigens to NKT cells has been established; however, the mechanisms by which NKT cells recognize infected or cancerous cells remain unclear. 5′-AMP activated protein kinase (AMPK) is a master regulator of lipogenic pathways. We hypothesized that activation of AMPK during infection and malignancy could alter the repertoire of antigens presented by CD1d and serve as a danger signal to NKT cells. In this study, we examined the effect of alterations in metabolism on CD1d-mediated antigen presentation to NKT cells and found that an infection with lymphocytic choriomeningitis virus rapidly increased CD1d-mediated antigen presentation. Hypoxia inducible factors (HIF) enhance T-cell effector functions during infection, therefore antigen presenting cells pretreated with pharmacological agents that inhibit glycolysis, induce HIF and activate AMPK were assessed for their ability to induce NKT-cell responses. Pretreatment with 2-deoxyglucose, cobalt chloride, AICAR and metformin significantly enhanced CD1d-mediated NKT-cell activation. In addition, NKT cells preferentially respond to malignant B cells and B-cell lymphomas express HIF-1α. These data suggest that targeting cellular metabolism may serve as a novel means of inducing innate immune responses

Mathematical Distinction in Action Potential between Primo-Vessels and Smooth Muscle

We studied the action potential of Primo-vessels in rats to determine the electrophysiological characteristics of these structures. We introduced a mathematical analysis method, a normalized Fourier transform that displays the sine and cosine components separately, to compare the action potentials of Primo-vessels with those for the smooth muscle. We found that Primo-vessels generated two types of action potential pulses that differed from those of smooth muscle: (1) Type I pulse had rapid depolarizing and repolarizing phases, and (2) Type II pulse had a rapid depolarizing phase and a gradually slowing repolarizing phase

Moderate Alcohol Use and Mortality from Ischaemic Heart Disease: A Prospective Study in Older Chinese People

Abstract Background: Moderate alcohol use is generally associated with lower ischaemic heart disease (IHD) mortality but it is difficult to ascertain whether this is due to attributes of moderate alcohol users or the properties of alcohol itself. Evidence from populations with different patterns of alcohol use and IHD can provide crucial evidence. We assessed the association of moderate alcohol use with IHD mortality in older Chinese people from Hong Kong. Methodology We used Cox regression to determine whether moderate alcohol use was associated with IHD mortality in a prospective, population-based cohort study of all 56167 attendees, aged 65 years or over, from July 1998 to December 2000 at all 18 Elderly Health Centers operated by the Department of Health in Hong Kong. Principal Findings After a median follow-up of 4.2 years, there were 406 (188 in men, 218 in women) deaths from IHD in 54,090 subjects (96.3% successful follow-up). Moderate alcohol use in men was not associated with IHD mortality adjusted only for age [Hazard Ratio, HR 1.01 (95% CI 0.55 to 1.84) compared with never drinkers] or additionally adjusted for socioeconomic status and lifestyle. Almost all women were occasional drinkers and their current alcohol use was not significantly associated with IHD mortality [HR 0.88, (95% CI 0.51 to 1.53)]. Conclusions Moderate alcohol use had no effect on IHD mortality in older Chinese men. Lack of replication of the usual protective effect of moderate alcohol use in a setting with a different pattern of alcohol use and IHD could be due to chance or could suggest that the protective effect of alcohol on IHD does not extend to all populations

Clinical Trypanosoma cruzi Disease after Cardiac Transplantation in a Cynomolgus Macaque (Macaca fascicularis)

A cynomolgus macaque received a heterotopic cardiac allograft as part of a transplant study, with monoclonal antibodies targeted to specific immune costimulation molecules (CD154, CD28) but no traditional immunosuppressive therapy after surgery. Clinical anemia was detected on postoperative day (POD) 35 and had worsened (Hgb, 2.3 g/dL; Hct = 7.3%) by POD 47, despite type-matched whole-blood transfusions. After a total of 4 blood transfusions, hematologic parameters were improved (Hgb, 5.9 g/dL; Hct, 18.7%). On POD 50, a peripheral blood smear revealed trypomastigotes, and qualitative RT-PCR of whole blood identified the organism as Trypanosoma cruzi. Although clinically stable initially, the macaque soon developed sufficient weight loss to necessitate euthanasia on POD 64. The final diagnosis was clinical anemia due to T. cruzi infection. This study represents the first reported case of Chagas disease after heart transplant in a NHP

Prediabetes Progression and Regression on Objectively- Measured Physical Function: A Prospective Cohort Study

Prediabetes leads to declines in physical function in older adults, but the impact of prediabetes progression or regression on physical function is unknown. This study assessed this longitudinal association, with physical function objectivelymeasured by grip strength, walking speed, and standing balance, based on the Health and Retirement Study enrolling United States adults aged >50 years. Participants with prediabetes were followed-up for 4-year to ascertain prediabetes status alteration (maintained, regressed, or progressed), and another 4-year to assess their impacts on physical function. Weak grip strength was defined as <26 kg for men and <16 kg for women, slow walking speed was as <0.8 m/sec, and poor standing balance was as an uncompleted fulltandem standing testing. Logistic and linear regression analyses were performed. Of the included 1,511 participants with prediabetes, 700 maintained as prediabetes, 306 progressed to diabetes, and 505 regressed to normoglycemia over 4 years. Grip strength and walking speed were declined from baseline during the 4-year followup, regardless of prediabetes status alteration. Compared with prediabetes maintenance, prediabetes progression increased the odds of developing weak grip strength by 89% (95% confidence interval [CI], 0.04 to 2.44) and exhibited larger declines in grip strength by 0.85 kg (95% CI, -1.65 to -0.04). However, prediabetes progression was not related to impairments in walking speed or standing balance. Prediabetes regression also did not affect any measures of physical function. Prediabetes progression accelerates grip strength decline in aging population, while prediabetes regression may not prevent physical function decline due to aging

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69+ subset of memory CD4+ and CD8+ T cells in lung and spleen that is distinct from that of CD69− TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8+ TRMs. Human TRMs in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced turnover compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together, our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies

The role of Akkermansia muciniphila in inflammatory bowel disease: Current knowledge and perspectives

Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, is a chronic relapsing gastrointestinal inflammatory disease mediated by dysregulated immune responses to resident intestinal microbiota. Current conventional approaches including aminosalicylates, corticosteroids, immunosuppressive agents, and biological therapies are focused on reducing intestinal inflammation besides inducing and maintaining disease remission, and managing complications. However, these therapies are not curative and are associated with various limitations, such as drug resistance, low responsiveness and adverse events. Recent accumulated evidence has revealed the involvement of mucin-degrading bacterium Akkermansia muciniphila (A. muciniphila) in the regulation of host barrier function and immune response, and how reduced intestinal colonisation of probiotic A. muciniphila can contribute to the process and development of inflammatory bowel diseases, suggesting that it may be a potential target and promising strategy for the therapy of inflammatory bowel disease. In this review, we summarise the current knowledge of the role of A. muciniphila in IBD, especially focusing on the related mechanisms, as well as the strategies based on supplementation with A. muciniphila, probiotics and prebiotics, natural diets, drugs, and herbs to promote its colonisation in the gut, and holds promise for A. muciniphila-targeted and -based therapies in the treatment of inflammatory bowel disease