Acute Plasma Biomarkers of T Cell Activation Set-Point Levels and of Disease Progression in HIV-1 Infection

T cell activation levels, viral load and CD4⁺ T cell counts at early stages of HIV-1 infection are predictive of the rate of progression towards AIDS. We evaluated whether the inflammatory profile during primary HIV-1 infection is predictive of the virological and immunological set-points and of disease progression. We quantified 28 plasma proteins during acute and post-acute HIV-1 infection in individuals with known disease progression profiles. Forty-six untreated patients, enrolled during primary HIV-1 infection, were categorized into rapid progressors, progressors and slow progressors according to their spontaneous progression profile over 42 months of follow-up. Already during primary infection, rapid progressors showed a higher number of increased plasma proteins than progressors or slow progressors. The plasma levels of TGF-β1 and IL-18 in primary HIV-1 infection were both positively associated with T cell activation level at set-point (6 months after acute infection) and together able to predict 74% of the T cell activation variation at set-point. Plasma IP-10 was positively and negatively associated with, respectively, T cell activation and CD4⁺ T cell counts at set-point and capable to predict 30% of the CD4⁺ T cell count variation at set-point. Moreover, plasma IP-10 levels during primary infection were predictive of rapid progression. In primary infection, IP-10 was an even better predictor of rapid disease progression than viremia or CD4⁺ T cell levels at this time point. The superior predictive capacity of IP-10 was confirmed in an independent group of 88 HIV-1 infected individuals. Altogether, this study shows that the inflammatory profile in primary HIV-1 infection is associated with T cell activation levels and CD4⁺ T cell counts at set-point. Plasma IP-10 levels were of strong predictive value for rapid disease progression. The data suggest IP-10 being an earlier marker of disease progression than CD4⁺ T cell counts or viremia levels.     

Cyclin E constrains Cdk5 activity to regulate synaptic plasticity and memory formation

Cyclin E is a component of the core cell cycle machinery, and it drives cell proliferation by regulating entry and progression of cells through the DNA synthesis phase. Cyclin E expression is normally restricted to proliferating cells. However, high levels of cyclin E are expressed in the adult brain. The function of cyclin E in quiescent, postmitotic nervous system remains unknown. Here we use a combination of in?vivo quantitative proteomics and analyses of cyclin E knockout mice to demonstrate that in terminally differentiated neurons cyclin E forms complexes with Cdk5 and controls synapse function by restraining Cdk5 activity. Ablation of cyclin E led to?a decreased number of synapses, reduced number and volume of dendritic spines, and resulted in impaired synaptic plasticity and memory formation in cyclin E-deficient animals. These results reveal a cell cycle-independent role for a core cell cycle protein, cyclin E, in synapse function and memory.     

Novel Risk Factors for Premature Peripheral Arterial Occlusive Disease in Non-Diabetic Patients: A Case-Control Study

Background

This study aimed to determine the prevalence of genetic and environmental vascular risk factors in non diabetic patients with premature peripheral arterial disease, either peripheral arterial occlusive disease or thromboangiitis obliterans, the two main entities of peripheral arterial disease, and to established whether some of them are specifically associated with one or another of the premature peripheral arterial disease subgroups.

Methods and Results

This study included 113 non diabetic patients with premature peripheral arterial disease (diagnosis <45-year old) presenting either a peripheral arterial occlusive disease (N = 64) or a thromboangiitis obliterans (N = 49), and 241 controls matched for age and gender. Both patient groups demonstrated common traits including cigarette smoking, low physical activity, decreased levels of HDL-cholesterol, apolipoprotein A–I, pyridoxal 5′-phosphate (active form of B6 vitamin) and zinc. Premature peripheral arterial occlusive disease was characterized by the presence of a family history of peripheral arterial and carotid artery diseases (OR 2.3 and 5.8 respectively, 95% CI), high lipoprotein (a) levels above 300 mg/L (OR 2.3, 95% CI), the presence of the factor V Leiden (OR 5.1, 95% CI) and the glycoprotein Ia^{807T,837T,873A} allele (OR 2.3, 95% CI). In thromboangiitis obliterans group, more patients were regular consumers of cannabis (OR 3.5, 95% CI) and higher levels in plasma copper has been shown (OR 6.5, 95% CI).

Conclusions

According to our results from a non exhaustive list of study parameters, we might hypothesize for 1) a genetic basis for premature peripheral arterial occlusive disease development and 2) the prevalence of environmental factors in the development of thromboangiitis obliterans (tobacco and cannabis). Moreover, for the first time, we demonstrated that the 807T/837T/873A allele of platelet glycoprotein Ia may confer an additional risk for development of peripheral atherosclerosis in premature peripheral arterial occlusive disease.     

Rutin improves glutamate uptake and inhibits glutamate excitotoxicity in rat brain slices

Molecular Biology Reports - Rutin is an important flavonoid consumed in the daily diet. It is also known as vitamin P and has been extensively investigated due to its pharmacological properties. On...     

Oligocene larger foraminifera from United Arab Emirates,Oman and Western Desert of Egypt

An early Oligocene (Rupelian) diagnostic larger foraminiferal assemblage is described and illustrated from marls and limestones of the Asmari Formation, at Jabals Hafit and Malaqet in the UAE. An equivalent assemblage is identified in the mudstones of the Tahwah Formation, Wadi Suq, Oman. Although Nummulites intermedius (D'Archiac 1846) and N. fichteli are fully synonymous (e.g. Roveda 1970; Schaub 1981; Sirel 2003), in this study both species are biometrically differentiated, distinct and both names are valid. N. fichteli Michelotti 1841, N. intermedius (D'Archiac 1846) and N. emiratus n. sp., which are index for the early Oligocene (Rupelian), and they are replacing each others competitively and environmentally.

The presence of Blondeauina bouillei n.gen., N. emiratus n.sp., N. intermedius, N. fichteli, Planoperculina complanata (Defrance 1822) and Austrotrillina asmariensis Adams 1968 ascribed the section of the Asmari Formation to the early Oligocene (Rupelian). The studied marls and limestones were deposited in outer and inner shelf environments, respectively. The Asmari Formation in the area studied consists mainly of marl in its lower portion and reefal limestone in its upper part, indicating a major marine regression. The Tahwah Formation in Oman is composed of bioturbated silty and muddy marls and is a facies equivalent to the Asmari Formation marls. The Asmari Formation facies change probably relates to a mid-Oligocene fall in global sea level.

In this study, the Dabaa Formation, a subsurface unit of late Eocene–Oligocene marine shales in the north Western Desert of Egypt, was chosen to correlate with the Oligocene of Emirates and Oman. The Dabaa Formation comprises Spiroclypeus ornatus (Henson 1937) and Eulepidina dilatata (Michelotti 1861). The environment of deposition was inner shelf to littoral, which become estuarine towards the top in many areas. This Oligocene Dabaa sequence is correlatable with Wadi El Arish sequence recently discovered by Kuss and Boukhary (2008) from Risan Aneiza, Northern Sinai, Egypt.     

Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-gamma-dependent IL-10 reactivation

The Jak, Tyk2, is activated in response to IL-12 and IFN-alphabeta and promotes IFN-gamma production by Th1-type CD4 cells. Mice deficient in Tyk2 function have been previously shown to be resistant to autoimmune arthritis and septic shock but are acutely susceptible to opportunistic pathogens such as Toxoplasma gondii. In this study, we show that Tyk2, in addition to mediating the biological effects of IL-12 and IFN-alphabeta, is an important regulator for the signaling and expression of the immunosuppressive cytokine IL-10. In the absence of Tyk2, Ag-reactive CD4 cells exhibit impaired IL-10 synthesis following rechallenge of T. gondii vaccine-primed mice. The impaired IL-10 reactivation leads to unopposed antimicrobial effector mechanisms which results in a paradoxically superior protection of immune Tyk2(-/-) mice against virulent T. gondii challenge. We further demonstrate that Tyk2 indirectly controls CD4 IL-10 reactivation by signaling for maximal IFN-gamma secretion. The unexpected role of IFN-gamma in mediating IL-10 reactivation by Th1 cells provides compelling evidence that conditions driving Th1 responses establish a negative feedback loop, which will ultimately lead to its autoregulation. Thus, Tyk2 can be viewed as a dual-function Jak, mediating both pro and anti-inflammatory cytokine responses.