Shinji Ashida

Total synthesis of vinigrol.

The longstanding challenge posed by the complex diterpene vinigrol has been answered for the first time. The notorious difficulty in synthesizing vinigrol stems from its unprecedented decahydro-1,5-butanonaphthalene ring system, eight contiguous stereocenters, and highly congested functionality. This Communication delineates a stereocontrolled 23-step route to vinigrol that is scalable (>5 g prepared of a late-stage intermediate), minimally reliant on protecting group chemistry, and facilitated by a number of unique and chemoselective transformations.

Very prolonged capsular warning syndrome.

Capsularwarning syndrome (CWS)wasfirst describedbyDonnan in 1993 to describe recurrent stereotyped episodes of transient ischemic attacks (TIAs) that often lead to infarction in the corresponding anatomical location, usually in the lenticulostriate artery territory [1]. The mechanism is believed to be small single perforating artery disease. A hemodynamic ischemic process in the territory of the penetrating arteries caused by high-grade stenosis of proximal penetrating arteries due to microatherosclerosis has been postulated [1–3]. The risk of developing a capsular stroke is considered to be high in patients with CWS [1,4]. Although various antithrombotic treatments such as antiplatelets [5], heparin [6], and thrombolytics [7] have been tried to halt the recurrence of TIAs and progression to stroke, it is still uncertain if any of these therapies are effective. We describe a case of very prolonged CWS that was finally resolved with an intensive anti-platelet treatment.

Signaling via toll-like receptor 4 and CD40 in B cells plays a regulatory role in the pathogenesis of multiple sclerosis through interleukin-10 production

BACKGROUND B cells play an important role in the development of multiple sclerosis (MS), but can also exhibit regulatory functions through IL-10 production. Toll-like receptors (TLR) and CD40 signaling are likely to be involved in this process. OBJECTIVE To investigate the ability of MS B cells to produce IL-10 in response to TLR stimulation in the presence or absence of CD40 co-stimulation. METHODS Peripheral blood mononuclear cells obtained from 34 MS patients and 24 matched healthy participants (HS) were stimulated through either TLR4 or TLR9 alone, or together with CD40. Intracellular cytokine production was analyzed by flow cytometry. RESULTS The frequency of IL-10-producing cells in total B cells after either TLR9 or CD40 stimulation was significantly lower in MS than HS, regardless of disease phase. The frequency of IL-10 producing B cells after TLR4 stimulation did not differ significantly between HS and MS, regardless of disease phase. TLR4 and CD40 co-stimulation synergistically increased the frequency of IL-10-producing but not pro-inflammatory cytokine-producing B cells at MS relapse. This effect was observed in both CD27- naïve and CD27+ memory B cells. The frequency of IL-10-producing B cells following CD40 stimulation was significantly higher in interferon-β responders than non-treated MS patients. Finally, we confirmed that the frequency of IL-10-producing B cells positively correlated with IL-10 production quantity by B cells using magnetic-isolated B cells. CONCLUSIONS Cross-talk between TLR4 and CD40 signaling plays a crucial role in regulating IL-10 production by B cells during MS relapses, which may promote recovery from relapse. CD40 signaling in B cells is involved in the response to interferon-β in MS. Collectively, TLR4 and CD40 signaling in B cells may provide a promising target for MS therapy.