Late signals from CD27 prevent Fas-dependent apoptosis of primary CD8+ T cells

The role of costimulation has previously been confined to the very early stages of the CD8+ T cell response. In this study, we demonstrate the requirement for CD27 costimulation during the later phase, but not programming of the primary CD8+ T cell response to influenza virus and reveal a novel mechanism of action for CD27 costimulation. CD27 signals, during the later phase of the primary CD8+ T cell response, prevent apoptosis of Ag-specific CD8+ T cells. Blocking CD27L (CD70) on days 6 and 8 after infection reduces the number of NP(366-374)-specific CD8+ T cells, increases their sensitivity to CD95/Fas-mediated apoptosis, and up-regulates FasL on CD4+ T cells. This reduction of NP(366-374)-specific CD8+ T cells requires the presence of CD4+ T cells and Fas signaling. Lack of CD27 signals also decreases the quality of memory CD8+ T cell responses. Memory CD8+ T cells, which express surface CD27 similar to naive cells, however, do not require CD27 costimulation during a secondary response. Thus, CD27 acts indirectly to regulate primary Ag-specific CD8+ T cell responses by preventing apoptosis of CD8+ T cells during the later phase of the primary response and is required for optimal quality of memory cells, but is not required during normally primed secondary CD8+ T cell responses.     

Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system?

One of the many functions of liver peroxisomes is the beta-oxidation of long-chain fatty acids. It is essential for the continuation of peroxisomal beta-oxidation that a redox shuttle system exist across the peroxisomal membrane to reoxidize NADH. We propose that this redox shuttle system consists of a substrate cycle between lactate and pyruvate. Here we present evidence that purified peroxisomal membranes contain both monocarboxylate transporter 1 (MCT 1) and MCT 2 and that along with peroxisomal lactate dehydrogenase (pLDH) form a Peroxisomal Lactate Shuttle. Peroxisomal beta-oxidation was greatly stimulated by the addition of pyruvate and this increase was partially inhibited by the addition of the MCT blocker alpha-cyano-4-hydroxycinnamate (CINN). We also found that peroxisomes generated lactate in the presence of pyruvate. Together these data provide compelling that the Peroxisome Lactate Shuttle helps maintain organelle redox and the proper functioning of peroxisomal beta-oxidation.     

The modular modality frame model: continuous body state estimation and plausibility-weighted information fusion

Humans show admirable capabilities in movement planning and execution. They can perform complex tasks in various contexts, using the available sensory information very effectively. Body models and continuous body state estimations appear necessary to realize such capabilities. We introduce the Modular Modality Frame (MMF) model, which maintains a highly distributed, modularized body model continuously updating, modularized probabilistic body state estimations over time. Modularization is realized with respect to modality frames, that is, sensory modalities in particular frames of reference and with respect to particular body parts. We evaluate MMF performance on a simulated, nine degree of freedom arm in 3D space. The results show that MMF is able to maintain accurate body state estimations despite high sensor and motor noise. Moreover, by comparing the sensory information available in different modality frames, MMF can identify faulty sensory measurements on the fly. In the near future, applications to lightweight robot control should be pursued. Moreover, MMF may be enhanced with neural encodings by introducing neural population codes and learning techniques. Finally, more dexterous goal-directed behavior should be realized by exploiting the available redundant state representations.     

Growth suppression induced by downregulation of E6-AP expression in human papillomavirus-positive cancer cell lines depends on p53

The ubiquitin-protein ligase E6-AP is utilized by the E6 oncoprotein of human papillomaviruses (HPVs) associated with cervical cancer to target the tumor suppressor p53 for degradation. Here, we report that downregulation of E6-AP expression by RNA interference results in both the accumulation of p53 and growth suppression of the HPV-positive cervical cancer cell lines HeLa and SiHa. In addition, HeLa cells, in which p53 expression was suppressed by RNA interference, are significantly less sensitive to the downregulation of E6-AP expression with respect to growth suppression than parental HeLa cells. These data indicate that the anti-growth-suppressive properties of E6-AP in HPV-positive cells depend on its ability to induce p53 degradation.     

Description and quantification of pteropod shell dissolution: a sensitive bioindicator of ocean acidification

Anthropogenic ocean acidification is likely to have negative effects on marine calcifying organisms, such as shelled pteropods, by promoting dissolution of aragonite shells. Study of shell dissolution requires an accurate and sensitive method for assessing shell damage. Shell dissolution was induced through incubations in CO₂‐enriched seawater for 4 and 14 days. We describe a procedure that allows the level of dissolution to be assessed and classified into three main types: Type I with partial dissolution of the prismatic layer; Type II with exposure of underlying crossed‐lamellar layer, and Type III, where crossed‐lamellar layer shows signs of dissolution. Levels of dissolution showed a good correspondence to the incubation conditions, with the most severe damage found in specimens held for 14 days in undersaturated condition (Ω ~ 0.8). This methodology enables the response of small pelagic calcifiers to acidified conditions to be detected at an early stage, thus making pteropods a valuable bioindicator of future ocean acidification.     

ConA的抗着床效应

本文用凝集素为探针,探索糖复合物在胚泡着床中的作用,报道了与甘露糖苷有专一结合的伴刀豆凝集素(ConA)有明显的抗小鼠胚泡着床作用。妊娠4d的小鼠,每只子宫角中注入Con A 25μg,22只子宫角中只有4只子宫角有胚泡着床,着床率为18.2％,与生理盐水对照组的着床率87.5％相比有明显差异。将相同剂量的Con A先与0.4mol/L α-甲基-D-甘露糖苷温育1—2h后再注入子宫,20只子宫角中有15只子宫角有胚泡着床,着床率提高到75％。用辣根过氧化物酶直接标记法证明,着床前子宫内膜细胞表面有Con A受体存在,并随着妊娠天数而增加,尤其是间质细胞,发情期时时为阴性反应,到着床期蜕膜细胞膜表面呈现出大量Con A受体。提示精复合物在着床中的重要作用。与甘露糖苷同样专一结合的,但寡糖结构专一性与Con A不同的豌豆凝集素注入子宫则无抗着床效应,着床率为85.7％。由此可以推测,N-连接的包含二个未被取代的或只在C-2位被取代的α-甘露糖苷的寡糖参于胚泡与子宫内膜相互作用的着床过程。     

Prestress as an optimal biomechanical parameter for needle penetration

Drug delivery requires precise intradermal and subcutaneous injections of formulations to clinically relevant penetration depths. However, penetration depth is confounded by skin deflection, which occurs prior to and during penetration as the skin surface deforms axially with the needle, and which varies profoundly due to differing intrinsic mechanical (e.g. viscoelastic) tissue properties, disease state, aging, and ethnicity. Herein, an ex vivo model was utilized to study factors that affect skin deflection and the efficacy of injection, including prestress applied at the tissue surface, needle gauge, velocity, and actuation depth. The application of prestress minimized skin deflection during needle penetration and allowed for needle actuation to the targeted penetration depths with minimum variability. The force required to achieve target penetration depths was found to increase with prestress and decrease with needle gauge. Our findings emphasize the need for prestress applied to the skin surface to minimize variation in skin properties and administer formulations for intradermal and subcutaneous treatments with maximum precision.