Mir-434-5p mediates skin whitening and lightening

Utilization of gene silencing effectors, such as microRNA (miRNA) and small hairpin RNA (shRNA), provides a powerful new strategy for human skin care in vivo, particularly for hyperpigmentation treatment and aging prevention. In this study, tyrosinase (Tyr), the rate-limiting enzyme of melanin (black pigment) biosynthesis, was served as a target for treatment of hyperpigmentation in mouse and human skins. There are over 54 native microRNA capable of silencing human tyrosinase for skin whitening and lightening. To this, we have designed a mir-434-5p homologue and used it to successfully demonstrate the feasibility of miRNA-mediated skin whitening and lightening in vitro and in vivo. Under the same experimental condition in the trials, Pol-II-directed intronic mir-434-5p expression did not cause any detectable sign of cytotoxicity, whereas siRNAs targeting the same sequence often induced certain nonspecific mRNA degradation as previously reported. Because the intronic miRNA-mediated gene silencing pathway is tightly regulated by multiple intracellular surveillance systems, including Pol-II transcription, RNA splicing, exosomal digestion and nonsense-mediated RNA decay (NMD), the current findings underscore the fact that intronic miRNA agents, such as manually re-designed mir-434-5p homologues, are effective, target-specific and safe to be used for skin whitening without any detectable cytotoxic effect. Given that the human skins also express a variety of other native miRNAs, we may re-design these miRNAs based on their individual functions for skin care, which may provide significant insights into areas of opportunity for new cosmetic and/or therapeutical applications

A single sub-km Kuiper Belt object from a stellar Occultation in archival data

The Kuiper belt is a remnant of the primordial Solar System. Measurements of its size distribution constrain its accretion and collisional history, and the importance of material strength of Kuiper belt objects (KBOs). Small, sub-km sized, KBOs elude direct detection, but the signature of their occultations of background stars should be detectable. Observations at both optical and X-ray wavelengths claim to have detected such occultations, but their implied KBO abundances are inconsistent with each other and far exceed theoretical expectations. Here, we report an analysis of archival data that reveals an occultation by a body with a 500 m radius at a distance of 45 AU. The probability of this event to occur due to random statistical fluctuations within our data set is about 2%. Our survey yields a surface density of KBOs with radii larger than 250 m of 2.1^{+4.8}_{-1.7} x 10^7 deg^{-2}, ruling out inferred surface densities from previous claimed detections by more than 5 sigma. The fact that we detected only one event, firmly shows a deficit of sub-km sized KBOs compared to a population extrapolated from objects with r>50 km. This implies that sub-km sized KBOs are undergoing collisional erosion, just like debris disks observed around other stars.Comment: To appear in Nature on December 17, 2009. Under press embargo until 1800 hours London time on 16 December. 19 pages; 7 figure

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays

A sleeping phantom leg awakened following hemicolectomy, thrombosis, and chemotherapy: a case report

INTRODUCTION: We describe the case of a patient who experienced phantom pain that began 42 years after right above-the-knee amputation. Immediately prior to phantom pain onset, this long-term amputee had experienced, in rapid succession, cancer, hemicolectomy, chemotherapy, and thrombotic occlusion. Very little has been published to date on the association between chemotherapy and exacerbation of neuropathic pain in amputees, let alone the phenomenon of bringing about pain in amputees who have been pain-free for many decades. While this patient presented with a unique profile following a rare sequence of medical events, his case should be recognized considering the frequent co-occurrence of osteomyelitis, chemotherapy, and amputation. CASE PRESENTATION: A 68-year-old Australian Caucasian man presented 42 years after right above-the-knee amputation with phantom pain immediately following hemicolectomy, thrombotic occlusion in the amputated leg, and chemotherapy treatment with leucovorin and 5-fluorouracil. He exhibited probable hyperalgesia with a reduced pinprick threshold and increased stump sensitivity, indicating likely peripheral and central sensitization. CONCLUSION: Our patient, who had long-term nerve injury due to amputation, together with recent ischemic nerve and tissue injury due to thrombosis, exhibited likely chemotherapy-induced neuropathy. While he presented with unique treatment needs, cases such as this one may actually be quite common considering that osteosarcoma can frequently lead to amputation and be followed by chemotherapy. The increased susceptibility of amputees to developing potentially intractable chemotherapy-induced neuropathic pain should be taken into consideration throughout the course of chemotherapy treatment. Patients in whom chronic phantom pain then develops, perhaps together with mobility issues, inevitably place greater demands on healthcare service providers that require treatment by various clinical specialists, including oncologists, neurologists, prosthetists, and, most frequently, general practitioners

Cascaded two-photon nonlinearity in a one-dimensional waveguide with multiple two-level emitters

We propose and theoretically investigate a model to realize cascaded optical nonlinearity with few atoms and photons in one-dimension (1D). The optical nonlinearity in our system is mediated by resonant interactions of photons with two-level emitters, such as atoms or quantum dots in a 1D photonic waveguide. Multi-photon transmission in the waveguide is nonreciprocal when the emitters have different transition energies. Our theory provides a clear physical understanding of the origin of nonreciprocity in the presence of cascaded nonlinearity. We show how various two-photon nonlinear effects including spatial attraction and repulsion between photons, background fluorescence can be tuned by changing the number of emitters and the coupling between emitters (controlled by the separation).Comment: 6 pages, 4 figure

Fracturing ranked surfaces

Discretized landscapes can be mapped onto ranked surfaces, where every element (site or bond) has a unique rank associated with its corresponding relative height. By sequentially allocating these elements according to their ranks and systematically preventing the occupation of bridges, namely elements that, if occupied, would provide global connectivity, we disclose that bridges hide a new tricritical point at an occupation fraction $p=p_{c}$, where $p_{c}$ is the percolation threshold of random percolation. For any value of $p$ in the interval $p_{c}< p \leq 1$, our results show that the set of bridges has a fractal dimension $d_{BB} \approx 1.22$ in two dimensions. In the limit $p \rightarrow 1$, a self-similar fracture is revealed as a singly connected line that divides the system in two domains. We then unveil how several seemingly unrelated physical models tumble into the same universality class and also present results for higher dimensions

Dynamic response of a cracked atomic force microscope cantilever used for nanomachining

The vibration behavior of an atomic force microscope [AFM] cantilever with a crack during the nanomachining process is studied. The cantilever is divided into two segments by the crack, and a rotational spring is used to simulate the crack. The two individual governing equations of transverse vibration for the cracked cantilever can be expressed. However, the corresponding boundary conditions are coupled because of the crack interaction. Analytical expressions for the vibration displacement and natural frequency of the cracked cantilever are obtained. In addition, the effects of crack flexibility, crack location, and tip length on the vibration displacement of the cantilever are analyzed. Results show that the crack occurs in the AFM cantilever that can significantly affect its vibration response

Constitutive cytoplasmic localization of p21Waf1/Cip1 affects the apoptotic process in monocytic leukaemia

In the present study, we analysed the expression and localization of p21Waf1/Cip1 in normal and malignant haematopoietic cells. We demonstrate that in normal monocytic cells, protein kinase C (PKC)-induced p21 gene activation, which is nuclear factor-κB (NF-κB) independent, results in predominantly cytoplasmic localized p21 protein. In acute monocytic leukaemia (M4, M5), monocytic blasts (N=12) show constitutive cytoplasmic p21 expression in 75% of the cases, while in myeloid leukaemic blasts (N=10), low nuclear and cytoplasmic localization of p21 could be detected, which is also PKC dependent. Constitutive p21 expression in monocytic leukaemia might have important antiapoptotic functions. This is supported by the finding that in U937 cells overexpressing p21, VP16-induced apoptosis is significantly reduced (20.0±0.9 vs 55.8±3.8%, P<0.01, N=5), reflected by a reduced phosphorylation of p38 and JNK. Similarly, AML blasts with high cytoplasmic p21 were less sensitive to VP16-induced apoptosis as compared to AML cases with low or undetectable p21 expression (42.25 vs 12.3%, P<0.01). Moreover, complex formation between p21 and ASK1 could be demonstrated in AML cells, by means of coimmunoprecipitation. In summary, these results indicate that p21 has an antiapoptotic role in monocytic leukaemia, and that p21 expression is regulated in a PKC-dependent and NF-κB independent manner.