Two-dimensional lateral heterojunctions based on monolayer transition-metal dichalcogenides (TMDs) have received increasing attention given that their direct band gap makes them very attractive for ...optoelectronic applications. Although bilayer TMDs present an indirect band gap, their electrical properties are expected to be less susceptible to ambient conditions, with higher mobilities and density of states when compared to monolayers. Bilayers and few-layers single domain devices have already demonstrated higher performance in radio frequency and photosensing applications. Despite these advantages, lateral heterostructures based on bilayer domains have been less explored. Here, we report the controlled synthesis of multi-junction bilayer lateral heterostructures based on MoS2-WS2 and MoSe2-WSe2 monodomains. The heterojunctions are created via sequential lateral edge-epitaxy that happens simultaneously in both the first and the second layers. A phenomenological mechanism is proposed to explain the growth mode with self-limited thickness that happens within a certain window of growth conditions. With respect to their as-grown monolayer counterparts, bilayer lateral heterostructures yield nearly 1 order of magnitude higher rectification currents. They also display a clear photovoltaic response, with short circuit currents ∼103 times larger than those extracted from the as-grown monolayers, in addition to room-temperature electroluminescence. The improved performance of bilayer heterostructures significantly expands the potential of two-dimensional materials for optoelectronics.
Background
A therapeutic approach for the treatment of glucocorticoid‐induced skeletal muscle atrophy should be based on the knowledge of the molecular mechanisms determining the unbalance between ...anabolic and catabolic processes and how to re‐establish this balance. Here, we investigated whether the obestatin/GPR39 system, an autocrine signalling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against chronic glucocorticoid‐induced muscle atrophy.
Methods
In this study, we used an in vivo model of muscle atrophy induced by the synthetic glucocorticoid dexamethasone to examine the liaison molecules that define the interaction between the glucocorticoid receptor and the obestatin/GPR39 systems. The findings were extended to in vitro effects on human atrophy using human KM155C25 myotubes.
Results
KLF15 and FoxO transcription factors were identified as direct targets of obestatin signalling in the control of proteostasis in skeletal muscle. The KLF15‐triggered gene expression program, including atrogenes and FoxOs, was regulated via KLF15 ubiquitination by the E3 ubiquitin ligase NEDD4. Additionally, a specific pattern of FoxO post‐translational modification, including FoxO4 phosphorylation by Akt pathway, was critical in the regulation of the ubiquitin–proteasome system. The functional cooperativity between Akt and NEDD4 in the regulation of FoxO and KLF15 provides integrated cues to counteract muscle proteostasis and re‐establish protein synthesis.
Conclusions
The effective control of FoxO activity in response to glucocorticoid is critical to counteract muscle‐related pathologies. These results highlight the potential of the obestatin/GPR39 system to fine‐tune the effects of glucocorticoids on skeletal muscle wasting.
Background
Many pathological states characterized by muscle atrophy are associated with an increase in circulating glucocorticoids and poor patient prognosis, making it an important target for ...treatment. The development of treatments for glucocorticoid‐induced and wasting disorder‐related skeletal muscle atrophy should be designed based on how the particular transcriptional program is orchestrated and how the balance of muscle protein synthesis and degradation is deregulated. Here, we investigated whether the obestatin/GPR39 system, an autocrine/paracrine signaling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against glucocorticoid‐induced muscle cell atrophy.
Methods
In the present study, we have utilized mouse C2C12 myotube cultures to examine whether the obestatin/GPR39 signaling pathways can affect the atrophy induced by the synthetic glucocorticoid dexamethasone. We have extended these findings to in vitro effects on human atrophy using human KM155C25 myotubes.
Results
The activation of the obestatin/GPR39 system protects from glucocorticoid‐induced atrophy by regulation of Akt, PKD/PKCμ, CAMKII and AMPK signaling and its downstream targets in the control of protein synthesis, ubiquitin–proteasome system and autophagy–lysosome system in mouse cells. We compared mouse and human myotube cells in their response to glucocorticoid and identified differences in both the triggering of the atrophic program and the response to obestatin stimulation. Notably, we demonstrate that specific patterns of post‐translational modifications of FoxO4 and FoxO1 play a key role in directing FoxO activity in response to obestatin in human myotubes.
Conclusions
Our findings emphasize the function of the obestatin/GPR39 system in coordinating a variety of pathways involved in the regulation of protein degradation during catabolic conditions.
Obestatin/GPR39 signaling stimulates skeletal muscle repair by inducing the expansion of satellite stem cells as well as myofiber hypertrophy. Here, we describe that the obestatin/GPR39 system acts ...as autocrine/paracrine factor on human myogenesis. Obestatin regulated multiple steps of myogenesis: myoblast proliferation, cell cycle exit, differentiation and recruitment to fuse and form multinucleated hypertrophic myotubes. Obestatin-induced mitogenic action was mediated by ERK1/2 and JunD activity, being orchestrated by a G-dependent mechanism. At a later stage of myogenesis, scaffolding proteins β-arrestin 1 and 2 were essential for the activation of cell cycle exit and differentiation through the transactivation of the epidermal growth factor receptor (EGFR). Upon obestatin stimulus, β-arrestins are recruited to the membrane, where they functionally interact with GPR39 leading to Src activation and signalplex formation to EGFR transactivation by matrix metalloproteinases. This signalplex regulated the mitotic arrest by p21 and p57 expression and the mid- to late stages of differentiation through JNK/c-Jun, CAMKII, Akt and p38 pathways. This finding not only provides the first functional activity for β-arrestins in myogenesis but also identify potential targets for therapeutic approaches by triggering specific signaling arms of the GPR39 signaling involved in myogenesis.
The present work analysed the main changes in subtidal algal assemblages in the last decade in an oceanic archipelago (Canary Islands – eastern Atlantic Ocean). Changes result from increases in cover ...of ephemeral benthic algae, such as the non-native chlorophyte Pseudotetraspora marina and the native cyanophytes Blennothrix lyngbyacea, Schizothrix calcicola and Schizothrix mexicana. Ephemeral algae overgrow subtidal assemblages which are extensively dominated by Lobophora variegata, but competitively do not exclude other species. Increases in the abundance of species coincided with a warming of about 2 °C in surface seawater temperature (SST) linked to the weakening of the Cold Canary Current and the Northwestern African upwelling. Shifts in the distribution and cover of ephemeral species follow the SST gradient from warmer waters in the western islands to colder waters in the eastern ones. While in the warmest western islands, species have spread quickly colonizing all type of substrates in just a few years (2005–2008), the occurrence of ephemerals towards the coldest eastern islands is yet inconspicuous.
► We examine changes in subtidal algal assemblages. ► We detected conspicuous increases in cover of ephemeral benthic algae. ► Ephemeral algae overgrow subtidal assemblages dominated by Lobophora variegata. ► Changes are related to a warming of about 2 °C in SST. ► Increases in cover of ephemeral algae follow a SST gradient along the Canary Islands.
Obestatin/GPR39 signaling stimulates skeletal muscle growth and repair by inducing both G-protein-dependent and -independent mechanisms linking the activated GPR39 receptor with distinct sets of ...accessory and effector proteins. In this work, we describe a new level of activity where obestatin signaling plays a role in the formation, contractile properties and metabolic profile of skeletal muscle through determination of oxidative fiber type. Our data indicate that obestatin regulates Mef2 activity and PGC-1α expression. Both mechanisms result in a shift in muscle metabolism and function. The increase in Mef2 and PGC-1α signaling activates oxidative capacity, whereas Akt/mTOR signaling positively regulates myofiber growth. Taken together, these data indicate that the obestatin signaling acts on muscle fiber-type program in skeletal muscle.
Most patients with multiple myeloma treated with current therapies, including immunomodulatory drugs, eventually develop relapsed/refractory disease. Clinical activity of lenalidomide relies on ...degradation of Ikaros and the consequent reduction in IRF4 expression, both required for myeloma cell survival and involved in the regulation of MYC transcription. Thus, we sought to determine the combinational effect of an MYC-interfering therapy with lenalidomide/dexamethasone. We analyzed the potential therapeutic effect of the combination of the BET bromodomain inhibitor CPI203 with the lenalidomide/dexamethasone regimen in myeloma cell lines. CPI203 exerted a dose-dependent cell growth inhibition in cell lines, indeed in lenalidomide/dexamethasone-resistant cells (median response at 0.5 μM: 65.4%), characterized by G1 cell cycle blockade and a concomitant inhibition of MYC and Ikaros signaling. These effects were potentiated by the addition of lenalidomide/dexamethasone. Results were validated in primary plasma cells from patients with multiple myeloma co-cultured with the mesenchymal stromal cell line stromaNKtert. Consistently, the drug combination evoked a 50% reduction in cell proliferation and correlated with basal Ikaros mRNA expression levels (
=0.04). Finally, in a SCID mouse xenotransplant model of myeloma, addition of CPI203 to lenalidomide/dexamethasone decreased tumor burden, evidenced by a lower glucose uptake and increase in the growth arrest marker GADD45B, with simultaneous downregulation of key transcription factors such as MYC, Ikaros and IRF4. Taken together, our data show that the combination of a BET bromodomain inhibitor with a lenalidomide-based regimen may represent a therapeutic approach to improve the response in relapsed/refractory patients with multiple myeloma, even in cases with suboptimal prior response to immunomodulatory drugs.
Despite the proven therapeutic role of capsaicin in human health, its usage is still hampered by its high pungency. In this sense, nonpungent capsaicin analogues as olvanil are a feasible alternative ...to the unpleasant sensations produced by capsaicin while maintaining a similar pharmacological profile. Olvanil can be obtained by a lipase‐catalyzed chemoenzymatic process. In the present work, recombinant Candida antarctica lipase B (CALB) was expressed in Pichia pastoris and subsequently immobilized by cross‐linked enzyme aggregate (CLEA) methodology for the synthesis of olvanil. The CALB‐CLEAs were obtained directly from the fermentation broth of P. pastoris without any purification step in order to assess the role of the contaminant proteins of the crude extract as co‐feeders. The CALB‐CLEAs were also bioimprinted to enhance the catalytic performance in olvanil synthesis. When CALB was precipitated with isopropanol, the obtained CALB‐CLEAs exhibited the highest activity in the synthesis of olvanil, regardless of the glutaraldehyde concentration. The maximum product synthesis was found at 72 hr obtaining 6.8 g L−1 of olvanil with a reaction yield of 16%. When CALB was bioimprinted with olvanil, the synthesis was enhanced 1.3 times, reaching 10.7 g L−1 of olvanil at 72 hr of reaction with a reaction yield of 25%. Scanning electron microscopy images indicated different morphologies of the CLEAs depending on the precipitating agent and the template used for bioimprinting. Recombinant CALB‐CLEAs obtained directly from the fermentation broth are a suitable alternative to commercial enzymatic preparations for the synthesis of olvanil in organic medium.
Pregnant female
Zootoca vivipara
select lower body temperatures than males or nonpregnant females, and this shift in the thermal preferendum is believed to be related to optimising the conditions for ...embryogenesis. Thus, subjecting embryos to the higher temperature selected by males and non-gravid females might have detrimental effects on embryonic development and on hatchling fitness, according to predictions of the “maternal manipulation” hypothesis on the evolution of viviparity. To test the role of gestation environment on embryonic development in oviparous
Z. vivipara
, we kept a number of gravid females at the temperature selected by non-gravid females in a laboratory thermal gradient, whereas control females were allowed to regulate their body temperature without restrictions. Developmental stage at oviposition was more advanced for embryos of the experimental clutches, which were heavier than those of the control group. Forced gestation temperature also affected hatching success (58.62% in the experimental treatment vs. 97.37% in the control group). In addition, hatchlings from females subjected to high temperatures during pregnancy were smaller, had shorter head length and performed worse in running trials. Our results fulfil the prediction of the “maternal manipulation” hypothesis, and suggest that the shift in female body temperature during pregnancy optimizes embryogenesis and hatchling phenotype by avoiding the negative effects of the high incubation temperatures preferred by non-gravid females.
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