Actin turnover protects the cytokinetic contractile ring from structural instability.

In common with other actomyosin contractile cellular machineries, actin turnover is required for normal function of the cytokinetic contractile ring. Cofilin is an actin-binding protein contributing to turnover by severing actin filaments, required for cytokinesis by many organisms. In fission yeast cofilin mutants, contractile rings suffer bridging instabilities in which segments of the ring peel away from the plasma membrane, forming straight bridges whose ends remain attached to the membrane. The origin of bridging instability is unclear. Here, we used molecularly explicit simulations of contractile rings to examine the role of cofilin. Simulations reproduced the experimentally observed cycles of bridging and reassembly during constriction, and the occurrence of bridging in ring segments with low density of the myosin II protein Myo2. The lack of cofilin severing produced ∼2-fold longer filaments and, consequently, ∼2-fold higher ring tensions. Simulations identified bridging as originating in the boosted ring tension, which increased centripetal forces that detached actin from Myo2, which was anchoring actin to the membrane. Thus, cofilin serves a critical role in cytokinesis by providing protection from bridging, the principal structural threat to contractile rings.

Cyclase-associated protein interacts with actin filament barbed ends to promote depolymerization and formin displacement.

Cyclase-associated protein (CAP) has emerged as a central player in cellular actin turnover, but its molecular mechanisms of action are not yet fully understood. Recent studies revealed that the N terminus of CAP interacts with the pointed ends of actin filaments to accelerate depolymerization in conjunction with cofilin. Here, we use in vitro microfluidics-assisted TIRF microscopy to show that the C terminus of CAP promotes depolymerization at the opposite (barbed) ends of actin filaments. In the absence of actin monomers, full-length mouse CAP1 and C-terminal halves of CAP1 (C-CAP1) and CAP2 (C-CAP2) accelerate barbed end depolymerization. Using mutagenesis and structural modeling, we show that these activities are mediated by the WH2 and CARP domains of CAP. In addition, we observe that CAP collaborates with profilin to accelerate barbed end depolymerization and that these effects depend on their direct interaction, providing the first known example of CAP-profilin collaborative effects in regulating actin. In the presence of actin monomers, CAP1 attenuates barbed end growth and promotes formin dissociation. Overall, these findings demonstrate that CAP uses distinct domains and mechanisms to interact with opposite ends of actin filaments and drive turnover. Further, they contribute to the emerging view of actin barbed ends as sites of dynamic molecular regulation, where numerous proteins compete and cooperate with each other to tune polymer dynamics, similar to the rich complexity seen at microtubule ends.

C-Type LECTIN receptor-like kinase 1 and ACTIN DEPOLYMERIZING FACTOR 3 are key components of plasmodesmata callose modulation.

Plasmodesmata (PDs) are intercellular organelles carrying multiple membranous nanochannels that allow the trafficking of cellular signalling molecules. The channel regulation of PDs occurs dynamically and is required in various developmental and physiological processes. It is well known that callose is a critical component in regulating PD permeability or symplasmic connectivity, but the understanding of the signalling pathways and mechanisms of its regulation is limited. Here, we used the reverse genetic approach to investigate the role of C-type lectin receptor-like kinase 1 (CLRLK1) in the aspect of PD callose-modulated symplasmic continuity. Here, we found that loss-of-function mutations in CLRLK1 resulted in excessive PD callose deposits and reduced symplasmic continuity, resulting in an accelerated gravitropic response. The protein interactome study also found that CLRLK1 interacted with actin depolymerizing factor 3 (ADF3) in vitro and in plants. Moreover, mutations in ADF3 result in elevated PD callose deposits and faster gravitropic response. Our results indicate that CLRLK1 and ADF3 negatively regulate PD callose accumulation, contributing to fine-tuning symplasmic opening apertures. Overall, our studies identified two key components involved in the deposits of PD callose and provided new insights into how symplasmic connectivity is maintained by the control of PD callose homoeostasis.

Stacking Structure of Vaterite Revealed by Atomic Imaging and Diffraction Analysis.

Anhydrous calcium carbonate crystals exist as three polymorphs: calcite, aragonite, and vaterite. Although vaterite is a metastable phase rarely found in the geological environment, it is intriguing that various biominerals are composed of vaterite. The processes of stable vaterite formation in biological systems cannot be understood without elucidating the nature of vaterite. The crystal structure of vaterite has been discussed for nearly a century but is still an open question. Here we propose the actual structure of vaterite by combining atomic imaging and diffraction analysis with simulations of disordered stacking sequences. Vaterite basically appears as layers of hexagonal calcium planes and carbonate (CO3 2-)-containing sheets stacked with +60°, -60°, or 180° rotations from the underlying layer. However, equivalent carbonate positions in alternating layers are forbidden, and four-layer stacking in which the fourth layer rotates 180° relative to the first layer are predominant, forming an orthogonal reciprocal lattice in diffraction patterns. These stacking characteristics replicate the intensity distribution in the electron and X-ray diffraction patterns. This study has almost completely elucidated the crystal structure and stacking sequence of vaterite. Our findings provide insights into the thermodynamic stability of vaterite, which facilitates comprehension of the biomineralization processes and growth dynamics of calcium carbonate.

Impact of siRNA-Mediated Cofilin-1 Knockdown and Obesity Associated Microenvironment on the Motility of Natural Killer Cells.

The anti-tumor capacity of natural killer (NK) cells heavily relies on their ability to migrate towards their target cells. This process is based on dynamic actinrearrangement, so-called actin treadmilling, andis tightly regulated by proteins such as cofilin-1. The aim of the present study was to identify the role of cofilin-1 (CFL-1) in the migratory behavior of NK cells and to investigate a possible impact of an obesity-associated micromilieu on these cells, as it is known that obesity correlates with various impaired NK cell functions. CFL-1 was knocked-down via transfection of NK-92 cells with respective siRNAs. Obesity associated micromilieu was mimicked by incubation of NK-92 cells with adipocyte-conditioned medium from human preadipocyte SGBS cells or leptin. Effects on CFL-1 levels, the degree of phosphorylation to the inactive pCFL-1 as well as NK-92 cell motility were analyzed. Surprisingly, siRNA-mediated CFL-1 knockdown led to a significant increase of migration, as determined by enhanced velocity and accumulated distance of migration. No effect on CFL-1 nor pCFL-1 expression levels, proportion of phosphorylation and cell migratory behavior could be demonstrated under the influence of an obesity-associated microenvironment. In conclusion, the results indicate a significant effect of a CFL-1 knockdown on NK cell motility.

MYB52 negatively regulates ADF9-meditated actin filament bundling in Arabidopsis pavement cell morphogenesis.

It has been proposed that cortical fine actin filaments are needed for the morphogenesis of pavement cells (PCs). However, the precise role and regulation mechanisms of actin filaments in PC morphogenesis are not well understood. Here, we found that Arabidopsis thaliana ACTIN DEPOLYMERIZING FACTOR9 (ADF9) is required for the morphogenesis of PC, which is negatively regulated by the R2R3 MYELOBLASTOSIS (MYB) transcription factor MYB52. In adf9 mutants, the lobe number of cotyledon PCs was significantly reduced, while the average lobe length did not differ significantly compared to that of wild type (Col-0), except for the variations in cell area and circularity, whereas the PC shapes in ADF9 overexpression seedlings showed different results. ADF9 decorated actin filaments, and colocalized with plasma membrane. The extent of filament bundling and actin filament bundling activity in adf9 mutant decreased. In addition, MYB52 directly targeted the promoter of ADF9 and negatively regulated its expression. The myb52-2 mutant showed increased lobe number and cell area, reduced cell circularity of PCs, and the PC phenotypes were suppressed when ADF9 was knocked out. Taken together, our data demonstrate that actin filaments play an important role in the morphogenesis of PC and reveal a transcriptional mechanism underlying MYB52 regulation of ADF9-mediated actin filament bundling in PC morphogenesis.

A review on abuse-deterrent formulations: formulation technology and regulatory stands in approval process.

Drug abuse has become a global health problem over the past few years. Opioid abuse increased with an increase in the prescription of opioids for pain management. Many other classes of drugs are also abused and misused like anti-depressants, stimulants, hallucinogens, anti-psychotic, and anticholinergic drugs. One of the major reasons is that patients falsely diagnosed with depression, anxiety, and severe pain are prescribed these drugs, which are likely to be addictive. Abuse-deterrent formulations are one means to control drug abuse and overdose of prescription opioids. In this review, we explained how abuse-deterrent technology works, key ingredients used in abuse-deterrent formulations, a brief about marketed opioid drug products with abuse-deterrent properties, and the stand of regulatory agencies in the approval process of opioid drug products. In the end, it summarized that pharmaceutical industries and the FDA put their efforts into reducing drug abuse by encouraging the development of ADFs. Most available drug product having abuse-deterrent features contains Polyethylene oxide, which degrades at high temperatures. It requires the attention of the researcher to find an alternate ingredient or process to overcome said problem. From a regulatory point of view, only a few regulatory agencies have published their guidance on ADFs. It is important to convey other regulatory organizations' perspectives on ADFs as well.

Antagonistic Activities of Fmn2 and ADF Regulate Axonal F-Actin Patch Dynamics and the Initiation of Collateral Branching.

Interstitial collateral branching of axons is a critical component in the development of functional neural circuits. Axon collateral branches are established through a series of cellular processes initiated by the development of a specialized, focal F-actin network in axons. The formation, maintenance and remodeling of this F-actin patch is critical for the initiation of axonal protrusions that are subsequently consolidated to form a collateral branch. However, the mechanisms regulating F-actin patch dynamics are poorly understood. Fmn2 is a formin family member implicated in multiple neurodevelopmental disorders. We find that Fmn2 regulates the initiation of axon collateral protrusions in chick spinal neurons and in zebrafish motor neurons. Fmn2 localizes to the protrusion-initiating axonal F-actin patches and regulates the lifetime and size of these F-actin networks. The F-actin nucleation activity of Fmn2 is necessary for F-actin patch stability but not for initiating patch formation. We show that Fmn2 insulates the F-actin patches from disassembly by the actin-depolymerizing factor, ADF, and promotes long-lived, larger patches that are competent to initiate axonal protrusions. The regulation of axonal branching can contribute to the neurodevelopmental pathologies associated with Fmn2 and the dynamic antagonism between Fmn2 and ADF may represent a general mechanism of formin-dependent protection of Arp2/3-initiated F-actin networks from disassembly.SIGNIFICANCE STATEMENT Axonal branching is a key process in the development of functional circuits and neural plasticity. Axon collateral branching is initiated by the elaboration of F-actin filaments from discrete axonal F-actin networks. We show that the neurodevelopmental disorder-associated formin, Fmn2, is a critical regulator of axon collateral branching. Fmn2 localizes to the collateral branch-inducing F-actin patches in axons and regulates the stability of these actin networks. The F-actin nucleation activity of Fmn2 protects the patches from ADF-mediated disassembly. Opposing activities of Fmn2 and ADF exert a dynamic regulatory control on axon collateral branch initiation and may underly the neurodevelopmental defects associated with Fmn2.

Functional non-equivalence of pollen ADF isovariants in Arabidopsis.

ADF/cofilin is a central regulator of actin dynamics. We previously demonstrated that two closely related Arabidopsis class IIa ADF isovariants, ADF7 and ADF10, are involved in the enhancement of actin turnover in pollen, but whether they have distinct functions remains unknown. Here, we further demonstrate that they exhibit distinct functions in regulating actin turnover both in vitro and in vivo. We found that ADF7 binds to ADP-G-actin with lower affinity, and severs and depolymerizes actin filaments less efficiently in vitro than ADF10. Accordingly, in pollen grains, ADF7 more extensively decorates actin filaments and is less freely distributed in the cytoplasm compared to ADF10. We further demonstrate that ADF7 and ADF10 show distinct intracellular localizations during pollen germination, and they have non-equivalent functions in promoting actin turnover in pollen. We thus propose that cooperation and labor division of ADF7 and ADF10 enable pollen cells to achieve exquisite control of the turnover of different actin structures to meet different cellular needs.

A cyclic lipopeptide produced by an antagonistic bacterium relies on its tail and transient receptor potential-type Ca2+ channels to immobilize a green alga.

The antagonistic bacterium Pseudomonas protegens secretes the cyclic lipopeptide (CLiP) orfamide A, which triggers a Ca2+ signal causing rapid deflagellation of the microalga Chlamydomonas reinhardtii. We performed chemical synthesis of orfamide A derivatives and used an aequorin reporter line to measure their Ca2+ responses. Immobilization of algae was studied using a modulator and mutants of transient receptor potential (TRP)-type channels. By investigating targeted synthetic orfamide A derivatives, we found that N-terminal amino acids of the linear part and the terminal fatty acid region are important for the specificity of the Ca2+ -signal causing deflagellation. Molecular editing indicates that at least two distinct Ca2+ -signaling pathways are triggered. One is involved in deflagellation (Thr3 change, fatty acid tail shortened by 4C), whereas the other still causes an increase in cytosolic Ca2+ in the algal cells, but does not cause substantial deflagellation (Leu1 change, fatty acid hydroxylation, fatty acid changes by 2C). Using mutants, we define four TRP-type channels that are involved in orfamide A signaling; only one (ADF1) responds additionally to low pH. These results suggest that the linear part of the CLiP plays one major role in Ca2+ signaling, and that orfamide A uses a network of algal TRP-type channels for deflagellation.

Actin filament oxidation by MICAL1 suppresses protections from cofilin-induced disassembly.

Proteins of the ADF/cofilin family play a central role in the disassembly of actin filaments, and their activity must be tightly regulated in cells. Recently, the oxidation of actin filaments by the enzyme MICAL1 was found to amplify the severing action of cofilin through unclear mechanisms. Using single filament experiments in vitro, we found that actin filament oxidation by MICAL1 increases, by several orders of magnitude, both cofilin binding and severing rates, explaining the dramatic synergy between oxidation and cofilin for filament disassembly. Remarkably, we found that actin oxidation bypasses the need for cofilin activation by dephosphorylation. Indeed, non-activated, phosphomimetic S3D-cofilin binds and severs oxidized actin filaments rapidly, in conditions where non-oxidized filaments are unaffected. Finally, tropomyosin Tpm1.8 loses its ability to protect filaments from cofilin severing activity when actin is oxidized by MICAL1. Together, our results show that MICAL1-induced oxidation of actin filaments suppresses their physiological protection from the action of cofilin. We propose that, in cells, direct post-translational modification of actin filaments by oxidation is a way to trigger their disassembly.

Does structural form matter? A comparative analysis of pooled procurement mechanisms for health commodities.

INTRODUCTION: Pooled procurement can be seen as a collaboration initiative of buyers. Such mechanisms have received increased attention during the Covid-19 pandemic to improve access to affordable and quality-assured health commodities. The structural form of pooled procurement mechanisms ranges from a third-party organization that procures on behalf of its buyers to a buyer's owned mechanism in which buyers operate more collaboratively. However, little is known about how these types of pooled procurement mechanisms differ in terms of characteristics, implementation and developmental process. To fill this gap, we compared four pooled procurement mechanisms. Two buyer's owned mechanisms: the Organisation of the Eastern Caribbean States (OECS) and the Pacific Island Countries (PIC). And two third-party mechanisms: the Global Drug Facility (GDF) and the Asthma Drug Facility (ADF). METHODS: For this qualitative study, we used a multiple case-study design. The cases were purposefully selected, based on a most-similar case study design. We used the Pooled Procurement Guidance to collect data on individual cases and compared our findings between the case studies. For our analysis, we drew upon peer-reviewed academic articles, grey literature documents and 9 semi-structured interviews with procurement experts. RESULTS: Buyers within a buyer's owned mechanisms differ in procurement systems, financing structures, product needs and regulatory and legal frameworks. Therefore, buyers within such mechanisms require relative alignment on motivations, goals and operations of the mechanism. Our study showed that buyers' relative homogeneity of characteristics and their perceived urgency of the problems was particularly relevant for achieving that alignment. Third-party organization mechanisms require less alignment and consensus-building between buyers. To participate, buyers need to align with the operations of the third-party organization, instead of other buyers. Elements that were essential for the successful implementation and operation of such mechanisms included the procurement secretariat's ability to create local and global awareness around the problem, to induce political will to act upon the problem, to mobilize sufficient funding and to attract qualified staff. CONCLUSION: To successfully sustain pooled procurement mechanisms over time, key actors should drive the mechanism through continuous and reflexive work on stakeholder engagement, mobilization of funding and alignment of interests and needs.

Comparing two surgical approaches for treating multilevel cervical spondylotic myelopathy: A meta-analysis.

PURPOSE: This meta-analysis aims to evaluate the therapeutic efficacy of anterior versus posterior surgical approaches for multisegment cervical spondylotic myelopathy (MCSM). METHODS: Eligible studies published between the period of January 2001 and April 2022 and comparing the anterior and posterior surgical approaches for treating cervical spondylotic myelopathy were retrieved from the PubMed, Web of Science, Embase, and Cochrane databases. RESULTS: A total of 17 articles were selected based on the inclusion and exclusion criteria. This meta-analysis failed to show any significant difference in the duration of surgery, the hospitalization time, or the improvement in the Japanese Orthopedic Association score between the anterior and posterior approaches. The anterior approach, however, exhibited increased efficacy in the improvement of the neck disability index, reduction in the visual analog scale for cervical pain, and improvement in the cervical curvature compared with the posterior approach. CONCLUSION: Bleeding was also less with the anterior surgical approach. The posterior approach provided a significantly higher range of motion of the cervical spine and showed fewer postoperative complications compared with the anterior approach. While both the surgical approaches have good clinical outcomes and show postoperative neurological function improvement, the meta-analysis shows that both anterior and posterior approaches have certain merits and shortcomings. A meta-analysis of a larger number of randomized controlled trials with longer follow-up can conclusively determine which of the surgical approaches is more beneficial in the treatment of MCSM.

Actin Depolymerization Factor ADF1 Regulated by MYB30 Plays an Important Role in Plant Thermal Adaptation.

Actin filaments are essential for plant adaptation to high temperatures. However, the molecular mechanisms of actin filaments in plant thermal adaptation remain unclear. Here, we found that the expression of Arabidopsis actin depolymerization factor 1 (AtADF1) was repressed by high temperatures. Compared with wild-type seedlings (WT), the mutation of AtADF1 and the overexpression of AtADF1 led to promoted and inhibited plant growth under high temperature conditions, respectively. Further, high temperatures induced the stability of actin filaments in plants. Compared with WT, Atadf1-1 mutant seedlings showed more stability of actin filaments under normal and high temperature conditions, while the AtADF1 overexpression seedlings showed the opposite results. Additionally, AtMYB30 directly bound to the promoter of AtADF1 at a known AtMYB30 binding site, AACAAAC, and promoted the transcription of AtADF1 under high temperature treatments. Genetic analysis further indicated that AtMYB30 regulated AtADF1 under high temperature treatments. Chinese cabbage ADF1 (BrADF1) was highly homologous with AtADF1. The expression of BrADF1 was inhibited by high temperatures. BrADF1 overexpression inhibited plant growth and reduced the percentage of actin cable and the average length of actin filaments in Arabidopsis, which were similar to those of AtADF1 overexpression seedlings. AtADF1 and BrADF1 also affected the expression of some key heat response genes. In conclusion, our results indicate that ADF1 plays an important role in plant thermal adaptation by blocking the high-temperature-induced stability of actin filaments and is directly regulated by MYB30.

Identification of Gut Microbiota Affecting Fiber Digestibility in Pigs.

Dietary fiber plays an important role in porcine gut health and welfare. Fiber is degraded by microbial fermentation in the intestine, and most gut microbiota related to fiber digestibility in pigs are worth pursuing. The aim of this study was to identify gut microbiota associated with the apparent total tract digestibility (ATTD) of neutral detergent fiber (NDF) and of acid detergent fiber (ADF) in pigs. Large phenotypic variations in the ATTD of NDF and of ADF were separately found among 274 Suhuai pigs. Microbial community structures were significantly different between high and low fiber digestibility groups. Fourteen genera separately dominated the communities found in the high ATTD (H-AD) of NDF and ADF samples and were in very low abundance in the low ATTD (L-AD) of NDF and ADF samples. In conclusion, norank_f__Bacteroidales_S24-7_group (p < 0.05), Ruminococcaceae_UCG-005 (p < 0.05), unclassified_f__Lachnospiraceae (p < 0.05), Treponema_2 (p < 0.01), and Ruminococcaceae_NK4A214_group (p < 0.01) were the main genera of gut microbiota affecting the ATTD of NDF in pigs. Christensenellaceae_R-7_group (p < 0.01), Treponema_2 (p < 0.05), Ruminococcaceae_NK4A214_group (p < 0.05), Ruminococcaceae_UCG-002 (p < 0.05), and [Eubacterium]_coprostanoligenes_group (p < 0.05) were the main genera of gut microbiota affecting the ATTD of ADF in pigs. The most important functions of the above different potential biomarkers were: carbohydrate transport and metabolism, general function prediction only, amino acid transport and metabolism, cell wall/membrane/envelope biogenesis, translation, transcription, replication, energy production and conversion, signal transduction mechanisms, and inorganic ion transport and metabolism. The most important metabolic pathways of the above different potential biomarkers were: membrane transport, carbohydrate metabolism, amino acid metabolism, replication and repair, translation, cell motility, energy metabolism, poorly characterized, nucleotide metabolism, metabolism of cofactors and vitamins, and cellular processes and signaling.

Formation of actin-cofilin rods by depletion forces.

Various stress conditions induce the formation of actin-cofilin rods in either the nucleus or the cytoplasm, although the mechanism of rod formation is unclear. In this study, we constituted actin-cofilin rods using purified actin, cofilin and actin interacting protein 1 (AIP1) in the presence of a physiological buffer containing a crowding agent, 0.8% methylcellulose (MC), which led to bundled actin filaments formed by depletion forces. Most of the F-actin bundles formed with methylcellulose were linear, whereas cofilin-bound F-actin bundles often had bent, looped, and often ring-like shapes. Increasing the amount of AIP1 shortened actin-cofilin bundles into rod-like bundles with tapering at both ends. As much shorter actin-cofilin filaments were formed in the presence of AIP1 before MC was added to the mixture, the rod-like bundle might be a mass of those short filaments. Furthermore, the small rods fused with each other to become larger rods, indicating that these rods were anisotropic liquid droplets. Several minutes after the addition of MC to the F-actin-cofilin-AIP1 mixture, we observed some long bundles in which the thick and thin parts appear alternately, reminiscent of a Plateau-Rayleigh instability observed in fluid columns. Simultaneously, we found images in which thin parts were interrupted, but the thick parts were arranged in a row in the longitudinal direction. These structures were also observed in cytoplasmic actin-cofilin rods in cells overexpressing cofilin-GFP, suggesting that cytoplasmic actin-cofilin rods have the same structure formation process as the rods reconstituted in vitro.

Revealing Resistive Switching Mechanism in CaFeOx Perovskite System with Electroforming-Free and Reset Voltage-Controlled Multilevel Resistance Characteristics.

Recently, perovskite (PV) oxides with ABO3 structures have attracted considerable interest from scientists owing to their functionality. In this study, CaFeOx is introduced to reveal the resistive switching properties and mechanism of oxygen vacancy transition in PV and brownmillerite (BM) structures. BM-CaFeO2.5 is grown on an Nb-STO conductive substrate epitaxially. CaFeOx exhibits excellent endurance and reliability. In addition, the CaFeOx also demonstrates an electroforming-free characteristic and multilevel resistance properties. To construct the switching mechanism, high-resolution transmission electron microscopy is used to observe the topotactic phase change in CaFeOx . In addition, scanning TEM and electron energy loss spectroscopy show the structural evolution and valence state variation of CaFeOx after the switching behavior. This study not only reveals the switching mechanism of CaFeOx , but also provides a PV oxide option for the dielectric material in resistive random-access memory (RRAM) devices.

The daily caloric restriction and alternate-day fasting ameliorated lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1.

PURPOSE: A possible link between pescadillo 1 (PES1) and lipid metabolism has been reported. However, whether PES1 is involved in the effects of daily caloric restriction (CR) and alternate-day fasting (ADF) interventions on diabetes-related lipid dysregulation is not elucidated. The current study aims are to explore the role of PES1 in effects of CR and ADF on diabetic mice and related mechanism. METHODS: Eight-week-old male db/db mice with type 2 diabetes mellitus (T2DM) were randomly divided into untreated T2DM, CR and ADF groups. McArdle hepatocytes were treated with 48 h high glucose (HG), 48 h normal glucose (NG) and 24 h HG plus 24 h NG, respectively. Pes1 siRNA and overexpression plasmid were, respectively, transfected into liver cells, and AAV9-Pes1-shRNA was injected into db/db mice. RESULTS: After 12-week interventions, the peroxisome proliferator-activated receptor alpha (PPAR-α) and carnitine palmitoyltransferase 1A (CPT1A) levels in livers of T2DM mice were enhanced by CR and ADF interventions with reductions of hepatic and plasma triglycerides. Unexpectedly, hepatic PES1 levels were downregulated by two interventions, consistent with the results of 48 h NG and 24 h HG plus 24 h NG-treated cells. Moreover, CPT1A level was upregulated in Pes1-siRNA-treated cells and AAV9-Pes1-shRNA injected murine livers, in contrast to Pes1 overexpression in cultured cells. Mechanistically, 48 h NG or 24 h HG plus 24 h NG treatment increased PPAR-α binding to Pes1 promoter, suppressing the PES1 expression, thereby lowering the PES1-mediated ubiquitination of CPT1A. CONCLUSION: The present study suggests that CR and ADF may improve lipid dysregulation in diabetic mice by downregulating hepatic PES1.

Blazing the trail: Social innovation supporting wildfire-resilient territories in Catalonia (Spain).

Mediterranean territories have co-evolved and been shaped by fire throughout history. However, global environmental change conditions are increasing the size, intensity and severity of wildfires, which have gone from a regular natural disturbance to a serious threat for civil protection, surpassing firefighting capacities. Therefore, building resilience in fire-prone territories is an increasingly relevant policy and management objective. However, the notion of resilience has been criticized for paying insufficient attention to key social issues such as socio-political dynamics, power imbalances and societal change. At the same time, social science contributions to wildfire research are still rather limited. In this paper, we bridge social innovation theory to resilience theory in order to create a territorially embedded and socially sensitive framework for assessing socio-ecological resilience. From this perspective, we then examine how Forest Defence Groups (ADFs, by their Catalan acronym) have evolved from grassroots, bottom-up initiatives to well-established bottom-linked institutions and we evaluate their contributions to socio-ecological resilience in the territories where they operate. Our results show that ADFs contribute in several aspects to socio-ecological resilience and that the pave the way for opening up spaces of dialogue and collaboration through which local communities can engage with the issues that directly affect them, such as wildfires.

Stock Index Prediction Based on Time Series Decomposition and Hybrid Model.

The stock index is an important indicator to measure stock market fluctuation, with a guiding role for investors' decision-making, thus being the object of much research. However, the stock market is affected by uncertainty and volatility, making accurate prediction a challenging task. We propose a new stock index forecasting model based on time series decomposition and a hybrid model. Complete Ensemble Empirical Mode Decomposition with Adaptive Noise (CEEMDAN) decomposes the stock index into a series of Intrinsic Mode Functions (IMFs) with different feature scales and trend term. The Augmented Dickey Fuller (ADF) method judges the stability of each IMFs and trend term. The Autoregressive Moving Average (ARMA) model is used on stationary time series, and a Long Short-Term Memory (LSTM) model extracts abstract features of unstable time series. The predicted results of each time sequence are reconstructed to obtain the final predicted value. Experiments are conducted on four stock index time series, and the results show that the prediction of the proposed model is closer to the real value than that of seven reference models, and has a good quantitative investment reference value.