Slc12a8 in the lateral hypothalamus maintains energy metabolism and skeletal muscle functions during aging

Sarcopenia and frailty are urgent socio-economic problems worldwide. Here we demonstrate a functional connection between the lateral hypothalamus (LH) and skeletal muscle through Slc12a8, a recently identified nicotinamide mononucleotide transporter, and its relationship to sarcopenia and frailty. Slc12a8-expressing cells are mainly localized in the LH. LH-specific knockdown of Slc12a8 in young mice decreases activity-dependent energy and carbohydrate expenditure and skeletal muscle functions, including muscle mass, muscle force, intramuscular glycolysis, and protein synthesis. LH-specific Slc12a8 knockdown also decreases sympathetic nerve signals at neuromuscular junctions and β2-adrenergic receptors in skeletal muscle, indicating the importance of the LH-sympathetic nerve-β2-adrenergic receptor axis. LH-specific overexpression of Slc12a8 in aged mice significantly ameliorates age-associated decreases in energy expenditure and skeletal muscle functions. Our results highlight an important role of Slc12a8 in the LH for regulation of whole-body metabolism and skeletal muscle functions and provide insights into the pathogenesis of sarcopenia and frailty during aging

On the Security Cost of Using a Free and Open Source Component in a Proprietary Product

The work presented in this paper is motivated by the need to estimate the security effort of consuming Free and Open Source Software (FOSS) components within a proprietary software supply chain of a large European software vendor. To this extent we have identified three different cost models: centralized (the company checks each component and propagates changes to the different product groups), distributed (each product group is in charge of evaluating and fixing its consumed FOSS components), and hybrid (only the least used components are checked individually by each development team). We investigated publicly available factors (\eg, development activity such as commits, code size, or fraction of code size in different programming languages) to identify which one has the major impact on the security effort of using a FOSS component in a larger software product

Mental Health of SME manager and Sole proprietor from a viewpoint of Risk Management

In this study, firstly we try to grasp the mental health dysfunction as one of the measure corporate risks from a viewpoint of business risk management theory. Secondly we endeavor to point out the importance to focus mental health issue of SME manager and Sole proprietor that have been neglected from the actual academic tendency to treat the employees only. The framework is based on the theory of Torres\u27 concerning suffering of SME managers

Candidate Brown-dwarf Microlensing Events with Very Short Timescales and Small Angular Einstein Radii

Short-timescale microlensing events are likely to be produced by substellar brown dwarfs (BDs), but it is difficult to securely identify BD lenses based on only event timescales t_E because short-timescale events can also be produced by stellar lenses with high relative lens-source proper motions. In this paper, we report three strong candidate BD-lens events found from the search for lensing events not only with short timescales (t_E ≲ 6 days) but also with very small angular Einstein radii (θ_E ≲ 0.05 mas) among the events that have been found in the 2016–2019 observing seasons. These events include MOA-2017-BLG-147, MOA-2017-BLG-241, and MOA-2019-BLG-256, in which the first two events are produced by single lenses and the last event is produced by a binary lens. From the Monte Carlo simulations of Galactic events conducted with the combined t_E and θ_E constraint, it is estimated that the lens masses of the individual events are 0.051^(+0.100)_(−0.027) M⊙, 0.044^(+0.090)_(−0.023) M⊙, and 0.046^(+0.067)_(−0.023) M⊙/0.038^(+0.056)_(−0.019) M⊙ and the probability of the lens mass smaller than the lower limit of stars is ~80% for all events. We point out that routine lens mass measurements of short-timescale lensing events require survey-mode space-based observations

Phase II study of ifosfamide, cisplatin, and vindesine combination in advanced non-small cell lung cancer.

Twenty-seven previously untreated patients with unresectable non-small cell lung cancer were treated with a 3-drug combination of ifosfamide, cisplatin, and vindesine as a phase II study. Patients received ifosfamide, 1.3g/m2, on days 1 to 5; cisplatin, 20mg/m2, on days 1 to 5; and vindesine, 3mg/m2, on days 1 and 8; with a sufficient parenteral hydration. Courses were repeated every 4 weeks. Twenty males and seven females with a median age of 61 years were treated and fully evaluated. Five patients had stage IIIA, seven had stage IIIB, and 15 had stage IV disease. One patient with adenocarcinoma achieved a complete response and 16 achieved a partial response, for an overall response rate of 63% (95% confidence limit: 45% to 81%). The median duration of response was 34 weeks (range: 9 to 52 weeks). The median survival time was 58 weeks for patients with IIIA/B disease, and 33 weeks for those with IV disease. The major toxicity was myelosuppression, however, it was generally well-tolerated. These results indicate that the 3-drug combination is active against non-small cell lung cancer and warrants further clinical trials.</p

Interaction between FIP5 and SNX18 regulates epithelial lumen formation

The Rab11 GTPase-binding protein FIP5 collaborates with the sorting nexin 18 to transport proteins to the apical surface and to tubulate membranes during epithelial apical lumen formatio

Suppression and Regression of Choroidal Neovascularization in Mice by a Novel CCR2 Antagonist, INCB3344

PURPOSE: To investigate the effect of an intravitreally administered CCR2 antagonist, INCB3344, on a mouse model of choroidal neovascularization (CNV). METHODS: CNV was induced by laser photocoagulation on Day 0 in wild type mice. INCB3344 or vehicle was administered intravitreally immediately after laser application. On Day 14, CNV areas were measured on retinal pigment epithelium (RPE)-choroid flat mounts and histopathologic examination was performed on 7 µm-thick sections. Macrophage infiltration was evaluated by immunohistochemistry on RPE-choroid flat mounts and quantified by flow cytometry on Day 3. Expression of vascular endothelial growth factor (VEGF) protein in RPE-choroid tissue was examined by immunohistochemistry and ELISA, VEGF mRNA in sorted macrophages in RPE-choroid tissue was examine by real-time PCR and expression of phosphorylated extracellular signal-regulated kinase (p-ERK 1/2) in RPE-choroid tissue was measured by Western blot analysis on Day 3. We also evaluated the efficacy of intravitreal INCB3344 to spontaneous CNV detected in Cu, Zn-superoxide dismutase (SOD1) deficient mice. Changes in CNV size were assessed between pre- and 1week post-INCB3344 or vehicle administration in fundus photography and fluorescence angiography (FA). RESULTS: The mean CNV area in INCB3344-treated mice decreased by 42.4% compared with the vehicle-treated control mice (p<0.001). INCB3344 treatment significantly inhibited macrophage infiltration into the laser-irradiated area (p<0.001), and suppressed the expression of VEGF protein (p = 0.012), VEGF mRNA in infiltrating macrophages (p<0.001) and the phosphorylation of ERK1/2 (p<0.001). The area of spontaneous CNV in Sod1⁻/⁻ mice regressed by 70.35% in INCB3344-treated animals while no change was detected in vehicle-treated control mice (p<0.001). CONCLUSIONS: INCB3344 both inhibits newly forming CNV and regresses established CNV. Controlling inflammation by suppressing macrophage infiltration and angiogenic ability via the CCR-2/MCP-1 signal may be a useful therapeutic strategy for treating CNV associated with age-related macular degeneration

Co-transplantation of Human Embryonic Stem Cell-derived Neural Progenitors and Schwann Cells in a Rat Spinal Cord Contusion Injury Model Elicits a Distinct Neurogenesis and Functional Recovery

Co-transplantation of neural progenitors (NPs) with Schwann cells (SCs) might be a way to overcome low rate of neuronal differentiation of NPs following transplantation in spinal cord injury (SCI) and the improvement of locomotor recovery. In this study, we initially generated NPs from human embryonic stem cells (hESCs) and investigated their potential for neuronal differentiation and functional recovery when co-cultured with SCs in vitro and co-transplanted in a rat acute model of contused SCI. Co-cultivation results revealed that the presence of SCs provided a consistent status for hESC-NPs and recharged their neural differentiation toward a predominantly neuronal fate. Following transplantation, a significant functional recovery was observed in all engrafted groups (NPs, SCs, NPs+SCs) relative to the vehicle and control groups. We also observed that animals receiving co-transplants established a better state as assessed with the BBB functional test. Immunohistofluorescence evaluation five weeks after transplantation showed invigorated neuronal differentiation and limited proliferation in the co-transplanted group when compared to the individual hESC-NPs grafted group. These findings have demonstrated that the co-transplantation of SCs with hESC-NPs could offer a synergistic effect, promoting neuronal differentiation and functional recovery

Mesenchymal stem cells secretome-induced axonal outgrowth is mediated by BDNF

Mesenchymal stem cells (MSCs) have been used for cell-based therapies in regenerative medicine, with increasing importance in central and peripheral nervous system repair. However, MSCs grafting present disadvantages, such as, a high number of cells required for transplantation and low survival rate when transplanted into the central nervous system (CNS). In line with this, MSCs secretome which present on its composition a wide range of molecules (neurotrophins, cytokines) and microvesicles, can be a solution to surpass these problems. However, the effect of MSCs secretome in axonal elongation is poorly understood. In this study, we demonstrate that application of MSCs secretome to both rat cortical and hippocampal neurons induces an increase in axonal length. In addition, we show that this growth effect is axonal intrinsic with no contribution from the cell body. To further understand which are the molecules required for secretome-induced axonal outgrowth effect, we depleted brain-derived neurotrophic factor (BDNF) from the secretome. Our results show that in the absence of BDNF, secretome-induced axonal elongation effect is lost and that axons present a reduced axonal growth rate. Altogether, our results demonstrate that MSCs secretome is able to promote axonal outgrowth in CNS neurons and this effect is mediated by BDNF.European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under project CENTRO-01–0145-FEDER-000008:BrainHealth 2020, and through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia, I.P., under projects PTDC/SAU-NEU/104100/2008, EXPL/NEU-NMC/0541/2012 and UID/NEU/04539/2013. This work was also funded by Marie Curie Actions - International reintegration grant #249288, 7th Framework programme, EU. Partially funded by Prémios Santa Casa Neurociências - Prize Melo e Castro for Spinal Cord Injury Research; Portuguese Foundation for Science and Technology (IF Development Grant to A.J.S.); NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme; by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by national funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038. The authors would also like to acknowledge Prof. J.E. Davies from the Institute of Biomaterials and Biomedical Engineering at the University of Toronto, Canada, for kindly providing some of the HUCPVCs lots used in the present workinfo:eu-repo/semantics/publishedVersio

The 2L1S/1L2S Degeneracy for Two Microlensing Planet Candidates Discovered by the KMTNet Survey in 2017

We report two microlensing planet candidates discovered by the KMTNet survey in $2017$. However, both events have the 2L1S/1L2S degeneracy, which is an obstacle to claiming the discovery of the planets with certainty unless the degeneracy can be resolved. For KMT-2017-BLG-0962, the degeneracy cannot be resolved. If the 2L1S solution is correct, KMT-2017-BLG-0962 might be produced by a super Jupiter-mass planet orbiting a mid-M dwarf host star. For KMT-2017-BLG-1119, the light curve modeling favors the 2L1S solution but higher-resolution observations of the baseline object tend to support the 1L2S interpretation rather than the planetary interpretation. This degeneracy might be resolved by a future measurement of the lens-source relative proper motion. This study shows the problem of resolving 2L1S/1L2S degeneracy exists over a much wider range of conditions than those considered by the theoretical study of Gaudi (1998).Comment: 15 pages, 12 figures, 4 tables, accepted in A