AMPK-Dependent Metabolic Regulation by PPAR Agonists

Comprehensive studies support the notion that the peroxisome proliferator-activated receptors, (PPARs), PPARα, PPARβ/δ, and PPARγ, regulate cell growth, morphogenesis, differentiation, and homeostasis. Agonists of each PPAR subtype exert their effects similarly or distinctly in different tissues such as liver, muscle, fat, and vessels. It is noteworthy that PPARα or PPARγ agonists have pharmacological effects by modulating the activity of AMPK, which is a key cellular energy sensor. However, the role of AMPK in the metabolic effects of PPAR agonists has not been thoroughly focused. Moreover, AMPK activation by PPAR agonists seems to be independent of the receptor activation. This intriguing action of PPAR agonists may account in part for the mechanistic basis of the therapeutics in the treatment of metabolic disease. In this paper, the effects of PPAR agonists on metabolic functions were summarized with particular reference to their AMPK activity regulation

Double Glomus Tumors Originating in the Submandibular and Parotid Regions

Glomus tumors are rare neoplasms that originate from the glomus bodies, an arteriovenous anastomosis with a specialized vascular structure. The most common site for these tumors is the subungal region of the fingers. Occasionally, glomus tumors are found in the middle ear, trachea, nasal cavities, stomach, and lungs. The occurrence in the parotid regions is very rare. While multiple glomus tumors in the whole body are thought to represent only 10% of all cases, instances of multiple tumors in the neck have not yet been reported in the literature. We report a case of double glomus tumors in the submandibular and parotid regions

Lovelock: Towards Smart NIC-hosted Clusters

Traditional cluster designs were originally server-centric, and have evolved recently to support hardware acceleration and storage disaggregation. In applications that leverage acceleration, the server CPU performs the role of orchestrating computation and data movement and data-intensive applications stress the memory bandwidth. Applications that leverage disaggregation can be adversely affected by the increased PCIe and network bandwidth resulting from disaggregation. In this paper, we advocate for a specialized cluster design for important data intensive applications, such as analytics, query processing and ML training. This design, Lovelock, replaces each server in a cluster with one or more headless smart NICs. Because smart NICs are significantly cheaper than servers on bandwidth, the resulting cluster can run these applications without adversely impacting performance, while obtaining cost and energy savings

Therapeutic genome editing for Charcot-marie-tooth disease type 1a

Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy without a known therapy, which is caused by a 1.4 Mb duplication on human chromosome 17, which includes the gene encoding the peripheral myelin protein of 22 kDa (PMP22). Overexpressed PMP22 protein from its gene duplication is thought to cause demyelination and subsequently axonal degeneration in the peripheral nervous system (PNS). Here, we targeted regulatory region of human PMP22 to normalize overexpressed PMP22 level in C22 mice, a mouse model of CMT1A harboring multi copies of human PMP22. Direct local intraneural delivery of CRISPR/Cas9 designed to target TATA-box of PMP22 before the onset of disease, downregulates gene expression of PMP22 and preserves both myelin and axons. Notably, the same approach was effective in partial rescue of demyelination even after the onset of disease. Collectively, our data present a potential therapeutic efficacy of CRISPR/Cas9-mediated targeting of regulatory region of PMP22 to treat CMT1A. Please click Additional Files below to see the full abstract

Genomic profile analysis of diffuse-type gastric cancers

Background: Stomach cancer is the third deadliest among all cancers worldwide. Although incidence of the intestinal-type gastric cancer has decreased, the incidence of diffuse-type is still increasing and its progression is notoriously aggressive. There is insufficient information on genome variations of diffuse-type gastric cancer because its cells are usually mixed with normal cells, and this low cellularity has made it difficult to analyze the genome. Results: We analyze whole genomes and corresponding exomes of diffuse-type gastric cancer, using matched tumor and normal samples from 14 diffuse-type and five intestinal-type gastric cancer patients. Somatic variations found in the diffuse-type gastric cancer are compared to those of the intestinal-type and to previously reported variants. We determine the average exonic somatic mutation rate of the two types. We find associated candidate driver genes, and identify seven novel somatic mutations in CDH1, which is a well-known gastric cancer-associated gene. Three-dimensional structure analysis of the mutated E-cadherin protein suggests that these new somatic mutations could cause significant functional perturbations of critical calcium-binding sites in the EC1-2 junction. Chromosomal instability analysis shows that the MDM2 gene is amplified. After thorough structural analysis, a novel fusion gene TSC2-RNF216 is identified, which may simultaneously disrupt tumor-suppressive pathways and activate tumorigenesis. Conclusions: We report the genomic profile of diffuse-type gastric cancers including new somatic variations, a novel fusion gene, and amplification and deletion of certain chromosomal regions that contain oncogenes and tumor suppressors.open121

Consecutive Junction-Induced Efficient Charge Separation Mechanisms for High-Performance MoS2/Quantum Dot Phototransistors.

Phototransistors that are based on a hybrid vertical heterojunction structure of two-dimensional (2D)/quantum dots (QDs) have recently attracted attention as a promising device architecture for enhancing the quantum efficiency of photodetectors. However, to optimize the device structure to allow for more efficient charge separation and transfer to the electrodes, a better understanding of the photophysical mechanisms that take place in these architectures is required. Here, we employ a novel concept involving the modulation of the built-in potential within the QD layers for creating a new hybrid MoS2/PbS QDs phototransistor with consecutive type II junctions. The effects of the built-in potential across the depletion region near the type II junction interface in the QD layers are found to improve the photoresponse as well as decrease the response times to 950 μs, which is the faster response time (by orders of magnitude) than that recorded for previously reported 2D/QD phototransistors. Also, by implementing an electric-field modulation of the MoS2 channel, our experimental results reveal that the detectivity can be as large as 1 × 1011 jones. This work demonstrates an important pathway toward designing hybrid phototransistors and mixed-dimensional van der Waals heterostructures.The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007−2013)/ERC Grant Agreement no. 340538. This work was also supported by the National Research Foundation of Korea (NRF) (2015M2A2A6A02045252) and Samsung Global Research Outreach (Samsung GRO) program. In addition, S.M.M. would like to thank The Royal Society for financial support

Effect of heat treatment and drawing on high-manganese steel pipe welded by gas tungsten arc

This study investigated the effect of post-weld processes including annealing and drawing on the microstructure and mechanical properties of high-Mn steel pipes welded by gas tungsten arc welding. The weld metal showed a solidified microstructure having coarse and elongated grains due to coalescence of columnar dendrite into welding heat direction. After post-annealing, the solidified microstructure changed into equiaxed grains due to recrystallization and grain growth. Mn segregation occurred during welding solidification and caused lower stacking fault energy (SFE) in the Mn-depleted region. Although epsilon-martensite formation in the as-welded state and during deformation was expected due to decreased SFE of the Mn-depleted zone, all regions showed a fully austenitic phase. The annealing process decreased strength due to grain coarsening but increased ductility. The drawing process increased strength of weld metal through work hardening. All pipes showed decreasing strain rate sensitivity (SRS) with deformation and negative SRS after certain strain levels. It was confirmed that negative SRS is related to less formation of mechanical twinning at a higher strain rate. This work provides fundamental insights into manufacturing a high-Mn steel pipe and manipulating its properties with annealing and drawing processes

LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Mitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer

Impact of pitavastatin on new-onset diabetes mellitus compared to atorvastatin and rosuvastatin: a distributed network analysis of 10 real-world databases

Statin treatment increases the risk of new-onset diabetes mellitus (NODM); however, data directly comparing the risk of NODM among individual statins is limited. We compared the risk of NODM between patients using pitavastatin and atorvastatin or rosuvastatin using reliable, large-scale data. Data of electronic health records from ten hospitals converted to the Observational Medical Outcomes Partnership Common Data Model (n = 14,605,368 patients) were used to identify new users of pitavastatin, atorvastatin, or rosuvastatin (atorvastatin + rosuvastatin) for ≥ 180 days without a previous history of diabetes or HbA1c level ≥ 5.7%. We conducted a cohort study using Cox regression analysis to examine the hazard ratio (HR) of NODM after propensity score matching (PSM) and then performed an aggregate meta-analysis of the HR. After 1:2 PSM, 10,238 new pitavastatin users (15,998 person-years of follow-up) and 18,605 atorvastatin + rosuvastatin users (33,477 person-years of follow-up) were pooled from 10 databases. The meta-analysis of the HRs demonstrated that pitavastatin resulted in a significantly reduced risk of NODM than atorvastatin + rosuvastatin (HR 0.72; 95% CI 0.59–0.87). In sub-analysis, pitavastatin was associated with a lower risk of NODM than atorvastatin or rosuvastatin after 1:1 PSM (HR 0.69; CI 0.54–0.88 and HR 0.74; CI 0.55–0.99, respectively). A consistently low risk of NODM in pitavastatin users was observed when compared with low-to-moderate-intensity atorvastatin + rosuvastatin users (HR 0.78; CI0.62–0.98). In this retrospective, multicenter active-comparator, new-user, cohort study, pitavastatin reduced the risk of NODM compared with atorvastatin or rosuvastatin