Background Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood. Methods We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function. Results Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network. Conclusions Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.

This study aims to investigate the effects of Y, Sr, and Nd additions on the microstructure and microfracture mechanism of the four squeeze-cast magnesium alloys based on the commercial AZ91 alloy. Microstructural observation, in situ fracture tests, and fractographic observation were conducted on the alloys to clarify the microfracture process. Microstructural analyses indicated that grain refinement could be achieved by small additions of alloying elements, although the discontinuously precipitated Mg 17 Al 12 phases still existed on grain boundaries. From in situ fracture observation of an AZ91-Sr alloy, it was seen that coarse needle-shaped compound particles and Mg 17 Al 12 phases located on the grain boundary provided easy intergranular fracture sites under low stress intensity factor levels, resulting in the drop in toughness. On the other hand, the AZ91-Y and AZ91-Nd alloys showed improved fracture toughness, since deformation and fracture paths proceeded into grains rather than to grain boundaries, as the planar slip bands and twinnings actively developed inside the grains. These findings suggested, on the basis of the well-developed planar slip bands and twinnings, that the small addition of Y or Nd was very effective in improving fracture toughness.

Background:Conventional intravenous patient-controlled analgesia (PCA), which usually involves constant-rate background infusion plus demand dosing, may cause adverse effects or insufficient analgesia. When variable-rate feedback infusion plus demand dosing mode is used, the infusion rate can be changed according to the patient's needs.Methods:In this prospective randomized double-blind study, 78 adults who were undergoing spinal fusion surgery were randomly allocated to either the constant-rate background infusion plus demand dosing group (group C) or the variable-rate feedback infusion plus demand dosing group (group V). The number of demands, volume delivered, numerical rating scale (NRS) score, adverse effects and the use of rescue analgesics were examined at 30 minutes after the operation in the post-anesthesia care unit, and at 6, 12, 24, and 48 hours.Results:The number of demands was significantly lower in group V than in group C at 12-24 hours (4.59 ± 4.31 vs 9.21 ± 6.79 times, P = .001) and over the total period. The volume delivered via PCA was significantly lower in group V than in group C at 12 to 24 hours (13.96 ± 13.45 vs 21.19 ± 8.66 mL, P = .006), 24 to 48 hours (13.39 ± 12.44 vs 33.6 ± 12.49 mL, P = .000), and over the total period. NRS scores, administration of rescue analgesics, and postoperative nausea and vomiting showed no between-group differences.Conclusions:Variable-rate feedback infusion plus the demand dosing mode can control postoperative pain more efficiently, with lower dosages of analgesics, than constant-rate background infusion plus demand dosing in patients who undergo spinal fusion surgery.

Rare stochastic mutations may accumulate during dormancy of stem-like cells, but technical limitations in DNA sequencing have limited exploring this possibility. In this study, we employed a recently established deep sequencing method termed Duplex Sequencing to conduct a genome-wide analysis of mitochondrial (mt) DNA mutations in a human breast stem cell model that recapitulates the sequential stages of breast carcinogenesis. Using this method, we found significant differences in mtDNA amongst normal stem cells, immortal/preneoplastic cells, and tumorigenic cells. Putative cancer stem-like cell (CSC) populations and mtDNA copy numbers increased as normal stem cells become tumorigenic cells. Transformed cells exhibited lower rare mutation frequencies of whole mtDNA than did normal stem cells. The predicted mtDNA rare mutation pathogenicity was significantly lower in tumorigenic cells than normal stem cells. Major rare mutation types in normal stem cells are C>T/G>A and T>C/A>G transitions, while only C>T/G>A are major types in transformed cells. We detected a total of 1220 rare point mutations, 678 of which were unreported previously. With only one possible exception (m10342T>C), we did not find specific mutations characterizing mtDNA in human breast CSC; rather, the mitochondrial genome of CSC displayed a decrease in rare mutations overall. Based on our work, we suggest that this decrease (in particular T>C/A>G transitions), rather than the presence of specific mitochondrial mutations, may constitute an early biomarker for breast cancer detection. Our findings support the hypothesis that the mitochondrial genome is altered greatly as a result of the transformation of normal stem cells to CSC, and that mtDNA mutation signatures may aid in delineating normal stem cells from CSC.

We present a genome-wide comparative and comprehensive analysis of three different sequencing methods (conventional next generation sequencing (NGS), tag-based single strand sequencing (e.g., SSCS), and Duplex Sequencing for investigating mitochondrial mutations in human breast epithelial cells. Duplex Sequencing produces a single strand consensus sequence (SSCS) and a duplex consensus sequence (DCS) analysis, respectively. Our study validates that although high-frequency mutations are detectable by all the three sequencing methods with the similar accuracy and reproducibility, rare (low-frequency) mutations are not accurately detectable by NGS and SSCS. Even with conservative bioinformatical modification to overcome the high error rate of NGS, the NGS frequency of rare mutations is 7.0 × 10−4. The frequency is reduced to 1.3 × 10−4 with SSCS and is further reduced to 1.0 × 10−5 using DCS. Rare mutation context spectra obtained from NGS significantly vary across independent experiments, and it is not possible to identify a dominant mutation context. In contrast, rare mutation context spectra are consistently similar in all independent DCS experiments. We have systematically identified heat-induced artifactual variants and corrected the artifacts using Duplex Sequencing. Specific sequence contexts were analyzed to examine the effects of neighboring bases on the accumulation of heat-induced artifactual variants. All of these artifacts are stochastically occurring rare mutations. C > A/G > T, a signature of oxidative damage, is the most increased (170-fold) heat-induced artifactual mutation type. Our results strongly support the claim that Duplex Sequencing accurately detects low-frequency mutations and identifies and corrects artifactual mutations introduced by heating during DNA preparation.

Plasmonic compound nanoparticles (NPs) have attracted great interest because they are prepared at lower cost and show unique optical properties. However, full replacement of the plasmonic noble metal NPs with the compound NPs has been difficult because most of the compound NPs exhibit plasmon resonance in the infrared range owing to low free carrier density and mobility. In order to overcome this limitation, we developed a new synthetic method for plasmonic MoO and MoO NPs. Those NPs exhibit plasmon resonance at ∼500 nm and 600-1000 nm, respectively, likely because of high carrier densities. The plasmonic properties of the NPs are tunable by changing the synthetic conditions or oxidizing and reducing the NPs. Their refractive index sensitivities are 115-260 nm RIU. Those molybdenum oxide NPs are expected to substitute for plasmonic noble metal NPs in optical, electronic, sensing and light harvesting devices and materials.

Compartment syndrome after total knee arthroplasty (TKA) is a rare complication. Because of its rarity, it may be overlooked and misdiagnosed as peroneal nerve palsy or deep vein thrombosis. This misdiagnosis could have a profound impact on the patient's outcome. We report a case of a 77-year-old female who developed unilateral compartment syndrome in the calf after staged bilateral TKA at an outside clinic. The patient presented with medical complications related to compartment syndrome: rhabdomyolysis and myoglobinuria, which caused acute renal failure. Thus, we performed late fasciotomy one week after symptom onset to debride necrotic tissue and salvage the compartment. In the discussion section, we will discuss risk factors for compartment syndrome after TKA, results of late fasciotomy and other indications for surgical treatment of compartment syndrome.

Plasmon-induced charge separation (PICS) allows direct conversion of localized surface plasmon resonance (LSPR) to electron flows and photoelectrochemical reactions. However, PICS has only been achieved using plasmonic noble metal nanoparticles, not with compound nanoparticles. In order to achieve compound PICS, MoO nanostructures were prepared that exhibit LSPR in the near infrared region by using metal oxides or metal nanoparticles as templates. Solid-state cells based on the MoO nanostructure were developed. Their photoresponse to 700-1400 nm infrared light was investigated and analyzed on the basis of their PICS mechanisms.