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Highlights Bulk molding compound (BMC) manufactured using fiber reinforced polymers (FRPs) has attracted extensive attention and is widely used because of its capability to fabricate structures with complex shapes. This study investigated the effects of aging on the mechanical properties of BMC composites made using an epoxy matrix and discontinuous carbon fibers of varying lengths. Tensile, compressive, and flexural tests were conducted. The results showed that longer fibers did not necessarily increase the moduli and strengths of BMC composites due to stress concentrations resulting from the curling and entanglement of the longer fibers. When aged, BMC composites using shorter carbon fibers exhibited more significant reductions in moduli and strengths due to higher void contents, resulting in more severe matrix epoxy degradation. When comparing epoxy and BMC, BMC experienced greater reductions in moduli and strengths even though carbon fiber, a type of artificial fiber, should be less affected by aging. This is because aging not only degraded the matrix epoxy but also affected the adhesion between the fibers and the matrix, leading to a larger displacement of the fibers, resulting in a more severe reduction in the mechanical properties of the BMC composites. BMC composites were manufactured using epoxy and discontinuous carbon fibers. Longer fibers did not necessarily increase strengths due to entanglement. BMC using shorter fibers had more voids and hence degraded more severely. BMC showed greater strength reductions than epoxy due to matrix degradation. Degradation of matrix epoxy affected the adhesion between fibers and matrix. [ABSTRACT FROM AUTHOR]

Composite sandwich structures are widely used in many areas. Light materials, such as honeycomb panels, are usually used as the cores, while stiff materials, such as fiber reinforced polymer laminates, are used as the facesheets. In this work, corrugated cores for sandwich structures were fabricated using carbon fiber reinforced polymers (CFRPs) featuring different stacking orientations. Paper, aluminum, and polypropylene honeycomb cores were also used. Additionally, CFRP was utilized as the facesheets for these sandwich structures. Bending tests, face-wise compression tests (FCT), edgewise compression tests (ECT), and accelerated aging were conducted. Finite element simulations were also performed and compared with experimental results. The results indicated that the corrugated CFRP cores with [0°]5 stacking orientation resulted in the largest flexural stiffness and ECT strength along the flute direction. Conversely, the corrugated cores with [90°]5 stacking orientation resulted in the largest transverse shear rigidity and modulus, FCT modulus and strength, and ECT strength perpendicular to the flute direction. Notably, the sandwich structures using aluminum honeycomb cores were degraded by aging the least. Since sandwich structures can be subjected to the bending load and loads in other directions, this work contributes to selecting core materials and structures of sandwich structures. [ABSTRACT FROM AUTHOR]

Powered ankle prostheses have been proven to improve the walking economy of people with transtibial amputation. All commercial powered ankle prostheses that are currently available can only perform one-degree-of-freedom motion in a limited range. However, studies have shown that the frontal plane motion during ambulation is associated with balancing. In addition, as more advanced neural interfaces have become available for people with amputation, it is possible to fully recover ankle function by combining neural signals and a robotic ankle. Accordingly, there is a need for a powered ankle prosthesis that can have active control on not only plantarflexion and dorsiflexion but also eversion and inversion. We designed, built, and evaluated a two-degree-of-freedom (2-DoF) powered ankle–foot prosthesis that is untethered and can support level-ground walking. Benchtop tests were conducted to characterize the dynamics of the system. Walking trials were performed with a 77 kg subject that has unilateral transtibial amputation to evaluate system performance under realistic conditions. Benchtop tests demonstrated a step response rise time of less than 50 milliseconds for a torque of 40 N·m on each actuator. The closed-loop torque bandwidth of the actuator is 9.74 Hz. Walking trials demonstrated torque tracking errors (root mean square) of less than 7 N·m. These results suggested that the device can perform adequate torque control and support level-ground walking. This prosthesis can serve as a platform for studying biomechanics related to balance and has the possibility of further recovering the biological function of the ankle–subtalar–foot complex beyond the existing powered ankles. [ABSTRACT FROM AUTHOR]

This work used short carbon fibers (SCFs) of different lengths to manufacture epoxy bulk mold compound (BMC) composites. Drop-weight-impact tests were performed on the intact carbon-fiber-reinforced-polymers (CFRPs) laminates to generate artificial damage. The damaged CFRP laminates were then repaired using the SCF-BMC composites. Compression after impact (CAI) tests were conducted to measure the compressive strength of the repaired laminates. Tensile properties and compressive properties of the SCF-BMC composites were also measured. The results show that 48-mm carbon fibers result in the largest tensile modulus, tensile strength, and compressive strength, while 12-mm carbon fibers result in the largest compressive modulus. CAI test results show that the compressive strength of the repaired laminate can be restored to 80.3% of that of the undamaged laminate. Therefore, SCF-BMC composites significantly contribute to repairing damaged composite laminates. [ABSTRACT FROM AUTHOR]

The pulmonary artery catheter (PAC)—despite its invasiveness—remains the gold standard for cardiac output (CO) monitoring. The FloTrac system, a less invasive hemodynamic monitor has been developed, which estimates CO using arterial pressure waveform analysis without external calibration. Recently, an upgraded version of FloTrac system with improved algorithm to follow changes in vascular resistance was introduced into the market. The aim of this study was to assess the reliability of the CO estimated from the fourth-generation FloTrac/EV1000 system (COFT) compared to that measured with PAC using the thermodilution method (COPAC) during robotic-assisted off-pump coronary artery bypass (OPCAB) surgery. COFT and COPAC were obtained simultaneously at 4 predefined time points during robotic-assisted OPCAB: 5 min after the induction of general anesthesia (T1), after starting one-lung ventilation (T2), after capnothorax (T3), and after mini-thoracotomy was performed (T4). The agreement of data was investigated by Bland–Altman analysis. Thirty-four patients were initially enrolled. After exclusion, 32 patients and a total of 128 paired CO measurements were obtained. The overall bias was 1.46 L/min, the 95% limits of agreements were − 3.40 to 6.33 L/min, and the percentage error was 72.98%. Regression analysis of the systemic vascular resistance index (SVRI) and the bias between COPAC and COFT showed that the bias was moderately correlated with the SVRI (r2 = 0.43; p < 0.0001). Despite a software upgrade, the reliability of the fourth-generation FloTrac/EV1000™ system during robotic-assisted OPCAB to estimate CO was not acceptable, especially in patients with low SVRI. [ABSTRACT FROM AUTHOR]

Background Mortality after myocardial infarction (MI) among patients undergoing dialysis is high. However, studies investigating the use of secondary prevention medications after MI and clinical outcomes in dialysis patients are lacking. This study aimed to examine the association of the number of guideline-recommended medications (antiplatelets, β-blockers, statins and renin–angiotensin–aldosterone system inhibitors) with all-cause mortality after MI in hemodialysis (HD) patients. Methods We conducted a nationwide cohort study of incident HD patients who were admitted for MI between 1 January 2010 and 31 December 2014 and were followed up until 31 December 2015, using Taiwan's national health insurance research database. Results Of 1471 patients (mean age 68 years, 41.9% women) included in the analysis, 281 (19.1%) were treated with one cardioprotective medication, 406 (27.6%) with two, 490 (33.3%) with three and 294 (20%) with four. During a median follow-up of 1.0 years, 458 (31.1%) patients died. In a multivariable Cox model, each additional use of guideline-recommended therapies was associated with a significant 12% reduction in the risk of mortality {hazard ratio [HR] 0.88 [95% confidence interval (CI) 0.80–0.97]}. Similar results were obtained in the analysis with the inverse probability of treatment weighting [HR 0.84 (95% CI 0.77–0.92)] and in the propensity score–matched subcohort [HR 0.87 (95% CI 0.77–0.98)]. The decreased mortality risk was consistently observed across all subgroups. Conclusions The use of more evidence-based medications for secondary prevention after MI was associated with a lower risk of all-cause mortality in HD patients. [ABSTRACT FROM AUTHOR]

The article discusses the impact of the intra-aortic balloon pump (IABP) on the reliability of the fourth-generation FloTrac/EV1000 system in patients undergoing robotic-assisted off-pump coronary artery bypass surgery. The study found that pulse contour analysis systems, including the FloTrac system, cannot accurately identify the systolic and diastolic portions of the arterial waveform when the IABP is used, leading to incorrect cardiac output (CO) values. However, during the mini-thoracotomy stage of the surgery, the CO values obtained from the FloTrac system showed agreement with the thermodilution method. The authors suggest that uncalibrated arterial pressure waveform analysis could potentially be used interchangeably with pulmonary artery catheter measurements in stable hemodynamic conditions. [Extracted from the article]

The organization of chromatin into higher order structures is essential for chromosome segregation, the repair of DNA-damage, and the regulation of gene expression. Using Micro-C XL to detect chromosomal interactions, we observed the pervasive presence of cohesin-dependent loops with defined positions throughout the genome of budding yeast, as seen in mammalian cells. In early S phase, cohesin stably binds to cohesin associated regions (CARs) genome-wide. Subsequently, positioned loops accumulate with CARs at the bases of the loops. Cohesin regulators Wpl1 and Pds5 alter the levels and distribution of cohesin at CARs, changing the pattern of positioned loops. From these observations, we propose that cohesin with loop extrusion activity is stopped by preexisting CAR-bound cohesins, generating positioned loops. The patterns of loops observed in a population of wild-type and mutant cells can be explained by this mechanism, coupled with a heterogeneous residency of cohesin at CARs in individual cells. [ABSTRACT FROM AUTHOR]

Background: Combination drug therapy appears a promising approach to overcome drug resistance and reduce drug-related toxicities in ovarian cancer treatments. In this in vitro study, we evaluated the antitumor efficacy of cisplatin in combination with Bithionol (BT) against a panel of ovarian cancer cell lines with special focus on cisplatin-sensitive and cisplatin-resistant cell lines. The primary objectives of this study are to determine the nature of the interactions between BT and cisplatin and to understand the mechanism(s) of action of BT-cisplatin combination.Methods: The cytotoxic effects of drugs either alone or in combination were evaluated using presto-blue assay. Cellular reactive oxygen species were measured by flow cytometry. Immunoblot analysis was carried out to investigate changes in levels of cleaved PARP, XIAP, bcl-2, bcl-xL, p21 and p27. Luminescent and colorimetric assays were used to test caspases 3/7 and ATX activity.Results: The efficacy of the BT-cisplatin combination depends upon the cell type and concentrations of cisplatin and BT. In cisplatin-sensitive cell lines, BT and cisplatin were mostly antagonistic except when used at low concentrations, where synergy was observed. In contrast, in cisplatin-resistant cells, BT-cisplatin combination treatment displayed synergistic effects at most of the drug ratios/concentrations. Our results further revealed that the synergistic interaction was linked to increased reactive oxygen species generation and apoptosis. Enhanced apoptosis was correlated with loss of pro-survival factors (XIAP, bcl-2, bcl-xL), expression of pro-apoptotic markers (caspases 3/7, PARP cleavage) and enhanced cell cycle regulators p21 and p27.Conclusion: In cisplatin-resistant cell lines, BT potentiated cisplatin-induced cytotoxicity at most drug ratios via enhanced ROS generation and modulation of key regulators of apoptosis. Low doses of BT and cisplatin enhanced efficiency of cisplatin treatment in all the ovarian cancer cell lines tested. Our results suggest that novel combinations such as BT and cisplatin might be an attractive therapeutic approach to enhance ovarian cancer chemosensitivity. Combining low doses of cisplatin with subtherapeutic doses of BT can ultimately lead to the development of an innovative combination therapy to reduce/prevent the side effects normally occurring when high doses of cisplatin are administered. [ABSTRACT FROM AUTHOR]

Abstract Nano-carbon aerogels (NCAs) have three-dimensional structures, and high porosities. They show promise as innovative materials because of their attractive properties such as high electrical conductivity, high-porosity structures, and high surface areas, which suggest that the material properties of polymer-based composites can be improved. In this study, NCAs were used to reinforce epoxy/carbon fiber composite (CFRP) laminates to investigate the impact and after-impact properties of the composites under three different impact energies 20, 25, and 30 J. The experimental results showed that the impact resistance properties of the CFRP laminates steadily improved with NCAs at the addition of 0.3 wt%. In addition, the damage to the NCAs/CFRP laminates at the low impact energy of 20 J was observed by nondestructive evaluation, including ultrasonic inspection (C-scan) and thermographic analysis, to understand the delamination behavior of the NCAs/CFRP laminate. [ABSTRACT FROM AUTHOR]

Graphene nanoplatelets are two-dimensional carbon structure materials with single or multilayers graphite plane which possesses attractive characteristics. In this study, the environmental aging effect on interlaminar properties of graphene nanoplatelet containing different proportions (0.25, 0.50, 0.75 wt%) reinforced epoxy/carbon fiber (carbon fiber reinforced plastic) composite laminates including interlaminar shear strength and fracture toughness were investigated. The interlaminar properties of graphene nanoplatelets/carbon fiber reinforced plastic composite laminates were improved over that of neat carbon fiber reinforced plastic composite laminates. Experimental results showed that the composite laminates containing graphene nanoplatelets possesses the appreciable improvement. The mechanisms responsible for the interlaminar enhancement were identified by studying the fracture surfaces using field emission scanning electron microscopy. [ABSTRACT FROM AUTHOR]

To evaluate the nanotube size effect on the material properties of nanotube‐modified nanocomposites, two types of multi‐walled carbon nanotubes with various dimensions were used to form nanocomposites, and then the mechanical properties and the toughness were measured. The well‐known issue of nanotube dispersion was examined using various microscopic observations, and an ideal dispersion process was identified. The results revealed that adding nanotubes led to increases in the Young's modulus and toughness of the nanocomposites. A maximum measured value of the fracture energy was recorded at 237 J m−2 for the nanocomposite toughened with 0.5 wt% of the longer nanotubes. This is ∼90% higher than the unmodified epoxy, and a 40% increase in the fracture energy compared with the sample containing the shorter nanotubes under identical nanotube loading. This indicated that the length of the nanotubes severely affected the toughness of the nanotube‐modified polymers. However, the increased moduli, triggered by the addition of the various types of carbon nanotubes, were similar. The toughening mechanisms were identified via studying the fracture surfaces of the nanocomposites. POLYM. COMPOS., 39:E1072–E1086, 2018. © 2017 Society of Plastics Engineers [ABSTRACT FROM AUTHOR]

Two different reaction pathways were observed in the sulfonylation of N‐phenylbenzamidoximes. The reaction with o‐NsCl at a heating temperature gave N,N′‐diphenylureas via Tiemann rearrangement, while the reaction with Ts2O at a lower temperature formed 2‐phenylbenzimidazoles via intramolecular electrophilic aromatic substitution. When the amide nitrogen was replaced with carbon substituents, oxime derivatives of benzoins and benzils underwent Beckmann fragmentation reactions upon sulfonylation, whereas sulfonylation of 2‐phenylacetophenone oxime afforded exclusively the Beckmann rearrangement adduct. [ABSTRACT FROM AUTHOR]

Carbon aerogels are a promising candidate for vibration insulation due to their three-dimensional networked structures interconnected with carbon nanoparticles. However, the effect of adding carbon aerogels to polymer-based composites on their dynamic properties remains unclear. In this study, an epoxy polymer matrix was modified with carbon aerogels, and this modified matrix was used to manufacture nanocomposite plates and carbon fiber-reinforced polymer composite laminates to investigate its dynamic properties. Force vibration tests were performed on cantilever beams of the composite beams. The frequency responses of the composite beams were measured experimentally and analytically; the half-power method was used to calculate the damping ratio for each vibration mode. According to the experimental results, the presence of carbon aerogel in the nanocomposites and laminates steadily increased the natural frequencies. Differences within 10% of the natural frequencies were obtained between the experimental and numerically. Furthermore, the damping ratios of the nanocomposite and laminate beams increased significantly with the increase in aerogel loading. For a nanocomposite with 0.3 wt% aerogel, a damping ratio approximately 44% greater than that of unmodified nanocomposite was obtained. The maximum damping ratio was 4.682% for the laminate with 0.5 wt% aerogel—an 88% increase compared with the unmodified laminate. [ABSTRACT FROM AUTHOR]

Carbon aerogels have excellent potential to act as reinforcements for improving the material properties of polymer-based composites because of their porous nanostructures and large surface areas. However, the addition of carbon aerogels to polymer-based composites has effects on the material properties of the final composites, and those effects are not clear. In this study, an epoxy matrix was modified with carbon aerogel, and this modified matrix was then used to manufacture carbon fiber-reinforced polymer (CFRP) laminates. The effects of the addition of the carbon aerogel to the laminates on the mechanical properties and delamination resistance were investigated. The modulus and strength of the laminates were slightly increased by the addition of the aerogel to the composite laminates. The addition of the aerogel to the laminates led to an appreciable improvement in the interfacial property and adhesion between the fibers and matrix, and consequently, the delamination fracture energy was increased. The Mode I delamination fracture energy was measured to be 265 J m for the laminate with the unmodified matrix, whereas that of the laminate with 0.1 wt% aerogel was 346 J m. The delamination fracture energy caused by Mode II loading was increased from 655 J m for the unmodified laminate to 1088 J m for laminate modified with 0.5 wt% aerogel. Fractographic observation showed significant differences in the fracture surface morphology between aerogel-modified and unmodified CFRP laminate. [ABSTRACT FROM AUTHOR]

Summary We describe a Hi-C-based method, Micro-C, in which micrococcal nuclease is used instead of restriction enzymes to fragment chromatin, enabling nucleosome resolution chromosome folding maps. Analysis of Micro-C maps for budding yeast reveals abundant self-associating domains similar to those reported in other species, but not previously observed in yeast. These structures, far shorter than topologically associating domains in mammals, typically encompass one to five genes in yeast. Strong boundaries between self-associating domains occur at promoters of highly transcribed genes and regions of rapid histone turnover that are typically bound by the RSC chromatin-remodeling complex. Investigation of chromosome folding in mutants confirms roles for RSC, “gene looping” factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and the N-terminal tail of H4 in folding of the yeast genome. This approach provides detailed structural maps of a eukaryotic genome, and our findings provide insights into the machinery underlying chromosome compaction. [ABSTRACT FROM AUTHOR]

Graphene nanoplatelets (GNPs) and carbon nanotubes (CNTs) are novel nanofillers possessing attractive characteristics, including robust compatibility with most polymers, high absolute strength, and cost effectiveness. In this study, an outstanding synergetic effect on the grapheme nanoplatelets (GNPs) and multiwalled carbon nanotubes (CNTs) hybrids were used to reinforce epoxy composite and epoxy/carbon fiber composite laminates to enhance their mechanical properties. The mechanical properties of CNTs/GNPs hybrids on a fixed weight fraction (1 wt%) with mixing different ratio reinforced epoxy nanocomposite, such as ultimate tensile strength and flexure properties, were investigated. The mechanical properties of epoxy/carbon fiber composite laminates containing different proportions of CNTs/GNPs hybrids (0.5, 1.0, 1.5 wt%) were increased over that of neat laminates. Consequently, significant improvement in the mechanical properties was attained for these epoxy resin composites and carbon fiber-reinforced epoxy composite laminates. [ABSTRACT FROM AUTHOR]

Because of their nanoporous structure and large surface area, carbon aerogels have high potential for improving the material properties of polymer-based composites. In the present study, the mechanical properties and toughness of epoxy polymers modified with an aerogel content of 0.0-0.5 wt% were considered. Experimental results showed that the stiffness and strength of the carbon aerogel toughened polymers steadily increased with the carbon aerogel content. The glass transition temperature of the unmodified epoxy polymer was 147 °C, and it was not appreciably affected by the addition of carbon aerogels. Blending the carbon aerogels with the epoxy polymer led to an appreciably improvement in the fracture performance of the resulting composites. For example, the fracture energy of the unmodified polymer was 125 J m, whereas that of an epoxy polymer reinforced with a carbon aerogel content of 0.3 wt% was 255 J m. The mechanisms responsible for the toughness enhancement were identified by studying the fracture surfaces using field emission gun scanning electron microscopy. Crack pinning, crack deflection, interfacial debonding, and plastic void growth were the main toughening mechanisms in the carbon aerogel toughened epoxy polymers. [ABSTRACT FROM AUTHOR]

Summary Covalent histone modifications are highly conserved and play multiple roles in eukaryotic transcription regulation. Here, we mapped 26 histone modifications genome-wide in exponentially growing yeast and during a dramatic transcriptional reprogramming—the response to diamide stress. We extend prior studies showing that steady-state histone modification patterns reflect genomic processes, especially transcription, and display limited combinatorial complexity. Interestingly, during the stress response we document a modest increase in the combinatorial complexity of histone modification space, resulting from roughly 3% of all nucleosomes transiently populating rare histone modification states. Most of these rare histone states result from differences in the kinetics of histone modification that transiently uncouple highly correlated marks, with slow histone methylation changes often lagging behind the more rapid acetylation changes. Explicit analysis of modification dynamics uncovers ordered sequences of events in gene activation and repression. Together, our results provide a comprehensive view of chromatin dynamics during a massive transcriptional upheaval. [ABSTRACT FROM AUTHOR]

This study deciphers miRNome and transcriptome of MB and AT/RT, uncovers a novel tumor suppressor, SUN2, plays a critical role in miR-221/222-mediated AT/RT malignancy, and supports miR-221/222 and SUN2 represent new promising targets for more active therapies in AT/RT.Embryonal tumors of the central nervous system represent a highly malignant tumor group of medulloblastoma (MB), atypical teratoid/rhabdoid tumor (AT/RT) and primitive neuroectodermal tumor that frequently afflict children. AT/RT is often misdiagnosed as MB/primitive neuroectodermal tumor but with higher recurrence and lower survival rates. Pathogenesis of AT/RT is largely unknown. In this study, we report both the miRNome and transcriptome traits in AT/RT and MB by using small RNA sequencing and gene expression microarray analyses. Our findings demonstrate that the miR-221/222-encoded micro RNAs are abundantly expressed in AT/RT but not in MB, which contribute substantially to the malignancy of embryonal tumors. miR-221/222 targeted SUN2, a newly discovered tumor suppressor, directly to increase cell proliferation and tumor malignancy in vitro and in vivo. Immunohistochemistry against SUN2 in a tissue microarray of 33 AT/RT and 154 MB tumor specimens also detected less SUN2 protein in AT/RT. Collectively, this study uncovers a novel tumor suppressor, SUN2, plays a critical role in miR-221/222-mediated AT/RT malignancy as well as supports miR-221/222 and SUN2 represent new promising targets for more active therapies in AT/RT. In addition, our miRNome and transcriptome data also provide a roadmap for further embryonal tumor research. [ABSTRACT FROM AUTHOR]

A facileand general synthesis of various N-substitutedcyanamides was accomplished by the Tiemann rearrangement of amidoximeswith benzenesulfonyl chlorides (TsCl or o-NsCl) andDIPEA. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma multiforme is a common and lethal malignant brain tumor, and occurrence of therapeutic resistance in GBM often causes relapse. Therefore, this study aimed to find a new therapeutic strategy to treat these malignant tumors. In the current study, combined abemaciclib with an autophagy inhibitor, MPT0L145, significantly reduced cell proliferation and elevated intracellular reactive oxygen species (ROS) level. A blood–brain barrier permeability assay also showed that MPT0L145 could penetrate endothelial cells and has a penetration ability similar to that of TMZ. Therefore, this work represents a potential therapeutic strategy for treating the GBM in the future. Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is still dismal. Therefore, a new therapeutic strategy is urgently needed. CDK4/6 inhibitors are newly FDA-approved agents to treat HR-positive, HER2-negative advanced, and metastatic breast cancers, and preclinical results showed that CDK4/6 inhibitors significantly reduced cell proliferation and tumor growth. However, several studies have suggested that CDK4/6 inhibitor-induced non-genetic changes caused treatment failure, including autophagy activation. Therefore, this study aimed to combine an autophagy inhibitor, MPT0L145, with abemaciclib to improve therapeutic efficiency. The use of abemaciclib effectively inhibited cell proliferation via suppression of RB phosphorylation and induced autophagy activation in GBM cancer cells. MPT0L145 treatment alone not only blocked autophagy activation, but also induced generation of ROS and DNA damage in a concentration-dependent manner. Importantly, MPT0L145 had a comparable penetration ability to TMZ in our blood brain barrier permeability assay. Combined MPT0L145 with abemaciclib significantly reduced cell proliferation, suppressed RB phosphorylation, and increased ROS production. In conclusion, the data suggested that blocking autophagy by MPT0L145 synergistically sensitized GBM cancer cells to abemaciclib and represents a potential therapeutic strategy for treating GBM in the future. [ABSTRACT FROM AUTHOR]

Abstract: The dynamic properties of sandwich beams with MWNT/polymer nanocomposites as core materials were investigated. The faces of sandwich beams are graphite/epoxy laminates. Epoxy and phenolic resins served as a matrix material, and multi-walled carbon nanotubes (MWNTs) provided reinforcement of the fabricated MWNT/polymer nanocomposites as core materials for sandwich beams. The frequency responses of sandwich beams under excitation were measured experimentally with a signal analyzer; the half-power method was used to find the loss factors of the sandwich beams for each mode. The finite element method was used for free vibration analysis of the sandwich beams; the natural frequencies and mode shapes of the sandwich beams were calculated numerically. The numerical and experimental results agreed satisfactorily. [Copyright &y& Elsevier]

Abstract: Carbon nanotubes have better physical and mechanical behavior than the traditional materials. In this study, the multi-walled carbon nanotubes (MWNTs) were added to the epoxy resin as a reinforcement to fabricate MWNTs/epoxy nanocomposites. The pressure and temperature were applied to cure the MWNTs/epoxy compound by hot press method. Mechanical properties such as tensile strength, Young''s modulus, and Poisson''s ratio were measured. The effect of weight percentages of the MWNTs was investigated. Morphologies of the fracture surface of MWNTs/epoxy nanocomposites were observed by scanning electron microscope. [Copyright &y& Elsevier]

Whereas folding of genomes at the large scale of epigenomic compartments and topologically associating domains (TADs) is now relatively well understood, how chromatin is folded at finer scales remains largely unexplored in mammals. Here, we overcome some limitations of conventional 3C-based methods by using high-resolution Micro-C to probe links between 3D genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregates TAD regions into various finer-scale structures with distinct regulatory features including stripes, dots, and domains linking promoters-to-promoters (P-P) or enhancers-to-promoters (E-P) and bundle contacts between Polycomb regions. E-P stripes extending from the edge of domains predominantly link co-expressed loci, often in the absence of CTCF and cohesin occupancy. Acute inhibition of transcription disrupts these gene-related folding features without altering higher-order chromatin structures. Our study uncovers previously obscured finer-scale genome organization, establishing functional links between chromatin folding and gene regulation. • Micro-C resolves mammalian chromatin folding down to single nucleosomes • Nested structures are the prevalent folding feature within TADs • Transcription drives short-range interactions connecting enhancers and promoters • Only a subset of fine-scale structures appears to be CTCF- and cohesin-specific Hsieh et al. describe chromatin folding at single-nucleosome resolution in mammalian cells using Micro-C, an enhanced chromosome conformation capture method. Micro-C uncovers genome-wide, fine-scale chromatin organizational features shaped by gene activity, transcriptional regulation, and gene silencing. [ABSTRACT FROM AUTHOR]

Mammalian genomes are folded into topologically associating domains (TADs), consisting of chromatin loops anchored by CTCF and cohesin. Some loops are cell-type specific. Here we asked whether CTCF loops are established by a universal or locus-specific mechanism. Investigating the molecular determinants of CTCF clustering, we found that CTCF self-association in vitro is RNase sensitive and that an internal RNA-binding region (RBR i) mediates CTCF clustering and RNA interaction in vivo. Strikingly, deleting the RBR i impairs about half of all chromatin loops in mESCs and causes deregulation of gene expression. Disrupted loop formation correlates with diminished clustering and chromatin binding of RBR i mutant CTCF, which in turn results in a failure to halt cohesin-mediated extrusion. Thus, CTCF loops fall into at least two classes: RBR i -independent and RBR i -dependent loops. We speculate that evidence for RBR i -dependent loops may provide a molecular mechanism for establishing cell-specific CTCF loops, potentially regulated by RNA(s) or other RBR i -interacting partners. • An RNA-binding region (RBR i) in CTCF mediates self-association and clustering • Reorganization of TADs, loops, and stripes in ΔRBR i mutant cells • About half of all CTCF loops are disrupted in ΔRBR i mutant cells • CTCF loops fall into two classes: RBR i dependent and RBR i independent CTCF is an architectural protein that mediates chromatin looping. Here, Hansen et al. demonstrate that an internal RNA-binding region (RBR i) in CTCF mediates CTCF clustering and that deletion of the RBR i causes disruption of about half of all chromatin loops in mouse embryonic stem cells. [ABSTRACT FROM AUTHOR]

Anticancer therapies reportedly promote pro-survival autophagy in cancer cells that confers drug resistance, rationalizing the concept to combine autophagy inhibitors to increase their therapeutic potential. We previously identified that MPT0L145 is a PIK3C3/FGFR inhibitor that not only increases autophagosome formation due to fibroblast growth factor receptor (FGFR) inhibition but also perturbs autophagic flux via PIK3C3 inhibition in bladder cancer cells harboring FGFR activation. In this study, we hypothesized that combined-use of MPT0L145 with agents that induce pro-survival autophagy may provide synthetic lethality in cancer cells without FGFR activation. The results showed that MPT0L145 synergistically sensitizes anticancer effects of gefitinib and gemcitabine in non-small cell lung cancer A549 cells and pancreatic cancer PANC-1 cells, respectively. Mechanistically, drug combination increased incomplete autophagy due to impaired PIK3C3 function by MPT0L145 as evidenced by p62 accumulation and no additional apoptotic cell death was observed. Meanwhile, drug combination perturbed survival pathways and increased vacuolization and ROS production in cancer cells. In conclusion, the data suggest that halting pro-survival autophagy by targeting PIK3C3 with MPT0L145 significantly sensitizes cancer cells to targeted or chemotherapeutic agents, fostering rational combination strategies for cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Aim: To investigate the efficacy and safety of beinaglutide as an adjunct to lifestyle intervention among non‐diabetic Chinese individuals with overweight or obesity. Methods: This multicentre, randomized, double‐blind, placebo‐controlled trial (ChiCTR1900023428) included 427 Chinese adults with a body mass index of 28 kg/m2 or higher (obesity) or 24‐27.9 kg/m2 (overweight) with weight‐related complications. Patients were randomized in a 2:1 ratio to receive 0.2 mg of beinaglutide (subcutaneous) thrice daily or placebo for 16 weeks. Co‐primary endpoints were body weight change and the proportion of patients with a weight reduction of 5% or more. Results: Mean body weight change from baseline to week 16 was −6.0% and −2.4% in the beinaglutide (n = 282) and placebo (n = 138) groups, respectively; the mixed model repeated measures difference was −3.6% (95% confidence interval: −4.6% to −2.6%; P <.0001). At week 16, more beinaglutide‐treated patients achieved a weight reduction of 5% or more (58.2% vs. 25.4% [placebo], odds ratio: 4.4; P <.0001) and of 10% or more (21.3% vs. 5.1% [placebo], odds ratio: 5.5; P <.0001). Beinaglutide also resulted in greater waist circumference reduction (difference: −1.81 cm; P <.01). The weight regain rate 12 weeks after beinaglutide treatment was 0.78%. Nausea (transient and mild‐to‐moderate) was the most common adverse event in the beinaglutide group (49.3% vs. 7.1% [placebo]). More patients receiving beinaglutide discontinued treatment because of adverse events (5.9% vs. 0.7% [placebo]). Pancreatitis or an increased resting heart rate was not observed in the beinaglutide group. Conclusion: Beinaglutide combined with lifestyle intervention resulted in significant and clinically meaningful weight reduction with good tolerance in non‐diabetic Chinese individuals with overweight or obesity. [ABSTRACT FROM AUTHOR]

Background: Atypical teratoid rhabdoid tumors (ATRT) is a rare but aggressive malignancy in the central nervous system, predominantly occurring in early childhood. Despite aggressive treatment, the prognosis of ATRT patients remains poor. RRM2, a subunit of ribonucleotide reductase, has been reported as a biomarker for aggressiveness and poor prognostic conditions in several cancers. However, little is known about the role of RRM2 in ATRT. Uncovering the role of RRM2 in ATRT will further promote the development of feasible strategies and effective drugs to treat ATRT. Methods: Expression of RRM2 was evaluated by molecular profiling analysis and was confirmed by IHC in both ATRT patients and PDX tissues. Follow-up in vitro studies used shRNA knockdown RRM2 in three different ATRT cells to elucidate the oncogenic role of RRM2. The efficacy of COH29, an RRM2 inhibitor, was assessed in vitro and in vivo. Western blot and RNA-sequencing were used to determine the mechanisms of RRM2 transcriptional activation in ATRT. Results: RRM2 was found to be significantly overexpressed in multiple independent ATRT clinical cohorts through comprehensive bioinformatics and clinical data analysis in this study. The expression level of RRM2 was strongly correlated with poor survival rates in patients. In addition, we employed shRNAs to silence RRM2, which led to significantly decrease in ATRT colony formation, cell proliferation, and migration. In vitro experiments showed that treatment with COH29 resulted in similar but more pronounced inhibitory effect. Therefore, ATRT orthotopic mouse model was utilized to validate this finding, and COH29 treatment showed significant tumor growth suppression and prolong overall survival. Moreover, we provide evidence that COH29 treatment led to genomic instability, suppressed homologous recombinant DNA damage repair, and subsequently induced ATRT cell death through apoptosis in ATRT cells. Conclusions: Collectively, our study uncovers the oncogenic functions of RRM2 in ATRT cell lines, and highlights the therapeutic potential of targeting RRM2 in ATRT. The promising effect of COH29 on ATRT suggests its potential suitability for clinical trials as a novel therapeutic approach for ATRT. [ABSTRACT FROM AUTHOR]

The genome is packaged and organized in an ordered, non-random manner and specific chromatin segments contact nuclear substructures to mediate this organization. Transfer RNA genes (tDNAs) are binding sites for transcription factors and architectural proteins and are thought to play an important role in the organization of the genome. In this study, we investigate the role of tDNAs in genomic organization and chromosome function by editing a chromosome so that it lacks any tDNAs. Surprisingly our analyses of this tDNA-less chromosome show that loss of tDNAs does not grossly affect chromatin architecture or chromosome tethering and mobility. However, loss of tDNAs affects local nucleosome positioning and the binding of SMC proteins at these loci. The absence of tDNAs also leads to changes in centromere clustering and a reduction in the frequency of long-range HML-HMR heterochromatin clustering with concomitant effects on gene silencing. We propose that the tDNAs primarily affect local chromatin structure that result in effects on long-range chromosome architecture. [ABSTRACT FROM AUTHOR]

Bamboo-fiber-reinforced polymers have gained popularity in numerous industries because of their mechanical properties, lightweight, and ecological benefits. In this study, to determine the effects of textile structure on the impact resistance performance of bamboo-textile-reinforced polymers (BTRPs), we evaluated three impact modes: simple support beam (SSB), drop weight, and Charpy impact. We then used 3D X-ray scanning to determine the effects of the textile structure and impact modes on the microscopic fracture and crack development. The results indicated that the woven structure allowed for energy transmission in all directions during the drop weight impact test. During the SSB impact test, the large quantity of bamboo tows parallel to the major axis of the specimen increased the absorbed energy. When additional layers were added in the loading direction, the deflection of the entire specimen decreased, thus leading to lower absorbed energy. According to 3D X-ray images and quasi-static bending fracture results, similar fracture patterns appeared on dynamic and static loaded specimens. Consequently, the energy required for internal fracture and the strain energy of deflection are the two significant reasons that enable the excellent impact resistance performance of BTRPs. • Three impact modes include simple support beam, drop weight, and Charpy were conducted. • Effects of woven structure factors on impact strength, absorbed energy and fractography were determined. • 3D Xray technique was used to identify fracture modes and fracture pattern. • The impact energy absorbed is nearly equal to the sum of the energy required for fracturing, crack propagation and the work done by deformation. [ABSTRACT FROM AUTHOR]

The article presents chemical equations related to the article "Practical Synthesis of N-Substituted Cyanamides via Tiemann Rearrangement of Amidoximes" by C. Lin and others, published in the periodical "Organic Letters" in 2014.

Previously, Bithionol (BT) was shown to enhance the chemosensitivity of ovarian cancer cell lines to cisplatin treatment. In the present study, we focused on the anti-tumor potential of the BT-paclitaxel combination when added to a panel of ovarian cancer cell lines. This in vitro study aimed to 1) determine the optimum schedule for combination of BT and paclitaxel and 2) assess the nature and mechanism(s) underlying BT-paclitaxel interactions. The cytotoxic effects of both drugs either alone or in combination were assessed by presto-blue cell viability assay using six human ovarian cancer cell lines. Inhibitory concentrations to achieve 50% cell death (IC50) were determined for BT and paclitaxel in each cell line. Changes in levels of cleaved PARP, XIAP, bcl-2, bcl-xL, p21 and p27 were determined via immunoblot. Luminescent and colorimetric assays were used to determine caspases 3/7 and autotaxin (ATX) activity. Cellular reactive oxygen species (ROS) were measured by flow cytometry. Our results show that the efficacy of the BT-paclitaxel combination depends upon the concentrations and sequence of addition of paclitaxel and BT. Pretreatment with BT followed by paclitaxel resulted in antagonistic interactions whereas synergistic interactions were observed when both drugs were added simultaneously or when cells were pretreated with paclitaxel followed by BT. Synergistic interactions between BT and paclitaxel were attributed to increased ROS generation and enhanced apoptosis. Decreased expression of pro-survival factors (XIAP, bcl-2, bcl-xL) and increased expression of pro-apoptotic factors (caspases 3/7, PARP cleavage) was observed. Additionally, increased expression of key cell cycle regulators p21 and p27 was observed. These results show that BT and paclitaxel interacted synergistically at most drug ratios which, however, was highly dependent on the sequence of the addition of drugs. Our results suggest that BT-paclitaxel combination therapy may be effective in sensitizing ovarian cancer cells to paclitaxel treatment, thus mitigating some of the toxic effects associated with high doses of paclitaxel. [ABSTRACT FROM AUTHOR]

Simple Summary: Interval-compressed chemotherapy was evaluated in Asian children and young adults with sarcomas to assess the feasibility of this treatment strategy. Ultimately, the goal is to improve survival in this group of individuals with high-risk malignancies without increasing short-term or long-term toxicities. The feasibility of this strategy in Asian patients with sarcomas needed to be established prior to evaluating the efficacy of this approach in a prospective trial. Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1200–2200 mg/m2) (VDC) alternating with a regimen of ifosfamide (9000 mg/m2) and etoposide (500 mg/m2) (IE), with filgrastim (5–10 mcg/kg/day) between cycles. Carboplatin (800 mg/m2) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15–24 days. Median nadirs (IQR) were neutrophil count, 134 (30–396) × 106/L at day 11 (10–12), recovery by day 15 (14–17) and platelet count, 35 (23–83) × 109/L at day 11 (10–13), recovery by day 17 (14–21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and CIC-DUX4 Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas. [ABSTRACT FROM AUTHOR]

Primary intracranial ependymoma is a challenging tumor to treat despite the availability of multidisciplinary therapeutic modalities, including surgical resection, radiotherapy, and adjuvant chemotherapy. After the completion of initial treatment, when resistant tumor cells recur, salvage therapy needs to be carried out with a more precise strategy. Circulating tumor cells (CTCs) have specifically been detected and validated for patients with primary or recurrent diffused glioma. The CTC drug screening platform can be used to perform a mini-invasive liquid biopsy for potential drug selection. The validation of potential drugs in a patient-derived xenograft (PDX) mouse model based on the same patient can serve as a preclinical testing platform. Here, we present the application of a drug testing model in a six-year-old girl with primary ependymoma on the posterior fossa, type A (EPN-PFA). She suffered from tumor recurrence with intracranial and spinal seeding at 2 years after her first operation and extraneural metastases in the pleura, lung, mediastinum, and distant femoral bone at 4 years after initial treatment. The CTC screening platform results showed that everolimus and entrectinib could be used to decrease CTC viability. The therapeutic efficacy of these two therapeutic agents has also been validated in a PDX mouse model from the same patient, and the results showed that these two therapeutic agents significantly decreased tumor growth. After precise drug screening and the combination of focal radiation on the femoral bone with everolimus chemotherapy, the whole-body bone scan showed significant shrinkage of the metastatic tumor on the right femoral bone. This novel approach can combine liquid biopsy, CTC drug testing platforms, and PDX model validation to achieve precision medicine in rare and challenging tumors with extraneural metastases. [ABSTRACT FROM AUTHOR]

Because it is an accessible and routine image test, medical personnel commonly use a chest X-ray for COVID-19 infections. Artificial intelligence (AI) is now widely applied to improve the precision of routine image tests. Hence, we investigated the clinical merit of the chest X-ray to detect COVID-19 when assisted by AI. We used PubMed, Cochrane Library, MedRxiv, ArXiv, and Embase to search for relevant research published between 1 January 2020 and 30 May 2022. We collected essays that dissected AI-based measures used for patients diagnosed with COVID-19 and excluded research lacking measurements using relevant parameters (i.e., sensitivity, specificity, and area under curve). Two independent researchers summarized the information, and discords were eliminated by consensus. A random effects model was used to calculate the pooled sensitivities and specificities. The sensitivity of the included research studies was enhanced by eliminating research with possible heterogeneity. A summary receiver operating characteristic curve (SROC) was generated to investigate the diagnostic value for detecting COVID-19 patients. Nine studies were recruited in this analysis, including 39,603 subjects. The pooled sensitivity and specificity were estimated as 0.9472 (p = 0.0338, 95% CI 0.9009–0.9959) and 0.9610 (p < 0.0001, 95% CI 0.9428–0.9795), respectively. The area under the SROC was 0.98 (95% CI 0.94–1.00). The heterogeneity of diagnostic odds ratio was presented in the recruited studies (I2 = 36.212, p = 0.129). The AI-assisted chest X-ray scan for COVID-19 detection offered excellent diagnostic potential and broader application. [ABSTRACT FROM AUTHOR]

Background: KRAS is a frequently mutated oncogene in human cancer. Clinical studies on the covalent inhibitors of the KRASG12C mutant have reported promising results. However, primary and acquired resistance may limit their clinical use. Methods: Sotorasib-resistant cell lines were established. We explored the signalling pathways activated in these resistant cell lines and their roles in sotorasib resistance. Results: The resistant cells exhibited increased cell–matrix adhesion with increased levels of stress fibres and focal adherens. p21-activated kinases (PAKs) were activated in resistant cells, which phosphorylate MEK at serine 298 of MEK and serine 338 of c-Raf to activate the mitogen-activated protein kinase pathway. The PAK inhibitors FRAX597 and FRAX486 in synergy with sotorasib reduced the viability of KRASG12C mutant cancer cells. Furthermore, the PI3K/AKT pathway was constitutively active in sotorasib-resistant cells. The overexpression of constitutively activated PI3K or the knockdown of PTEN resulted in resistance to sotorasib. PI3K inhibitor alpelisib was synergistic with sotorasib in compromising the viability of KRASG12C mutant cancer cells. Moreover, PI3K and PAK pathways formed a mutual positive regulatory loop that mediated sotorasib resistance. Conclusions: Our results indicate that the cell–matrix interaction-dependent activation of PAK mediates resistance to sotorasib through the activation of MAPK and PI3K pathways. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is an extremely common head and neck cancer with a poor 5‐year survival rate, especially in cases of metastatic disease. Interleukin (IL)‐11 reportedly promotes cell growth and the epithelial–mesenchymal transition process in metastasis. However, the molecular mechanisms of IL‐11 in OSCC metastasis are unclear. This study found that IL‐11 upregulates matrix metalloproteinase 13 (MMP‐13) expression in OSCC via the IL‐11 receptor alpha subunit/glycoprotein 130 receptors that activate phosphatidyl‐inositol 3‐kinase, Ak strain transforming, and activator protein 1 signaling, which subsequently enhance MMP‐13‐induced tumor metastasis. TIMER2.0 analysis revealed a positive correlation between MMP‐13 and IL‐11 levels (r = 0.454). Moreover, a strong positive association was observed between higher levels of IL‐11 expression in OSCC tissue (p < 0.01), lymph node metastasis (p = 0.0154), and clinical disease stage (p = 0.0337). IL‐11 knockdown suppressed the migration of OSCC cells (p < 0.05). The evidence indicates that IL‐11 can serve as a new molecular therapeutic target in OSCC metastasis. [ABSTRACT FROM AUTHOR]

Antipsychotic drug (APD) treatment has been associated with metabolic abnormalities. Brown adipose tissue (BAT) is the main site of adaptive thermogenesis and secretes various metabolism-improving factors known as batokines. We explored the association of BAT activity with APD treatment and metabolic abnormalities in patients with schizophrenia by measuring the blood levels of bone morphogenetic protein 8b (BMP8b), a batokine secreted by mature BAT. BMP8b levels were compared among 50 drug-free, 32 aripiprazole-treated, and 91 clozapine-treated patients with schizophrenia. Regression analysis was used to explore factors, including APD types, that might be associated with BMP8b levels and the potential effect of BMP8b on metabolic syndrome (MS). APD-treated patients had decreased BMP8b levels relative to drug-free patients. The difference still existed after adjustment for body mass index and Brief Psychiatric Rating Scale scores. Among APD-treated group, clozapine was associated with even lower BMP8b levels than the less obesogenic APD, aripiprazole. Furthermore, higher BMP8b levels were associated with lower risks of MS after adjustment for BMI and APD treatment. Using drug-free patients as the comparison group to understand the effect of APDs, this is the first study to show APD treatment is associated with reduced BAT activity that is measured by BMP8b levels, with clozapine associated a more significant reduction than aripiprazole treatment. BMP8b might have a beneficial effect against metabolic abnormalities and this effect is independent of APD treatment. Future studies exploring the causal relationship between APD treatment and BMP8b levels and the underlying mechanisms are warranted. • BAT is the main site of adaptive thermogenesis that improves metabolic problems. • BMP8b is a batokine secreted by BAT, with levels correlated to BAT activity. • Antipsychotic-treated patients had lower BMP8b levels than drug-free patients. • Clozapine treatment was associated with even lower BMP8b levels than aripiprazole. • Higher BMP8b levels were associated with lower metabolic risks in our patients. [ABSTRACT FROM AUTHOR]

Background: Inflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), a negative cochaperone of glucocorticoid receptor (GR), is a stress-inducible gene and has been linked to psychiatric disorders. Yet, the role of FKBP51 in the inflammatory stress-associated mental disturbance remained unclear.Methods: Fkbp5-deficient (Fkbp5-KO) mice were used to study inflammatory stress by a single intraperitoneal injection of lipopolysaccharide (LPS). The anxiety-like behaviors, neuroimaging, immunofluorescence staining, immunohistochemistry, protein and mRNA expression analysis of inflammation- and neurotransmission-related mediators were evaluated. A dexamethasone drinking model was also applied to examine the effect of Fkbp5-KO in glucocorticoid-induced stress.Results: LPS administration induced FKBP51 elevation in the liver and hippocampus accompanied with transient sickness. Notably, Fkbp5-KO but not wild-type (WT) mice showed anxiety-like behaviors 7 days after LPS injection (LPS-D7). LPS challenge rapidly increased peripheral and central immune responses and hippocampal microglial activation followed by a delayed GR upregulation on LPS-D7, and these effects were attenuated in Fkbp5-KO mice. Whole-brain [18F]-FEPPA neuroimaging, which target translocator protein (TSPO) to indicate neuroinflammation, showed that Fkbp5-KO reduced LPS-induced neuroinflammation in various brain regions including hippocampus. Interestingly, LPS elevated glutamic acid decarboxylase 65 (GAD65), the membrane-associated GABA-synthesizing enzyme, in the hippocampus of WT but not Fkbp5-KO mice on LPS-D7. This FKBP51-dependent GAD65 upregulation was observed in the ventral hippocampal CA1 accompanied by the reduction of c-Fos-indicated neuronal activity, whereas both GAD65 and neuronal activity were reduced in dorsal CA1 in a FKBP51-independent manner. GC-induced anxiety was also examined, which was attenuated in Fkbp5-KO and hippocampal GAD65 expression was unaffected.Conclusions: These results suggest that FKBP51/FKBP5 is involved in the systemic inflammation-induced neuroinflammation and hippocampal GR activation, which may contribute to the enhancement of GAD65 expression for GABA synthesis in the ventral hippocampus, thereby facilitating resilience to inflammation-induced anxiety. [ABSTRACT FROM AUTHOR]

Animal genomes are folded into loops and topologically associating domains (TADs) by CTCF and loop-extruding cohesins, but the live dynamics of loop formation and stability remain unknown. Here, we directly visualized chromatin looping at the Fbn2 TAD in mouse embryonic stem cells using super-resolution live-cell imaging and quantified looping dynamics by Bayesian inference. Unexpectedly, the Fbn2 loop was both rare and dynamic, with a looped fraction of approximately 3 to 6.5% and a median loop lifetime of approximately 10 to 30 minutes. Our results establish that the Fbn2 TAD is highly dynamic, and about 92% of the time, cohesin-extruded loops exist within the TAD without bridging both CTCF boundaries. This suggests that single CTCF boundaries, rather than the fully CTCF-CTCF looped state, may be the primary regulators of functional interactions. [ABSTRACT FROM AUTHOR]

Objective: Several transient receptor potential (TRP) channels are expressed in pancreatic beta cells and have been proposed to be involved in insulin secretion. However, the endogenous ligands for these channels are far from clear. Here, we demonstrate the expression of the transient receptor potential ankyrin 1 (TRPA1) ion channel in the pancreatic beta cells and its role in insulin release. TRPA1 is an attractive candidate for inducing insulin release because it is calcium permeable and is activated by molecules that are produced during oxidative glycolysis. Methods: Immunohistochemistry, RT-PCR, and Western blot techniques were used to determine the expression of TRPA1 channel. Ca2+ fluorescence imaging and electrophysiology (voltage- and current-clamp) techniques were used to study the channel properties. TRPA1-mediated insulin release was determined using ELISA. Results: TRPA1 is abundantly expressed in a rat pancreatic beta cell line and freshly isolated rat pancreatic beta cells, but not in pancreatic alpha cells. Activation of TRPA1 by allyl isothiocyanate (AITC), hydrogen peroxide (H2O2), 4-hydroxynonenal (4- HNE), and cyclopentenone prostaglandins (PGJ2) and a novel agonist methylglyoxal (MG) induces membrane current, depolarization, and Ca2+ influx leading to generation of action potentials in a pancreatic beta cell line and primary cultured pancreatic beta cells. Activation of TRPA1 by agonists stimulates insulin release in pancreatic beta cells that can be inhibited by TRPA1 antagonists such as HC030031 or AP-18 and by RNA interference. TRPA1-mediated insulin release is also observed in conditions of voltage-gated Na+ and Ca2+ channel blockade as well as ATP sensitive potassium (KATP) channel activation. Conclusions: We propose that endogenous and exogenous ligands of TRPA1 cause Ca2+ influx and induce basal insulin release and that TRPA1-mediated depolarization acts synergistically with KATP channel blockade to facilitate insulin release. [ABSTRACT FROM AUTHOR]

Intracranial myxoid mesenchymal tumors (IMMTs) with fusions between EWSR1/FUS and CREB transcription factors have morphologic overlap with myxoid angiomatoid fibrous histiocytoma (mAFH) and myoepithelial tumor/carcinoma (MET/MEC). We aimed to study the clinicopathologic and genetic spectrum of extracranial IMMT-like tumors and their relationships with mAFH and MET/MEC. Twelve extracranial tumors harboring EWSR1/FUS - CREB fusions across different histologic groups were characterized using RNA sequencing, FISH and/or RT-PCR. There were 4 IMMT-like neoplasms, 3 MET/MECs, and 5 mAFHs from the tibia (n=1), oral cavity (n=2), and soft tissues (n=9; 5 in the extremities), harboring EWSR1-ATF1 in 4 cases, FUS-CREM and EWSR1-CREM in 3 each , and EWSR1-CREB1 in 2. Multinodular growth, reticular/cording/trabecular arrangements, myxocollagenous matrix, and lymphocytic infiltrates variably prevailed among the 3 groups. mAFHs were characterized by cells with syncytial cytoplasm. IMMT-like neoplasms and MET/MECs shared cells with distinct boundaries, but only MET/MECs expressed GFAP and/or S100. MUC4 and ALK were expressed in some IMMT-like neoplasms (2/4; 2/4) and mAFH (2/5; 1/5). Pan-TRK reactivity was observed in two IMMT-like neoplasms with upregulated NTRK3 mRNA and one MEC. Local recurrences, typically ≥ 12 months postoperatively, developed in 2/3 IMMT-like neoplasms, 1/2 MET/MECs, and 0/4 mAFHs with follow-up. No definite associations were found between fusion types and histology, immunoprofile or outcome. We demonstrated the similarities and differences among 3 extracranial myxocollagenous tumor groups sharing EWSR1/FUS - CREB fusions. Oral IMMT-like neoplasms harboring FUS-CREM or EWSR1-ATF1 and FUS-CREM -positive. ● Molecular testing enables identification of rare extracranial FET-CREB -positive myxocollagenous tumors, including morphologically overlapped myxoid angiomatoid fibrous histiocytoma, myoepithelial neoplasm, and those resembling so-called intracranial myxoid mesenchymal tumor (IMMT). ● Oral IMMT-like neoplasms harboring FUS-CREM or EWSR1-ATF1 and FUS-CREM -positive myoepithelial neoplasm should join as new members of this ever-expanding family with clinicopathologic heterogeneity. ● These tumor types often but variably express MUC4, ALK, and pan-TRK with NTRK3 mRNA upregulation. [ABSTRACT FROM AUTHOR]

Near-field lattice spectroscopy has shown that the structure information for a lattice or periodic pattern can be obtained by measuring the diffracted spectrum of a broad-band light source at one spatial position. This technique is verified experimentally using a transmitting grating, supercontinuum white light laser, and a reflective concave mirror. The calculated grating's period from the detected lattice spectroscopy is close to the measured period with an optical microscope, which demonstrates the validity and feasibility of this scheme. [ABSTRACT FROM AUTHOR]

Polymer composite samples were prepared consisting of NC-826 epoxy and approximately 0.1–0.5 wt% aerographite nanomaterial. The compression properties of the various samples were evaluated at strain rates of 10−3–10−1 s−1 using a universal testing machine. The fracture surfaces of the tested samples were examined by scanning electron microscope. Additional composite samples consisting of NC-826 epoxy and 0.3 wt% multiwalled carbon nanotubes (MWCNTs) were prepared and tested under the same compression strain rates of approximately 10−1–10−3 s−1. In general, the results showed that the addition of aerographite nanomaterials to the resin matrix is beneficial in suppressing crack propagation under compression loads and therefore leads to an improved stress, toughness, and fracture strain compared to the pure resin sample. The results additionally showed that the use of MWCNTs as a reinforcement material yields a further small improvement in the mechanical properties of the sample. [ABSTRACT FROM AUTHOR]

Background: Predicting the survival of non-cancer related end-stage-liver-disease patients in general practice has been difficult for physicians because of the extremely variable trajectories due to multiple complex clinical factors, hence it remains a challenging issue to date. This study aimed to develop and validate a specific prognostic scoring system to early recognize the prognosis and improve the quality of end-of life care for non-cancer end-stage-liver-disease population. Materials and methods: A multicentre, retrospective cohort study was conducted during January 2010 ~ December 2012 and continued follow-up until December 2014. A cox proportional hazard regression analysis was used to derive and validate an optimized model. The main outcome measures were the 28-day, 3-month, 6-month, and 12-month mortality prediction. The performance of the novel model was evaluated, including discrimination and calibration. Results: A total of 4,080 consecutive subjects were enrolled. The AUROCs for the 3-month survival discrimination in the MELD, MELD-Na and novel model were 0.787, 0.705 and 0.804 (P<0.001); the 6-month survival discrimination were 0.781, 0.702 and 0.797 (P<0.001); the overall survival discrimination were 0.771, 0.694 and 0.785 (P = 0.002) respectively, whereas the novel model showed a significantly higher discrimination power than did the MELD and MELD-Na for the 3-month, 6-month and overall survival prediction. In addition, calibration of external validation cohort showed no statistical difference in all 5 groups compared with the observed groups. Conclusion: This is a clinically relevant, validated scoring system that can be used sequentially to stratify the prognosis in non-cancer cirrhotic populations, which may help the patients along with medical team in decision making to improve the quality of end-of-life care. [ABSTRACT FROM AUTHOR]

Treatment-resistant depression (TRD) is a condition wherein patients with depression fail to respond to antidepressant trials. A new form of repetitive transcranial magnetic stimulation (rTMS), called theta-burst stimulation (TBS), which includes intermittent theta-burst stimulation (iTBS) and continuous theta-burst stimulation (cTBS), is non-inferior to rTMS in TRD treatment. However, the mechanism of iTBS and cTBS underlying the treatment of TRD in the prefrontal cortex (PFC) remains unclear. Hence, we applied foot-shock stress as a traumatic event to develop a TRD rat model and investigated the different mechanisms of iTBS and cTBS. The iTBS and cTBS treatment were effective in depressive-like behavior and active coping behavior. The iTBS treatments improved impaired long-term potentiation and long-term depression (LTD), whereas the cTBS treatment only improved aberrant LTD. Moreover, the decrease in mature brain-derived neurotrophic factor (BDNF)-related protein levels were reversed by iTBS treatment. The decrease in proBDNF-related protein expression was improved by iTBS and cTBS treatment. Both iTBS and cTBS improved the decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and downregulation of mammalian target of the rapamycin (mTOR) signaling pathway. The iTBS produces both excitatory and inhibitory synaptic effects, and the cTBS only produces inhibitory synaptic effects in the PFC. • In an treatment-resistant rat model, depressive-like behaviors were improved by both the iTBS and cTBS. • The iTBS treatment improved the aberrant LTP and LTD, whereas the cTBS treatment only improved the aberrant LTD in the treatment-resistant rat model. • The mechanism of iTBS treatment was involved in the expression of proBDNF and mature BDNF, whereas the cTBS treatment was only involved in the expression of proBDNF in the treatment-resistant rat model. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a metabolic disease that is increasing worldwide. Furthermore, it is associated with the deregulation of vascular-related functions, which can develop into major complications among DM patients. Endothelial colony forming cells (ECFCs) have the potential to bring about medical repairs because of their post-natal angiogenic activities; however, such activities are impaired by high glucose- (HG) and the DM-associated conditions. Far-infrared radiation (FIR) transfers energy as heat that is perceived by the thermoreceptors in human skin. Several studies have revealed that FIR improves vascular endothelial functioning and boost angiogenesis. FIR has been used as anti-inflammatory therapy and as a clinical treatment for peripheral circulation improvement. In addition to vascular repair, there is increasing evidence to show that FIR can be applied to a variety of diseases, including cardiovascular disorders, hypertension and arthritis. Yet mechanism of action of FIR and the biomarkers that indicate FIR effects remain unclear. MicroRNA-134 (miR-134-5p) was identified by small RNA sequencing as being increased in high glucose (HG) treated dfECFCs (HG-dfECFCs). Highly expressed miR-134 was also validated in dmECFCs by RT-qPCR and it is associated with impaired angiogenic activities of ECFCs. The functioning of ECFCs is improved by FIR treatment and this occurs via a reduction in the level of miR-134 and an increase in the NRIP1 transcript, a direct target of miR-134. Using a mouse ischemic hindlimb model, the recovery of impaired blood flow in the presence of HG-dfECFCs was improved by FIR pretreatment and this enhanced functionality was decreased when there was miR-134 overexpression in the FIR pretreated HG-dfECFCs. In conclusion, our results reveal that the deregulation of miR-134 is involved in angiogenic defects found in DM patients. FIR treatment improves the angiogenic activity of HG-dfECFCs and dmECFCs and FIR has potential as a treatment for DM. Detection of miR-134 expression in FIR-treated ECFCs should help us to explore further the effectiveness of FIR therapy. [ABSTRACT FROM AUTHOR]

Oxaliplatin, a third-generation platinum derivative, has become one of the main chemotherapeutic treatments for esophagus, gastric and colorectal cancer; however, it is still unclear the potential effectiveness for pancreatic ductal adenocarcinoma (PDAC) with gemcitabine resistance. Here, we observed that PDAC tumors have low level of organic cation transporter 2 (OCT2, also known as SLC22A2) compared with non-tumor tissues and identified that OCT2 expression is positively correlated with oxaliplatin sensitivity in PDAC cells. Treatment of OCT2 inhibitors or knockdown of OCT2 expression significantly decreased the sensitivity to oxaliplatin in PANC-1 cells. In addition, bisulfite sequencing polymerase chain reaction analysis revealed that higher methylation frequency represses OCT2 expression in gemcitabine-resistant PANC-1 (PANC-1/GR) cells. Moreover, we found that treatment of DNA methyltransferase (DNMT) inhibitors, decitabine or 5-azacytidine recover OCT2 expression and oxaliplatin sensitivity in PANC-1/GR cells, and DNMT1 level has inverse correlation with OCT2 expression in PDAC cells and tumors. Our findings jointly suggest that OCT2 expression is a potential and predictive marker for evaluating oxaliplatin sensitivity and developing alternative treatments for PDAC patients with gemcitabine resistance. [Display omitted] • Low level of OCT2 expression in PDAC tumors. • OCT2 expression is positively correlated with oxaliplatin sensitivity. • Inhibition of DNMTs upregulates OCT2 expression and oxaliplatin sensitivity. • The negative correlation between DNMT1 and OCT2 expression in PDAC. [ABSTRACT FROM AUTHOR]

Background and Aim Epidermal growth factor receptor ( EGFR) overexpression is associated with disease progression and poor survival in a variety of solid tumors. The role of EGFR in hepatocellular carcinoma ( HCC) remains controversial. Methods One hundred thirty-eight HCCs were analyzed for total EGFR (t- EGFR) and phospho- EGFR (p- EGFR) expression and gene amplification using immunohistochemistry and fluorescence in situ hybridization. The role of EGFR was analyzed in relation to the clinicopathological features. Results Weak to strong p- EGFR immunostaining was noted in 42 of the 138 HCCs. p- EGFR expression correlated with alcoholism ( P = 0.03) and chronic hepatitis B infection ( P = 0.041). There was no correlation between t- EGFR expression and any of the clinicopathological features. Amplification of the EGFR gene was not identified in the 138 HCCs, but 39.1% of the HCCs showed balanced polysomy of both the EGFR gene and centromere 7. Moreover, 65 tumors showed > 2.2 copies per tumor cell. EGFR copy number gain ( CNG) was significantly correlated with gender ( P = 0.0491), tumor grade ( P = 0.006), and vascular invasion ( P = 0.005). HCCs with EGFR CNG also had a poor recurrence-free survival ( RFS), as compared with HCCs without EGFR CNG ( P = 0.031). When exploring the impact of gender, a significant association of EGFR CNG was found with tumor grade ( P = 0.044) and cirrhosis ( P = 0.015) exclusively in the male group only; however, the OS and RFS analysis show no significant difference between male and female groups. Conclusions EGFR CNG was related to crucial clinicopathological features and early recurrence, indicating that EGFR CNG might be a poor prognosis factor for Taiwanese HCC. [ABSTRACT FROM AUTHOR]