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This work presents a correlation between the behavior of formic acid oxidation (FAO) on various Bi-modified Pt(poly) disk electrodes and their morphologies observed on Bi-modified Pt(111) disk electrodes using electrochemical scanning tunneling microscopy (EC-STM) to understand the effects of Bi on Pt. To distinguish the FAO activities of Bi on Pt and plain Pt around Bi, additional Pt was intentionally deposited using two different routes: direct route and iodine route. In direct route, Pt was directly deposited on Bi islands and plain Pt sites around Bi islands, while in iodine route, Pt was exclusively deposited on Bi islands by protecting plain Pt sites with adsorbed iodine. Thus, a comparison of FAO performances on the two Bi-modified Pt electrodes with additional Pt (deposited in the different ways) disclosed a difference in FAO performances on plain Pt sites and Bi islands. When Bi coverage was ~0.04, the Bi deposits were scattered Bi islands enhancing FAO on Pt(poly). The additional Pt deposits using direct route increased FAO efficiency, while the ones using iodine route slightly decreased FAO current. The EC-STM observations indicated that Pt deposits around Bi islands, not on Bi islands, were responsible for the FAO current increase on Bi-modified Pt(poly). The FAO efficiency on Bi-modified Pt(poly) with a Bi coverage of ~0.25 increased by a factor of 2. However, the additional Pt deposits using the two Pt deposition routes notably decreased the FAO current. The dependency of FAO on Bi coverage was discussed in terms of electronic effect and ensemble effect.

Due to advancements in modern mobile communication technology, massive numbers of devices are now connected to the internet, but the associated information also has to be well protected. Many studies have proposed physical layer security (PLS) approaches utilizing artificial noise (AN), which is a simple approach to protecting information from an illegal receiver. However, this approach requires additional power allocation for AN. This paper proposes an efficient power balancing method for the Alamouti scheme, which provides efficient security capability as well as enhancement of power efficiency. The simulation results investigated in this paper reveal that the proposed scheme requires about 5 dB smaller power to achieve the same performance as that of the conventional AN-aided scheme, and eventually, about 2 dB less power than the conventional scheme without PLS.

The advent of human pluripotent stem cells (hPSCs) presented a new paradigm to employ hPSC-derived cardiomyocytes (hPSC-CMs) in drug screening and disease modeling. However, hPSC-CMs differentiated in conventional two-dimensional systems are structurally and functionally immature. Moreover, these differentiation systems generate predominantly one type of cell. Since the heart includes not only CMs but other cell types, such monolayer cultures have limitations in simulating the native heart. Accordingly, three-dimensional (3D) cardiac tissues have been developed as a better platform by including various cardiac cell types and extracellular matrices. Two advances were made for 3D cardiac tissue generation. One type is engineered heart tissues (EHTs), which are constructed by 3D cell culture of cardiac cells using an engineering technology. This system provides a convenient real-time analysis of cardiac function, as well as a precise control of the input/output flow and mechanical/electrical stimulation. The other type is cardiac organoids, which are formed through self-organization of differentiating cardiac lineage cells from hPSCs. While mature cardiac organoids are more desirable, at present only primitive forms of organoids are available. In this review, we discuss various models of hEHTs and cardiac organoids emulating the human heart, focusing on their unique features, utility, and limitations.

Abdominal wall blocks (AWBs) can reduce pain during surgery and lessen opioid demand. Since it is difficult to know the exact level of intraoperative pain, it is not known how much the opioid dose should be reduced. In this study, using the surgical pleth index (SPI), which indicates pain index from sympathetic fibers, the amount of remifentanil consumption was investigated. We conducted single-port laparoscopic hernia repair in 64 patients, as follows: the regional block group (R group) was treated with AWB, while the control group (C group) was only subjected to general anesthesia. In both groups, the remifentanil concentration was adjusted to maintain the SPI score between 30 and 40 during surgery. The primary parameter was the amount of remifentanil. A total of 52 patients completed the study (24 in the R group, 28 in the C group). The remifentanil dose during surgery was decreased in the R group (29 ± 21 vs. 56 ± 36 ng/kg/min; p = 0.002). Visual analogue scale score and additional administrated analgesics were also low in the R group. As such, AWB can reduce the remifentanil dose while maintaining the same pain level.

This work presents a contrasting behavior of formic acid oxidation (FAO) on the Pt and Bi deposits on different Pt substrates. Using irreversible adsorption method, Bi and Pt were sequentially deposited on Pt electrodes of nanoparticle (Pt NP) and disk (Pt disk). The deposited layers of Bi and Pt on the Pt substrates were characterized with X-ray photoelectron spectroscopy, transmission microscopy and scanning tunneling microscopy. The electrochemical behaviors and FAO enhancements of Pt NP and Pt disk with deposited Bi only (i.e., Bi/Pt NP and Bi/Pt disk), were similar to each other. However, additional deposition of Pt on Bi/Pt NP and Bi/Pt disk (i.e., Pt/Bi/Pt NP and Pt/Bi/Pt disk) changed the electrochemical behavior and FAO activity in different ways depending on the shapes of the Pt substrates. With Pt/Bi/Pt NP, the hydrogen adsorption was suppressed and the surface oxidation of Pt was enhanced; while with Pt/Bi/Pt disk, the opposite behavior was observed. This difference was interpreted as a stronger interaction between the deposited Bi and Pt on Pt NP than that on Pt disk. The FAO performance on Pt/Bi/Pt NP is much better than that on Pt/Bi/Pt disk, most likely due to the difference in the interaction between the deposited Pt and Bi depending on the shapes of Pt substrates. In designing FAO electrochemical catalysts using Pt and Bi, the shape of a Pt substrate was concluded to be critically considered.

Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here, we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types via the microRNA-mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells into the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.

Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC. From 2012 to 2019, treatment-naive CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan–Meier method. In total, 1810 patients (1525 and 285 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p = 0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR = 0.973; p = 0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR = 0.949; p = 0.743). These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.

Hye Won Lee,1– 3,* Hyun Woong Lee,4,* Jae Seung Lee,1– 3 Yun Ho Roh,5 Hyein Lee,3 Seung Up Kim,1– 3 Jun Yong Park,1– 3 Do Young Kim,1– 3 Sang Hoon Ahn,1– 3 Beom Kyung Kim1– 3 1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea; 4Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Beom Kyung KimDepartment of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun–Gu, Seoul, 03722, Republic of KoreaTel +82-2-2228-1930Fax +82-2-393-6884Email beomkkim@yuhs.acBackground: Dynamic changes in fibrosis markers occur under long-term antiviral treatment (AVT) for chronic hepatitis B. We evaluated prognostic values of on-treatment liver stiffness (LS) compared to ultrasonography findings and determined its optimal cutoff.Methods: The cumulative probability of hepatocellular carcinoma (HCC) was assessed among 880 patients receiving entecavir or tenofovir for ≥ 2 years. LS was measured using transient elastography.Results: After ≥ 2 years’ AVT, the proportion of patients with cirrhosis on ultrasonography decreased from 54.7% to 44.9% and the mean LS decreased from 13.6 to 8.2 kPa (both p< 0.001). However, unlike cirrhosis on ultrasonography before AVT (p< 0.001), that after ≥ 2 years’ AVT did not discriminate HCC risk (p=0.792). Using the Contal and O’Quigley’s method, pre-AVT and on-treatment LS of 12.0 and 6.4 kPa, respectively, were chosen as optimal cutoffs to successfully discriminate HCC risk (both p< 0.001). However, through stratification using both pre-AVT and on-treatment LS, the prognosis was finally determined according to on-treatment LS of 6.4 kPa, regardless of pre-AVT LS of 12.0 kPa. Using on-treatment LS of 12 kPa suggested by Caucasians with CHB receiving long-term AVT, patients with higher LS were more likely to develop HCC than those with lower LS (p=0.017); however, there was no significant difference between those with on-treatment LS of 6.4– 11.9 and ≥ 12.0 kPa (p=0.920).Conclusion: For HCC risk stratification in patients receiving long-term AVT, on-treatment LS cutoff should be lowered to 6.4 kPa, which is more predictive than 12 kPa or cirrhosis on ultrasonography. Further studies are required for validation.Keywords: antiviral treatment, hepatitis B, liver stiffness, hepatocellular carcinoma

We compared the clinical efficacies of hepatic arterial infusion chemotherapy (HAIC) vs. sorafenib as sequential maintenance therapy following liver-directed concurrent chemoradiotherapy (LD-CCRT) for locally advanced-stage hepatocellular carcinoma (HCC). Patients undergoing HAIC with 5-fluorouracil and cisplatin (HAIC-maintain group, n = 151) or sorafenib (Sorafenib-maintain group, n = 37) after LD-CCRT were consecutively enrolled. The study endpoints were overall survival (OS), progression-free survival (PFS), and treatment response rates. The median OS among HAIC-maintain and Sorafenib-maintain groups were 15.9 and 24.3 months (p = 0.287), whereas the median PFS were 8.1 and 9.1 months (p = 0.651), respectively. During the planned treatments, the radiological objective response rate (54.3% vs. 64.9%; p = 0.246), and conversion rate to surgical resection or liver transplantation after successful down-staging (15.9% vs. 18.9%; p = 0.657) were comparable between the HAIC-maintain and Sorafenib-maintain groups. Similar results were found after the inverse probability of treatment weighting and propensity score-matching analyses. Regarding treatment-related adverse events, the HAIC-maintain group showed worse profiles in terms of leukopenia (all grades [p = 0.001] and grades 3 or 4 [p = 0.041]) and hypoalbuminemia (p = 0.001) than the Sorafenib-maintain group. The overall clinical efficacies between the sequential treatment of HAIC vs. sorafenib after LD-CCRT were comparable for locally advanced HCC.

Genomic analysis indicated that the genome of

Fully depleted silicon on insulator (FDSOI) is attractive for its low cost and low power; the mixed-Vt and body-bias levers that it affords expand the performance-power solution space. However, in FDSOI, different-Vt (i.e., low Vt and regular Vt) devices must be isolated from each other, which makes realization of fine-grained mixed-Vt/body-biasing in layout extremely challenging. In this article, we study heuristic methods aimed at exploitation of fine-grained mixed-Vt in FDSOI implementation. We propose a novel speed domain partitioning (SDP) problem formulation that comprehends the spatial contiguity restrictions arising from flip-well structure of low Vt regions in popular 28-nm commercial FDSOI offerings. We explore a wide space of implementation flows that include an integer linear programming (ILP)-based approach, and a heuristic (sensitivity-based) optimization. Our experimental studies have been performed across multiple commercial enablements. We observe that outcomes are library- and design-dependent. For implementations using generic library options, up to 20% speed improvement with 54% low Vt region is seen for one out of four testcases studied. For implementations using “rich” library options, up to 7% speed improvement with 26% low Vt region is achieved. We provide a discussion that summarizes root-cause, intrinsic difficulties of fine-grained exploitation of mixed-Vt. Finally, we suggest a “decision tree” to help assess a design’s amenability to fine-grained mixed-Vt implementation, and to help guide design flow selection for better design QoR.

Objectives; The accumulation and usefulness of clinical data have increased with IT development. While using clinical data that needs to be identifiable to obtain meaningful information, it is essential to ensure that data is de-identified and unnecessary clinical information is minimized to protect personal information. This process requires criteria and an appropriate method as there are clear identifiers as well as quasi-identifiers that are not readily identifiable. Methods; To formulate such a method, first, primary quasi-identifiers were selected by classifying information in 20 clinical personal information database tables into Direct-Identifier (DID), Quasi-Identifier (QI), Sensitive Attribute (SA), and Non-Sensitive Attribute (NSA) according to its type. Secondary QIs were then selected by assessing the risk for outliers by measuring uniqueness values of the selected data and scoring re-identification by calculating equivalence class of the influence on other data on QI removal. Third, the risk of re-identification of data users was numeralized and classified. Lastly, the final QI according to user class was determined by comparing the calculated re-identification scores to the threshold values of user classes. Results; Eventually, final QIs ranging from a minimum of 18 to a maximum of 28 were selected by making an assumption about user classes and using it as criteria. Conclusions; The QI selection method presented by the current investigators can be used by researchers at the final checkup stage before they de-identify the selected QIs. Therefore, clinical data users can securely and efficiently use clinical data containing personal information by objectively selecting QIs using the method proposed in the present study.

The induction of leaf injuries, including leaf chlorosis and epinasty, by continuous light in tomato plants is one of the most interesting and mysterious phenomena regarding plant interactions with light, the mechanism of which has not yet been revealed. To gain further insights into this particular response of tomato plants, we cultivated tomato seedlings (Solanum lycopersicum cv. Momotaro) for 14 days under continuous light with different ratios of red and blue light and compared their performance to those grown under continuous or 14/10-h photoperiodic white light using novel methods to quantitatively evaluate the level of leaf chlorosis and epinasty. Continuous monochromatic blue light induced severe chlorosis but almost completely alleviated epinasty in tomato leaf. In contrast, continuous monochromatic red light caused a lower level of leaf chlorosis but very severe epinasty. The combination of red and blue light at different ratios significantly reduced both leaf chlorosis and epinasty under continuous light condition. Carbohydrate contents showed no correlation with leaf chlorosis, while glucose and fructose contents showed correlations with the petiole and leaflet curvatures. Histochemical staining with 3,3'-diaminobenzidine and nitro blue tetrazodium chloride also did not reveal any significant buildup of hydrogen peroxide and superoxide anion in monochromatic blue light treatment. Taken together, these results suggest that chlorosis and epinasty are two distinctive leaf injuries caused by continuous light that may follow very different mechanisms, and an overaccumulation of carbohydrates in the leaf may not be the main cause of continuous light-induced leaf chlorosis in tomato.

For many years, discrete gate sizing has been widely used for timing and power optimization in VLSI designs. The importance of gate sizing optimization has been emphasized by academia for many years, especially since the 2012/2013 ISPD gate sizing contests [1, 2]. These contests have provided practical impetus to academic sizers through the use of realistic constraints and benchmark formats. At the same time, due to simplified delay/power Liberty models and timing constraints, the contests fail to address real-world criteria for gate sizing that are highly challenging in practice. We observe that lack of consideration of practical issues such as electrical and multi-corner constraints – along with limited sets of benchmarks – can misguide the development of contest-focused academic sizers. Thus, we study implications of the “gap” between academic sizers and product design use cases. In this paper, we note important constraints of modern industrial designs that are generally not comprehended by academic sizers. We also point out that various optimization techniques used in academic sizers can fail to offer benefits in product design contexts due to differences in the underlying optimization formulation and constraints. To address this gap, we develop a new robust academic sizer, Sizer, from a fresh implementation of Trident [3]. Experimental results show that Sizer is able to achieve up to 10% leakage power and 4% total power reductions compared to leading commercial tools on designs implemented with foundry technologies, and 7% leakage power reduction on a modern industrial design in the multi-corner multi-mode (MCMM) context.

Neuromyelitis optica (NMO) is an autoimmune disease that primarily targets astrocytes. Autoantibodies (NMO-IgG) against the water channel protein, aquaporin 4 (AQP4), are a serologic marker in NMO patients, and they are known to be responsible for the pathophysiology of the disease. In the brain, AQP4 is mainly expressed in astrocytes, especially at the end-feet, where they form the blood-brain barrier. Following the interaction between NMO-IgG and AQP4 in astrocytes, rapid AQP4 endocytosis initiates pathogenesis. However, the cellular and molecular mechanisms of astrocyte destruction by autoantibodies remain largely elusive. We established an in vitro human astrocyte model system using induced pluripotent stem cells (iPSCs) technology in combination with NMO patient-derived serum and IgG to elucidate the cellular and functional changes caused by NMO-IgG. Herein, we observed that NMO-IgG induces structural alterations in mitochondria and their association with the endoplasmic reticulum (ER) and lysosomes at the ultrastructural level, which potentially leads to impaired mitochondrial functions and dynamics. Indeed, human astrocytes display impaired mitochondrial bioenergetics and autophagy activity in the presence of NMO-IgG. We further demonstrated NMO-IgG-driven ER membrane deformation into a multilamellar structure in human astrocytes. Together, we show that NMO-IgG rearranges cellular organelles and alter their functions and that our in vitro system using human iPSCs offers previously unavailable experimental opportunities to study the pathophysiological mechanisms of NMO in human astrocytes or conduct large-scale screening for potential therapeutic compounds targeting astrocytic abnormalities in patients with NMO.

Background & aims: Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC.Methods: From 2012 to 2019, treatment-naïve CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan-Meier method.Results: In total, 1,810 patients (1,525 and 286 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p=0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR=0.973; p=0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR=0.949; p=0.743).Conclusions: These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.

Summary The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer’s disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-β (Aβ) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal Aβ production. Secretory factors in conditioned media from ApoE4 astrocytes significantly increased amyloid precursor protein (APP) levels and Aβ secretion in neurons. We further found that increased cholesterol secretion from ApoE4 astrocytes was necessary and sufficient to induce the formation of lipid rafts that potentially provide a physical platform for APP localization and facilitate its processing. Our study reveals the contribution of ApoE4 astrocytes to amyloidosis in neurons by expanding lipid rafts and facilitating Aβ production through an oversupply of cholesterol., Graphical abstract, Highlights • ApoE4 ACM induces neuronal lipid raft expansion and Aβ42 overproduction • Co-localization of lipid rafts and APP increases in neurons by ApoE4 ACM • Increasing cholesterol in media recapitulates the effects of ApoE4 ACM on neurons • Cholesterol depletion in ApoE4 ACM abolishes its effects on neurons, In this report, Seo and colleagues use human iPSCs to generate isogenic neurons and astrocytes carrying either APOE ε3 or APOE ε4 allele and demonstrate that ApoE4 astrocytes secrete more cholesterol to the extracellular space, which is sufficient and necessary to induce lipid raft expansion and Aβ42 overproduction in neurons.

Here, we present the controllable synthesis of dendrimer-encapsulated Pt nanoparticles (Pt DENs) utilizing repetitively coupled chemical reduction and galvanic exchange reactions. This facile method allowed controllable synthesis of the Pt DENs with fair homogeneity in size and composition. In particular, in contrast to the conventional dendrimer-templating methods, the proposed synthesis method allowed substantial increase in the applicable number of Pt atoms up to 1320 in Pt DENs without being limited by the fixed number of complexation sites for the Pt2+ precursor ions in dendrimers. We also present a detailed investigation on the oxidase-mimetic activity of the Pt DENs for catalytic oxidation of Amplex Red to resorufin with O2. Importantly, after clarifying intrinsic oxidase-mimetic activity of the Pt DENs, we disclosed that the Pt DENs’ oxidase-mimetic activity was tailorable for the oxidation of Amplex Red to resorufin especially with fine-tuning of the Pt2+/dendrimer ratios by using the proposed synthesis method.

Background: The onset of Alzheimer’s disease (AD) typically occurs later in life. Recent genetic analysis of patients and unaffected individuals revealed multiple genetic variants associated with late-onset AD. One of the strongest genetic risk factors for AD is 𝜀4 allele of APOE encoding apolipoprotein (ApoE), which is predominantly expressed in astrocytes. The role and mechanism of ApoE in initiating AD-associated pathologies, including amyloid-β (Aβ) accumulation and neurodegeneration in neurons, remains to be elucidated.Methods: Human induced pluripotent stem cells (hiPSCs) from healthy individuals and isogenic cells in which the ApoE 𝜀3 allele was replaced with an 𝜀4 allele were selected to generate human neurons and astrocytes. To investigate the effect of astrocytic ApoE4 on neuronal Aβ production, iPSC-derived neurons carrying the ApoE 𝜀3 allele were cultured in conditioned media from healthy iPSC-derived astrocytes (ApoE3/E4 heterozygote) for five weeks. Then, the media were replaced with either ApoE3 or ApoE4 astrocyte conditioned media (ACM), cultured for four days, and neuronal amyloid precursor protein (APP) expression and Aβ production were measured. To determine potential mechanisms for upregulation of APP in neurons by ApoE4 ACM, changes in plasma membrane lipid rafts were investigated by staining for cholera toxin B. Methyl-b-cyclodextrin (MβCD) was applied to deplete cholesterol in ApoE4 ACM.Results: Secretory factors in conditioned media from hiPSC-derived astrocytes carrying APOE4 significantly increased the levels of APP and Aβ secretion in hiPSC-derived neurons. Increasing cholesterol levels in culture media mimicked the effects of ApoE4 ACM by inducing the formation of lipid rafts that potentially provide a physical platform for APP localization on the membrane. We further found that reducing cholesterol levels in ApoE4 ACM with MβCD abolished its effects on neuronal lipid raft expansion and Aβ generation.Conclusions: Our study suggests that ApoE4 astrocytes contribute to amyloidosis by the expansion of lipid rafts and facilitate neuronal Ab production through oversupply of cholesterol.

We compared the clinical efficacies of hepatic arterial infusion chemotherapy (HAIC) vs. sorafenib as sequential maintenance therapy following liver-directed concurrent chemoradiotherapy (LD-CCRT) for locally advanced-stage hepatocellular carcinoma (HCC).Patients undergoing HAIC with 5-fluorouracil and cisplatin (HAIC-maintain group, n = 151) or sorafenib (Sorafenib-maintain group, n = 37) after LD-CCRT were consecutively enrolled. The study endpoints were overall survival (OS), progression-free survival (PFS), and treatment response rates.The median OS among HAIC-maintain and Sorafenib-maintain groups were 15.9 and 24.3 months (p = 0.287), whereas the median PFS were 8.1 and 9.1 months (p = 0.651), respectively. During the planned treatments, the radiological objective response rate (54.3% vs. 64.9%; p = 0.246), and conversion rate to surgical resection or liver transplantation after successful down-staging (15.9% vs. 18.9%; p = 0.657) were comparable between the HAIC-maintain and Sorafenib-maintain groups. Similar results were found after the inverse probability of treatment weighting and propensity score-matching analyses. Regarding treatment-related adverse events, the HAIC-maintain group showed worse profiles in terms of leukopenia (all grades [p = 0.001] and grades 3 or 4 [p = 0.041]) and hypoalbuminemia (p = 0.001) than the Sorafenib-maintain group.The overall clinical efficacies between the sequential treatment of HAIC vs. sorafenib after LD-CCRT were comparable for locally advanced HCC.

In advanced technology nodes, correctly choosing among available back-end-of-line (BEOL) stack options is important to meet stringent design quality of results requirements. However, it is nontrivial to evaluate BEOL stack options since the routing outcomes highly depend on the input design (e.g., netlist, placement, etc.). In this paper, we propose a systematic framework to measure routing capacity of a BEOL stack as well as inherent capability of routers. Based on our experimental results, we observe consistent results across mesh-like placement and placements from various placers. Also, our proposed framework enables new insights into important questions regarding BEOL stack options. Using our framework, we further study the relation between the routing hotspot size and routing failure empirically. Lastly, we present an analytical study based on exponentiation of a Markov transition matrix about the impact of design size on routing failure.

Self-aligned multiple patterning, due to its low overlay error, has emerged as the leading option for 1-D gridded back-end-of-line (BEOL) in sub-14-nm nodes. To form actual routing patterns from a uniform “sea of wires,” cut masks are needed for line-end cutting or realization of space between routing segments. The line-end cutting results in nonfunctional (i.e., dummy fill) patterns that change wire capacitance, and hence design timing and power. Therefore, to remove such dummy fill patterns, extra 2-D block masks are used. However, 2-D block masks cannot remove arbitrary dummy fill patterns, due to design rule constraints on the block mask shapes. In this paper, we address the timing-aware optimization of 2-D block mask layouts under various sets of mask rules that are derived from mask patterning technology options (e.g., 193i and 193d) for foundry 7-/5-nm (N7/N5) BEOL. Our central contribution is a mixed integer linear programming (MILP) optimization that minimizes timing impact due to dummy metal segments while satisfying block mask rules and metal density constraints. We also propose a distributed optimization flow to improve the scalability. With our optimizer, we recover up to 84% of the worst negative slack impact from dummy segments, with up to 64% dummy removal rate. We further extend our MILP to a co-optimization of cut and block masks. This paper gives new insights into fundamental limits of benefit from emerging cut and block mask technology options.

Assembling circuits on breadboards using reference designs is a common activity among makers. While tools like Fritzing offer a simplified visualization of how components and wires are connected, such pictorial depictions of circuits are rare in formal educational materials and the vast bulk of online technical documentation. Electronic schematics are more common but are perceived as challenging and confusing by novice makers. To improve access to schematics, we propose SchemaBoard, a system for assisting makers in assembling and inspecting circuits on breadboards from schematic source materials. SchemaBoard uses an LED matrix integrated underneath a working breadboard to visualize via light patterns where and how components should be placed, or to highlight elements of circuit topology such as electrical nets and connected pins. This paper presents a formative study with 16 makers, the SchemaBoard system, and a summative evaluation with an additional 16 users. Results indicate that SchemaBoard is effective in reducing both the time and the number of errors associated with building a circuit based on a reference schematic, and for inspecting the circuit for correctness after its assembly.

Significant knowledge about the pathophysiology of Alzheimer’s disease (AD) has been gained in the last century; however, the understanding of its causes of onset remains limited. Late-onset AD is observed in about 95% of patients, and APOE4-encoding apolipoprotein E4 (ApoE4) is strongly associated with these cases. As an apolipoprotein, the function of ApoE in brain cholesterol transport has been extensively studied and widely appreciated. Development of new technologies such as human-induced pluripotent stem cells (hiPSCs) and CRISPR-Cas9 genome editing tools have enabled us to develop human brain model systems in vitro and readily manipulate genomic information. In the context of these advances, recent studies provide strong evidence that abnormal cholesterol metabolism by ApoE4 could be linked to AD-associated pathology. In this review, we discuss novel discoveries in brain cholesterol dysregulation by ApoE4. We further elaborate cell type-specific roles in cholesterol regulation of four major brain cell types, neurons, astrocytes, microglia, and oligodendrocytes, and how its dysregulation can be linked to AD pathology.

This work presents the catalysts of Pt-Bi shells on Au nanoparticle cores and Pt overlayers on the Pt-Bi shells toward formic acid oxidation (FAO). Pt and Bi were co-deposited on Au nanoparticles (Au NP) via the irreversible adsorption method using a mixed precursor solution of Pt and Bi ions, and the amount of the co-deposits was controlled with the repetition of the deposition cycle. Rinsing of the co-adsorbed ionic layers of Pt and Bi with a H2SO4 solution selectively removed the Bi ions to leave Pt-rich and Bi-lean (&lt, 0.4 atomic %) co-deposits on Au NP (Pt-Bi/Au NP), conceptually similar to de-alloying. Additional Pt was deposited over Pt-Bi/Au NPs (Pt/Pt-Bi/Au NPs) to manipulate further the physicochemical properties of Pt-Bi/Au NPs. Transmission electron microscopy revealed the core–shell structures of Pt-Bi/Au NPs and Pt/Pt-Bi/Au NPs, whose shell thickness ranged from roughly four to six atomic layers. Moreover, the low crystallinity of the Pt-containing shells was confirmed with X-ray diffraction. Electrochemical studies showed that the surfaces of Pt-Bi/Au NPs were characterized by low hydrogen adsorption abilities, which increased after the deposition of additional Pt. Durability tests were carried out with 1000 voltammetric cycles between −0.26 and 0.4 V (versus Ag/AgCl) in a solution of 1.0 M HCOOH + 0.1 M H2SO4. The initial averaged FAO performance on Pt-Bi/Au NPs and Pt/Pt-Bi/Au NPs (0.11 ± 0.01 A/mg, normalized to the catalyst weight) was higher than that of a commercial Pt nanoparticle catalyst (Pt NP, 0.023 A/mg) by a factor of ~5, mainly due to enhancement of dehydrogenation and suppression of dehydration. The catalytic activity of Pt/Pt-Bi/Au NP (0.04 ± 0.01 A/mg) in the 1000th cycle was greater than that of Pt-Bi/Au NP (0.026 ± 0.003 A/mg) and that of Pt NP (0.006 A/mg). The reason for the higher durability was suggested to be the low mobility of surface Pt atoms on the investigated catalysts.

One of the challenges of using nanoparticles as catalysts is the presence of reaction-disturbing stabilizers that surround the nanoparticle surface. In this report, we demonstrate a method to synthesize stabilizer-free bismuth oxychloride (BiOCl) nanoparticles to increase photocatalytic activity. This synthesis method is remarkably simple, involving only BiCl3 and deionized water. After heating an aqueous solution containing BiCl3, plate-shaped BiOCl nanoparticles were formed. The stabilizer-free BiOCl nanoplates exhibited higher photocatalytic activities compared to polyvinylpyrrolidone- and polyethyleneimine-stabilized nanoplates for the degradation of methylene blue.

The purpose of this study was to investigate the effect of driving career and secondary cognitive task on dual-tasking performances and visual search behavior. Twenty male participants were grouped in the following two groups: the experienced group and the novice group. All participants were asked to drive at a speed of 120 km/h while keeping to a lane on the highway and engaging with the following three levels of secondary cognitive task: no cognitive task, easy level, and hard level. The results showed significantly lower correct response rates in the dual task condition (driving + cognitive task) than in the driving only task condition. Novice drivers showed greater decrements in cognitive task performance, particularly in the dual task condition, as compared to the experienced drivers. The total fixation duration decreased as the level of the secondary task increased in difficulty. Experienced drivers showed significantly longer fixation duration on the far-area of the road, and also on specific areas, whereas novice drivers fixated longer on the near-area of the road. In conclusion, we suggest that the importance of perceptual skills in driving should be emphasized and effective training methods need to be applied, especially among high-risk drivers.

Pulsed latches, latches driven by a brief clock pulse, offer the same convenience of timing verification and optimization as flip-flop-based circuits, while retaining the advantages of latches over flip-flops. But a pulsed latch that uses a single pulse width has a lower bound on its clock period, limiting its capacity to deal with higher frequencies or operate at lower Vdd. The limitation still exists even when clock skew scheduling is employed, since the amount of skew that can be assigned and realized is practically limited due to process variation. For the first time, we formulate the problem of allocating pulse widths, out of a small discrete number of predefined widths, and scheduling clock skews, within a predefined upper bound on skew, for optimizing pulsed latch-based sequential circuits. We then present an algorithm called PWCS_Optimize (pulse width allocation and clock skew scheduling, PWCS) to solve the problem. The allocated skews are realized through synthesis of local clock trees between pulse generators and latches, and a global clock tree between a clock source and pulse generators. Experiments with 65-nm technology demonstrate that combining a small number of different pulse widths with clock skews of up to 10% of the clock period yield the minimum achievable clock period for many benchmark circuits. The results have an average figure of merit of 0.86, where 1.0 indicates a minimum clock period, and the average reduction in area by 11%. The design flow including PWCS_Optimize, placement and routing, and synthesis of local and global clock trees is presented and assessed with example circuits.