Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

Exploring the effects of two-segment loop tunnels on termite food transport efficiency: a simulation study.

This study explores the food transport efficiency (E) in a termite tunnel consisting of a main tunnel and a 2-segment loop tunnel through a model simulation. Simulated termites navigate between the main and loop tunnels through branching nodes (a, b, c, d) with associated probabilities (P1, P2, P3, P4). The loop tunnel locations (δ) are considered: near the nest (δ = 1), at the center of the main tunnel (δ = 2), and close to the food site (δ = 3). The results reveal that for δ = 1, paths such as a → d → b → c and c → d → b → a exhibited high E values. Conversely, for δ = 2, P3 and P4 demonstrate elevated E values ranging from 0.4 to 0.6. For δ = 3, paths like c → d or c → b display high E values, emphasizing the significance of in-loop separation tunnels (characterized by P3 and P4) in alleviating traffic congestion. Partial rank correlation validates that P1 and P2 minimally influence E, while P3 and P4 significantly negatively impact E, regardless of δ. However, for δ = 2, the influence of P3 and P4 is notably reduced due to the positional symmetry of the loop tunnel. In the discussion, we address model limitations and propose strategies to overcome them. Additionally, we outline potential experimental validations to ensure a comprehensive understanding of the dynamics governing termite food transport within tunnels.

Synthesis of dithioacetals via gold-catalysed hydrothiolation of vinyl sulfides.

The synthesis of unsymmetrical dithioacetals based on gold catalysis is described. Although many approaches to the preparation of symmetrical dithioacetals have been developed, the methods to access unsymmetrical ones remain limited. In this regard, we report a mild synthetic method with a broad substrate scope. Screening of various gold catalysts identified a catalyst, which allows the hydrothiolation of both activated and unactivated vinyl sulfides with high efficiency. Moreover, the reaction displays broad compatibility for both aryl and aliphatic thiols.

Effects of the surface irregularity of termite tunnels on food transport efficiency: a simulation study.

Termites are believed to have evolved in a way that optimizes their foraging efficiency, which involves both searching for food and transporting it efficiently. Although the search efficiency has been well-studied through tunnel pattern analysis, transport efficiency has received limited attention due to the challenges of directly observing behavior that is highly influenced by environmental conditions. In this study, we introduce an individual-based model to simulate transport behavior and examine transport efficiency (E) by considering the tunnel surface irregularities and curvature, which are critical environmental factors. The model is characterized by four control variables: tunnel curvature (k1), termite stopping time at irregularity sites (k2), irregularity distribution (k3), and irregularity density (k4). The simulation results indicate that as k1 increases, E decreases, while k3 has little impact on E. The impact of k4 on E is decisive; when k4 ≤ 6, an increase in k4 results in increased traffic jam frequency and a faster reduction in E. However, when k4 > 6, the jamming frequency is not significantly affected, reducing the decrease in E. k2 strongly contributes to reducing E without significantly affecting the frequency. In the discussion section, we explore potential mechanisms that termites use to maintain transport efficiency in heterogeneous soils, and discuss how to improve the model to better reflect real-termite systems.

Catalyst-free electrosynthesis of benzothiophenes from 2-alkenylaryl disulfides.

The synthesis of benzothiophenes through electrosynthesis under oxidant- and metal-free conditions has been discovered. Electrolysis of symmetrical 2-alkenylaryl disulfides using an undivided cell leads to the formation of the corresponding benzothiophenes in good to moderate yields with good functional group tolerance. The usefulness of this methodology was further investigated with a scale-up experiment, which delivered a similar result to that of the small scale reaction. Several mechanistic investigations including DFT calculations were carried out to elucidate the reaction mechanism.

Novel Features for Binary Time Series Based on Branch Length Similarity Entropy.

Branch length similarity (BLS) entropy is defined in a network consisting of a single node and branches. In this study, we mapped the binary time-series signal to the circumference of the time circle so that the BLS entropy can be calculated for the binary time-series. We obtained the BLS entropy values for "1" signals on the time circle. The set of values are the BLS entropy profile. We selected the local maximum (minimum) point, slope, and inflection point of the entropy profile as the characteristic features of the binary time-series and investigated and explored their significance. The local maximum (minimum) point indicates the time at which the rate of change in the signal density becomes zero. The slope and inflection points correspond to the degree of change in the signal density and the time at which the signal density changes occur, respectively. Moreover, we show that the characteristic features can be widely used in binary time-series analysis by characterizing the movement trajectory of Caenorhabditis elegans. We also mention the problems that need to be explored mathematically in relation to the features and propose candidates for additional features based on the BLS entropy profile.

A New Measure to Characterize the Degree of Self-Similarity of a Shape and Its Applicability.

We propose a new measure (Γ) to quantify the degree of self-similarity of a shape using branch length similarity (BLS) entropy which is defined on a simple network consisting of a single node and its branches. To investigate the properties of this measure, we computed the Γ values for 70 object groups (20 shapes in each group) in the MPEG-7 shape database and performed grouping on the values. With relatively high Γ values, identical groups had visually similar shapes. On the other hand, the identical groups with low Γ values had visually different shapes. However, the aspect of topological similarity of the shapes also warrants consideration. The shapes of statistically different groups exhibited significant visual difference from each other. Also, in order to show that the Γ can have a wide variety of applicability when properly used with other variables, we showed that the finger gestures in the (Γ, Z) space are successfully classified. Here, the Z means a correlation coefficient value between entropy profiles for gesture shapes. As shown in the applications, Γ has a strong advantage over conventional geometric measures in that it captures the geometrical and topological properties of a shape together. If we could define the BLS entropy for color, Γ could be used to characterize images expressed in RGB. We briefly discussed the problems to be solved before the applicability of Γ can be expanded to various fields.

Electrosynthesis of Dihydropyrano[4,3-b]indoles Based on a Double Oxidative [3+3] Cycloaddition.

Oxidative [3+3] cycloadditions offer an efficient route for six-membered-ring formation. This approach has been realized based on an electrochemical oxidative coupling of indoles/enamines with active methylene compounds followed by tandem 6π-electrocyclization leading to the synthesis of dihydropyrano[4,3-b]indoles and 2,3-dihydrofurans. The radical-radical cross-coupling of the radical species generated by anodic oxidation combined with the cathodic generation of the base from O2 allows for mild reaction conditions for the synthesis of structurally complex heterocycles.

Second shot arterial phase to overcome degraded hepatic arterial phase in liver MR imaging.

OBJECTIVES: Second shot arterial phase (SSAP) imaging is an additional arterial phase image obtained by re-injecting a small amount of contrast medium after routine dynamic imaging in gadoxetic acid-enhanced liver MRI. We aimed to evaluate the feasibility and additional value of a SSAP image in gadoxetic acid-enhanced liver MRI. METHODS: One hundred seventy-two patients who underwent SSAP imaging after re-injection of 4 mL of contrast material after routine dynamic imaging (original) in gadoxetic acid-enhanced liver MRIs were included. Motion artifacts on arterial phase (AP) images were rated using a 5-point scale and were compared between the original AP images and SSAP images. We evaluated visual detection rates of arterial hypervascularity on the original AP and SSAP images and their subtraction images in patients with hypervascular hepatocellular carcinoma (HCC). RESULTS: The motion artifact of the SSAP images was significantly lower than that of the original AP images (mean score, 1.76 vs 2.06; p < 0.001). In particular, motion artifacts reduced significantly in the SSAP images of patients with substantial motion artifacts in their original AP images (2.28 vs 3.28; p < 0.001). Among the 30 HCC lesions showing hypervascularity on original AP images, only four (4/30, 13.3%) appeared hyperintense on SSAP images. However, subtraction images of SSAP clearly demonstrated arterial hypervascularity in all HCCs. CONCLUSION: SSAP images showed significantly fewer motion artifacts than the original AP images. Subtraction images of SSAP maintained the detectability of arterial hypervascularity, although SSAP images showed poor visual detection of arterial hypervascularity of HCC. KEY POINTS: • Arterial phase images obtained after a second injection of a small amount of contrast medium (second shot arterial phase [SSAP]) improved motion artifacts compared to the original AP images. • The motion artifacts improved significantly in the SSAP images of patients with substantial motion artifacts in their original AP images. • Subtraction images of SSAP demonstrated the arterial hypervascularity characteristic of HCC at a level comparable to that of the original AP image.

Newly Categorized Seromucinous Tumor of the Ovary: Magnetic Resonance Imaging Findings.

OBJECTIVE: The aim of this study was to describe magnetic resonance imaging findings of newly categorized ovarian seromucinous tumors. METHODS: We retrospectively reviewed the images of 29 patients with seromucinous tumor for the following factors: size, configuration, signal intensity (SI), and accompanying ovarian endometriosis. RESULTS: Thirty-two tumors (17 benign, 7 borderline, 8 carcinoma) were found on computed tomography or magnetic resonance imaging. Their mean size was 11.4 cm. Benign tumors appeared as unilocular or multilocular cystic masses. Borderline tumors and carcinomas appeared as complex cystic-solid masses. T2-weighted SI of the solid portion was hyperintense in borderline tumors and intermediate in carcinomas. Endometriosis was present in 18 tumors, and hemorrhage (on images) in 20. CONCLUSIONS: The imaging features of seromucinous tumors varied by tumor type. More than half of tumors were accompanied by endometriosis. High T2-weighted SI of the solid portion could be a specific feature of borderline tumors. It is hard to differentiate seromucinous carcinomas from other endometriosis-related carcinomas.

Desmoid-type fibromatosis mimicking cystic retroperitoneal mass: case report and literature review.

BACKGROUND: Retroperitoneal desmoid-type fibromatosis (DF) is an uncommon mesenchymal neoplasm presenting as a firm mass with locally aggressive features. It usually manifests as a well-circumscribed or ill-defined, solid mass on cross-sectional imaging. Cystic changes of DF have been described in the literature in association with prolonged medical treatment or abscess formation. However, spontaneous cystic change is rarely reported. CASE PRESENTATION: Here we report the case of a 46-year-old patient with a DF mimicked a large cystic tumor in the retroperitoneum. Ultrasonography and computed tomography were performed in order to search for localizations and characteristics of the cystic tumor. Radiological findings showed an oval cystic mass with a relatively thick wall, measuring 18.3 × 12.3 × 21.5 cm in the left upper abdomen. Laparoscopic spleen-preserving distal pancreatectomy was performed and histopathological examination by immunohistochemical study enabled us to diagnose a DF invading the pancreatic parenchyma. The patient remained asymptomatic during an 8-month follow up period. CONCLUSIONS: We report an extremely rare case of retroperitoneal DF with spontaneous cystic change. DF can manifest as a mainly cystic mass with a thick wall, as in our case, which makes the correct diagnosis difficult. DF should be included in the preoperative differential diagnosis of a cystic retroperitoneal mass, regardless of its rarity.

Washout appearance in Gd-EOB-DTPA-enhanced MR imaging: A differentiating feature between hepatocellular carcinoma with paradoxical uptake on the hepatobiliary phase and focal nodular hyperplasia-like nodules.

PURPOSE: To identify the most reliable imaging features for differentiating hepatocellular carcinoma with paradoxical uptake on the hepatobiliary phase (HCCpara ) from focal nodular hyperplasia (FNH)-like nodules using Gd-EOB-DTPA-enhanced MRI. MATERIALS AND METHODS: This was a retrospective study. Twenty patients with HCCpara and 21 patients with FNH-like nodules were included. The following MRI features were evaluated using 3.0 Tesla unit by two radiologists: signal intensity (SI) on T1-, T2-, and diffusion-weighted imaging (DWI), arterial enhancement pattern, washout appearance on the portal venous phase (PVP) and/or transitional phase (TP), uptake pattern on the hepatobiliary phase (HBP), "T2 scar," "EOB scar," and chemical shift on in- and out-of-phase images. Multivariate logistic regression analysis was performed to assess MRI features for prediction of HCCpara . RESULTS: Compared with FNH-like nodules, HCCpara had significantly more frequent heterogeneous T1 SI (P < 0.0001), T2 hyperintensity (P = 0.032), heterogeneous arterial enhancement (P < 0.0001), washout appearance on the PVP and/or TP (P < 0.0001), heterogeneous uptake on the HBP (P < 0.0001), absence of "EOB scar" (P < 0.0001), and hyperintensity on DWI (P = 0.004). Multivariate logistic regression analysis revealed washout appearance as the only independent imaging feature associated with HCCpara (odds ratio, 7.019; P = 0.042). Washout appearance also showed the best diagnostic performance with a sensitivity of 90% and a specificity of 100%. CONCLUSION: Washout appearance on the PVP and/or TP is the most reliable imaging feature for differentiating HCCpara from FNH-like nodules. LEVEL OF EVIDENCE: 3 J. MAGN. RESON. IMAGING 2017;45:1599-1608.

Strategic Design of 2,2'-Bipyridine Derivatives to Modulate Metal-Amyloid-ß Aggregation.

The complexity of Alzheimer's disease (AD) stems from the inter-relation of multiple pathological factors upon initiation and progression of the disease. To identify the involvement of metal-bound amyloid-ß (metal-Aß) aggregation in AD pathology, among the pathogenic features found in the AD-affected brain, small molecules as chemical tools capable of controlling metal-Aß aggregation were developed. Herein, we report a new class of 2,2'-bipyridine (bpy) derivatives (1-4) rationally designed to be chemical modulators toward metal-Aß aggregation over metal-free Aß analogue. The bpy derivatives were constructed through a rational design strategy employing straightforward structural variations onto the backbone of a metal chelator, bpy: (i) incorporation of an Aß interacting moiety; (ii) introduction of a methyl group at different positions. The newly prepared bpy derivatives were observed to bind to metal ions [i.e., Cu(II) and Zn(II)] and interact with metal-Aß over metal-free Aß to varying degrees. Distinguishable from bpy, the bpy derivatives (1-3) were indicated to noticeably modulate the aggregation pathways of Cu(II)-Aß and Zn(II)-Aß over metal-free Aß. Overall, our studies of the bpy derivatives demonstrate that the alteration of metal binding properties as well as the installation of an Aß interacting capability onto a metal chelating framework, devised via the rational structure-based design, were able to achieve evident modulating reactivity against metal-Aß aggregation. Obviating the need for complicated structures, our design approach, presented in this work, could be appropriately utilized for inventing small molecules as chemical tools for studying desired metal-related targets in biological systems.

Low-Tube Voltage Computed Tomography During Hepatic Arterial Phase: The Effect of Body Habitus on Image Quality.

PURPOSE: This study aimed to evaluate the impact of body habitus factors on image quality of low-tube voltage computed tomography (CT) during the hepatic arterial phase. MATERIALS AND METHODS: Ninety-seven patients (66 men, 31 women; age range, 26-78 years) who underwent clinically indicated liver dynamic CT examination were enrolled in the study. Analysis with 80-kVp CT and intermediate tube current (277-337 mA) was performed in the late hepatic arterial phase using a 320-detector row scanner with adaptive iterative dose reduction 3-dimensional reconstruction. Patient body habitus was measured using body weight (BW), body mass index (BMI), lateral width (LW) of the abdomen, and muscle volume (MV) of the abdominal wall. On hepatic arterial phase, the mean image noise and contrast-to-noise ratio (CNR) for the aorta and liver were assessed. The correlations between body habitus factors and image quality parameters were evaluated. RESULTS: In all patients, MV showed the strongest correlation with image noise, followed by BW and LW (r = 0.684, 0.570, and 0.555, respectively). The BMI showed the fourth strongest correlation with image noise among all body habitus factors (r = 0.377). With respect to CNR of the aorta, MV and BW showed the strongest inverse correlation (r = -0.590 and -0.600, respectively), followed by LW and BMI (r = -0.557 and -0.423, respectively). Regarding the CNR of the liver, MV showed the strongest inverse correlation (r = -0.279), although the correlation efficiency was weak compared with other correlations. CONCLUSIONS: Among various body habitus factors, MV showed the strongest association with image noise and CNR in the hepatic arterial phase using 80-kVp CT.

Intravoxel incoherent motion magnetic resonance imaging to predict vesicoureteral reflux in children with urinary tract infection.

OBJECTIVES: To compare the diffusion parameters of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) between the "reflux" and the "non-reflux" kidneys, and to evaluate the feasibility of using IVIM DWI to predict vesicoureteral reflux (VUR) in children with a urinary tract infection (UTI). METHODS: Eighty-three kidneys from 57 pediatric patients with a UTI were classified into "reflux" and "non-reflux" groups according to voiding cystourethrography (VCUG) results. The apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (PF) were measured and compared in the renal pelvis of both groups. Four indices (D*/ADC, PF/ADC, D*/D, and PF/D) were calculated and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: VURs were detected on VCUG in 21 kidneys. PF and D* were significantly higher in the "reflux" group than in the "non-reflux" group. The indices were all significantly higher. The PF/D index showed the best diagnostic performance in predicting VUR in children with UTI (Az = 0.864). CONCLUSION: PF and D* were significantly higher in the "reflux" kidney than in the "non-reflux" kidney. Our new index (PF/D) could prove useful for predicting VUR. KEY POINTS: • IVIM DWI is both radiation-free and contrast media-free. • IVIM DWI index is easily calculated by combining diffusion parameters. • IVIM DWI may help predict VUR in children with UTI. • PF is significantly higher in the "reflux" than the "non-reflux" kidneys. • A new VUR index, PF/D could prove useful for predicting VUR.

Using intravoxel incoherent motion MR imaging to evaluate cortical defects in the first episode of upper urinary tract infections: preliminary results.

PURPOSE: To compare intravoxel incoherent motion diffusion weight imaging IVIM-DWI MRI with DMSA for the evaluation of cortical defect in pediatric upper urinary tract infection (UTI) patients. MATERIALS AND METHODS: Forty-three kidneys of 22 pediatric patients with the first episode of febrile upper UTI were evaluated. DWI using IVIM model was performed with eight b factors. The presence of cortical defect was evaluated on apparent diffusion coefficient (ADC) map. DMSA was used as the standard of reference. ADC, true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (F) in both defect and nondefect area were calculated and compared. RESULTS: Cortical defects were detected in 14 kidneys by IVIM-DWI. The sensitivity, specificity, positive predictive value, and negative predictive value of IVIM-DWI MRI for the detection of defects was 93.3%, 100%, 100%, and 96.5%, respectively. Mean values of ADC, D, D*, and F were 1.12 ± 0.15, 1.05 ± 0.10, 33 ± 17 (× 10(-3) mm(2) /s), and 0.14 ± 0.09 in the defect foci. In normal foci, ADC, D, D*, and F were 1.37 ± 0.09, 1.31 ± 0.10, 43 ± 19 (× 10(-3) mm(2) /s), and 0.12 ± 0.04, respectively. ADC and D were significantly lower in defect group than nondefect group (P < 0.01). CONCLUSION: IVIM-DWI can allow both direct visualization and quantitative measurement of cortical defects.

Intraoperative contrast-enhanced sonographic portography combined with indigo carmine dye injection for anatomic liver resection in hepatocellular carcinoma: a new technique.

We present a method of intraoperative contrast-enhanced sonographic portography combined with indigo carmine dye injection for anatomic liver resection in hepatocellular carcinoma. During surgery, before dye infusion into the feeding portal vein, the targeted portal vein branch was directly punctured, and a microbubble contrast agent was administered under sonographic guidance. Simultaneous enhancement of the resected hepatic parenchyma with a microbubble contrast agent and blue dye improved estimation of the segmental border in the cutting plane and the tumor resection margin during liver surgery.

Metallic anodes for next generation secondary batteries.

Li-air(O2) and Li-S batteries have gained much attention recently and most relevant research has aimed to improve the electrochemical performance of air(O2) or sulfur cathode materials. However, many technical problems associated with the Li metal anode have yet to be overcome. This review mainly focuses on the electrochemical behaviors and technical issues related to metallic Li anode materials as well as other metallic anode materials such as alkali (Na) and alkaline earth (Mg) metals, including Zn and Al when these metal anodes were employed for various types of secondary batteries.

Exploring the role of loop tunnels in enhancing termite food transport efficiency: A simulation approach.

Subterranean termites construct a network of tunnels beneath the ground, comprising a main tunnel and branch tunnels. While termites do not construct tunnels that turn back in a "U" shape, the intersection of main and branch tunnels often forms closed curved structures (a loop). The loop structure can have either a positive or negative effect on the transport efficiency of termites in food transportation. However, little research has been conducted on the impact of loop tunnels on transport efficiency (E) due to the technical difficulties associated with direct observation. In this study, we used an individual-based model to simulate termite behavior during food transportation within a tunnel composed of a main tunnel and a loop tunnel. The model incorporates four control variables: the number of introduced simulated termites (k1), the probability of a simulated termite using a loop tunnel when walking towards a food or nest site (k2 or k3), and the length of the loop tunnel (k4). The simulation results reveal that the E value is high for (k2, k3) = (high, high), (low, low), (high, low), and (low, high) when the length of the loop tunnel is relatively short. However, when the length of the loop tunnel is relatively long, E is high only for (k2, k3) = (high, low) and (low, high). We found that these results are primarily influenced by the frequency of traffic jams. Therefore, termites would benefit from adopting strategies that reduce the occurrence of traffic jams during food transportation. In the Discussion section, we briefly touch on the strategy from an ecological perspective.

The effect of avian eggshell membrane structure on microbial penetration: A simulation study.

Avian eggshells exhibit excellent antimicrobial properties. In this study, we conducted simulation experiments to explore the defense mechanisms of eggshell membranes with regards to their physical features. We developed a mathematical model for the movement of microorganisms and estimated their penetration ratio into eggshell membranes based on several factors, including membrane thickness, microbial size, directional drift, and attachment probability to membrane fibers. These results not only suggest that an eggshell membrane with multiple layers and low porosity indicates high antimicrobial performance, but also imply that the fibrous network structure of the membrane might contribute to effective defense. Our simulation results aligned with experimental findings, specifically in measuring the penetration time of Escherichia coli through the eggshell membrane. We briefly discuss the significance and limitations of this pilot study, as well as the potential for these results, to serve as a foundation for the development of antimicrobial materials.