Total Syntheses of Phorbol and 11 Tigliane Diterpenoids and Their Evaluation as HIV Latency-Reversing Agents.

Tigliane diterpenoids possess exceptionally complex structures comprising common 5/7/6/3-membered ABCD-rings and disparate oxygen functionalities. While tiglianes display a wide range of biological activities, compounds with HIV latency-reversing activity can eliminate viral reservoirs, thereby serving as promising leads for new anti-HIV agents. Herein, we report collective total syntheses of phorbol (13) and 11 tiglianes 14-24 with various acylation patterns and oxidation states, and their evaluation as HIV latency-reversing agents. The syntheses were strategically divided into five stages to increase the structural complexity. First, our previously established sequence enabled the expeditious preparation of ABC-tricycle 9 in 15 steps. Second, hydroxylation of 9 and ring-contractive D-ring formation furnished phorbol (13). Third, site-selective attachment of two acyl groups to 13 produced four phorbol diesters 14-17. Fourth, the oxygen functionalities were regio- and stereoselectively installed to yield five tiglianes 18-22. Fifth, further oxidation to the most densely oxygenated acerifolin A (23) and tigilanol tiglate (24) was realized through organizing a 3D shape of the B-ring. Assessment of the HIV latency-reversing activities of the 12 tiglianes revealed seven tiglianes (14-17 and 22-24) with 20- to 300-fold improved efficacy compared with prostratin (12), a representative latency-reversing agent. Therefore, the robust synthetic routes to a variety of tiglianes with promising activities devised in this study provide opportunities for advancing HIV eradication strategies.

Unified Total Syntheses of Rhamnofolane, Tigliane, and Daphnane Diterpenoids.

Rhamnofolane, tigliane, and daphnane diterpenoids are structurally complex natural products with multiple oxygen functionalities, making them synthetically challenging. While these diterpenoids share a 5/7/6-trans-fused ring system (ABC-ring), the three-carbon substitutions at the C13- and C14-positions on the C-ring and appending oxygen functional groups differ among them, accounting for the disparate biological activities of these natural products. Here, we developed a new, unified strategy for expeditious total syntheses of five representative members of these three families, crotophorbolone (1), langduin A (2), prostratin (3), resiniferatoxin (4), and tinyatoxin (5). Retrosynthetically, 1-5 were simplified into their common ABC-ring 6 by detaching the three-carbon units and the oxygen-appended groups. Intermediate 6 with six stereocenters was assembled from four achiral fragments in 12 steps by integrating three powerful transformations, as follows: (i) asymmetric Diels-Alder reaction to induce formation of the C-ring; (ii) π-allyl Stille coupling reaction to set the trisubstituted E-olefin of the B-ring; and (iii) Eu(fod)3-promoted 7-endo cyclization of the B-ring via the generation of a bridgehead radical. Then 6 was diversified into 1-5 by selective installation of the different functional groups. Attachment of the C14-ß-isopropenyl and isopropyl groups led to 1 and 2, respectively, while oxidative acetoxylation and C13,14-ß-dimethylcyclopropane formation gave rise to 3. Finally, formation of an α-oriented caged orthoester by C13-stereochemical inversion and esterification with two different homovanillic acids delivered 4 and 5 with a C13-ß-isopropenyl group. This unified synthetic route to 1-5 required only 16-20 total steps, demonstrating the exceptional efficiency of the present strategy.

Sequential therapy including regorafenib for unresectable hepatocellular carcinoma: Effect of early relative changes in hepatic functional reserve after regorafenib administration on prognosis.

AIM: Regorafenib is a second-line treatment for unresectable hepatocellular carcinoma after sorafenib-refractory treatment. This study examined the effects of regorafenib administration on hepatic functional reserve and the treatment course after regorafenib discontinuation. METHODS: This retrospective, multicenter study involved 51 patients treated with regorafenib after sorafenib-refractory treatment for u-HCC at seven institutions before March 2021. RESULTS: Fourteen, 13, and 24 patients were classified based on modified albumin-bilirubin (mALBI) grade 1, 2a, and 2b, respectively. The median survival time and progression-free survival were 16.7 and 3.3 months, respectively. Only mALBI grade 2b or 3 was significantly associated with survival rate (hazard ratio, 2.13; 95% confidence interval, 1.01-4.49; p = 0.047). A comparison of median ALBI scores at the initiation of regorafenib (-2.35) with those at 4 weeks (-1.93) revealed a significant relative change (p = 0.0001). After 4 weeks, grade 1 or 2a persisted in 15 patients (Group 1); grade 1 or 2a deteriorated to 2b in 12 patients (Group 2); grade 2b or 3 before regorafenib administration was present in 22 patients (Group 3); and MST was 33.3, 12.8, and 11.3 months in the three groups, respectively (p = 0.05). Patients treated with lenvatinib (LEN) (n = 27, MST = 23.4 months) after regorafenib had a significantly longer survival time from regorafenib initiation than those not treated with LEN (n = 24, 11.8 months; p = 0.043). CONCLUSIONS: Hepatic functional reserve significantly declined after regorafenib administration. During regorafenib treatment, favorable hepatic functional reserve before administration and maintenance of favorable hepatic reserve after administration lead to prolonged prognosis.

Comparison of therapeutic outcomes of sorafenib and lenvatinib as primary treatments for hepatocellular carcinoma with a focus on molecular-targeted agent sequential therapy: A propensity score-matched analysis.

AIM: The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients. METHODS: This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n = 52) or SOR (n = 85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n = 52 for the SOR and LEN cohorts). RESULTS: The median overall survival was 21.8 months for LEN and 20.4 months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], p < 0.01; progression-free survival: 10 months [LEN] vs. 5.1 months [SOR], p < 0.01). No significant intergroup differences were noted in the rate of transition to secondary MTA treatments (SOR: 58.7%; LEN: 48.4%), adverse events (SOR: 86%; LEN: 95%), and maintenance of the Child-Pugh (CP) score during treatment. Compared to non-MTA treatments, secondary MTA treatment achieved a greater improvement in survival (4.3  vs. 2.8 months, p = 0.0047). Multivariate analysis demonstrated that the CP score (p < 0.01) and alpha-fetoprotein level (p < 0.01) were independent prognostic factors. CONCLUSIONS: Both SOR and LEN treatments showed a clinically comparable therapeutic efficacy as the first-line treatments for u-HCC patients in an MTA sequential therapy.

A successful case of deceased donor liver transplantation for a patient with intrahepatic arterioportal fistula.

Intrahepatic arterioportal fistula (IAPF) is a rare cause of portal hypertension that is often difficult to treat with interventional radiology or surgery. Liver transplantation for IAPF is extremely rare. We report a case of bilateral diffuse IAPF with severe portal hypertension requiring deceased donor liver transplantation (DDLT). A 51-year-old woman with no past medical history was admitted to another hospital complaining of abdominal distension and marasmus. A computed tomography scan and digital subtraction angiography indicated a massive pleural effusion, ascites, and a very large IAPF. Several attempts of interventional embolization of the feeding artery failed to ameliorate arterioportal shunt flow. As ruptures of the esophageal varices became more frequent, hepatic encephalopathy worsened. After repeated, uncontrollable attacks of hepatic coma, the patient was referred to our facility for further treatment. Surgical approaches to IAPF other than liver transplantation were challenging because of diffuse collateralization; therefore, we placed the patient on the national waiting list for DDLT. Although her Model for End-Stage Liver Disease score was relatively low, she received a DDLT 2 months after the waiting period. The postoperative course was uneventful, and the patient was discharged 44 days after her transplant. Liver transplantation may be a valid treatment option for uncontrollable IAPF with severe portal hypertension.

Skin-Penetrating Interfaces for Millimeter-Wave Non-Invasive Glucose Concentration Estimation: Numerical Analysis.

Millimeter-wave (MMW) glucose concentration estimation possesses a great advantage of non-invasiveness. The long history of investigation, however, has not yet reached practical applications because of its insufficient accuracy and stability. To solve these problems, this paper proposes two high skin-penetration interfaces, which we name equivalent quarter-wavelength interface and equivalent Brewster's-angle interface. We analyze their scattering characteristics in a frequency range of 60 - 90 GHz. Analysis results show that both the interfaces suppress the body-surface scattering, allowing the MMWs to penetrate through body surface into tissues to extract information on blood-glucose concentration with higher sensitivity, e.g., with 147-times enhancement of phase changes. These interfaces can be an important step toward realizing non-invasive blood glucose concentration estimation.

Robust Symbol Detection Based on Quaternion Neural Networks in Wireless Polarization-Shift-Keying Communications.

Quaternion neural networks (QNNs) form a class of neural networks constructed with quaternion numbers. They are suitable for processing 3-D features with fewer trainable free parameters than real-valued neural networks (RVNNs). This article proposes symbol detection in wireless polarization-shift-keying (PolSK) communications by employing QNNs. We demonstrate that quaternion plays a crucial role in the symbol detection of PolSK signals. Existing artificial-intelligence communication studies mainly focus on RVNN-based symbol detection in digital modulations having constellations in complex plane. However, in PolSK, information symbols are represented as the state of polarization, which can be mapped on the Poincare sphere and thus its symbols have a 3-D data structure. Quaternion algebra offers a unified representation to process 3-D data with rotational invariance and, therefore, it keeps the internal relationship among three components of a PolSK symbol. Hence, we can expect that QNNs learn the distribution of received symbols on the Poincare sphere with higher consistency to detect the transmitted symbols more efficiently than RVNNs. We compare PolSK symbol detection accuracy of two types of QNNs, RVNN, existing methods such as least-square and minimum-mean-square-error channel estimations, as well as detection knowing perfect channel state information (CSI). Simulation results including symbol error rate show that the proposed QNNs outperform the existing estimation methods and that they reach better results with two to three times fewer free parameters than the RVNN. We find that QNN processing will bring practical use of PolSK communications.

Æ©excessA1C index, the sum of yearly excess HbA1c values during the total period of diabetes, may have the potential to predict retinopathy by a linear regression setting regardless of duration in type 1 diabetes: a subgroup analysis of DCCT/EDIC data.

Aims: To find an index of glycemic exposure that predicts retinopathy by a simple regression setting regardless of duration in type 1 diabetes which might be useful for the care of diabetes. Materials and methods: To exclude the possible disturbing effect of metabolic memory, we examined a subgroup of patients with glycohemoglobin A1c (A1C) data for the total period of type 1 diabetes selected from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications data. Three indices-(1) mean value of yearly A1C (mA1C), (2) sum of yearly A1C values (Æ©A1C), and (3) sum of yearly A1C values above 6.5% (Æ©excessA1C)-were assessed as potential candidates. Development of retinopathy was defined by ≥ 3-steps' progression of retinopathy from baseline. Results: The areas under the receiver operating characteristics curves of the indices for development of retinopathy at years 5, 9, and 13 after the onset of diabetes were the same: 0.8481, 0.8762, and 0.8213, respectively, indicating that each index was substantially capable of predicting development of retinopathy at each timepoint. Linear regression analyses showed that each index had significant and substantial linear relations to retinopathy at each timepoint: all P < 0.0001 for slopes; contribution rate R2 = 0.21 (year 5), 0.46 (year 9), and 0.48 (year 13) for each index. But only Æ©excessA1C index appeared to have similar linear relations to retinopathy at all three timepoints (interactions by timepoint: for slopes: P = 0.1393; for intercepts: P = 0.9366). Conclusion: Æ©excessA1C may have the potential to predict retinopathy by just one linear regression setting regardless of duration in type 1 diabetes.

Correction: Æ©excessA1C index, the sum of yearly excess HbA1c values during the total period of diabetes, may have the potential to predict retinopathy by a linear regression setting regardless of duration in type 1 diabetes: a subgroup analysis of DCCT/EDIC data.

[This corrects the article DOI: 10.1007/s13340-023-00654-w.].

Comparison of the Effect of Bromfenac versus Betamethasone Ophthalmic Solutions in Patients with Diabetic Macular Edema.

PURPOSE: To examine the effect of 0.1% bromfenac (BF) ophthalmic solution and 0.1% betamethasone (BM) ophthalmic solution on diabetic macular edema (DME). METHODS: This was a prospective trial. Nineteen patients (mean age of 66.6 ± 10.1 years) with DME and mean retinal thickness within a diameter of 1 mm from the fovea (central subfield thickness: CST) of 250-500 µm were randomized and instilled with BF or BM. CST, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) were measured at 4, 8, and 12 weeks after administration. RESULTS: CST at baseline (p = .128) and that at 4, 8, and 12 weeks of administration was not significantly different between the BF (10 patients) and BM groups (9 patients). In patients with glycated hemoglobin (HbA1c) <8.0%, CST, compared with baseline, was significantly decreased in the BF group (seven patients) at 8 (p = .025) and 12 weeks (p = .043) of administration. When compared with the baseline, no significant changes in BCVA were observed at any point in time in either group. Baseline IOP was comparable between the groups. In the BM group, the values of change in IOP from baseline significantly increased at 8 (p = .025) and 12 weeks (p = .044) of administration, with no significant changes in IOP over the 12 weeks of administration in the BF group. CONCLUSIONS: BF did not affect IOP even after 12 weeks of administration, suggesting its effect in reducing CST in DME with good glycemic control. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN-CTR); UMIN000026201, February 18, 2017; Japan Registry of Clinical Trials; jRCTs031180308, March 15, 2019.

Overlap of Thrombotic Microangiopathy and Mesangial Proliferative Glomerulonephritis Caused by Combination Therapy with Atezolizumab and Bevacizumab.

Vascular endothelial growth factor inhibitors and checkpoint inhibitors are effective treatments for solid tumors. These new classes of anti-cancer agents frequently cause kidney-related side effects. Although their anti-cancer effects may be enhanced when used in combination, the severity of their kidney-related side effects is unknown. We herein report the first case of thrombotic microangiopathy and mesangial proliferative glomerulonephritis caused by combined treatment with atezolizumab and bevacizumab in a 74-year-old man with hepatocellular carcinoma. The combination therapy was discontinued and replaced with intravenous methylprednisolone followed by oral prednisolone. Subsequently, the urinary protein excretion levels declined.

Non-local energy transport in tunneling and plasmonic structures.

Various definitions of the velocity of propagation of the electromagnetic field have been adopted in experimental and theoretical studies of tunneling and plasmonic systems. Tunneling problems are often analyzed by invoking the group delay (or dwell time) velocities. On the other hand, slow light and plasmonic systems are considered by using the wave packet group velocity. This paper discusses various definitions for the velocity of the electromagnetic wave propagation and compares them in applications to the problems of slow light and superluminality in resonant and tunneling structures. Energy propagation is, in general, a nonlocal quantity and depends on the global properties of the system, rather than being simply a local quantity. The energy propagation velocity takes into account the non-local characteristics of the wave propagation and offers a natural generalization for those situations when the group velocity is ill defined or gives unphysical results. It is shown that the group delay velocity, which may be superluminal away from the resonance, becomes equal to the energy velocity at the resonant point.

A novel and comprehensive mouse model of human non-alcoholic steatohepatitis with the full range of dysmetabolic and histological abnormalities induced by gold thioglucose and a high-fat diet.

BACKGROUND: The search for effective treatments of non-alcoholic steatohepatitis (NASH), now the most common chronic liver disease in affluent countries, is hindered by a lack of animal models having the range of anthropometric and pathophysiological features as human NASH. AIMS: To examine if mice treated with gold thioglucose (GTG) - known to induce lesions in the ventromedial hypothalamus, leading to hyperphagia and obesity - and then fed a high-fat diet (HF) had a comprehensive histological and dysmetabolic phenotype resembling human NASH. METHODS: C57BL/6 mice were injected intraperitoneally with GTG and then fed HF for 12 weeks (GTG+HF). The extent of abdominal adiposity was assayed by CT scanning. A glucose tolerance test and an insulin tolerance test were performed to evaluate insulin resistance (IR). Histological, molecular and biochemical analyses were also performed. RESULTS: Gold thioglucose+HF induced dysmetabolism, with hyperphagia, obesity with increased abdominal adiposity, IR and consequent steatohepatitis, with hepatocyte ballooning, Mallory-Denk bodies, perivenular and pericellular fibrosis as seen in adult NASH, paralleled by an increased expression of the profibrogenic factors, transforming growth factor-ß1 and TIMP-1. Plasma adiponectin and the expression of adiponectin receptor 1 and receptor 2 were decreased, while PPAR-γ and FAS were increased in the livers of GTG+HF mice. In addition, GTG+HF mice showed glucose intolerance and severe IR. CONCLUSIONS: Treatment with GTG and HF diet induce, in mice, a comprehensive model of human NASH, with the full range of dysmetabolic and histological abnormalities.

Super paramagnetic iron oxide MRI shows defective Kupffer cell uptake function in non-alcoholic fatty liver disease.

BACKGROUND: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is incompletely understood. Kupffer cells (KCs), phagocytic liver-resident macrophages, provide a protective barrier against egress of endotoxin from the portal to the systemic circulation. It is not known if KC phagocytic function is impaired in NAFLD. Super-paramagnetic iron oxide (SPIO) magnetic resonance imaging is a comparative technology dependent on KC phagocytic function. OBJECTIVE: To evaluate KC uptake function, in patients and experimental animals with NAFLD, using SPIO. METHODS: Abdominal CT and histological examination of liver biopsy specimens were used to estimate the degree of steatosis in patients with NAFLD and controls with chronic hepatitis C. SPIO-MRI was then performed in all patients. Normal rats fed a methionine-choline-deficient diet to induce non-alcoholic steatohepatitis (NASH), the more severe stage of NAFLD, and obese, insulin resistant, Zucker fa/fa rats with steatohepatitis, were also studied with SPIO-MRI and analysed for hepatic uptake of fluorescent microbeads. Immunohistochemical analysis evaluated the numbers of KCs in patients and rat livers. RESULTS: Relative signal enhancement (RSE), inversely proportional to KC function, was higher in patients with NAFLD than in controls and with the degree of steatosis on CT. RSE also positively correlated with the degree of steatosis on histology and was similarly higher in rats with induced severe NAFLD (NASH). On immunohistochemistry, defective phagocytic function was the result of reduced phagocytic uptake and not due to reduced KC numbers in rats or patients with NAFLD. CONCLUSIONS: KC uptake function is significantly impaired in patients with NAFLD and experimental animals with NASH, worsens with the degree of steatosis and is not due to a reduction of KC numbers.

Proposal of higher-order tensor independent component analysis for signal separation in multiple-input multiple-output respiration/heartbeat remote sensing.

This paper proposes higher-order tensor independent component analysis (HOT-ICA). HOT-ICA is a tensor ICA that makes effective use of the relationships among the axes of a separating tensor. We deal with multiple-target signal separation in a multiple-input multiple-output (MIMO) radar system to detect respiration and heartbeat. Numerical physical experiments demonstrate the significance of the HOT-ICA which keeps the tensor structure unchanged to fully utilizes the high-dimensionality of the separation tensor.

Development of a broad band AC power amplifier for real time turbulence feedback control experiment in the Saskatchewan Torus-modified (STOR-M) tokamak.

A gated oscillating power amplifier has been developed for high frequency biasing and real time turbulent feedback experiments in the Saskatchewan Torus-modified tokamak. This oscillator is capable of providing a peak to peak oscillating output voltage of around ±60 V with a current around 30 A within the frequency band 1 kHz-50 kHz without any distortions. The overall output power is amplified by a two-stage metal oxide semiconductor field-effect transistor power op-amp as well as nine identical push-pull amplifiers in the final stages. The power amplifier input signal, collected from the plasma floating potential during the tokamak discharge, is optically isolated from the tokamak vessel ground. The filtered floating potential fluctuations with a band width of 5 kHz-40 kHz were amplified and fed to an electrode inserted into the plasma edge to study the response of the plasma turbulence. We observe that magnetic fluctuations are suppressed due to real time feedback of the floating potential.

Spatially Arranged Sparse Recurrent Neural Networks for Energy Efficient Associative Memory.

The development of hardware neural networks, including neuromorphic hardware, has been accelerated over the past few years. However, it is challenging to operate very large-scale neural networks with low-power hardware devices, partly due to signal transmissions through a massive number of interconnections. Our aim is to deal with the issue of communication cost from an algorithmic viewpoint and study learning algorithms for energy-efficient information processing. Here, we consider two approaches to finding spatially arranged sparse recurrent neural networks with the high cost-performance ratio for associative memory. In the first approach following classical methods, we focus on sparse modular network structures inspired by biological brain networks and examine their storage capacity under an iterative learning rule. We show that incorporating long-range intermodule connections into purely modular networks can enhance the cost-performance ratio. In the second approach, we formulate for the first time an optimization problem where the network sparsity is maximized under the constraints imposed by a pattern embedding condition. We show that there is a tradeoff between the interconnection cost and the computational performance in the optimized networks. We demonstrate that the optimized networks can achieve a better cost-performance ratio compared with those considered in the first approach. We show the effectiveness of the optimization approach mainly using binary patterns and apply it also to gray-scale image restoration. Our results suggest that the presented approaches are useful in seeking more sparse and less costly connectivity of neural networks for the enhancement of energy efficiency in hardware neural networks.

Recent advances in physical reservoir computing: A review.

Reservoir computing is a computational framework suited for temporal/sequential data processing. It is derived from several recurrent neural network models, including echo state networks and liquid state machines. A reservoir computing system consists of a reservoir for mapping inputs into a high-dimensional space and a readout for pattern analysis from the high-dimensional states in the reservoir. The reservoir is fixed and only the readout is trained with a simple method such as linear regression and classification. Thus, the major advantage of reservoir computing compared to other recurrent neural networks is fast learning, resulting in low training cost. Another advantage is that the reservoir without adaptive updating is amenable to hardware implementation using a variety of physical systems, substrates, and devices. In fact, such physical reservoir computing has attracted increasing attention in diverse fields of research. The purpose of this review is to provide an overview of recent advances in physical reservoir computing by classifying them according to the type of the reservoir. We discuss the current issues and perspectives related to physical reservoir computing, in order to further expand its practical applications and develop next-generation machine learning systems.

High-quality frame interpolation in computer generated holographic movies using coherent neural networks with a hybrid learning method.

Computer generated holograms (CGHs) are widely used in optical tweezers, which will be employed in various research fields. We previously proposed an efficient generation method of CGH movies based on frame interpolation using coherent neural networks (CNNs) to reduce the high calculation cost of three-dimensional CGHs. At the same time, however, we also found that the quality observed in the interpolated CGH images needed to be improved even further so that the method could be accepted for general use. We report a successful error reduction in interpolated images by developing a new learning method of CNNs. We reduce the error by combining locally connected correlation learning and steepest descent learning in a sequential manner.

Frequency-multiplexing ability of complex-valued Hebbian learning in logic gates.

Lightwave has attractive characteristics such as spatial parallelism, temporal rapidity in signal processing, and frequency band vastness. In particular, the vast carrier frequency bandwidth promises novel information processing. In this paper, we propose a novel optical logic gate that learns multiple functions at frequencies different from one another, and analyze the frequency-domain multiplexing ability in the learning based on complex-valued Hebbian rule. We evaluate the averaged error function values in the learning process and the error probabilities in the realized logic functions. We investigate optimal learning parameters as well as performance dependence on the number of learning iterations and the number of parallel paths per neuron. Results show a trade-off among the learning parameters such as learning time constant and learning gain. We also find that when we prepare 10 optical path differences and conduct 200 learning iterations, the error probability completely decreases to zero in a three-function multiplexing case. However, at the same time, the error probability is tolerant of the path number. That is, even if the path number is reduced by half, error probability is found almost zero. The results can be useful to determine neural parameters for future optical neural network systems and devices that utilize the vast frequency bandwidth for frequency-domain multiplexing.