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This document contains supplemental figures 1-7 and detailed supplemental methods

Supplemental tables 1-10.

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC.Significance:With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, nontransformed livers that fat induces glucose metabolism similar to an oncogenic transformation.

In this retrospective cohort study, we evaluated the efficacy of baricitinib in the treatment of coronavirus disease 2019 (COVID-19). Among 404 adult patients with COVID-19 who were admitted to our hospital between October 23, 2020, and July 31, 2021, 229 patients with respiratory failure were included. Among these, 41 patients in the baricitinib group and 41 patients in the control group were selected by propensity score matching to adjust for background factors. We compared the survival rates of the two groups at 30 and 60 days after admission. The 30-day survival rate was significantly higher in the baricitinib group than in the control group. However, there was no significant difference in 60-day survival in the two groups. Baricitinib may improve the early prognosis of patients with respiratory failure associated with COVID-19. However, efforts should be made to improve the long-term prognosis.

Purpose Docetaxel plus ramucirumab (DTX + RAM) therapy is a standard treatment for previously treated lung cancer, but many adverse events has been reported. Therefore, this retrospective study was conducted to examine if the side effects of DTX + RAM therapy can be minimized by the combined use of oral dexamethasone and to assess the therapeutic effect of DTX + RAM in patients with recurrent lung cancer. Methods Forty patients with relapsed non-small cell lung cancer who underwent DTX + RAM therapy were divided into two groups based on the concomitant use of oral dexamethasone and compared the therapeutic effects and toxicities of the two groups. Results The objective response and tumor shrinkage rates were significantly better in the dexamethasone group (p = 0.0203 and 0.0238, respectively). The median progression-free survival (PFS) was 5.20 months vs. 2.87 months (p = 0.064). On the other hand, the median overall survival (OS) was significantly better in the dexamethasone group (15.17 months vs. 7.37 months, p = 0.0317). Febrile neutropenia was more common in the dexamethasone group, but other side effects were not significantly different between the groups. The frequency of fluid retention within six months of the start of treatment was 10.0% vs. 42.5%, and the fluid retention rate was significantly higher in the non-dexamethasone group (p = 0.039). Conclusion Concomitant use of oral dexamethasone during DTX + RAM therapy did not reduce the side effects, but may facilitate the long-term continuation of treatment and contribute to OS prolongation.

We report a case of false-positive results for SARS-CoV-2-specific antigen. A patient initially had positive results on immunochromatographic SARS-CoV-2-specific antigen test, followed by negative results on RT-PCR assay of saliva and SARS-CoV-2-specific antibody test. Nasopharyngeal swab reexamination using immunochromatographic tests showed weakly positive results, warranting confirmation with high-specificity tests.

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC. Significance: With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, nontransformed livers that fat induces glucose metabolism similar to an oncogenic transformation.

Background Animals living in well-lit environments utilize optical stimuli for detecting visual information, regulating the homeostatic pacemaker, and controlling patterns of body pigmentation. In contrast, many subterranean animal species without optical stimuli have evolved regressed binocular eyes and body pigmentation. Interestingly, some fossorial and cave-dwelling animals with regressed eyes still respond to light. These light-dependent responses may be simply evolutionary residuals or they may be adaptive, where negative phototaxis provides avoidance of predator-rich surface environments. However, the relationship between these non-ocular light responses and the underlying light-sensing Opsin proteins has not been fully elucidated. Methods To highlight the potential functions of opsins in a blind subterranean animal, we used the Mexican cave tetra to investigate opsin gene expression in the eyes and several brain regions of both surface and cave-dwelling adults. We performed database surveys, expression analyses by quantitative reverse transcription PCR (RT-qPCR), and light-dependent locomotor activity analysis using pinealectomized fish, one of the high-opsin expressing organs of cavefish. Results Based on conservative criteria, we identified 33 opsin genes in the cavefish genome. Surveys of available RNAseq data found 26 of these expressed in the surface fish eye as compared to 24 expressed in cavefish extraocular tissues, 20 of which were expressed in the brain. RT-qPCR of 26 opsins in surface and cavefish eye and brain tissues showed the highest opsin-expressing tissue in cavefish was the pineal organ, which expressed exo-rhodopsin at 72.7% of the expression levels in surface fish pineal. However, a pinealectomy resulted in no change to the light-dependent locomotor activity in juvenile cavefish and surface fish. Therefore, we conclude that, after 20,000 or more years of evolution in darkness, cavefish light-dependent basal activity is regulated by a non-pineal extraocular organ.

High-silica CHA-type zeolite membranes (HS-CHA membranes) have attracted considerable attention as zeolite membranes with high permeability, separation performance, and stability. However, long hydrothermal reaction times are required to form HS-CHA membranes. Therefore, in this study we investigated more rapid preparation methods to produce high performance HS-CHA membranes for practical applications. In our preparation process, FAU-type zeolite and N,N,N-trimethtyl-1-adamantammonium hydroxide were used as a raw material and structure-directing agent, respectively, through the secondary growth of seed crystals. As a result, the HS-CHA membranes could be prepared in a 5-h hydrothermal reaction. The permeation properties of the membranes were determined for pervaporation for either ethanol (EtOH), 2-propanol (IPA), or acetic acid (AcOH) solution containing water at 348 K. The permeation flux and separation factor of 80 wt% IPA solution with the use of the HS-CHA zeolite membrane with a Si/Al ratio of 11 were 20 kg m−2 h−1 and 1128, respectively. Furthermore, the gas separation performances of the HS-CHA membranes for binary mixtures of CO2 and CH4 were evaluated. For an equimolar mixture of the gases at 313 K, the CO2 permeance and the selectivity were 1.5 × 10−6 mol m−2 s−1 Pa−1 and 115, respectively.

Background Animals living in well-lit environments utilize optical stimuli for detecting visual information, regulating the homeostatic pacemaker, and controlling patterns of body pigmentation. In contrast, many subterranean animal species without optical stimuli have evolved regressed binocular eyes and body pigmentation. Interestingly, some fossorial and cave-dwelling animals with regressed eyes still respond to light. These light-dependent responses may be simply evolutionary residuals or they may be adaptive, where negative phototaxis provides avoidance of predator-rich surface environments. However, the relationship between these non-ocular light responses and the underlying light-sensing Opsin proteins has not been fully elucidated. Methods To highlight the potential functions of opsins in a blind subterranean animal, we used the Mexican cave tetra to investigate opsin gene expression in the eyes and several brain regions of both surface and cave-dwelling adults. We performed database surveys, expression analyses by quantitative reverse transcription PCR (RT-qPCR), and light-dependent locomotor activity analysis using pinealectomized fish, one of the high-opsin expressing organs of cavefish. Results Based on conservative criteria, we identified 33 opsin genes in the cavefish genome. Surveys of available RNAseq data found 26 of these expressed in the surface fish eye as compared to 24 expressed in cavefish extraocular tissues, 20 of which were expressed in the brain. RT-qPCR of 26 opsins in surface and cavefish eye and brain tissues showed the highest opsin-expressing tissue in cavefish was the pineal organ, which expressed exo-rhodopsin at 72.7% of the expression levels in surface fish pineal. However, a pinealectomy resulted in no change to the light-dependent locomotor activity in juvenile cavefish and surface fish. Therefore, we conclude that, after 20,000 or more years of evolution in darkness, cavefish light-dependent basal activity is regulated by a non-pineal extraocular organ.

Excessive increase in blood glucose level after eating increases the risk of macroangiopathy, and a method for not increasing the postprandial blood glucose level is desired. However, a logical design method of the dietary ingestion pattern controlling the postprandial blood glucose level has not yet been established. We constructed a mathematical model of blood glucose control by oral glucose ingestion in three healthy human subjects, and predicted that intermittent ingestion 30 min apart was the optimal glucose ingestion patterns that minimized the peak value of blood glucose level. We confirmed with subjects that this intermittent pattern consistently decreased the peak value of blood glucose level. We also predicted insulin minimization pattern, and found that the intermittent ingestion 30 min apart was optimal, which is similar to that of glucose minimization pattern. Taken together, these results suggest that the glucose minimization is achieved by suppressing the peak value of insulin concentration, rather than by enhancing insulin concentration. This approach could be applied to design optimal dietary ingestion patterns., The key points of this study are three-fold: The first point is the physiological impact. Intuitively, an ingestion pattern that minimizes the maximum blood glucose level is expected to be a slow, continuous ingestion. We found that the optimal minimization pattern was an intermittent pattern with 30 min intervals. The second point is the methodology. We constructed the mathematical model as a forward problem, and in turn, predicted input pattern by control the output pattern of interest as an inverse problem. The third point is the experiment design used to generate the mathematical model; dense time course data for six ingestion patterns combining of 3 doses of glucose level and 2 durations of ingestion.

Introduction We investigated relationships between therapeutic outcomes of patients with emphysematous pyelonephritis (EPN) and changes in the Sequential Organ Failure Assessment (SOFA) score. Materials and methods We retrospectively evaluated EPN patients treated in our hospitals using the SOFA score incorporated in the Sepsis-3 updated in 2016. Results Seventeen typical EPN patients were included in this study, and were treated with medical management with no drainage (n = 3), retrograde stenting (n = 10), or percutaneous drainage (n = 3). One patient without drainage died of sepsis, yielding an overall mortality rate of 5.9%. Twelve patients recovered without increase in the SOFA score during hospitalization. However, the SOFA score deteriorated in the other patients from admission, with the initial scores not significantly different from those of the 12 cases. The changes in the SOFA score were significantly affected by the selected approaches of drainage (100% patients for no drainage, 22% for stenting, and 0% for percutaneous drainage, p = 0.029), but not by other clinical data. Conclusion Most EPN patients can currently be conservatively managed successfully. However, it should be noted that less-invasive management could cause deterioration in SOFA after admission, yielding a risk of septic mortality.

A novel millimeter-wave packaging structure was developed in which a micromachined low-loss planar component and flip-chip devices were integrated on a silicon substrate. A low-loss planar filter was achieved on a 7-mm-square silicon substrate employing an inverted microstrip line and a unique resonator. High attenuation in the stopband was also obtained by introducing a pole control technique. Fabrication of a compact K-band receiver front-end incorporating a built-in filter was realized using multilayered benzocyclobutene (BCB) and flip-chip bonding techniques. Furthermore, we propose an alternative BCB suspended structure and demonstrate a planar antenna for Ka-band applications. These technologies bring to reality high-performance compact packaged systems in millimeter-wave region applications.

Recently, Ultra Wideband (UWB) has become attractive as an ultra high-speed transmission technique in WPAN. Impulse Radio (IR) UWB promises to bring a low power consumption and low cost. Effective mapping methods for a high-order IR modulation have been not considered yet, although a high-order IR modulation should be employed to a ultra high-speed wireless link above 1 Giga-bit per second (Gbps). In this paper, a novel Hamming distance enlarging pulse mapping method is proposed to IR UWB systems. It is presented by using an exemplary modulation scheme and its mapping table that the proposed mapping method can achieve a maximum Hamming distance between all neighboring pulses. A larger Hamming distance can increase the correction ability of forward error codes and improve the system BER performance. The effectiveness of proposed pulse mapping method to the conventional Gray mapping method was also demonstrated in a computer simulation.

This paper presents a performance evaluation in terms of bit error rate (BER) of a 26 GHz-band ultra-wideband (UWB) communication system through measurement-based simulation. We measured real channel responses in an office to obtain responses for use in simulations. The simulation results demonstrate that the 26-GHz-band UWB system can achieve high-speed data transmission of 500 Mbps or more, in and indoor office by using a directional antenna.

We presents the results from ultra wideband propagation channel measurements in an office environment at the 26 GHz band. To evaluate the differences in a multipath environment by antenna radiation pattern, two directional types of receiver antenna were used for channel measurements. A threshold level was used to remove noise components from the measurement data and was defined as the median value of the received power before the direct path arrived + 10 dB. The delay spread was lower in the main beam area, and this lower value had a greater reach when a directional antenna with high antenna gain was used as compared to an omni-directional antenna. The influence from the multipath environment can be reduced by using a directional antenna as compared to an omni-directional antenna.

A novel three-dimensional K-band receiver front-end IC was developed in which a micromachined low-loss filter and flip-chip devices ware integrated on a silicon substrate. An inverted microstrip line and a new resonator are newly introduced in the filter. Multilayered BCB and flip-chip bonding technologies are also adopted.

A new MM-wave IC, constructed by flip-chip bonded heterojunction transistors and microstrip lines formed on Si substrate, has been proposed and demonstrated. Good agreements between calculated and measured characteristics of this new IC (named MFIC: millimeter-wave flip-chip IC) have been obtained up to 60 GHz band by using micro bump bonding technology. Several MFICs such as HFET/HBT amplifiers have been fabricated to confirm their designed performance. >

Three-dimensional millimeter-wave IC applying multi-layer BCB thin film and silicon micromachining technology was developed. Low loss characteristics were achieved by applying micromachining technology, despite being a quasi-planar structure, and a K-band filter was developed. Moreover, manufacture of the receiver front-end with built-in filter integrated into one package was realized by using flip-chip bonding techniques. Furthermore, we proposed an alternative BCB suspended structure and demonstrated a Ka-band antenna for the proposed package.

A novel millimeter-wave transceiver MCM using multi-layer BCB was proposed. This MCM is based on a glass substrate laminated with three layers of BCB thin film, enabling four-layer 3-D circuitry. We report two different Ka-band MCMs of this structure; namely, a flip-chip assembled 28 GHz transceiver MCM integrating four MMICs of independent functions, and a 38 GHz receiver MCM with built-in four-element slot antenna array and flip-chip assembled MMIC.

2′(or 3′)-0-(2,4,6-trinitrophenyl) adenosine 5′-triphosphate (TNP-ATP), a fluorescent analog of ATP, and the derivatives were used to fluorescently label the myosin head in skinned skeletal muscle fibers. It has been known that a secondary site for TNP-ADP other than the active site exists in myosin S1. We found by fluorescence resonance energy transfer between mant ATP and TNP-AMP that the secondary site for TNP-nucleotides is located within 2 nm of the active site in skeletal muscle fibers. The changes in fluorescence intensity of muscle fibers in 20 μM TNP-AMP when nucleotides are bound may reflect changes of the structure of the active site of myosin heads. It was also shown that actin affected the extent of the fluorescence changes induced by ATP binding to the active site. Both ATP and caged ATP affected the fluorescence intensity, thus caged ATP interacts with the active site. When ATP was released from caged ATP by pulse photolysis in muscle fibers in TNP-AMP showed a transient increase in fluorescence intensity, and still greater fluorescence signal can be detected when the fiber actively contracted when Ca2+ was present.