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Dissolved organic matter (DOM) plays an important role in the ocean's biological carbon pump by providing an advective/mixing pathway for ∼ 20% of export production. DOM is known to have a stoichiometry depleted in nitrogen (N) and phosphorus (P) compared to the particulate organic matter pool, a fact that is often omitted from biogeochemical ocean general circulation models. However the variable C : N : P stoichiometry of DOM becomes important when quantifying carbon export from the upper ocean and linking the nutrient cycles of N and P with that of carbon. Here we utilize recent advances in DOM observational data coverage and offline tracer-modeling techniques to objectively constrain the variable production and remineralization rates of the DOM C : N : P pools in a simple biogeochemical-ocean model of DOM cycling. The optimized DOM cycling parameters are then incorporated within the Biogeochemical Elemental Cycling (BEC) component of the Community Earth System Model (CESM) and validated against the compilation of marine DOM observations. The optimized BEC simulation including variable DOM C : N : P cycling was found to better reproduce the observed DOM spatial gradients than simulations that used the canonical Redfield ratio. Global annual average export of dissolved organic C, N, and P below 100 m was found to be 2.28 Pg C yr-1 (143 Tmol C yr-1, 16.4 Tmol N yrg1, and 1 Tmol P yr-1, respectively, with an average export C : N : P stoichiometry of 225 : 19 : 1 for the semilabile (degradable) DOM pool. Dissolved organic carbon (DOC) export contributed ∼ 25% of the combined organic C export to depths greater than 100 m.

The ratio of carbon (C) to phosphorus (P) in marine phytoplankton is thought to be constant throughout the worlds'oceans. Known as the Redfield ratio, this relationship describes the links between carbon and phosphorus cycling and marine ecosystems. However, variations in the stoichiometry of phytoplankton have recently been identified, in particular strong latitudinal variability. Here we assess the impact of this variability in the C:P ratio of biomass on the C:P ratio of organic matter that is exported to the deep ocean using a biogeochemical inverse-model based on a data-constrained ocean circulation model and a global database of dissolved inorganic carbon and phosphate measurements. We identify global patterns of variability in the C:P ratios of exported organic matter, with higher values in the nutrient-depleted subtropical gyres, where organic matter export is relatively low, and lower ratios in nutrient-rich upwelling zones and high-latitude regions, where organic matter export is high. This suggests that total carbon export is relatively constant throughout the oceans, in agreement with recent estimates of carbon fluxes. We conclude that the latitudinal patterns of C:P in exported organic matter are consistent with the large-scale stoichiometric variations in phytoplankton C:P. We suggest that a future expansion of nutrient-depleted waters could result in a shift to more efficient C export that compensates for the expected decline in productivity.

Phytosterols are lipophilic compounds found in plants with structural similarity to mammalian cholesterol. They cannot be endogenously produced by mammals and therefore always originate from diet. There has been increased interest in dietary phytosterols over the last few decades due to their association with a variety of beneficial health effects including low-density lipoprotein cholesterol lowering, anti-inflammatory and anti-cancerous effects. They are proposed as potential moderators for diseases associated with the central nervous system where cholesterol homeostasis is found to be imperative (multiple sclerosis, dementia, etc.) due to their ability to reach the brain. Here we utilised an enzyme-assisted derivatisation for sterol analysis (EADSA) in combination with a liquid chromatography tandem mass spectrometry (LC-MS n ) to characterise phytosterol content in human serum. As little as 100 fg of plant sterol was injected on a reversed phase LC column. The method allows semi-quantitative measurements of phytosterols and their derivatives simultaneously with measurement of cholesterol metabolites. The identification of phytosterols in human serum was based on comparison of their LC retention times and MS 2 , MS 3 spectra with a library of authentic standards. Free campesterol serum concentration was in the range from 0.30-4.10 µg/mL, β-sitosterol 0.16-3.37 µg/mL and fucosterol was at lowest concentration range from 0.05-0.38 µg/mL in ten individuals. This analytical methodology could be applied to the analysis of other biological fluids and tissues., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We successfully demonstrated an intelligent adaptive beam alignment scheme using a reinforcement learning (RL) algorithm integrated with an 8 × 8 photonic array antenna operating in the 40 GHz millimeter wave (MMW) band. In our proposed scheme, the three key elements of RL: state, action, and reward, are represented as the phase values in the photonic array antenna, phase changes with specified steps, and an obtained error vector magnitude (EVM) value, respectively. Furthermore, thanks to the Q-table, the RL agent can effectively choose the most suitable action based on its prior experiences. As a result, the proposed scheme autonomously achieves the best EVM performance by determining the optimal phase. In this Letter, we verify the capability of the proposed scheme in single- and multiple-user scenarios and experimentally demonstrate the performance of beam alignment to the user's location optimized by the RL algorithm. The achieved results always meet the signal quality requirement specified by the 3rd Generation Partnership Project (3GPP) criterion for 64-QAM orthogonal frequency division multiplexing (OFDM).

Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

NeuMANTA is a new generation boron neutron capture therapy (BNCT)-specific treatment planning system developed by the Neuboron Medical Group and upgraded to an important feature, a Hounsfield unit (HU)-based material conversion algorithm. The range of HU values was refined to 96 specific groups and established corresponding to tissue information. The elemental compositions and mass densities have an important effect on the calculated dose distribution. The region of interest defined in the treatment plan can be converted into multiple material compositions based on HU values or assigned specified single material composition in NeuMANTA. Different material compositions may cause normal tissue maximum dose rates to differ by more than 10% in biologically equivalent doses and to differ by up to 6% in physically absorbed doses. Although the tumor has a lower proportion of BNCT background dose, the material composition difference may affect the minimum dose of biologically equivalent dose and physically absorbed dose by more than 3%. In addition, the difference in material composition could lead to a change in neutron moderation as well as scattering. Therefore, the material composition has a significant impact on the assessment of normal tissue side effects and tumor control probability. It is essential for accurate dose estimation in BNCT., (© 2023. Springer Nature Limited.)

Most treatment planning systems of boron neutron capture therapy perform dose calculations based on the assumption of a homogeneous boron distribution in tumors, which leads to dose distortion due to the difference between the tumor-to-normal tissue ratio (TNR) range measured in positron emission tomography images (PET) and the target delineation in computed tomography images of the treatment plan. The heterogeneous boron distribution in the target of the treatment plan can be obtained by image fusion. This study provides a way to quantify a heterogeneous boron distribution based on PET images. Theoretically, the same mean TNR for dose calculation by homogeneous or heterogeneous boron distribution should get almost the same mean dose. However, slightly different mean doses are found due to the partial volume effect for a small target volume. The wider the boron distribution is, the higher the impact on the dose-volume histogram distribution is. Dose distribution with homogeneous boron distribution may be overestimated in low boron uptake regions by wrong boron concentration and neutron flux depression. To accurately give the tumor prescription dose and achieve better tumor control, for low dose regions of the tumor should be considered more boron neutron capture therapy treatments or combined with other treatment modalities. The heterogeneous boron distribution must be taken into consideration to have an accurate dose estimation. Therefore, the way how medical physicists and clinicians process the TNR in gross tumor volume should be refined, and the method demonstrated in the work provides a good reference., (© 2023. Springer Nature Limited.)

The Monte Carlo method is the most commonly used dose calculation method in the field of boron neutron capture therapy (BNCT). General-purpose Monte Carlo (MC) code (e.g., MCNP) has been used in most treatment planning systems (TPS) to calculate dose distribution, which takes overmuch time in radiotherapy planning. Based on this, we developed COMPASS (COMpact PArticle Simulation System), an MC engine specifically for BNCT dose calculation. Several optimization algorithms are used in COMPASS to make it faster than general-purpose MC code. The parallel computation of COMPASS is performed by the message passing interface (MPI) library and OpenMP commands, which allows the user to increase computational speed by increasing the computer configurations. The physical dose of each voxel is calculated for developing a treatment plan. Comparison results show that the computed dose distribution of COMPASS is in good agreement with MCNP, and the computational efficiency is better than MCNP. These results validate that COMPASS has better performance than MCNP in BNCT dose calculation., (© 2023. The Author(s).)

Toxic substance usage remains one of the major concerns that must be addressed toward the commercialization of perovskite photovoltaics. Herein, we report a highly efficient perovskite solar module (>13%) fabricated via a wet process that uses a unique aqueous Pb(NO3)2 precursor, eliminating the use of toxic organic solvents during perovskite film preparation. In addition, we demonstrate a unique pattern in a monolithically interconnected module structure to check the uniformity of perovskite film and the quality of laser scribing. Finally, we highlight that this aqueous Pb(NO3)2 precursor protocol could achieve an enormous cost reduction over conventional PbI2 organic solutions whether in the laboratory research stage or at mass production scale, strengthening the core competitiveness of perovskite solar cells in the Darwinian ocean of photovoltaic technologies.

Cataracts, characterized by crystalline lens opacities in human eyes, is the leading cause of blindness globally. Due to its multifactorial complexity, the molecular mechanisms remain poorly understood. Larger cohorts of genome-wide association studies (GWAS) are needed to investigate cataracts’ genetic basis. In this study, a GWAS was performed on the largest Han population to date, analyzing a total of 7079 patients and 13,256 controls from the Taiwan Biobank (TWB) 2.0 cohort. Two cataract-associated SNPs with an adjustment of p < 1 × 10−7 in the older groups and nine SNPs with an adjustment of p < 1 × 10−6 in the younger group were identified. Except for the reported AGMO in animal models, most variations, including rs74774546 in GJA1 and rs237885 in OXTR, were not identified before this study. Furthermore, a polygenic risk score (PRS) was created for the young and old populations to identify high-risk cataract individuals, with areas under the receiver operating curve (AUROCs) of 0.829 and 0.785, respectively, after covariate adjustments. Younger individuals had 17.45 times the risk while older people had 10.97 times the risk when comparing individuals in the highest and lowest PRS quantiles. Validation analysis on an independent TWB1.0 cohort revealed AUROCs of 0.744 and 0.659.

Objective: To investigate the mechanism of the effect of acupuncture and moxibustion on improving liver injury by observing the changes of cysteine protease (Caspase) associated with hepatocyte apoptosis based on cisplatin (DDP) induced liver injury model mice., Methods: Forty KM mice were randomly divided into control group, model group, acupuncture group and moxibustion group, with 10 mice in each group. The liver injury model was replicated by intraperitoneal injection of DDP. In the acupuncture group and the moxibustion group, acupuncture and moxibustion were performed at"Dazhui"(GV14), and bilateral "Ganshu"(BL18), "Shenshu"(BL23), and "Zusanli"(ST36), respectively, once per day for 5 d. General condition of mice in each group were observed;The activities of AST, ALT and GLDH in mice serum were detected by biochemical method. ELISA and Western blot assay were used to detect Caspase-3, Caspase-8 and Caspase-9 contents and protein expression in the liver tissues of each group of mice, respectively., Results: Compared with the control group, the general condition of the mice in the model group was poorer, and the Caspase-3, Caspase-8 and Caspase-9 contents and protein expressions in liver tissues and the activities of AST, ALT and GLDH in serum were increased ( P <0.05). Compared with the model group, the general condition of the mice in the acupuncture and moxibustion groups improved, and the Caspase-3, Caspase-8 and Caspase-9 contents and protein expressions in liver tissues and activities of AST, ALT and GLDH in serum were decreased ( P <0.05)., Conclusion: Acupuncture and moxibustion can reduce liver injury due to DDP chemotherapy by modulating the expression of apoptotic factors Caspase-3, Caspase-8 and Caspase-9 in liver tissues of DDP model mice and improving liver function, which may be one of the mechanisms of the effect of acupuncture and moxibustion to ameliorates liver injury after DDP chemotherapy.

Background: The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging., Methods: Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging., Results: Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age., Conclusions: Our findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2., (© 2022. The Author(s).)

Objective: To clarify the possible influence of miR-135b on CXCL12 and airway inflammation in children and experimental mice with asthma., Methods: The expressions of miR-135b and CXCL12 were detected using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in the serum of asthmatic children. Besides, the experimental asthmatic mice were established by aerosol inhalation of ovalbumin (OVA) followed by the treatment with agomiR-135b and antagomir-135b. Pathological changes of lung tissues were observed via HE staining and PAS staining. Besides, the airway hyperresponsiveness of mice was elevated and bronchoalveolar lavage fluid (BALF) was isolated for cell categorization and counting. The inflammatory cytokines in BALF were determined by enzyme-linked immunosorbent assay (ELISA), and the infiltration of Th17 cells in lung tissues was measured using flow cytometry., Results: MiR-135b was downregulated and CXCL12 was upregulated in asthmatic children and mice. Overexpression of miR-135b may down-regulate CXCL12 expression in the lung of OVA mice, resulting in significant decreases in inflammatory infiltration, hyperplasia of goblet cell, airway hyperresponsiveness, cell quantity, as well as the quantity of eosinophilic granulocytes, neutrophils and lymphocytes in BALF. Also, the levels of inflammatory cytokines (IL-4, IL-5, IL-13 and IL-17) and the ratio of Th17 cells and IL-17 levels in lung tissues were decreased. However, miR-135b downregulation reversed these changes in OVA mice., Conclusion: MiR-135b may inhibit immune responses of Th17 cells to alleviate airway inflammation and hyperresponsiveness in asthma possibly by targeting CXCL12, showing the potential value in asthma treatment.

Objective: This study aims to investigate the sleep quality of pregnant women in Xuhui District, Shanghai, and the related factors of sleep disturbances during pregnancy. Methods: From February 2019 to February 2021, we used online integrated sleep questionnaire (including PSQI, BQ, ESS, AIS) in Shanghai Jiao Tong University School of Medicine Affiliated Sixth People's Hospital, The International Peace Maternity and Child Health Hospitals of China Welfare Institution, and Shanghai Eighth People's Hospital, to investigate the sleep quality across pregnancy. We also collected maternal physical examination results, childbearing history, sociodemographic, and other clinical data. The prevalences and related factors of various sleep disturbances in pregnant women were analyzed, including insufficient/excessive nighttime sleep, low sleep efficiency, difficulty falling asleep, poor sleep quality, insomnia, daytime sleepiness, and high risk of sleep-disordered breathing (SDB). Results: This study includes 1 898 cases in the first trimester (T1), 3 099 cases in the second trimester (T2), and 1 539 cases in the third trimester (T3). Poor sleep quality (38.6%), daytime sleepiness (mild 41.9%, moderate 17.7%, severe 2.1%), and suspicious insomnia (32.3%) are most prevalent among women in T1 ( P <0.01). In comparison, short sleep time (2.7%), long sleep time (8.6%), difficulty falling asleep (12.2%), poor sleep efficiency (35.4%), very poor sleep quality (6.7%), clinical insomnia (21.8%), and high-risk SDB (6.4%) are most prevalent among women in T3 ( P <0.05). During pregnancy, late gestation ( OR =1.016, 95%CI : 1.006-1.025) and multiple induced/drug abortions ( OR =1.329, 95%CI : 1.043-1.692) are risk factors for poor sleep quality (PSQI>5), while multiple full-term deliveries ( OR =0.800, 95%CI : 0.675-0.949) is its protective factor. Advanced maternal age ( OR =0.976, 95%CI : 0.956-0.997), multiple full-term deliveries ( OR =0.808, 95%CI : 0.680-0.959), late gestation ( OR =0.983, 95%CI : 0.974-0.992) and hypertension ( OR =0.572, 95%CI : 0.401-0.814) are protective factors for daytime sleepiness (ESS>6). The high-risk pregnancy category ( OR =9.312, 95%CI : 1.156-74.978) is a risk factor for insomnia (AIS≥4), while multiple full-term deliveries ( OR =0.815, 95%CI : 0.691-0.961) is its protective factor. High BMI ( OR =1.334, 95%CI : 1.270-1.402) and hypertension ( OR =4.427, 95%CI : 2.539-7.719) are risk factors for high-risk SDB in pregnant women. Conclusions: The prevalences of various sleep disturbances are high throughout pregnancy. Noticeably, symptoms of maternal SDB develop along with pregnancy. Different types of sleep disturbances are associated with different factors. Women of high-risk pregnancy category, in late gestation, with high BMI, hypertension, a history of induced/drug abortion, or without a history of full-term delivery can be at high risk of sleep disturbances during pregnancy.

Circular RNAs (circRNAs) are noncoding products of backsplicing of pre-mRNAs which have been established to possess potent biological functions. Dysregulated circRNA expression has been linked to diseases including different types of cancer. Cancer progression is known to result from the dysregulation of several molecular mechanisms responsible for the maintenance of cellular and tissue homeostasis. The dysregulation of these processes is defined as cancer hallmarks, and the molecular pathways implicated in them are regarded as the targets of therapeutic interference. In this review, we summarize the literature on the investigation of circRNAs implicated in cancer hallmark molecular signaling. First, we present general information on the properties of circRNAs, such as their biogenesis and degradation mechanisms, as well as their basic molecular functions. Subsequently, we summarize the roles of circRNAs in the framework of each cancer hallmark and finally discuss the potential as therapeutic targets.

Background: Nanoparticles have wide potential applications in biolabeling, bioimaging, and cell tracking. Development of dual functional nanoparticles increases the versatility., Methods: We combined the fluorescent property of nano-epoxy (N-Epo) and the magnetic characteristic of FePt to fabricate the FePt-decorated N-Epo (N-Epo-FePt). The size in diameter of N-Epo-FePt (177.38 ± 39.25 nm) was bigger than N-Epo (2.28 ± 1.01 nm), both could be absorbed into mesenchymal stem cells (MSCs) via clathrin-mediated endocytosis and have multiple fluorescent properties (blue, green, and red)., Results: N-Epo-FePt prevented N-Epo-induced platelet activation, CD68+-macrophage differentiation in blood, and intracellular ROS generation in MSCs. The induction of apoptosis and the inhibitory effects of N-Epo-FePt on cell migration, MMP-9 activity, and secretion of SDF-1α were less than that of N-Epo in MSCs., Conclusion: N-Epo-FePt was more biocompatible without altering biological performance than N-Epo in MSCs. These results suggest that N-Epo-FePt nanoparticle can be used for fluorescence labeling of MSCs and is potential to apply to bioimaging and cell tracking of MSCs in vivo by magnetic resonance imaging or computed tomography., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Background: Turning difficulties has been reported in stroke patients, but most studies have indicated no differences in turning direction regarding turn time or steps. Recent evidence shows that turning difficulty may correlate with trunk control. Trunk flexibility and strength are considered essential to trunk control, but their association with turning performance has not been elucidated., Aim: The study investigated the differences in turning direction in terms of turn duration and angular velocity and the relationship between turning performance and trunk function in patients with chronic stroke., Design: Cross-sectional study., Setting: Outpatient clinic at the Department of Physical Medicine and Rehabilitation., Population: Chronic stroke patients., Methods: Twenty-eight stroke patients were evaluated for turning performance and trunk function. Turn duration and angular velocity were assessed using three wearable sensors during 360° turning in place towards both sides. Trunk function, such as flexibility, strength, and control was measured using a tape measure, a microFET3 dynamometer, and the Trunk Impairment Scale., Results: Stroke patients showed significantly longer turn durations (4.62±2.08 vs. 3.59±1.93 s, P=0.036) and lower angular velocity (118.67±35.78 vs. 135.26±42.41°/s, P=0.009) during turning toward the paretic side than towards the nonparetic side. The turning parameters towards the paretic side associated with trunk flexion (r=-0.550, P=0.003) and rotation (r=0.409, P=0.034), trunk flexor strength (r=-0.387, P=0.046), dynamic sitting balance (r=-0.383, P=0.049) and coordination of trunk movement (r=-0.494, P=0.009). However, no relationship was observed between trunk function and turning towards the nonparetic side., Conclusions: Stroke participants experienced greater difficulty turning towards the paretic side. Trunk flexibility, strength, and control may affect turning performance, especially when turning towards the paretic side, which could explain the occurrence of falls after a turn towards the paretic side., Clinical Rehabilitation Impact: Stroke patients experience turning difficulties, particularly during turning towards the paretic side. Stroke patients with limited trunk function are more likely to experience turning dysfunction. Clinical therapists should develop effective strategies for enhancing turning ability through improvement of trunk flexibility, strength, and control for clinical rehabilitation practice.

Lung cancer is the leading cause of cancer-related mortality worldwide, and its tumorigenesis involves the accumulation of genetic and epigenetic events in the respiratory epithelium. Epigenetic modifications, such as DNA methylation, RNA modification, and histone modifications, have been widely reported to play an important role in lung cancer development and in other pulmonary diseases. Whereas the functionality of DNA and chromatin modifications referred to as epigenetics is widely characterized, various modifications of RNA nucleotides have recently come into prominence as functionally important. N6-methyladosine (m6A) is the most prevalent internal modification in mRNAs, and its machinery of writers, erasers, and readers is well-characterized. However, several other nucleotide modifications of mRNAs and various noncoding RNAs have also been shown to play an important role in the regulation of biological processes and pathology. Such epitranscriptomic modifications play an important role in regulating various aspects of RNA metabolism, including transcription, translation, splicing, and stability. The dysregulation of epitranscriptomic machinery has been implicated in the pathological processes associated with carcinogenesis including uncontrolled cell proliferation, migration, invasion, and epithelial-mesenchymal transition. In recent years, with the advancement of RNA sequencing technology, high-resolution maps of different modifications in various tissues, organs, or disease models are being constantly reported at a dramatic speed. This facilitates further understanding of the relationship between disease development and epitranscriptomics, shedding light on new therapeutic possibilities. In this review, we summarize the basic information on RNA modifications, including m6A, m1A, m5C, m7G, pseudouridine, and A-to-I editing. We then demonstrate their relation to different kinds of lung diseases, especially lung cancer. By comparing the different roles RNA modifications play in the development processes of different diseases, this review may provide some new insights and offer a better understanding of RNA epigenetics and its involvement in pulmonary diseases.

The coronavirus disease 2019 (COVID-19) pandemic with high infectivity and mortality has caused severe social and economic impacts worldwide. Growing reports of COVID-19 patients with multi-organ damage indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may also disturb the cardiovascular system. Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) as the in vitro platform to examine the consequence of SARS-CoV2 infection on iCMs. Differentiated iCMs expressed the primary SARS-CoV2 receptor angiotensin-converting enzyme-II (ACE2) and the transmembrane protease serine type 2 (TMPRSS2) receptor suggesting the susceptibility of iCMs to SARS-CoV2. Following the infection of iCMs with SARS-CoV2, the viral nucleocapsid (N) protein was detected in the host cells, demonstrating the successful infection. Bioinformatics analysis revealed that the SARS-CoV2 infection upregulates several inflammation-related genes, including the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The pretreatment of iCMs with TNF-α for 24 h, significantly increased the expression of ACE2 and TMPRSS2, SASR-CoV2 entry receptors. The TNF-α pretreatment enhanced the entry of GFP-expressing SARS-CoV2 pseudovirus into iCMs, and the neutralization of TNF-α ameliorated the TNF-α-enhanced viral entry. Collectively, SARS-CoV2 elevated TNF-α expression, which in turn enhanced the SARS-CoV2 viral entry. Our findings suggest that, TNF-α may participate in the cytokine storm and aggravate the myocardial damage in COVID-19 patients.

Cancer stem cells (CSCs) are heterogeneous cells with stem cell-like properties that are responsible for therapeutic resistance, recurrence, and metastasis, and are the major cause for cancer treatment failure. Since CSCs have distinct metabolic characteristics that plays an important role in cancer development and progression, targeting metabolic pathways of CSCs appears to be a promising therapeutic approach for cancer treatment. Here we classify and discuss the unique metabolisms that CSCs rely on for energy production and survival, including mitochondrial respiration, glycolysis, glutaminolysis, and fatty acid metabolism. Because of metabolic plasticity, CSCs can switch between these metabolisms to acquire energy for tumor progression in different microenvironments compare to the rest of tumor bulk. Thus, we highlight the specific conditions and factors that promote or suppress CSCs properties to portray distinct metabolic phenotypes that attribute to CSCs in common cancers. Identification and characterization of the features in these metabolisms can offer new anticancer opportunities and improve the prognosis of cancer. However, the therapeutic window of metabolic inhibitors used alone or in combination may be rather narrow due to cytotoxicity to normal cells. In this review, we present current findings of potential targets in these four metabolic pathways for the development of more effective and alternative strategies to eradicate CSCs and treat cancer more effectively in the future.

ATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with a number of the MCM replication complex subunits and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.

Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), are the most common chronic liver diseases worldwide. However, drugs to treat NAFLD and NASH are an unmet clinical need. This study sought to provide evidence that Cisd2 is a molecular target for the development of treatments targeting NAFLD and NASH. Several discoveries are pinpointed. The first is that Cisd2 dosage modulates the severity of Western diet-induced (WD-induced) NAFLD. Specifically, Cisd2 haploinsufficiency accelerates NAFLD development and exacerbates progression toward NASH. Conversely, an enhanced Cisd2 copy number attenuates liver pathogenesis. Secondly, when a WD is fed to mice, transcriptomic analysis reveals that the major alterations affecting biological processes are related to inflammation, lipid metabolism, and DNA replication/repair. Thirdly, among these differentially expressed genes, the most significant changes involve Nrf2-mediated oxidative stress, cholesterol biosynthesis, and fatty acid metabolism. Finally, increased Cisd2 expression protects the liver from oxidative stress and reduces the occurrence of mitochondrial DNA deletions. Taken together, our mouse model reveals that Cisd2 plays a crucial role in protecting the liver from WD-induced damages. The development of therapeutic agents that effectively enhance Cisd2 expression is one potential approach to the treatment of WD-induced fatty liver diseases.

Background: Co-trimoxazole, a sulfonamide antibiotic, is used to treat a variety of infections worldwide, and it remains a common first-line medicine for prophylaxis against Pneumocystis jiroveci pneumonia. However, it can cause severe cutaneous adverse reaction (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. The pathomechanism of co-trimoxazole-induced SCAR remains unclear., Objective: We aimed to investigate the genetic predisposition of co-trimoxazole-induced SCAR., Methods: We conducted a multicountry case-control association study that included 151 patients with of co-trimoxazole-induced SCAR and 4631 population controls from Taiwan, Thailand, and Malaysia, as well as 138 tolerant controls from Taiwan. Whole-genome sequencing was performed for the patients and population controls from Taiwan; it further validated the results from Thailand and Malaysia., Results: The whole-genome sequencing study (43 case patients vs 507 controls) discovered that the single-nucleotide polymorphism rs41554616, which is located between the HLA-B and MICA loci, had the strongest association with co-trimoxazole-induced SCAR (P = 8.2 × 10 -9 ; odds ratio [OR] = 7.7). There were weak associations of variants in co-trimoxazole-related metabolizing enzymes (CYP2D6, GSTP1, GCLC, N-acetyltransferase [NAT2], and CYP2C8). A replication study using HLA genotyping revealed that HLA-B∗13:01 was strongly associated with co-trimoxazole-induced SCAR (the combined sample comprised 91 case patients vs 2545 controls [P = 7.2 × 10 -21 ; OR = 8.7]). A strong HLA association was also observed in the case patients from Thailand (P = 3.2 × 10 -5 ; OR = 3.6) and Malaysia (P = .002; OR = 12.8), respectively. A meta-analysis and phenotype stratification study further indicated a strong association between HLA-B∗13:01 and co-trimoxazole-induced drug reaction with eosinophilia and systemic symptoms (P = 4.2 × 10 -23 ; OR = 40.1)., Conclusion: This study identified HLA-B∗13:01 as an important genetic factor associated with co-trimoxazole-induced SCAR in Asians., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

CDGSH Iron Sulfur Domain 2 (CISD2) is the causative gene for the disease Wolfram syndrome 2 (WFS2; MIM 604928), which is an autosomal recessive disorder showing metabolic and neurodegenerative manifestations. CISD2 protein can be localized on the endoplasmic reticulum (ER), outer mitochondrial membrane (OMM) and mitochondria-associated membrane (MAM). CISD2 plays a crucial role in the regulation of cytosolic Ca 2+ homeostasis, ER integrity and mitochondrial function. Here we summarize the most updated publications and discuss the central role of CISD2 in maintaining cellular homeostasis. This review mainly focuses on the following topics. Firstly, that CISD2 has been recognized as a prolongevity gene and the level of CISD2 is a key determinant of lifespan and healthspan. In mice, Cisd2 deficiency shortens lifespan and accelerates aging. Conversely, a persistently high level of Cisd2 promotes longevity. Intriguingly, exercise stimulates Cisd2 gene expression and thus, the beneficial effects offered by exercise may be partly related to Cisd2 activation. Secondly, that Cisd2 is down-regulated in a variety of tissues and organs during natural aging. Three potential mechanisms that may mediate the age-dependent decrease of Cisd2, via regulating at different levels of gene expression, are discussed. Thirdly, the relationship between CISD2 and cell survival, as well as the potential mechanisms underlying the cell death control, are discussed. Finally we discuss that, in cancers, CISD2 may functions as a double-edged sword, either suppressing or promoting cancer development. This review highlights the importance of the CISD2 in aging and age-related diseases and identifies the urgent need for the translation of available genetic evidence into pharmaceutic interventions in order to alleviate age-related disorders and extend a healthy lifespan in humans., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Peripheral arterial disease (PAD) affects millions of people and compromises quality of life. Critical limb ischemia (CLI), which is the most advanced stage of PAD, can cause nonhealing ulcers and strong chronic pain, and it shortens the patients' life expectancy. Cell-based angiogenic therapies are becoming a real therapeutic approach to treat CLI. Pericytes are cells that surround vascular endothelial cells to reinforce vessel integrity and regulate local blood pressure and metabolism. In the past decade, researchers also found that pericytes may function as stem or progenitor cells in the body, showing the potential to differentiate into several cell types. We investigated the gene expression profiles of pericytes during the early stages of limb ischemia, as well as the alterations in pericyte subpopulations to better understand the behavior of pericytes under ischemic conditions., Methods: In this study, we used a hindlimb ischemia model to mimic CLI in C57/BL6 mice and explore the role of pericytes in regeneration. To this end, muscle pericytes were isolated at different time points after the induction of ischemia. The phenotypes and transcriptomic profiles of the pericytes isolated at these discrete time points were assessed using flow cytometry and RNA sequencing., Results: Ischemia triggered proliferation and migration and upregulated the expression of myogenesis-related transcripts in pericytes. Furthermore, the transcriptomic analysis also revealed that pericytes induce or upregulate the expression of a number of cytokines with effects on endothelial cells, leukocyte chemoattraction, or the activation of inflammatory cells., Conclusions: Our findings provide a database that will improve our understanding of skeletal muscle pericyte biology under ischemic conditions, which may be useful for the development of novel pericyte-based cell and gene therapies.

Background: Bullous skin disorders are induced by different pathomechanisms and several are emergent, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Rapid diagnostic methods for SJS/TEN or cytotoxic T-lymphocyte (CTL)-mediated bullous disorders are crucial for early treatment. Granulysin, primarily expressed by CTLs, is a specific cytotoxic protein responsible for SJS/TEN and similar skin reactions., Objective: To assess granulysin levels in blister fluids to differentiate SJS/TEN and similar CTL-mediated bullous reactions from other autoimmune bullous disorders., Methods: Using ELISA, we measured granulysin in blister fluids from patients with bullous skin disorders, including SJS/TEN, erythema multiforme major, bullous fixed-drug eruption, bullous lupus erythematosus, paraneoplastic pemphigus, pemphigus vulgaris, bullous pemphigoid, purpura fulminans-related bullae, and hand-foot syndrome/hand-foot-skin reactions. We compared serum and blister granulysin levels in patients with SJS/TEN presenting varying severity, monitoring serial granulysin levels from acute to late stages., Results: Overall, 144 patients presenting with bullous skin disorders were enrolled. Blister granulysin levels (mean ± SD) in CTL-mediated disorders, including TEN (n = 28; 3938.7 ± 3475.7), SJS-TEN overlapping (n = 22; 1440.4 ± 1179.6), SJS (n = 14; 542.0 ± 503.2), erythema multiforme major (n = 7; 766.3 ± 1073.7), generalized bullous fixed-drug eruption (n = 10; 720.4 ± 858.3), and localized bullous fixed-drug eruption (n = 16; 69.0 ± 56.4), were significantly higher than in non-CTL-mediated bullous disorders (P < .0001), including bullous lupus erythematosus (n = 3; 22.7 ± 20.1), paraneoplastic pemphigus (n = 3; 20.3 ± 8.6), pemphigus vulgaris (n = 3; 4.4 ± 2.8), bullous pemphigoid (n = 18; 4.0 ± 2.7), purpura fulminans (n = 4; 5.9 ± 5.5), and hand-foot syndrome/hand-foot-skin reactions (n = 6; 4.6 ± 3.5). Blister granulysin levels correlated with clinical severity of SJS/TEN (P < .0001)., Conclusions: Determination of blister granulysin levels is a noninvasive and useful tool for rapid differential diagnosis of SJS/TEN and other similar CTL-mediated bullous skin disorders for treatment selection., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aging is an evolutionally conserved process that limits life activity. Cellular aging is the result of accumulated genetic damage, epigenetic damage and molecular exhaustion, as well as altered inter-cellular communication; these lead to impaired organ function and increased vulnerability to death. Skeletal muscle constitutes ~40% of the human body's mass. In addition to maintaining skeletal structure and allowing locomotion, which enables essential daily activities to be completed, skeletal muscle also plays major roles in thermogenesis, metabolism and the functioning of the endocrine system. Unlike many other organs that have a defined size once adulthood is reached, skeletal muscle is able to alter its structural and functional properties in response to changes in environmental conditions. Muscle mass usually remains stable during early life; however, it begins to decline at a rate of ~1% year in men and ~0.5% in women after the age of 50 years. On the other hand, different exercise training regimens are able to restore muscle homeostasis at the molecular, cellular and organismal levels, thereby improving systemic health. Here we give an overview of the molecular factors that contribute to lifespan and healthspan, and discuss the effects of the longevity gene Cisd2 and middle-to-old age exercise on muscle metabolism and changes in the muscle transcriptome in mice during very old age.

Background: Information on the association between long-term exposure to PM 2.5 and gastrointestinal cancer mortality is scarce., Objectives: This study investigated the association between long-term exposure to PM 2.5 and deaths from gastrointestinal cancer and its subtypes in adults in Taiwan., Methods: A total of 385,650 Taiwanese adults (≥18 years old) jointed a standard medical examination program between 2001 and 2014 and were followed up until 2016. Their vital data were obtained from the National Death Registry maintained by the Ministry of Health and Welfare in Taiwan. We estimated the ambient PM 2.5 concentration at individual's address utilising a satellite-based spatiotemporal model at a resolution of 1 km 2 . Cox proportional hazard regression model was used to investigate the associations between ambient PM 2.5 and deaths from gastrointestinal, stomach, colorectal and liver cancers., Results: We found that each 10 µg/m 3 increase in PM 2.5 was associated with an increased hazard risk (HR) of 1.09 (95% confidence interval (CI): 1.03-1.16) and 1.13 (95%CI: 1.02-1.24) in deaths from gastrointestinal and liver cancers, respectively. The association between PM 2.5 and death from colorectal cancer was marginally statistically significant [HR: 1.13 (95%CI: 1.00-1.26)]. We did not find significant associations between PM 2.5 and mortality from stomach cancer., Conclusions: Long-term exposure to ambient PM 2.5 was associated with an increased risk of deaths from gastrointestinal cancers, liver cancer and also potentially colorectal cancer. Air pollution control strategies are necessary to reduce the burden of gastrointestinal cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In mammals, microRNAs can be actively secreted from cells to blood. miR-29b-3p has been shown to play a pivotal role in muscle atrophy, but its role in intercellular communication is largely unknown. Here, we showed that miR-29b-3p was upregulated in normal and premature aging mouse muscle and plasma. miR-29b-3p was also upregulated in the blood of aging individuals, and circulating levels of miR-29b-3p were negatively correlated with relative appendicular skeletal muscle. Consistently, miR-29b-3p was observed in exosomes isolated from long-term differentiated atrophic C2C12 cells. When C2C12-derived miR-29b-3p-containing exosomes were uptaken by neuronal SH-SY5Y cells, increased miR-29b-3p levels in recipient cells were observed. Moreover, miR-29b-3p overexpression led to downregulation of neuronal-related genes and inhibition of neuronal differentiation. Interestingly, we identified HIF1α-AS2 as a novel c-FOS targeting lncRNA that is induced by miR-29b-3p through down-modulation of c-FOS and is required for miR-29b-3p-mediated neuronal differentiation inhibition. Our results suggest that atrophy-associated circulating miR-29b-3p may mediate distal communication between muscle cells and neurons., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Mutations in lamin A (LMNA) are responsible for a variety of human dystrophic and metabolic diseases. Here, we created a mouse model in which progerin, the lamin A mutant protein that causes Hutchinson-Gilford progeria syndrome (HGPS), can be inducibly overexpressed. Muscle-specific overexpression of progerin was sufficient to induce muscular dystrophy and alter whole-body energy expenditure, leading to premature death. Intriguingly, sarcolipin (Sln), an endoplasmic reticulum (ER)-associated protein involved in heat production, is upregulated in progerin-expressing and Lmna knockout (Lmna -/- ) skeletal muscle. The depletion of Sln accelerated the early death of Lmna -/- mice. An examination at the molecular level revealed that progerin recruits Sln and Calnexin to the nuclear periphery. Furthermore, progerin-expressing myoblasts presented enhanced store-operated Ca 2+ entry, as well as increased co-localization of STIM1 and ORAI1. These findings suggest that progerin dysregulates calcium homeostasis through an interaction with a subset of ER-associated proteins, resulting in thermogenic and metabolic abnormalities., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, kills over 1 million people worldwide annually. Development of drug resistance (DR) in the pathogen is a major challenge for TB control. We conducted whole-genome analysis of seven Taiwan M. tuberculosis isolates: One drug susceptible (DS) and five DR Beijing lineage isolates and one DR Euro-American lineage isolate. Developing a new method for DR mutation identification and applying it to the next-generation sequencing (NGS) data from the 6 Beijing lineage isolates, we identified 13 known and 6 candidate DR mutations and provided experimental support for 4 of them. We assembled the genomes of one DS and two DR Beijing lineage isolates and the Euro-American lineage isolate using NGS data. Moreover, using both PacBio and NGS sequencing data, we obtained a high-quality assembly of an extensive DR Beijing lineage isolate. Comparative analysis of these five newly assembled genomes and two published complete genomes revealed a large number of genetic changes, including gene gains and losses, indels and translocations, suggesting rapid evolution of M. tuberculosis. We found the MazEF toxin-antitoxin system in all the seven isolates studied and several interesting mutations in MazEF proteins. Finally, we used the four assembled Beijing lineage genomes to construct a high-quality Beijing lineage reference genome that is DS and contains all the genes in the four genomes. It contains 212 genes not found in the standard reference H37Rv, which is Euro-American. It is therefore a better reference than H37Rv for the Beijing lineage, the predominant lineage in Asia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart's electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction., Competing Interests: The authors have declared that no competing interests exist.

Nine patients with recurrent head and neck (H&N) cancer received boron neutron capture therapy (BNCT) in one fraction at the Tsing-Hua Open pool reactor (THOR) utilizing the THORplan treatment planning system (TPS). The aims of the present study were to evaluate the use of intensity modulated radiation therapy (IMRT) of 45 Gy in 20 fractions to compensate for the dose heterogeneity in gross tumor volume observed with single-fraction BNCT with mean prescription dose 19 Gy (w), and to evaluate planning quality indices of simulated BNCT+IMRT versus single-fraction BNCT alone. All IMRT plans were generated using the Eclipse TPS which employs the analytical anisotropic algorithm. The conformity index for the gross tumor volume (GTV) was better for the BNCT+IMRT plan than for the BNCT-alone plan (p = 0.003). In addition, the BNCT+IMRT plan provided significantly better homogeneity in the GTV (p = 0.03). The cold spots in inhomogeneous dose distribution in the BNCT plan may be a key factor for H&N cancer recurrence. Our results suggest that single-fraction BNCT combined with compensated multi-fraction IMRT improves treatment homogeneity and conformity than single-fraction BNCT alone, especially for tumor volumes >100 cm3, and possibly increases local tumor control., Competing Interests: The authors have declared that no competing interests exist.

Blood sampling by the dried blood spot (DBS) technique has become commonly applied in newborn screening. It is often used for analysis of small molecules, such as metabolites. Recently, DBS sampling has been applied for quantification of post-translational protein modifications. Glyoxal and methylglyoxal are two simple oxoaldehydes released from glycated proteins in the Maillard reaction. They are widely distributed in the environment (e.g. cigarette smoke) and found in foods and beverages. Glyoxal and methylglyoxal are shown to react with biomolecules including DNA and proteins. In this laboratory, we previously identified the sites of modification by these two oxoaldehydes in human hemoglobin and found that the extents of modification at certain sites of lysine and arginine residues are significantly higher in type 2 diabetes mellitus patients than in nondiabetic individuals. In this study, we examine the stability of these modifications of hemoglobin stored on DBS cards at room temperature or 4 °C in the ambient air. After hemoglobin was extracted from the DBS cards, it was digested by trypsin and analyzed by nanoflow liquid chromatography coupled with nanospray ionization tandem mass spectrometry. The results show that the extents of all these PTMs are stable within 14 and 21 days when stored on DBS at room temperature and at 4 °C, respectively. Extraction of globin from DBS cards is mostly advantageous for hemolytic blood samples. This assay is sensitive as only a quarter of a DBS card containing ca. 12 μL of blood is required. Thus, it is practically useful to measure the extents of glyoxal- and methylglyoxal-induced hemoglobin modifications from DBS cards., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

In this paper, an end-to-end CMOS application specific integrated circuit (ASIC) for readout channel in a cardiac electrical impedance tomography system is presented. The ASIC consists of an integrated current driver for current injection, an instrumentation amplifier, variable gain amplifier at the analog front end for voltage readout from electrodes, and an on-chip 10-bit successive approximation register analog to digital converter with serial peripheral interface. The ASIC is fabricated in the CMOS 0.18 $\mu$ m process with a supply voltage of 3.3 V. Amplitude and phase extraction of the voltages is performed in the digital domain with a matched filter. A fully integrated solution for use in multiple electrode system is demonstrated. The readout chain in the ASIC achieves a minimum signal-to-noise ratio of 71 dB over the frequency range of 500 Hz-700 kHz, while maintaining an average accuracy of 99.7 $\%$. Frame rates of 21 frames per second for a 32 electrode system is feasible, and the ASIC has an overall power consumption of 11.8 mW.

Skeletal muscle has emerged as one of the most important tissues involved in regulating systemic metabolism. The gastrocnemius is a powerful skeletal muscle composed of predominantly glycolytic fast-twitch fibers that are preferentially lost among old age. This decrease in gastrocnemius muscle mass is remarkable during aging; however, the underlying molecular mechanism is not fully understood. Strikingly, there is a ~70% decrease in Cisd2 protein, a key regulator of lifespan in mice and the disease gene for Wolfram syndrome 2 in humans, within the gastrocnemius after middle age among mice. A proteomics approach was used to investigate the gastrocnemius of naturally aged mice, and this was compared to the autonomous effect of Cisd2 on gastrocnemius aging using muscle-specific Cisd2 knockout (mKO) mice as a premature aging model. Intriguingly, dysregulation of calcium signaling and activation of UPR/ER stress stand out as the top two pathways. Additionally, the activity of Serca1 was significantly impaired and this impairment is mainly attributable to irreversibly oxidative modifications of Serca. Our results reveal that the overall characteristics of the gastrocnemius are very similar when naturally aged mice and the Cisd2 mKO mice are compared in terms of pathological alterations, ultrastructural abnormalities, and proteomics profiling. This suggests that Cisd2 mKO mouse is a unique model for understanding the aging mechanism of skeletal muscle. Furthermore, this work substantiates the hypothesis that Cisd2 is crucial to the gastrocnemius muscle and suggests that Cisd2 is a potential therapeutic target for muscle aging., (© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

This paper presents the design and implementation of a read-out chain for electrical impedance tomography (EIT) imaging. The EIT imaging approach can be incorporated to take spectral images of the tissue under study, offering an affordable, portable device for home health monitoring. A fast read-out channel covering a wide range of frequencies is a must for such applications. The proposed read-out channel comprising a programmable gain instrumentation amplifier, an analog-to-digital converter (ADC), and an ADC driver is designed and fabricated in a 0.18  m CMOS technology. The proposed read-out chain operates over the wide frequency range of 100 Hz to 10 MHz, with an average signal-to-noise ratio of more than 60 dB. The entire read-out channel consumes between 6.9 and 21.8 mW, depending on its frequency of operation.

Glyoxal (gx) is a bifunctional electrophile capable of cross-linking DNA. Although it is present in foods and from the environment, endogenous formation of glyoxal occurs through metabolism of carbohydrates and oxidation of lipids and nucleic acids. Plasma concentrations of glyoxal are elevated in in diabetes mellitus patients compared to nondiabetics. The most abundant 2'-deoxyribonucleoside adducts cross-linked by glyoxal are dG-gx-dC, dG-gx-dA, and dG-gx-dG. These DNA cross-links can be mutagenic by damaging the integrity of the DNA structure. Herein, we developed a highly sensitive and specific assay for the simultaneous detection and quantification of the dG-gx-dC and dG-gx-dA cross-links based on stable isotope dilution (SID) nanoflow liquid chromatography nanospray ionization tandem mass spectrometry (nanoLC-NSI/MS/MS) under the highly selected reaction monitoring mode and using a triple quadrupole mass spectrometer. The entire assay procedure involved addition of the stable isotope standards [ 15 N 5 ]dG-gx-dC and [ 15 N 5 ]dG-gx-dA as internal standards, enzyme hydrolysis to release the cross-links as nucleosides, enrichment by a reversed-phase solid-phase extraction column, and nanoLC-NSI/MS/MS analysis. The detection limit is 0.19 amol for dG-gx-dC and 0.89 amol for dG-gx-dA, which is 400 and 80 times more sensitive, respectively, than capillary LC-NSI/MS/MS assay of these adducts. The lower limit of quantification was 94 and 90 amol for dG-gx-dC and dG-gx-dA, respectively, which is equivalent to 0.056 and 0.065 adducts in 10 8 normal nucleotides in 50 μg of DNA. In type 2 diabetes mellitus (T2DM) patients (n = 38), the levels of dG-gx-dC and dG-gx-dA in leukocyte DNA were 1.94 ± 1.20 and 2.10 ± 1.77 in 10 8 normal nucleotides, respectively, which were significantly higher than those in nondiabetics (n = 39: 0.83 ± 0.92 and 1.05 ± 0.99 in 10 8 normal nucleotides, respectively). Excluding the factor of smoking, an exogenous source of glyoxal, levels of these two cross-linked adducts were found to be significantly higher in nonsmoking T2DM patients than in nonsmoking control subjects. Furthermore, the levels of dG-gx-dC and dG-gx-dA correlated with HbA1c with statistical significance. To our best knowledge, this is the first report of the identification and quantification of glyoxal-derived cross-linked DNA adducts in human leukocyte DNA and their association with T2DM. This SID nanoLC-NSI/MS/MS assay is highly sensitive and specific and it requires only 50 μg of leukocyte DNA isolated from 2-3 mL of blood to accurately quantify these two cross-linked adducts simultaneously. Our assay thus provides a useful biomarker for the evaluation of glyoxal-derived DNA damage.

Objectives: Ectopic pregnancies are among the leading causes of maternal morbidity and mortality in both developed and emerging nations, but tests for early, accurate, and convenient detection are lacking., Study Design: Between January 2013 and February 2015, 504 women with tubal pregnancy were prospectively recruited, and their clinical characteristics were recorded. Samples of peritoneal fluid were collected by culdocentesis, and venous blood was drawn from the antecubital vein. In samples from each source, levels of the following biochemical markers were measured: cancer antigen 125 (CA125), human chorionic gonadotropin (hCG), progesterone, vascular endothelial growth factor, and creatine kinase., Results: The ratios of biochemical markers in the peritoneal fluid and in the blood (R p/v ) were calculated. The median of R p/v -CA125 and R p/v -hCG were significantly lower in the ruptured ectopic pregnancy group than in the unruptured group. The optimal cutoff value to detect ectopic pregnancy rupture was 401.5U/mL as the upper limit for peritoneal CA125, with a sensitivity of 93.5% and specificity of 74.2%. The optimal cutoff value was 18.7 as the upper limit in the peritoneal fluid/blood ratio (R p/v ) of CA125, with a sensitivity of 77.5% and specificity of 68.4%., Conclusions: In countries with poor access to laparoscopy, culdocentesis is useful. In this study, culdocentesis provided additional information for management of abdominal pain when laparoscopy is not available. The authors propose R p/v cutoff values that can be used conveniently and quickly to diagnose ruptured ectopic pregnancies and bleeding, enabling rapid and appropriate therapeutic responses., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and has a poor prognosis and a low survival rate; its incidence is on the rise. Hepatitis B virus (HBV) infection is one of the main causes of HCC. A high prevalence of pre-S deletions of HBV surface antigen, which encompass T-cell and/or B-cell epitopes, is found in HBV carriers; antiviral therapy and viral immune escape may cause and select for these HBV mutants. In particular, the presence of pre-S2 deletion mutants is an important risk factor associated with cirrhosis and HCC. We generated Alb-preΔS2 transgenic mice that express a naturally occurring pre-S2 mutant protein containing a 33-nucleotide deletion (preΔS2); the aim was to investigate its effect on hepatocarcinogenesis. After 30 months of follow-up, the liver pathology of the mice fell into four groups: G1, chronic inflammation solely; G2, chronic inflammation and fibrosis; G3, inflammation, fibrosis, and hepatomegaly accompanied by rectal prolapse (4-12%); and G4, hepatomegaly and spontaneous HCC (12-15%). Striking degeneration of the endoplasmic reticulum (ER) was present in the mouse livers at an early stage (4 months old). At 8 months, overt ER stress and the Atf6 pathway of the unfolded protein response (UPR) were induced; at the same time, metabolic pathways associated with mevalonate and cholesterol biogenesis, involving the peroxisomes and the ER, were disturbed. At 20 months and older, the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway of the UPR was induced and the Hippo transducer Yap was activated. Together, these ultrastructural aberrations and metabolic disturbance all seem to contribute to the molecular pathogenesis and hepatocarcinogenesis present in the Alb-preΔS2 mice. These findings may contribute to the development of therapies for the liver disorders and HCC associated with pre-S2 deletion mutations among HBV carriers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The effects of a computer-aided diagnosis (CAD) system based on quantitative intensity features with magnetic resonance (MR) imaging (MRI) were evaluated by examining radiologists' performance in grading gliomas. The acquired MRI database included 71 lower-grade gliomas and 34 glioblastomas. Quantitative image features were extracted from the tumor area and combined in a CAD system to generate a prediction model. The effect of the CAD system was evaluated in a two-stage procedure. First, a radiologist performed a conventional reading. A sequential second reading was determined with a malignancy estimation by the CAD system. Each MR image was regularly read by one radiologist out of a group of three radiologists. The CAD system achieved an accuracy of 87% (91/105), a sensitivity of 79% (27/34), a specificity of 90% (64/71), and an area under the receiver operating characteristic curve (Az) of 0.89. In the evaluation, the radiologists' Az values significantly improved from 0.81, 0.87, and 0.84 to 0.90, 0.90, and 0.88 with p = 0.0011, 0.0076, and 0.0167, respectively. Based on the MR image features, the proposed CAD system not only performed well in distinguishing glioblastomas from lower-grade gliomas but also provided suggestions about glioma grading to reinforce radiologists' confidence rating., Competing Interests: The authors have declared that no competing interests exist.

3β-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss.

Background/aims: Providing preabortion contraceptive counseling for the method of contraception may reduce the incidence of repeat abortions. This study aimed to compare the acceptance and continuation rates of intrauterine devices (IUDs), combined oral contraceptives (COCs), and condom use after abortion in women who received preabortion contraceptive counseling., Methods: Women seeking a first-trimester abortion prospectively received preabortion contraceptive counseling and the choice of method of contraception was based on the counseling and not related to prior methods of birth control. Outcomes included continuation of postabortion contraceptive use and repeat abortions over a 6-month follow-up period., Results: Four hundred and fifty-five women (IUD group: n = 161; COC group: n = 149; condom group: n = 135) completed 6-month follow-up after the abortions. At the sixth month follow-up, patients continued using the IUD, COC, and condoms for contraception were 64.2, 10, and 51.5%, respectively. Higher age, being married, parity ≥1, and previous abortion were factors that were associated with more frequent selection of an IUD, while a higher education level was associated with a more frequent selection of COC and condoms., Conclusion: The continued use of COCs after abortion is low even with preabortion contraceptive counseling. The IUD offers reliable birth control with a lower discontinuation rate than COCs or condoms., (© 2016 S. Karger AG, Basel.)

Background: Cases of dengue fever have increased in areas of Southeast Asia in recent years. Taiwan hit a record-high 42,856 cases in 2015, with the majority in southern Tainan and Kaohsiung Cities. Leveraging spatial statistics and geo-visualization techniques, we aim to design an online analytical tool for local public health workers to prospectively identify ongoing hot spots of dengue fever weekly at the village level., Methods: A total of 57,516 confirmed cases of dengue fever in 2014 and 2015 were obtained from the Taiwan Centers for Disease Control (TCDC). Incorporating demographic information as covariates with cumulative cases (365 days) in a discrete Poisson model, we iteratively applied space-time scan statistics by SaTScan software to detect the currently active cluster of dengue fever (reported as relative risk) in each village of Tainan and Kaohsiung every week. A village with a relative risk >1 and p value <0.05 was identified as a dengue-epidemic area. Assuming an ongoing transmission might continuously spread for two consecutive weeks, we estimated the sensitivity and specificity for detecting outbreaks by comparing the scan-based classification (dengue-epidemic vs. dengue-free village) with the true cumulative case numbers from the TCDC's surveillance statistics., Results: Among the 1648 villages in Tainan and Kaohsiung, the overall sensitivity for detecting outbreaks increases as case numbers grow in a total of 92 weekly simulations. The specificity for detecting outbreaks behaves inversely, compared to the sensitivity. On average, the mean sensitivity and specificity of 2-week hot spot detection were 0.615 and 0.891 respectively (p value <0.001) for the covariate adjustment model, as the maximum spatial and temporal windows were specified as 50% of the total population at risk and 28 days. Dengue-epidemic villages were visualized and explored in an interactive map., Conclusions: We designed an online analytical tool for front-line public health workers to prospectively detect ongoing dengue fever transmission on a weekly basis at the village level by using the routine surveillance data.

Dysfunction of nuclear factor-κB (NF-κB) signaling has been causally associated with numerous human malignancies. Although the NF-κB family of genes has been implicated in endometrial carcinogenesis, information regarding the involvement of central regulators of NF-κB signaling in human endometrial cancer (EC) is limited. Here, we investigated the specific roles of canonical and noncanonical NF-κB signaling in endometrial tumorigenesis. We found that NF-κB RelB protein, but not RelA, displayed high expression in EC samples and cell lines, with predominant elevation in endometrioid adenocarcinoma (EEC). Moreover, tumor cell-intrinsic RelB was responsible for the abundant levels of c-Myc, cyclin D1, Bcl-2 and Bcl-xL, which are key regulators of cell cycle transition, apoptosis and proliferation in EEC. In contrast, p27 expression was enhanced by RelB depletion. Thus, increased RelB in human EC is associated with enhanced EEC cell growth, leading to endometrial cell tumorigenicity. Our results reveal that regulatory RelB in noncanonical NF-κB signaling may serve as a therapeutic target to block EC initiation.

The multifactorial and multistage pathogenesis of hepatocellular carcinoma (HCC) has fascinated a wide spectrum of scientists for decades. While a number of major risk factors have been identified, their mechanistic roles in hepatocarcinogenesis still need to be elucidated. Many tumor suppressor genes (TSGs) have been identified as being involved in HCC. These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors: the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele. Hepatitis B virus (HBV) is one of the most important risk factors associated with HCC. Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor, one advantage of mouse models for HBV/HCC research is the numerous and powerful genetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs. Here, we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner. Discoveries obtained using mouse models will have a great impact on HCC translational medicine.

Whether sleep problems of menopausal women are associated with vasomotor symptoms and/or changes in estrogen levels associated with menopause or age-related changes in sleep architecture is unclear. This study aimed to determine if poor sleep in middle-aged women is correlated with menopause. This study recruited women seeking care for the first time at the menopause outpatient department of our hospital. Inclusion criteria were an age ≥40 years, not taking any medications for menopausal symptoms, and no sleeping problems or depression. Patients were assessed with the Pittsburgh Sleep Quality Index (PSQI), modified Kupperman Index (KI), and Menopause Rating Scale (MRS). A PSQI score of <7 indicated no sleep disorder and ≥7 indicated a sleep disorder. Blood specimens were analyzed for follicle-stimulating hormone and estradiol levels. A total of 244 women were included in the study; 103 (42.2%) were identified as having a sleep disorder and 141 as not having one. In addition, 156 (64%) women were postmenopausal and 88 (36%) were not menopausal. Follicle-stimulating hormone and estradiol levels were similar between the groups. Patients with a sleep disorder had a significantly higher total modified KI score and total MRS score (both, P<0.001) compared with those without a sleep disorder. Correlations of the PSQI total score with the KI and MRS were similar in menopausal and non-menopausal women. These results do not support that menopause per se specifically contributes to sleep problems.

At present, there have been no standard research outcomes as to whether the levonorgestrel intrauterine system (LNG-IUS) or thermal balloon ablation (TBA) is superior for the treatment of patients suffering from heavy menstrual bleeding (HMB). Therefore, in the present study, a meta-analysis of randomized controlled trials (RCTs) was conducted in order to compare the effectiveness and affordability of the LNG-IUS with TBA in the treatment of HMB. A literature search of the following electronic databases was conducted: PubMed, EMBASE, the Cochrane Library, Google Scholar, the Chinese Scientific Journals Database, and the China National Knowledge Infrastructure; and a statistical analysis was performed using RevMan 5.2 software. Seven RCTs involving 467 patients (235 LNG-IUS, 232 TBA) met the inclusion criteria for the present study. As assessed by pictorial blood loss assessment chart (PBAC) scores, the LNG-IUS significantly reduced menstrual bleeding after 24 months [standardized mean difference (SMD), -0.86; 95% confidence interval (CI), -1.22 to -0.50; P<0.00001]. Furthermore, the total treatment cost of the LNG-IUS was lower than that of TBA (SMD, -2.35; 95% CI, -2.98 to -1.72; P<0.00001). However, at the 24 month follow-up, side effects such as amenorrhea occurred more frequently in patients treated with the LNG-IUS, as compared with TBA (relative risk, 2.49; 95% CI, 1.46-4.25; P=0.0008). No significant differences in hemoglobin levels and quality of life were demonstrated between the two treatment groups. The results of the present meta-analysis suggest that the LNG-IUS may be more effective and affordable than TBA as a long-term treatment (24 months) for HMB. However, following 12-24 months of treatment, side effects such as amenorrhea may be more frequent in patients treated with the LNG-IUS. When considering short-term treatment for HMB, controversy remains regarding the two methods and further studies are required to precisely evaluate the outcomes.