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Introduction: Impaired lung function has been observed in patients following COVID‐19 infection, with studies reporting persistent lung volume and diffusing capacity impairments. Some studies have demonstrated significantly higher small airway resistance in COVID‐19 positive cases. This retrospective study aims to examine impulse oscillometry (IOS) data of patients with persistent symptoms after COVID‐19 infection, focusing on the relationship between time and symptoms. Material and Method: The study analyzed data from adult patients with persistent symptoms who underwent IOS testing within and after 84 days from the diagnosis date. Result: The results showed that patients within 84 days and those between 31 and 84 days had higher small airway resistance values, indicating peripheral airway disease. Patients with dyspnea exhibited higher IOS values compared to those with cough symptoms, suggesting more significant impairment in the peripheral airways. Conclusion: The study highlights the importance of using comprehensive diagnostic tools like IOS to assess respiratory impairments in post‐COVID‐19 patients, particularly in the small airways. Understanding the relationship between time and symptoms can provide valuable insights for the treatment of peripheral airway dysfunction in post‐COVID‐19 patients. [ABSTRACT FROM AUTHOR]

To understand the effect of diet on gut bacteria of Cnaphalocrocis medinalis (rice leaf folder, RLF), we compared the composition and diversity of gut bacterial community in C. medinalis larvae collected from three different rice variety fields of Minghui 82 (RLF1), Youngyong 15 (RLF2) and Minghui 2155 (RLF3), using culture‐independent PCR (V3 variable region)‐denaturing gradient gel electrophoresis (PCR‐DGGE) methods and hypervariable region (V4) of 16S rRNA sequenced by Illumina HiSeq platform. The DGGE result showed that the bacteria genera Asaia, Bacillus, Stenotrophomonas, Achromobacter and Serratia coexisted in the guts of RLF1, RLF2 and RLF3, while Cedecea, Burkholderia and Acinetobacter coexisted in the guts of RLF2 and RLF3. However, only the genus Enterococcus existed in the guts of RLF1, and Pantoea, Wolbachia and Tumebacillus in RLF3 larvae. A total of 25 bacterial phyla, 48 classes, 127 orders, 223 families, and 406 genera were identified when using 16s RNA sequencing, with 35 genera coexisted in RLF1, RLF2 and RLF3 larval guts, while 83, 36, 141 unique genera existed in RLF1, RLF2 and RLF3, respectively. The indices of ACE and Shannon were not significantly different among RLF1, RLF2 and RLF3. The dominant bacterial taxa were Proteobacteria, Bacteroidetes and Firmicutes at the phylum level, and Acinetobacter and Wolbachia at the genus level. The relative genus abundance for the genera with relative abundance (≥0.01) was significantly different among RLF1, RLF2 and RLF3. The findings indicated that different rice varieties had significant effects on the relative abundance of gut bacteria in RLF, which could provide new insights into the relationship between insect gut bacteria and their associated host plants. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous studies of brown planthopper (BPH), Nilaparvata lugens, showed that carrying the plant pathogenic virus, rice ragged stunt virus (RRSV), enhanced the lethality of the entomopathogenic fungus, Metarhizium anisopliae (YTTR). The underlying mechanism for this was not established but a serine protease cascade was hypothesized to be involved. RESULTS: Two immune response genes, NlKPI and NlVenomase, were identified and shown to be involved. The synthesized double‐strand RNA (dsRNA) techniques used in this study to explore gene function revealed that treatment with dsRNA to silence either gene led to a higher BPH mortality from M. anisopliae infection than the dsRNA control treatment. NlKPI and NlVenomase play vital roles in BPH immunity to defend against alien pathogens. Both genes participate in the immune response process of BPH against co‐infection with RRSV and M. anisopliae YTTR by regulating the expression of antimicrobial peptides and phenoloxidase activity. CONCLUSION: Our study provided new targets for BPH biocontrol and laid a solid foundation for further research on the interaction of virus‐insect‐EPF (entomopathogenic fungus). © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Multiple mediation analysis is a powerful methodology to assess causal effects in the presence of multiple mediators. Several methodologies, such as G‐computation and inverse‐probability‐weighting, have been widely used to draw inferences about natural indirect effects (NIEs). However, a limitation of these methods is their potential for model misspecification. Although powerful semiparametric methods with high robustness and consistency have been developed for inferring average causal effects and for analyzing the effects of a single mediator, a comparably robust method for multiple mediation analysis is still lacking. Therefore, this theoretical study proposes a method of using multiply robust estimators of NIEs in the presence of multiple ordered mediators. We show that the proposed estimators not only enjoy the multiply robustness to model misspecification, they are also consistent and asymptotically normal under regular conditions. We also performed simulations for empirical comparisons of the finite‐sample properties between our multiply robust estimators and existing methods. In an illustrative example, a dataset for liver disease patients in Taiwan is used to examine the mediating roles of liver damage and liver cancer in the pathway from hepatitis B/C virus infection to mortality. The model is implemented in the open‐source R package "MedMR." [ABSTRACT FROM AUTHOR]

Purpose: To develop a portable MR perfusion phantom for quality‐controlled assessment and reproducibility of arterial spin labeled (ASL) perfusion measurement. Methods: A 3D‐printed perfusion phantom was developed that mimics the branching of arterial vessels, capillaries, and a chamber containing cellulose sponge representing tissue characteristics. A peristaltic pump circulated distilled water through the phantom, and was first evaluated at 300, 400, and 500 mL/min. Longitudinal reproducibility of perfusion was performed using 2D pseudo‐continuous ASL at 20 post‐label delays (PLDs, ranging between 0.2 and 7.8 s at 0.4‐s intervals) over a period of 16 weeks, with three repetitions each week. Multi‐PLD data were fitted into a general kinetic model for perfusion quantification (f) and arterial transit time (ATT). Intraclass correlation coefficient was used to assess intersession reproducibility. Results: MR perfusion signals acquired in the 3D‐printed perfusion phantom agreed well with the experimental conditions, with progressively increasing signal intensities and decreasing ATT for pump flow rates from 300 to 500 mL/min. The perfusion signal at 400 mL/min and the general kinetic model–derived f and ATT maps were similar across all PLDs for both intrasession and intersession reproducibility. Across all 48 experimental time points, the average f was 75.55 ± 3.83 × 10−3 mL/mL/s, the corresponding ATT was 2.10 ± 0.20 s, and the T1 was 1.84 ± 0.102 s. Intraclass correlation coefficient was 0.92 (95% confidence interval 0.83–0.97) for f, 0.96 (0.91–0.99) for ATT, and 0.94 (0.88–0.98) for T1, demonstrating excellent reproducibility. Conclusion: A simple, portable 3D‐printed perfusion phantom with excellent reproducibility of 2D pseudo‐continuous ASL measurements was demonstrated that can serve for quality‐controlled and reliable measurements of ASL perfusion. [ABSTRACT FROM AUTHOR]

Wind power input to oceanic near‐inertial oscillations (NIOs) plays a crucial role in sustaining the global ocean conveyor belt. However, the impact of tropical cyclones (TCs) on wind power input to NIOs, despite being the most vigorous atmospheric dynamics capable of exciting NIOs, is often overlooked in global estimations due to their transient nature and a lack of observations. Utilizing hourly wind and ocean current records, we quantified the wind power on NIOs induced by TCs from 1990 to 2019. Our findings reveal that the wind power on NIOs due to TCs is estimated to be between 0.028 and 0.065 TW, which accounts for a significant proportion, that is, 8%–17%, of that over the globe. This study highlights the importance of incorporating the wind power induced by TCs when estimating the global wind power on NIOs, as its impact is non‐negligible. Our findings contribute to a better understanding of the global energy balance by improving the estimation of wind power on NIOs. Plain Language Summary: Wind power input to oceanic near‐inertial oscillations (NIOs) is important for sustaining the global ocean conveyor belt. However, the influence of tropical cyclones (TCs) on wind power input to NIOs, despite being the most intense atmospheric dynamics that could easily excite NIOs, is often overlooked in global estimations due to their transient nature and a lack of observations. By analyzing wind and ocean current records from 1990 to 2019, the wind power on NIOs induced by TCs was quantified. We found that wind power on NIOs due to TCs is non‐negligible and accounts for a significant portion of that over the globe. This study highlights the importance of considering the wind power induced by TCs when estimating the global wind power on NIOs, which helps to achieve a more accurate estimation of wind power on NIOs, leading to an improved understanding of the global energy balance. Key Points: Observed data shows tropical cyclones contribute 8%–17% of global wind power on near‐inertial oscillationsTropical cyclones could contribute up to 90% of wind power on near‐inertial oscillations in their prone regionsAccounting for tropical cyclones is essential when estimating wind power on near‐inertial oscillations [ABSTRACT FROM AUTHOR]

This article discusses a case of cutaneous angiosarcoma of the scalp and its dermoscopic findings. Cutaneous angiosarcoma is a rare and aggressive tumor that can invade locally and metastasize. The patient in this case was an 82-year-old woman who presented with a large erythematous plaque on her scalp, surrounded by punctate vessels. Dermoscopic examination revealed a polymorphous vascular pattern consisting of serpentine, hairpin-like, and comma-shaped vessels. The presence of these polymorphous vessels can serve as a useful diagnostic clue for angiosarcoma. Early recognition of these characteristic vessels may enable early diagnosis. [Extracted from the article]

The hypoxic tumor microenvironment (TME) significantly affects cancer treatment. Conventional chemotherapeutic agents cannot effectively target hypoxic tumor tissue, which decreases efficacy and results in severe toxic side effects. To alleviate this problem, a self‐driving biomotor is developed by functionalizing MCDP nanoparticles containing calcium peroxide and doxorubicin (DOX) loaded onto polydopamine‐coated metal–organic frameworks（MOF）, with the anaerobic Bifidobacterium infantis (Bif) for synergistic chemotherapy and chemodynamic therapy (CDT) against breast cancer. The materials of institute Lavoisier (MIL) frameworks + CaO2 + DOX + polydopamine (MCDP)@Bif biohybrid actively targets hypoxic regions of solid tumors via the inherent targeting ability of Bif. Once it has accumulated in the tumor tissue, MCDP generates hydroxyl radicals through the enhanced Fenton‐type reactions between Fe2+ and self‐generated hydrogen peroxide in the acidic TME. The disruption of Ca2+ homeostasis and resulting mitochondrial Ca2+ overload triggers apoptosis and enhances oxidative stress, promoting tumor cell death. The results found that the DOX concentration in MCDP@Bif‐treated tumors is 3.8 times higher than that in free‐DOX‐treated tumors, which significantly prolongs the median survival of the tumor‐bearing mice to 69 days and reduces the toxic side effects of DOX. Therefore, the novel bacteria‐driven drug delivery system is highly effective in achieving synergistic chemotherapy and CDT against solid tumors. [ABSTRACT FROM AUTHOR]

The receptor‐binding domain (RBD) of spike recognizing the receptor angiotensin‐converting enzyme 2 (ACE2) initiates membrane fusion between severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and cell membrane. Although the structure of the RBD_ACE2 complex has been well studied, its functional mechanism in membrane fusion is still not fully understood. Here, using an in vitro cell–vesicle content‐mixing assay, it is found that the cleavage at the S2' site by thrombin (Thr) protease strongly accelerates membrane fusion, compared to that of cleavage at the S1/S2 site by PreScission (3C) protease. Moreover, mutations at the RBD_ACE2 interface resulted in a positive correlation between binding affinity and fusion probability. In both the cell–vesicle and cell–cell fusion assays, by crosslinking two membranes via the neutravidin (NTV)_biotin interaction or complementary DNA strands, it is found that spike drives membrane fusion in the absence of ACE2, and a suitable distance between two membranes is critical for spike‐mediated membrane fusion. Finally, unsuitable membrane crosslinkers significantly inhibited the fusion probability in the presence of ACE2. Taken together, the results suggest that the RBD_ACE2 complex may act as a crosslinker to bridge the viral and cell membranes at a suitable distance, which is critical, but also substitutable for spike‐mediated SARS‐CoV‐2 entry. [ABSTRACT FROM AUTHOR]

Background: Periodontal disease is an inflammatory disease of periodontal tissues that is closely connected with systemic diseases. During periodontitis, the inappropriate recruitment and activation of monocytes–macrophages causes an increase in osteoclast activity and disrupts bone homeostasis. Therefore, it is a promising therapeutic strategy to treat periodontitis by regulating the functions of monocytes–macrophages. Litcubanine A (LA) is an isoquinoline alkaloid extracted from the traditional Chinese medicine Litsea cubeba, which was proven to have reproducible anti‐inflammatory effects, but its regulatory role on bone homeostasis in periodontitis is still not clear. Methods: In this study, zebrafish experiments and a mouse ligature‐induced periodontitis model were performed, and histological analysis was used to investigate the effect of LA on macrophage chemotaxis under the inflammatory environment. Real‐time PCR was used to detect the regulatory effect of LA (100 nM ~ 100 μM) on the chemotaxis function of macrophages induced by LPS. Apoptosis assay and flow cytometry were used to elucidate the influence of LA on macrophage apoptosis and proliferation. To further clarify the regulatory role of LA on macrophage osteoclast differentiation, real‐time PCR, histological analysis, western blot, and micro‐computed tomography (micro‐CT) were performed in vivo and in vitro to verify the impact of LA on bone homeostasis. Results: Compared with the control group, the chemotaxis function of macrophage was significantly attenuated by LA in vivo. LA could significantly inhibit the expression of genes encoding the chemokine receptors Ccr1 and Cxcr4, and its ligand chemokine Cxcl12 in macrophages, and suppresses the differentiation of osteoclastic precursors to osteoclasts through the MAPK signaling pathway. There were significantly lower osteoclast differentiation and bone loss in the LA group compared with the control in the ligature‐induced periodontitis model. Conclusion: LA is a promising candidate for the treatment of periodontitis through its reproducible functions of inhibiting monocyte–macrophage chemotaxis and osteoclast differentiation. Litcubanine A can significantly prevent periodontitis by inhibiting macrophage chemotaxis and osteoclast differentiation via the MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Exposure to BTEX has been suggested to be a potential risk factor for asthma,[[1], [3]] a heterogeneous disease with unclear etiology, but its individual risk for adult asthma and its phenotypic clusters remains unclear. An hourly grid-scale model was utilized to estimate the residence-based ambient air BTEX levels and the time-lag effect (lag-0, lag-1, lag-2, lag-3, lag-4, and lag-5) on the daily asthma ERVs and outpatient visits. Abbreviations 2,4-DPMA N -acetyl- S -(2,4-dimethylbenzene)- l -cysteine 4-HNE 4-hydroxynonenal BMA N -acetyl- S -(benzyl)- l -cysteine BTEX benzene, toluene, ethylbenzene, and xylene C1P ceramide-1-phosphate ERV emergency room visit HEL N -(hexanoyl)-lysine LC-MS liquid chromatography-tandem mass spectrometry NHIRD National Health Insurance Research Database PGA phenylglyoxylic acid PMA N -acetyl- S -phenyl- l -cysteine RR relative risk S1P sphingosine-1-phosphate SL sphingolipid VOCs volatile organic compounds In a combined population-based and case-control study, exposure to benzene, toluene, ethylbenzene, and xylene (BTEX), particularly benzene, concomitant with increased oxidative stress and sphingolipid dysregulation, posed a significant, but differential, risk for current asthma, its severity, and phenotypic clusters. [Extracted from the article]

BACKGROUND: Apple polyphenols (APs) with multiple biological effects have attracted extensive attention due to their broad opportunities for application. However, the use of APs is hampered by their instability in the face of environmental changes. Designing efficient carriers to improve the bioavailability of APs is the key to solving these problems. In this study, gelatin‐chitooligosaccharide nanoparticles produced by the Maillard reaction (GCM) were fabricated to encapsulate AP, and the structure, antioxidant activity, and stability of the GMM‐AP nanoparticle system were evaluated. RESULTS: The results of endogenous fluorescence spectrum, Fourier‐transform infrared (FTIR) spectroscopy, X‐ray diffraction, and simultaneous thermal analysis confirmed structural changes and interactions between GCM and AP. Combination with GCM did not adversely affect the antioxidant properties of AP, and the GCM‐AP nanoparticles possessed superior temperature and storage stability. In comparison with fish gelatin‐apple polyphenol nanoparticles, the GCM‐AP nanoparticles were more stable at a wider pH range, and were more resistant to the electrostatic shielding effect of NaCl. After simulating gastric digestion, the particle size and polydispersity index (PDI) of GCM‐AP nanoparticles were almost unchanged. CONCLUSION: The findings suggest that GCM nanoparticles loaded with AP could be used as good carriers with good antioxidant activity and stability. This study therefore provides a theoretical foundation for the development and industrial application of food functional factors. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ratoon rice cropping has been introduced for increased rice production in southern China and, as a result, has been becoming increasingly popular. However, only a few studies have addressed the regulatory mechanism underlying grain quality improvement induced by rice ratooning. RESULTS: In this study, parameters of rice quality, including head rice yield, chalky grain percentage, grain chalkiness degree, hardness and taste value, were shown to be much improved in the ratooning season rice as compared to its counterparts main and late cropping season rice, indicating that such an improvement was irrespective of seasonal effects. In addition, the nutritional components of grains varied greatly between main‐cropping season rice, ratooning season rice and late‐cropping season rice and displayed a significant correlation with rice quality. Finally, the regulatory mechanism underlying rice quality improvement revealed that gibberellin‐dominated regulation and plant hormone signal transduction jointly contributed to a decrease in formation of chalky grains. CONCLUSION: This work improves our knowledge on rice quality improvement under rice ratooning, particularly on the regulatory mechanism of plant hormones. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Aim: Buprenorphine is one of the strongest opioids used for the relief of cancer pain. This study aims to evaluate the real‐world clinical experiences of transdermal buprenorphine used in moderate to severe cancer pain in the Asian population. Methods: This is an open‐labeled, multicenter, 4‐week observational study. Stable cancer pain patients who decided to switch the previous opioid to transdermal buprenorphine will be enrolled in this study. The safety and effectiveness were observed and collected. Pain assessment was performed using a numerical rating scale by the investigators and the Brief Pain Inventory Short Form (BPI‐SF) by the patient. The safety profiles included concomitant medications and adverse events (AEs). Results: A total of 83 patients were enrolled in this study. The global pain scores in the BPI, as well as the four individual pain parameters (worst, least, average, and right now), showed a continued decrease (p <.05) from week 2 to week 4. Significant improvements were observed in normal work activities, relations with other people, sleep, enjoyment of life, and global BPI pain interference score on week 4. Pain assessments conducted by investigators demonstrated significant, continuous improvements during the study periods. In addition, transdermal buprenorphine demonstrated good safety/tolerability with limited drug‐related AEs in the Asian population with cancer pain. Conclusion: This study demonstrated that transdermal buprenorphine in the Asian population has good safety profiles and continued improvements in pain relief, sleep, and pain interferences. Transdermal buprenorphine can be an effective and convenient option as a transdermal opioid for patients with moderate to severe cancer pain in Taiwan. (NCT Number: NCT04315831) [ABSTRACT FROM AUTHOR]

Background and Aim: Immune‐mediated neuroinflammation has been proposed to underlie the loss of lower esophageal sphincter (LES) myenteric neurons in achalasia. However, the immune status and key pathogenic immune subpopulations remain unclear. This study aims to evaluate the inflammatory status of patients with achalasia and their correlation with clinical characteristics, and further explore the key pathogenic subpopulations. Methods: We investigated the complete blood cell count and inflammatory markers in a large population of patients with achalasia (n = 341) and healthy controls (n = 80). The subpopulations of lymphocytes were analyzed by flow cytometry. Immunofluorescence was used to determine immune cell infiltration in the LES. Transcriptome changes of the key subpopulation were determined by RNA sequencing analysis. Results: NLR, MLR, CRP, globulin, IL‐6 and IL‐10 were significantly elevated in patients with achalasia. MLR and globulin were positively correlated with disease duration. The absolute count and percentage of CD8+ T cells in peripheral blood and its infiltration around ganglion in the LES were significantly increased in achalasia. Transcriptome analysis indicated that CD8+ T cells were activated and proliferative. In addition to multiple inflammatory pathways, regulation of neuroinflammatory response pathway was also significantly up‐regulated in achalasia. GSEA analysis revealed a close association with autoimmune diseases. Conclusions: Patients with achalasia suffered from chronic low‐grade inflammation with dysregulated immune cells and mediators associated with disease duration. CD8+ T cells might be the key pathogenic subpopulation of achalasia. Our results provide an important immune cell signature of the pathogenesis of achalasia. [ABSTRACT FROM AUTHOR]

Since the concept of aggregation‐induced emission (AIE) was proposed by Benzhong Tang's research group in 2001, the exploration of the mechanism of AIE and the development of new high‐performance AIE materials have been the focus and goal of this field. On the basis of a large number of experiment results, AIE mechanism has been well explained by lots of works, such as restricted intramolecular motion (RIM), J‐aggregate et al. As tetraphenylethlene (TPE) molecules are stacked, the rotation of the benzene ring rotor is blocked, and the energy attenuation is released in the form of radiation, showing the AIE effect. In order to further explore the AIE effect of TPE, we performed electronic structure, spectrum simulation, and AIE mechanism calculations of the anthryl‐tetraphenylethene (TPE‐an) monomer and dimer in the gas phase, tetrahydrofuran (THF), and aqueous solutions at the B3LYP/6‐31G** level. The calculation results show that TPE‐an molecule is in a propeller‐like configuration, and its fluorescence intensity is weak; compared with the monomer, the fluorescence intensity of the dimer increases by 87% in aqueous solution; the fluorescence intensity in the gas phase, THF solution, and aqueous solution gradually enhances with the increase of the degree of aggregation, which are consistent with the experimental results. The enhancement of fluorescence intensity is caused by the change of molecular structure caused by aggregation. This detailed AIE luminescence mechanism will provide theoretical guidance for AIE material design. [ABSTRACT FROM AUTHOR]

Single‐atom catalysts (SACs) are regarded as promising electrocatalysts for various reactions in the field of energy conversion and storage owing to their maximized atom utilization efficiency and unique electronic properties. The modifications of local coordination structures of single metal centers play significant roles in dominating catalytic performances, thus the SACs are resurveyed with different local coordination environments in order to explore such a paramount structure–performance relationship in various energy‐conversion reactions, including O2/CO2 reduction reaction and hydrogen evolution reaction. Notably, the atomically dispersed metal atoms that are subject to working conditions will undergo dynamic changes and then affect the catalytic properties, consequently, understanding the dynamic nature of SACs during reactions is highly significant but is still lacking to date. To this endeavor, this review particularly summarizes the dynamic evolutions of local coordination structures of SACs in various electrochemical reactions based on advanced operando/in situ techniques, aiming to precisely demonstrate the correlation between the dynamic coordination environment of SACs and the electrocatalytic activity. Finally, the challenges and perspectives are highlighted in the mechanistic studying for understanding the accurate active sites of SACs under realistic working conditions. [ABSTRACT FROM AUTHOR]

Arsenic compounds have been applied treating acute promyelocytic 1eukemia and solid tumors with brief mechanism investigations. In fact, we have demonstrated that sodium arsenite plus dimethylarsenic acid could activate apoptosis in MA‐10 mouse Leydig tumor cells by inducing caspase pathways. However, detail underlying mechanisms how caspase cascade is regulated remains elusive. Therefore, the apoptotic mechanism of sodium arsenite plus dimethylarsenic acid were examined in MA‐10 cells in this study. Our results reveal that Fas/FasL protein expressions were stimulated by sodium arsenite plus dimethylarsenic acid in MA‐10 cells. In addition, reactive oxygen species (ROS) generation, cytochrome C release, Bid truncation, and Bax translocation were induced in MA‐10 cells by arsenic compounds. Moreover, activation of p38, JNK and ERK1/2, MAPK pathways was stimulated while Akt phosphorylated levels and Akt expression were decreased by sodium arsenite plus dimethylarsenic in MA‐10 cells. In conclusion, sodium arsenite and dimethylarsenic acid did activate MAPK pathway plus ROS generation, but suppress Akt pathway, to modulate caspase pathway and then induce MA‐10 cell apoptosis. [ABSTRACT FROM AUTHOR]

To improve the computing speed and energy efficiency of deep neural network (DNN) applications, in‐memory computing with nonvolatile memory (NVM) is proposed to address the time‐consuming and energy‐hungry data shuttling issue. Herein, a digital in‐memory computing method for convolution computing, which holds the key to DNNs, is proposed. Based on the proposed method, a floating gate transistor‐based in‐memory computing chip for accurate convolution computing with high parallelism is created. The proposed digital in‐memory computing method can achieve the central processing unit (CPU)‐equivalent precision with the same neural network architecture and parameters, different from the analogue or digital–analogue‐mixed in‐memory computing techniques. Based on the fabricated floating gate transistor‐based in‐memory computing chip, a hardware LeNet‐5 neural network is built. The chip achieves 96.25% accuracy on the full Modified National Institute of Standards and Technology database, which is the same as the result computed by the CPU with the same neural network architecture and parameters. [ABSTRACT FROM AUTHOR]

The vicious invasive alien plant Amaranthus palmeri poses a serious threat to ecological security and food security due to its strong adaptability, competitiveness, and herbicide resistance. Predicting its potential habitats under current and future climate change is critical for monitoring and early warning. In this study, we used two sets of climate data, namely, WorldClim1.4 and RCPs (the historical climate data of WorldClim version 1.4 and future climate data of RCPs), WorldClim2.1 and SSPs (the historical climate data of WorldClim version 2.1 and future climate data of SSPs), to analyze the dominant environmental variables affecting the habitat suitability and predict the potential distribution of A. palmeri to climate change in China based on the MaxEnt model. The results show that (i) Temperature has a greater impact on the distribution of A. palmeri. The relative contributions of temperature‐related variables count to 70% or more, and the annual mean temperature (bio1) reached more than 40%. (ii) At present, the potentially suitable area is widely distributed in the central‐east and parts of southwest China, and the high suitable area is focused on the North China Plain. The potential suitable area predicted by WorldClim1.4 and WorldClim2.1 both accounts for about 31% of China's total land area. (iii) Future climate change will expand the suitable habitats to high latitudes and altitudes. The overall suitable area maximum increased to 44.93% under SSPs and 38.91% under RCPs. We conclude that climate change would increase the risk of A. palmeri expanding to high latitudes and altitudes, the results have practical implications for the effective long‐term management in response to the global warming of A. palmeri. [ABSTRACT FROM AUTHOR]

Copper‐decorated iron carbide nanoparticles (Cu@ICNPs) are prepared following an organometallic approach, producing a multifunctional catalytic system that can be heated magnetically. ICNPs act as heating agents, generating thermal energy from the alternating current magnetic field in an extremely localized, rapid, and efficient manner, thereby heating and activating the catalytically active Cu‐containing NPs present at their surface. Upon exposure to magnetic induction, the Cu@ICNPs catalyst is capable of selectively hydrodeoxygenating aromatic aldehydes under mild observable conditions (≈100 °C, 3 bar H2), without hydrogenation of the aromatic ring. A large scope of benzylic and non‐benzylic aldehydes including key biomass‐derived platform chemicals could be effectively converted to valuable aromatic alkanes. In addition, the Cu@ICNPs catalytic system is found adaptive to intermittent electricity supply, which is of great interest when considering the use of alternative renewable energy sources. In contrast, Cu@ICNPs, ICNPs, or Cu NPs show low activity when heated conventionally, even up to 200 °C. This work demonstrates the possibility to use magnetic induction heating to perform challenging hydrodeoxygenation reactions at mild pressure and temperature with noble metal‐free catalysts, while being able to cope with fluctuating energy sources. [ABSTRACT FROM AUTHOR]

Counterfactual‐model‐based mediation analysis can yield substantial insight into the causal mechanism through the assessment of natural direct effects (NDEs) and natural indirect effects (NIEs). However, the assumptions regarding unmeasured mediator‐outcome confounding and intermediate mediator‐outcome confounding that are required for the determination of NDEs and NIEs present practical challenges. To address this problem, we introduce an instrumental blocker, a novel quasi‐instrumental variable, to relax both of these assumptions, and we define a swapped direct effect (SDE) and a swapped indirect effect (SIE) to assess the mediation. We show that the SDE and SIE are identical to the NDE and NIE, respectively, based on a causal interpretation. Moreover, the empirical expressions of the SDE and SIE are derived with and without an intermediate mediator‐outcome confounder. Then, a multiply robust estimation method is derived to mitigate the model misspecification problem. We prove that the proposed estimator is consistent, asymptotically normal, and achieves the semiparametric efficiency bound. As an illustration, we apply the proposed method to genomic datasets of lung cancer to investigate the potential role of the epidermal growth factor receptor in the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP), one of the most widely used antipyretics and analgesics, principally results in acute liver injury (ALI) in developed countries when taken overdose. Ferulic acid (FA) is a natural polyphenol compound existing in many plants that has free radical scavenging, anti‐inflammatory, and liver‐protective properties. However, the effect and underlying mechanism of FA in treating APAP‐induced ALI have not been fully elucidated. Herein, we established a mouse model of APAP‐induced ALI and used APAP‐stimulated MPHs for biochemical assessment of molecular parameters. After constructing networks and obtaining predicted targets from public databases, we further verified the putative pathways using immune‐blotting assays both in vivo and in vitro. The reign of liver necrosis, serum levels of ALT and AST, and oxidative stress in livers significantly elevated after APAP treatment, which were almost recovered back to normal levels by FA administration. In addition, FA significantly upregulated the APAP‐induced downregulation of hepatic specific markers, including HNF4a, Foxa2, and ALB. Then, the results of functional enrichment indicated the possible signaling pathways of FA against APAP challenge, mainly including AMPK, autophagy, apoptosis, and other metabolic process. Furthermore, FA markedly reversed the APAP‐induced decline of mitochondria membrane potential, increased ratio of BAX/BCL2 and CASPASE 3 expression, and promoted autophagy flux of hepatocytes by upregulating AMPK phosphorylation, which were abrogated by a specific AMPK inhibitor, compound C. Overall, the hepatoprotective effect of FA on APAP‐induced ALI might be associated with anti‐oxidant and anti‐apoptosis, which were at least partly attributed to AMPK‐mediated protective autophagy. [ABSTRACT FROM AUTHOR]

Introduction: The most striking feature of depression is sadness and a loss of interest in activities, which represents a major cause of disability globally. Therefore, it is necessary to identify novel antidepressants for clinical practice. Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides that can be extracted from Panax ginseng and has been demonstrated to improve both memory and learning. The purpose of this study was to provide broad insight into the mechanisms underlying depression and gain greater insights into antidepressant therapy. Methods: In this study, we first established an effective and feasible depression animal model of chronic unpredictable mild stress (CUMS) and behavioral testing was evaluated by the forced swim test (FST), the tail suspension test (TST) and the sucrose preference test. Following pretreatment with Rh2 (10 and 20 mg/kg), the immobility time of mice was reduced without affecting locomotor activity in both the FST and TST. Western blotting and immunofluorescence were used to investigate the activation of the hippocampal BDNF signaling pathway and hippocampal neurogenesis. Results: Different concentrations of Rh2 significantly reduced depressive‐like symptoms in CUMS‐induced mice and downregulated the effects of the BDNF signaling cascade and neurogenesis in the hippocampus. Furthermore, the administration of K252a completely prevented the antidepressant‐like activity of Rh2 in mice. Conclusion: The results indicated that Rh2 possesses the antidepression action via the positive regulation of the BDNF‐TrkB pathway. [ABSTRACT FROM AUTHOR]

Negative Poisson's ratio (NPR) structures, also known as auxetics, are attracting growing interest due to their unique mechanical properties and a wide range of potential deployment. More attention has been paid to explore novel auxetic structures through bionics, lattice cells, or origami. However, the systemic design method of NPR structures has not yet matured. Herein, a design framework of NPR structures is proposed by integrating freedom, actuation, and constraint topologies (FACT) theory and isogeometric analysis. Based on the isogeometric method, the shape and mechanical properties of the curved beam can be changed by adjusting the control points of the curved beam. The configuration library is established by encapsulating curved beams to the straight beam. FACT theory is used to synthesize the cellular structure whose compliant elements are chosen from the curved beam configuration library. In this way, two NPR structures are designed. Simulation and experiments demonstrate the feasibility of the proposed design framework of NPR structure. The results of this study have a wide range of potential applications for designing future NPR structures. A new idea to design architected metamaterial systems exhibiting other properties is provided. [ABSTRACT FROM AUTHOR]

Background: Identifying patients with stage I non‐small cell lung cancer (NSCLC) at increased risk of tumor recurrence following surgery remains a major challenge. The current study aimed to compare disease‐free survival (DFS) rates after surgery between patients with clinically node‐positive (cN+) and ‐negative (cN0) stage I NSCLC. Methods: Patients with pathological stage I resected NSCLC were identified from the lung cancer database of Changhua Christian Hospital in Taiwan. Patients with clinical N status 1 or 2 and pathological N status 0 were identified as the cN+/pN0 cohort, whereas others were identified as the cN0/pN0 cohort. Propensity score matching (PSM) was used to balance the baseline characteristics between both cohorts. Kaplan–Meier method and Cox proportional hazards model were used to evaluate DFS. Results: From January 2010 to July 2019, 754 eligible patients were enrolled into the study, among whom 41 (5.4%) were cN+/pN0. The median follow‐up time was 43.4 months. Before PSM, the 5‐year DFS rate was 79.0% and 90.3% in cN+/pN0 and cN0/pN0 cohorts (log‐rank test, p = 0.009), respectively. After a 1:4 PSM, multivariate analysis showed that the cN+/pN0 cohort still had a poorer DFS compared to the cN0/pN0 cohort in (hazard ratio, 3.17; p = 0.040). Conclusion: Among patients with stage I resected NSCLC, cN+ patients had a worse DFS compared to cN0 patients. Surgeons should therefore consider more aggressive adjuvant therapy or frequent follow‐up in patients with surgically resected stage I NSCLC with cN+ status. [ABSTRACT FROM AUTHOR]

A series of cross‐linked and physical blends of nitrocellulose (NC) with oxirane‐tetrahydrofuran copolyether (PEOT) in different proportions were prepared using toluene‐2,4‐diisocyanate (TDI) as a crosslinking agent. The critical mechanical properties were evaluated by a universal material tensile testing machine and the dynamic mechanical thermal analyses (DMA). The reaction mechanism of the crosslinking process as well as the interaction between NC and PEOT were studied through Fourier transform infrared spectroscopy (FT‐IR). It was shown that as the mass fraction of PEOT increases, the Tg of the polymer blends gradually decreases, which can reach as low as −22.3 °C. It was further indicated that the low‐temperature mechanical properties of NC were significantly improved after blending. In comparison to the physical blending polymers, the miscibility between NC and PEOT was improved after cross‐linking reaction with TDI. When the mass fraction of NC was 50 %, the tensile strength of NC/PEOT physical blend and NC/PEOT/TDI cross‐linked blend reaches 20.82 MPa and 24.93 MPa, respectively. The corresponding elongation at break of these two systems was 96.58 % and 102.7 %, which means the toughening effect of PEOT on NC could be enhanced by crosslinking. [ABSTRACT FROM AUTHOR]

Effect decomposition is a critical technique for mechanism investigation in settings with multiple causally ordered mediators. Causal mediation analysis is a standard method for effect decomposition, but the assumptions required for the identification process are extremely strong. Moreover, mediation analysis focuses on addressing mediating mechanisms rather than interacting mechanisms. Mediation and interaction for mediators both contribute to the occurrence of disease, and therefore unifying mediation and interaction in effect decomposition is important to causal mechanism investigation. By extending the framework of controlled direct effects, this study proposes the effect attributable to mediators (EAM) as a novel measure for effect decomposition. For policymaking, EAM represents how much an effect can be eliminated by setting mediators to certain values. From the perspective of mechanism investigation, EAM contains information about how much a particular mediator or set of mediators is involved in the causal mechanism through mediation, interaction, or both. EAM is more appropriate than the conventional path‐specific effect for application in clinical or medical studies. The assumptions of EAM for identification are considerably weaker than those of causal mediation analysis. We develop a semiparametric estimator of EAM with robustness to model misspecification. The asymptotic property is fully realized. We applied EAM to assess the magnitude of the effect of hepatitis C virus infection on mortality, which was eliminated by controlling alanine aminotransferase and treating hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Simulating quantum many‐body dynamics on classical computers is a challenging problem due to the exponential growth of the Hilbert space. Artificial neural networks have recently been introduced as a new tool to approximate quantum many‐body states. The variational power of the restricted Boltzmann machine quantum states and different shallow and deep neural autoregressive quantum states to simulate the global quench dynamics of a non‐integrable quantum Ising chain is benchmarked. It is found that the number of parameters required to represent the quantum state at a given accuracy increases exponentially in time. The growth rate is only slightly affected by the network architecture over a wide range of different design choices: shallow and deep networks, small and large filter sizes, dilated and normal convolutions, and with and without shortcut connections. [ABSTRACT FROM AUTHOR]

Earlier works have reported that rectifier AC faults also can cause commutation failure during fault‐off recovery process. Whereas the occurrence of CF is merely ascribed to inverter AC faults in conventional wisdom. Note that the existing CF mitigation approaches are designed mostly by the evolution of inverter electrical quantities, which will fail to take action to CF caused by rectifier faults, posing threat to the operation of power system. Thus, the paper firstly presents the essential reasons for CF caused by rectifier ac faults, combined with the fault information transmission process and control response. It is found that DC current surge and improper control interaction are the main reasons. Accordingly, a novel current cooperative optimization (CCO) control strategy is proposed, which aimed at reducing the risk of CF caused by rectifier ac faults. Simulation results verify the correctness of the mechanism and the effectiveness of the proposed control strategy. [ABSTRACT FROM AUTHOR]

The undesirable loss of methane (CH4) at remote locations welcomes approaches that ambiently functionalize CH4 on‐site without intense infrastructure investment. Recently, we found that electrochemical oxidation of vanadium(V)‐oxo with bisulfate ligand leads to CH4 activation at ambient conditions. The key question is whether such an observation is a one‐off coincidence or a general strategy for electrocatalyst design. Here, a general scheme of electrocatalytic CH4 activation with d0 early transition metals is established. The pre‐catalysts' molecular structure, electrocatalytic kinetics, and mechanism were detailed for titanium (IV), vanadium (V), and chromium (VI) species as model systems. After a turnover‐limiting one‐electron electrochemical oxidation, the yielded ligand‐centered cation radicals activate CH4 with low activation energy and high selectivity. The reactivities are universal among early transition metals from Period 4 to 6, and the reactivities trend for different early transition metals correlate with their d orbital energies across periodic table. Our results offer new chemical insights towards developing advanced ambient electrocatalysts of natural gas. [ABSTRACT FROM AUTHOR]

Copper chromite is decorated with iron carbide nanoparticles, producing a magnetically activatable multifunctional catalytic system. This system (ICNPs@Cu2Cr2O5) can reduce aromatic ketones to aromatic alcohols when exposed to magnetic induction. Under magnetic excitation, the ICNPs generate locally confined hot spots, selectively activating the Cu2Cr2O5 surface while the global temperature remains low (≈80 °C). The catalyst selectively hydrogenates a scope of benzylic and non‐benzylic ketones under mild conditions (3 bar H2, heptane), while ICNPs@Cu2Cr2O5 or Cu2Cr2O5 are inactive when the same global temperature is adjusted by conventional heating. A flow reactor is presented that allows the use of magnetic induction for continuous‐flow hydrogenation at elevated pressure. The excellent catalytic properties of ICNPs@Cu2Cr2O5 for the hydrogenation of biomass‐derived furfuralacetone are conserved for at least 17 h on stream, demonstrating for the first time the application of a magnetically heated catalyst to a continuously operated hydrogenation reaction in the liquid phase. [ABSTRACT FROM AUTHOR]

Aims: In contrast to Western patients with breast cancer, Asian patients are relatively younger at diagnosis, and most are free from traditional cardiovascular risk factors. Despite trastuzumab‐related major adverse cardiac and cerebrovascular event (MACCE) being reported, its incidence and predictors remain unknown in Taiwan. Methods and results: Through a three‐hospital retrospective cohort study, we analysed the incidence of MACCE in 386 breast cancer patients' exposure to trastuzumab from 2010 to 2018. To further reconfirm our findings, in a nationwide study using the Taiwanese National Health Insurance Research Database and National Cancer Registry, we identified 13 502 women diagnosed with breast cancer who received chemotherapy from 2010 to 2015 and found 6751 women who received initial treatment with trastuzumab. After 1:1 propensity score matching with trastuzumab non‐users, the incidence of MACCE was measured with a median follow‐up of 36 months. In the hospital‐based study, among 386 patients receiving trastuzumab, the 5‐year incidences of MACCE and heart failure (HF) were 5.4 and 2.8%, respectively. In the national cohort, the crude incidences of MACCEs and HF were 4.67 and 3.21%, respectively. After adjustment for age and comorbidities, the hazard ratio of MACCE was 1.485 (95% CI 1.246–1.769). Notably, among the endpoints, only the hazard ratio of HF was significantly higher in patients receiving trastuzumab than in nonusers. In the subgroup analysis, except for patients also using taxanes, those receiving trastuzumab had a higher risk of MACCE than non‐users. Conclusions: From clinical observations in a nationwide cohort, we found an increased risk of MACCE, especially HF, in patients receiving trastuzumab. Given that its cardiotoxicity is independent of traditional cardiovascular risks, our findings highlight critical concerns regarding the cardiac safety of trastuzumab use. [ABSTRACT FROM AUTHOR]

Characterizing the mechanistic interactions between exposures and diseases is one of the most critical issues in epidemiologic studies. Previous studies have proposed a stochastic sufficient component cause framework, under which each sufficient cause is treated as a stochastic process instead of a time-invariant random variable. However, different types of mechanistic interactions such as synergism and agonism cannot be further identified. In this study, we proposed a stochastic marginal sufficient component cause model to conceptualize and identify agonism and synergism by exploiting the additional information. We further provided six approaches to identify and estimate agonism and synergism based on an additive hazard model and a complementary log model. Researchers can easily adjust confounding factors by including appropriate covariates into a regression model. Simulations have proven that approaches under three models are all valid tests. The power of an additive hazard model increases as the total follow-up time increases and is higher than that of the other two models. We applied this method to a Taiwanese cohort data set to investigate the mechanistic interaction among hepatitis B and C viruses on the incidence of hepatocellular carcinoma. The hazard of people with agonistic interaction is 1.28×10-5 (95% CI: 6.97×10-6 , 1.87×10-5 ), and the cumulative hazard of those people is 7.41×10-2 (95% CI: 4.09×10-2 , 1.07×10-1 ), which is approximately 3.5 times stronger than that of synergistic interaction. The proposed method makes it possible to quantify different types of mechanistic interactions in longitudinal studies with censored data. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Emerging evidence suggests that expression quantitative trait loci (eQTLs) are more likely to associate with complex diseases. Transient receptor potential cation channel subfamily M member 5 (TRPM5) is a ubiquitously expressed voltage‐gated cation channel that acts indispensably to trigger insulin secretion in pancreatic β‐cells. The present study evaluated the association between TRPM5 eQTL single‐nucleotide polymorphisms and the risk of gestational diabetes mellitus (GDM) in a Chinese population. Materials and Methods: A total of 380 unrelated Chinese pregnant women including 241 GDM patients and 139 controls were included in this study. The eQTL single‐nucleotide polymorphisms of TRPM5 were obtained from the GTEx eQTL Browser, and were subsequently genotyped using the Agena MassARRAY iPLEX platform. Results: Logistic regression analysis and linear regression analysis showed that rs35197079 and rs74848824 were significantly associated with reduced GDM risk and lower fasting plasma glucose levels after adjusting confounder factors in dominant genetic models. Stratification analysis based on pre‐pregnancy body mass index validated a strong association between rs35197079 and GDM susceptibility in underweight and normal weight individuals. Luciferase and electrophoretic mobility shift assays carried out in rat pancreatic β‐cells showed that rs35197079 was functional. Conclusions: The TRPM5 eQTL single‐nucleotide polymorphism rs35197079 was associated with decreased GDM susceptibility in a Chinese population, especially in underweight and normal weight pregnant women, and it was functional in modulating gene transcription. [ABSTRACT FROM AUTHOR]

Recent methodological developments in causal mediation analysis have addressed several issues regarding multiple mediators. However, these developed methods differ in their definitions of causal parameters, assumptions for identification, and interpretations of causal effects, making it unclear which method ought to be selected when investigating a given causal effect. Thus, in this study, we construct an integrated framework, which unifies all existing methodologies, as a standard for mediation analysis with multiple mediators. To clarify the relationship between existing methods, we propose four strategies for effect decomposition: two‐way, partially forward, partially backward, and complete decompositions. This study reveals how the direct and indirect effects of each strategy are explicitly and correctly interpreted as path‐specific effects under different causal mediation structures. In the integrated framework, we further verify the utility of the interventional analogues of direct and indirect effects, especially when natural direct and indirect effects cannot be identified or when crossworld exchangeability is invalid. Consequently, this study yields a robustness‐specificity trade‐off in the choice of strategies. Inverse probability weighting is considered for estimation. The four strategies are further applied to a simulation study for performance evaluation and for analyzing the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer dataset from Taiwan to investigate the causal effect of hepatitis C virus infection on mortality. [ABSTRACT FROM AUTHOR]

We reported herein a visible light promoted difluoroalkylated cascade of imidazoles and alkenes to afford highly functionalized polycyclic imidazoles. This method features a direct radical cyclization of imidazoles with alkenes using BrCF2R as radical sources. The reaction conditions tolerate a wide range of substrate scope and afford the desired products with up to 95 % isolated yield under mild conditions. Radical‐trapping and light‐on/off experiments indicated a photocatalytic radical mechanism. [ABSTRACT FROM AUTHOR]

The active‐matrix organic light emitting diode (AMOLED) folding display can easily realize the inner folding, outer folding, and curling the display. After folding or curling the display, in addition to greatly minimize the display size of the smart phone, the folding display can also achieve future technical trends such as smart tablet‐phone and laptop‐phone after unfolding display. With the increase in the market share of foldable display in the consumer electronics market, we all think foldable display application will rapidly expand to the industrial and automotive markets within three years. Therefore, the next generation of smart folding display will create the whole new experience of human life with powerful wireless hardware functions and diversity of software APP applied in a wider field. [ABSTRACT FROM AUTHOR]

In medical research, the development of mediation analysis with a survival outcome has facilitated investigation into causal mechanisms. However, studies have not discussed the death‐truncation problem for mediators, the problem being that conventional mediation parameters cannot be well defined in the presence of a truncated mediator. In the present study, we systematically defined the completeness of causal effects to uncover the gap, in conventional causal definitions, between the survival and nonsurvival settings. We propose a novel approach to redefining natural direct and indirect effects, which are generalized forms of conventional causal effects for survival outcomes. Furthermore, we developed three statistical methods for the binary outcome of survival status and formulated a Cox model for survival time. We performed simulations to demonstrate that the proposed methods are unbiased and robust. We also applied the proposed method to explore the effect of hepatitis C virus infection on mortality, as mediated through hepatitis B viral load. [ABSTRACT FROM AUTHOR]

Both Colony‐stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells‐2 (TREM2) are trans‐membrane receptors and are expressed in the brain primarily by microglia. Mutations in these two microglia‐expressed genes associated with neurodegenerative disease have recently been grouped under the term "microgliopathy". Several literatures have indicated that CSF1R and TREM2 encounters a stepwise shedding and TREM2 variants impair or accelerate the processing. However, whether CSF1R variant affects the shedding of CSF1R remains elusive. Here, plasmids containing human CSF1R or TREM2 were transiently transfected into the human embryonic kidney (HEK) 293T cells. Using Western Blot and/or ELISA assay, we demonstrated that, similar to those of TREM2, an N‐terminal fragment (NTF) shedding of CSF1R ectodomain and a subsequent C‐terminal fragment (CTF) of CSF1R intra‐membrane were generated by a disintegrin and metalloprotease (ADAM) family member and by γ‐secretase, respectively. And the shedding was inhibited by treatment with Batimastat, an ADAM inhibitor, or DAPT or compound E, a γ‐secretase inhibitor. Importantly, we show that the cleaved fragments, both extracellular domain and intracellular domain of a common disease associated I794T variant, were decreased significantly. Together, our studies demonstrate a stepwise approach of human CSF1R cleavage and contribute to understand the pathogenicity of CSF1R I794T variant in adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). These studies also suggest that the cleaved ectodomain fragment released from CSF1R may be proposed as a diagnostic biomarker for ALSP. [ABSTRACT FROM AUTHOR]

Agonistic interaction is one of the most important types of mechanistic interaction, which is difficult to be distinguished from synergistic interaction by empirical data. In this study, we propose four approaches that suffice to identify and estimate the agonistic interaction: (1) to make a strong assumption that synergism does not exist; (2) to exploit information from a third factor by assuming that this factor is a necessary component for the background condition of synergistic interaction but is not involved in other mechanisms; (3) to consider a third factor necessary for the background condition of agonistic interaction but not involved in other mechanisms; and (4) similar to (3) but to allow flexibility that the third factor may have a main effect on the outcome and/or a synergistic effect with the two risk factors of interest. We applied the proposed methods to quantify the agonism of Hepatitis B and C viruses (HBV and HCV) infections on liver cancer using a Taiwanese cohort study (n = 23 820; HBV carrier n = 4149 (17.44%), HCV carrier n = 1313 (5.52%)). The result demonstrated that agonistic interaction is more dominant compared with synergistic interaction, which explains the findings that the dual infected patients do not have a significantly higher risk of liver cancer than those with single infection. By exploiting an additional risk factor that satisfies certain assumptions, these approaches potentially fill the gap between mechanistic and causal interactions, contributing the comprehensive understanding of causal mechanisms. [ABSTRACT FROM AUTHOR]