Tuning nitrogen adsorption and activation performances of Three-Atom transition metal clusters by modulating external electric fields.

Three-atom transition metal clusters (TATMCs) with remarkable catalytic activities, especially Nb3, Zr3, and Y3, are proven to be suitable candidates for efficient ammonia production. The pursuit of effective strategies to further promote the ammonia synthesis performance of TATMCs is necessary. In this study, we systematically investigate the effect of external electric fields on tuning the N2 adsorption and NN* activation performances of Nb3, Zr3, and Y3. Our findings demonstrate that the medium and low positive fields promote the N2 adsorption performance of Nb3, while both positive and negative fields enhance nitrogen adsorption on Zr3. Additionally, electric fields may impede N2 fixation on Y3, yet the N2 adsorption performance of Y3 remains considerable. Negative electric fields enhance the NN* activation performance of Nb3 and Y3. But only high negative fields weaken the NN bond on Zr3, which is attributed to the promotion of the charge accumulation around two N atoms. Notably, Nb3 and Zr3 are identified as two TATMCs with the potential for simultaneous optimization of their EN and ICOHP values. This work sheds light on the field effects on the N2 adsorption and NN* activation performances of TATMCs and guides the design of catalysts for achieving more sustainable ammonia synthesis.

Associations Between Metabolic Obesity Phenotypes and Pathological Characteristics of Papillary Thyroid Carcinoma.

OBJECTIVE: The association between obesity, metabolic dysregulation, and the aggressive pathological traits of papillary thyroid carcinoma (PTC) continues to be a contentious issue. To date, no investigations have examined the impact of metabolic status on the malignant pathological features of PTC in relation to obesity. METHODS: This research involved 855 adult patients with PTC from Shandong Provincial Hospital, classified into 4 groups based on metabolic and obesity status: metabolically healthy nonobese, metabolically unhealthy nonobese (MUNO), metabolically healthy obese, and metabolically unhealthy obese. We employed logistic regression to investigate the relationship between these metabolic obesity phenotypes and PTC's pathological characteristics. Mediation analysis was also performed to determine metabolic abnormalities' mediating role in the nexus between obesity and these characteristics. RESULTS: Relative to metabolically healthy nonobese individuals, the metabolically unhealthy obese group was significantly associated with an elevated risk of larger tumor sizes and a greater number of tumor foci in PTC. Mediation analysis indicated that obesity directly influences tumor size, whereas its effect on tumor multifocality is mediated through metabolic dysfunctions. Specifically, high-density lipoprotein cholesterol levels were notably associated with tumor multifocality within obese subjects, serving as a mediator in obesity's impact on this trait. CONCLUSION: The concurrent presence of obesity and metabolic dysregulation is often connected to more aggressive pathological features in PTC. The mediation analysis suggests obesity directly affects tumor size and indirectly influences tumor multifocality via low high-density lipoprotein cholesterol levels.

MORE FLORET1 controls anther development by negatively regulating key tapetal genes in both diploid and tetraploid rice.

Polyploid hybrid rice (Oryza sativa) has great potential for increasing yields. However, hybrid rice depends on male fertility and its regulation, which is less well studied in polyploid rice than in diploid rice. We previously identified a MYB transcription factor, MORE FLORET1 (MOF1), whose mutation causes male sterility in neo-tetraploid rice. MOF1 expression in anthers peaks at anther Stage 7 (S7) and progressively decreases to low levels at S10. However, it remains unclear how the dynamics of MOF1 expression contribute to male fertility. Here, we carefully examined anther development in both diploid and tetraploid mof1 rice mutants, as well as lines ectopically expressing MOF1 in a temporal manner. MOF1 mutations caused delayed degeneration of the tapetum and middle layer of anthers and aberrant pollen wall organization. Ectopic MOF1 expression at later stages of anther development led to retarded cytoplasmic reorganization of tapetal cells. In both cases, pollen grains were aborted and seed production was abolished, indicating that precise control of MOF1 expression is essential for male reproduction. We demonstrated that five key tapetal genes, CYP703A3 (CYTOCHROME P450 HYDROXYLASE 703A3), OsABCG26 (Oryza sativa ATP BINDING CASSETTE G26), PTC1 (PERSISTENT TAPETAL CELL1), PKS2 (POLYKETIDE SYNTHASE 2), and OsABCG15 (Oryza sativa ATP BINDING CASSETTE G15), exhibit expression patterns opposite to those of MOF1 and are negatively regulated by MOF1. Moreover, DNA affinity purification sequencing (DAP-seq), luciferase activity assays, and electrophoretic mobility shift assays indicated that MOF1 binds directly to the PKS2 promoter for transcriptional repression. Our results provide a mechanistic basis for the regulation of male reproduction by MOF1 in both diploid and tetraploid rice. This study will facilitate the development of polyploid male sterile lines, which are useful for breeding of polyploid hybrid rice.

Association of obesity and different metabolic status with prognosis in patients with bladder cancer: a retrospective cohort study.

Background and objectives: Patients with bladder cancer (BC) are at high risk for recurrence rates and readmission costs. However, the evidence about obesity and metabolic abnormalities on the BC prognosis was inconsistent. Our primary aim was to determine the impact of obesity and different metabolic status on the readmission risk in patients with BC. Design and methods: We identified 16,649 patients with BC using the 2018 Nationwide Readmissions Database who were hospitalized from January to June 2018 and followed for 180 days. The primary outcome was 180-day readmission. The multivariate Cox regression analysis and ordered logistic regression were performed to analyze data. Results: Obesity and metabolic abnormalities were associated with an increased readmission risk in patients with BC [obesity: adjusted hazard ratio (aHR) = 1.08, 95% confidence interval (CI): 1.01-1.16; hyperglycemia: aHR = 1.11, 95% CI: 1.05-1.17; hypertension: aHR = 1.09, 95% CI: 1.03-1.15]. Compared with non-obese and no metabolic abnormalities, the risk of readmission was significantly increased in patients with metabolic abnormalities, irrespective of obesity (non-obese and metabolic abnormalities: aHR = 1.07, 95% CI: 1.02-1.13; obese and metabolic abnormalities: aHR = 1.20, 95% CI: 1.10-1.31), but not in obese and no metabolic abnormalities. These associations were consistent in patients aged 60 years or older and the surgery group. Moreover, hyperglycemia, hypertension, and a graded increment of metabolic risk were associated with an increased readmission risk. We also found increased length of stay for readmission in patients with obesity and metabolic abnormalities (aOR = 1.17, 95% CI: 1.00-1.36). Conclusion: Obesity with metabolic abnormalities and metabolic abnormalities alone were associated with higher readmission risks in patients with BC. It is suggested that prevention should focus not only on obesity but also on metabolic abnormalities to decrease the risk of readmission.

7,8,3'-Trihydroxyflavone prevents doxorubicin-induced cardiotoxicity and mitochondrial dysfunction via activating Akt signaling pathway in H9c2 cells.

Clinical application of the widely used chemotherapeutic agent, doxorubicin (DOX), is limited by its cardiotoxicity. Mitochondrial dysfunction has been revealed as a crucial factor in DOX-induced cardiotoxicity. 7,8,3'-Trihydroxyflavone (THF) is a mimetic brain-derived neurotrophic factor with neuroprotective effects. However, the potential effects of THF on DOX-induced cardiomyocyte damage and mitochondrial disorders remain unclear. H9c2 cardiomyoblasts were exposed to DOX and/or THF at different concentrations. Cardiomyocyte injury was evaluated using lactate dehydrogenase (LDH) assay and Live/Dead cytotoxicity kit. Meanwhile, mitochondrial membrane potential (MMP), morphology, mitochondrial reactive oxygen species (mito-ROS) production, and the oxygen consumption rate of cardiomyocytes were measured. The protein levels of key mitochondria-related factors such as adenosine monophosphate-activated protein kinase (AMPK), mitofusin 2 (Mfn2), dynamin-related protein 1 (Drp1), and optic atrophy protein 1 (OPA1) were examined. We found that THF reduced LDH content and death ratio of DOX-treated cardiomyocytes in a concentration-dependent manner, while increasing MMP without significantly affecting the routine and maximum capacity of mitochondrial respiration. Mechanistically, THF increased the activity of Akt and protein levels of Mfn2 and heme oxygenase 1 (HO-1). Moreover, inhibition of Akt reversed the protective role of THF, increased mito-ROS levels, and repressed Mfn2 and HO-1 expression. Therefore, we conclude, THF relieves DOX-induced cardiotoxicity and improves mitochondrial function by activating Akt-mediated Mfn2 and HO-1 pathways. This finding provides promising therapeutic insights for DOX-induced cardiac dysfunction.

Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice.

Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signalling is blunted and accompanied by hyperinsulinaemia, the promotion of hepatic DNL continues unabated and hepatic steatosis increases. Here, we show that WD40 repeat-containing protein 6 (WDR6) promotes hepatic DNL during IR. Mechanistically, WDR6 interacts with the beta-type catalytic subunit of serine/threonine-protein phosphatase 1 (PPP1CB) to facilitate PPP1CB dephosphorylation at Thr316, which subsequently enhances fatty acid synthases transcription through DNA-dependent protein kinase and upstream stimulatory factor 1. Using molecular dynamics simulation analysis, we find a small natural compound, XLIX, that inhibits the interaction of WDR6 with PPP1CB, thus reducing DNL in IR states. Together, these results reveal WDR6 as a promising target for the treatment of hepatic steatosis.

Isolated diffuse choroidal hemangioma without systemic symptoms: a case report.

BACKGROUND: Sturge-Weber syndrome is a nonhereditary congenital neurocutaneous syndrome characterized by a distinctive facial capillary malformation,neurological abnormalities, and ocular abnormalities such as glaucoma and choroidal hemangioma.It can be divided into different subtypes according to different clinical manifestations. It is rare for a patient to present with isolated difuse choroidal hemangioma and ipsilateral abnormal conjunctival and episcleral vessels without other systemic symptoms. CASE PRESENTATION: We report a 30-year-old man with isolated diffuse choroidal hemangioma in his right eye without systemic symptoms, such as vascular malformations in the skin or leptomeningeal angiomatosis. The only additional ophthalmic finding was ipsilateral abnormal conjunctival and episcleral vessels without glaucoma. However, there was no evidence of leptomeningeal angiomatosis or port-wine stain on the right side of the face, or glaucoma, which are common clinical manifestations of the Sturge-Weber syndrome (SWS).The absence of these characteristic symptoms did not preclude the diagnosis, and the patient could be diagnosed with a particular subtype of SWS. CONCLUSIONS: This is a rare case of documented isolated difuse choroidal hemangioma with ipsilateral abnormal conjunctival and episcleral vessels without glaucoma which we think it is belonging to a particular subtype of SWS.In addition to the traditional clinical manifestations, more and more atypical clinical manifestations are also accompanied by SWS, which requires our clinicians to continuously discover and report, so as to help more clinicians understand this disease.

Cortisol dysregulation in anxiety infertile women and the influence on IVF treatment outcome.

Introduction: Dysregulation of the stress-regulatory hormone cortisol is associated with anxiety, but its potential impact on infertile women and in vitro fertilization (IVF) treatment remains unclear. This prospective cross-sectional study aimed at evaluating the dysregulation of cortisol and its correlation to anxiety in infertile women. The influence of stress on IVF outcomes was also investigated. Methods: A point-of-care test was used for the measurement of morning serum cortisol in 110 infertile women and 112 age-matching healthy individuals. A Self-Rating Anxiety Scale (SAS) was used for the anxiety assessment of infertile women, and 109 of them underwent IVF treatment starting with the GnRH-antagonist protocol. If clinical pregnancy was not achieved, more IVF cycles were conducted with adjusted protocols until the patients got pregnant or gave up. Results: Higher morning serum cortisol level was identified for infertile patients, especially for the elder. Women with no anxiety showed significant differences in cortisol levels, monthly income, and BMI compared with those with severe anxiety. A strong correlation was found between the morning cortisol level and the SAS score. When the cutoff value is 22.25 µg/dL, cortisol concentration could predict the onset of anxiety with high accuracy (95.45%) among infertile women. After IVF treatments, women with high SAS scores (>50) or cortisol levels (>22.25 µg/dL) demonstrated a lower rate of pregnancy (8.0%-10.3%) and more IVF cycles, although the impact of anxiety was not affirmative. Conclusion: Hypersecretion of cortisol related to anxiety was prevalent among infertile women, but the influence of anxiety on multi-cycle IVF treatment was not affirmative due to the complicated treatment procedures. This study suggested that the assessment of psychological disorders and stress hormone dysregulation should not be overlooked. An anxiety questionnaire and rapid cortisol test might be included in the treatment protocol to provide better medical care.

The effects of obesity and metabolic abnormalities on severe COVID-19-related outcomes after vaccination: A population-based study.

Breakthrough SARS-CoV-2 infections of vaccinated individuals are being reported globally, resulting in an increased risk of hospitalization and death among such patients. Therefore, it is crucial to identify the modifiable risk factors that may affect the protective efficacy of vaccine use against the development of severe COVID-19 and thus to initiate early medical interventions. Here, in population-based studies using the UK Biobank database and the 2021 National Health Interview Survey (NHIS), we analyzed 20,362 participants aged 50 years or older and 2,588 aged 18 years or older from both databases who tested positive for SARS-COV-2, of whom 33.1% and 67.7% received one or more doses of vaccine, respectively. In the UK Biobank, participants are followed from the vaccination date until October 18, 2021. We found that obesity and metabolic abnormalities (namely, hyperglycemia, hyperlipidemia, and hypertension) were modifiable factors for severe COVID-19 in vaccinated patients (all p < 0.05). When metabolic abnormalities were present, regardless of obesity, the risk of severe COVID-19 was higher than that of metabolically normal individuals (all p < 0.05). Moreover, pharmacological interventions targeting such abnormalities (namely, antihypertensive [adjusted hazard ratio (aHR) 0.64, 95% CI 0.48-0.86; p = 0.003], glucose-lowering [aHR 0.55, 95% CI 0.36-0.83; p = 0.004], and lipid-lowering treatments [aHR 0.50, 95% CI 0.37-0.68; p < 0.001]) were significantly associated with a reduced risk for this outcome. These results show that more proactive health management of patients with obesity and metabolic abnormalities is critical to reduce the incidence of severe COVID-19 after vaccination.

BDNF mimetic 7,8-dihydroxyflavone rescues rotenone-induced cytotoxicity in cardiomyocytes by ameliorating mitochondrial dysfunction.

The relationship between mitochondrial dysfunction and cardiovascular disease pathogenesis is well recognized. 7,8-Dihydroxyflavone (7,8-DHF), a mimetic of brain-derived neurotrophic factor, inhibits mitochondrial impairments and improves cardiac function. However, the regulatory role of 7,8-DHF in the mitochondrial function of cardiomyocytes is not fully understood. To investigate the potential mito-protective effects of 7,8-DHF in cardiomyocytes, we treated H9c2 or HL-1 cells with the mitochondrial respiratory complex I inhibitor rotenone (Rot) as an in vitro model of mitochondrial dysfunction. We found that 7,8-DHF effectively eliminated various concentrations of Rot-induced cell death and reduced lactate dehydrogenase release. 7,8-DHF significantly improved mitochondrial membrane potential and inhibited mitochondrial reactive oxygen species. Moreover, 7,8-DHF decreased routine and leak respiration, restored protein levels of mitochondrial complex I-IV, and increased ATP production in Rot-treated H9c2 cells. The protective role of 7,8-DHF in Rot-induced damage was validated in HL-1 cells. Nuclear phosphorylation protein expression of signal transducer and activator of transcription 3 (STAT3) was significantly increased by 7,8-DHF. The present study suggests that 7,8-DHF rescues Rot-induced cytotoxicity by inhibiting mitochondrial dysfunction and promoting nuclear translocation of p-STAT3 in cardiomyocytes, thus nominating 7,8-DHF as a new pharmacological candidate agent against mitochondrial dysfunction in cardiac diseases.

Distribution, Risk Assessment, and Source Apportionment of Heavy Metal Pollution in Cultivated Soil of a Typical Mining Area in Southwest China.

The present study investigates heavy metal pollution and its sources in cultivated soils in Bijie City, Guizhou Province, China. The ground accumulation index method was used to evaluate the associated risks, while correlation, principal component, and positive matrix factor model analyses were used to identify sources. The results show that the overall contamination levels, except for Cd, were not serious. Agricultural materials, industrial activities, transportation, coal combustion and atmospheric deposition, parent rock, and irrigation accounted for 19.66%, 14.11%, 14.54%, 16.33%, 20.70%, and 14.67% of the total accumulation of metals, respectively. Copper, Ni, Zn, and Cr came mainly from parent rocks; Pb was mainly from traffic emissions; Hg was mainly from coal deposition; As was mainly from irrigation; and Cd was mainly from industrial activities. The main sources of soil metals were irrigation, agricultural activities, and coal deposition in the east and industrial activities and soil-forming parent rocks in the west. Environ Toxicol Chem 2023;42:888-900. © 2023 SETAC.

CRPGAN: Learning image-to-image translation of two unpaired images by cross-attention mechanism and parallelization strategy.

Unsupervised image-to-image translation (UI2I) tasks aim to find a mapping between the source and the target domains from unpaired training data. Previous methods can not effectively capture the differences between the source and the target domain on different scales and often leads to poor quality of the generated images, noise, distortion, and other conditions that do not match human vision perception, and has high time complexity. To address this problem, we propose a multi-scale training structure and a progressive growth generator method to solve UI2I task. Our method refines the generated images from global structures to local details by adding new convolution blocks continuously and shares the network parameters in different scales and also in the same scale of network. Finally, we propose a new Cross-CBAM mechanism (CRCBAM), which uses a multi-layer spatial attention and channel attention cross structure to generate more refined style images. Experiments on our collected Opera Face, and other open datasets Summer↔Winter, Horse↔Zebra, Photo↔Van Gogh, show that the proposed algorithm is superior to other state-of-art algorithms.

A DFT study of plasma-catalytic ammonia synthesis: the effect of electric fields, excess electrons and catalyst surfaces on N2 dissociation.

Plasma catalytic synthesis of ammonia has the advantages of flexible on-off and environmental friendliness, making ammonia a potential vector for renewable energy storage. The synergistic interaction between plasmas and catalyst surfaces remains unclear. In this work, we develop a quantum chemical model based on density functional theory where the plasma environment is simplified. The effect of electric fields and surface electrons on N2 adsorption and dissociation is studied on the typical catalysts (Ru and Ni) with different surface morphologies. The combined effect of the electric fields and excess electrons will promote the adsorption of N2 and the weakening of the NN triple bond. It is shown that the electron distribution on the surface is optimized, and the electrostatic interaction between surface atoms and adsorbates is strengthened. The marginal effect has been observed, and the promotion effect on the catalysts with better performance in thermal-catalytic N2 dissociation is weaker.

Crosslinked zwitterionic microcapsules to overcome gastrointestinal barriers for oral insulin delivery.

Oral insulin delivery has been extensively considered to achieve great patient compliance and convenience as well as favourable glucose homeostasis. However, its application is highly limited by the low insulin bioavailability owing to gastrointestinal barriers. Herein, we developed crosslinked zwitterionic microcapsules (CB-MCs@INS) based on a carboxyl betaine (CB)-modified poly(acryloyl carbonate-co-caprolactone) copolymer via the combination of microfluidics and UV-crosslinking to improve oral insulin delivery. CB-MC@INS microcapsules with high drug loading capacity (>40%) protected insulin from acid degradation in the harsh gastric environment. Through the introduction of CB-moieties, CB-MCs@INS possessed superior affinity for epithelial cells and improved insulin transport as compared to non-CB modified MCs@INS (5.15-fold), which was mainly attributed to the CB-mediated cell surface transporter via the PAT1 pathway. Moreover, the oral administration of CB-MCs@INS exhibited an excellent hypoglycaemic effect and maintained normoglycemia for up to 8 h in diabetic mice, demonstrating the great potential of crosslinked zwitterionic microcapsules as an oral insulin delivery platform for diabetes therapy.

Geochemical characteristics of heavy metals of bedrock, soil, and tea in a metamorphic rock area of Guizhou Province, China.

Through field surveys, sampling, and laboratory experiments, the content, enrichment, and migration characteristics of heavy metals in the rock-soil-tea system in the Guizhou metamorphic rock area were analyzed herein. The results show that the As and Hg contents in metamorphic sandstone in the study area are higher than those in slate, while the Mn, Zn, Pb, and Ni contents in slate are higher. The content of heavy metals in the sandstone of the Jialu formation of the Xiajiang group in Neoproterozoic is the highest, and that of the slate of the Fanzhao formation is the lowest. The content of As in the rock samples in the study area is higher than that in the Epicontinental crust, while Cd is found to be deficient. The heavy metals at some soil points exceed the standard, but this does not affect the growth and development of tea. The content of heavy metals in most tea is lower than the safety limit standards, and the THQ value is less than 1, indicating that the heavy metals in tea in Guizhou metamorphic rock areas pose no concern for human health. In the metamorphic rock distribution areas of Guizhou, tea does not enrich As, Cr, Hg, and Pb in soil, but enriches Mn, Cu, Ni, and Zn to varying degrees, with the enrichment of Mn being the strongest.

Data-driven Shape Sensing of Continuum Dexterous Manipulators Using Embedded Capacitive Sensor.

We propose a novel inexpensive embedded capacitive sensor (ECS) for sensing the shape of Continuum Dexterous Manipulators (CDMs). Our approach addresses some limitations associated with the prevalent Fiber Bragg Grating (FBG) sensors, such as temperature sensitivity and high production costs. ECSs are calibrated using a vision-based system. The calibration of the ECS is performed by a recurrent neural network that uses the kinematic data collected from the vision-based system along with the uncalibrated data from ECSs. We evaluated the performance on a 3D printed prototype of a cable-driven CDM with multiple markers along its length. Using data from three ECSs along the length of the CDM, we computed the angle and position of its tip with respect to its base and compared the results to the measurements of the visual-based system. We found a 6.6% tip position error normalized to the length of the CDM. The work shows the early feasibility of using ECSs for shape sensing and feedback control of CDMs and discusses potential future improvements.

Design, synthesis and evaluation of fused hybrids with acetylcholinesterase inhibiting and Nrf2 activating functions for Alzheimer's disease.

Designing of multiple-target directed ligands (MTDLs) has emerged as an attractive strategy for Alzheimer's disease (AD). Fusing the benzylpiperidine motif from AChE inhibitor donepezil and the 1,2,4-oxadiazole core from the Nrf2 activator 25 that was previously reported, we designed and synthesized a series of multifunctional anti-AD hybrids. The optimal hybrid 15a exhibited excellent AChE inhibitory (eeAChE IC50 = 0.07 ± 0.01 µM; hAChE IC50 = 0.38 ± 0.04 µM) and significant Nrf2 inductivity. It upregulated the protein and transcription level of Nrf2 and its downstream proteins HO-1, NQO1, and GCLM and promoted Nrf2 translocation from cytoplasm into nuclei. Additionally, 15a exhibited important neuroprotective function in protecting the cells from being damaged by H2O2 and Aß1-42 aggregation and exerted antioxidant stress and anti-inflammatory activities in reducing the production of ROS and pro-inflammatory cytokines. Moreover, 15a effectively shortened the latency time and escape distance to the target, increased the arrival times, and simplified the tracks in Morris water maze test induced by scopolamine and Aß1-42. At the same time, it significantly reduced the levels of proinflammatory factors in the mice model brains. These effects of 15a in improving cognition and alleviating inflammation were even better than the combination of AChE inhibitor and Nrf2 activator, suggesting a remarkable benefit for AD treatment. 15a could serve as a novel hit compound with Nrf2 inductive activity and AChE inhibitory activity for further research.

Association of longitudinal changes in serum lipids with the natural history of subclinical hypothyroidism: A retrospective cohort study using data from the REACTION study.

Background: Subclinical hypothyroidism (SCH) often leads to alterations in lipid profile, which may negatively impact humans health. Whether lipids in turn affect the natural history of SCH is unknown. We aimed to assess the association between longitudinal changes in serum lipid levels and the natural history of SCH. Methods: This retrospective cohort study using data from the REACTION study included 581 patients with SCH who were enrolled between July 1, 2011, and December 19, 2014, with a median follow-up of three [IQR, 2·86-3·21] years. Patients with missing data or conditions that can affect thyroid function were excluded. Changes in serum lipid levels were calculated from serum lipid measurements 3 years apart and classified in two ways: 1) the first, second, and third tertiles of the difference between baseline and follow-up and 2) the percent change from baseline, namely, serum lipid decrease ≥ 25%, minor change, and serum lipid increase ≥ 25%. The natural history of SCH includes regression to euthyroidism, SCH persistence, or progression to overt hypothyroidism (OH). Odds ratios (ORs) were estimated by multivariable logistic regression. Validation was performed on data from a health management cohort study conducted from January 1, 2012, to December 31, 2016, with a median follow-up of two [IQR, 1·92-2·08] years. After using the same inclusion and exclusion criteria as the REACTION cohort study, 412 patients with SCH were eligible for the validation analysis. Findings: There were 132 (22·7%) men and 449 (77·3%) women in the study, with a median age of 56 [IQR,49-62] years. During follow-up, 270 (46·5%), 266 (45·8%), and 27 (4·6%) patients had regression to euthyroidism, persistent SCH, and progression to OH, respectively. Both grouping manners showed a significant association between changes in lipid levels and the natural history of SCH. A total cholesterol (TC)-level increase was independently associated with a greater risk of progression to OH (OR for ≥ 25% TC increase vs. minor change: 5·40; 95% CI 1·46-21·65), whereas TC-level declines increased the likelihood of regressing to euthyroidism (OR for ≥ 25% TC decrease vs. minor change: 3·45; 95% CI 1·09-12·43). Similarly, the likelihood of regression according to changes in triglyceride (TG) levels exhibited a consistent trend with that according to TC-level changes. A similar pattern of association was observed in the validation cohort. Interpretation: Changes in serum lipid levels in SCH are associated with future progression or regression risk, suggesting that the changes in serum lipid levels may affect the natural history of SCH. Clinicians should pay attention to the long-term control of serum lipids levels in populations with SCH, which may benefit thyroid function. Funding: This work was supported by grants from the National Key Research and Development Program of China (2017YFC1309800), the National Natural Science Foundation (81430020, 82070818), and the "Outstanding University Driven by Talents" Program and Academic Promotion Program of Shandong First Medical University (2019LJ007).

N-Benzyl Benzamide Derivatives as Selective Sub-Nanomolar Butyrylcholinesterase Inhibitors for Possible Treatment in Advanced Alzheimer's Disease.

Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel N-benzyl benzamide scaffold, inhibited BChE with IC50 from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar KD value, which revealed that the compounds exert the inhibitory effect through directly binding to BChE. Several compounds showed neuroprotective effects verified by the oxidative damage model. Furthermore, the safety of S11-1014 and S11-1033 was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg S11-1014 or S11-1033 exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Aß1-42. The pharmacokinetics studies characterized the metabolic stability of S11-1014. Thus, N-benzyl benzamide inhibitors are promising compounds with drug-like properties for improving cognitive dysfunction, providing a potential strategy for the treatment of Alzheimer's disease.

The Value of HPA Axis Hormones as Biomarkers for Screening and Early Diagnosis of Postpartum Depression: Updated Information About Methodology.

Because of the high prevalence of postpartum depression (PPD) and the suffering involved, early diagnosis is urgent; however, current screening tools and diagnosis are inadequate. In addition to conventional methods such as the Edinburgh Postnatal Depression Scale and clinical interviews, several hormones in the hypothalamic-pituitary-adrenal (HPA) axis, such as corticotrophin-releasing hormone, adrenocorticotropic hormone, and cortisol, have been considered because of their critical roles in stress regulation in the mothers. The study designs are complicated, however, and so the effectiveness of these hormones as biomarkers for PPD is still controversial. Such inconsistency may have resulted from the variation in methodology between studies. The methodology problems in the investigation of PPD and HPA axis hormones have not been reported extensively. We therefore sought to summarize the methodological problems of studies published in the past decade, including the strengths and weaknesses of the examinations and the technological difficulties involved. Our findings suggest that (a) suitable samples and appropriate detection methods would reduce heterogeneity among trials; (b) the cutoff value of the scale test should be carefully selected for determining the performance of biomarker tests; (c) evaluation methods and criteria should be chosen with consideration of the tools feasible for use in local hospitals and population; and (d) the cost of diagnosis should be reduced. We hope that these findings provide insight for future investigations of HPA axis hormones as biomarkers for screening and early diagnosis of PPD.