Biothiols-activated near-infrared frequency up-conversion luminescence probe for early evaluation of drug-induced hepatotoxicity.

A novel biothiols-sensitive near-infrared (NIR) fluorescent probe RhDN based on a rhodamine skeleton was developed for early detection of drug-induced hepatotoxicity in living mice. RhDN can be used not only as a conventional large stokes shift fluorescent (FL) probe, but also as a kind of anti-Stokes frequency upconversion luminescence (FUCL) molecular probe, which represents a long wavelength excitation (808 nm) to short wavelength emission (760 nm), and response to Cys/Hcy/GSH with high sensitivity. Compared with traditional FL methods, the FUCL method exhibited a lower detection limit of Cys, Hcy, and GSH in 75.1 nM, 101.8 nM, and 84.9 nM, respectively. We exemplify RhDN for tracking endogenously biothiols distribution in living cells and further realize real-time in vivo bioimaging of biothiols activity in mice with dual-mode luminescence system. Moreover, RhDN has been successfully applied to visualize the detection of drug-induced hepatotoxicity in living mice. Overall, this report presents a unique approach to the development of large stokes shift NIR FUCL molecular probes for in vitro and in vivo biothiols biosensing.

Helicobacter pylori Treatment and Gastric Cancer Risk Among Individuals With High Genetic Risk for Gastric Cancer.

Importance: Helicobacter pylori treatment and nutrition supplementation may protect against gastric cancer (GC), but whether the beneficial effects only apply to potential genetic subgroups and whether high genetic risk may be counteracted by these chemoprevention strategies remains unknown. Objective: To examine genetic variants associated with the progression of gastric lesions and GC risk and to assess the benefits of H pylori treatment and nutrition supplementation by levels of genetic risk. Design, Setting, and Participants: This cohort study used follow-up data of the Shandong Intervention Trial (SIT, 1989-2022) and China Kadoorie Biobank (CKB, 2004-2018) in China. Based on the SIT, a longitudinal genome-wide association study was conducted to identify genetic variants for gastric lesion progression. Significant variants were examined for incident GC in a randomly sampled set of CKB participants (set 1). Polygenic risk scores (PRSs) combining independent variants were assessed for GC risk in the remaining CKB participants (set 2) and in an independent case-control study in Linqu. Exposures: H pylori treatment and nutrition supplementation. Main Outcomes and Measures: Primary outcomes were the progression of gastric lesions (in SIT only) and the risk of GC. The associations of H pylori treatment and nutrition supplementation with GC were evaluated among SIT participants with different levels of genetic risk. Results: Our analyses included 2816 participants (mean [SD] age, 46.95 [9.12] years; 1429 [50.75%] women) in SIT and 100 228 participants (mean [SD] age, 53.69 [11.00] years; 57 357 [57.23%] women) in CKB, with 147 GC cases in SIT and 825 GC cases in CKB identified during follow-up. A PRS integrating 12 genomic loci associated with gastric lesion progression and incident GC risk was derived, which was associated with GC risk in CKB (highest vs lowest decile of PRS: hazard ratio [HR], 2.54; 95% CI, 1.80-3.57) and further validated in the analysis of 702 case participants and 692 control participants (mean [SD] age, 54.54 [7.66] years; 527 [37.80%] women; odds ratio, 1.83; 95% CI, 1.11-3.05). H pylori treatment was associated with reduced GC risk only for individuals with high genetic risk (top 25% of PRS: HR, 0.45; 95% CI, 0.25-0.82) but not for those with low genetic risk (HR, 0.81; 95% CI, 0.50-1.34; P for interaction = .03). Such effect modification was not found for vitamin (P for interaction = .93) or garlic (P for interaction = .41) supplementation. Conclusions and Relevance: The findings of this cohort study indicate that a high genetic risk of GC may be counteracted by H pylori treatment, suggesting primary prevention could be tailored to genetic risk for more effective prevention.

Disruption of PABPN1 phase separation by SNRPD2 drives colorectal cancer cell proliferation and migration through promoting alternative polyadenylation of CTNNBIP1.

Generally shortened 3' UTR due to alternative polyadenylation (APA) is widely observed in cancer, but its regulation mechanisms for cancer are not well characterized. Here, with profiling of APA in colorectal cancer tissues and poly(A) signal editing, we firstly identified that the shortened 3' UTR of CTNNIBP1 in colorectal cancer promotes cell proliferation and migration. We found that liquid-liquid phase separation (LLPS) of PABPN1 is reduced albeit with higher expression in cancer, and the reduction of LLPS leads to the shortened 3' UTR of CTNNBIP1 and promotes cell proliferation and migration. Notably, the splicing factor SNRPD2 upregulated in colorectal cancer, can interact with glutamic-proline (EP) domain of PABPN1, and then disrupt LLPS of PABPN1, which attenuates the repression effect of PABPN1 on the proximal poly(A) sites. Our results firstly reveal a new regulation mechanism of APA by disruption of LLPS of PABPN1, suggesting that regulation of APA by interfering LLPS of 3' end processing factor may have the potential as a new way for the treatment of cancer.

OTUD1 enhances gastric cancer aggressiveness by deubiquitinating EBV-encoded protein BALF1 to stabilize the apoptosis inhibitor Bcl-2.

The Epstein-Barr virus (EBV) is implicated in several cancers, including EBV-associated gastric cancer (EBVaGC). This study focuses on EBV-encoded BALF1 (BamH1 A fragment leftward reading frame 1), a key apoptosis regulator in EBV-related cancers, whose specific impact on EBVaGC was previously unknown. Our findings indicate that BALF1 overexpression in gastric cancer cells significantly enhances their proliferation, migration, and resistance to chemotherapy-induced apoptosis, confirming BALF1's oncogenic potential. A novel discovery is that BALF1 undergoes degradation via the ubiquitin-proteasome pathway. Through analysis of 69 deubiquitinating enzymes (DUBs), ovarian tumor protease (OTU) domain-containing protein 1 (OTUD1) emerged as a vital regulator for maintaining BALF1 protein stability. Furthermore, BALF1 was found to play a role in regulating the stability of the B-cell lymphoma-2 (Bcl-2) protein, increasing its levels through deubiquitination. This mechanism reveals BALF1's multifaceted oncogenic role in gastric cancer, as it contributes both directly and indirectly to cancer progression, particularly by stabilizing Bcl-2, known for its anti-apoptotic characteristics. These insights significantly deepen our understanding of EBV's involvement in the pathogenesis of gastric cancer. The elucidation of OTUD1's role in BALF1 regulation and its influence on Bcl-2 stabilization provide new avenues for therapeutic intervention in EBVaGC, bridging the gap between viral oncogenesis and cellular protein regulation and offering a more holistic view of gastric cancer development under the influence of EBV.

A Single-Shot Scattering Medium Imaging Method via Bispectrum Truncation.

Imaging using scattering media is a very important yet challenging technology. As one of the most widely used scattering imaging methods, speckle autocorrelation technology has important applications in several fields. However, traditional speckle autocorrelation imaging methods usually use iterative phase recovery algorithms to obtain the Fourier phase of hidden objects, posing issues such as large data calculation volumes and uncertain reconstruction results. Here, we propose a single-shot scattering imaging method based on the bispectrum truncation method. The bispectrum analysis is utilized for hidden object phase recovery, the truncation method is used to avoid the computation of redundant data when calculating the bispectrum data, and the method is experimentally verified. The experimental results show that our method does not require uncertain iterative calculations and can reduce the bispectrum data computation by more than 80% by adjusting the truncation factor without damaging the imaging quality, which greatly improves imaging efficiency. This method paves the way for rapid imaging through scattering media and brings benefits for imaging in dynamic situations.

The effects of video double-lumen tubes on intubation complications in patients undergoing thoracic surgery: A randomised controlled study.

BACKGROUND: Tracheal injuries, vocal cord injuries, sore throat and hoarseness are common complications of double-lumen tube (DLT) intubation. OBJECTIVE: This study aimed to evaluate the effects of 'video double-lumen tubes' (VDLTs) on intubation complications in patients undergoing thoracic surgery. DESIGN: A randomised controlled study. SETTINGT: Xuzhou Cancer Hospital, Xuzhou, China, from January 2023 to June 2023. PATIENTS: One hundred eighty-two patients undergoing elective thoracic surgery with one-lung ventilation were randomised into two groups: 90 in the DLT group and 92 in the VDLT group. INTERVENTION: VDLT was selected for intubation in the VDLT group, and DLT was selected for intubation in the DLT group. A fibreoptic bronchoscope (FOB) was used to record tracheal and vocal cord injuries. MAIN OUTCOME MEASURES: The primary outcomes were the incidence of moderate-to-severe tracheal injury and the incidence of vocal cord injury. The secondary outcomes included the incidence and severity of postoperative 24 and 48 h sore throat and hoarseness. RESULTS: The incidence of moderate-to-severe tracheal injury was 32/90 (35.6%) in the DLT group, and 45/92 (48.9%) in the VDLT group ( P  = 0.077; relative risk 1.38, 95% CI, 0.97 to 1.95). The incidence of vocal cord injury was 31/90 (34.4%) and 34/92 (37%) in the DLT and VDLT groups, respectively ( P  = 0.449). The incidence of postoperative 24 h sore throat and hoarseness was significantly higher in the VDLT group than in the DLT group (for sore throat: P  = 0.032, relative risk 1.63, 95% CI, 1.03 to 2.57; for hoarseness: P  = 0.018, relative risk 1.48, 95% CI, 1.06 to 2.06). CONCLUSION: There was no statistically significant difference in the incidence of moderate-to-severe tracheal injury and vocal cord injury between DLTs and VDLTs. While improving the first-attempt success rate, intubation with VDLT increased the incidence of postoperative 24 h sore throat and hoarseness. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR2300067348.

Using Diffraction Deep Neural Networks for Indirect Phase Recovery Based on Zernike Polynomials.

The phase recovery module is dedicated to acquiring phase distribution information within imaging systems, enabling the monitoring and adjustment of a system's performance. Traditional phase inversion techniques exhibit limitations, such as the speed of the sensor and complexity of the system. Therefore, we propose an indirect phase retrieval approach based on a diffraction neural network. By utilizing non-source diffraction through multiple layers of diffraction units, this approach reconstructs coefficients based on Zernike polynomials from incident beams with distorted phases, thereby indirectly synthesizing interference phases. Through network training and simulation testing, we validate the effectiveness of this approach, showcasing the trained network's capacity for single-order phase recognition and multi-order composite phase inversion. We conduct an analysis of the network's generalization and evaluate the impact of the network depth on the restoration accuracy. The test results reveal an average root mean square error of 0.086λ for phase inversion. This research provides new insights and methodologies for the development of the phase recovery component in adaptive optics systems.

PSEUDO-ETIOLATION IN LIGHT proteins reduce greening by binding GLK transcription factors.

Knocking out genes encoding proteins that downregulate the accumulation of pigments may lead to increases in crop quality and yield. PSEUDO-ETIOLATION IN LIGHT 1 (PEL1) downregulates the accumulation of carotenoids in carrot and chlorophyll in Arabidopsis and rice and may inhibit GOLDEN 2-LIKE (GLK) transcription factors. PEL1 belongs to a previously unstudied gene family found only in plants. We used CRISPR/Cas9 technology to knock out each member of the 4-member PEL gene family and both GLK genes in Arabidopsis. In pel mutants, chlorophyll levels were elevated in seedlings; after flowering, chloroplasts increased in size, and anthocyanin levels increased. Although the chlorophyll-deficient phenotype of glk1 glk2 was epistatic to pel1 pel2 pel3 pel4 in most of our experiments, glk1 glk2 was not epistatic to pel1 pel2 pel3 pel4 for the accumulation of anthocyanins in most of our experiments. The pel alleles attenuated growth, altered the accumulation of nutrients in seeds, disrupted an abscisic acid-inducible inhibition of seedling growth response that promotes drought tolerance, and affected the expression of genes associated with diverse biological functions, such as stress responses, cell wall metabolism hormone responses, signaling, growth, and the accumulation of phenylpropanoids and pigments. We found that PEL proteins specifically bind 6 transcription factors that influence the accumulation of anthocyanins, GLK2, and the carboxy termini of GLK1 and Arabidopsis thaliana myeloblastosis oncogene homolog 4 (AtMYB4). Our data indicate that the PEL proteins influence the accumulation of chlorophyll and many other processes, possibly by inhibiting GLK transcription factors and via other mechanisms, and that multiple mechanisms downregulate chlorophyll content.

Developing Computerized Adaptive Testing for a National Health Professionals Exam: An Attempt from Psychometric Simulations.

Introduction: The accurate assessment of health professionals' competence is critical for ensuring public health safety and quality of care. Computerized Adaptive Testing (CAT) based on the Item Response Theory (IRT) has the potential to improve measurement accuracy and reduce respondent burden. In this study, we conducted psychometric simulations to develop a CAT for evaluating the candidates' competence of health professionals. Methods: The initial CAT item bank was sourced from the Standardized Competence Test for Clinical Medicine Undergraduates (SCTCMU), a nationwide summative test in China, consisting of 300 multiple-choice items. We randomly selected response data from 2000 Chinese clinical medicine undergraduates for analysis. Two types of analyses were performed: first, evaluating the psychometric properties of all items to meet the requirements of CAT; and second, conducting multiple CAT simulations using both simulated and real response data. Results: The final CAT item bank consisted of 121 items, for which item parameters were calculated using a two-parameter logistic model (2PLM). The CAT simulations, based on both simulated and real data, revealed sufficient marginal reliability (coefficient of marginal reliability above 0.750) and criterion-related validity (Pearson's correlations between CAT scores and aggregate scores of the SCTCMU exceeding 0.850). Discussion: In national-level medical education assessment, there is an increasing need for concise yet valid evaluations of candidates' competence of health professionals. The CAT developed in this study demonstrated satisfactory reliability and validity, offering a more efficient assessment of candidates' competence of health professionals. The psychometric properties of the CAT could lead to shorter test durations, reduced information loss, and a decreased testing burden for participants.

Determination of seroprevalence and kinetics of humoral response using mpox virus A29 protein.

BACKGROUND: Mpox virus (MPXV), previously known as monkeypox virus, has spread globally in 2022. An accurate and convenient antibody test is essential for the determination of seroprevalence and for studying immune response after natural infection or vaccination. Most seroprevalence or vaccine studies used either live MPXV (or vaccinia virus [VACV]) or inactivated MPXV (or VACV) culture lysate for serological assays, but MPXV culture can only be performed in biosafety level 3 (BSL-3) facilities. Here, we developed and evaluated an enzyme immunoassay (EIA) based on the MPXV A29 surface envelope protein. METHODS: We compared the specificity of the MPXV A29, VACV A27, and VACV lysate EIA using serum specimens collected prior to the global spread of MPXV. Next, we performed these EIAs for serum specimens collected from two mpox patients and an MVA-BN vaccine recipient. We also assessed the kinetics of plasmblast and MPXV A29-specific B-cell response. RESULTS: Using sera collected from different age groups in Hong Kong, we found that most individuals, including those born before 1981 who have received the smallpox vaccine, tested negative using the MPXV A29 protein. MPXV A29-specific antibody could be detected in the serum of mpox patients and an MVA-BN recipient. In a mpox patient, the frequency of plasmablast and MPXV A29-specific B cell peaked on day 8 post-symptom onset and gradually decreased. Finally, we demonstrated that antibodies against the A29 protein can be used for immunofluorescence staining of MPXV-infected cells. CONCLUSIONS: MPXV A29 protein is suitable for studying the immune response against MPXV infection.

Since early 2022, mpox (monkeypox) has been reported in many countries where the disease is not regularly found to occur. The aim of the study was to develop and evaluate the performance of laboratory assays based on the mpox virus surface protein, named A29. We found our assays could accurately distinguish naturally infected cases from smallpox vaccine recipients as well as those who were neither infected nor vaccinated. Our assays provide a useful tool for studying the host immune response to mpox virus.

A comparison of micro-flocculation and ozonation as pretreatments for ultrafiltration: organic removal and membrane fouling.

Micro-flocculation and ozone were applied as pretreatments of ultrafiltration to treat sodium alginate (SA) and humic acid (HA) simulated water, respectively, to investigate the effects of different pretreatments of ultrafiltration (UF) on filtration flux and removal of organic matters. Regarding the SA simulated water, micro-flocculation helped to improve the dissolved organic carbon (DOC) removal efficiency highly, maximum DOC removal efficiency reached to 79.77%, due to the rejection of gel layer introduced by the alginate-aluminum complexes, but the gel layer had a negative impact on membrane flux. Compared with micro-flocculation, ozone as pretreatments had better ability to enhance the membrane specific flux, the maximum final specific flux remained as 0.786, larger than that of MF-UF process (0.574). Ozonation oxidizing SA into small organic molecules significantly reduced membrane fouling and filtration resistance, but also produced some dissolved organic matters hindering DOC removal of effluent. As for HA simulated water, both the micro-flocculation and ozone could effectively improve the specific flux, the final specific flux of MF-UF and ozone-UF were about 0.930, but MF-UF exhibited better DOC removal than ozone-UF, which avoided the introduction of additional dissolved organic matters.

Integrated transcriptomics and metabolomics reveal protective effects on heart of hibernating Daurian ground squirrels.

Hibernating mammals are natural models of resistance to ischemia, hypoxia-reperfusion injury, and hypothermia. Daurian ground squirrels (spermophilus dauricus) can adapt to endure multiple torpor-arousal cycles without sustaining cardiac damage. However, the molecular regulatory mechanisms that underlie this adaptive response are not yet fully understood. This study investigates morphological, functional, genetic, and metabolic changes that occur in the heart of ground squirrels in three groups: summer active (SA), late torpor (LT), and interbout arousal (IBA). Morphological and functional changes in the heart were measured using hematoxylin-eosin (HE) staining, Masson staining, echocardiography, and enzyme-linked immunosorbent assay (ELISA). Results showed significant changes in cardiac function in the LT group as compared with SA or IBA groups, but no irreversible damage occurred. To understand the molecular mechanisms underlying these phenotypic changes, transcriptomic and metabolomic analyses were conducted to assess differential changes in gene expression and metabolite levels in the three groups of ground squirrels, with a focus on GO and KEGG pathway analysis. Transcriptomic analysis showed that differentially expressed genes were involved in the remodeling of cytoskeletal proteins, reduction in protein synthesis, and downregulation of the ubiquitin-proteasome pathway during hibernation (including LT and IBA groups), as compared with the SA group. Metabolomic analysis revealed increased free amino acids, activation of the glutathione antioxidant system, altered cardiac fatty acid metabolic preferences, and enhanced pentose phosphate pathway activity during hibernation as compared with the SA group. Combining the transcriptomic and metabolomic data, active mitochondrial oxidative phosphorylation and creatine-phosphocreatine energy shuttle systems were observed, as well as inhibition of ferroptosis signaling pathways during hibernation as compared with the SA group. In conclusion, these results provide new insights into cardio-protection in hibernators from the perspective of gene and metabolite changes and deepen our understanding of adaptive cardio-protection mechanisms in mammalian hibernators.

Current status of porous coordination networks (PCNs) derived porphyrin spacers for cancer therapy.

INTRODUCTION: Porous coordination networks (PCNs) have been widely used in large number of applications such as light harvesting, catalysis, and biomedical applications. Inserting porphyrins into PCNs scaffolds can alleviate the solubility and chemical stability problems associated with porphyrin ligands and add functionality to PCNs. The discovery that some PCNs materials have photosensitizer and acoustic sensitizer properties has attracted significant attention in the field of biomedicine, particularly in cancer therapy. This article describes the latest applications of the porphyrin ligand-based family of PCNs in cancer chemodynamic therapy (CDT), photodynamic therapy (PDT), sonodynamic therapy (SDT), photothermal therapy (PTT), and combination therapies and offers some observations and reflections on them. AREAS COVERED: This article discusses the use of the PCN family of MOFs in cancer treatment, specifically focusing on chemodynamic therapy, sonodynamic therapy, photodynamic therapy, photothermal therapy, and combination therapy. EXPERT OPINION: Although a large number of PCNs have been developed for use in novel cancer therapeutic approaches, further improvements are needed to advance the use of PCNs in the clinic. For example, the main mechanism of action of PCNs against cancer and the metabolic processes in organisms, and how to construct PCNs that maintain good stability in the complex environment of organisms.

The NEAT Equating Via Chaining Random Forests in the Context of Small Sample Sizes: A Machine-Learning Method.

The part of responses that is absent in the nonequivalent groups with anchor test (NEAT) design can be managed to a planned missing scenario. In the context of small sample sizes, we present a machine learning (ML)-based imputation technique called chaining random forests (CRF) to perform equating tasks within the NEAT design. Specifically, seven CRF-based imputation equating methods are proposed based on different data augmentation methods. The equating performance of the proposed methods is examined through a simulation study. Five factors are considered: (a) test length (20, 30, 40, 50), (b) sample size per test form (50 versus 100), (c) ratio of common/anchor items (0.2 versus 0.3), and (d) equivalent versus nonequivalent groups taking the two forms (no mean difference versus a mean difference of 0.5), and (e) three different types of anchors (random, easy, and hard), resulting in 96 conditions. In addition, five traditional equating methods, (1) Tucker method; (2) Levine observed score method; (3) equipercentile equating method; (4) circle-arc method; and (5) concurrent calibration based on Rasch model, were also considered, plus seven CRF-based imputation equating methods for a total of 12 methods in this study. The findings suggest that benefiting from the advantages of ML techniques, CRF-based methods that incorporate the equating result of the Tucker method, such as IMP_total_Tucker, IMP_pair_Tucker, and IMP_Tucker_cirlce methods, can yield more robust and trustable estimates for the "missingness" in an equating task and therefore result in more accurate equated scores than other counterparts in short-length tests with small samples.

Evaluation of the Effects of e-Cigarette Aerosol Extracts and Tobacco Cigarette Smoke Extracts on RAW264.7 Cells.

With the advancement of society, electronic cigarettes (e-cigarettes) have gained popularity among a growing number of individuals. While numerous toxicological studies have suggested that e-cigarettes are a safer alternative to traditional cigarettes, there is also a body of literature presenting contrasting findings. This in vitro study aimed to compare the effects of e-cigarettes and tobacco cigarettes (t-cigarettes) on RAW264.7 cells by using four e-cigarette aerosol extracts (ECA) and cigarette smoking extracts (CS) containing different nicotine concentrations. The results revealed that low concentration of nicotine in CS as well as in ECA with grape, watermelon, and cola flavors could promote cell viability. Conversely, high nicotine concentration in CS and ECA with four flavors decreased cell viability. Furthermore, our study demonstrated that CS significantly reduced the phagocytic capability of RAW264.7 cells and increased the levels of inflammatory cytokines (IL-6, TNF-α, and IL-1ß) and reactive oxygen species (ROS) compared to ECA. Overall, our findings indicate all four e-cigarettes induced less cytotoxicity to RAW264.7 cells and might be safer than t-cigarettes.

Wide Temperature Range and Low Temperature Drift Eddy Current Displacement Sensor Using Digital Correlation Demodulation.

Conventional eddy-current sensors have the advantages of being contactless and having high bandwidth and high sensitivity. They are widely used in micro-displacement measurement, micro-angle measurement, and rotational speed measurement. However, they are based on the principle of impedance measurement, so the influence of temperature drift on sensor accuracy is difficult to overcome. A differential digital demodulation eddy current sensor system was designed to reduce the influence of temperature drift on the output accuracy of the eddy current sensor. The differential sensor probe was used to eliminate common-mode interference caused by temperature, and the differential analog carrier signal was digitized by a high-speed ADC. In the FPGA, the amplitude information is resolved using the double correlation demodulation method. The main sources of system errors were determined, and a test device was designed using a laser autocollimator. Tests were conducted to measure various aspects of sensor performance. Testing showed the following metrics for the differential digital demodulation eddy current sensor: nonlinearity 0.68% in the range of ±2.5 mm, resolution 760 nm, maximum bandwidth 25 kHz, and significant suppression in the temperature drift compared to analog demodulation methods. The tests show that the sensor has high precision, low temperature drift and great flexibility, and it can instead of conventional sensors in applications with large temperature variability.

Duration-dependent impact of cardiometabolic diseases and multimorbidity on all-cause and cause-specific mortality: a prospective cohort study of 0.5 million participants.

BACKGROUND: The association of incident cardiometabolic multimorbidity (CMM) with mortality risk is rarely studied, and neither are the durations of cardiometabolic diseases (CMDs). Whether the association patterns of CMD durations with mortality change as individuals progress from one CMD to CMM is unclear. METHODS: Data from China Kadoorie Biobank of 512,720 participants aged 30-79 was used. CMM was defined as the simultaneous presence of two or more CMDs of interest, including diabetes, ischemic heart disease, and stroke. Cox regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the duration-dependent associations of CMDs and CMM with all-cause and cause-specific mortality. All information on exposures of interest was updated during follow-up. RESULTS: During a median follow-up of 12.1 years, 99,770 participants experienced at least one incident CMD, and 56,549 deaths were documented. Among 463,178 participants free of three CMDs at baseline, compared with no CMD during follow-up, the adjusted HRs (95% CIs) between CMM and all-cause mortality, mortality from circulatory system diseases, respiratory system diseases, cancer, and other causes were 2.93 (2.80-3.07), 5.05 (4.74-5.37), 2.72 (2.35-3.14), 1.30 (1.16-1.45), and 2.30 (2.02-2.61), respectively. All CMDs exhibited a high mortality risk in the first year of diagnosis. Subsequently, with prolonged disease duration, mortality risk increased for diabetes, decreased for IHD, and sustained at a high level for stroke. With the presence of CMM, the above association estimates inflated, but the pattern of which remained. CONCLUSION: Among Chinese adults, mortality risk increased with the number of the CMDs and changed with prolonged disease duration, the patterns of which varied among the three CMDs.

Is the Area Under Curve Appropriate for Evaluating the Fit of Psychometric Models?

In the literature of modern psychometric modeling, mostly related to item response theory (IRT), the fit of model is evaluated through known indices, such as χ2, M2, and root mean square error of approximation (RMSEA) for absolute assessments as well as Akaike information criterion (AIC), consistent AIC (CAIC), and Bayesian information criterion (BIC) for relative comparisons. Recent developments show a merging trend of psychometric and machine learnings, yet there remains a gap in the model fit evaluation, specifically the use of the area under curve (AUC). This study focuses on the behaviors of AUC in fitting IRT models. Rounds of simulations were conducted to investigate AUC's appropriateness (e.g., power and Type I error rate) under various conditions. The results show that AUC possessed certain advantages under certain conditions such as high-dimensional structure with two-parameter logistic (2PL) and some three-parameter logistic (3PL) models, while disadvantages were also obvious when the true model is unidimensional. It cautions researchers about the dangers of using AUC solely in evaluating psychometric models.

Neuroprotective Effects of a Novel Tetrapeptide SGGY from Walnut against H2O2-Stimulated Oxidative Stress in SH-SY5Y Cells: Possible Involved JNK, p38 and Nrf2 Signaling Pathways.

SGGY, an antioxidant tetrapeptide identified from walnut protein hydrolysate in our previous study, has been suggested to possess the potential to alleviate oxidative stress in cells. In this paper, the neuroprotective effects of SGGY on H2O2-stimulated oxidative stress in SH-SY5Y cells and the underlying mechanisms were investigated. Results showed that SGGY alleviated H2O2-induced oxidative stress by decreasing the intracellular reactive oxygen species (ROS) level and altering the mitochondrial membrane potential (MMP), thereby inhibiting apoptosis and increasing cell viability. SGGY significantly restored antioxidant enzyme activities and reduced malondialdehyde (MDA) content accordingly. Moreover, SGGY promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and suppressed the H2O2-induced activation of JNK and p38 mitogen-activated protein kinases (MAPKs). Taken together, these results suggested that SGGY protected SH-SY5Y cells from H2O2-provoked oxidative stress by enhancing the ability of cellular antioxidant defense, and the possible mechanism involved MAPKs and Nrf2 signaling pathways.

Intranasal Boosting with Spike Fc-RBD of Wild-Type SARS-CoV-2 Induces Neutralizing Antibodies against Omicron Subvariants and Reduces Viral Load in the Nasal Turbinate of Mice.

The emergence of new immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and subvariants outpaces the development of vaccines specific against the dominant circulating strains. In terms of the only accepted immune correlate of protection, the inactivated whole-virion vaccine using wild-type SARS-CoV-2 spike induces a much lower serum neutralizing antibody titre against the Omicron subvariants. Since the inactivated vaccine given intramuscularly is one of the most commonly used coronavirus disease 2019 (COVID-19) vaccines in developing regions, we tested the hypothesis that intranasal boosting after intramuscular priming would provide a broader level of protection. Here, we showed that one or two intranasal boosts with the Fc-linked trimeric spike receptor-binding domain from wild-type SARS-CoV-2 can induce significantly higher serum neutralizing antibodies against wild-type SARS-CoV-2 and the Omicron subvariants, including BA.5.2 and XBB.1, with a lower titre in the bronchoalveolar lavage of vaccinated Balb/c mice than vaccination with four intramuscular doses of inactivated whole virion vaccine. The intranasally vaccinated K18-hACE2-transgenic mice also had a significantly lower nasal turbinate viral load, suggesting a better protection of the upper airway, which is the predilected site of infection by Omicron subvariants. This intramuscular priming and intranasal boosting approach that achieves broader cross-protection against Omicron variants and subvariants may lengthen the interval required for changing the vaccine immunogen from months to years.