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Therapeutic antibody design has garnered widespread attention, highlighting its interdisciplinary importance. Advancements in technology emphasize the critical role of designing nanobodies and humanized antibodies in antibody engineering. However, current experimental methods are costly and time-consuming. Computational approaches, while progressing, faced limitations due to insufficient structural data and the absence of a standardized protocol. To tackle these challenges, our lab previously developed IsAb1.0, an in silico antibody design protocol. Yet, IsAb1.0 lacked accuracy, had a complex procedure, and required extensive antibody bioinformation. Moreover, it overlooked nanobody and humanized antibody design, hindering therapeutic antibody development. Building upon IsAb1.0, we enhanced our design protocol with artificial intelligence methods to create IsAb2.0. IsAb2.0 utilized AlphaFold-Multimer (2.3/3.0) for accurate modeling and complex construction without templates and employed the precise FlexddG method for in silico antibody optimization. Validated through optimization of a humanized nanobody J3 (HuJ3) targeting HIV-1 gp120, IsAb2.0 predicted five mutations that can improve HuJ3-gp120 binding affinity. These predictions were confirmed by commercial software and validated through binding and neutralization assays. IsAb2.0 streamlined antibody design, offering insights into future techniques to accelerate immunotherapy development. [ABSTRACT FROM AUTHOR]

The virtues of electrolytic MnO2 aqueous batteries are high theoretical energy density, affordability and safety. However, the continuous dead MnO2 and unstable Mn2+/MnO2 electrolysis pose challenges to the practical output energy and lifespan. Herein, we demonstrate bifunctional cationic redox mediation and catalysis kinetics metrics to rescue dead MnO2 and construct a stable and fast electrolytic Zn–Mn redox-flow battery (eZMRFB). Spectroscopic characterizations and electrochemical evaluation reveal the superior mediation kinetics of a cationic Fe2+ redox mediator compared with the anionic ones (e.g. I– and Br–), thus eliminating dead MnO2 effectively. With intensified oxygen vacancies, density functional theory simulations of the reaction pathways further verify the concomitant Fe-catalysed Mn2+/MnO2 electrolysis kinetics via charge delocalization and activated O 2p electron states, boosting its rate capability. As a result, the elaborated eZMRFB achieves a coulombic efficiency of nearly 100%, ultra-high areal capacity of 80 mAh cm–2, rate capability of 20 C and a long lifespan of 2500 cycles. This work may advance high-energy aqueous batteries to next-generation scalable energy storage. [ABSTRACT FROM AUTHOR]

Opioid pain medications, such as morphine, remain the mainstay for treating severe and chronic pain. Prolonged morphine use, however, triggers analgesic tolerance and hyperalgesia (OIH), which can last for a long period after morphine withdrawal. How morphine induces these detrimental side effects remains unclear. Here, we show that morphine tolerance and OIH are mediated by Tiam1-coordinated synaptic structural and functional plasticity in the spinal nociceptive network. Tiam1 is a Rac1 GTPase guanine nucleotide exchange factor that promotes excitatory synaptogenesis by modulating actin cytoskeletal dynamics. We found that prolonged morphine treatment activated Tiam1 in the spinal dorsal horn and Tiam1 ablation from spinal neurons eliminated morphine antinociceptive tolerance and OIH. At the same time, the pharmacological blockade of Tiam1-Rac1 signalling prevented the development and reserved the established tolerance and OIH. Prolonged morphine treatment increased dendritic spine density and synaptic NMDA receptor activity in spinal dorsal horn neurons, both of which required Tiam1. Furthermore, co-administration of the Tiam1 signalling inhibitor NSC23766 was sufficient to abrogate morphine tolerance in chronic pain management. These findings identify Tiam1-mediated maladaptive plasticity in the spinal nociceptive network as an underlying cause for the development and maintenance of morphine tolerance and OIH and provide a promising therapeutic target to reduce tolerance and prolong morphine use in chronic pain management. [ABSTRACT FROM AUTHOR]

Background Plasma circular (circ)RNAs detected by droplet digital polymerase chain reaction (ddPCR) may be ideal markers for liquid biopsy. However, ddPCR detection of circRNAs in plasma for diagnosis of lung adenocarcinoma has been rarely reported. Methods An RNA sequencing analysis was performed in plasma from patients with early lung adenocarcinoma and healthy individuals. Droplet digital PCR was used to verify the differentially expressed genes. Results The copy numbers of circle RNA LZIC (circ LZIC)and circle RNA CEP350 (circ CEP350) in the plasma of lung adenocarcinoma patients were significantly higher than in plasma of healthy people, and the copy numbers in postoperative plasma of the same patients were significantly lower than those in preoperative plasma. Circ LZIC and circ CEP350 alone and in combination had diagnostic value in lung adenocarcinoma and early lung adenocarcinoma. Circ LZIC and circ CEP350 had more binding sites with multiple microRNAs. Their target genes were enriched in several signaling pathways. Conclusion The copy numbers of circ LZIC and circ CEP350 were higher in plasma of lung adenocarcinoma patients than in plasma of healthy controls, significantly correlated with tumor size and TNM stage, and closely related to the occurrence and development of tumors. These circRNAs may serve as molecular markers for the diagnosis of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background and Aims Many adult patients with congenital heart disease (ACHD) are still afflicted by premature death. Previous reports suggested natriuretic peptides may identify ACHD patients with adverse outcome. The study investigated prognostic power of B-type natriuretic peptide (BNP) across the spectrum of ACHD in a large contemporary cohort. Methods The cohort included 3392 consecutive ACHD patients under long-term follow-up at a tertiary ACHD centre between 2006 and 2019. The primary study endpoint was all-cause mortality. Results A total of 11 974 BNP measurements were analysed. The median BNP at baseline was 47 (24–107) ng/L. During a median follow-up of 8.6 years (29 115 patient-years), 615 (18.1%) patients died. On univariable and multivariable analysis, baseline BNP [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.15–1.18 and HR 1.13, 95% CI 1.08–1.18, respectively] and temporal changes in BNP levels (HR 1.22, 95% CI 1.19–1.26 and HR 1.19, 95% CI 1.12–1.26, respectively) were predictive of mortality (P <.001 for both) independently of congenital heart disease diagnosis, complexity, anatomic/haemodynamic features, and/or systolic systemic ventricular function. Patients within the highest quartile of baseline BNP (>107 ng/L) and those within the highest quartile of temporal BNP change (>35 ng/L) had significantly increased risk of death (HR 5.8, 95% CI 4.91–6.79, P <.001, and HR 3.6, 95% CI 2.93–4.40, P <.001, respectively). Conclusions Baseline BNP and temporal BNP changes are both significantly associated with all-cause mortality in ACHD independent of congenital heart disease diagnosis, complexity, anatomic/haemodynamic features, and/or systolic systemic ventricular function. B-type natriuretic peptide levels represent an easy to obtain and inexpensive marker conveying prognostic information and should be used for the routine surveillance of patients with ACHD. [ABSTRACT FROM AUTHOR]

As highlighted in Dawid (2000) and Pearl & Mackenzie (2018) , deducing the causes of given effects is a more challenging problem than evaluating the effects of causes in causal inference. Lu et al. (2023) proposed an approach for deducing causes of a single effect variable based on posterior causal effects. In many applications, there are multiple effect variables, and they can be used simultaneously to more accurately deduce the causes. To retrospectively deduce causes from multiple effects, we propose multivariate posterior total, intervention and direct causal effects conditional on the observed evidence. We describe the assumptions of no confounding and monotonicity, under which we prove identifiability of the multivariate posterior causal effects and provide their identification equations. The proposed approach can be applied for causal attributions, medical diagnosis, blame and responsibility in various studies with multiple effect or outcome variables. Two examples are used to illustrate the proposed approach. [ABSTRACT FROM AUTHOR]

Background Pelvic floor muscle training (PFMT) has emerged as a potential intervention to improve post–total hysterectomy (TH) sexual function. Electromyographic (EMG) biofeedback is an adjunct that may improve outcomes. Aim In this study we aimed to compare the EMG biofeedback–assisted PFMT and PFMT alone for improving sexual function in women after TH. Methods For this prospective study we enrolled women undergoing TH in our hospital between January 2022 and April 2023. Participants were divided according to the treatment they selected: EMG biofeedback–assisted PFMT or PFMT alone. Outcomes The primary study outcome was change in patient sexual function evaluated by use of the Female Sexual Function Index. Secondary outcomes were changes in anxiety and depression evaluated with the Hospital Anxiety and Depression Scale score and pelvic floor muscle strength was evaluated with the Glazer assessment performed from before to after treatment. Results A total of 73 patients were included, with 38 patients treated with Electromyographic biofeedback–assisted pelvic floor muscle training. After treatment, sexual function was significantly improved compared to baseline in all patients (all P  < .001). Compared to patients with pelvic floor muscle training, the changes in total Female Sexual Function Index scores from before to after treatment in patients with Electromyographic biofeedback–assisted pelvic floor muscle training were significantly higher (all P  < .05). There were no significant differences between the 2 groups in the changes in the Glazer score and Hospital Anxiety and Depression Scale scores from before to after treatment (both P  > .05). Clinical Translation The results demonstrate that Electromyographic biofeedback–assisted pelvic floor muscle training may be used to improve the sexual function of patients following TH. Strengths and Limitations This study is limited by its single-center design, small sample size, lack of randomization, and absence of estrogen monitoring in enrolled participants. Conclusions Electromyographic biofeedback–assisted pelvic floor muscle training appears to be more effective than pelvic floor muscle training alone in improving sexual function among patients after total hysterectomy. [ABSTRACT FROM AUTHOR]

Objective This study aimed to determine the predictive values of informant-reported memory decline (IMD) among subjective cognitive decline (SCD) older adults from a 7-year community-based cohort study. Method Ninety SCD participants were included. Demographic data and neuropsychological test scores at both baseline and 7-year follow-up were collected. Differences between SCD with IMD (+IMD) and SCD without IMD (−IMD) were compared. Logistic regression models were used to determine whether baseline IMD could predict diagnostic outcomes at 7-year follow-up. Results Forty-one percent of SCD adults had IMD. At baseline, the +IMD group showed more depressive symptoms (p  = 0.016) than the −IMD group. Furthermore, the Beijing-version Montreal Cognitive Assessment (MoCA), Digit Span Test-Forward, Visual Matching and Reasoning, and Wechsler Adult Intelligence Scale-RC Picture Completion (WAIS-PC) scores in the +IMD group were significantly lower than those in the −IMD group. Fifty-four percent of +IMD participants converted to mild cognitive impairment (MCI) or dementia at follow-up, and 22.6% of the −IMD participants converted to MCI. Follow-up Mini-Mental State Examination, MoCA, and Verbal Fluency Test scores of the +IMD group were significantly lower than those in the −IMD group. The +IMD group was more likely to progress to cognitive impairment at 7-year follow-up (OR = 3.361, p  = 0.028). Conclusions SCD participants with +IMD may have poorer cognition and are more likely to convert to cognitive impairment over time. Our long-term follow-up study confirmed the importance of informants' perceptions of SCD, which can help clinicians identify individuals at risk of cognitive decline. [ABSTRACT FROM AUTHOR]

Plant senescence, as a highly integrated developmental stage, involves functional degeneration and nutrient redistribution. NAM/ATAF1/CUC (NAC) transcription factors orchestrate various senescence-related signals and mediate the fine-tuning underlying plant senescence. Previous data revealed that knockout of either NtNAC028 or NtNAC080 leads to delayed leaf senescence in tobacco (Nicotiana tabacum), which implies that NtNAC028 and NtNAC080 play respective roles in the regulation of leaf senescence, although they share 91.87% identity with each other. However, the mechanism underlying NtNAC028- and NtNAC080-regulated leaf senescence remains obscure. Here, we determined that NtNAC028 and NtNAC080 activate a putative jasmonic acid (JA) biosynthetic gene, NtLOX3 , and enhance the JA level in vivo. We found that NtNAC028 and NtNAC080 interact with each other and themselves through their NA-terminal region. Remarkably, only the dimerization between NtNAC028 and NtNAC080 stimulated the transcriptional activation activity, but not the DNA binding activity of this heterodimer on NtLOX3. Metabolome analysis indicated that overexpression of either NtNAC028 or NtNAC080 augments both biosynthesis and degradation of nicotine in the senescent stages. Thus, we conclude that NtNAC028 cooperates with NtNAC080 and forms a heterodimer to enhance NtLOX3 expression and JA biosynthesis to trigger the onset of leaf senescence and impact secondary metabolism in tobacco. [ABSTRACT FROM AUTHOR]

When the popular means of transportation—high-speed trains meet the increasing rate of pacemaker implantation year by year, the research on the magnetic field environment on the health of pacemaker wearers in the carriage becomes an urgent problem. In this work, models of an electric multiple unit carriage with a pantograph as well as passengers with pacemakers were built by using COMSOL Multiphysics software. The B , E in and J in of human heart and other tissues, and the induced voltage (Vin) at the pacemaker electrode were calculated under the pantograph operating condition, so as to assess the effect of its magnetic field on the health of pacemaker wearers. The results showed that B max in the carriage without passengers is 121.246 μT, occurs near the window. In the carriage, the B max, E in max and J in max of heart and body, Vin at the pacemaker electrode of the passenger next to the window are greater than that in the middle of the carriage. The B max, E in max and J in max of passengers' heart are 11.301μT, 1.613 mV/m and 139.030 μA/m2, respectively. The B max, E in max and J in max of passengers' body are 12.597μT, 0.788 mV/m and 75.299 μA/m2, respectively. The maximum value of Vin at the tip of the pacemaker electrode of the passengers' is 0.048 mV. The B max, E in max in all tissues of passengers are much smaller than the basic limits of electromagnetic exposure to the public set by the International Commission on Non-Ionizing Radiation. Vin at the electrode tip of passengers' pacemakers are less than the perception sensitivity set by the International Organization for Standardization. This work illustrated that the magnetic field generated by the pantograph is within the recognized accepted limits for passengers with pacemakers, but we still recommended that passengers wearing pacemakers should stay as far away from windows as possible. [ABSTRACT FROM AUTHOR]

The performance of two thermoluminescent dosimetry systems (RGD-3D and RE2000) manufactured in China and Finland was compared. Both of these dosimetry systems demonstrated satisfactory results as their performance met the requirements of the standard. The two dosimetry systems showed similar performance in the energy response. The RGD-3D dosimetry system performed better in nonlinear response, minimum detectable level and blind sample tests, whereas the RE2000 dosimetry system showed better stability. [ABSTRACT FROM AUTHOR]

Due to their uncontrollable assembly and crystallization process, the synthesis of mesoporous metal oxide single crystals remains a formidable challenge. Herein, we report the synthesis of single-crystal-like mesoporous Li2TiSiO5 by using soft micelles as templates. The key lies in the atomic-scale self-assembly and step-crystallization processes, which ensure the formation of single-crystal-like mesoporous Li2TiSiO5 microparticles via an oriented attachment growth mechanism under the confinement of an in-situ formed carbon matrix. The mesoporous Li2TiSiO5 anode achieves a superior rate capability (148 mAh g−1 at 5.0 A g−1) and outstanding long-term cycling stability (138 mAh g−1 after 3000 cycles at 2.0 A g−1) for lithium storage as a result of the ultrafast Li+ diffusion caused by penetrating mesochannels and nanosized crystal frameworks (5–10 nm). In comparison, bulk Li2TiSiO5 exhibits poor rate capability and cycle performance due to micron-scale diffusion lengths. This method is very simple and reproducible, heralding a new way of designing and synthesizing mesoporous single crystals with controllable frameworks and chemical functionalities. [ABSTRACT FROM AUTHOR]

Solid solutions are ubiquitous in metals and alloys. Local chemical ordering (LCO) is a fundamental sub-nano/nanoscale process that occurs in many solid solutions and can be used as a microstructure to optimize strength and ductility. However, the formation of LCO has not been fully elucidated, let alone how to provide efficient routes for designing LCO to achieve synergistic effects on both superb strength and ductility. Herein, we propose the formation and control of LCO in negative enthalpy alloys. With engineering negative enthalpy in solid solutions, genetic LCO components are formed in negative enthalpy refractory high-entropy alloys (RHEAs). In contrast to conventional 'trial-and-error' approaches, the control of LCO by using engineering negative enthalpy in RHEAs is instructive and results in superior strength (1160 MPa) and uniform ductility (24.5%) under tension at ambient temperature, which are among the best reported so far. LCO can promote dislocation cross-slip, enhancing the interaction between dislocations and their accumulation at large tensile strains; sustainable strain hardening can thereby be attained to ensure high ductility of the alloy. This work paves the way for new research fields on negative enthalpy solid solutions and alloys for the synergy of strength and ductility as well as new functions. [ABSTRACT FROM AUTHOR]

Determining cell types by single-cell transcriptomics data is fundamental for downstream analysis. However, cell clustering and data imputation still face the computation challenges, due to the high dropout rate, sparsity and dimensionality of single-cell data. Although some deep learning based solutions have been proposed to handle these challenges, they still can not leverage gene attribute information and cell topology in a sensible way to explore the consistent clustering. In this paper, we present scDeepFC, a deep information fusion-based single-cell data clustering method for cell clustering and data imputation. Specifically, scDeepFC uses a deep auto-encoder (DAE) network and a deep graph convolution network to embed high-dimensional gene attribute information and high-order cell–cell topological information into different low-dimensional representations, and then fuses them to generate a more comprehensive and accurate consensus representation via a deep information fusion network. In addition, scDeepFC integrates the zero-inflated negative binomial (ZINB) into DAE to model the dropout events. By jointly optimizing the ZINB loss and cell graph reconstruction loss, scDeepFC generates a salient embedding representation for clustering cells and imputing missing data. Extensive experiments on real single-cell datasets prove that scDeepFC outperforms other popular single-cell analysis methods. Both the gene attribute and cell topology information can improve the cell clustering. [ABSTRACT FROM AUTHOR]

Local adaptation is critical in speciation and evolution, yet comprehensive studies on proximate and ultimate causes of local adaptation are generally scarce. Here, we integrated field ecological experiments, genome sequencing, and genetic verification to demonstrate both driving forces and molecular mechanisms governing local adaptation of body coloration in a lizard from the Qinghai-Tibet Plateau. We found dark lizards from the cold meadow population had lower spectrum reflectance but higher melanin contents than light counterparts from the warm dune population. Additionally, the colorations of both dark and light lizards facilitated the camouflage and thermoregulation in their respective microhabitat simultaneously. More importantly, by genome resequencing analysis, we detected a novel mutation in Tyrp1 that underpinned this color adaptation. The allele frequencies at the site of SNP 459# in the gene of Tyrp1 are 22.22% G/C and 77.78% C/C in dark lizards and 100% G/G in light lizards. Model-predicted structure and catalytic activity showed that this mutation increased structure flexibility and catalytic activity in enzyme TYRP1, and thereby facilitated the generation of eumelanin in dark lizards. The function of the mutation in Tyrp1 was further verified by more melanin contents and darker coloration detected in the zebrafish injected with the genotype of Tyrp1 from dark lizards. Therefore, our study demonstrates that a novel mutation of a major melanin-generating gene underpins skin color variation co-selected by camouflage and thermoregulation in a lizard. The resulting strong selection may reinforce adaptive genetic divergence and enable the persistence of adjacent populations with distinct body coloration. [ABSTRACT FROM AUTHOR]

Plant terrestrialization (i.e. the transition to a terrestrial environment) is a significant evolutionary event that has been intensively studied. While certain plant lineages, particularly in angiosperms, have re-adapted to freshwater habitats after colonizing terrene, however, the molecular mechanism of the terrestrial–freshwater (T–F) transition remains limited. Here, the basal monocot Araceae was selected as the study object to explore the T–F transition adaptation mechanism by comparative genomic analysis. Our findings revealed that the substitution rates significantly increased in the lineage of freshwater Araceae, which may promote their adaptation to the freshwater habitat. Additionally, 20 gene sets across all four freshwater species displayed signs of positive selection contributing to tissue development and defense responses in freshwater plants. Comparative synteny analysis showed that genes specific to submerged plants were enriched in cellular respiration and photosynthesis. In contrast, floating plants were involved in regulating gene expression, suggesting that gene and genome duplications may provide the original material for plants to adapt to the freshwater environment. Our study provides valuable insights into the genomic aspects of the transition from terrestrial to aquatic environments in Araceae, laying the groundwork for future research in the angiosperm. [ABSTRACT FROM AUTHOR]

Graph products have been extensively applied to model complex networks with striking properties observed in real-world complex systems. In this paper, we study the hitting times for random walks on a class of graphs generated iteratively by edge corona product. We first derive recursive solutions to the eigenvalues and eigenvectors of the normalized adjacency matrix associated with the graphs. Based on these results, we further obtain interesting quantities about hitting times of random walks, providing iterative formulas for two-node hitting time, as well as closed-form expressions for the Kemeny's constant defined as a weighted average of hitting times over all node pairs, as well as the arithmetic mean of hitting times of all pairs of nodes. [ABSTRACT FROM AUTHOR]

The spectral element method is currently the method of choice for computing accurate synthetic seismic wavefields in realistic 3-D earth models at the global scale. However, it requires significantly more computational time, compared to normal mode-based approximate methods. Source stacking, whereby multiple earthquake sources are aligned on their origin time and simultaneously triggered, can reduce the computational costs by several orders of magnitude. We present the results of synthetic tests performed on a realistic radially anisotropic 3-D model, slightly modified from model SEMUCB-WM1 with three component synthetic waveform 'data' for a duration of 10 000 s, and filtered at periods longer than 60 s, for a set of 273 events and 515 stations. We consider two definitions of the misfit function, one based on the stacked records at individual stations and another based on station-pair cross-correlations of the stacked records. The inverse step is performed using a Gauss–Newton approach where the gradient and Hessian are computed using normal mode perturbation theory. We investigate the retrieval of radially anisotropic long wavelength structure in the upper mantle in the depth range 100–800 km, after fixing the crust and uppermost mantle structure constrained by fundamental mode Love and Rayleigh wave dispersion data. The results show good performance using both definitions of the misfit function, even in the presence of realistic noise, with degraded amplitudes of lateral variations in the anisotropic parameter ξ. Interestingly, we show that we can retrieve the long wavelength structure in the upper mantle, when considering one or the other of three portions of the cross-correlation time series, corresponding to where we expect the energy from surface wave overtone, fundamental mode or a mixture of the two to be dominant, respectively. We also considered the issue of missing data, by randomly removing a successively larger proportion of the available synthetic data. We replace the missing data by synthetics computed in the current 3-D model using normal mode perturbation theory. The inversion results degrade with the proportion of missing data, especially for ξ , and we find that a data availability of 45 per cent or more leads to acceptable results. We also present a strategy for grouping events and stations to minimize the number of missing data in each group. This leads to an increased number of computations but can be significantly more efficient than conventional single-event-at-a-time inversion. We apply the grouping strategy to a real picking scenario, and show promising resolution capability despite the use of fewer waveforms and uneven ray path distribution. Source stacking approach can be used to rapidly obtain a starting 3-D model for more conventional full-waveform inversion at higher resolution, and to investigate assumptions made in the inversion, such as trade-offs between isotropic, anisotropic or anelastic structure, different model parametrizations or how crustal structure is accounted for. [ABSTRACT FROM AUTHOR]

In this paper, we design a decoupled scheme for solving a fluid–fluid interaction problem, which includes two Navier–Stokes equations coupled by some nonlinear interface conditions. Compared with two decoupled schemes proposed by Connors et al. (2012, Decoupled time stepping methods for fluid–fluid interaction. SIAM J. Numer. Anal. , 50 , 1297–1319) for the fluid–fluid interaction problem, we deal with these nonlinear interface conditions by applying explicit scheme. The presented fully discrete scheme is a combination of a mixed finite element approximation for spatial discretization, the first-order backward Euler scheme for temporal discretization and explicit treatment for the interface conditions and the nonlinear terms. Moreover, the unconditional energy stability is established and error estimate for the fully discrete scheme is also showed. Finally, some numerical experiments are provided to verify the theoretical results, which illustrate the accuracy and efficiency of the presented scheme. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Low-grade neural and peripheral inflammation are among the proposed pathophysiological mechanisms of schizophrenia. White matter impairment is one of the more consistent findings in schizophrenia but the underlying mechanism remains obscure. Many cerebral white matter components are sensitive to neuroinflammatory conditions that can result in demyelination, altered oligodendrocyte differentiation, and other changes. We tested the hypothesis that altered immune-inflammatory response system (IRS) and compensatory immune-regulatory reflex system (IRS/CIRS) dynamics are associated with reduced white matter integrity in patients with schizophrenia. Study Design Patients with schizophrenia (SCZ, 70M/50F, age = 40.76 ± 13.10) and healthy controls (HCs, 38M/27F, age = 37.48 ± 12.31) underwent neuroimaging and plasma collection. A panel of cytokines were assessed using enzyme-linked immunosorbent assay. White matter integrity was measured by fractional anisotropy (FA) from diffusion tensor imaging using a 3-T Prisma MRI scanner. The cytokines were used to generate 3 composite scores: IRS, CIRS, and IRS/CIRS ratio. Study Results The IRS/CIRS ratio in SCZ was significantly higher than that in HCs (P  = .009). SCZ had a significantly lower whole-brain white matter average FA (P  < .001), and genu of corpus callosum (GCC) was the most affected white matter tract and its FA was significantly associated with IRS/CIRS (r  = 0.29, P  = .002). FA of GCC was negatively associated with negative symptom scores in SCZ (r  = −0.23, P  = .016). There was no mediation effect taking FA of GCC as mediator, for that IRS/CIRS was not associated with negative symptom score significantly (P  = .217) in SCZ. Conclusions Elevated IRS/CIRS might partly account for the severity of negative symptoms through targeting the integrity of GCC. [ABSTRACT FROM AUTHOR]

Context Type B insulin resistance syndrome (TBIRS) is a rare condition, for which effective treatment remains challenging. Objective This work aimed to summarize the clinical characteristics of TBIRS and explore effective therapeutic strategies. Methods The clinical manifestations, biochemical indices, and treatment of 8 patients (3 men and 5 women) with TBIRS from Peking Union Medical College Hospital were retrospectively analyzed and their clinical outcomes were evaluated. Results The average age of the patients was 49.5 ± 16.5 years, and the duration of the disease ranged from 2 months to 1 year. Seven patients with hyperglycemia had normal/lower triglycerides (TGs) and lower insulin-like growth factor 1 (IGF-1) levels. One patient complained of intractable hypoglycemia. Five patients had accompanied systemic lupus erythematosus, 2 had mixed connective tissue disease, and 1 had undifferentiated connective tissue disease. Five patients had acanthosis nigricans and 3 women of child-bearing age had hyperandrogenism. All 8 patients were treated with glucocorticoids combined with immunosuppressants, among whom, 5 received high-dose glucocorticoid pulse therapy followed by conventional-dose glucocorticoid therapy, all of whom achieved partial remission within 2 to 4 weeks. Among the 3 patients receiving conventional glucocorticoid therapy, 2 achieved partial remission within 2 to 4 weeks. Six patients were tracked for 10 weeks to 4 years; 4 and 2 achieved complete and partial remission, respectively. Conclusion Decreased serum complement 3 and IGF-1 levels and normal/decreased TG levels act as striking biochemical features of TBIRS. High-dose glucocorticoid pulse therapy followed by conventional-dose long-term therapy combined with immunosuppressants achieves good clinical efficacy. [ABSTRACT FROM AUTHOR]

Recently, an astrocytic aquaporin 4-dependent drainage system, that is, the glymphatic system, has been identified in the live murine and human brain. Growing evidence suggests that glymphatic function is impaired in patients with several neurodegenerative diseases, including Alzheimer's and Parkinson's disease. As the third most common neurodegenerative disease, although animal studies have indicated that early glymphatic dysfunction is likely an important pathological mechanism underpinning amyotrophic lateral sclerosis (ALS), no available study has been conducted to thoroughly assess glymphatic function in vivo in ALS patients to date, particularly in patients with early-stage ALS. Thus, using diffusion tensor imaging analysis along the perivascular space (ALPS) index, an approximate measure of glymphatic function in vivo , we aimed to explore whether glymphatic function is impaired in patients with patients with early-stage ALS, and the diagnostic performance of the ALPS index in distinguishing between patients with early-stage ALS and healthy subjects. We also aimed to identify the relationships between glymphatic dysfunction and clinical disabilities and sleep problems in patients with early-stage ALS. In this retrospective study, King's Stage 1 ALS patients were defined as patients with early-stage ALS. We enrolled 56 patients with early-stage ALS and 32 age- and sex-matched healthy control subjects. All participants completed clinical screening, sleep assessment and ALPS index analysis. For the sleep assessment, the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and polysomnography were used. Compared with healthy control subjects, patients with early-stage ALS had a significantly lower ALPS index after family-wise error correction (P < 0.05). Moreover, receiver operating characteristic analysis showed that the area under the curve for the ALPS index was 0.792 (95% confidence interval 0.700–0.884). Partial correlation analyses showed that the ALPS index was significantly correlated with clinical disability and sleep disturbances in patients with early-stage ALS. Multivariate analysis showed that sleep efficiency (r = 0.419, P = 0.002) and periodic limb movements in sleep index (r = −0.294, P = 0.017) were significant predictive factors of the ALPS index in patients with early-stage ALS. In conclusion, our study continues to support an important role for glymphatic dysfunction in ALS pathology, and we provide additional insights into the early diagnostic value of glymphatic dysfunction and its correlation with sleep disturbances in vivo in patients with early-stage ALS. Moreover, we suggest that early improvement of glymphatic function may be a promising strategy for slowing the neurodegenerative process in ALS. Future studies are needed to explore the diagnostic and therapeutic value of glymphatic dysfunction in individuals with presymptomatic-stage neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Aims To assess the additional prognostic significance of echocardiographic parameters of subpulmonary left ventricular (LV) size and function in patients with a systemic right ventricle (SRV). Methods and results All adults with an SRV who underwent transthoracic echocardiography in 2010–18 at a large tertiary centre were identified. Biventricular size and function were assessed at the most recent examination. The study endpoint was all-cause mortality or heart/heart–lung transplantation. We included 180 patients, with 100 (55.6%) males, with a mean age of 42.4 ± 12.3 years, of whom 103 (57.2%) had undergone Mustard/Senning operations and 77 (42.8%) had congenitally corrected transposition of great arteries. Over 4.9 (3.8–5.7) years, 28 (15.6%) patients died and 4 (2.2%) underwent heart or heart–lung transplantation. Univariable predictors of the study endpoint included age, New York Heart Association functional Class III or IV, history of atrial arrhythmias, presence of a pacemaker or cardioverter defibrillator, high B-type natriuretic peptide, and echocardiographic markers of SRV and subpulmonary LV size and function. On multivariable Cox analysis of echocardiographic variables, indexed LV end-systolic diameter [ESDi; hazard ratio (HR) 2.77 (95% confidence interval, CI) 1.35–5.68, P = 0.01], LV fractional area change [FAC; HR 0.7 (95% CI 0.57–0.85), P = 0.002), SRV basal diameter [HR 1.66 (95% CI 1.21–2.29), P = 0.005], and SRV FAC [HR 0.65 (95% CI 0.49–0.87), P = 0.008] remained predictive of mortality or transplantation. On receiver-operating characteristic analysis, subpulmonary LV parameters performed better than SRV markers in predicting adverse events. Conclusion SRV basal diameter, SRV FAC, LV ESDi, and LV FAC are significantly and independently associated with mortality and transplantation in adults with an SRV. Accurate echocardiographic assessment of both SRV and subpulmonary LV is, therefore, essential to inform risk stratification and management. [ABSTRACT FROM AUTHOR]

Objectives This study aims to evaluate the morphological features of gubernacular tract (GT) for erupting permanent mandibular canines at different ages from 5 to 9 years old with a three-dimensional (3D) measurement method. Methods The cone-beam CT images of 50 patients were divided into five age groups. The 3D models of the GT for mandibular canines were reconstructed and analysed. The characteristics of the GT, including length, diameter, ellipticity, tortuosity, superficial area, volume, and the angle between the canine and GT, were evaluated using a centreline fitting algorithm. Results Among the 100 GTs that were examined, the length of the GT for mandibular canines decreased between the ages of 5 and 9 years, while the diameter increased until the age of 7 years. Additionally, the ellipticity and tortuosity of the GT decreased as age advanced. The superficial area and volume exhibited a trend of initially increasing and then decreasing. The morphological variations of the GT displayed heterogeneous changes during different periods. Conclusions The 3D measurement method effectively portrayed the morphological attributes of the GT for mandibular canines. The morphological characteristics of the GT during the eruption process exhibited significant variations. The variations in morphological changes may indicate different stages of mandibular canine eruption. [ABSTRACT FROM AUTHOR]

Graphical Abstract [ABSTRACT FROM AUTHOR]

Technological advances have now made it possible to simultaneously profile the changes of epigenomic, transcriptomic and proteomic at the single cell level, allowing a more unified view of cellular phenotypes and heterogeneities. However, current computational tools for single-cell multi-omics data integration are mainly tailored for bi-modality data, so new tools are urgently needed to integrate tri-modality data with complex associations. To this end, we develop scMHNN to integrate single-cell multi-omics data based on hypergraph neural network. After modeling the complex data associations among various modalities, scMHNN performs message passing process on the multi-omics hypergraph, which can capture the high-order data relationships and integrate the multiple heterogeneous features. Followingly, scMHNN learns discriminative cell representation via a dual-contrastive loss in self-supervised manner. Based on the pretrained hypergraph encoder, we further introduce the pre-training and fine-tuning paradigm, which allows more accurate cell-type annotation with only a small number of labeled cells as reference. Benchmarking results on real and simulated single-cell tri-modality datasets indicate that scMHNN outperforms other competing methods on both cell clustering and cell-type annotation tasks. In addition, we also demonstrate scMHNN facilitates various downstream tasks, such as cell marker detection and enrichment analysis. [ABSTRACT FROM AUTHOR]

Studies have shown that the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is detrimental to the functional recovery of the sciatic nerve, but the regulatory mechanisms of the NLRP3 inflammasome in peripheral nerves are unclear. C-X-C motif chemokine 12 (CXCL12) can bind to C-X-C chemokine receptor type 4 (CXCR4) and participate in a wide range of nerve inflammation by regulating the NLRP3 inflammasome. Based on these, we explore whether CXCL12-CXCR4 axis regulates the NLRP3 inflammasome in the peripheral nerve. We found that CXCR4/CXCL12, NLRP3 inflammasome-related components, pyroptosis-related proteins and inflammatory factors in the sciatic nerve injured rats were markedly increased compared with the sham-operated group. AMD3100, a CXCR4 antagonist, reverses the activation of NLRP3 inflammasome, Schwann cell pyroptosis and sciatic nerve demyelination. We further treated rat Schwann cells with LPS (lipopolysaccharide) and adenosine triphosphate (ATP) to mimic the cellular inflammation model of sciatic nerve injury, and the results were consistent with those in vivo. In addition, both in vivo and in vitro experiments demonstrated that AMD3100 treatment reduced the phosphorylation of nuclear factor κB (NF-κB) and the expression of thioredoxin interacting protein (TXNIP), which contributes to activating NLRP3 inflammasome. Therefore, our findings suggest that, after sciatic nerve injury, CXCL12-CXCR4 axis may promote Schwann cell pyroptosis and sciatic nerve demyelination through activating NLRP3 inflammasome and slow the recovery process of the sciatic nerve. Studies have shown that the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is detrimental to the functional recovery of the sciatic nerve, and C-X-C motif chemokine 12 (CXCL12) can bind to C-X-C chemokine receptor type 4 (CXCR4) and participate in a wide range of nerve inflammation by regulating the NLRP3 inflammasome. However, the regulatory mechanisms of the NLRP3 inflammasome in peripheral nerves are unclear. Our findings suggest that, after sciatic nerve injury, CXCL12-CXCR4 axis may promote Schwann cell pyroptosis and sciatic nerve demyelination through activating NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

Cold acclimation is a crucial biological process that enables conifers to overwinter safely. The late embryogenesis abundant (LEA) protein family plays a pivotal role in enhancing freezing tolerance during this process. Despite its importance, the identification, molecular functions and regulatory networks of the LEA protein family have not been extensively studied in conifers or gymnosperms. Pinus tabuliformis , a conifer with high ecological and economic values and with high-quality genome sequence, is an ideal candidate for such studies. Here, a total of 104 LEA genes were identified from P. tabuliformis , and we renamed them according to their subfamily group: PtLEA1 – PtLEA92 (group LEA1–LEA6), PtSMP1 – PtSMP6 (group seed maturation protein) and PtDHN1 – PtDHN6 (group Dehydrin). While the sequence structure of P. tabuliformis   LEA genes are conserved, their physicochemical properties exhibit unique characteristics within different subfamily groupings. Notably, the abundance of low-temperature responsive elements in PtLEA genes was observed. Using annual rhythm and temperature gradient transcriptome data, PtLEA22 was identified as a key gene that responds to low-temperature induction while conforming to the annual cycle of cold acclimation. Overexpression of PtLEA22 enhanced Arabidopsis freezing tolerance. Furthermore, several transcription factors potentially co-expressed with PtLEA22 were validated using yeast one-hybrid and dual-luciferase assays, revealing that PtDREB1 could directly bind PtLEA22 promoter to positively regulate its expression. These findings reveal the genome-wide characterization of P. tabuliformis   LEA genes and their importance in the cold acclimation, while providing a theoretical basis for studying the molecular mechanisms of cold acclimation in conifers. [ABSTRACT FROM AUTHOR]

Background Adipose-derived stem cells (ADSCs) are crucial in cell-assisted lipotransfer (CAL). ADSC-derived exosomes could improve the survival of CAL. Almost all relevant research now ignores ADSCs in favor of studying the proangiogenic potential of extracellular vesicles (EVs) on human umbilical vein endothelial cells (HUVECs). Objectives Given the significance of ADSCs in CAL, the authors sought to verify that EVs from ADSCs under hypoxia treatment can enhance the angiogenic potential of ADSCs. Methods EVs were harvested from human ADSCs (hADSCs) under normoxia and hypoxia. A Cell Counting Kit-8 (CCK-8) assay was used to measure the proliferation of hADSCs. By examining the expression of CD31, vascular endothelial growth factor receptor 2, and vascular endothelial growth factor, the pro-angiogenic differentiation potential was assessed. Moreover, a tube formation experiment was carried out to evaluate the pro-angiogenic differentiation potential. Results Hypoxic EVs showed more significant pro-proliferative and pro-angiogenic potential. Angiogenesis was more vigorous in hADSCs treated with hypoxic EVs than in those treated with nomorxic EVs. The hADSCs treated with hypoxic EVs expressed higher angiogenic markers, according to real-time polymerase chain reaction (RT-PCR) and Western blot analysis, which revealed more angiogenic marker expression in hypoxic EV–treated hADSCs. The same result was demonstrated by tube formation on Matrigel in vitro. Conclusions Hypoxic EVs significantly increased the proliferation and angiogenic differentiation potential of hADSCs. Hypoxic EV–treated ADSCs may be beneficial to CAL and prevascularized tissue-engineered constructs. [ABSTRACT FROM AUTHOR]

This article, published in Current Zoology, discusses infanticide in golden snub-nosed monkeys. The study reports two cases of infanticide by a dominant male who had taken over a one-male unit (OMU) of monkeys in China. The researchers used behavior and genetic analyses to test the sexual selection hypotheses. The study found that the infanticide events occurred after the infants had become independent and that the females in the OMU showed agonistic behavior towards the male. The findings provide evidence for understanding the sexual selection hypothesis associated with animal infanticide. [Extracted from the article]

The personal dose levels of medical radiation workers in Chongqing from 2008 to 2020 were investigated and analysed. The results showed that a total of 68 379 people were monitored from 2008 to 2020. The number of radiation workers increased year by year, and the number of female radiation workers increased rapidly. The monitoring data were analysed by Mann–Whitney test, Mann-Kendall test and Bonferroni method. The annual mean effective dose from 2008 to 2020 showed a decreasing trend (P  < 0.0001). At the 5% significance level, six occupational categories showed a significant decreasing trend (P  < 0.0001).The average annual effective dose for medical radiation workers in Chongqing in 2020 was 0.4482 mSv and 94.73% of radiation workers received annual doses less than the public dose limit (1 mSv). Personal dose monitoring results for most radiation workers were low. The protection of radiation workers in interventional radiology and nuclear medicine should be concerned. [ABSTRACT FROM AUTHOR]

Moho determination is an important issue in studying the Earth's interior structure. In accordance with the isostasy-compensation hypothesis in geodesy, it is possible to recover regional or global Moho by employing gravimetric data. The nonlinear property is one of the main difficulties in solving the inverse problem of isostasy. To effectively address this issue, we propose an improved iterative inversion method that combines 3-D integration and linear regularization to achieve an approximate nonlinear solution. To estimate the contributions of different components in the gravity-gradient tensor from the Gravity field and steady-state Ocean Circulation Explorer (GOCE), other than the vertical component, we additionally develop two joint inversion scenarios that utilize diagonal horizontal components and all five non-vertical components. The validating experiments are implemented in Qinghai–Tibet Plateau and its near zone. Simulations and applications illustrate that horizontal responses of Moho undulation are also significant. Yet the off-diagonal components provide minimal contributions, adding only 0.25 km of bias to the joint inversion results. Truncation effects serve as the primary source of systematic errors, resulting in ∼1 km error in vertical inversion results and ∼2.3 km error in joint inversion results. Then, the gravimetric Moho results are compared with CRUST1.0, and they show a generally strong correlation. Differences are obvious at the northern and eastern margins of the plateau. It is maybe due to the local changes in crust–mantle density contrasts. Upwelling of asthenospheric materials and fluid flow in the middle-lower crust are the two main factors. Based on high-precision satellite gravimetry, our study could provide new insights into the tectonic structure of Qinghai–Tibet Plateau. [ABSTRACT FROM AUTHOR]

Background Lenvatinib is a first-line agent for advanced hepatocellular carcinoma (HCC), but individual responses to treatment are highly heterogeneous. The aim of this study was to investigate the clinical parameters that influence the efficacy of Lenvatinib and to develop a prognostic model. Methods We retrospectively enrolled 333 Lenvatinib-treated patients with HCC with a median age of 57 years. Two hundred nd sixty-three of these patients had BCLC (2022) stage C. The median overall survival (mOS) time within the cohort was 12.1 months, and the median progression-free survival (mPFS) time was 4.7 months. Univariate Cox regression, best subset regression, and Lasso regression were used to screen primary variables for possible contribution to OS, multivariate Cox analysis was used to fit selected models, and the final model was selected using the maximum area under the curve (AUC) and minimum AIC. Receiver operating curves (ROC), calibration curves, and decision curve analysis were plotted to assess model performance, and 5-fold cross-validation was performed for internal validation. X-tile software was used to select the best cutoff points and to divide the study cohort into 3 different risk groups. Results Seven variables were included in the final model: BCLC stage, prior transarterial chemoembolization and immunotherapy history, tumor number, prognostic nutritional index, log (alpha-fetoprotein), and log (platelet-to-lymphocyte ratio). We named this final model the "multivariate prognostic model for Lenvatinib" (MPML), and a nomogram was constructed to predict the probability of survival at 6, 9, and 12 months. The MPML had good discrimination, calibration, and applicability. Cross-validation showed mean AUC values of 0.7779, 0.7738, and 0.7871 at 6, 9, and 12 months, respectively. According to nomogram points, mOS time was 21.57, 8.70, and 5.37 months in the low, medium, and high-risk groups, respectively (P <.001), and these differences were also observed in the PFS survival curve (P <.001). Conclusions The MPML stratified patients according to baseline clinical characteristics had a strong performance in predicting Lenvatinib efficacy and has the potential for use as an auxiliary clinical tool for individualized decision-making. [ABSTRACT FROM AUTHOR]

Background Although depression has been a serious neuropsychiatric disorder worldwide, current antidepressants used in clinical practice have various weaknesses, including delayed onset and low rates of efficacy. Recently, the development of new antidepressants from natural herbal medicine has become one of the important research hotspots. Cucurbitacin B is a natural compound widely distributed in the Cucurbitaceae and Cruciferae families and has many pharmacological activities. The present study aimed to investigate whether cucurbitacin B possess antidepressant-like effects in mice. Methods The antidepressant-like effects of cucurbitacin B on mice behaviors were explored using the forced swim test, tail suspension test, open field test, sucrose preference test, and a chronic unpredictable mild stress model of depression together. Then, western blotting and immunofluorescence were used to examine the effects of cucurbitacin B on the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling cascade and neurogenesis in the hippocampus of mice. Furthermore, BDNF-short hairpin RNA, K252a, and p-chlorophenylalanine methyl ester were adopted together to determine the antidepressant mechanism of cucurbitacin B. Results It was found that administration of cucurbitacin B indeed produced notable antidepressant-like effects in mice, which were accompanied with significant promotion in both the hippocampal BDNF-TrkB pathway and neurogenesis. The antidepressant mechanism of cucurbitacin B involves the hippocampal BDNF-TrkB system but not the serotonin system. Conclusions Cucurbitacin B has the potential to be a novel antidepressant candidate. [ABSTRACT FROM AUTHOR]

Background Although thought of as a multimodal-acting antidepressant targeting the serotonin system, more molecules are being shown to participate in the antidepressant mechanism of vortioxetine. A previous report has shown that vortioxetine administration enhanced the expression of rapamycin complex 1 (mTORC1) in neurons. It has been well demonstrated that mTORC1 participates in not only the pathogenesis of depression but also the pharmacological mechanisms of many antidepressants. Therefore, we speculate that the antidepressant mechanism of vortioxetine may require mTORC1. Methods Two mouse models of depression (chronic social defeat stress and chronic unpredictable mild stress) and western blotting were first used together to examine whether vortioxetine administration produced reversal effects against the chronic stress–induced downregulation in the whole mTORC1 signaling cascade in both the hippocampus and medial prefrontal cortex (mPFC). Then, LY294002, U0126, and rapamycin were used together to explore whether the antidepressant effects of vortioxetine in mouse models of depression were attenuated by pharmacological blockade of the mTORC1 system. Furthermore, lentiviral-mTORC1-short hairpin RNA-enhanced green fluorescence protein (LV-mTORC1-shRNA-EGFP) was adopted to examine if genetic blockade of mTORC1 also abolished the antidepressant actions of vortioxetine in mice. Results Vortioxetine administration produced significant reversal effects against the chronic stress–induced downregulation in the whole mTORC1 signaling cascade in both the hippocampus and mPFC. Both pharmacological and genetic blockade of the mTORC1 system notably attenuated the antidepressant effects of vortioxetine in mice. Conclusions Activation of the mTORC1 system in the hippocampus and mPFC is required for the antidepressant actions of vortioxetine in mice. [ABSTRACT FROM AUTHOR]

Receptor-like kinases (RLKs) are the most important class of cell surface receptors, and play crucial roles in plant development and stress responses. However, few studies have been reported about the biofunctions of RLKs in leaf senescence. Here, we characterized a novel Arabidopsis RLK-encoding gene, SENESCENCE-RELATED RECEPTOR KINASE 1 (SENRK1), which was significantly down-regulated during leaf senescence. Notably, the loss-of-function senrk1 mutants displayed an early leaf senescence phenotype, while overexpression of SENRK1 significantly delayed leaf senescence, indicating that SENRK1 negatively regulates age-dependent leaf senescence in Arabidopsis. Furthermore, the senescence-promoting transcription factor WRKY53 repressed the expression of SENRK1. While the wrky53 mutant showed a delayed senescence phenotype as previously reported, the wrky53 senrk1-1 double mutant exhibited precocious leaf senescence, suggesting that SENRK1 functions downstream of WRKY53 in regulating age-dependent leaf senescence in Arabidopsis. [ABSTRACT FROM AUTHOR]

The advent of single-cell RNA sequencing (scRNA-seq) technologies has enabled gene expression profiling at the single-cell resolution, thereby enabling the quantification and comparison of transcriptional variability among individual cells. Although alterations in transcriptional variability have been observed in various biological states, statistical methods for quantifying and testing differential variability between groups of cells are still lacking. To identify the best practices in differential variability analysis of single-cell gene expression data, we propose and compare 12 statistical pipelines using different combinations of methods for normalization, feature selection, dimensionality reduction and variability calculation. Using high-quality synthetic scRNA-seq datasets, we benchmarked the proposed pipelines and found that the most powerful and accurate pipeline performs simple library size normalization, retains all genes in analysis and uses denSNE-based distances to cluster medoids as the variability measure. By applying this pipeline to scRNA-seq datasets of COVID-19 and autism patients, we have identified cellular variability changes between patients with different severity status or between patients and healthy controls. [ABSTRACT FROM AUTHOR]

Objective Thyroid-stimulating hormone (TSH) levels are associated with serum lipid concentrations in the general nonpregnant population. Here, we aimed to establish trimester-specific reference intervals and to explore the associations of their variations within the specific reference intervals during pregnancy. Methods Trimester-specific reference intervals were established according to the Clinical and Laboratory Standard Institute EP28-A3c guidelines using a direct sampling method based on a large prospective cohort. After making one-to-one matches, correlation analyses between TSH and lipid index levels, especially within the reference intervals, were conducted. Result A total of 1648 pregnant women for TSH and 2045 subjects for lipids were recruited to establish the trimester-specific reference intervals. The upper reference limit (90% confidence interval) of TSH for pregnant women in the first trimester is 3.95 (3.66–4.29) mIU/L, which is very close to the default value (4.0 mIU/L) recommended by the American Thyroid Association in 2017. Apart from triglyceride and high-density lipoprotein cholesterol, TSH levels were positively associated with the serum concentrations of total cholesterol, low-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol (non–HDL-C), and remnant cholesterol (RC) either in the entire range or within the specific reference intervals. Of note, the positive correlations between TSH and non–HDL-C and RC were, albeit similarly weak (r  < 0.25), relatively more robust (P  < .001). Conclusion In this study, we showed positive correlations between TSH and lipid components within trimester-specific reference intervals, highlighting the need for the integrated management of pregnant women over age 35 and with nonoptimal lipid status in China. [ABSTRACT FROM AUTHOR]

Silicosis is a global occupational pulmonary disease due to the accumulation of silica dust in the lung. Lacking effective clinical drugs makes the treatment of this disease quite challenging in clinics largely because the pathogenic mechanisms remain obscure. Interleukin 33 (IL33), a pleiotropic cytokine, could promote wound healing and tissue repair via the receptor ST2. However, the mechanisms governing the involvement of IL33 in silicosis progression remain to be further explored. Here, we demonstrated that the IL33 levels in the lung sections were significantly overexpressed after bleomycin and silica treatment. Chromatin immunoprecipitation assay, knockdown, and reverse experiments were performed in lung fibroblasts to prove gene interaction following exogenous IL33 treatment or cocultured with silica-treated lung epithelial cells. Mechanistically, we illustrated that silica-stimulated lung epithelial cells secreted IL33 and further promoted the activation, proliferation, and migration of pulmonary fibroblasts by activating the ERK/AP-1/NPM1 signaling pathway in vitro. And more, treatment with NPM1 siRNA-loaded liposomes markedly protected mice from silica-induced pulmonary fibrosis in vivo. In conclusion, the involvement of NPM1 in the progression of silicosis is regulated by the IL33/ERK/AP-1 signaling axis, which is the potential therapeutic target candidate in developing novel antifibrotic strategies for pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Motivation Since the development of single-cell RNA sequencing (scRNA-seq) technologies, clustering analysis of single-cell gene expression data has been an essential tool for distinguishing cell types and identifying novel cell types. Even though many methods have been available for scRNA-seq clustering analysis, the majority of them are constrained by the requirement on predetermined cluster numbers or the dependence on selected initial cluster assignment. Results In this article, we propose an adaptive embedding and clustering method named scAce, which constructs a variational autoencoder to simultaneously learn cell embeddings and cluster assignments. In the scAce method, we develop an adaptive cluster merging approach which achieves improved clustering results without the need to estimate the number of clusters in advance. In addition, scAce provides an option to perform clustering enhancement, which can update and enhance cluster assignments based on previous clustering results from other methods. Based on computational analysis of both simulated and real datasets, we demonstrate that scAce outperforms state-of-the-art clustering methods for scRNA-seq data, and achieves better clustering accuracy and robustness. Availability and implementation The scAce package is implemented in python 3.8 and is freely available from https://github.com/sldyns/scAce. [ABSTRACT FROM AUTHOR]

Objectives Mortality of dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 antibody (anti-MDA5-DM) is alarming, especially during the first several months. Infection is an important cause of early death. As there are no reports regarding the effect of prophylactic use of compounded sulfamethoxazole (coSMZ; each tablet contains 400 mg of sulfamethoxazole and 80 mg of trimethoprim) in anti-MDA5-DM patients, we conducted this study to evaluate the efficacy of coSMZ in reducing the incidence of Pneumocystis jirovecii pneumonia (PJP). Methods Consecutive patients with new-onset anti-MDA5-DM from June 2018 to October 2021 in our centre were retrospectively reviewed for >12 months. They were divided into two groups—coSMZ and non-coSMZ—based on the initial use of prophylactic coSMZ. Mortality and the incidence of severe infection within 12 months were compared between two groups. Results Compared with the non-coSMZ group (n  = 93), the coSMZ group (n  = 121) had lower mortality (18.8% vs 51.1%; P   <  0.001) and a lower incidence of PJP (6.8% vs 15.2%; P  = 0.040) and fatal infection (16.1% vs 3.3%; P  = 0.001) during the first 12 months from diagnosis. After adjusting for age, gender, disease duration, peripheral blood lymphocyte count, anti-MDA5 antibody titres, ground-glass opacity scores and treatments, an inverse association was revealed between the prophylactic use of coSMZ and incidence of PJP [adjusted odds ratio 0.299 (95% CI 0.102–0.878), P  = 0.028]. Conclusion Prophylactic use of coSMZ is an effective and safe way to improve the prognosis of anti-MDA5-DM patients by preventing the incidence of PJP. [ABSTRACT FROM AUTHOR]