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Tris (2,6-dimethylphenyl) phosphate (TDMPP), a novel organic phosphorus flame retardant (OPFR), has been found to have estrogenic activity. Estrogens are critical in regulating various biological responses during liver development. However, the effects of TDMPP on zebrafish liver development remain largely unexplored. Here, we utilized a chemical genetic screening approach to assess the estrogenic effects of TDMPP on liver development and to elucidate the underlying molecular mechanism. Our findings revealed that zebrafish larvae exposed to environmentally relevant concentrations of TDMPP (0.05 and 0.5 μM) exhibited concentration-dependent liver impairments, including reduced liver size, histopathological changes, and hepatocyte apoptosis. In addition, E2 caused similar adverse effects to TDMPP, but the pharmacological blockade of estrogen synthesis alleviated the effects on liver development. Chemical inhibitors and morpholino knockdown assays indicated that the reduction of esr2a blocked TDMPP-induced liver impairments, which was further confirmed in the esr2a-/- mutant line. Subsequently, transcriptomic analysis showed that the estrogen receptor activated by TDMPP inhibited the expression of smc2, which was linked to the suppression of liver development through p53 activation. Consistently, overexpression of smc2 and inhibition of p53 evidently rescued hepatic damages induced by TDMPP. Taken together, the above findings identified esr2a, downstream smc2, and p53 as important regulators for the estrogenic effects of TDMPP on liver development. Our work fills crucial gaps in the current knowledge of TDMPP's hepatotoxicity, providing new insights into the adverse effects of TDMPP and the molecular mechanisms of action. These findings underscore the need for further ecological risk assessment and regulatory considerations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Inevitable leaching and corrosion under anodic oxidative environment greatly restrict the lifespan of most catalysts with excellent primitive activity for oxygen production. Here, based on Fick' s Law, we present a surface cladding strategy to mitigate Ni dissolution and stabilize lattice oxygen triggering by directional flow of interfacial electrons and strong electronic interactions via constructing elaborately cladding-type NiO/NiS heterostructure with controlled surface thickness. Multiple in-situ characterization technologies indicated that this strategy can effectively prevent the irreversible Ni ions leaching and inhibit lattice oxygen from participating in anodic reaction. Combined with density functional theory calculations, we reveal that the stable interfacial O-Ni-S arrangement can facilitate the accumulation of electrons on surficial NiO side and weaken its Ni-O covalency. This would suppress the overoxidation of Ni and simultaneously fixing the lattice oxygen, thus enabling catalysts with boosted corrosion resistance without sacrificing its activity. Consequently, this cladding-type NiO/NiS heterostructure exhibits excellent performance with a low overpotential of 256 mV after 500 h. Based on Fick's law, this work demonstrates the positive effect of surface modification through precisely adjusting of the oxygen-sulfur exchange process, which has paved an innovative and effective way to solve the instability problem of anodic oxidation., (© 2024 Wiley‐VCH GmbH.)

Background: Diarrheal irritable bowel syndrome (IBS-D), characterized primarily by the presence of diarrhea and abdominal pain, is a clinical manifestation resulting from a multitude of causative factors. Furthermore, Sishen Wan (SSW) has demonstrated efficacy in treating IBS-D. Nevertheless, its mechanism of action remains unclear., Methods: A model of IBS-D was induced by a diet containing 45 % lactose and chronic unpredictable mild stress. Additionally, the impact of SSW was assessed by measuring body weight, visceral sensitivity, defecation parameters, intestinal transport velocity, intestinal neurotransmitter levels, immunohistochemistry, and transmission electron microscopy analysis. Immunofluorescent staining was used to detect the expression of Mucin 2 (MUC2) and Occludin in the colon. Western blotting was used to detect changes in proteins related to tight junction (TJ), autophagy, and endoplasmic reticulum (ER) stress in the colon. Finally, 16S rRNA amplicon sequencing was used to monitor the alteration of gut microbiota after SSW treatment., Results: Our study revealed that SSW administration resulted in reduced visceral sensitivity, improved defecation parameters, decreased intestinal transport velocity, and reduced intestinal permeability in IBS-D mice. Furthermore, SSW promotes the secretion of colonic mucus by enhancing autophagy and inhibiting ER stress. SSW treatment caused remodeling of the gut microbiome by increasing the abundance of Blautia, Muribaculum and Ruminococcus torques group., Conclusion: SSW can improve intestinal barrier function by promoting autophagy and inhibiting ER stress, thus exerting a therapeutic effect on IBS-D., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Figures were created with BioRender software, biorender.com., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

This study aims to identify key regulators of paraptosis in gastric cancer (GC) and explore their potential in guiding therapeutic strategies, especially in stomach adenocarcinoma (STAD). Genes associated with paraptosis were identified from the references and subjected to Cox regression analysis in the TCGA-STAD cohort. Using machine learning models, LPAR1 consistently ranked highest in feature importance. Multiple sequencing data showed that LPAR1 was significantly overexpressed in cancer-associated fibroblasts (CAFs). LPAR1 expression was significantly higher in normal tissues, and ROC analysis demonstrated its discriminative ability. Copy number alterations and microsatellite instability were significantly associated with LPAR1 expression. High LPAR1 expression correlated with advanced tumor grades and specific cancer immune subtypes, and multivariate analysis confirmed LPAR1 as an independent predictor of poor prognosis. LPAR1 expression was associated with different immune response metrics, including immune effector activation and upregulated chemokine secretion. High LPAR1 expression also correlated with increased sensitivity to compounds, such as BET bromodomain inhibitors I-BET151 and RITA, suggesting LPAR1 as a biomarker for predicting drug activity. FOXP2 showed a strong positive correlation with LPAR1 transcriptional regulation, while increased methylation of LPAR1 promoter regions was negatively correlated with gene expression. Knockdown of LPAR1 affected cell growth in most tumor cell lines, and in vitro experiments demonstrated that LPAR1 influenced extracellular matrix (ECM) contraction and cell viability in the paraptosis of CAFs. These findings suggest that LPAR1 is a critical regulator of paraptosis in GC and a potential biomarker for drug sensitivity and immunotherapy response. This underscores the role of CAFs in mediating tumorigenic effects and suggests that targeting LPAR1 could be a promising strategy for precision medicine in GC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Solid electrolyte interphases (SEIs) are sought to protect high-capacity anodes, which suffer from severe volume changes and fast degradations. The previously proposed effective SEIs were of high strength yet abhesive, inducing a yolk-shell structure to decouple the rigid SEI from the anode for accommodating the volume change. Ambivalently, the interfacial void-evolved electro-chemo-mechanical vulnerabilities become inherent defects. Here, we establish a new rationale for SEIs that resilience and adhesivity are both requirements and pioneer a design of a resilient yet adhesive SEI (re-ad-SEI), integrated into a conjugated surface bilayer structure. The re-ad-SEI and its protected particles exhibit excellent stability almost free from the thickening of SEI and the particle pulverization during cycling. More promisingly, the dynamically bonded intact SEI-anode interfaces enable a high-efficiency ion transport and provide a unique mechanical confinement effect for structural integrity of anodes. The high Coulombic efficiency (>99.8%), excellent cycling stability (500 cycles), and superior rate performance have been demonstrated in microsized Si-based anodes.

Background: There is a lack of relevant studies to grade the evidence on the risk factors of chronic pain after total knee arthroplasty (TKA), and only quantitative methods are used for systematic evaluation. The review aimed to systematically identify risk factors of chronic postoperative pain following TKA and to evaluate the strength of the evidence underlying these correlations., Methods: PubMed, Web of Science, Cochrane Library, Embase, and CINAHL databases were searched from initiation to September 2023. Cohort studies, case-control studies, and cross-sectional studies involving patients undergoing total knee replacement were included. A semi-quantitative approach was used to grade the strength of the evidence-based on the number of investigations, the quality of the studies, and the consistency of the associations reported by the studies., Results: Thirty-two articles involving 18,792 patients were included in the final systematic review. Ten variables were found to be strongly associated with postoperative pain, including Age, body mass index (BMI), comorbidities condition, preoperative pain, chronic widespread pain, preoperative adverse health beliefs, preoperative sleep disorders, central sensitization, preoperative anxiety, and preoperative function. Sixteen factors were identified as inconclusive evidence., Conclusions: This systematic review clarifies which risk factors could be involved in future research on TKA pain management for surgeons and patients. It highlights those factors that have been controversial or weakly correlated, emphasizing the need for further high-quality studies to validate them. Most crucially, it can furnish clinicians with vital information regarding high-risk patients and their clinical attributes, thereby aiding in the development of preventive strategies to mitigate postoperative pain following TKA., Trial Registration: This systematic review has been registered on the PROSPERO platform (CRD42023444097)., (© 2024. The Author(s).)

A high strain rate occurs when the strain rate exceeds 100 s -1 . The mechanical behavior of materials at a high strain rate is different from that at middle and low strain rates. In order to study the dynamic compressive mechanical properties of ultra-high-performance steel-fiber-reinforced concrete (UHPSFRC) at high strain rates, an electro-hydraulic servo universal testing machine and a separate Hopkinson pressure bar (SHPB) with a diameter of 120 mm were used, respectively. A quasi-static compression test (strain rate 0.001 s -1 ) and impact compression test with a strain rate range of 90~200 s -1 were carried out to study the failure process, failure mode, and stress-strain curve characteristics of UHPSFRC at different strain rates and quantify the strain rate strengthening effect and fiber toughening effect. Based on the statistical damage theory and energy conversion principle, a dynamic damage constitutive model considering the effects of strain rate and fiber content was constructed. The results showed that the rate correlation of UHPSFRC and the fiber toughening properties showed a certain coupling competition mechanism. When the fiber content was less than 1.5%, with an increase in the steel fiber content, the crack initiation and propagation time of the specimen was extended, and the strain rate sensitivity gradually decreased. When the fiber content was 2%, the impact compressive strength of the specimen was optimal. Compared with UHPC, the dynamic increase factor (DIF) of UHPSFRC was significantly lower. The dynamic damage constitutive model established in this paper, considering the influence of strain rate and fiber content, has a good applicability and can describe the mechanical behavior of UHPSFRC at a high strain rate.

Water-soluble quantum dots (QDs) are necessary to prepare patterned pixels or films for high-resolution displays with less environmental burden but are very limited by the trade-off between photoluminescence and stability of QDs. In this work, we proposed synthesizing water-soluble QDs with simultaneous excellent luminescence properties and high stability by coating the amphiphilic poly(maleic anhydride- alt -1-octadecene)-ethanol amine (PMAO-EA) polymer on the surface of silane-treated QDs. These coated QDs show a photoluminescence quantum yield (PLQY) as high as 94%, and they have good photoluminescence stability against light irradiation and thermal attacks, owing to the suppression of the nonradiative recombination by the polymer layer and the isolation of oxygen and water by the silica layer. The water-soluble QDs, mixed with ethylene glycol, enable inkjet printing of QD color conversion films (QD-CCFs) with an average diameter of 68 μm for each pixel and a high PLQY of 91%. The QD-CCFs are demonstrated to fabricate red-emitting mini-LEDs by combining with blue mini-LED chips, which have an external quantum efficiency as high as 25.86% and a luminance of 2.44 × 10 7 cd/m 2 . We believe that the proposed strategy is applicable to other water-soluble QDs and paves an avenue for inkjet printing environmentally friendly QD-CCFs for mini/micro-LED displays.

Nonalcoholic steatohepatitis (NASH) is a metabolism-associated fatty liver disease with accumulated mitochondrial stress, and targeting mitochondrial function is a potential therapy. The mitochondrial genome-encoded bioactive peptide MOTS-c plays broad physiological roles, but its effectiveness and direct targets in NASH treatment are still unclear. Here, we show that long-term preventive and short-term therapeutic effects of MOTS-c treatments alleviate NASH-diet-induced liver steatosis, cellular apoptosis, inflammation, and fibrosis. Mitochondrial oxidative capacity and metabolites profiling analysis show that MOTS-c significantly reverses NASH-induced mitochondrial metabolic deficiency. Moreover, we identify that MOTS-c directly interacts with the BH3 domain of antiapoptotic B cell lymphoma-2 (Bcl-2), increases Bcl-2 protein stability, and suppresses Bcl-2 ubiquitination. By using a Bcl-2 inhibitor or adeno-associated virus (AAV)-mediated Bcl-2 knockdown, we further confirm that MOTS-c improves NASH-induced mitochondrial dysfunction, inflammation, and fibrosis, which are dependent on Bcl-2 function. Therefore, our findings show that MOTS-c is a potential therapeutic agent to inhibit the progression of NASH., Competing Interests: Declaration of interests The authors declare competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Gradient poly(methyl methacrylate/ n -butyl acrylate) copolymers, P(MMA/BA), with various compositional ratios, were grafted from surface-modified silica nanoparticles (SiO 2 - g -PMMA- grad -PBA) via complete conversion surface-initiated activator regenerated by electron transfer (SI-ARGET) atom transfer radical polymerization (ATRP). Miniemulsion as the reaction medium effectively confined the interparticle brush coupling within micellar compartments, preventing macroscopic gelation and enabling complete conversion. Isolation of dispersed and gelled fractions revealed dispersed particle brushes to feature a higher Young's modulus, toughness, and ultimate strain compared with those of the "gel" counterparts. Upon purification, brush nanoparticles from the dispersed phase formed uniform microstructures. Uniaxial tension testing revealed a "mechanical synergy" for copolymers with MMA/BA = 3:2 molar ratio to concurrently exhibit higher toughness and stiffness. When compared with linear analogues of similar composition, the brush nanoparticles with gradient copolymers had better mechanical properties, attributed to the synergistic effects of the combination of composition and propagation orientation, highlighting the significance of architectural design for tethered brush layers of such hybrid materials., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

FIGLA and NOBOX are important oocyte-specific transcription factors. Both figla-/- and nobox-/- mutants showed all-male phenotype in zebrafish due to increased dominance of the male-promoting pathway. The early diversion towards males in these mutants has precluded analysis of their roles in folliculogenesis. In this study, we attenuated the male-promoting pathway by deleting dmrt1, a key male-promoting gene, in figla-/- and nobox-/- fish, which allows a sufficient display of defects in folliculogenesis. Germ cells in figla-/-;dmrt1-/- double mutant remained in cysts without forming follicles. In contrast, follicles could form well but exhibited deficient growth in nobox-/-;dmrt1-/- double mutants. Follicles in nobox-/-;dmrt1-/- ovary could progress to previtellogenic (PV) stage but failed to enter vitellogenic growth. Such arrest at PV stage suggested a possible deficiency in estrogen signaling. This was supported by lines of evidence in nobox-/-;dmrt1-/-, including reduced expression of ovarian aromatase (cyp19a1a) and level of serum estradiol (E2), regressed genital papilla (female secondary sex characteristics), and more importantly the resumption of vitellogenic growth by E2 treatment. Expression analysis suggested Nobox might regulate cyp19a1a by controlling Gdf9 and/or Bmp15. Our discoveries indicate that Figla is essential for ovarian differentiation and follicle formation whereas Nobox is important for driving subsequent follicle development., (© 2023. The Author(s).)

Inorganic mercury (Hg 2+ ) is a highly toxic heavy metal in the environment. To date, the impacts of Hg 2+ on the development of monocytes, or monopoiesis, have not been fully addressed. The aim of the present study was to investigate the impact of Hg 2+ on monopoiesis. In this study, we treated B10.S mice and DBA/2 mice with 10 μM or 50 μM HgCl 2 via drinking water for 4 wk, and we then evaluated the development of monocytes. Treatment with 50 μM HgCl 2 , but not 10 μM HgCl 2 , increased the number of monocytes in the blood, spleen and bone marrow (BM) of B10.S mice. Accordingly, treatment with 50 μM HgCl 2 , but not 10 μM HgCl 2 , increased the number of common myeloid progenitors (CMP) and granulocyte-macrophage progenitors (GMP) in the BM. Functional analyses indicated that treatment with 50 μM HgCl 2 promoted the differentiation of CMP and GMP to monocytes in the BM of B10.S mice. Mechanistically, treatment with 50 μM HgCl 2 induced the production of IFNγ, which activated the Jak1/3-STAT1/3-IRF1 signaling in CMP and GMP and enhanced their differentiation potential for monocytes in the BM, thus likely leading to increased number of mature monocytes in B10.S mice. Moreover, the increased monopoiesis by Hg 2+ was associated with the increased inflammatory status in B10.S mice. In contrast, treatment with 50 μM HgCl 2 did not impact the monopoiesis in DBA/2 mice. Our study reveals the impact of Hg on the development of monocytes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Upon cold exposure, aged people with lower metabolic rate cannot rapidly increase the higher levels of heat production, and are seriously threatened by the hypothermia, extensive cold stress responses and risk of mortality. Here, we show that brown fat thermogenic activity is obviously deficient in aged mice, associating with reduction of UCP1 expression and inhibition of its mRNA translation. As we considered, aging aggravates brown fat oxidative stress and activates the integrated stress response (ISR), inducing the phosphorylation of eIF2α to block the global mRNA translation. Therefore, small-molecule ISR inhibitor (ISRIB) treatment attenuates the higher level of eIF2α phosphorylation, restores the repression of Ucp1 mRNA translation and improves UCP1-mediated thermogenic function to defend cold stress in aged mice. Furthermore, ISRIB treatment increases the relative lower metabolic rates, and alleviates glucose intolerance and insulin resistance in aged mice. Thus, we have uncovered a promising drug that reverses the aged-related the deficiency of UCP1-mediated thermogenesis to combat cold stress and associated metabolic diseases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Huanyu Lu reports financial support was provided by National Natural Science Foundation of China., (Copyright © 2023 Elsevier Inc. All rights reserved.)

As an oocyte-specific growth factor, bone morphogenetic protein 15 (BMP15) plays a critical role in controlling folliculogenesis. However, the mechanism of BMP15 action remains elusive. Using zebrafish as the model, we created a bmp15 mutant using CRISPR/Cas9 and demonstrated that bmp15 deficiency caused a significant delay in follicle activation and puberty onset followed by a complete arrest of follicle development at previtellogenic (PV) stage without yolk accumulation. The mutant females eventually underwent female-to-male sex reversal to become functional males, which was accompanied by a series of changes in secondary sexual characteristics. Interestingly, the blockade of folliculogenesis and sex reversal in bmp15 mutant could be partially rescued by the loss of inhibin (inha-/-). The follicles of double mutant (bmp15-/-;inha-/-) could progress to mid-vitellogenic (MV) stage with yolk accumulation and the fish maintained their femaleness without sex reversal. Transcriptome analysis revealed up-regulation of pathways related to TGF-β signaling and endocytosis in the double mutant follicles. Interestingly, the expression of inhibin/activin βAa subunit (inhbaa) increased significantly in the double mutant ovary. Further knockout of inhbaa in the triple mutant (bmp15-/-;inha-/-;inhbaa-/-) resulted in the loss of yolk granules again. The serum levels of estradiol (E2) and vitellogenin (Vtg) both decreased significantly in bmp15 single mutant females (bmp15-/-), returned to normal in the double mutant (bmp15-/-;inha-/-), but reduced again significantly in the triple mutant (bmp15-/-;inha-/-;inhbaa-/-). E2 treatment could rescue the arrested follicles in bmp15-/-, and fadrozole (a nonsteroidal aromatase inhibitor) treatment blocked yolk accumulation in bmp15-/-;inha-/- fish. The loss of inhbaa also caused a reduction of Vtg receptor-like molecules (e.g., lrp1ab and lrp2a). In summary, the present study provided comprehensive genetic evidence that Bmp15 acts together with the activin-inhibin system in the follicle to control E2 production from the follicle, Vtg biosynthesis in the liver and its uptake by the developing oocytes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Standardized care plans are being increasingly introduced to health facilities; however, their level of adoption remains unsatisfactory. Little is known about nurses' use of standardized care plans in China. This study aims to investigate acute care nurses' practices and experiences of care planning within a clinical decision support system embedded with standardized nursing languages. We explored the importance and performance of nursing interventions by retrospective analysis of 400 standardized care plans (performance) and a survey among nurses (importance). Semistructured interviews were conducted to supplement quantitative findings and delve deeper into nurses' experience with standardized care plans. A total of six core nursing diagnoses were determined, each corresponding to seven to 15 nursing interventions. The correlations between nurses' perceived importance and actual performance of nursing interventions in the care plan were weak. Qualitative interviews identified three themes: negative attitudes toward the care plan, uncertainty regarding care planning, and new routines with the care plan. Our findings indicate that nurses' care planning may not reflect their professional judgments. Effective leadership from nurse administrators is warranted to engage nurses with standardized care plan implementation. The content of the standardized nursing language embedded-knowledge base should be continuously adapted to clinical needs to facilitate nurses' care planning practices., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Lead (Pb) is a heavy metal highly toxic to human health in the environment. The aim of this study was to investigate the mechanism of Pb impact on the quiescence of hematopoietic stem cells (HSC). WT C57BL/6 (B6) mice treated with 1250 ppm Pb via drinking water for 8 weeks had increased the quiescence of HSC in the bone marrow (BM), which was caused by the suppressed activation of the Wnt3a/β-catenin signaling. Mechanically, a synergistic action of Pb and IFNγ on BM-resident macrophages (BM-Mφ) reduced their surface expression of CD70, which thereby dampened the Wnt3a/β-catenin signaling to suppress the proliferation of HSC in mice. In addition, a joint action of Pb and IFNγ also suppressed the expression of CD70 on human Mφ to impair the Wnt3a/β-catenin signaling and reduce the proliferation of human HSC purified from umbilical cord blood of healthy donors. Moreover, correlation analyses showed that the blood Pb concentration was or tended to be positively associated with the quiescence of HSC, and was or tended to be negatively associated with the activation of the Wnt3a/β-catenin signaling in HSC in human subjects occupationally exposed to Pb. Collectively, these data indicate that an occupationally relevant level of Pb exposure suppresses the Wnt3a/β-catenin signaling to increase the quiescence of HSC via reducing the expression of CD70 on BM-Mφ in both mice and humans., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Due to the different sensitivities of the 2 E and 4 T 2 energy levels of Cr 3+ to the local environment, Cr 3+ -doped fluorescent materials appear as excellent candidates for highly sensitive temperature sensing based on luminescence intensity ratio technology. However, a way to broaden the strict Boltzmann temperature measuring range is rarely reported. In this work, through Al 3+ alloying strategy, a series of SrGa 12- x Al x O 19 :0.5%Cr 3+ ( x = 0, 2, 4, and 6) solid-solution phosphors were synthesized. Remarkably, the introduction of Al 3+ can play a role in regulating the crystal field around Cr 3+ and the symmetry of [Ga/AlO 6 ] octahedron, realizing the synchronous tuning of 2 E and 4 T 2 energy levels when the temperature changes in a wide range, achieving the purpose of increasing the intensity difference of 2 E → 4 A 2 and 4 T 2 → 4 A 2 transitions, so as to extend the temperature sensing range. Among all samples, SrGa 6 Al 6 O 19 :0.5%Cr 3+ showed the widest temperature measuring range from 130 K to 423 K with S a of 0.0066 K -1 and S r of 1% K -1 @130 K. This work proposed a feasible way to extend the temperature sensing range for transition metal-doped LIR-mode thermometers.

Van der Waals-driven self-healing in copolymers with "lock-and-key" architecture has emerged as a concept to endow engineering-type polymers with the capacity to recover from structural damage. Complicating the realization of "lock-and-key"-enabled self-healing is the tendency of copolymers to form nonuniform sequence distributions during polymerization reactions. This limits favorable site interactions and renders the evaluation of van der Waals-driven healing difficult. Here, methods for the synthesis of lock-and-key copolymers with prescribed sequence were used to overcome this limitation and enable the deliberate synthesis of "lock-and-key" architectures most conducive to self-healing. The effect of molecular sequence on the material's recovery behavior was evaluated for the particular case of three poly( n -butyl acrylate/methyl methacrylate) [P(BA/MMA)] copolymers with similar molecular weights, dispersity, and overall composition but with different sequences: alternating ( alt ), statistical ( stat ), and gradient ( grad ). They were synthesized using atom transfer radical polymerization (ATRP). Copolymers with alt and stat sequence displayed a 10-fold increase of recovery rate compared to the grad copolymer variant despite a similar overall glass transition temperature. Investigation with small-angle neutron scattering (SANS) revealed that rapid property recovery is contingent on a uniform microstructure of copolymers in the solid state, thus avoiding the pinning of chains in glassy MMA-rich cluster regions. The results delineate strategies for the deliberate design and synthesis of engineering polymers that combine structural and thermal stability with the ability to recover from structural damage.

Studying the mechanical behavior of rocks under real-time high-temperature conditions is of great significance for the development of energy caverns, nuclear waste disposal projects, and tunneling engineering. In this study, a real-time high-temperature impact compression test was conducted on Sejila Mountain granite to explore the effects of temperature and external load on its mechanical properties. Based on the concepts of damage mechanics and statistics, a coupled thermal-mechanical (T-M) damage constitutive model was established, which considers the temperature effect and uses the double-shear unified strength as the yield criterion. The parameter expressions were clarified, and the accuracy and applicability of the model were verified by experimental data. The research results indicated that high temperatures had an obvious damaging and deteriorating effect on the strength of the granite, while an increase in impact velocity had an enhancing effect on the strength of the granite. The established constitutive model theoretical curve and test curve showed a high degree of agreement, indicating that the coupled T-M model can objectively represent the evolution process of damage in rocks and the physical meaning of its parameters is clear.

Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4 + T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4 + T cell responses and autoantibody production in autoimmune diseases.

To improve the performance of individual DNA sequencing results, researchers often use replicates from the same individual and various statistical clustering models to reconstruct a high-performance callset. Here, three technical replicates of genome NA12878 were considered and five model types were compared (consensus, latent class, Gaussian mixture, Kamila-adapted k-means, and random forest) regarding four performance indicators: sensitivity, precision, accuracy, and F1-score. In comparison with no use of a combination model, i) the consensus model improved precision by 0.1%; ii) the latent class model brought 1% precision improvement (97%-98%) without compromising sensitivity (= 98.9%); iii) the Gaussian mixture model and random forest provided callsets with higher precisions (both >99%) but lower sensitivities; iv) Kamila increased precision (>99%) and kept a high sensitivity (98.8%); it showed the best overall performance. According to precision and F1-score indicators, the compared non-supervised clustering models that combine multiple callsets are able to improve sequencing performance vs. previously used supervised models. Among the models compared, the Gaussian mixture model and Kamila offered non-negligible precision and F1-score improvements. These models may be thus recommended for callset reconstruction (from either biological or technical replicates) for diagnostic or precision medicine purposes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhai, Bardel, Vallée, Iwaz and Roy.)

Tris(2,6-dimethylphenyl) phosphate (TDMPP), an emerging organophosphate flame retardant, is frequently detected in multiple environmental media. Although TDMPP has been proven as a compound with estrogenic activity, its feminizing effects on reproductive system remain unclear. This study investigated the adverse effects of TDMPP on gonadal development by exposing zebrafish for 105 days from 15 days post-fertilization. Exposure to TDMPP (0.5 and 5 μM, corresponding to about 200 and 2000 μg/L) induced ovarian formation in aromatase mutant (cyp19a1a-/-) line which normally presents all-male phenotype for deficiency of endogenous estrogen (E2), suggesting its feminizing effect on sexual differentiation. In addition, TDMPP also interfered with other aspects of reproduction by delaying puberty onset, retarding sexual maturation, impairing gametogenesis and subfertility. Molecular docking and reporter gene assay indicated that all three nuclear estrogen receptors (nERs) can be binded to and activated by TDMPP. Using a series of nERs mutant lines, we confirmed the indispensable role of esr2a and esr2b in mediating the feminizing effects of TDMPP. Further analysis revealed that the prominent effects of TDMPP on sexual differentiation correlated to upregulation of female-promoting genes and downregulation of male-promoting genes. Taken together, the present study provided unequivocal genetic evidence for estrogenic effects of TDMPP on reproductive system and its molecular mechanisms of action., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Understanding bacteria inactivation mechanisms of nanomaterials on the surface molecular level is of prime importance for the development of antibacterial materials and their application in restraining the transmission of pathogenic microorganisms. This study prepared an oxygen vacancy-mediated bactericidal nanocatalyst α-MoO 3 which exhibited excellent antibacterial activity against Escherichia coli and Staphylococcus aureus in the dark. By manipulating the surface structure of α-MoO 3 , the facile tuning of superoxide radical (•O 2 - ) generation can be achieved, which was confirmed by electron paramagnetic resonance. •O 2 - disrupted bacterial membrane through attacking lipopolysaccharide (LPS) and phosphatidylethanolamine (PE). Intracellular reactive oxygen species (ROS) experiments confirm that oxidative stress induced by •O 2 - also played a vital role in bacterial inactivation, which might account for DNA damage verified by comet assays. The α-MoO 3 with rich oxygen vacancies also exhibited good antibacterial efficiency (＞99.00 %) toward airborne microbes under dark conditions, indicating its potential to impede the transmission of pathogenic microbes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The contradiction between the limited service capacity of system and the explosive growth of demand has hampered the sustainable development of logistics system. Taking into account the structure of logistics system, this study introduces a system dynamics approach to explore the complex correlation and coupling structure of system, analyzes the multiple feedback loops and design the different scenarios. Results show that the validity and rationality of logistics system model, and the error percentage of GDP and logistics demand factors less than 6%. The influence of the investment in reverse logistics, logistics management, information and organizational management factor on the service quality of logistics system increases in turn. Additionally, adjustment of industrial structure has a significant impact on the investment in information management factor, and highway transportation plays a key role in influencing logistics energy consumption and carbon emissions indexes. The findings can provide valuable references and methodologies, as well as support for decision-making in the sustainable development of logistics system., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study., (Copyright: © 2023 Ji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

All-inorganic cesium lead halide CsPbX 3 (X = Cl, Br, I) perovskite quantum dots (PQDs) have shown promising potential in current Mini/Micro-LED display applications due to their excellent photoluminescence performance. However, lead ions in PQDs are easily to leak owing to the unstable structure of PQDs, which hinders their commercial applications. Herein, we adopt Rb + ions co-doping strategy to regulate the doping characteristics of Mn 2+ ions in CsPbCl 3 PQDs. The synthesized CsPbCl 3 :(Rb + , Mn 2+ ) PQDs possess enhanced photoluminescence quantum yield of 71.1% due to the reduction of intrinsic defect states and Mn-Mn or Mn-traps in co-doped PQDs. Moreover, the white light emission of CsPb(Cl/Br) 3 :(Rb + , Mn 2+ ) PQDs is achieved by anion exchange reaction and the constructed WLED exhibits the CIE coordinate of (0.33, 0.29) and the correlated color temperature of 5497 K. Benefiting from the substitution strategy, these doped CsPbX 3 PQDs can be widely used as fluorescence conversion materials for the construction of Mini/Micro-LED., (© 2023 IOP Publishing Ltd.)

Perovskites based on CsPbX 3 (X = Cl, Br, I) have promising applications in solar cells, light-emitting diodes, and photodetectors. In this paper, the phase stability of inorganic metal halide perovskite CsPbCl 3 under hydrostatic pressure and anion substitution is studied using density functional theory (DFT), and this modification is explained by the interaction of the octahedrons and transformation of the bond-orbital coupling. In addition, two space groups, P 4/ mbm and Amm 2, which are stable under stress, are subjected to anion substitution; then, the structural stability and band gap change of CsPbCl 3- y X y (X = Br, I; y = 0, 1, 2, 3) are analyzed after applying stress; finally, the electronic structures and optical properties of the six most stable components are presented. The effect of stress and anions on the components' optoelectronic properties is closely linked with the crystal's structural alteration mechanism. These results show that stress and anion modulation can significantly change the optoelectronic properties of materials, which make these materials have broad application prospects. Furthermore, stress can be used as an effective tool for screening the most stable material structure.

Cadmium (Cd) is a highly toxic heavy metal in the environment. The aim of this study was to investigate the impact of Cd on natural killer (NK) cells. C57BL/6 mice were treated with 10 ppm Cd via drinking water for 3 months, and the development of NK cells in the bone marrow (BM) and the cytotoxicity of mature NK (mNK) cells in the peripheral immune organs were evaluated thereafter; the impact of Cd on the cytotoxicity of mNK cells from human peripheral blood mononuclear cells (PBMC) was also investigated. Whereas Cd treatment impaired the differentiation of NK progenitors in the BM, Cd treatment activated the JAK3/STAT5 signaling to drive the proliferation of mNK cells and thereby lead to a compensation increase of mNK cells in the peripheral immune organs of mice. Additionally, Cd treatment bidirectionally regulated the cytotoxicity of mouse mNK cells to differential tumor cells, dependent on the levels of Fas expression in the tumor cells; mechanically, Cd treatment activated the JAK3/STAT5 signaling to promote the expression of FasL in mNK cells to increase their cytotoxicity, while Cd treatment reduced the expression of granzyme B in mNK cells to impair their cytotoxicity in the peripheral immune organs of mice. Likewise, in vitro assays indicated that Cd treatment also activated the JAK3/STAT5 signaling to increase the expression of FasL, whereas Cd treatment reduced the expression of granzyme B in human mNK cells. Thus Cd treatment impaired the development of NK cells in the BM and bidirectionally regulated the cytotoxicity of mNK cells in the peripheral immune organs, which may extend our current understanding for the immunotoxicity of Cd., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: Guided by the social embeddedness model of thriving at work, this paper explores how nursing organizational culture, work engagement and affective commitment affect nurses' thriving at work., Background: Thriving at work has implications for better employee and organization outcomes. The antecedents of thriving at work among the nursing population needs to be expanded by analysing the cross-level impact of organizational and individual characteristics., Methods: A cross-sectional design was used to collect data from 1437 frontline nurses in a tertiary teaching hospital in China between April and May 2020 through an online survey about perceived nursing culture, work engagement, affective commitment and thriving at work. Data were analysed using SPSS, and a structural equation model was established using the PROCESS macro., Results: Our results showed that work engagement and affective commitment mediated the relationship between nurses' perceived nursing culture and their thriving at work. Among nurses, work engagement was positively correlated to affective commitment., Conclusion: Our study confirmed the social embeddedness model of thriving at work by showing that both contextual and dispositional factors can influence nurses' thriving at work. Nurse leaders can foster nursing staff's thriving at work by building an inclusive work environment and by providing adequate resources to staff. Future research is needed to elaborate on employee and organizational outcomes associated with thriving at work., Impact: Nurse leaders should be the advocate for nurses to improve their organizational identification, fostering their thriving at work. Individual nurses can also take an active role in developing work-related resources to sustain their thriving through self-adaption processes. Collective thriving in the nursing workforce is needed to overcome adversity and hardship in the ever-changing and increasingly demanding health care industry and to further contribute to the vitality of the broader social and public environments., Patient or Public Contribution: No patient or public contribution. This study did not involve patients, service users, caregivers or members of the public., (© 2022 John Wiley & Sons Ltd.)

Growth differentiation factor 9 (GDF9) was the first oocyte-specific growth factor identified; however, most information about GDF9 functions comes from studies in the mouse model. In this study, we created a mutant for Gdf9 gene (gdf9-/-) in zebrafish using TALEN approach. The loss of Gdf9 caused a complete arrest of follicle development at primary growth (PG) stage. These follicles eventually degenerated, and all mutant females gradually changed to males through sex reversal, which could be prevented by mutation of the male-promoting gene dmrt1. Interestingly, the phenotypes of gdf9-/- could be rescued by simultaneous mutation of inhibin α (inha-/-) but not estradiol treatment, suggesting a potential role for the activin-inhibin system or its signaling pathway in Gdf9 actions. In gdf9-null follicles, the expression of activin βAa (inhbaa), but not βAb (inhbab) and βB (inhbb), decreased dramatically; however, its expression rebounded in the double mutant (gdf9-/-;inha-/-). These results indicate clearly that the activation of PG follicles to enter the secondary growth (SG) requires intrinsic factors from the oocyte, such as Gdf9, which in turn works on the neighboring follicle cells to trigger follicle activation, probably involving activins. In addition, our data also support the view that estrogens are not involved in follicle activation as recently reported., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Activin and inhibin are both dimeric proteins sharing the same β subunits that belong to the TGF-β superfamily. They are well known for stimulating and inhibiting pituitary FSH secretion, respectively, in mammals. In addition, activin also acts as a mesoderm-inducing factor in frogs. However, their functions in development and reproduction of other species are poorly defined. In this study, we disrupted all three activin/inhibin β subunits (βAa, inhbaa; βAb, inhbab; and βB, inhbb) in zebrafish using CRISPR/Cas9. The loss of βAa/b but not βB led to a high mortality rate in the post-hatching stage. Surprisingly, the expression of fshb but not lhb in the pituitary increased in the female βA mutant together with aromatase (cyp19a1a) in the ovary. The single mutant of βAa/b showed normal folliculogenesis in young females; however, their double mutant (inhbaa-/-;inhbab-/-) showed delayed follicle activation, granulosa cell hypertrophy, stromal cell accumulation and tissue fibrosis. The ovary of inhbaa-/- deteriorated progressively after 180 dpf with reduced fecundity and the folliculogenesis ceased completely around 540 dpf. In addition, tumor- or cyst-like tissues started to appear in the inhbaa-/- ovary after about one year. In contrast to females, activin βAa/b mutant males showed normal spermatogenesis and fertility. As for activin βB subunit, the inhbb-/- mutant exhibited normal folliculogenesis, spermatogenesis and fertility in both sexes; however, the fecundity of mutant females decreased dramatically at 270 dpf with accumulation of early follicles. In summary, the activin-inhibin system plays an indispensable role in fish reproduction, in particular folliculogenesis and ovarian homeostasis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Nursing information systems embedded with standardized nursing language and clinical decision support have been increasingly introduced in health care settings. User experience is key to the adoption of health information technologies. Despite extensive research into the user experience with nursing information systems, few studies have focused on the interaction between user, technology and organizational attributes during its implementation. Guided by the human, organization and technology-fit framework, this study aimed to investigate nurses' perceptions and experiences with transition to a new nursing information system (Care Direct) 2 years after its first introduction., Methods: This is a mixed-method study using an embedded design. An online survey was launched to collect nurses' self-reported use of the new system, perceived system effectiveness and experience of participation in system optimization. Twenty-two semi structured interviews were conducted with twenty nurses with clinical or administrative roles. The quantitative and qualitative data were merged using the Pillar Integration Process., Results: The average score of system use behavior was 3.76 ± 0.79. Regarding perceived system effectiveness, the score of each dimension ranged 3.07-3.34 out of 5. Despite large variations in approaches to participating in system optimization, nurses had generally positive experiences with management and technical support. Eight main categories emerged from the integrated findings, which were further condensed into three themes: perceptions on system content, structure, and functionality; perceptions on interdisciplinary and cross-level cooperation; and embracing and accepting the change., Conclusions: Effective collaboration between clinicians, administrators and technical staff is required during system promotion to enhance system usability and user experience. Clear communication of organizational missions to staff and support from top management is needed to smooth the system implementation process and achieve broader system adoption., (© 2022. The Author(s).)

Background: The melanocortin receptor accessory proteins (MRAP1 and MRAP2) are well-known endocrine regulators for the trafficking and signalling of all five melanocortin receptors (MC1R-MC5R). The observation of MRAP2 on regulating several non-melanocortin G protein-coupled receptors (GPCRs) has been sporadically reported, whereas other endogenous GPCR partners of the MRAP protein family are largely unknown., Methods: Here, we performed single-cell transcriptome analysis and drew a fine GPCR blueprint and MRAPs-associated network of two major endocrine organs, the hypothalamus and adrenal gland at single-cell resolution. We also integrated multiple bulk RNA-seq profiles and single-cell datasets of human and mouse tissues, and narrowed down a list of 48 GPCRs with strong endogenous co-expression correlation with MRAPs., Results: 36 and 46 metabolic-related GPCRs were consequently identified as novel interacting partners of MRAP1 or MRAP2, respectively. MRAPs exhibited protein-protein interactions and varying pharmacological properties on the surface translocation, constitutive activities and ligand-stimulated downstream signalling of these GPCRs. Knockdown of MRAP2 expression by hypothalamic administration of adeno-associated virus (AAV) packed shRNA stimulated body weight gain in mouse model. Co-injection of corticotropinreleasing factor (CRF), the agonist of corticotropin releasing hormone receptor 1 (CRHR1), suppressed feeding behaviour in a MRAP2-dependent manner., Conclusions: Collectively, our study has comprehensively elucidated the complex GPCR networks in two major endocrine organs and redefined the MRAP protein family as broad-spectrum GPCR modulators. MRAP proteins not only serve as a vital endocrine pivot on the regulation of global GPCR activities in vivo that could explain the composite physiological phenotypes of the MRAP2 null murine model but also provide us with new insights of the phenotyping investigation of GPCR-MRAP functional complexes., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Polymer-grafted nanoparticles (PGNPs) have attracted extensive research interest due to their potential for enhancing mechanical and electrical properties of both bulk polymer composite materials, as well as thin polymer films incorporating these nanoparticles (NPs). In previous studies, we have shown that an entropic driving force serves to organize low-molecular-mass PGNPs in imprinted blend films of PGNPs with low-molecular-mass homopolymers. In this work, we developed a novel solvent vapor annealing soft lithography (SVA-SL) method to overcome the technical difficulties in processing the high-molecular-mass PGNP blends due to the intrinsically sluggish melt annealing kinetics found in the phase separation of these blend PGNP materials. In particular, we utilized SVA-SL to create nanopatterns in blends of PGNPs having relatively high-molecular-mass-grafted layers but with cores of NPs having greatly different sizes. The minimization of the entropic free energy in the present system corresponded to larger PGNPs partitioning almost exclusively into the "mesa" regions of the imprinted PGNP blend films, as quantified by the estimation of the partition coefficient, K p . The use of the SVA-SL processing method is important because it allows facile imprint patterning of PGNP materials and large-scale organization of the PGNPs even when the grafted chain lengths are long enough for the chains to be highly entangled, allowing enhanced thermo-mechanical property enhancements of the resulting films and a corresponding extended range of potential nanotech applications.

Peripheral neuroblastic tumors (PNTs) represent a spectrum of neural-crest-derived tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Malignant cells in PNTs are theorized to interconvert between adrenergic/noradrenergic and mesenchymal/neural crest cell states. Here, single-cell RNA-sequencing analysis of 10 PNTs demonstrates extensive transcriptomic heterogeneity. Trajectory modeling suggests that malignant neuroblasts move between adrenergic and mesenchymal cell states via an intermediate state that we term "transitional." Transitional cells express programs linked to a sympathoadrenal development and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature is predictive of poor prognosis compared with adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identifies a similar transitional H3K27-acetylation super-enhancer landscape. Collectively, our study supports the concept that PNTs have phenotypic plasticity and uncovers potential biomarkers and therapeutic targets., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Splenomegaly is a symptom characterized by the presence of an enlarged spleen. The impact of environmental factors on splenomegaly is largely unknown. In this study, C57BL/6 mice were treated with 125 ppm or 1250 ppm lead (Pb) via drinking water for 8 wk, and the process of splenomegaly was evaluated. Treatment with 1250 ppm Pb, but not 125 ppm Pb, caused splenomegaly, which was associated with increased capacity for erythrocyte clearance. Intriguingly, Pb-caused splenomegaly was independent of lymphoid tissue inducer (LTi) cells, which produce lymphotoxins α and β (LTα/β) to activate endothelial cells and LT organizer (LTo) cells and drive the development of spleen physiologically. A direct action of Pb on endothelial cells and LTo cells did not impact their proliferation. On the other hand, during steady state, a tonic level of interferon (IFN)γ acted on endothelial cells and LTo cells to suppress splenomegaly, as IFNγ receptor (IFNγR)-deficient mice had enlarged spleens relative to wild-type mice; during Pb exposure, splenic IFNγ production was suppressed, thus leading to a loss of the inhibitory effect of IFNγ on splenomegaly. Mechanically, Pb acted on splenic CD4 + T cells to suppress IFNγ production, which impaired the Janus kinase (Jak)1/ signal transducer and activator of transcription (STAT)1 signaling in endothelial cells and LTo cells; the weakened Jak1/STAT1 signaling resulted in the enhanced nuclear factor-κB (NF-κB) signaling in endothelial cells and LTo cells, which drove their proliferation and caused splenomegaly. The present study reveals a previously unrecognized mechanism for the immunotoxicity of Pb, which may extend our current understanding for Pb toxicology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Clinical decision support systems (CDSSs) have been increasingly introduced to health care settings; however, their adoption is far from ideal. Guided by the FITT framework, this study aims to explore barriers and facilitators to the implementation of a CDSS from the perspective of nurses., Methods: A qualitative study with 200 h of participatory observation and 21 semi structured interviews was conducted from February to August 2021 in four medical-surgical wards in a 2000-bed tertiary hospital in Shanghai, China. The field notes were typed and the audio-recorded interviews were transcribed to texts verbatim and were coded with a four-step approach. We used the FITT framework to interpret our findings based on the technology, individual and task attributes and the fit between them., Results: A total of twelve categories were identified, which were integrated into two themes: barriers and facilitators to system implementation. All categories but one can be mapped to the three attributes of the FITT framework: technology, individual and task. We assumed that management has a vital role to play in the following areas: addressing user resistance, improving system usability, setting standards on practice and, finally, building connectivity between nurses and the technical staff to improve the fit between the technology, individual and task attribute and thus promote system implementation., Conclusion: Barriers and facilitators to CDSS implementation include system-related, user-related and organizational factors which can largely be fit into the FITT framework. There is potential to extend the FITT framework to represent management intervention on inter-disciplinary collaboration. Future empirical studies on facilitating strategies from the management to improve user experience and willingness of CDSS adoption are needed., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cadmium (Cd) is a highly toxic heavy metal in our environment. The influence of Cd on the development of platelets, or megakaryocytopoiesis, remains to be defined. The aim of this study was to investigate the impact of Cd on megakaryocytopoiesis. C57BL/6 (B6) mice aged 6-8 weeks were treated with 10 ppm Cd via drinking water or control for 3 months, and megakaryocytopoiesis was evaluated thereafter. Mice treated with Cd had a decreased number of platelets in the blood, which was associated with the reduced number of megakaryocyte progenitors (MkP) and megakaryocytes (MK) in the bone marrow (BM). Functional analyses indicate that Cd treatment impaired the proliferation and differentiation of MkP as well as the maturation of MK in the BM, suggesting that Cd treatment impeded megakaryocytopoiesis. Intriguingly, the impaired megakaryocytopoiesis in the BM of mice treated with Cd was not caused by increased apoptosis of MkP. Moreover, in vitro treatment of MkP with Cd did not impact their proliferation or differentiation, indicating that the impeded megakaryocytopoiesis in the BM of mice was likely not caused by direct action of Cd on MkP. On the other hand, Cd treatment selectively suppressed thrombopoietin (TPO) production in the BM and decreased the cellular myelocytomatosis oncogene signaling in MkP, thus likely leading to the impeded megakaryocytopoiesis in the BM and thrombocytopenia in the blood of mice. This study revealed a previously unrecognized hematopoietic toxicity of Cd, which may extend our current understanding of Cd toxicity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Melanin concentrating hormone (MCH), an orexigenic neuropeptide, is primarily secreted by the hypothalamus and acts on its receptor, the melanin-concentrating hormone receptor 1 (MCHR1), to regulate appetite and energy homeostasis. The Melanocortin Receptor Accessory Protein 2 (MRAP2), a small single transmembrane protein broadly expressed in multiple tissues, has been defined as a vital endocrine modulator of five melanocortin receptors (MC1R-MC5R) and several other GPCRs in the regulation of central neuronal activities and peripheral energy balance. Here, we demonstrated the interaction between MRAP2 and MCHR1 by immunoprecipitation and bimolecular fluorescent assay and found that MRAP2 could inhibit MCHR1 signaling in vitro . A series of functional truncations of different regions further identified that the C-terminal domains of MRAP2 protein were required for the pharmacological modulation of intracellular Ca 2+ coupled cascades and membrane transport. These findings elucidated the broad regulatory profile of MRAP2 protein in the central nervous system and may provide implications for the modulation of central MCHR1 function in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhai, Lei, Xu, Jiang, Kuang, Zhang, Liu, Bian, Yang, Zan, Jin, Li and Zhang.)

Objective: To explore the effects of transforming growth factor-β2 (TGF-β2) and TGF-β1 on the odontogenic and osteogenic differentiation of mesenchymal stem cells (MSCs)., Design: We used lentiviral transduction to knock down TGF-β1 or TGF-β2 in stem cells from dental apical papilla (SCAPs), and to generate bone marrow mesenchymal stem cells (BMSCs) with overexpression of TGF-β1 or TGF-β2. We investigated the odontogenic and osteogenic differentiation abilities of these transductants in vitro and in vivo., Results: In vitro, TGF-β2 knockdown in SCAPs reduced the expression of odontoblast-related markers DSPP and DMP-1, and increased the expression of osteoblast-related markers OCN and RUNX-2. Conversely, TGF-β1 knockdown had the opposite effects. TGF-β2 overexpression promoted expression of odontoblast-related markers in BMSCs at early differentiation, but inhibited the expression of odontoblast-related markers at later stages. TGF-β2 overexpression attenuated expression of osteogenic-related markers in BMSCs, while TGF-β1 overexpression enhanced odontoblast-related and osteoblast-related markers. SCAP or BMSC transductants were transplanted underneath kidneys in vivo. Masson staining showed that knockdown of TGF-β1, but not TGF-β2 promoted the expression of type I collagen in SCAPs. Immunohistochemical staining showed that TGF-β2 knockdown inhibited DSPP expression in SCAPs, but TGF-β1 knockdown had no obvious effect on DSPP expression. In vivo, TGF-β1 overexpression and TGF-β2 overexpression had no effect on the expression of type I collagen and DSPP in BMSCs., Conclusions: TGF-β2 promotes odontogenic differentiation of SCAPs and attenuates osteogenic differentiation of SCAPs and BMSCs. TGF-β1 promotes osteogenic differentiation of BMSCs and plays a complex role in regulating odontogenic differentiation of MSCs., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cadmium (Cd) is a highly toxic heavy metal in our living environment. Hematopoietic stem cells (HSC) are ancestors for all blood cells. Therefore understanding the impact of Cd on HSC is significant for public health. The aim of this study was to investigate the impact of Cd 2+ on energy metabolism of HSC and its involvement in hematopoiesis. Wild-type C57BL/6 mice were treated with 10 ppm of Cd 2+ via drinking water for 3 months, and thereafter glycolysis and mitochondrial (MT) oxidative phosphorylation (OXPHOS) of HSC in the bone marrow (BM) and their impact on hematopoiesis were evaluated. After Cd 2+ treatment, HSC had reduced lactate dehydrogenase (LDH) activity and lactate production while having increased pyruvate dehydrogenase (PDH) activity, MT membrane potential, ATP production, oxygen (O 2 ) consumption and reactive oxygen species (ROS), indicating that Cd 2+ switched the pattern of energy metabolism from glycolysis to OXPHOS in HSC. Moreover, Cd 2+ switch of HSC energy metabolism was critically dependent on Wnt5a/Cdc42/calcium (Ca 2+ ) signaling triggered by a direct action of Cd 2+ on HSC. To test the biological significance of Cd 2+ impact on HSC energy metabolism, HSC were intervened for Ca 2+ , OXPHOS, or ROS in vitro, and thereafter the HSC were transplanted into lethally irradiated recipients to reconstitute the immune system; the transplantation assay indicated that Ca 2+ -dependent MT OXPHOS dominated the skewed myelopoiesis of HSC by Cd 2+ exposure. Collectively, we revealed that Cd 2+ exposure activated Wnt5a/Cdc42/Ca 2+ signaling to reprogram the energy metabolism of HSC to drive myelopoiesis at the expense of lymphopoiesis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In epidemiology, left-truncated data may bias exposure effect estimates. We analyzed the bias induced by left truncation in estimating breast cancer risk associated with exposure to airborne dioxins. Simulations were run with exposure estimates from a Geographic Information System (GIS)-based metric and considered two hypotheses for historical exposure, three scenarios for intra-individual correlation of annual exposures, and three exposure-effect models. For each correlation/model combination, 500 nested matched case-control studies were simulated and data fitted using a conditional logistic regression model. Bias magnitude was assessed by estimated odds-ratios (ORs) versus theoretical relative risks (TRRs) comparisons. With strong intra-individual correlation and continuous exposure, left truncation overestimated the Beta parameter associated with cumulative dioxin exposure. Versus a theoretical Beta of 4.17, the estimated mean Beta (5%; 95%) was 73.2 (67.7; 78.8) with left-truncated exposure and 4.37 (4.05; 4.66) with lifetime exposure. With exposure categorized in quintiles, the TRR was 2.0, the estimated OR Q5 vs. Q1 2.19 (2.04; 2.33) with truncated exposure versus 2.17 (2.02; 2.32) with lifetime exposure. However, the difference in exposure between Q5 and Q1 was 18× smaller with truncated data, indicating an important overestimation of the dose effect. No intra-individual correlation resulted in effect dilution and statistical power loss. Left truncation induced substantial bias in estimating breast cancer risk associated with exposure with continuous and categorical models. With strong intra-individual exposure correlation, both models detected associations, but categorical models provided better estimates of effect trends. This calls for careful consideration of left truncation-induced bias in interpreting environmental epidemiological data., (© 2021. Springer Nature B.V.)

In recent years, the scale of population exposure and food poisoning caused by Vibrio parahaemolyticus ( V. parahaemolyticus ) has shown a significant upward trend, becoming one of the primary food-borne pathogens. Herein, we developed a rapid and sensitive detection of V. parahaemolyticus by integrating the technology of magnetic nanobeads (MBs) based immunoseparation (IMS) with quantum dots (QDs) based immunofluorescence. Firstly, specific rabbit polyclone IgG antibodies (IgG) and chicken egg yolk antibodies (IgY) of V. parahaemolyticus were prepared. Then two sizes of MBs (1 μm; 180 nm) were coupled with IgG to form immuno-MB (IMB) capture probes for evaluating the effect of different sizes on the detection efficiency. For QDs, they were conjugated with IgY to form fluorescent reporting probes. In the process of detection, IMB probes were used to separate V. parahaemolyticus and then these complexes were labeled by QD probes on the principle of double antibody sandwich. The fluorescence intensity of the IMB- V. parahaemolyticus -QD complexes was measured by a fluorescence spectrophotometer. The detection method takes 150 min with a detection limit of 10 2 cfu mL -1 ranging from 10 2 to 10 6 cfu mL -1 and it has been shown to work satisfactorily in real food samples., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

As a member of the seven-transmembrane rhodopsin-like G protein-coupled receptor superfamily, the melanocortin-3 receptor (MC3R) is vital for the regulation of energy homeostasis and rhythms synchronizing in mammals, and its pharmacological effect could be directly influenced by the presence of melanocortin receptor accessory proteins (MRAPs), MRAP1 and MRAP2. The tetrapod amphibian Xenopus laevis (xl) retains higher duplicated genome than extant teleosts and serves as an ideal model system for embryonic development and physiological studies. However, the melanocortin system of the Xenopus laevis has not yet been thoroughly evaluated. In this work, we performed sequence alignment, phylogenetic tree, and synteny analysis of two xlMC3Rs. Co-immunoprecipitation and immunofluorescence assay further confirmed the co-localization and in vitro interaction of xlMC3Rs with xlMRAPs on the plasma membrane. Our results demonstrated that xlMRAP2.L/S could improve α-MSH-stimulated xlMC3Rs signaling and suppress their surface expression. Moreover, xlMC3R.L showed a similar profile on the ligands and surface expression in the presence of xlMRAP1.L. Overall, the distinct pharmacological modulation of xlMC3R.L and xlMC3R.S by dual MRAP2 proteins elucidated the functional consistency of melanocortin system during genomic duplication of tetrapod vertebrates.

Objective: Homo- or heterodimerization of G protein-coupled receptors (GPCRs) generally alters the normal functioning of these receptors and mediates their responses to a variety of physiological stimuli in vivo. It is well known that melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) are key regulators of appetite and energy homeostasis in the central nervous system (CNS). However, the GPCR partners of MC3R and MC4R are not well understood. Our objective is to analyze single cell RNA-seq datasets of the hypothalamus to explore and identify novel GPCR partners of MC3R and MC4R and examine the pharmacological effect on the downstream signal transduction and membrane translocation of melanocortin receptors., Methods: We conducted an integrative analysis of multiple single cell RNA-seq datasets to reveal the expression pattern and correlation of GPCR families in the mouse hypothalamus. The emerging GPCRs with important metabolic functions were selected for cloning and co-immunoprecipitation validation. The positive GPCR partners were then tested for the pharmacological activation, competitive binding assay and surface translocation ELISA experiments., Results: Based on the expression pattern of GPCRs and their function enrichment results, we narrowed down the range of potential GPCR interaction with MC3R and MC4R for further confirmation. Co-immunoprecipitation assay verified 23 and 32 novel GPCR partners that interacted with MC3R and MC4R in vitro. The presence of these GPCR partners exhibited different effects in the physiological regulation and signal transduction of MC3R and MC4R., Conclusions: This work represented the first large-scale screen for the functional GPCR complex of central melanocortin receptors and defined a composite metabolic regulatory GPCR network of the hypothalamic nucleuses., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The melanocortin receptor accessory protein 2 (MRAP2) plays an essential role in the regulation of metabolic homeostasis and deletion of which results in severe obesity syndrome in mice and human. Mammalian MRAP2 is recognized as an endogenous physiological mediator through the potentiation of the MC4R signaling in vivo. Two isoforms of MRAP2 are identified in zebrafish genome, zMRAP2a and zMRAP2b. However, the mechanism of assembling dual topology and the regulatory roles of each complex on the melanocortin cascades remains unclear. In this study, we showed the bidirectional homo- and hetero-dimeric topologies of two zebrafish MRAP2 isoforms on the plasma membrane. Orientation fixed chimeric proteins could affect the trafficking and pharmacological properties of zMC4R signaling. Reciprocal replacement of zMRAP2a and zMRAP2b proteins elucidated the major participation of the carboxyl terminal as the functional domain for modulating zMC4R signaling. Our findings revealed the complex and dynamic conformational regulation of dual zebrafish MRAP2 proteins in vitro., (© 2021 Wiley Periodicals LLC.)

β-Defensins are a family of conserved small cationic antimicrobial peptides with different significant biological functions. The majority of mammalian β-defensins are expressed in epididymis, and many of them are predicted to have post-translational modifications. However, only a few of its members have been well studied due to the limitations of expressing and purifying bioactive proteins with correct post-translational modifications efficiently. Here we developed a novel Fc tagged lentiviral system and Fc tagged prokaryotic expression systems provided new options for β-defensins expression and purification. The novel lentiviral system contains a secretive signal peptide, an N-terminal IgG Fc tag, a green fluorescent protein (GFP), and a puromycin selection marker to facilitate efficient expression and fast purification of β-defensins by protein A magnetic or agarose beads. It also enables stable and large-scale expression of β-defensins with regular biological activities and post-translational modification. Purified β-defensins such as Bin1b and a novel human β-defensin hBD129 showed antimicrobial activity, immuno-regulatory activity, and expected post-translational phosphorylation, which were not found in Escherichia coli (E. coli) in expressed form. Furthermore, we successfully applied the novel system to identify mBin1b interacting proteins, explaining Bin1b in a better way. These results suggest that the novel lentiviral system is a powerful approach to produce correct post-translational processed β-defensins with bioactivities and is useful to identify their interacting proteins. This study has laid the foundation for future studies to characterize function and mechanism of novel β-defensins., (© 2021 Wiley-VCH GmbH.)