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The intestinal microbiota plays a crucial role in the health and development of fish, engaging in intricate interactions with the host organism. As a significant species in aquaculture, Lateolabrax japonicus serves as an exemplary model for investigating these interactions and their subsequent effects on growth and health. This study utilized a multi-omics approach, incorporating metagenomic sequencing and non-targeted metabolomics, to delineate the gut microbiota and metabolome of L. japonicus throughout various developmental phases. Collected from a meticulously controlled aquaculture setting, the intestinal microbiota of L. japonicus underwent high-throughput sequencing to scrutinize microbial DNA and enumerate metabolites. The metagenomic analysis uncovered a heterogeneous gut microbiota in L. japonicus, predominantly composed of Proteobacteria and Firmicutes, with marked heterogeneity in microbial composition across developmental stages. A particularly noteworthy discovery was the prevalence of the genus Acinetobacter, which may significantly influence health and disease resistance. The metabolomic profiling discerned 4479 metabolites, each exhibiting pronounced stage-specific metabolic signatures, particularly within lipid, amino acid, and energy metabolism pathways. The correlation analysis between microbiota and metabolites highlighted the substantial impact of specific genera, such as Acinetobacter and Gaeumannomyces, on the metabolic milieu. This study provides a comprehensive overview of the dynamic shifts in the gut microbiota and metabolome of L. japonicus, highlighting stage-specific transitions that could be pivotal for refining aquaculture practices. The findings underscore the complex interdependence between microbiota composition and metabolic function, providing valuable insights into the modulation of fish health and growth., 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 Inc. All rights reserved.)

Poultry, a vital economic animal, provide a high-quality protein source for human nutrition. Over the past decade, the poultry industry has witnessed substantial achievements in breeding, precision feeding, and welfare farming. However, there are still many challenges restricting the sustainable development of the poultry industry. First, overly focused breeding strategies on production performance have been shown to induce metabolic diseases in poultry. Second, a lack of robust methods for assessing the nutritional requirements poses a challenge to the practical implementation of precision feeding. Third, antibiotic alternatives and feed safety management remain pressing concerns within the poultry industry. Lastly, environmental pollution and inadequate welfare management in farming have a negative effect on poultry health. Despite numerous proposed strategies and innovative approaches, each faces its own set of strengths and limitations. In this review, we aim to provide a comprehensive understanding of the poultry industry over the past decade, by examining its achievements, challenges, and strategies, to guide its future direction., Competing Interests: Conflict of interest The authors report no conflicts of interest., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Objective: To study the relationship between umbilical cord blood vitamin A (VA) and neonatal lung diseases and explore the impact of umbilical cord blood VA on neonatal lung diseases., Method: Umbilical vein blood was collected at birth, and its VA content was measured. According to the VA levels in umbilical cord blood, a VA deficiency (VAD) group, a marginal deficiency group and a normal group were created and followed up until 28 days after birth., Results: The umbilical cord blood VA level in the neonatal group with lung disease was 0.13 ± 0.05 mg/L, while the result for the VA level in the non-lung disease group was 0.15 ± 0.05 mg/L. The umbilical cord blood VA levels in the neonatal lung disease group were significantly lower than those in the non-lung disease group. The incidence of neonatal pulmonary diseases was highest in the VAD group, and the incidence decreased as the level of VA in umbilical cord blood increased. Umbilical cord blood VAD and premature birth were found to be independent risk factors for neonatal respiratory disease., Conclusion: Umbilical cord blood VAD and premature birth are independent risk factors for neonatal pulmonary diseases. The lower the level of VA in umbilical cord blood, the more susceptible infants will be to neonatal respiratory infections in the neonatal period., Competing Interests: Declaration of competing interest All of the authors had no any personal, financial, commercial, or academic conflicts of interest separately., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Natriuretic peptide receptor-C (NPR-C) is highly expressed in adipose tissues and regulates obesity-related diseases; however, the detailed mechanism remains unknown. In this research, we aimed to explore the potential role of NPR-C in cold exposure and high-fat/high-sugar (HF/HS) diet-induced metabolic changes, especially in regulating white adipose tissue (WAT) mitochondrial function. Our findings showed that NPR-C expression, especially in epididymal WAT (eWAT), was reduced after cold exposure. Global Npr3 (gene encoding NPR-C protein) deficiency led to reduced body weight, increased WAT browning, thermogenesis, and enhanced expression of genes related to mitochondrial biogenesis. RNA-sequencing of eWAT showed that Npr3 deficiency enhanced the expression of mitochondrial respiratory chain complex genes and promoted mitochondrial oxidative phosphorylation in response to cold exposure. In addition, Npr3 KO mice were able to resist obesity induced by HF/HS diet. Npr3 knockdown in stromal vascular fraction (SVF)-induced white adipocytes promoted the expression of proliferator-activated receptor gamma coactivator 1α (PGC1α), uncoupling protein one (UCP1), and mitochondrial respiratory chain complexes. Mechanistically, NPR-C inhibited cGMP and calcium signaling in an NPR-B-dependent manner but suppressed cAMP signaling in an NPR-B-independent manner. Moreover, Npr3 knockdown induced browning via AKT and p38 pathway activation, which were attenuated by Npr2 knockdown. Importantly, treatment with the NPR-C-specific antagonist, AP-811, decreased WAT mass and increased PGC-1α, UCP1, and mitochondrial complex expression. Our findings reveal that NPR-C deficiency enhances mitochondrial function and energy expenditure in white adipose tissue, contributing to improved metabolic health and resistance to obesity., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sodium para-aminosalicylic acid (PAS-Na) treatment for manganese (Mn) intoxication has shown efficacy in experimental and clinical studies, giving rise to additional studies on its efficacy for lead (Pb) neurotoxicity and its associated mechanisms of neuroprotection. The difference between PAS-Na and other metal complexing agents, such as edetate calcium sodium (CaNa 2 -EDTA), is firstly that PAS-Na can readily pass through the blood-brain barrier (BBB), and complex and facilitate the excretion of manganese and lead. Secondly, PAS-Na has anti-inflammatory effects. Recent studies have broadened the understanding on the mechanisms associated with efficacy of PAS-Na. The latter has been shown to modulate multifarious manganese- and lead- induced neurotoxicity, via its anti-apoptotic and anti-inflammatory effects, as well as its ability to inhibit pyroptosis, and regulate abnormal autophagic processes. These observations provide novel scientific bases and new concepts for the treatment of lead, mercury, copper, thallium, as well as other toxic encephalopathies, and implicate PAS-Na as a compound with greater prospects for clinical medical application., 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.)

Tetracycline antibiotics (TCs) are extensively used in clinical medicine, animal husbandry, and aquaculture because of their cost-effectiveness and high antibacterial efficacy. However, the presence of TCs residues in the environment poses risks to humans. In this study, an inner filter effect (IFE) fluorescent probe, 2,2'-(ethane-1,2-diylbis((2-((2-methylquinolin-8-yl)amino)-2-oxoethyl)azanediyl))diacetic acid (MQDA), was developed for the rapid detection of Eu 3+ within 30 s. And its complex [MQDA-Eu 3+ ] was successfully used for the detection of TCs. Upon coordination of a carboxyl of MQDA with Eu 3+ to form a [MQDA-Eu 3+ ] complex, the carboxyl served as an antenna ligand for the effective detection of Eu 3+ to intensify the emission intensity of MQDA via "antenna effect", the process was the energy absorbed by TCs via UV excitation was effectively transferred to Eu 3+ . Fluorescence quenching of the [MQDA-Eu 3+ ] complex was caused by the IFE in multicolor fluorescence systems. The limits of detection of [MQDA-Eu 3+ ] for oxytetracycline, chlorotetracycline hydrochloride, and tetracycline were 0.80, 0.93, and 1.7 μM in DMSO/HEPES (7:3, v/v, pH = 7.0), respectively. [MQDA-Eu 3+ ] demonstrated sensitive detection of TCs in environmental and food samples with satisfactory recoveries and exhibited excellent imaging capabilities for TCs in living cells and zebrafish with low cytotoxicity. The proposed approach demonstrated considerable potential for the quantitative detection of TCs., 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.)

Interleukin (IL)-33, a cytokine involved in immune responses, can activate its receptor, suppression of tumorigenicity 2 (ST2), is elevated during atrial fibrillation (AF). However, the role of IL-33/ST2 signaling in atrial arrhythmia is unclear. This study explored the pathological effects of the IL-33/ST2 axis on atrial remodeling and arrhythmogenesis. Patch clamping, confocal microscopy, and Western blotting were used to analyze the electrical characteristics of and protein activity in atrial myocytes (HL-1) treated with recombinant IL-33 protein and/or ST2-neutralizing antibodies for 48 hrs. Telemetric electrocardiographic recordings, Masson's trichrome staining, and immunohistochemistry staining of the atrium were performed in mice receiving tail vein injections with nonspecific immunoglobulin (control), IL-33, and IL-33 combined with anti-ST2 antibody for 2 weeks. IL-33-treated HL-1 cells had a reduced action potential duration, lower L-type Ca 2+ current, greater sarcoplasmic reticulum (SR) Ca 2+ content, increased Na + /Ca 2+ exchanger (NCX) current, elevation of K + currents, and increased intracellular calcium transient. IL-33-treated HL-1 myocytes had greater activation of the calcium-calmodulin-dependent protein kinase II (CaMKII)/ryanodine receptor 2 (RyR2) axis and nuclear factor kappa B (NF-κB) / NLR family pyrin domain containing 3 (NLRP3) signaling than did control cells. IL-33 treated cells also had greater expression of Nav1.5, Kv1.5, NCX, and NLRP3 than did control cells. Pretreatment with neutralizing anti-ST2 antibody attenuated IL-33-mediated activation of CaMKII/RyR2 and NF-κB/NLRP3 signaling. IL-33-injected mice had more atrial ectopic beats and increased AF episodes, greater atrial fibrosis, and elevation of NF-κB/NLRP3 signaling than did controls or mice treated with IL-33 combined with anti-ST2 antibody. Thus, IL-33 recombinant protein treatment promotes atrial remodeling through ST2 signaling. Blocking the IL-33/ST2 axis might be an innovative therapeutic approach for patients with atrial arrhythmia and elevated serum IL-33., (Copyright © 2024. Published by Elsevier Inc.)

At present, there are no standardized guidelines for determining patient eligibility for pyoderma gangrenosum (PG) clinical trials. Thus, we aim to determine which clinical features, histopathological features, or laboratory features should be included in active ulcerative PG clinical trial eligibility criteria for treatment-naïve patients and patients already treated with immunomodulating medications (treatment-exposed patients). This study employed 4 rounds of the Delphi technique. Electronic surveys were administered to 21 international board-certified dermatologists and plastic surgeon PG experts (June 2022-December 2022). Our results demonstrated that for a patient to be eligible for a PG trial, they must meet the following criteria: (i) presence of ulcer(s) with erythematous/violaceous undermining wound borders, (ii) presence of a painful or tender ulcer, (iii) history/presence of rapidly progressing disease, (iv) exclusion of infection and other causes of cutaneous ulceration, (v) biopsy for H&E staining, and (vi) a presence/history of pathergy. These criteria vary in importance for treatment-naïve versus treatment-exposed patients. Given the international cohort, we were unable to facilitate live discussions between rounds. This Delphi consensus study provides a set of specific, standardized eligibility criteria for PG clinical trials, thus addressing one of the main issues hampering progress toward Food and Drug Administration approval of medications for PG., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Neonatal Intrahepatic Cholestasis (NICCD), as the early-age stage of Citrin deficiency involving liver dysfunction, lacks efficient diagnostic markers. Procalcitonin (PCT) has been identified as a biomarker for infection as well as various organ damage. This study aimed to explore the potential of PCT as a biomarker for NICCD., Methods: In a single-center retrospective case-control study. Serum PCT concentrations before and after treatment of 120 NICCD patients, as the study group, were compared to the same number of cholestatic hepatitis patients, as the control group. The potential value of PCT to discriminate NICCD from control disease was further explored using Receiver Operating Characteristic (ROC) curve analysis and compared to those of other inflammatory markers., Results: There was a significantly higher level of PCT in NICCD patients than in the control group. PCT concentrations were only weakly correlated with neutrophil counts and CRP levels (p ˂ 0.05). At a cut-off value of 0.495 ng/mL, PCT exhibited a significantly higher diagnostic value compared to other inflammatory markers for discriminating NICCD from the control, with a sensitivity of 90.8 % and specificity of 98.3 %., Conclusion: PCT might be used as an initial biomarker to discriminate children with NICCD from another hepatitis disease., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Resistance to temozolomide (TMZ), the frontline chemotherapeutic agent for glioblastoma (GBM), has emerged as a formidable obstacle, underscoring the imperative to identify alternative therapeutic strategies to improve patient outcomes. In this study, we comprehensively evaluated a novel agent, O6-methyl-2'-deoxyguanosine-5'-triphosphate (O6-methyl-dGTP) for its anti-GBM activity both in vitro and in vivo. Notably, O6-methyl-dGTP exhibited pronounced cytotoxicity against GBM cells, including those resistant to TMZ and overexpressing O6-methylguanine-DNA methyltransferase (MGMT). Mechanistic investigations revealed that O6-methyl-dGTP could be incorporated into genomic DNA, disrupting nucleotide pools balance, and inducing replication stress, resulting in S-phase arrest and DNA damage. The compound exerted its anti-tumor properties through the activation of AIF-mediated apoptosis and the parthanatos pathway. In vivo studies using U251 and Ln229 cell xenografts supported the robust tumor-inhibitory capacity of O6-methyl-dGTP. In an orthotopic transplantation model with U87MG cells, O6-methyl-dGTP showcased marginally superior tumor-suppressive activity compared to TMZ. In summary, our research, for the first time, underscores the potential of O6-methyl-dGTP as an effective candidate against GBM, laying a robust scientific groundwork for its potential clinical adoption in GBM treatment regimens., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Fine particulate matter (PM 2.5 ) is thought to exacerbate Parkinson's disease (PD) in the elderly, and early detection of PD progression may prevent further irreversible damage. Therefore, we used diffusion tensor imaging (DTI) for probing microstructural changes after late-life chronic traffic-related PM 2.5 exposure. Herein, 1.5-year-old Fischer 344 rats were exposed to clean air (control), high-efficiency particulate air (HEPA)-filtered ambient air (HEPA group), and ambient traffic-related PM 2.5 (PM 2.5 group, 9.933 ± 1.021 µg/m 3 ) for 3 months. Rotarod test, DTI tractographic analysis, and immunohistochemistry were performed in the end of study period. Aged rats exposed to PM 2.5 exhibited motor impairment with decreased fractional anisotropy and tyrosine hydroxylase expression in olfactory and nigrostriatal circuits, indicating disrupted white matter integrity and dopaminergic (DA) neuronal loss. Additionally, increased radial diffusivity and lower expression of myelin basic protein in PM 2.5 group suggested ageing progression of demyelination exacerbated by PM 2.5 exposure. Significant production of tumor necrosis factor-α was also observed after PM 2.5 exposure, revealing potential inflammation of injury to multiple fiber tracts of DA pathways. Microstructural changes demonstrated potential links between PM 2.5 -induced inflammatory white matter demyelination and behavioral performance, with indication of pre-manifestation of DTI-based biomarkers for early detection of PD progression in the elderly., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Although progress has been made in developing outcome measures for AA, the use of these measures remains unstandardized. A scoping review was conducted to identify the clinician-reported outcome measures (ClinROMs) and patient-reported outcome measures (PROMs) used in assessing and treating AA, the results of which revealed heterogeneity in AA outcome measures. Of 23 research studies ultimately included, only 2 ClinROMs were used by >15% of studies; likewise, of 110 clinical trials evaluated, numerous outcome instruments were used, but only one ClinROM was used by >5% of trials (Severity of Alopecia Tool). These results suggest the need for consensus and standardization in both research and trial settings., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Mounting evidence has shown that antimicrobial agents can interfere synergistically with bacterial viability and proliferation when acting together at both the planktonic and biofilm levels without clear underlying molecular mechanisms. Here, multiplexed proteomics by iTRAQ was used to study the interplay between two biocides, the isothiazolone 1,2-benzisothiazolin-3-one (BIT) and the chelating agent disodium ethylenediaminetetraacetic acid (EDTA-2Na), employing the Citrobacter werkmanii as a model system. We first confirmed that these two biocides act synergistically on this bacterial species and then extracted the proteomic profiles of C. werkmanii cells in the presence of BIT, EDTA-2Na, and their combinations. In particular, we identified 43 core proteins that are differentially expressed in all three conditions simultaneously. Meanwhile, we found that these core proteins are consistently up-regulated when these two biocides are present, but not for single biocides, where we found a balanced mix of up- and down-regulation. Meanwhile, most of the deletion mutants of the core DEPs exhibited biofilm growth inhibition under joint biocide action, while their response was very heterogenous, with respect to the wild-type strain. Together, our results show that while BIT and EDTA-2Na act on multiple protein targets, they interact synergistically at the protein level in a very consistent manner. SIGNIFICANCE: Our preliminary experiments have demonstrated that a combination of 1,2-benzisothiazolin-3-one (BIT) and EDTA-2Na shows higher inhibitory effects on planktonic growth and biofilm formation in both C. werkmanii and Staphylococcus aureus than when these two biocides act alone. However, the mechanistic basis of such synergistic interaction is still unknown. Therefore, the key proteins involved in the above-mentioned enhanced antimicrobial synergy were elucidated using multiplexed proteomics analysis by isobaric tags for relative and absolute quantification (iTRAQ). Our results reveal that the joint action of BIT and EDTA-2Na induces consistent protein expression alteration in a set of core proteins of C. werkmanii, which underlies a strong synergistic antimicrobial effect, which increase our understanding of the action modes of BIT and EDTA-2Na as well as their combinations., Competing Interests: Declaration of Competing Interest The authors of the manuscript declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

We investigated the effects of antibiotics, drugs, and metals on lung and intestinal microbiomes after sub-chronic exposure of low-level air pollution in ageing rats. Male 1.5-year-old Fischer 344 ageing rats were exposed to low-level traffic-related air pollution via whole-body exposure system for 3 months with/without high-efficiency particulate air (HEPA) filtration (gaseous vs. particulate matter with aerodynamic diameter of ≤2.5 µm (PM 2.5 ) pollution). Lung functions, antibiotics, drugs, and metals in lungs were examined and linked to lung and fecal microbiome analyses by high-throughput sequencing analysis of 16 s ribosomal (r)DNA. Rats were exposed to 8.7 μg/m 3 PM 2.5 , 10.1 ppb NO 2 , 1.6 ppb SO 2 , and 23.9 ppb O 3 in average during the study period. Air pollution exposure decreased forced vital capacity (FVC), peak expiratory flow (PEF), forced expiratory volume in 20 ms (FEV 20 ), and FEF at 25∼75% of FVC (FEF 25-75 ). Air pollution exposure increased antibiotics and drugs (benzotriazole, methamphetamine, methyl-1 H-benzotriazole, ketamine, ampicillin, ciprofloxacin, pentoxifylline, erythromycin, clarithromycin, ceftriaxone, penicillin G, and penicillin V) and altered metals (V, Cr, Cu, Zn, and Ba) levels in lungs. Fusobacteria and Verrucomicrobia at phylum level were increased in lung microbiome by air pollution, whereas increased alpha diversity, Bacteroidetes and Proteobacteria and decreased Firmicutes at phylum level were occurred in intestinal microbiome. Lung function decline was correlated with increasing antibiotics, drugs, and metals in lungs as well as lung and intestinal microbiome dysbiosis. The antibiotics, drugs, and Cr, Co, Ca, and Cu levels in lung were correlated with lung and intestinal microbiome dysbiosis. The lung microbiome was correlated with intestinal microbiome at several phylum and family levels after air pollution exposure. Our results revealed that antibiotics, drugs, and metals in the lung caused lung and intestinal microbiome dysbiosis in ageing rats exposed to air pollution, which may lead to lung function decline., 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.)

Background: Although numerous studies have examined the development of preterm children born very low birth weight (VLBW, birth body weight < 1500 g), variations of developmental progress within individuals have rarely been explored. The aim of this research was to examine the cognitive and motor trajectories in preterm children born VLBW at early ages and to assess the risk factors and predictability of these trajectories., Method: Five hundred and eighty preterm infants born VLBW from three cohort studies (2003 to 2014) were prospectively assessed their mental and motor development using the Bayley Scales at 6, 12, 24, and 36 months, and cognitive, motor and behavioral outcomes using the Movement Assessment Battery for Children and the Child Behavior Checklist for Ages 1.5-5 at 4 years of age., Results: Preterm children born VLBW manifested three cognitive patterns (stably normal [64.0 %], deteriorating [31.4 %], and persistently delayed [4.6 %]) and four motor patterns (above average [6.3 %], stably normal [60.0 %], deteriorating [28.5 %], and persistently delayed [5.2 %]) during 6-36 months. Low birth body weight, stage III-IV retinopathy of prematurity and low parental socio-economic status were associated with the deteriorating patterns; prolonged hospitalization and major brain damage were additionally associated with the persistently delayed patterns. Furthermore, the cognitive and motor deteriorating pattern was each predictive of cognitive and motor impairment at 4 years of age; whereas, the persistently delayed patterns were predictive of multiple impairments., Conclusion and Implications: Preterm children born VLBW display heterogeneous trajectories in early cognitive and motor development that predict subsequent developmental and behavioral outcomes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Major depressive disorder is a devastating psychiatric illness that affects approximately 17% of the population worldwide. Astrocyte dysfunction has been implicated in its pathophysiology. Traumatic experiences and stress contribute to the onset of major depressive disorder, but how astrocytes respond to stress is poorly understood., Methods: Using Western blotting analysis, we identified that stress vulnerability was associated with reduced astrocytic glucocorticoid receptor (GR) expression in mouse models of depression. We further investigated the functions of astrocytic GRs in regulating depression and the underlying mechanisms by using a combination of behavioral studies, fiber photometry, biochemical experiments, and RNA sequencing methods., Results: GRs in astrocytes were more sensitive to stress than those in neurons. GR absence in astrocytes induced depressive-like behaviors, whereas restoring astrocytic GR expression in the medial prefrontal cortex prevented the depressive-like phenotype. Furthermore, we found that GRs in the medial prefrontal cortex affected astrocytic Ca 2+ activity and dynamic ATP (adenosine 5'-triphosphate) release in response to stress. RNA sequencing of astrocytes isolated from GR deletion mice identified the PI3K-Akt (phosphoinositide 3-kinase-Akt) signaling pathway, which was required for astrocytic GR-mediated ATP release., Conclusions: These findings reveal that astrocytic GRs play an important role in stress response and that reduced astrocytic GR expression in the stressed subject decreases ATP release to mediate stress vulnerability., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Lead (Pb) is a naturally occurring heavy metal, which can damage the brain and affect learning and memory. Sodium para-aminosalicylic acid (PAS-Na), a non-steroidal anti-inflammatory drug, can readily cross the blood-brain barrier. Our previous studies have found that PAS-Na alleviated Pb-induced hippocampal ultrastructural damage and neurodegeneration, but the mechanism has yet to be defined. Here, we investigated the molecular mechanisms that mediate Pb-induced apoptosis in hippocampal neurons, and the efficacy of PAS-Na in alleviating its effects. This work showed that juvenile developmental Pb exposure impaired rats cognitive ability by inducing apoptotic cell death in hippocampal neurons. Pb-induced neuronal apoptosis was accompanied by increased inositol 1,4,5-trisphosphate receptor (IP 3 R) expression and enhanced intracellular calcium [Ca 2+ ] i levels, which resulted in increased phosphorylation of neuronal apoptosis signal-regulating kinase 1 (ASK1) and p38. Activation of ASK1 and p38 was blocked by IP 3 R inhibitor and a Ca 2+ chelator. Importantly, PAS-Na treatment improved the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. In addition, PAS-Na reduced the expression of IP 3 R and the ensuing increase in intracellular Ca 2+ and decreased the phosphorylation of ASK1 and p38 in Pb-exposed neurons. Taken together, this study demonstrates that the IP 3 R-Ca 2+ -ASK1-p38 signaling pathway mediates Pb-induced apoptosis in hippocampal neurons, and that PAS-Na, at a specific dose-range, ameliorates these changes. Collectively, this study sheds novel light on the cellular mechanisms that mediate PAS-Na efficacy, laying the groundwork for future research to examine the treatment potential of PAS-Na upon Pb poisoning., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Heat stress is directly correlated to mammary gland dysfunction in dairy cows, especially in summer. Abnormally high environmental temperature induces oxidative stress and apoptosis in bovine mammary epithelial cells (BMECs). Nicotinamide mononucleotide (NMN) has beneficial effects in maintaining the cellular physiological functions. In this study, we evaluate the protective effect of NMN on heat stress-induced apoptosis of BMECs and explore the potential underlying mechanisms. Our results showed that heat stress considerably decreased cell viability in BMECs, whereas pretreatment of BMECs with NMN (150 μM) for 24 h significantly alleviated the negative effects of heat stress on cells. NMN protected BMECs from heat stress-induced oxidative stress by inhibiting the excessive accumulation of reactive oxygen species (ROS) and increasing the activity of antioxidant enzymes. It also inhibited apoptosis by reducing the ratio of Bax/Bcl2 and blocking proteolytic the cleavage of Caspase-3 in heat stressed-BMECs. Importantly, NMN treatment could reduce mitochondrial damage through mediating the expression of mitochondrial fission and fusion-related genes, including Dynamin related protein 1 (Drp1), Mitochondrial fission 1 protein (Fis1), and Mitofusin1, 2 (MFN1, 2); and suppress endoplasmic reticulum stress through unfolded protein response regulator Glucose regulated protein 78 (GRP78), and downstream elements Recombinant activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). Above all, our results demonstrate that NMN supplemention attenuates heat stress-induced oxidative stress and apoptosis in BMECs by maintaining mitochondrial fission and fusion, and regulating endoplasmic reticulum stress, which provides the convincing evidence that NMN has valuable potential in alleviating mammary gland injury of dairy cows caused by environmental heat stress., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Blood purification therapy is widely used in patients with renal insufficiency and severe infections, where membrane-associated thrombosis is a side effect. How to improve the hemocompatibility of dialysis membranes and reduce thrombosis is a focus of current research, in which platelets play a key role. However, few dialysis membranes that directly inhibit platelets have been developed to date. In this study, a polyethersulfone (PES) membrane was modified with ticagrelor, a platelet P2Y 12 receptor inhibitor, and detailed characterization was performed. The ticagrelor modified PES membrane (TMPES) showed good hydrophilicity and anti-protein adsorption and significantly inhibited platelet adhesion, aggregation, and activation, which demonstrated good antithrombotic properties. In addition, the membrane had excellent red blood cell (RBC) compatibility, anticoagulant, and antiinflammatory effects, which demonstrated superior biosafety in cell and animal experiments. Therefore, the TMPES dialysis membrane could have potential in clinical applications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ruminants have a superficial implantation pattern. The extended conceptus attaches to the receptive endometrium to form the cotyledonary placenta. During the attachment, a large number of events occur at the maternal-fetal interface. However, the related molecular mechanisms have not been fully understood. Integrin beta8 (ITGB8) is a subunit of integrin beta involved in embryo implantation. In this study, we determined peri-implantation expression and regulation of ITGB8 in goat uterus. The mRNA and protein levels of ITGB8 were both high in goat endometrial luminal epithelium (LE) and superficial glandular epithelium (sGE) during the adhesion period (Days 16-19 of pregnancy). Such expression profile was opposite to that of microRNA-187 (miR-187). Then, we validated that miR-187 targeted the 3' untranslated region (UTR) of ITGB8 in primary goat endometrial epithelial cells (EECs). In EECs, inhibition of miR-187 resulted in not only up-regulated ITGB8 level but also reduced cell proliferation and focal adhesion kinase (FAK) activity. Moreover, ITGB8 and miR-187 were regulated by interferon tau (IFNT). Altogether, in goat, the miR-187/ITGB8 axis may be involved in conceptus attachment and is downstream of IFNT. Our results will help us better understand the mechanisms of ruminant implantation and may provide a useful tool to improve the reproduction ratio for ruminants., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The ability of SARS-CoV-2 to replicate in host cells is dependent on its main protease (M pro , also called 3CLpro) that cut the viral precursor polyproteins and is a major target for antiviral drug design. Here, we showed that heparin interacts with the M pro of SARS-CoV-2 and inhibits its activity. Protein fluorescence quenching showed that heparin strongly binds to the M pro protein with dissociation constants K D of 16.66 and 31.60 μM at 25 and 35 °C, respectively. From thermodynamic parameters of the interaction, there are hydrophobic and hydrogen bond interactions between them. Fluorescence resonance energy transfer (FRET) assay demonstrated that heparin inhibits the proteolytic activity of M pro with an inhibition constant Ki of 6.9 nM and a half maximal inhibitory concentrations (IC 50 ) of 7.8 ± 2.6 nM. Furthermore, molecular docking analysis revealed that the recognition and binding groups of heparin within the active site of SARS-CoV-2 M pro provide important new information for the characteristics of the interactions of heparin with the protease. Our finding suggested that heparin might have a potential role in inhibiting SARS-CoV-2 infection through inhibiting M pro activity of SARS-CoV-2., 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 © 2021 Elsevier B.V. All rights reserved.)

Xanthine oxidase (XO) is a purine catabolic enzyme related to hyperuricemia and gout. Porphyra polysaccharide (PP) is a kind of sulfated polysaccharide with potent biological activity. Herein, the interaction mechanism between PP and XO was studied by enzyme kinetics and multi-spectroscopy methods for the first time. Inhibition kinetics assay showed that PP reversibly inhibited XO activity in a mixed competitive manner with an IC 50 of 10.53 ± 0.69 mg/ml. Fluorescence titration studies and thermodynamic parameter calculations revealed that PP could spontaneously bind to XO through hydrophobic interactions, with a class of binding site. Circular dichroism analysis demonstrated that PP induced secondary structure rearrangement and conformational change of XO. Molecular docking further revealed that PP inserted into the hydrophobic cavity of XO, occupying the catalytic center, leading to the inhibition of XO activity. This study may provide new insights into the inhibitory mechanism of PP as a promising XO inhibitor., 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 © 2021 Elsevier B.V. All rights reserved.)

Convergent studies have highlighted the amygdala-based and dorsal anterior cingulate cortex (dACC)-based circuit or network dysfunction in post-traumatic stress disorder (PTSD). However, previous studies are often complicated by various traumatic types, psychiatric comorbidities, chronic illness duration, and medication effect on brain function. Besides, little is known whether the functional integration with amygdala-dACC interaction disrupted or not in PTSD. Here, we investigated effective connectivity (EC) between the amygdala-dACC and rest of the cortex by applying psycho-physiological interaction (PPI) approach to resting-state functional magnetic resonance imaging data of 63 drug-naive PTSD patients and 74 matched trauma-exposed non-PTSD controls. Pearson correlation analysis was performed between EC values extracted from regions with between-group difference and clinical profiles in PTSD patients. We observed distinct amygdala-dACC interaction pattern between PTSD group and the control group, which is composed primarily by positive EC in the former and negative in the latter. In addition, compared with non-PTSD controls, PTSD patients showed increased EC between amygdala-dACC and the prefrontal cortex, left inferior parietal lobule, and bilateral ventral occipital cortex, and decreased EC between amygdala-dACC and the left fusiform gyrus. The EC increase between amygdala-dACC and the right middle frontal gyrus was negatively correlated with the clinician-administered PTSD scale scores in PTSD patients. Aberrent communication between amgydala-dACC and brain regions involved in central executive network and visual systems might be associated with the pathophysiology of PTSD. Further, these findings suggested that dysconnectivity of the amygdala and dACC could be adapted as a relatively early course diagnostic biomarker of PTSD., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Next generation sequencing (NGS)-based single nucleotide polymorphism (SNP) genotyping is widely used in the field of forensics. SNP genotyping data from several NGS platforms have been published, but forensic application trials of DNA nanoball sequencing platforms have been very limited. In this work, we developed a 448-plex SNP panel on the BGISEQ-500RS platform. The sequencing metrics of a total of 261 samples that were sequenced with this panel are reported in detail. The average sequencing depth was 8373 × and the average heterozygosity of the 448-plex assay was 0.85. Sensitivity analysis showed that 325 SNPs were successfully genotyped with as little as 50 pg of genomic DNA, with the mean quality score of the sequencing data above Q30. Forensic parameters were calculated based on the data of 142 unrelated Chinese Han individuals and the combined matching probability was as low as 5.21 × 10 -101 . Kinship analyses based on experiments and computer simulations showed that the 448-panel was as effective as the ForenSeq™ DNA Signature Prep Kit for second-degree kinship identification, and when the two panels were merged, the related pairs were almost completely distinguished from unrelated pairs. The 448-plex SNP panel on the BGISEQ-500RS platform provides a powerful tool for forensic individual identification and kinship analysis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Drug-resistant tuberculosis (DR-TB), diabetes and exposure to air pollution are thought to be important threat to human health, but no studies have explored the effects of ambient air pollutants on DR-TB when adjusting diabetes status so far., Methods: We performed a study among 3759 newly diagnosed TB cases with drug-susceptibility testing results, diabetes status, and individual air pollution data in Shandong from 2015 to 2019. Generalized linear mixed models (GLMM) including three models (Model 1: without covariates, Model 2: adjusted by diabetes status only, Model 3: with all covariates) were applied., Results: Of 3759 TB patients enrolled, 716 (19.05%) were DR-TB, and 333 (8.86%) had diabetes. High exposure to O 3 was associated with an increased risk of RFP-resistance (Model 2 or 3: odds ratio (OR) = 1.008, 95% confidence intervals (CI): 1.002-1.014), ethambutol-resistance (Model 3: OR = 1.015, 95%CI: 1.004-1.027) and any rifampicin+streptomycin resistance (Model 1,2,3: OR = 1.01, 95%CI: 1.002-1.018) at 90 days. In contrast, NO 2 was associated with a reduced risk of DR-TB (Model 3: OR = 0.99, 95%CI: 0.981-0.999) and multidrug-resistant TB (MDR-TB) (Model 3: OR = 0.977, 95%CI: 0.96-0.994) at 360 days. Additionally, SO 2 (Model 1, 2, 3: OR = 0.987, 95%CI: 0.977-0.998) showed a protective effect on MDR-TB at 90 days. PM 2.5 (90 days, Model 2: OR = 0.991, 95%CI: 0.983-0.999), PM 10 (360 days, Model 2: OR = 0.992, 95%CI: 0.985-0.999) had protective effects on any RFP+SM resistance., Conclusions: O 3 contributed to an elevated risk of TB resistance but PM 2.5 , PM 10 , SO 2 , NO 2 showed an inverse effect. Air pollutants may affect the development of drug resistance among TB cases by adjusting the status of diabetes., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Inhibiting the activity of the intestinal enzyme α-amylase that catalyzes the degradation of starch into glucose can control blood glucose and provide an essential way for the treatment of Type-II diabetes mellitus (T2DM). Here, we compared the structural information of chondroitin sulfate (CS) from different origins and the effects on activity of α-amylase and blood glucose have been investigated. The inhibitory effects of shark and porcine CSs against α-amylase activity is obvious with IC 50 values of 11.97 and 14.42 mg/ml, respectively, but the bovine CS almost no effect. From the data of fluorescence spectroscopic analyses, CSs from shark and pig quench Try fluorescence intensity of the enzyme, whereas bovine CS induces an increase. In vivo, oral administration of shark and porcine CSs efficiently suppresses postprandial blood glucose levels in normal and diabetic mice. Our study found that CSs from different sources showed different biological functions even if both molecular weight and disaccharide subunit composition are almost the same, and demonstrated that the CSs from shark and pig as α-amylase inhibitors could be regarded as a novel functional food ingredient in T2DM management., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sr 3.8 Fe 25.7 O 70.4 -chitosan magnetic microparticles (Sr 3.8 Fe 25.7 O 70.4 -CMNs) with a core-shell structure were synthesized, characterized and applied for the removal of two model cationic dyes. The results showed that these magnetic microparticles possess fast adsorption rate and high adsorption efficiency for both crystal violet (CV) and basic red 9 (BR9) at a temperature ranging 30 °C to 40 °C and suitable pH range (pH ≥ 7). The maximum removal efficiency for CV and BR9 attained to 94.5% and 97.5% in 30 min, which was significantly faster and higher than that of chitosan (<50% in 60 min) (P<0.01). And its maximum adsorption capacity for CV and BR9 reached 29.46 mg/g and 32.16 mg/g, respectively. The adsorption process of Sr 3.8 Fe 25.7 O 70.4 -CMNs follows the Langmuir isotherm with a high correlation coefficient (R 2  > 0.97) and the pseudo-second-order model. Additionally, the synthesized Sr 3.8 Fe 25.7 O 70.4 -CMNs were easy to regeneration and reuse, and the removal rate remained above 90% after 5 recycle times. This study would provide a new more environmental friendly material and method for the treatment of wastewater containing toxic dyes., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Over-expression of the human epidermal growth factor receptor-2 (HER2) is related to aggressive tumors and poor prognosis in breast cancer. Trastuzumab (TRA) resistance leads to tumor recurrence and metastasis, resulting in poor prognosis in HER2-positive breast cancer. POU Class 4 Homeobox 1 (POU4F1) is a member of the POU domain family transcription factors, and has a key role in regulating cancers. However, its effects on TRA-resistant HER2-positive breast cancer are still vague. In the present study, we found that POU4F1 expression was dramatically increased in clinical breast cancer specimens with TRA resistance. Higher POU4F1 was also detected in HER2-positive breast cancer cells with TRA resistance than that of the parental ones. Poor prognosis was detected in breast cancer patients with high POU4F1 expression. Under TRA treatment, POU4F1 knockdown significantly reduced the proliferative capacity of HER2-positive breast cancer cells with TRA resistance. POU4F1 silence also sensitized resistant HER-positive breast cancer cells to TRA treatment in vivo using a xenograft mouse model, along with the markedly reduced tumor growth rate and tumor weight. Moreover, we found that POU4F1 deletion greatly decreased the activation of mitogen-activated or extracellular signal-regulated protein kinase kinases 1 and 2 (MEK1/2) and extracellular-regulated kinase 1/2 (ERK1/2) signaling pathways in breast cancer cells with TRA resistance. Migration and invasion were also effectively hindered by POU4F1 knockdown in TRA-resistant HER2-positive breast cancer cells. Notably, we found that POU4F1 deletion-improved chemosensitivity of HER2-positive breast cancer cells with drug-resistance to TRA treatment was closely associated with the blockage of ERK1/2 signaling. Collectively, our findings reported a critical role of POU4F1 in regulating TRA resistance, and demonstrated the underlying molecular mechanisms in HER2-positive breast cancer. Thus, POU4F1 may be a promising prognostic and therapeutic target to develop effective treatment for overcoming TRA resistance., (Copyright © 2020 Elsevier Inc. All rights reserved.)

There are no tools to evaluate eyebrow involvement in patients with alopecia areata. We developed and assessed the reliability of the Brigham Eyebrow Tool for Alopecia (BETA) as a quantitative evaluation of eyebrow alopecia areata. BETA uses facial landmarks of eyebrow anatomy and is calculated using surface area and density. A total of 50 eyebrow images with varying levels of hair loss were distributed to six board-certified dermatologists at three academic medical centers with standardized instructions and examples. Interrater and intrarater reliability were calculated using intraclass correlation coefficients (ICCs). BETA demonstrated high interrater (ICC = 0.88, confidence interval = 0.83-0.92 right eyebrow scores and ICC = 0.90, confidence interval = 0.85-0.94 left eyebrow scores) and intrarater (ICC = 0.90, confidence interval = 0.85-0.93 right eyebrow scores and ICC = 0.91, confidence interval = 0.87-0.94 left eyebrow scores) reliability. When measured in the same patient with varying degrees of hair loss over time, BETA demonstrated sensitivity to change. BETA is a simple and reliable objective assessment of eyebrow alopecia areata. BETA is easy-to-use and quick to calculate, making it feasible for a variety of clinical and research settings. Although developed for alopecia areata, we hope that BETA will be investigated in other etiologies of eyebrow alopecia to serve as a universal tool for monitoring disease progression, improvement, and response to treatment., (Copyright © 2020 Brigham and Women's Hospital. Published by Elsevier Inc. All rights reserved.)

Objective: Acute grief, in an important minority of older adults, can become protracted, intense, and debilitating, leading to the development of complicated grief (CG). However, the neurobiologic mechanisms underlying a maladaptive grief response after an attachment loss are unknown. The current study aimed to examine the amygdala brain network features that cross-sectionally explain the symptom variance and longitudinally relate to grief symptom trajectories after an attachment loss., Methods: Baseline amygdala functional connectivity (Fc) was assessed using a seed-based resting-state functional magnetic resonance imaging method in 35 adults who were within 1-year after death of a loved one and 21 healthy comparison (HC) participants. Magnetic resonance imaging scans were obtained at baseline, and clinical assessments, including the inventory of complicated grief (ICG) were completed at weeks 0, 8, 16, and 26 (endpoint)., Results: Relative to HC participants, grief participants showed increased amygdala Fc in the posterior default mode (bilateral medial temporal lobes and left precuneus) and thalamus. Amygdala Fc in the default mode and ventral affective regions positively correlated with ICG scores at baseline. Furthermore, increased baseline amygdala functional connections with the dorsal frontal executive control and salience network regions correlated with worsening ICG scores over time. These longitudinal findings persisted after controlling for covariates, including baseline depressive and anxiety symptoms., Conclusion: These results provide novel preliminary evidence suggesting amygdala-based brain network measures to cross-sectionally explain symptom variance and longitudinally correlate with grief symptom trajectories in grievers. Amygdala brain network function measures may have the potential to serve as biomarkers of CG., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: A percutaneous approach for pulmonary valve replacement (PVR) is a feasible alternative to surgical PVR in selected patients with severe pulmonary regurgitation after repair of tetralogy of Fallot. However, large right ventricular outflow tract (diameter ≥ 25 mm) remains challenging., Methods: This retrospective multicenter study enrolled consecutive patients with large right ventricular outflow tract who underwent percutaneous PVR (Venus P-valve, Venus MedTech Inc, Hangzhou, China) (n = 35) or surgical PVR (homograft valve; n = 30) between May 2014 and April 2017. Patients were followed up at 1, 3, 6, and 12 months, and yearly thereafter. Main study outcomes were pulmonary valve function and right ventricular function at discharge and midterm follow-up., Results: PVR was successful in all patients. Percutaneous compared with surgical PVR group had: similarly distributed baseline characteristics; shorter hospitalization, intensive care unit stay, and endotracheal intubation duration; lower cost; lower pulmonary valve gradient before discharge; lower pulmonary valve regurgitant grade (mean difference, -0.63; 95% CI -1.11 to -0.20, P = .022), pulmonary valve gradient (mean difference, -5.7 mm Hg; 95% CI -9.4 to -2.2 mm Hg, P = .005), and right ventricular end-diastolic volume index (mean difference, -9.5 mL/m 2 ; 95% CI -16.9 to -3.1 mL/m 2 , P = .022); and greater right ventricular ejection fraction (mean difference, 5.4%; 95% CI 2.4%-8.3%, P = .002) at median 36 months follow-up, without deaths in either group., Conclusions: Percutaneous PVR using Venus P-valve appeared to be a safe, efficacious and minimally invasive alternative to surgical PVR in selected patients with large right ventricular outflow tract yielding better right ventricular and pulmonary valve function at midterm follow-up., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The lignin amine (LA) was exploited to prepare dually N/S-doped carbon (NSC), which was endowed with intriguing porous structure by Fe 3 O 4 template. N and S elements, originating from LA, are doped into the materials. NSC possesses diverse-scale 3D pores. The macropores are made by Fe 3 O 4 , which facilitate to produce meso and micro pores on their walls by KOH activation. The sample prepared at 700 °C (NSC-700) is found to have the largest specific surface area (1199 cm 2  g -1 ) and specific capacity (241 F g -1 at current density of 1 A g -1 ). Its capacity is 260% as high as that of lignin amine carbon (LAC) prepared without adding Fe 3 O 4 . Excellent rate performance is unraveled because of possessing 82% specific capacity at 20 A g -1 and 27.2 Wh kg -1 energy density at 10000 W kg -1 power density. Moreover, the specific capacity maintains 95.0% after 3000 cycles, indicating good electrochemical stability. The good electrical performance of NSC-700 is attributed to its interesting electronic properties that are induced by special pore structure. Because of having merits such as high rate performance, long life, large specific capacity and low cost, our NSC is anticipated to be a promising capacitor as electrode material., Competing Interests: Declaration of competing interest 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 © 2020 Elsevier B.V. All rights reserved.)

Background: Although the association between diabetes mellitus (DM) and tuberculosis (TB) has been well-documented for centuries, evidence of the link between diabetes and drug resistance among previously treated TB patients remains limited and inconsistent., Methods: An observational study was performed that involved 1791 retreated TB-no DM patients (refers to TB cases without diabetes) and 93 retreated TB-DM patients (refers to TB cases with diabetes) in Shandong, China from 2004 to 2017. Baseline data including demographic and clinical characteristics, drug susceptibility test (DST) results, and diabetes status were collected. Categorical baseline characteristics were compared by Fisher's exact or Pearson Chi-square test. Univariable analysis and multivariable logistic models were used to estimate the association between diabetes and different drug resistance profiles., Results: Retreated TB-DM patients have a higher rate of drug resistance than TB-no DM patients (34.41% vs 25.00%, P < 0.01). Diabetes co-morbidity was significantly associated with any drug-resistant tuberculosis (DR-TB, odds ratio (OR):1.56, 95% confidence interval (CI): 1.01-2.43), multidrug resistant tuberculosis (MDR-TB, OR: 2.48, 95%CI:1.39-4.41; adjusted OR (aOR):2.94, 95%CI:1.57-5.48), isoniazid-related resistance (OR:1.71, 95%CI:1.04-2.81), rifampin-related resistance (OR:2.56, 0.54, 95%CI: 1.54-4.26; aOR:2.69, 95%CI:1.524-4.74), isoniazid + rifampin resistance (OR: 3.55, 95%CI:1.33-9.44; aOR:4.13, 95%CI:1.46-11.66), any resistance to isoniazid + streptomycin (OR:2.34, 95%CI:1.41-3.89; aOR:2.22, 95%CI:1.26-3.94), and any resistance to rifampin + isoniazid (OR:2.48, 95%CI:1.39-4.41; aOR:2.94, 95%CI: 1.57-5.48), compared with pan susceptible TB cases, P < 0.05., Conclusions: The risk of acquired drug resistance increased significantly among retreated TB-DM patients compared with retreated TB-no DM patients, underlining the necessity of more interventions during the clinical management of TB-DM cases., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In recent years, mesh structures have attracted significant interest for structural and functional applications. However, the mechanical strength and energy absorption ability of uniform mesh structured materials degrade with density. To address this challenge, we propose the concept of functionally graded mesh structures. The objective of the proposed research is to fundamentally understand the compressive behavior of graded mesh structures. The compression-compression fatigue behavior of functionally graded Ti-6Al-4V mesh structure under identical bulk stress condition is studied here. During cyclic deformation, it was observed that the local stress distribution in the struts was not uniform because of inhomogeneous mechanical properties of the constituents. Fatigue cracks first initiated in the lowest strength constituent, and then propagated until structural failure occurred. However, no obvious damage was observed in other constituents during the entire process. In contrast with iso-strain state, the fatigue life of graded structure is mainly determined by the constituent with the lowest strength., 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 © 2019 Elsevier Ltd. All rights reserved.)

A novel and highly selective fluorescent 1,8-naphthalimide-based probe, 3, was designed and synthesized for rapid Cu 2+ detection in a CH 3 CN-H 2 O (3:1, v/v, pH = 7.4) solution by means of a distinct hydrolysis mechanism via its Cu 2+ -promoting feature. Upon treatment with Cu 2+ , the fluorescence response of probe 3 at 550 nm abruptly decreased, which was visible to the naked eye, and this response was accompanied by a clear change of the color of the solution; the color changed from the original yellow color to colorless. This color change occurred due to the Cu 2+ -promoted hydrolysis of 3, which yielded a fluorescence-quenched product. It is inspiring that probe 3 exhibited excellent sensitivity, a short response time and strong anti-interference recognition. Compared with the allowable amount of Cu 2+ (∼20 μM) in drinking water, the detection limit of 3 for Cu 2+ is calculated to be 9.15 nM, which is much lower than the amount defined by standards. The probe can be successfully applied for the determination of Cu 2+ in real aqueous samples. Furthermore, probe 3 can be used as a fluorescent sensor to detect Cu 2+ in biological environments, demonstrating its low toxicity to organisms and good cell permeability in live cell imaging., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Atherosclerotic lesions create obvious vascular stenosis due to the presence of plaque, and a large number of inflammatory macrophages are enriched in the thrombus. In this study, we develop a composite hydrogel drug delivery system that is capable of both mechanically-sensitive drug release and of targeting inflammatory macrophages at the thrombus. The hydrogel is a high molecular weight hyaluronic acid (HA) modified with glycidyl methacrylate as a hydrogel precursor; a cross-linkable block copolymer (CBC) is used as the drug coating material and a microscopic cross-linking agent. The difference in drug release rate of the composite hydrogel (HACBC) in simulated blood vessels with 0 % and 75 % occlusion was as high as 49.3 %. Under long-term cycling conditions in stenotic vessels, dynamic shear rheometry revealed that the HACBC still maintained the hydrogel properties. However, the micelles were deformed and recombined to produce smaller sized micelles. An in vitro cell culture demonstrated precise targeting of the HACBC to inflammatory macrophages, and our rabbit experiments with simvastatin-coated HACBC confirmed the effective release of simvastatin in the plaque of the drug carrier. Moreover, we demonstrated the precise targeting of HACBC in vivo in apoE-/- mice by using HACBC coated with cy7. The mechanical stress-sensitive and CD44 receptor-targeted dual-response drug delivery system prepared by micellar composite hydrogel is the first application in the field of atherosclerosis, which provides a new method for diagnosing and treating atherosclerosis., 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 © 2019 Elsevier B.V. All rights reserved.)

Mounting evidences indicated that elevated iron levels in the substantia nigra (SN) have been concerned as the underlying mechanisms of neurodegenerative diseases, including Parkinson's disease (PD). The present study used the 1-Methyl-4-phenyl-1, 2, 3, 6 -tetrahydropyridine (MPTP)-treated cynomolgus monkeys for PD to evaluate the usability of SWI for assessing iron deposition in the cerebral nuclei of PD. The results showed that susceptibility-weighted imaging (SWI) phase values of the ipsilateral (MPTP-lesion side) SN of MPTP-treated monkeys were lower than those in the contralateral SN of MPTP-treated monkeys and the same side of Control monkeys, suggesting that iron deposition were elevated in the affected side SN of MPTP-treated monkeys. Whereas MPTP has not effects on the SWI phase values in other detected brain regions of monkeys, including red nucleus (RN), putamen (PUT) and caudate nucleus (CA). Furthermore, ICP-MS results showed that MPTP increased the iron levels in MPTP injection side, but no in the ipsilateral striatum. Additionally, MPTP treatment did not affect the calcium and manganese levels in the detected brain regions of monkeys. However, Pearson correlation analysis results indicated that there were not relationship between SWI phase values in MPTP-lesion side of SN with the behavioral score, tyrosine hydroxylase (TH)-positive cells number and iron levels in the MPTP-lesion side of midbrain. Taken together, the results confirm the involvement of SN iron accumulations in the MPTP-treated monkey models for PD, and indirectly verify the usability of SWI for the measurement of iron deposition in the cerebral nuclei of PD., (Copyright © 2019. Published by Elsevier Inc.)

Influences of proteins on degradation of magnesium alloys are of great significance but not well understood. In particular the roles of amino acids, the basic unit of proteins in regulating the progress of biodegradation of magnesium based materials remain unclear. This study aims to investigate the impacts of alanine, glutamic acid and lysine on degradation of pure magnesium in phosphate buffer solution through SEM, XPS, FTIR, potentiodynamic polarisation curves, electrochemical impedance spectroscopy and immersion tests. The changed contents of amino acids in solutions were detected by UV-vis spectrophotometer. Results demonstrate that the charges of the selected amino acids imposed significant contribution to suppressing the degradation of pure magnesium in phosphate buffer solution. The presence of amino acids led to the formation of phosphate-based corrosion products, increasing free corrosion potential, and reduction in corrosion current density and solution pH depending on their isoelectric points and molecular structures. A plausible corrosion mechanism organised by amino acids on pure magnesium was proposed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

An effective morpholine-type naphthalimide chemsensor, N-p-chlorophenyl-4-(2-aminoethyl)morpholine-1,8-naphthalimide (CMN) has been developed as a lysosome-targeted fluorometric sensor for trivalent metal ions (Fe 3+ , Al 3+ and Cr 3+ ). Upon the addition of Fe 3+ , Al 3+ or Cr 3+ ions, the probe CMN showed an evident naked-eye color changes which pale yellow solution of CMN turned deepened and it displayed turn-on fluorescence response in methanol. CMN showed a significant selective and sensitive toward Fe 3+ , Al 3+ or Cr 3+ ions, while there was no obvious behavior to other monovalent or divalent metal ions from the UV-vis and fluorescence spectrum. Based on the Job's plot analyses the 1:1 coordination mode of CMN with Fe 3+ , Al 3+ or Cr 3+ was proposed. The limit of detection (LOD) observed were 0.65, 0.69 and 0.68 μM for Fe 3+ , Al 3+ and Cr 3+ ions, respectively. The N-atom of morpholine directly involved in complex formation, CMN emitted fluorescence through inhibition of photoinduced electron transfer (PET). This probe exhibited excellent imaging ability for Fe 3+ , Al 3+ and Cr 3+ ions in living cells with low cytotoxicity. Significantly, the cellular confocal microscopic research indicated that the lysosome-targeted group of morpholine moiety was introduced which realized the capability of imaging lysosomal trivalent metal ions in living cells for the first time., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Social deficit is a core symptom in autism spectrum disorder (ASD). Although deep brain stimulation (DBS) has been proposed as a potential treatment for ASD, an ideal target nucleus is yet to be identified. DBS at the central thalamic nucleus (CTN) is known to alter corticostriatal and limbic circuits, and subsequently increase the exploratory motor behaviors, cognitive performance, and skill learning in neuropsychiatric and neurodegenerative disorders., Objective: We first investigated the ability of CTN-DBS to selectively engage distinct brain circuits and compared the spatial distribution of evoked network activity and modulation. Second, we investigated whether CTN-DBS intervention improves social interaction in a valproic acid-exposed ASD rat offspring model., Methods: Brain regions activated through CTN-DBS by using a magnetic resonance (MR)-compatible neural probe, which is capable of inducing site-selective microstimulations during functional MRI (fMRI), were investigated. We then performed functional connectivity MRI, the three-chamber social interaction test, and Western blotting analyses to evaluate the therapeutic efficacy of CTN-DBS in an ASD rat offspring model., Results: The DBS-evoked fMRI results indicated that the activated brain regions were mainly located in cortical areas, limbic-related areas, and the dorsal striatum. We observed restoration of brain functional connectivity (FC) in corticostriatal and corticolimbic circuits after CTN-DBS, accompanied with increased social interaction and decreased social avoidance in the three-chamber social interaction test. The dopamine D2 receptor decreased significantly after CTN-DBS treatment, suggesting changes in synaptic plasticity and alterations in the brain circuits., Conclusions: Applying CTN-DBS to ASD rat offspring increased FC and altered the synaptic plasticity in the corticolimbic and the corticostriatal circuits. This suggests that CTN-DBS could be an effective treatment for improving the social behaviors of individuals with ASD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Nonalcoholic fatty liver disease (NAFLD) is a severe liver disease, which influences the health of people worldwide. However, the specific mechanism of the disease remains unknown, and effective treatments are still lacking. It was reported that Nuclear enriched abundant transcript 1 (NEAT1) obviously was up-regulated in NAFLD model. But the role and underlying mechanism of NEAT1 in NAFLD is unclear., Methods: HepG2 cells were treated by free fatty acids (FFA) and C57BL/6J mice were treated by high-fat diet to establish NAFLD in vitro and in vivo models, respectively. Cell transfection was applied to regulate the expression of NEAT1, ROCK1, and miR-146a-5p. Western blotting and qRT-PCR were used for measuring expression of protein and mRNA level, respectively. Dual luciferase assay was used to detect the target relationship. Oil Red O staining was used to measure the lipid accumulation. HE staining was used for observing pathological feature of liver tissues., Results: High levels of NEAT1 and ROCK1, and low level of miR-146a-5p were identified in NAFLD models. NEAT1 could target miR-146a-5p to promote ROCK1 expression. Knockdown of NEAT1, overexpression of miR-146a-5p and knockdown of ROCK1 inhibited lipid accumulation through activating AMPK pathway., Conclusion: NEAT1 may regulate NAFLD through miR-146a-5p targeting ROCK1, and further affect AMPK/SREBP pathway. This study may provide a new thought for the treatment of NAFLD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: To investigate if intraoperative ultrasounds by laparoscopic and transvaginal ultrasonography (LUS and TVS) could improve enucleating the residual fibroids following laparoscopic myomectomy (LM)., Methods: From March to December 2016, 78 women with uterine fibroids underwent LM, LUS and TVS were applied to detect residual fibroids and to guide surgeons to enucleate them after the visible fibroids were removed during LM operation., Results: The total number of residual fibroids found by LUS was 140, and the total number found by TVS was 127 following LM (P = 0.03). LUS is statistically superior to TVS in the detection of residual fibroids in the anterior wall (P = 0.004), in the detection of intramural fibroids (P = 0.002), and in the detection of fibroids with a diameter ranging from 0.5 to 1 cm (P = 0.002). According to the total number of enucleated fibroids by LM, patients were divided into three groups (Group 1: 2 to 4, Group 2: 5 to 7 and Group 3: ≥8 fibroid counts). The percentages of patients in each group with residual fibroids at the end of surgery were 22.2%, 51.9% and 66.7% respectively., Conclusions: Both LUS and TVS are beneficial to surgical treatment of fibroids by assisting enucleation of residual fibroids following LM, while LUS is more effective in localizing residual fibroids than TVS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Heart is a high energy demand organ and cardiac fat is the main local energy source for heart. Alteration in cardiac fat may affect cardiac energy and contribute to heart dysfunction. We previously observed a link between alteration in pericardial fat (PAT) and local adverse effects on myocardial fibrosis in obese minipigs. This study investigated the role of PAT on cardiac energy and mitochondrial function, and elucidated a potential mechanism for PAT in cardiac fibrosis., Materials and Methods: Five-month-old Lee-Sung minipigs were made obese by feeding a high-fat diet (HFD) for 6 months. The conditioned medium from PAT of obese minipigs (PAT-CM) was collected and H9C2 cells were treated with it to study mechanisms., Results: HFD caused a cardiac energy deficit and fibrosis in the left ventricle. An elevated content of IL6 and malondialdehyde was found in the PAT of obese pigs. Obese pigs exhibited an increased level of oleic acid and a reduced level of saturated fatty acids in PAT compared to control pigs. HFD did not alter the metabolic characteristics of epicardial fat. PAT-CM caused apoptosis of H9C2 cells and inhibited basal mitochondrial respiration and ATP production. Protein expressions for mitochondrial dynamics- (Mfn2, Opa1, Drp1, and Fis1) and a mitophagy-related protein (Parkin) were suppressed by PAT-CM. PAT-CM enhanced the protein expression of LC3II, and the ratio of LC3II/LC3I. To conclude, PAT was involved in cardiac fibrosis of HFD-fed minipigs. The secretomes of PAT impaired mitochondrial functions and caused cardiomyocyte apoptosis in a paracrine manner., (Copyright © 2019 Elsevier B.V. All rights reserved.)

High glucose (HG)-induced oxidative stress contributes to the dysfunction of pancreatic β cells in diabetes. The voltage-gated proton channel Hv1 has been proposed to support reactive oxygen species (ROS) production during respiratory bursts. However, the effect of Hv1 on glucotoxicity in pancreatic β cells is not clear yet. In this study, we examined the protective effects of Hv1-deficiency in HG cultured β cells. Following 48 h of treatment with 30 mM high glucose, Hv1 KO β cells showed higher cell viability, lower cell apoptosis and a more stable insulin gene expression level compared to WT β cells. In both control and HG cultured β cells, deficiency of Hv1 decreased the glucose- and PMA-induced ROS production. Finally, HG incubation led to NOX4 upregulation in WT β cells, which could be inhibited by HV1 deficiency. In conclusion, Hv1-deficiency prevents the HG treatment-induced NOX4 upregulation and protects β cells from glucotoxicity., (Copyright © 2019. Published by Elsevier Inc.)

To study adaptation of largemouth bass (Micropterus salmoides) to hypoxic stress, we investigated physiological responses and lactate metabolism of the fish under acute hypoxia. The objectives of this study were to (a) observe changes in glucose, glycogen, and lactate content; (b) detect the activity of lactate dehydrogenase (LDH) in serum, brain, heart, and liver tissues; and (c) quantify the dynamic gene expression of AMP activated protein kinase alpha (AMPKα), hypoxia-inducible factor-1 alpha (HIF-1α), monocarboxylate transporter 1 (MCT1), monocarboxylate transporter 4 (MCT4), and lactate dehydrogenase-a (LDHa) following exposure to hypoxia. The fish were subjected to two hypoxia stresses (dissolved oxygen [DO] 1.20 ± 0.2 mg/L and 3.50 ± 0.3 mg/L, respectively) for 24 h. Our results showed that hypoxic stress significantly increased the decomposition of liver glycogen and significantly increased the concentration of blood glucose; however, the muscle glycogen content was not significantly decreased, which indicates that liver glycogen was the main energy source under acute hypoxia. Moreover, hypoxia led to accumulation of a large amount of lactic acid in tissues, possibly due to the activity of lactic acid dehydrogenase, but this process was delayed in the heart and brain relative to the liver. Additionally, hypoxia induced the expression of AMPKα, HIF-1α, MCT1, MCT4, and LDHa, suggesting that glycometabolism had switched from aerobic to anaerobic. Our results contribute to a better understanding of the molecular mechanisms of the response to hypoxia in largemouth bass., (Copyright © 2019. Published by Elsevier B.V.)

This study examined the in vitro characteristics and in vivo wound healing effect of novel Lithospermi radix (LR) extract-containing bilayer scaffolds in a rat model. LR extract, which has been used as a traditional herbal medicine for treating skin wounds, was added to a biocompatible gelatin solution. After glutaraldehyde vapor was used to modify the surface of chitosan scaffolds, various ratios of mammalian gelatin and fish collagen (GF100, GF91 and GF82) were electrospun onto the chitosan scaffolds to manufacture bilayer scaffolds. The porous chitosan scaffolds with a high swelling ratio showed efficient exudate absorption ability. GF91 gelatin nanofibers electrospun at a constant flow rate at 0.1 mL/h and a voltage of 20 kV displayed the optimal characteristics required for cell attachment and skin tissue regeneration. Moreover, the LR extract was successfully released slowly from the GF91 nanofibers. The investigation of the wound-healing activity of the chitosan/gelatin (CGF) bilayer scaffolds revealed that CGF91L provided the highest wound recovery rate in vivo in Sprague-Dawley (SD) rats. Based on its wound-healing effect and beneficial characteristics, the novel LR extract-containing CGF91 bilayer scaffold demonstrates potential as a material for treating skin wounds., (Copyright © 2018 Elsevier B.V. All rights reserved.)