Generation and emission mechanism of polycyclic aromatic hydrocarbon (PAHs) during the coking process in Shanxi, China.

Although coking process is the important source of polycyclic aromatic hydrocarbons (PAHs) in the environment, the generation and emission of PAHs during this process is unclear. It is crucial to clarify the formation mechanism of PAHs in coal pyrolysis during the coking process for effectively identifying and controlling the emission of these organic pollutants. In this study, the combination of laboratory simulation and field sampling was used to analyze the mechanism of PAHs formation and emission in coking process. The release of PAHs from the pyrolysis process of coal blends used in coking plants was 1778.20 ±â€¯111.95 µg · g-1, which was much higher than the content of free PAHs in raw coal (76.50 ±â€¯12.46 µg · g-1). 3-ring PAHs were the most abundant components of free PAHs and pyrolysis-generated PAHs. PAH formation during pyrolysis of coal blends was primarily attributed to the cracking of the macromolecular structure of coal, with minimal influence of free PAHs in blended coal. The emission of PAHs from coal-charging was higher (62.93 ±â€¯17.75 µg · m-3) than that from pushing of coke (11.79 ±â€¯1.91 µg · m-3·, PC) and combustion of coke oven gas (5.53 ±â€¯1.20 µg · m-3, CG), and was mainly related to free PAHs in coal. In contrast, the characteristics of PAHs in the flue gas of PC and CG were similar to those from blended coal pyrolysis. PAHs in fugitive emission from coke oven were primarily affected by flue gas leakage and were mainly related to coal pyrolysis and free PAHs in blended coal.

Pegylated recombinant human granulocyte colony-stimulating factor for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy: a prospective study.

BACKGROUND: This study aimed to investigate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy. METHODS: In this prospective, single-center, single-arm study, we enrolled patients (18-70 years) with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1r-IVA and IVB (distant metastasis only with inguinal lymph node metastasis) cervical cancer. Eligible patients should have normal function of the bone marrow (absolute neutrophil count (ANC) ≥ 2.0 × 109/L) and adequate hepatic and renal functions. Key exclusion criteria included: previous chemotherapy and/or radiotherapy; a history of bone marrow dysplasia or other hematopoietic abnormalities. All patients underwent radical radiotherapy (pelvic radiotherapy or extended-field irradiation) plus brachytherapy. The chemotherapy regimen included four cycles of 3-weekly paclitaxel and cisplatin. PEG-rhG-CSF was administered 48-72 h after each treatment cycle. Salvage granulocyte colony-stimulating factor (G-CSF) was only permitted in certain circumstances. The primary endpoint was the incidence of grade 3-4 neutropenia. The secondary endpoints included frequency of febrile neutropenia (FN), chemotherapy completion rate in cycles 2-4, time to complete radiotherapy, and safety. RESULTS: Overall, 52 patients were enrolled in this study from July 2019 to October 2020. The incidence of grade 3-4 neutropenia was 28.8%, with an average duration of grade 3-4 neutropenia persistence of 3.85 days (1-7 days). The incidence rate of FN was 3.8%. The chemotherapy completion rate was 94.2%, 82.7%, and 75.0% for cycles 2-4, respectively. The incidences of grade 3-4 neutropenia for cycles 1-4 were 9.6% (5/52), 8.2% (4/49), 14.0% (6/43), and 2.6% (1/39), respectively. All patients completed radiotherapy within 8 weeks (median, 48 days; range: 41-56 days), except one patient who withdrew consent and did not receive radiotherapy. Severe non-hematologic toxicity was not observed in any patient. CONCLUSION: PEG-rhG-CSF is an effective and safe prophylactic treatment for neutropenia in patients with cervical cancer undergoing concurrent chemoradiotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024494. Date of Registration:13/July/2019.

Acute hematologic toxicity prediction using dosimetric and radiomics features in patients with cervical cancer: does the treatment regimen matter?

Background: Acute hematologic toxicity (HT) is a prevalent adverse tissue reaction observed in cervical cancer patients undergoing chemoradiotherapy (CRT), which may lead to various negative effects such as compromised therapeutic efficacy and prolonged treatment duration. Accurate prediction of HT occurrence prior to CRT remains challenging. Methods: A discovery dataset comprising 478 continuous cervical cancer patients (140 HT patients) and a validation dataset consisting of 205 patients (52 HT patients) were retrospectively enrolled. Both datasets were categorized into the CRT group and radiotherapy (RT)-alone group based on the treatment regimen, i.e., whether chemotherapy was administered within the focused RT duration. Radiomics features were derived by contouring three regions of interest (ROIs)-bone marrow (BM), femoral head (FH), and clinical target volume (CTV)-on the treatment planning CT images before RT. A comprehensive model combining the radiomics features as well as the demographic, clinical, and dosimetric features was constructed to classify patients exhibiting acute HT symptoms in the CRT group, RT group, and combination group. Furthermore, the time-to-event analysis of the discriminative ROI was performed on all patients with acute HT to understand the HT temporal progression. Results: Among three ROIs, BM exhibited the best performance in classifying acute HT, which was verified across all patient groups in both discovery and validation datasets. Among different patient groups in the discovery dataset, acute HT was more precisely predicted in the CRT group [area under the curve (AUC) = 0.779, 95% CI: 0.657-0.874] than that in the RT-alone (AUC = 0.686, 95% CI: 0.529-0.817) or combination group (AUC = 0.748, 95% CI: 0.655-0.827). The predictive results in the validation dataset similarly coincided with those in the discovery dataset: CRT group (AUC = 0.802, 95% CI: 0.669-0.914), RT-alone group (AUC = 0.737, 95% CI: 0.612-0.862), and combination group (AUC = 0.793, 95% CI: 0.713-0.874). In addition, distinct feature sets were adopted for different patient groups. Moreover, the predicted HT risk of BM was also indicative of the HT temporal progression. Conclusions: HT prediction in cervical patients is dependent on both the treatment regimen and ROI selection, and BM is closely related to the occurrence and progression of HT, especially for CRT patients.

A hemodynamic study of the relationship between the left and right liver volumes and the blood flow distribution in portal vein branches.

BACKGROUND: Cirrhosis patients often exhibit clinical symptoms such as right liver atrophy, portal hypertension, spleen enlargement and increased blood supply, which exhibit considerable variation between the left and right liver sections. These differences are hypothesized to stem from disparities in blood flow within the left and right portal vein (PV) branches. However, rigorous quantitative evidence remains scarce. PURPOSE: We mainly aim at quantitatively revealing the relationship between the blood flow rates of two PV branches and liver volumes, and providing quantitative evidence and theoretical support for the diagnosis and treatment of cirrhosis from the perspective of hemodynamics. METHODS: Five cirrhotic patients and two healthy volunteers from Beijing Friendship Hospital are investigated. Their PV blood flow models are established based on computed tomography (CT) images and finite volume simulations. The volume of the left and right liver lobes are measured in 3-matic. The distributions of blood source in the PV branches are tracked by streamline analysis. The blood flow rates are quantitatively counted by integrating the blood source velocities. Linear analysis is performed to build the relationship between liver volumes and PV blood flow distributions. RESULTS: Streamline analysis reveals significant differences in blood distribution between the left and right PV branches. The majority of blood from the superior mesenteric vein (SMV) flowed into the right portal vein (RPV), while most blood from the splenic vein (SV) entered the left portal vein (LPV). The main PV pressure drop linearly increases with the SV blood velocity for all PV structures of patients and healthy volunteers. The flow rate ratio QRPV/QLPV demonstrates an increase in tandem with the volume ratio VR/VL, exhibiting a linear correlation with the Pearson correlation coefficient being 0.93. CONCLUSION: The differences in the blood distributions are consistent with the clinicians' knowledge and validate our simulations. We demonstrated a linear increase in PV pressure with elevated SV blood velocity. Additionally, the volumes of the left and right hepatic lobes exhibited a positive correlation with blood flow rates in the corresponding PV branches.

Thiol-ene Click Chemistry Synthesis of L-Cysteine-Grafted Graphene Oxide As a New Corrosion Inhibitor for Q235 Steel in Acidic Environment.

l-cysteine, as an eco-friendly and nontoxic corrosion inhibitor, was directly covalently linked to the carbon/carbon double bonds of the GO flakes by a thiol-ene click reaction to avoid decreasing the number of hydrophilic oxygen-containing polar functionalities. The corrosion inhibition performances of Cys-GO toward Q235 steel (QS) in diluted hydrochloric acid were studied by electrochemical methods. The corrosion was a charge transfer-controlled process, and Cys-GO manifested as a mixed-type corrosion inhibitor. The corrosion inhibition efficiency (η) for QS showed a first-increase-and-then-decrease trend with increasing Cys-GO concentrations. The optimum concentration of Cys-GO was 15 mg L-1, and the according η value was up to 90%. The Cys-GO adsorbed on the QS surface to form a protective barrier was responsible for the efficient corrosion inhibition. Langmuir adsorption isotherm model was fitted well with the experiment data, indicating a monolayer adsorption. Furthermore, the coordinate covalent bonds, π-back-donation effect, and electrostatic attraction were responsible for the Cys-GO adsorption on the QS surface.

PEDOT-Integrated Fish Swim Bladders as Conductive Nerve Conduits.

Advanced artificial nerve conduits offer a promising alternative for nerve injury repair. Current research focuses on improving the therapeutic effectiveness of nerve conduits by optimizing scaffold materials and functional components. In this study, a novel poly(3,4-ethylenedioxythiophene) (PEDOT)-integrated fish swim bladder (FSB) is presented as a conductive nerve conduit with ordered topology and electrical stimulation to promote nerve regeneration. PEDOT nanomaterials and adhesive peptides (IKVAV) are successfully incorporated onto the decellularized FSB substrate through pre-coating with polydopamine. The obtained PEDOT/IKVAV-integrated FSB substrate exhibits outstanding mechanical properties, high electrical conductivity, stability, as well as excellent biocompatibility and bioadhesive properties. In vitro studies confirm that the PEDOT/IKVAV-integrated FSB can effectively facilitate the growth and directional extension of pheochromocytoma 12 cells and dorsal root ganglion neurites. In addition, in vivo experiments demonstrate that the proposed PEDOT/IKVAV-integrated FSB conduit can accelerate defective nerve repair and functional restoration. The findings indicate that the FSB-derived conductive nerve conduits with multiple regenerative inducing signals integration provide a conducive milieu for nerve regeneration, exhibiting great potential for repairing long-segment neural defects.

Gut-brain bidirectional determination in regulating the residual feed intake of small-sized meat ducks.

The gut-brain axis is essential in maintaining the homeostasis of neuronal system, endocrine system, and intestinal microbiota in both the afferent and efferent directions. This axis is considered to be a key mechanism that regulates feed efficiency (FE). This study aimed to investigate the regulatory mechanisms of gut-brain axis-related genes on the residual feed intake (RFI) in H-strain small-sized meat ducks. A total of 500 ducks with similar initial BW (635.2 ± 15.1 g) were selected and reared in the same experimental facility until slaughter at 42 d of age. RFI was calculated from the average daily gain (ADG), average daily feed intake (ADFI), and metabolic body weight (MBW0.75). Thirty high-RFI (H-RFI) and 30 low-RFI (L-RFI) birds were selected for further evaluation of growth performance, carcass characteristics, and blood biochemical parameter measurements. Six L-RFI and 6 H-RFI birds were then subjected to hypothalamic transcriptomic and cecal microbial sequencing analyses. Results indicated that L-RFI birds exhibited lower production performance (ADFI, FCR, and RFI) and blood biochemical indices (total cholesterol and ghrelin content) compared with H-RFI birds (P < 0.05). Gene expression differed significantly between the L-RFI and H-RFI birds, with 70 upregulated and 50 downregulated genes. The bacterial communities of L-RFI birds showed higher abundances of Bacteroides, Bifidobacterium, and Lactococcus, and lower abundances of Erysipelatoclostridium, Parasutterella, Fournierella, and Blautia compared with H-RFI birds (P < 0.05). Interactive analysis revealed bacterial communities associated with FE were significantly correlated with hypothalamic genes (P < 0.05), for example, Bacteroides was positively correlated with DGKH and LIPT2, while negatively correlated with CAPN9, GABRD, and PDE1A. Bifidobacterium showed significant correlations with ATP2A3, CALHM6, and TMEM121B. Overall, RFI was a crucial indicator of FE, regulated by interactions between brain gene expression and gut microbiota through cAMP signaling, neuroactive ligand-receptor interaction, and calcium signaling pathways. Notably, increased expression of hypothalamic genes and abundance of carbohydrate-utilization microbiota in L-RFI meat ducks improved FE by enhancing energy metabolism and volatile fatty acids absorption.

Risk Prediction Model for Radiation-induced Dermatitis in Patients with Cervical Carcinoma Undergoing Chemoradiotherapy.

PURPOSE: Radiation-induced dermatitis (RD) is a common side-effect of therapeutic ionizing radiation that can severely affect patient quality of life. This study aimed to develop a risk prediction model for the occurrence of RD in patients with cervical carcinoma undergoing chemoradiotherapy using electronic medical records (EMRs). METHODS: Using EMRs, the clinical data of patients who underwent simultaneous radiotherapy and chemotherapy at a tertiary cancer hospital between 2017 and 2022 were retrospectively collected, and the patients were divided into two groups: a training group and a validation group. A predictive model was constructed to predict the development of RD in patients who underwent concurrent radiotherapy and chemotherapy for cervical cancer. Finally, the model's efficacy was validated using a receiver operating characteristic curve. RESULTS: The incidence of radiation dermatitis was 89.5% (560/626) in the entire cohort, 88.6% (388/438) in the training group, and 91.5% (172/188) in the experimental group. The nomogram was established based on the following factors: age, the days between the beginning and conclusion of radiotherapy, the serum albumin after chemoradiotherapy, the use of single or multiple drugs for concurrent chemotherapy, and the total dose of afterloading radiotherapy. Internal and external verification indicated that the model had good discriminatory ability. Overall, the model achieved an area under the receiver operating characteristic curve of .66. CONCLUSIONS: The risk of RD in patients with cervical carcinoma undergoing chemoradiotherapy is high. A risk prediction model can be developed for RD in cervical carcinoma patients undergoing chemoradiotherapy, based on over 5 years of EMR data from a tertiary cancer hospital.

PTEN and P-4E-BP1 might be associated with postoperative recurrence of rectal cancer patients undergoing concurrent radiochemotherapy.

BACKGROUND: Local recurrence after surgery and radiochemotherapy seriously affects the prognosis of locally advanced rectal cancer (LARC) patients. Studies on molecular markers related to the radiochemotherapy sensitivity of cancers have been widely carried out, which might provide valued information for clinicians to carry out individual treatment. AIM: To find potential biomarkers of tumors for predicting postoperative recurrence. METHODS: In this study, LARC patients undergoing surgery and concurrent radiochemotherapy were enrolled. We focused on clinicopathological factors and PTEN, SIRT1, p-4E-BP1, and pS6 protein expression assessed by immunohistochemistry in 73 rectal cancer patients with local recurrence and 76 patients without local recurrence. RESULTS: The expression of PTEN was higher, while the expression of p-4E-BP1 was lower in patients without local recurrence than in patients with local recurrence. Moreover, TNM stage, lymphatic vessel invasion (LVI), PTEN and p-4E-BP1 might be independent risk factors for local recurrence after LARC surgery combined with concurrent radiochemotherapy. CONCLUSIONS: This study suggests that PTEN and p-4E-BP1 might be potential biomarkers for prognostic prediction and therapeutic targets for LARC.

Application of Recombinant Human Superoxide Dismutase in Radical Concurrent Chemoradiotherapy for Cervical Cancer to Prevent and Treat Radiation-induced Acute Rectal Injury: A Multicenter, Randomized, Open-label, Prospective Trial.

PURPOSE: The purpose of this study was to evaluate the efficacy of recombinant human superoxide dismutase (rhSOD) enemas in radiation-induced acute rectal injury (RARI) in patients with locally advanced cervical cancer. METHODS AND MATERIALS: In this phase 3, randomized, open-label trial (NCT04819685) conducted across 14 medical centers in China from June 2021 to August 2023, all patients received concurrent chemoradiation therapy (CCRT). The experimental group was treated with a rhSOD enema during chemoradiation therapy, and the control group had no enema. The Common Terminology Criteria for Adverse Events (version 5.0) was used to evaluate radiation therapy-induced side effects. Endoscopic appearance was assessed using the Vienna Rectoscopy Score. The primary endpoint in the acute phase was the occurrence rate and duration of grade ≥1 (≥G1) diarrhea during CCRT. Secondary endpoints included the occurrence rate and duration of ≥G2 and ≥G3 diarrhea, ≥G1 and ≥G2 diarrhea lasting at least 3 days, and damage to the rectal mucosa due to radiation therapy measured by endoscopy. RESULTS: Two hundred and eighty-three patients were randomly divided into the experimental (n = 141) or control group (n = 142). The mean number of ≥G1 and ≥G2 diarrhea days were significantly lower in the experimental group than in the control group (3.5 and 0.8 days vs 14.8 and 4.5 days, respectively; P < .001). The incidence of ≥G2 diarrhea decreased from 53.6% to 24.1% when rhSOD enemas were used. Use of antidiarrheals was lower in the experimental group (36.2% vs 55.7%, P < .001). Three patients felt intolerable or abdominal pain after rhSOD enema. RARI grades in the experimental group tended to be lower than those in the control group (P = .061). Logistic regression analysis revealed that rhSOD enema was associated with a lower occurrence rate of ≥G1/2 diarrhea for at least 3 days (P < .001). CONCLUSIONS: The results of this study suggest that rhSOD enema is safe and significantly reduces the incidence, severity, and duration of RARI, protecting the rectal mucosa.

Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease and 5XFAD mice.

Approximately 22% of Alzheimer's disease (AD) patients suffer from seizures, and the co-occurrence of seizures and epileptiform activity exacerbates AD pathology and related cognitive deficits, suggesting that seizures may be a targetable component of AD progression. Given that alterations in neuronal excitatory:inhibitory (E:I) balance occur in epilepsy, we hypothesized that decreased markers of inhibition relative to those of excitation would be present in AD patients. We similarly hypothesized that in 5XFAD mice, the E:I imbalance would progress from an early stage (prodromal) to later symptomatic stages and be further exacerbated by pentylenetetrazol (PTZ) kindling. Post-mortem AD temporal cortical tissues from patients with or without seizure history were examined for changes in several markers of E:I balance, including levels of the inhibitory GABAA receptor, the sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2) and the excitatory NMDA and AMPA type glutamate receptors. We performed patch-clamp electrophysiological recordings from CA1 neurons in hippocampal slices and examined the same markers of E:I balance in prodromal 5XFAD mice. We next examined 5XFAD mice at chronic stages, after PTZ or control protocols, and in response to chronic mTORC1 inhibitor rapamycin, administered following kindled seizures, for markers of E:I balance. We found that AD patients with comorbid seizures had worsened cognitive and functional scores and decreased GABAA receptor subunit expression, as well as increased NKCC1/KCC2 ratios, indicative of depolarizing GABA responses. Patch clamp recordings of prodromal 5XFAD CA1 neurons showed increased intrinsic excitability, along with decreased GABAergic inhibitory transmission and altered glutamatergic neurotransmission, indicating that E:I imbalance may occur in early disease stages. Furthermore, seizure induction in prodromal 5XFAD mice led to later dysregulation of NKCC1/KCC2 and a reduction in GluA2 AMPA glutamate receptor subunit expression, indicative of depolarizing GABA receptors and calcium permeable AMPA receptors. Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced amyloid-ß pathology and cognitive deficits, could also reverse elevations of the NKCC1/KCC2 ratio in these mice. Our data demonstrate novel mechanisms of interaction between AD and epilepsy and indicate that targeting E:I balance, potentially with US Food and Drug Administration-approved mTOR inhibitors, hold therapeutic promise for AD patients with a seizure history.

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock-in mice.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.

Incidence of hyperkalemia in anuric hemodialysis patients treated with sacubitril/valsartan.

INTRODUCTION: Sacubitril/valsartan is increasingly used in hemodialysis patients due to its cardioprotective benefits. However, its impact on serum potassium levels in anuric patients undergoing hemodialysis remains controversial. METHODS: We conducted a retrospective data from patients undergoing hemodialysis at two dialysis centers. A total of 71 out of 332 patients receiving hemodialysis treatment were enrolled. Mean serum potassium (mean value of 6-8 determinations), peak serum potassium (maximum K value observed during follow-up observations), and other biochemical parameters were recorded at baseline and during the follow-up period. FINDINGS: After 6 months of follow-up, mean serum potassium increased from 4.84 ± 0.45 mmol/L at baseline to 5.07 ± 0.46 mmol/L at 3 months and 5.04 ± 0.46 mmol/L at 6 months (p < 0.001). Notably, no significant group differences were found in peak serum potassium concentrations between baseline and 6 months after sacubitril/valsartan therapy (5.69 ± 0.56 vs. 5.75 ± 0.41, p = 0.419). Prior to starting sacubitril/valsartan treatment, none of the patients had severe hyperkalemia; however, after 3 and 6 months of sacubitril/valsartan therapy, two (2.80%) and three (4.20%) patients experienced severe hyperkalemia, respectively; however, this difference was not statistically significant. Additionally, there was a significant reduction in blood pressure; however, serum sodium, bicarbonate, and Kt/V values did not change significantly during either period. DISCUSSION: Sacubitril/valsartan therapy is associated with an increase in serum potassium levels in anuric hemodialysis patients. Nevertheless, the proportion of patients with severe hyperkalemia did not increase significantly. This suggests that the use of sacubitril/valsartan in anuric patients on hemodialysis is relatively safe.

Achieving robust synthetic tolerance in industrial E. coli through negative auto-regulation of a DsrA-Hfq module.

In industrial fermentation processes, microorganisms often encounter acid stress, which significantly impact their productivity. This study focused on the acid-resistant module composed of small RNA (sRNA) DsrA and the sRNA chaperone Hfq. Our previous study had shown that this module improved the cell growth of Escherichia coli MG1655 at low pH, but failed to obtain this desired phenotype in industrial strains. Here, we performed a quantitative analysis of DsrA-Hfq module to determine the optimal expression mode. We then assessed the potential of the CymR-based negative auto-regulation (NAR) circuit for industrial application, under different media, strains and pH levels. Growth assay at pH 4.5 revealed that NAR-05D04H circuit was the best acid-resistant circuit to improve the cell growth of E. coli MG1655. This circuit was robust and worked well in the industrial lysine-producing strain E. coli SCEcL3 at a starting pH of 6.8 and without pH control, resulting in a 250 % increase in lysine titer and comparable biomass in shaking flask fermentation compared to the parent strain. This study showed the practical application of NAR circuit in regulating DsrA-Hfq module, effectively and robustly improving the acid tolerance of industrial strains, which provides a new approach for breeding industrial strains with tolerance phenotype.

Key roles for phosphorylation and the Coiled-coil domain in TRIM56-mediated positive regulation of TLR3-TRIF-dependent innate immunity.

Tripartite-motif protein-56 (TRIM56) positively regulates the induction of type I interferon response via the TLR3 pathway by enhancing IRF3 activation and depends on its C-terminal residues 621-750 for interacting with the adaptor TRIF. However, the precise underlying mechanism and detailed TRIM56 determinants remain unclear. Herein, we show ectopic expression of murine TRIM56 also enhances TLR3-dependent interferon-ß promoter activation, suggesting functional conservation. We found that endogenous TRIM56 and TRIF formed a complex early (0.5-2 h) after poly-I:C stimulation and that TRIM56 overexpression also promoted activation of NF-κB by poly-I:C but not that by TNF-α or IL-1ß, consistent with a specific effect on TRIF prior to the bifurcation of NF-κB and IRF3. Using transient transfection and Tet-regulated cell lines expressing various TRIM56 mutants, we demonstrated the Coiled-coil domain and a segment spanning residues ∼434-610, but not the B-box or residues 355-433, were required for TRIM56 augmentation of TLR3 signaling. Moreover, alanine substitution at each putative phosphorylation site, Ser471, Ser475, and Ser710, abrogated TRIM56 function. Concordantly, mutants bearing Ser471Ala, Ser475Ala, or Ser710Ala, or lacking the Coiled-coil domain, all lost the capacity to enhance poly-I:C-induced establishment of an antiviral state. Furthermore, the Ser710Ala mutation disrupted the TRIM56-TRIF association. Using phospho-specific antibodies, we detected biphasic phosphorylation of TRIM56 at Ser471 and Ser475 following TLR3 stimulation, with the early phase occurring at ∼0.5 to 1 h, prior to IRF3 phosphorylation. Together, these data reveal novel molecular details critical for the TRIM56 augmentation of TLR3-dependent antiviral response and highlight important roles for TRIM56 scaffolding and phosphorylation.

Clinical features and management of germline CEBPA-mutated carriers.

Familial acute myeloid leukemia (AML) pedigrees with germline CCAAT/enhancer-binding protein-α (CEBPA) mutation have been rarely reported due to insufficient knowledge of their clinical features. Here, we report two Chinese families with multiple AML cases carrying germline CEBPA mutations, one of which had 11 cases spanning four consecutive generations. Additionally, we collected clinical data of 57 AML patients from 22 families with germline CEBPA mutations, with 58.3% of them harboring double CEBPA mutations. The first mutation frequently occurred at the N-terminal of CEBP/α (78.6%), resulting in an exclusive expression of p30 of CEBPA (CEBPAp30). The second mutation was mostly found at the C-terminal of CEBP/α (CEBPAothers). Germline CEBPAp30 carriers had higher incidences of AML (80.36% vs. 42.86%) and earlier onset of AML (18 vs. 38.5 years old) compared to germline CEBPAothers carriers. Despite the high rates of relapse, most familial AML cases exhibited favorable overall survival (OS), with germline CEBPAp30 carriers having better survival outcomes (>25 years vs. 11 years for CEBPAothers carriers). Among the 27 healthy germline CEBPA-mutated carriers, we detected a pre-leukemia clone harboring a pathogenic IDH2 variant (R140Q)in one individual. These findings should aid in the genetic counseling and management of AML patients and healthy carriers with germline CEBPA mutations.

Frontostriatal circuit dysfunction leads to cognitive inflexibility in neuroligin-3 R451C knockin mice.

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.

Production of antibodies and antibody fragments containing non-natural amino acids in Escherichia coli.

Therapeutic bioconjugates are emerging as an essential tool to combat human disease. Site-specific conjugation technologies are widely recognized as the optimal approach for producing homogeneous drug products. Non-natural amino acid (nnAA) incorporation allows the introduction of bioconjugation handles at genetically defined locations. Escherichia coli (E. coli) is a facile host for therapeutic nnAA protein synthesis because it can stably replicate plasmids encoding genes for product and nnAA incorporation. Here, we demonstrate that by engineering E. coli to incorporate high levels of nnAAs, it is feasible to produce nnAA-containing antibody fragments and full-length immunoglobulin Gs (IgGs) in the cytoplasm of E. coli. Using high-density fermentation, it was possible to produce both of these types of molecules with site-specifically incorporated nnAAs at titers > 1 g/L. We anticipate this strategy will help simplify the production and manufacture of promising antibody therapeutics.

The Crystallization and Melting Behavior of Neodymium-Based Butadiene Rubber Blends.

This study investigates the influence of poly(butadiene-isoprene) copolymer rubber (BIR) and TDAE oil on the crystallization and melting behavior of neodymium-based butadiene rubber (Nd-BR). The study demonstrates that the melting points of Nd-BR and its blends decrease with lower crystallization temperatures. Below the critical crystallization temperature (Tc,c), the melting behavior shows dual peaks in distinct temperature ranges, which are attributed to different spherulitic sizes. The addition of BIR or TDAE oil lowers the Tc,c, with TDAE oil exerting a more substantial effect. These diluents mainly influence the nucleation temperature and crystallinity level of Nd-BR while having a minimal effect on the crystallization mechanism. A master curve, which overlaps for various samples, is developed by correlating the peak melting temperature (Tm,peak) with the Tc. This curve facilitates a quantitative assessment of the effects of BIR and TDAE oil on Nd-BR, highlighting the greater influence of TDAE oil on the crystalline structure compared with BIR at equivalent mass fractions. By applying the Lorentz equation and multi-peak fitting, a relationship between the melting points and crystallization temperatures is established, enabling the calculation of the equilibrium melting points (Tm0) for different samples. The findings show a reduction in the Tm0 due to the diluents; specifically, the Tm0 is approximately 0 °C for pure Nd-BR, and it decreases to -4.579 °C and -6.579 °C for samples with 50 PHR TDAE oil and 60 wt.% BIR, respectively.

The causal effect and autonomous buffering mechanisms of large-scale internal migration on carbon emissions: evidence from China.

Large-scale internal migration and unprecedented urbanization have dramatically promoted economic growth in China, resulting in a rapid surge in carbon emissions in urban areas. However, few studies have investigated the causal effect of mass internal migration on carbon emissions or examined the effects of autonomous mitigation mechanisms, such as population agglomeration and technological innovation. This study identifies the causal effect of internal migration on prefectural-level cities' carbon emissions in China by employing an instrumental variable and further investigates the buffering effect of population agglomeration and technological innovation using mediating effect models. The results show that mass internal migration has a substantial impact on increasing carbon emissions in prefectural-level cities. If the proportion of inflowed migrants rises by 1% point, prefectural-level cities' carbon emissions per capita will increase by 1.9%. A series of robustness tests confirms the result. Population migration also promotes population agglomeration and technological innovation in urban areas. Two autonomous mechanisms buffer 11.9% and 5.4% of prefectural-level cities' incremental carbon emissions per capita caused by population migration, respectively. This study highlights the crucial role of population agglomeration and technological innovation in mitigating carbon emissions in cities experiencing significant migrant inflows and provides several implications for formulating relevant policies.