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BACKGROUND: The mechanistic effects of gamma transcranial alternating current stimulation (tACS) on hippocampal gamma oscillation activity in Alzheimer's Disease (AD) remains unclear. This study aimed to clarify beneficial effects of gamma tACS on cognitive functioning in AD and to elucidate effects on hippocampal gamma oscillation activity. METHODS: This is a double-blind, randomized controlled single-center trial. Participants with mild AD were randomized to tACS group or sham group, and underwent 30 one-hour sessions of either 40 Hz tACS or sham stimulation over consecutive 15 days. Cognitive functioning, structural magnetic resonance imaging (MRI), and simultaneous electroencephalography-functional MRI (EEG-fMRI) were evaluated at baseline, the end of the intervention and at 3-month follow-up from the randomization. RESULTS: A total of 46 patients were enrolled (23 in the tACS group, 23 in the sham group). There were no group differences in the change of the primary outcome, 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) score after intervention (group*time, p = 0.449). For secondary outcomes, compared to the control group, the intervention group showed significant improvement in MMSE (group*time, p = 0.041) and MoCA scores (non-parametric test, p = 0.025), which were not sustained at 3-month follow-up. We found an enhancement of theta-gamma coupling in the hippocampus, which was positively correlated with improvements of MMSE score and delayed recall. Additionally, fMRI revealed increase of the local neural activity in the hippocampus. CONCLUSION: Effects on the enhancement of theta-gamma coupling and neural activity within the hippocampus suggest mechanistic models for potential therapeutic mechanisms of tACS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03920826; Registration Date: 2019-04-19.

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Owing to the presence of drugs targeting adrenergic receptors in aquatic ecosystems, considerable attention has been directed towards their environmental distribution and fate in recent decades. However, their potential impacts on non-target aquatic organisms, particularly fish, have received relatively limited investigation. In this study, moxisylyte (MOX) and propranolol (PRO) were selected as representatives of α- or ß-adrenergic receptor antagonist, respectively, and we assessed their effects on the early life stages of zebrafish, especially on the nervous and cardiovascular systems. Although both compounds exhibited marginal effects on zebrafish survival, hatching and gross abnormality following exposure to concentrations ranging from 1 to 625 µg/L, they adversely affected the development of cardiovascular and nervous systems, but through different mechanisms of action, as evidenced by variations in gene transcriptional responses and enzyme activities. Notably, cardiovascular responses appear promising for use as potential biomarkers for exposure to drugs targeting adrenergic receptors. This study enhances our understanding of the ecotoxicological risks posed by α- and ß-blockers in fish. Nonetheless, further investigation is needed to elucidate the precise mechanisms underlying the impacts of drugs targeting adrenergic receptors due to our limited knowledge of the physiological functions of the adrenergic system in fish.

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Mountain cultivated ginseng (MCG) is planted in mountain forests to simulate traditional wild ginseng; therefore, it has a greater pharmacological effect than cultivated ginseng (CG) in the garden; however, insufficient evidence confirms this theory. In light of the health-promoting and life-extending properties of ginseng, we analyzed the efficacy of MCG and CG. Initial observations revealed that the phytosterols content of MCG was higher than that of CG, with a positive correlation to the duration of growth. The distinction between phytosterols in MCG and in CG is predominately determined by the stigmasterol content using High-Performance Liquid Chromatography (HPLC). The lifespan of Drosophila melanogaster (fruit flies) that aged naturally was prolonged by phytosterols in MCG and CG and stigmasterols. Further, they prolonged healthy ageing as measured by progeny numbers, length of sleep, climbing distance, and survival following oxidative damage. The findings of behavioral observations revealed that phytosterols in MCG were more efficacious than in CG in promoting health maintenance and life extension; moreover, stigmasterol indicated that these effects were dose-dependent. Stigmasterols, phytosterols in MCG and CG have restored age-associated decreases in steroid hormone levels. Notably, molecular docking was predicted to promote stigmasterol's binding to the steroid hormone receptor ECR due to its similarity to steroid hormones. In addition, stigmasterols triggered the steroid hormone signaling pathway by increasing the activity of key genes Eip75B and Br in 20E signaling and Jhamt, HmGR, Met, and Kr-h1 in JH signaling. Phytosterols, as a natural product, regulated health and longevity as a dietary supplement similar to that of steroids, which supported the social requirements of healthy ageing.

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BACKGROUND: High glucose levels are a primary cause of diabetes-associated cellular dysfunction and tissue damage. Muscles are the key insulin target organ and therefore, have a high level of sensitivity to hyperglycemia. Our previous study revealed that 20(S)-ginsenoside Rg3 (S-Rg3) is a monomer with a good myogenic differentiation effect in ginsenoside. Furthermore, it can alleviate dexamethasone-induced muscle atrophy by protecting mitochondrial function. However, whether S-Rg3 is effective for diabetic-induced muscle atrophy has not been reported. PURPOSE: This study aimed to investigate the protective effect of S-Rg3 on diabetic-induced muscle atrophy. METHODS: C2C12 myoblasts, Drosophila, and mice were used as model systems, and the protective effect of S-Rg3 on diabetes was evaluated by assessing the levels of glucose and lipids. Furthermore, H&E, toluidine blue, Giemsa, and immunofluorescence staining were performed to detect the effects of S-Rg3 on muscle atrophy and myogenic differentiation. Moreover, the effects of S-Rg3 on mitochondrial morphology and function were also evaluated by electron microscopy, flow cytometry, and Seahorse. In addition, the underlying pathways of S-Rg3 effects were detected by Western blot. The related inhibitors and gene mutations in Drosophila were used for validation. RESULTS: The analysis of diabetic mice model fed with a high-fat diet (HFD) and high glucose (HG) revealed that in the injured C2C12 myoblasts, S-Rg3 treatment significantly reduced the levels of triglycerides and glucose. Furthermore, it promoted the differentiation of myoblasts and inhibited mitochondrial dysfunction. In the Drosophila HG and HFD diabetic model, S-Rg3 reduced triglyceride and trehalose levels, increased climbing distance values, promoted myoblasts differentiation, preserved mitochondrial function, and inhibited muscle atrophy. Mechanistically, the beneficial effects of S-Rg3 were at least partially associated with the phosphorylation of AMPK and FoxO3 together with the inhibition of Smad3 phosphorylation, this pathway was validated by the UAS-AMPKα-RNAi Drosophila model. CONCLUSION: In summary, this study revealed mechanistic insights into how S-Rg3 protects against diabetes-associated muscle atrophy in cells, Drosophila, and mice.

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BACKGROUND: Ventriculoperitoneal (VP) shunts are commonly used for managing hydrocephalus, with mechanical dysfunction being the most common cause of complications that require revision. A VP shunt placed using a real-time three-dimensional (3D) robotic C-arm navigation system may have better outcomes and fewer complications. METHODS: In this technical note, we introduced the workflow of the use of the real-time 3D robotic C-arm navigation system for ventriculoperitoneal shunting. CONCLUSION: The real-time 3D robotic C-arm can provide a more precise approach to the target. Furthermore, this technique may lower the risk of complications and increase the success rate of shunt placements.

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Ginseng, a highly esteemed herbal medicine, has been utilized over 5000 years, predominantly in Far Eastern countries. Ginseng is categorized into garden ginseng (GG) and ginseng under forest (FG). However, in contrast to FG, excessive intake of GG may lead to potential adverse effects due to disruption of epithelial cell integrity, and the specific population groups that may be at higher risk. In this work, untargeted metabolomics were used to determine the heterogeneity between GG and FG, the data indicates that the content of Ethyl caffeate, Homoorientin, Citric acid and Quinic acid in GG were higher than in FG. Mass spectrometry imaging showed that ethyl caffeate and Homoorientin were concentrated on the brownish yellow exocarp of the primary root. Our experiments demonstrated that excessive exposure to ethyl caffeate and Homoorientin exacerbated the inflammatory response of HUVECs and reduced the expression of cell junctions. This suggest that the compounds causing adverse effects from excessive intake of GG are mainly concentrated in the yellow exocarp of the primary root of GG. These results suggest that untargeted metabolomics coupled with MALDI-MSI can visualize the spatial distribution of endogenous differential molecules of the same herb in different growth environments or developmental stages.

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Enhanced denitrification has been reported under weak electric fields. However, it is difficult to investigate the mechanism of enhanced denitrification due to the complex interspecific interactions of mixed-culture systems. In this study, Pseudomonas stutzeri, capable of denitrification under anaerobic conditions, was selected for treating low COD/N (2.0, ratio between concentration of chemical oxygen demand and NO3--N) artificial wastewater under constant external voltages of 0.2, 0.4, and 0.6 V. The results revealed that P. stutzeri exhibited the highest efficiency in nitrate reduction at 0.2 V. Moreover, the maximum nitrate removal rate was 15.96 mg/(L·h) among the closed-circuit groups, 19.39% higher than that under the open-circuit group. Additionally, a notable reduction in nitrite accumulation was observed under weak electric fields. Enzyme activity analysis showed that the nitrate reductase activities were significantly increased among the closed-circuit groups, while nitrite reductase activities were inhibited. Transcriptomic analysis indicated that amino acid metabolism, carbohydrate metabolism, and energy metabolism were increased, enhancing the resistance of P. stutzeri to environmental stress and the efficiency of carbon source utilization for denitrification. The current study examined the impacts of weak electric fields on enzyme activities and microbial metabolic pathways and offers valuable insights into the mechanism by which denitrification is enhanced by weak electric fields.

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ETHNOPHARMACOLOGICAL RELEVANCE: Jiedu Tongluo Tiaogan Formula (JTTF), a traditional Chinese herbal decoction, exhibits the potential to treat type 2 diabetes mellitus (T2DM) by inhibiting endoplasmic reticulum stress (ERS) and excessive autophagy, which are the risk factors for the abnormal development and progression of ß cells. AIM OF THE STUDY: We aimed to assess the effect of JTTF on pancreatic glucotoxicity by inhibiting ERS and excessive autophagy, for which db/db mice and INS-1 insulinoma cells were used. MATERIALS AND METHODS: The chemical composition of the JTTF was analyzed by UPLC-Q/TOF-MS. Diabetic (db/db) mice were treated with distilled water or JTTF (2.4 and 7.2 g/kg/day) for 8 weeks. Furthermore, INS-1 cells induced by high glucose (HG) levels were treated with or without JTTF (50, 100, and 200 µg/mL) for 48 h to elucidate the protective mechanism of JTTF on glucose toxicity. The experimental methods included an oral glucose tolerance test, hematoxylin-eosin staining, immunohistochemistry, western blotting, RT-qPCR, and acridine orange staining. RESULT: 28 chemical components of JTTF were identified. Additionally, treatment with JTTF significantly decreased the severity of glycemic symptoms in the db/db mice. Moreover, the treatment partially restored glucose homeostasis in the db/db mice and protected the pancreatic ß-cell function. JTTF protected INS-1 cells from HG injury by upregulating GSIS and PDX1, MafA mRNA expression. Further, treatment with JTTF downregulated GRP78 and ATF6 expression, whereas it inhibited Beclin-1 and LC3 activation. The treatment protected the cells from HG-induced ERS and excessive autophagy by downregulating the CaMKKß/AMPK pathway. CONCLUSIONS: The present study findings show that JTTF may protects ß-cells by inhibiting the CaMKKß/AMPK pathway, which deepens our understanding of the effectiveness of JTTF as a treatment strategy against T2DM.

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Objective: Insulin attaches insulin receptor to activate the PI3-kinase/Akt signaling to maintain glucose homeostasis and inhibit apoptosis. This study determined whether preconditioning with insulin and glucose protects the kidney against ischemia-reperfusion injury (IRI). Methods: Kidney IRI was performed in C57BL/6 mice by clamping the renal vessels for 30 min, followed by reperfusion for 24 h. A total subcutaneous 0.1 unit of insulin along with 10% glucose in drinking water was treated on the mice for 24 h before kidney IRI. The kidney function and injuries were investigated through the determination of BUN and Cr in blood plasma, as well as the apoptosis and the expression of P-AKT, BAX, and caspase-3 in the kidneys. The role of P-AKT in insulin-treated IRI kidneys was tested using an AKT inhibitor. The effects of the preconditional duration of insulin and glucose on IRI kidneys were investigated by expanding the treatment duration to 1, 3, and 6 days. Results: Preconditioning with insulin and glucose protected the kidney against IRI as manifested by a decrease in creatinine and BUN and a reduction of kidney tubular injury. The protection effect was mediated by P-AKT-BAX-caspase-3 signaling pathway resulting in suppression of apoptotic cell death. An AKT inhibitor partially reversed the protective effects of preconditional insulin. The preconditional duration for 1, 3, and 6 days had no differences in improving kidney functions and pathology. Conclusion: A short-term preconditioning with insulin and glucose protected the kidney from IRI through the activation of p-AKT and subsequent reduction of BAX-caspase-3-induced apoptosis. The short-term precondition provides a practicable strategy for protecting the kidney against predictable IRI, such as kidney transplant and major surgical operations with high risk of hypotension.

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Objective: This study aimed to estimate the effects of the volume of preperitoneal balloon (PPB) on arterial and venous hemorrhage in a swine pelvic fracture model. Methods: Twenty-four swine were randomized into 0-mL, 500-mL, 800-mL, and 1000-mL intra-hematoma PPB groups. They were subjected to open-book pelvic fracture and reproducible injuries in the external iliac artery and vein. The pelvic binder and IH-PPBs with different volumes of fluid were applied to control the active hemorrhage after arterial and venous injuries. The survival time and rate during 60-min observation and digital subtraction angiography (DSA) images were the primary endpoints in this study. Secondary endpoints included survival rate within 70 min, peritoneal pressure, hemodynamics, blood loss, infusion fluid, blood pH, and lactate concentration. Results: Our results indicated that the 800-mL and 1000-mL groups had a higher survival rate (0%, 50%, 100% and 100% for 0, 500, 800, and 1000-mL groups respectively; p < 0.0001) and longer survival time (13.83 ± 2.64, 24.50 ± 6.29, 55.00 ± 6.33, and 60.00 ± 0.00 min for 0, 500, 800, and 1,000 groups respectively; p < 0.0005) than the 0-mL or 500-mL groups during the 60 min observation. Contrastingly, survival rate and time were comparable between 800-mL and 1000-mL groups during the 60-min observation. The IH-PPB volume was associated with an increase in the pressure of the balloon and the preperitoneal pressure but had no effect on the bladder pressure. Lastly, the 1000-mL group had a higher mean arterial pressure and systemic vascular resistance than the 800-mL group. Conclusion: IH-PPB volume-dependently controls vascular bleeding after pelvic fracture in the swine model. IH-PPB with a volume of 800 mL and 1000 mL efficiently managed pelvic fracture-associated arterial and venous hemorrhage and enhanced survival time and rate in the swine model without evidences of visceral injury.

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The incidence of chronic wound healing is promoted by the growing trend of elderly population, obesity, and type II diabetes. Although numerous wound dressings have been studied over the years, it is still challenging for many wound dressings to perfectly adapt to the healing process due to the dynamic and complicated wound microenvironment. Aiming at an optimal reproduction of the physiological environment, multifunctional electrospinning nanofibrous membranes (ENMs) have emerged as a promising platform for the wound treatment owing to their resemblance to extracellular matrix (ECM), adjustable preparation processes, porousness, and good conformability to the wound site. Moreover, profiting from the booming development of human-machine interaction and artificial intelligence, a next generation of intelligent electrospinning nanofibrous membranes (iENMs) based wound dressing substrates that could realize the real-time monitoring of wound proceeding and individual-based wound therapy has evoked a surge of interest. In this regard, general wound-related biomarkers and process are overviewed firstly and representative iENMs stimuli-responsive materials are briefly summarized. Subsequently, the emergent applications of iENMs for the wound healing are highlighted. Finally, the opportunities and challenges for the development of next-generation iENMs as well as translating iENMs into clinical practice are evaluated.

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The incidence of allergic reactions has risen steadily in recent years, prompting growing interest in the identification of efficacious and safe natural compounds that can prevent or treat allergic diseases. Phellodendron amurense Rupr. has long been applied as a treatment for allergic diseases, whose primary component is phellodendrine. However, the efficacy of phellodendrine as a treatment for allergic diseases remains to be assessed. Mast cells are the primary effectors of allergic reactions, which are not only activated by IgE-dependent pathway, but also by IgE-independent pathways via human MRGPRX2, rat counterpart MRGPRB3. As such, this study explored the effect and mechanism of phellodendrine through this family receptors in treating allergic diseases in vitro and in vivo. These analyses revealed that phellodendrine administration was sufficient to protect against C48/80-induced foot swelling and Evans blue exudation in mice, and suppressed C48/80-induced RBL-2H3 rat basophilic leukemia cells degranulation, and ß-HEX, HIS, IL-4, and TNF-α release. Moreover, phellodendrine could reduce the mRNA expression of MRGPRB3 and responsiveness of MRGPRX2 by altering its structure. It was able to decrease Ca2+ levels, phosphorylation levels of CaMK, PLCß1, PKC, ERK, JNK, p38, and p65, and inhibit the degradation of IκB-α. These analyses indicate that berberine inhibits the activation of PLC and downregulates the release of Ca2+ in the endoplasmic reticulum by altering the conformation of MRGPRB3/MRGPRX2 protein, thereby inhibiting the activation of PKC and subsequently inhibiting downstream MAPK and NF-κB signaling, ultimately suppressing allergic reactions. There may thus be further value in studies focused on developing phellodendrine as a novel anti-allergic drug.

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Microenvironments, such as student dormitories, differ from general residential environments. They are characterized by small spaces, poor air circulation, high personnel densities, and electronic products, such as computers that are turned on for extended periods, leading to increased pollution concentrations. The limited space and poor air circulation reduce migration of contaminants, such as polybrominated diphenyl ethers (PBDEs), making it easier for PBDEs to accumulate. However, few studies have been conducted on small group dwellings, including student dormitory dwellings. We collected dust samples from student dormitories of a university to analyze the characteristics and traceability of PBDEs in dormitory microenvironments. The results showed that PBDE congeners were widely present in university dormitories and the order of median concentration of ∑10PBDEs was as follows: male old-fashioned dormitory (273 ng/g) > female four-person dormitory (132 ng/g) > female two-person dormitory (132 ng/g) > male two-person dormitory (96.2 ng/g) > female old-fashioned dormitory (91.6 ng/g) > male four-person apartment (51.8 ng/g). BDE-209 was the most abundant PBDE congener, followed by BDE-47, and BDE-28. PBDEs were also found in typical electrical appliances, with higher concentrations in laptops than in desktops, and higher concentrations in desktops than in idle ones. According to Spearman correlation and Principal Component Analysis (PCA), we also found that boards and wallpaper materials were common sources of contamination in the microenvironment of student dormitories, and that female dormitories had more sources of PBDE emissions. Human exposure to PBDEs in students is below the US Environmental Protection Agency reference dose. Although exposure to PBDEs generated in dormitories does not pose a significant health risk, the potential hazards of PBDEs to the reagent environment remain to be investigated.

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Cancer and diabetes are significant diseases that pose a threat to human health. Their interconnection is complex, particularly when they coexist, often necessitating multiple therapeutic approaches to attain remission. Sodium-glucose cotransporter protein two inhibitors (SGLT-2i) emerged as a treatment for hyperglycemia, but subsequently exhibited noteworthy extra-glycemic properties, such as being registered for the treatment of heart failure and chronic kidney disease, especially with co-existing albuminuria, prompting its assessment as a potential treatment for various non-metabolic diseases. Considering its overall tolerability and established use in diabetes management, SGLT-2i may be a promising candidate for cancer therapy and as a supplementary component to conventional treatments. This narrative review aimed to examine the potential roles and mechanisms of SGLT-2i in the management of diverse types of cancer. Future investigations should focus on elucidating the antitumor efficacy of individual SGLT-2i in different cancer types and exploring the underlying mechanisms. Additionally, clinical trials to evaluate the safety and feasibility of incorporating SGLT-2i into the treatment regimen of specific cancer patients and determining appropriate dosage combinations with established antitumor agents would be of significant interest.

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Pesticide additives (PAs) are auxiliary ingredients added to the pesticide manufacturing and use processes, constituting 1% to 99% of the pesticide and often composed of benzene and chlorinated hydrocarbons. We selected three typical PAs, toluene, chloroform, and trichloroethylene, to evaluate their retention function toxicity and ecological risk in soil. Soil immobilization techniques and aquatic model organisms were used to demonstrate the effectiveness of the immobilized soil method to determine the ecological risk of chemicals. The 48-h median lethal concentrations of toluene, chloroform, and trichloroethylene alone in spiked soil on Daphnia magna were 10.5, 2.3, and 1.1 mg/L (medium, high, and high toxicity, respectively). The toxicity of the three-PA mixtures showed an antagonistic effect. The risk levels of toluene, chloroform, and trichloroethylene in the soil were evaluated as moderate to high, low to high, and high risk, respectively. The toxicity of two pesticide-contaminated sites in the Yangtze River Delta before and after remediation was successfully evaluated by immobilized soil technology. The toxicity of two soil sampling points was reduced from medium toxic to low toxic and no toxic, respectively, after remediation. The results of our study give a rationale for and prove the validity of the aquatic model organisms and soil immobilization techniques in assessing the soil retention functions toxicity of PAs. Environ Toxicol Chem 2024;43:1677-1689. © 2024 SETAC.

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Background: Patients with age-related hearing loss (ARHL) often struggle with tracking and locating sound sources, but the neural signature associated with these impairments remains unclear. Materials and methods: Using a passive listening task with stimuli from five different horizontal directions in functional magnetic resonance imaging, we defined functional regions of interest (ROIs) of the auditory "where" pathway based on the data of previous literatures and young normal hearing listeners (n = 20). Then, we investigated associations of the demographic, cognitive, and behavioral features of sound localization with task-based activation and connectivity of the ROIs in ARHL patients (n = 22). Results: We found that the increased high-level region activation, such as the premotor cortex and inferior parietal lobule, was associated with increased localization accuracy and cognitive function. Moreover, increased connectivity between the left planum temporale and left superior frontal gyrus was associated with increased localization accuracy in ARHL. Increased connectivity between right primary auditory cortex and right middle temporal gyrus, right premotor cortex and left anterior cingulate cortex, and right planum temporale and left lingual gyrus in ARHL was associated with decreased localization accuracy. Among the ARHL patients, the task-dependent brain activation and connectivity of certain ROIs were associated with education, hearing loss duration, and cognitive function. Conclusion: Consistent with the sensory deprivation hypothesis, in ARHL, sound source identification, which requires advanced processing in the high-level cortex, is impaired, whereas the right-left discrimination, which relies on the primary sensory cortex, is compensated with a tendency to recruit more resources concerning cognition and attention to the auditory sensory cortex. Overall, this study expanded our understanding of the neural mechanisms contributing to sound localization deficits associated with ARHL and may serve as a potential imaging biomarker for investigating and predicting anomalous sound localization.

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In this work, the electro-coalescence process of three nanodroplets under a constant DC electric field is investigated via molecular dynamics simulations (MD), aiming to explore the electric manipulation of multiple droplets coalescence on the molecular level. The symmetrical and asymmetrical dynamic evolutions of electrocoalescence process can be observed. Our MD simulations show that there are two types of critical electric fields to induce the special dynamics. The chain configuration can be formed, when one of the critical electric field is exceeded, referred to as Ecc. On the other hand, there is another critical electric field to change the coalescence pattern from complete coalescence to partial coalescence, the so-called Ecn. Finally, we find that the use of the pulsed DC electric field can overcome the drawbacks of the constant DC electric field in the crude oil industry, and the mechanisms behind the suppressed effect of the water chain or non-coalescence are further revealed.

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To understand the prevalence of rhinovirus (RV) among acute respiratory infection (ARI) patients, 10-year ARI surveillance in multiple provinces of China were conducted during 2012-2021. Of 15 645 ARI patients, 1180 (7.54%) were confirmed to have RV infection and 820 (69.49%) were children under 5 years of age. RV typing was performed on the 527 VP1 gene sequences, and species A, B, and C accounted for 73.24%, 4.93%, and 21.82%, respectively. Although no significant difference in the proportions of age groups or disease severity was found between RV species, RV-C was more frequently detected in children under 5 years of age, RV-A was more frequently detected in elderly individuals (≥60), and the proportions of pneumonia in RV-A and RV-C patients were higher than those in RV-B patients. The epidemic peak of RV-A was earlier than that of RV-C. A total of 57 types of RV-A, 13 types of RV-B, and 35 types of RV-C were identified in RV-infected patients, and two uncertain RV types were also detected. The findings showed a few differences in epidemiological and clinical features between RV species in ARI patients, and RV-A and RV-C were more prevalent than RV-B.

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Failure of oocyte activation, including polyspermy and defects in pronuclear (PN) formation, triggers early embryonic developmental arrest. Many studies have shown that phospholipase C zeta 1 ( PLCZ1 ) mutations cause failure of PN formation following intracytoplasmic sperm injection (ICSI); however, whether PLCZ1 mutation is associated with polyspermy during in vitro fertilization (IVF) remains unknown. Whole-exome sequencing (WES) was performed to identify candidate mutations in couples with primary infertility. Sanger sequencing was used to validate the mutations. Multiple PLCZ1 -mutated sperm were injected into human and mouse oocytes to explore whether PN formation was induced. Assisted oocyte activation (AOA) after ICSI was performed to overcome the failure of oocyte activation. We identified three PLCZ1 mutations in three patients who experienced polyspermy during IVF cycles, including a novel missense mutation c.1154C>T, p.R385Q. PN formation failure was observed during the ICSI cycle. However, injection of multiple PLCZ1- mutated sperm induced PN formation, suggesting that the Ca 2+ oscillations induced by the sperm exceeded the necessary threshold for PN formation. AOA after ICSI enabled normal fertilization, and all patients achieved successful pregnancies. These findings expand the mutational spectrum of PLCZ1 and suggest an important role for PLCZ1 in terms of blocking polyspermy. Furthermore, this study may benefit genetic diagnoses in cases of abnormal fertilization and provide potential appropriate therapeutic measures for these patients with sperm-derived polyspermy.

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The world is rich in coalbed methane (CBM) resources and has broad exploration and development prospects. In this paper, first, the technical difficulties of drilling and completion in deep shale formations in the Sichuan and Chongqing region is systematically summarized. Second, a systematic evaluation was conducted on the optimization of temperature resistance performance and trajectory control technology of the rotary guidance system. Third, evaluation and economic analysis were conducted on the experimental effects of different technologies. Results show that: (a) the optimization technology for temperature resistance performance of integrated high-temperature resistant guide head and surface cooling equipment has been formed, which can effectively reduce the circulation cooling time and improve drilling efficiency. (b) Real time measurement of underground engineering parameters and monitoring and evaluation of wellbore cleanliness can reduce drilling risks, while achieving quantitative evaluation of drilling fluid gas content. (c) Assisted by real-time optimization technology of mechanical drilling speed based on underground surface engineering parameters, the acceleration effect has been significantly improved.