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Abstract The integration of flexible micro‐ and nanodevices plays a pivotal role in investigating stress‐enhanced performances and underlying intrinsic mechanisms for two‐dimensional materials. This study presents the fabrication of single‐crystal flexible devices using monolayer MoS2 and its catalytic activities for the hydrogen evolution reaction under stress conditions. A metallic conductive layer was deposited on the photoresist surface via magnetron sputtering, overcoming the challenges associated with lithography on insulating substrates using electron beam lithography (EBL). The results demonstrate optimal etch patterns with a metal modification layer thickness of 10.97 nm. Leveraging this flexible device fabrication process, a single‐layer MoS2 single‐nanosheet flexible micro/nano device was developed and subsequently strain‐modulated (stretched along the zigzag lattice direction with the armchair lattice direction as the axis). A significant enhancement is observed in the electrocatalytic hydrogen evolution performance as the strain increases from 0 % to 0.40 %. Notably, the onset overpotential decreased from 155.6 to 95.7 mV, and the Tafel slope decreased from 175.3 to 98.6 mV dec−1. This study provides new insights into the design and performance of strain devices for two‐dimensional (2D) monocrystalline/polycrystalline materials.

Unilateral auditory deprivation (UAD) results in cross-modal reorganization of the auditory cortex (AC), which can impair auditory and cognitive functions and diminish the recovery effect of cochlear implantation. Moreover, the subcortical areas provide extensive ascending projections to the AC. To date, a thorough systematic study of subcortical auditory neural plasticity has not been undertaken. Therefore, this review aims to summarize the current evidence on the bidirectional remodeling of the central auditory system caused by UAD, particularly the changes in subcortical neural plasticity. Lateral changes occur in the cochlear nucleus, lateral superior olive, medial nucleus of the trapezoid body, inferior colliculus, and AC of individuals with UAD. Moreover, asymmetric neural activity becomes less prominent in the higher auditory nuclei, which may be due to cross-projection regulation of the bilateral pathway. As a result, subcortical auditory neural plasticity caused by UAD may contribute to the outcomes of cochlear implantation in patients with single-sided deafness (SSD), and the development of intervention strategies for patients with SSD is crucial. Considering that previous studies have focused predominantly on the neural plasticity of the AC, we believe that bidirectional remodeling of subcortical areas after UAD is also crucial for investigating the mechanisms of interventions.

ObjectivesThe auditory spatial processing abilities mature throughout childhood and degenerate in older adults. This study aimed to compare the differences in onset cortical auditory evoked potentials (CAEPs) and location-evoked acoustic change complex (ACC) responses among children, adults, and the elderly and to investigate the impact of aging and development on ACC responses.DesignOne hundred and seventeen people were recruited in the study, including 57 typically-developed children, 30 adults, and 30 elderlies. The onset-CAEP evoked by white noise and ACC by sequential changes in azimuths were recorded. Latencies and amplitudes as a function of azimuths were analyzed using the analysis of variance, Pearson correlation analysis, and multiple linear regression model.ResultsThe ACC N1’-P2’ amplitudes and latencies in adults, P1’-N1’ amplitudes in children, and N1’ amplitudes and latencies in the elderly were correlated with angles of shifts. The N1’-P2’ and P2’ amplitudes decreased in the elderly compared to adults. In Children, the ACC P1’-N1’ responses gradually differentiated into the P1’-N1’-P2’ complex. Multiple regression analysis showed that N1’-P2’ amplitudes (R2 = 0.33) and P2’ latencies (R2 = 0.18) were the two most variable predictors in adults, while in the elderly, N1’ latencies (R2 = 0.26) explained most variances. Although the amplitudes of onset-CAEP differed at some angles, it could not predict angle changes as effectively as ACC responses.ConclusionThe location-evoked ACC responses varied among children, adults, and the elderly. The N1’-P2’ amplitudes and P2’ latencies in adults and N1’ latencies in the elderly explained most variances of changes in spatial position. The differentiation of the N1’ waveform was observed in children. Further research should be conducted across all age groups, along with behavioral assessments, to confirm the relationship between aging and immaturity in objective ACC responses and poorer subjective spatial performance.SignificanceACCs evoked by location changes were assessed in adults, children, and the elderly to explore the impact of aging and development on these differences.

Abstract Liquid biopsy of cancers, detecting tumor-related information from liquid samples, has attracted wide attentions as an emerging technology. Our previously reported large-area PERFECT (Precise-Efficient-Robust-Flexible-Easy-Controllable-Thin) filter has demonstrated competitive sensitivity in recovering rare tumor cells from clinical samples. However, it is time-consuming and easily biased to manually inspect rare target cells among numerous background cells distributed in a large area (Φ ≥ 13 mm). This puts forward an urgent demand for rapid and bias-free inspection. Hereby, this paper implemented deep learning-based object detection for the inspection of rare tumor cells from large-field images of PERFECT filters with hematoxylin-eosin (HE)-stained cells recovered from bronchoalveolar lavage fluid (BALF). CenterNet, EfficientDet, and YOLOv5 were trained and validated with 240 and 60 image blocks containing tumor and/or background cells, respectively. YOLOv5 was selected as the basic network given the highest mAP@0.5 of 92.1%, compared to those of CenterNet and EfficientDet at 85.2% and 91.6%, respectively. Then, tricks including CIoU loss, image flip, mosaic, HSV augmentation and TTA were applied to enhance the performance of the YOLOv5 network, improving mAP@0.5 to 96.2%. This enhanced YOLOv5 network-based object detection, named as BALFilter Reader, was tested and cross-validated on 24 clinical cases. The overall diagnosis performance (~2 min) with sensitivity@66.7% ± 16.7%, specificity@100.0% ± 0.0% and accuracy@75.0% ± 12.5% was superior to that from two experienced pathologists (10–30 min) with sensitivity@61.1%, specificity@16.7% and accuracy@50.0%, with the histopathological result as the gold standard. The AUC of the BALFilter Reader is 0.84 ± 0.08. Moreover, a customized Web was developed for a user-friendly interface and the promotion of wide applications. The current results revealed that the developed BALFilter Reader is a rapid, bias-free and easily accessible AI-enabled tool to promote the transplantation of the BALFilter technique. This work can easily expand to other cytopathological diagnoses and improve the application value of micro/nanotechnology-based liquid biopsy in the era of intelligent pathology.

Malignant tumors of the biliary tract exhibit a high degree of malignancy and heterogeneity with a poor overall prognosis. Immunotherapy has limited benefits for patients with cholangiocarcinoma. Radiation therapy can change the tumor microenvironment, but its effect heavily depends on radiation dose and fraction. We report a case of advanced intrahepatic cholangiocarcinoma in a 43-year-old male patient, with a huge liver mass of 16.5 cm in diameter, with bone and liver metastases at the first diagnosis. First-line treatment with chemotherapy and PD1 inhibitor was sustained only for 8 months. In second-line treatment, radiotherapy was administered, with 5 Gy in 5 fractions administered to the entire tumor area and 25 Gy in 5 fractions to the solid lesions of the tumor. After the completion of radiotherapy, programmed cell death 1 inhibitor combined with tyrosine kinase inhibitor was maintained. The patient achieved a progression-free-survival time of 12 months and an overall survival time of 25 months. The success of our case suggests that mixed low- and high-dose radiation can significantly improve tumor control and survival time. In clinical practice, based on the characteristics of the tumor and existing treatment options, the rational combination of existing treatment regimens can improve the prognosis of cholangiocarcinoma.

Successful design and execution of slim-hole cementing operations depend on reliable prediction of the annular pressure and the efficiency of mud displacement by cement. A 3D model of the flow inside the casing and in the annulus during mud displacement/cement placement operations was created. The yield-power-law fluid model was used for the rheological behavior of mud, spacers, and cement. Mud displacement was analyzed by splitting the well into multiple sections and analyzing the efficiency of mud removal by spacers and cement, as well as the associated pressure gradients in each section for applicable combinations of pump rate and casing rotation speed. The results from the various computational steps were then integrated to compute the overall pressure and cement placement efficiency during the cementing operation. Using the new 3D model, a field case study was performed for a slim hole casing cementation on an unconventional shale well. The simulated peak surface pressure was only 0.3% lower than the measured data, and the trend of the pressure matched the measured data. This work provides a new tool for the well construction industry to predict and analyze the pressure during complicated cementing operations, thereby enabling safer and more cost-effective operations.

Purpose: To compare the sensitivity of ArcCHECK (AC), portal dosimetry (PD), and an in-house logfile-based system (LF) to multileaf collimators (MLC) aperture errors and the ability to identify these errors. Methods and Materials: For 12 retrospective original head and neck volumetric modulated arc therapy (VMAT) plans, MLC aperture errors of ± 0.4mm, ± 1.2mm, ± 2mm, and ± 3mm were introduced for each plan, resulting in 96 plans with errors. AC, PD, and LF were used for the gamma evaluation at 3%/3mm, 3%/2mm, and 2%/2mm criteria. Gradient analysis was used to evaluate the sensitivity to MLC aperture errors. The area under the curve (AUC) obtained from the receiver operating characteristic (ROC) curve was used to evaluate the ability to identify MLC aperture errors and dose errors, and the optimal cut-off value to identify the error was obtained. Results: The gamma pass rate (%GP) of LF had the smallest descent gradient as the MLC error increases in any case. The descent gradient of PD was larger than AC, except for the case at the 2%/2mm criteria. For the 3%/3mm criteria, the MLC aperture errors that can be perfectly identified by AC, PD, and LF were ± 3mm, ± 2mm, and ± 1.2mm, respectively, and the average percent dose error (%DEs) of dose metrics in targets that can be perfectly identified were 4% to 5%, 3% to 4%, and 2% to 3%, respectively. For the 3%/2mm criteria, the errors that AC, PD, and LF can perfectly identify were the same as the 3%/3mm criteria. For the 2%/2mm criteria, AC can perfectly identify the MLC error of ± 2mm and the %DE of 3% to 4%. PD and LF can identify the MLC error of ± 1.2mm and the %DE of 2% to 3%. Conclusion: Different patient-specific quality assurance (PSQA) systems have different sensitivity and recognition abilities to MLC aperture errors. Institutions should formulate their own customized %GP limits based on their PSQA process through ROC or other methods.

As the important role of enhanced oil recovery (EOR) in meeting the world’s energy requirement is growing, use of nanoparticles in lieu of, or in combination with, the existing EOR agents to expand EOR’s applicable range is receiving significant attention. Two of the most actively investigated applications are: 1) wettability alteration by addition of nanoparticles into the waterflood injection water, and 2) use of nanoparticle-stabilized Pickering foams and emulsions mainly for EOR process mobility control. As comprehensive reviews are recently available on these topics, two other emerging nanoparticle applications are critically reviewed here: 1) nanoparticle addition for enhanced polymer flooding, and 2) use of magnetic nanoparticles for oil displacement control. Three and five proposed mechanisms of these two applications are critically reviewed, respectively. The most recent progresses are covered, and the challenges and possible future works are discussed.

Cholangiocarcinoma (CCA) originates from the epithelium of the bile duct and is highly malignant with a poor prognosis. Radical resection is the only treatment option to completely cure primary CCA. Due to the insidious onset of CCA, most patients are already in an advanced stage at the time of the initial diagnosis and may lose the chance of radical surgery. Radiotherapy is an important method of local treatment, which plays a crucial role in preoperative neoadjuvant therapy, postoperative adjuvant therapy, and palliative treatment of locally advanced lesions. However, there is still no unified and clear recommendation on the timing, delineating the range of target area, and the radiotherapy dose for CCA. This article reviews recent clinical studies on CCA, including the timing of radiotherapy, delineation of the target area, and dose of radiotherapy. Further, we summarize large fraction radiotherapy (stereotactic body radiotherapy [SBRT]; proton therapy) in CCA and the development of immunotherapy and the use of targeted drugs combined with radiotherapy.

Introduction: Previous research has suggested that individuals with different blood groups show varied incidences of noise-induced hearing loss. The reduced otoacoustic emissions amplitudes indicate the higher possibilities of outer hair cell damage for noise exposure. Objective: The objective is to analyze the characteristics of otoacoustic emissions, including the occurrence of spontaneous otoacoustic emission and the amplitudes of distortion product otoacoustic emission at certain frequencies in full term neonates with different ABO blood groups. Methods: A total of 80 selected full-term female neonates who passed the initial newborn hearing screen were enrolled into the study, with equal number of participants in four ABO blood groups (Blood Group A, Blood Group B, Blood Group AB, Blood Group O). Measurements of spontaneous otoacoustic emission and distortion product otoacoustic emission were performed in both ears for all participants. Results: (1) The blood group O participants showed significantly fewer spontaneous otoacoustic emission occurrences than the other three blood groups (A = 70%, B = 80%, AB = 67%, O = 25%, p

By investigating the influence of initial electrons on dosimetric characteristics, reasonable incident electron parameters for the nominal 6 MV photon beam of the XHA600D accelerator are finally established, i.e., a 6 MeV monoenergetic electron beam with a radial intensity FWHM of 2.5 mm and an angular divergency of 0.15°. Based on reasonable initial parameters, Percentage Depth Doses (PDDs), Off-Axis Ratios (OARs), total scatter factors, beam qualities, and penumbra widths of both flatteningfilter (FF) and flattening-filter-free (FFF) beams for fields ranging from 4 × 4 to 30 × 30 cm2 are simulated systematically with EGSnrc codes. Not only the simulated dosimetric properties are in excellent agreement with the measurements, but also the dosimetric discrepancies between FF and FFF beams are consistent with the laws of previous studies on other accelerators. Therefore, reasonable incident electron parameters are able to accurately verify the performance of the XHA600D accelerator and can be used for further dosimetry research.

Bacterial meningitis is a rare event in children with cochlear implants. A 7-year-old child who underwent cochlear implantation (CI) for the right ear 6 years ago was admitted to our hospital with the chief complaint of intermittent fever and headache for 6 months. Cochlear implant infection was suspected. The right cochlear implant removal and middle ear exploration were performed. Postoperatively, the bacterial cultures of cerebrospinal fluid (CSF), cochlear implant and inserting electrodes all suggested Pseudomonas aeruginosa . The body temperature of the child was controlled within 2 weeks after the operation by using meropenem, and other symptoms like headache and abdominal pain disappeared. During 20-month follow-up visit, the child did not suffer any discomforts. In conclusion, we reported a child who developed Pseudomonas aeruginosa meningitis following head injury after CI. This case should serve as a reminder for clinical doctors.

Interaural time difference and interaural level difference signals are insufficient in patients with single-sided deafness (SSD). This insufficiency leads to an absence of sound localization abilities and a decrease in speech intelligibility in noisy environments. SSD occurring in children further affects their language learning and cognitive abilities and their academic performance because they lack spatial abilities and binaural hearing. The early stages of central auditory system development are critical for auditory function development and morphological refinement. SSD occurring in the critical period can cause significant lateralization in the bilateral auditory pathway. This may increase the risk that affected individuals cannot re-establish binaural benefits after rehabilitation of hearing loss in the post-sensitive period. For otorhinolaryngologists, there is the concern that children with congenital SSD cannot benefit from cochlear implantation. Only a few studies have investigated auditory rehabilitation in children with congenital SSD with cochlear implantation and their results were inconsistent. The present review aims to clarify the main problems and challenges of clinical rehabilitation of congenital SSD, particularly focusing on the effect of CI on sound localization ability in children with congenital SSD.

Objective This study was performed to investigate the process of ectopic tooth formation. Methods A patient with an ectopic tooth was followed for 6 years. The tooth size and mineralization were evaluated by paranasal sinus computed tomography every 3 years. Results The ectopic tooth was present in the nasal crest of the maxilla and did not change significantly during the 6-year follow-up period. However, the patient developed a new ectopic tooth in the maxillary sinus (ETm). This tooth, located in the posterior wall of the left maxillary sinus, initially appeared as a small region of soft tissue on computed tomography. After 3 years, the area of mixed density had significantly increased, and some of it had significantly mineralized to form an ETm. After 6 years, the ETm had further mineralized and enlarged in situ. The width between the left and right sides of the ETm in 2018 (9.08 ± 2.09 mm) was significantly larger than that in 2015 (7.51 ± 2.18 mm), indicating that ETm formation is a gradual process of mineralization . Conclusion Ectopic teeth can gradually form by in situ mineralization after adolescence, suggesting that ectopic teeth are genetically regulated and result from a programmed formation process occurring at a specific time point.

Background: Cancer is still a major public health issue worldwide, and new therapeutics with anti-tumor activity are still urgently needed. Methods: The anti-tumor activity of TH-39, which shows potent anti-proliferative activity against K562 cells with an IC50 of 0.78 µM, was investigated using immunoblot, co-immunoprecipitation, the MTT assay, and flow cytometry. Results: Mechanistically, TH-39 may disrupt the interaction between Hec1 and Nek2 in K562 cells. Moreover, TH-39 inhibited cell proliferation in a concentration- and time-dependent manner by influencing the morphology of K562 cells and inducing G0/G1 phase arrest. G0/G1 phase arrest was associated with down-regulation of CDK2-cyclin E complex and CDK4/6-cyclin D complex activities. Furthermore, TH-39 also induced cell apoptosis, which was associated with activation of caspase-3, down-regulation of Bcl-2 expression and up-regulation of Bax. TH-39 could also decrease mitochondrial membrane potential (Δψm) and increase reactive oxygen species (ROS) accumulation in K562 cells. The results indicated that TH-39 might induce apoptosis via the ROS-mitochondrial apoptotic pathway. Conclusion: This study highlights the potential therapeutic efficacy of the anti-cancer compound TH-39 in treatment-resistant chronic myeloid leukemia.

Background: Breast cancer is the leading cause of cancer death among women worldwide and metastasis is the major cause of treatment failure. Thus, new treatment options for breast cancer, especially, drugs which could prevent metastasis, are pressingly needed. Methods: In the present study, we designed and synthesized a novel cinnamide derivative, (E)-N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-3-(3,4,5-trimethoxyphenyl)acrylamide (YLT26), which displayed potent inhibitory effects on breast cancer cells. The cell viability, apoptosis-inducing effect and reactive oxygen species (ROS) production were examined in 4T1 cells following treatment with YLT26. Meanwhile, apoptosis-related proteins levels were determined by western blotting. Finally, we evaluated the effects of YLT26 on breast tumor growth, lung metastases in vivo and the infiltration of myeloid-derived suppressor cells (MDSCs) in lung tissue. Results: Our results showed that the proliferation inhibitory effects of YLT26 were correlated with its apoptosis-inducing effect. Exposure to YLT26 induced mitochondrial transmembrane potential (∆Ψm) change, activated caspase-9, and downregulated the Bcl-2 expression, as well as enhanced ROS accumulation in 4T1 cells. Moreover, YLT26 significantly inhibited tumor growth without obvious side effects in the 4T1 tumor-bearing mice model. Immunohistochemistry analyze revealed YLT26 also induced apoptosis in vivo. More importantly, YLT26 also significantly inhibited lung metastases, which may be associated with the reduction of MDSCs. Conclusion: The present study suggested that YLT26 could inhibit breast cancer cells proliferation via ROS-mitochondrial apoptotic pathway, delay breast tumor progression, and suppress lung metastases by impacting on the immunologic microenvironment in vivo.

Background: Colorectal cancer continues to be one of the most common causes of cancer death, and the poor survival rates and liver metastases at the time of diagnosis urgently need more effective strategy for colorectal cancer treatment. Methods: The activities of N-(5-bromopyridin-2-yl)-2-((6-(2-chloroacetamido)benzo[d]thiazol-2-yl)thio)acetamide (YLT205), which is a novel small molecule compound synthesized by us, were investigated using MTT assay, flow cytometry, western blotting and mice tumor xenograft models. Results: YLT205 induced apoptosis of human colorectal cell lines in a dose-dependent manner. The occurrence of apoptosis was associated with activation of caspases-9 and -3, down-regulation of Bcl-2 and up-regulation of Bax in HCT116 cells. Moreover, YLT205 disrupted mitochondrial membranes and induced the release of cytochrome c into cytosol. Impaired phosphorylation of p44/42 mitogen-activated protein kinase was also observed while the expression of phosphorylated protein kinase B (Akt) was not affected. Furthermore, in HCT116 and SW620 tumor-bearing nude mice models, YLT205 dose-dependently inhibited tumor growth without obvious adverse effects. Immunohistochemistry analyses revealed YLT205 also induced apoptosis and inhibited tumor cell proliferation in vivo. Conclusion: These studies suggested that YLT205 might be a potential drug candidate for human colorectal cancer therapy.

This article models the contact between the drillstring with large slenderness ratio and the extending rigid wellbore based on the multibody dynamics method. The drillstring is modeled as absolute nodal coordinate formulation beams with contact detection points. An algorithm is developed to locate the contact points and calculate the contact forces when the drillstring is sliding and rotating in the wellbore. This provides support force and friction for the moving drillstring and effectively confines it inside the wellbore. A rock penetration model is established based on the rock-breaking velocity equation. The governing equation for the full-hole drilling system including the drillstring and the contact model is established and solved. A rock penetration correction method is proposed to stabilize the computation and to model and simulate the slide drilling process. A field drilling process is modeled and simulated. The simulation result fits the experimental result well.

Breast carcinoma is the most common female cancer with considerable metastatic potential. Discovery of new therapeutic approaches for treatment of metastatic breast cancer is still needed. Here, we reported our finding with niclosamide, an FDA approved anthelmintic drug. The potency of niclosamide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that niclosamide showed a dramatic growth inhibition against breast cancer cell lines and induced apoptosis of 4T1 cells in a dose-dependent manner. Further, Western blot analysis demonstrated the occurrence of its apoptosis was associated with activation of Cleaved caspases-3, down-regulation of Bcl-2, Mcl-1 and Survivin. Moreover, niclosamide blocked breast cancer cells migration and invasion, and the reduction of phosphorylated STAT3(Tyr705), phosphorylated FAK(Tyr925) and phosphorylated Src(Tyr416) were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 20 mg/kg/d niclosamide suppressed 4T1 tumor growth without detectable toxicity. Histological and immunohistochemical analyses revealed a decrease in Ki67-positive cells, VEGF-positive cells and microvessel density (MVD) and an increase in Cleaved caspase-3-positive cells upon niclosamide. Notably, niclosamide reduced the number of myeloid-derived suppressor cells (MDSCs) in tumor tissues and blocked formation of pulmonary metastases. Taken together, these results demonstrated that niclosamide may be a promising candidate for breast cancer.

The inferior colliculus (IC) represents a crucial relay station in the auditory pathway, located in the midbrain's tectum and primarily projecting to the thalamus. Despite the identification of distinct cell classes based on various biomarkers in the IC, their specific contributions to the organization of auditory tectothalamic pathways have remained poorly understood. In this study, we demonstrate that IC neurons expressing parvalbumin (ICPV+) or somatostatin (ICSOM+) represent two minimally overlapping cell classes throughout the three IC subdivisions in mice of both sexes. Strikingly, regardless of their location within the IC, these neurons predominantly project to the primary and secondary auditory thalamic nuclei, respectively. Cell class-specific input tracing suggested that ICPV+ neurons primarily receive auditory inputs, whereas ICSOM+ neurons receive significantly more inputs from the periaqueductal gray and the superior colliculus (SC), which are sensorimotor regions critically involved in innate behaviors. Furthermore, ICPV+ neurons exhibit significant heterogeneity in both intrinsic electrophysiological properties and presynaptic terminal size compared with ICSOM+ neurons. Notably, approximately one-quarter of ICPV+ neurons are inhibitory neurons, whereas all ICSOM+ neurons are excitatory neurons. Collectively, our findings suggest that parvalbumin and somatostatin expression in the IC can serve as biomarkers for two functionally distinct, parallel tectothalamic pathways. This discovery suggests an alternative way to define tectothalamic pathways and highlights the potential usefulness of Cre mice in understanding the multifaceted roles of the IC at the circuit level. [ABSTRACT FROM AUTHOR]