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Background Purpose Methods Results Conclusions Determining the optimal energy layer (EL) for each field, under considering both dose constraints and delivery efficiency, is crucial to promoting the development of proton arc therapy (PAT) technology.This study aimed to explore the feasibility and potential clinical benefits of utilizing machine learning (ML) technique to automatically select EL for each field in PAT plans of lung cancer.Proton Bragg peak position (BPP) was employed to characterize EL. The ground truth BPPs for each field were determined using the modified ELO‐SPAT framework. Features in geometric, water‐equivalent thicknesses (WET) and beamlet were defined and extracted. By analyzing the relationship between the extracted features and ground truth, a polynomial regression model with L2‐norm regularization (Ridge regression) was constructed and trained. The performance of the regression model was reported as an error between the predictions and the ground truth. Besides, the predictions were used to make PAT plans (PAT_PRED). These plans were compared with those using the ground truth BPPs (PAT_TRUTH) and the mid‐WET of the target volumes (PAT_MID) in terms of relative biological effectiveness‐weighted dose (RWD) distributions. One hundred ten patients with lung cancer, a total of 7920 samples, were enrolled retrospectively, with 5940 cases randomly selected as the training set and the remaining 1980 cases as the testing set. Nine patients (648 samples) were collected additionally to evaluate the regression model in terms of plan quality and robustness.With regard to the prediction errors, the root mean squared errors and mean absolute errors between the ML‐predicted and ground truth BPPs for the testing set were 9.165 and 6.572 mm, respectively, indicating differences of approximately two to three ELs. As for plan quality, the PAT_TRUTH and PAT_PRED plans performed similarly in terms of plan robustness, target coverage and organs at risk (OARs) protection, with differences smaller than 0.5 Gy(RBE). This trend was also observed for dose conformity and uniformity. The PAT_MID plans produced the lowest robustness index and lowest doses to OARs, along with the highest heterogeneity index, indicating better protection for OARs, improved plan robustness, but compromised dose homogeneity. Additionally, for relatively small tumor sizes, the PAT_MID plan demonstrated a notably poor dose conformity index.Within this cohort under investigation, our study demonstrated the feasibility of using ML technique to predict ELs for each field, offering a fast (within 2 s) and memory‐efficient reduced way to select ELs for PAT plan. [ABSTRACT FROM AUTHOR]

Stable machining process state is critical to product quality. However, existing method for monitoring the cutting process state cannot manifest the actual machining situation accurately because it only focuses on a single abnormality while ignoring the simultaneous occurrence of different abnormal states. Aiming at the three typical anomalies and multi-factor anomalies commonly observed in machining, a multi-delay ordinal pattern (OP) (MDOP) image feature based on OP analysis and a complex machining state recognition method based on dictionary template matching are proposed. First, an OP method is developed to extract the inherent wave pattern of monitoring signal under specific parameters. Second, the MDOP image features based on multi-parameters are established to optimize the parameter selection process and enrich the state information. With strong anti-noise and easy data processing, the MDOP method can obtain rich processing state information from the perspective of visual knowledge. Third, an image matching method based on multi-template and a machining state recognition method based on maximum template matching degree are proposed. Finally, a machining experiment that included eight states was designed to verify the effectiveness of the method. Result shows that the proposed method can identify different cutting states accurately, and the multi-source signals can improve the accuracy of the model further. Compared with other methods, the MDOP method has evident advantages. [ABSTRACT FROM AUTHOR]

Remote image semantic segmentation technology is one of the core research elements in the field of computer vision and has a wide range of applications in production life. Most remote image semantic segmentation methods are based on CNN. Recently, Transformer provided a view of long-distance dependencies in images. In this paper, we propose RCCT-ASPPNet, which includes the dual-encoder structure of Residual Multiscale Channel Cross-Fusion with Transformer (RCCT) and Atrous Spatial Pyramid Pooling (ASPP). RCCT uses Transformer to cross fuse global multiscale semantic information; the residual structure is then used to connect the inputs and outputs. ASPP based on CNN extracts contextual information of high-level semantics from different perspectives and uses Convolutional Block Attention Module (CBAM) to extract spatial and channel information, which will further improve the model segmentation ability. The experimental results show that the mIoU of our method is 94.14% and 61.30% on the datasets Farmland and AeroScapes, respectively, and that the mPA is 97.12% and 84.36%, respectively, both outperforming DeepLabV3+ and UCTransNet. [ABSTRACT FROM AUTHOR]

• Pipeline elbow made of 304L stainless steel at a natural gas receiving station suffered a perforation failure after 6 years of service. • Standard failure analysis methods such as physical and chemical properties are used to analyze the root cause of failure. • The thinning of elbow wall and perforation failure are mainly caused by high pressure erosion. During the daily inspection process at a natural gas receiving station, ice was found to be present at the elbow of the pipeline, with a fog emerging from the elbow itself. This elbow was suspected of leaking. After investigation, it was found that the outer arc side of the elbow contained perforations resulting in the leaking of combustible gas. In this work, the causes for failure of such a low-temperature 304L stainless steel pipe elbow are analyzed and discussed. Macromorphological analysis, nondestructive testing analysis, chemical composition analysis, Charpy impact test, hardness test and microstructural analysis were performed to determine the root cause of the failure. The field investigation shows that the perforated failure pipe section is located downstream of the flow-limiting orifice plate, and that the pipe medium can contain small particles. Macroscopic observation reveals that the perforation defect is located at 3 points on the outer arc side, and the defect takes the shape of a bowl, with a perforation aperture diameter of approximately 0.7 mm. Microscopic observation reveals that the defective area has a honeycomb shape with tiny spheres on the surface, with many slip lines observed in the metallographic structure near the defect, indicating that the small deformation was caused by a large impact load. Based on the evidence of failure, the formation of the perforation defect is attributed to the excessive flow rate generated by the high pressure difference between the front and back sides of the single-stage orifice plate, which leads to the intensification of erosion. Moreover, when combined with the actual situation, it is found that the fine solid particles mixed in the medium can aggravate the thinning of the pipe wall section. [ABSTRACT FROM AUTHOR]

Glucagon‐like peptide‐1 (GLP‐1) is best known for its insulinotropic action following food intake. Its metabolite, GLP‐1 (9‐36), was assumed biologically inactive because of low GLP‐1 receptor (GLP‐1R) affinity and non‐insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP‐1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP‐1 (9‐36)'s biological role. We use human SH‐SY5Y neuroblastoma cells and a GLP‐1R over‐expressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP‐1 (9‐36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP‐1 (9‐36)'s signaling pathways, including cyclic‐adenosine monophosphate (cAMP), protein kinase‐A (PKA), and 5' adenosine monophosphate‐activated protein kinase (AMPK) via the use of ELISA, pharmacological inhibitors, or GLP‐1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti‐inflammatory effects of GLP‐1 (9‐36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP‐1 (9‐36) to primary dissociation cultures challenged with α‐synuclein or amyloid‐β and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP‐1R, cAMP, PKA, and AMPK‐mediated neurotrophic and neuroprotective effects of GLP‐1 (9‐36). The metabolite significantly reduced IL‐6 and TNF‐α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP‐1 (9‐36) in primary neuron cultures challenged with α‐synuclein or amyloid‐β. These studies enhance understanding of GLP‐1 (9‐36)'s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts. [ABSTRACT FROM AUTHOR]

Hot-point drills have been widely used for drilling boreholes in glaciers, ice caps and ice sheets. A hot-point drill melts ice through the thermal head at its bottom end. Penetration occurs through a close-contact melting (CCM) process, in which the ice is melted, and the meltwater is squeezed out by the exerted force applied on the thermal head. During the drilling, a thin water film is formed to separate the thermal head from the surrounding ice. For the hot-point drill, the rate of penetration (ROP) is influenced by several variables, such as thermal head shape, buoyancy corrected force (BCF), thermal head power (or temperature) and ice temperature. In this study, we developed a model to describe the CCM process, where a constant power or temperature on the working surface of a thermal head is assumed. The model was developed using COMSOL Multiphysics 5.3a software to evaluate the effects of different variables on the CCM process. It was discovered that the effect of thermal head shape and the cone angle of conical thermal head on ROP is less significant, whereas the increase in the BCF and the power (or temperature) of the thermal head can continuously enhance the ROP. [ABSTRACT FROM AUTHOR]

The temperature at the Antarctic Ice Sheet bed and the temperature gradient in subglacial rocks have been directly measured only a few times, although extensive thermodynamic modeling has been used to estimate the geothermal heat flux (GHF) under the ice sheet. During the last 5 decades, deep ice-core drilling projects at six sites – Byrd, WAIS Divide, Dome C, Kohnen, Dome F, and Vostok – have succeeded in reaching or nearly reaching the bed at inland locations in Antarctica. When temperature profiles in these boreholes and steady-state heat flow modeling are combined with estimates of vertical velocity, the heat flow at the ice-sheet base is translated to a geothermal heat flux of 57.9 ± 6.4 mW m -2 at Dome C, 78.9 ± 5.0 mW m -2 at Dome F, and 86.9 ± 16.6 mW m -2 at Kohnen, all higher than the predicted values at these sites. This warm base under the East Antarctic Ice Sheet (EAIS) could be caused by radiogenic heat effects or hydrothermal circulation not accounted for by the models. The GHF at the base of the ice sheet at Vostok has a negative value of - 3.6 ± 5.3 mW m -2 , indicating that water from Lake Vostok is freezing onto the ice-sheet base. Correlation analyses between modeled and measured depth–age scales at the EAIS sites indicate that all of them can be adequately approximated by a steady-state model. Horizontal velocities and their variation over ice-age cycles are much greater for the West Antarctic Ice Sheet than for the interior EAIS sites; a steady-state model cannot precisely describe the temperature distribution here. Even if the correlation factors for the best fitting age–depth curve are only moderate for the West Antarctic sites, the GHF values estimated here of 88.4 ± 7.6 mW m -2 at Byrd and 113.3 ± 16.9 mW m -2 at WAIS Divide can be used as references before more precise estimates are made on the subject. [ABSTRACT FROM AUTHOR]

Antarctic subglacial lakes are often considered suitable analogues to extraterrestrial subglacial aqueous environments. Recently, an environmentally friendly RECoverable Autonomous Sonde (RECAS) was designed at the Polar Research Center of Jilin University (JLU) to sample the water of subglacial lakes without contamination. In this regard, the development of a fast-penetration thermal head is the key issue for RECAS. Two different prototypes were designed and tested at the JLU ice-well to determine the optimal design and operation parameters of the thermal heads. Practical top and bottom thermal heads were then designed based on one of the prototypes, which can penetrate ice at an average rate of 1.88 m/h. The test results for the RECAS thermal heads show that the rate of penetration (ROP) can be 1.80–1.95 m/h in −10°C ice, and the axial load on the thermal head only affects the ROP when it is lower than a specified threshold. The decrease of the ice temperature from −10°C to −30°C leads to a decrease of 17% in the ROP. The bottom thermal head can drill into dirty ice, and a simple collector positioned above the head can collect solid particles suspended in the melted ice. The top thermal head exhibited a long lifetime and stable heating performance after being powered in water for 2 weeks. In addition, the ice temperature near the borehole was monitored to evaluate the range of heat disturbance caused by the thermal head. [ABSTRACT FROM AUTHOR]

The successful cryopreservation of organs is a strong and widespread demand around the world but faces great challenges. The mechanisms of cold tolerance of organisms in nature inspirit researchers to find new solutions for these challenges. Especially, the thermal, mechanical, biological and biophysical changes during the regulation of freezing tolerance process should be studied and coordinated to improve the cryopreservation technique and quality of complex organs. Here the cold tolerance of the Japanese carpenter ants, Camponotus japonicus Mayr, was greatly improved by using optimal protocols and feeding on L-proline-augmented diets for 5 days. When cooling to −27.66 °C, the survival rate of frozen ants increased from 37.50% ± 1.73% to 83.88% ± 3.67%. Profiling of metabolites identified the concentration of whole-body L-proline of ants increased from 1.78 to 4.64 ng g−1 after 5-day feeding. High L-proline level, together with a low rate of osmotically active water and osmotically inactive water facilitated the prevention of cryoinjury. More importantly, gene analysis showed that the expression of ribosome genes was significantly up-regulated and played an important role in manipulating freezing tolerance. To the best of our knowledge, this is the first study to link genetic variation to the enhancement of ants' cold tolerance by feeding exogenous cryoprotective compound. It is worth noting that the findings provide the theoretical and technical foundation for the cryopreservation of more complex tissues, organs, and living organisms. [ABSTRACT FROM AUTHOR]

• A novel early warning method based on improved MSET and CCPR is proposed. • HDB construction method is proposed for dynamic deviation calculation. • The dynamic MM is constructed by clustering center and weight vector of MSET. • An anomaly detection method based on eight control chart patterns is proposed. • The validity of the proposed method is verified by two kinds of different data. Prompt fault early warning is a significant approach to improve the reliability of mechanical equipment. An abnormal state recognition method based on improved multivariate state estimation technology (MSET) and control chart pattern recognition (CCPR) is proposed. First, the health data band (HDB) of equipment is established through a k-nearest neighbor algorithm. Meanwhile, a dynamic memory matrix construction approach based on a clustering algorithm is presented to improve the calculation efficiency of MSET. The CCPR is integrated to reduce limitations such as artificial interference in the traditional threshold method of fault early warning. The proposed method is applied into two cases of rolling bearing and control moment gyro so as to compare its performance with other MSET modeling methods. According to the results, the proposed method can detect equipment abnormalities hours to weeks in advance, and significantly reduce the false alarm rate and calculation time. [ABSTRACT FROM AUTHOR]

Abstract Electrically heated hot points are widely used for drilling in glaciers and ice sheets. To study the effect of input power, axial load, ice temperature, shape, and material of the thermal tip on the hot-point rate of penetration (ROP), a 0.8-m-long drill with 18 changeable thermal tips was designed. The ROP increased with input power for all the thermal tips. Seven tip shapes (cylinder, cosine, ogive, sphere, catenary, parabola, and cone) were tested at the same power level, axial load, and ice temperature, and they exhibited the same ice contact area. The 60° cone-shaped tip demonstrated the highest ROP. The horizontal ring and longitude grooves on the surface of the thermal tips did not improve the drilling performance. The ROP decreased linearly with decreasing ice temperature. Increases in the axial load resulted in increase in the ROP only within the limited range (<20 N or < 8.2 kPa). The ROP of the thermal tip made of copper was more than twice that of the aluminum thermal tip of the same shape. All tested tips were also modeled for temperature distribution inside the thermal tips, and the temperature and heat flux distribution along the outside operating surface of the tips. Highlights • 18 changeable thermal tips were tested for drilling in ice. • The 60° cone-shaped tip demonstrated the highest rate of penetration. • The input power was the primary influence on the efficiency of thermal drilling. [ABSTRACT FROM AUTHOR]

Abstract Traumatic brain injury (TBI) is a neurodegenerative disorder for which no effective pharmacological treatment is available. Glucagon-like peptide 1 (GLP-1) analogues such as Exenatide have previously demonstrated neurotrophic and neuroprotective effects in cellular and animal models of TBI. However, chronic or repeated administration was needed for efficacy. In this study, the pharmacokinetics and efficacy of PT302, a clinically available sustained-release Exenatide formulation (SR-Exenatide) were evaluated in a concussive mild (m)TBI mouse model. A single subcutaneous (s.c.) injection of PT302 (0.6, 0.12, and 0.024 mg/kg) was administered and plasma Exenatide concentrations were time-dependently measured over 3 weeks. An initial rapid regulated release of Exenatide in plasma was followed by a secondary phase of sustained-release in a dose-dependent manner. Short- and longer-term (7 and 30 day) cognitive impairments (visual and spatial deficits) induced by weight drop mTBI were mitigated by a single post-injury treatment with Exenatide delivered by s.c. injection of PT302 in clinically translatable doses. Immunohistochemical evaluation of neuronal cell death and inflammatory markers, likewise, cross-validated the neurotrophic and neuroprotective effects of SR-Exenatide in this mouse mTBI model. Exenatide central nervous system concentrations were 1.5% to 2.0% of concomitant plasma levels under steady-state conditions. These data demonstrate a positive beneficial action of PT302 in mTBI. This convenient single, sustained-release dosing regimen also has application for other neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple system atrophy and multiple sclerosis where prior preclinical studies, likewise, have demonstrated positive Exenatide actions. Highlights • PT302 is a sustained-release formulation of Exenatide that generates steady-state plasma levels. • PT302 post-treatment mitigates neuronal loss induced by mild TBI in mice. • PT302 post-treatment mitigates neuroinflammation induced by mild TBI in mice. • PT302 post-treatment mitigates behavioral impairments induced by mild TBI in mice. • All the above was achieved at clinically translatable doses of PT302. [ABSTRACT FROM AUTHOR]

The optimal linear estimation problems are investigated in this paper for a class of discrete linear systems with fading measurements and correlated noises. Firstly, the fading measurements occur in a random way where the fading probabilities are regulated by probability mass functions in a given interval. Furthermore, time-delay exists in the system state and observation simultaneously. Additionally, the multiplicative noises are considered to describe the uncertainty of the state. Based on the projection theory, the linear minimum variance optimal linear estimators, including filter, predictor, and smoother are presented in the paper. Compared with conventional state augmentation, the new algorithm is finite-dimensionally computable and does not increase computational and storage load when the delay is large. A numerical example is provided to illustrate the effectiveness of the proposed algorithms. [ABSTRACT FROM AUTHOR]

Lead-cooled Fast Reactor (LFR) has been chosen as one of the six Generation-IV reactor concept candidates due to its high performance in neutronics, thermal hydraulics and inherent safety features. Passive residual heat removal system (PRHRS) is a passive system that guarantees the residual heat removal of LFR even in the hypothetical beyond-design basis conditions. Based on a 1000 MW th lead-bismuth cooled fast reactor, the design and performance analysis of PRHRS were conducted using RELAP5 code. First, a PRHRS removing heat by Independent Heat EXchanger (IHEX) was designed, which utilizes natural circulation, gravity field and has the characteristics of high reliability and inherent safety. Secondly, the lead-bismuth heat transfer model was developed and verified based on RELAP5/MOD 4.0 code, as the heat transfer model of Pressurized Water Reactor (PWR) is not suitable for the lead-bismuth heat transfer calculation. The RELAP5 model of LFR was established and verified by comparison with design parameters. The PRHRS performance was investigated under Loss of Power (LOP) transient to assess the feasibility of the PRHRS design. The results demonstrated that the heat removal rate of the PRHRS removing heat by IHEX exceeded the core decay rate at about 5 h. The cladding peak temperature of the PRHRS reached 562 °C, which was below the limit (750 °C). Therefore, the PRHRS removing heat by IHEX has the capability to remove the LFR residual heat and has the characteristics of high performance and inherent safety, which can be used as an independent residual heat removal system for commercial LFR. The work provides reference for the design and performance analysis of LFR PRHRS in the future. [ABSTRACT FROM AUTHOR]

Multiple‐spiro/fused‐heterocyclic frameworks containing indazolone are structurally unique and represent a class of potentially dominant skeletons. In this work, we successfully fulfilled Rh(III)‐catalyst mediated substrate‐ and pH‐ controlled strategies to construct four novel types of complicated penta‐spiro/fused‐heterocyclic frameworks via C−H activation/[4+1] and [4+2] annulation cascades. This method had mild reaction conditions, a broad scope of substrates, moderate to good yields, and valuable applications, which could realize for the first time the generation of the novel di‐spiro‐heterocyclic and multiple fused‐heterocyclic products with unique structures. More importantly, novel spiro[cyclohexane‐indazolo[1,2‐a]indazole] scaffold constructed by this method exhibited potent antitumor activity against a variety of refractory solid tumors and hematological malignancies in vitro. Overall, our work provided new insights into the construction of complex and diverse multiple spiro/fused‐heterocyclic systems and offered novel valuable lead compounds for the discovery of antitumor drugs. [ABSTRACT FROM AUTHOR]

Proglucagon-derived peptides, especially glucagon-like peptide-1 (GLP-1) and its long-acting mimetics, have exhibited neuroprotective effects in animal models of stroke. Several of these peptides are in clinical trials for stroke. Oxyntomodulin (OXM) is a proglucagon-derived peptide that co-activates the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR). The neuroprotective action of OXM, however, has not been thoroughly investigated. In this study, the neuroprotective effect of OXM was first examined in human neuroblastoma (SH-SY5Y) cells and rat primary cortical neurons. GLP-1R and GCGR antagonists, and inhibitors of various signaling pathways were used in cell culture to characterize the mechanisms of action of OXM. To evaluate translation in vivo, OXM-mediated neuroprotection was assessed in a 60-min, transient middle cerebral artery occlusion (MCAo) rat model of stroke. We found that OXM dose- and time-dependently increased cell viability and protected cells from glutamate toxicity and oxidative stress. These neuroprotective actions of OXM were mainly mediated through the GLP-1R. OXM induced intracellular cAMP production and activated cAMP-response element-binding protein (CREB). Furthermore, inhibition of the PKA and MAPK pathways, but not inhibition of the PI3K pathway, significantly attenuated the OXM neuroprotective actions. Intracerebroventricular administration of OXM significantly reduced cerebral infarct size and improved locomotor activities in MCAo stroke rats. Therefore, we conclude that OXM is neuroprotective against ischemic brain injury. The mechanisms of action involve induction of intracellular cAMP, activation of PKA and MAPK pathways and phosphorylation of CREB. [ABSTRACT FROM AUTHOR]

The fast-increasing demand for high-performance carbon conductive paints has motivated the use of inexpensive precursors and easy-to-manufacture methods to scale up production. The performance of carbon conductive paints highly depends on the precursor types, carbonization conditions and the coordination between carbon pigment and binder. This work investigated the effect of precursors (by-products of coking industry including coal tar pitch, anthracene oil, naphthalene oil, and washing oil) on the structure and properties of carbon pigment, as well as the influences of binders polyvinylidene fluoride (PVDF), styrene-butadiene emulsion, and acrylic emulsion on the electrothermal properties and adhesion of carbon paint coating. The conductive pigment prepared from coal pitch has nano-sheet structure, high sp2 content, large sp2 cluster size and high disordered structure, resulting high carrier concentration and mobility, and low volume resistivity. The carbon conductive coating fabricated from coal pitch-based pigment and PVDF (PC-PVDF) has good electrothermal properties, excellent stability, low volume resistivity, good adhesion and corrosion resistance. The electrical conductivity of carbon-PVDF composites prepared from coal tar pitch, anthracene oil, naphthalene oil, and washing oil as precursors were 15.7, 3.0, 4.4, and 4.0 S/m, respectively. Coal pitch-derived conductive pigment-PVDF carbon coating exhibits excellent Joule heating performance, i.e., up to 147 °C at 20 V when heating at 122 °C/min, uniform temperature distribution, and excellent reusability. This work demonstrates the potential application of coal pitch-based pigment-PVDF coating for Joule heating. [Display omitted] • The effects of precursor and binder types on the properties of conductive coating were investigated. • Coal pitch-based conductive pigment has nano-sheet structure, high sp2 content, large sp2 cluster size. • PVDF is an ideal binder for highly conductive coal tar-based carbon pigments. • Coal pitch-based conductive coating has good electrothermal properties, excellent stability, and good adhesion and corrosion resistance. [ABSTRACT FROM AUTHOR]

Under the single-mode approximate, we theoretically investigate the properties of entanglement for four-mode Fermi GHZ state when some observers are in uniform acceleration with respective to others. We use two different definitions for calculating the degree of entanglement, i.e., the arithmetic and geometric average of tangles. It is shown that a maximally entangled state in an inertial frame shall become one with less entanglement in noninertial frame and the partial and the whole entanglements decrease as the number of accelerated observers. In particular, for 1–3 accelerated observers, there is still entanglement in the limit of infinite acceleration for all tangles. However, the sudden death shall be present for both the whole and the part one only when four observers are accelerated. In addition, we make a comparison for these two definitions of entanglement. It is interesting to notice that, for three accelerated observers, the difference first increases and then decreases as the increasing parameter r . [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), a brain dysfunction for which there is no present effective treatment, is often caused by a concussive impact to the head and affects an estimated 1.7 million Americans annually. Our laboratory previously demonstrated that exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of TBI. Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pre-treatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced Read the Editorial Highlight neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro. The cAMP/PKA/pCREB pathway appears to play an important role in this neuroprotective activity of liraglutide. Furthermore, our findings in cell culture were welltranslated in a weight drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI when evaluated 7 and 30 days post trauma. These data crossvalidate former studies of exendin-4 and suggest that liraglutide holds therapeutic potential for the treatment of mTBI. [ABSTRACT FROM AUTHOR]

Air-vented ion chambers are generally used in radiation therapy dosimetry to determine the absorbed radiation dose with superior precision. However, in ion chamber detector arrays, the number of array elements and their spacing do not provide sufficient spatial sampling, which can be overcome by interpolating measured data. Herein, we investigated the potential principle of the linear interpolation algorithm in volumetric dose reconstruction based on computed tomography images in the volumetric modulated arc therapy (VMAT) technique and evaluated how the ion chamber spacing and anatomical mass density affect the accuracy of interpolating new data points. Plane measurement doses on 83 VMAT treatment plans at different anatomical sites were acquired using Octavius 729, Octavius1500, and MatriXX ion chamber detector arrays, followed by the linear interpolation to reconstruct volumetric doses. Dosimetric differences in planning target volumes (PTVs) and organs at risk (OARs) between treatment planning system and reconstruction were evaluated by dose volume histogram metrics. The average percentage dose deviations in the mean dose (Dmean) of PTVs reconstructed by 729 and 1500 arrays ranged from 4.7 to 7.3% and from 1.5 to 2.3%, while the maximum dose (Dmax) counterparts ranged from 2.3 to 5.5% and from 1.6 to 7.6%, respectively. The average percentage dose/volume deviations of mixed PTVs and OARs in the abdomen/gastric and pelvic sites were 7.6%, 3.5%, and 7.2%, while mediastinum and lung plans showed slightly larger values of 8.7%, 5.1%, and 8.9% for 729, 1500, and MatriXX detector arrays, respectively. Our findings indicated that the smaller the spacing between neighbouring detectors and the more ion chambers present, the smaller the error in interpolating new data points. Anatomical regions with small local mass density inhomogeneity were associated with superior dose reconstruction. Given a large mass density difference in the various human anatomical structures and the characteristics of the linear interpolation algorithm, we suggest that an alternative data interpolation method should be used in radiotherapy dosimetry. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a wound healing response triggered by liver injury. In severe cases, it may develop into liver cirrhosis, liver cancer and liver failure. Long non-coding RNAs (lncRNAs) play key roles in the development of liver fibrosis. The present study aimed to investigate the role of lncRNA-MBI-52 (lnc-MBI-52) in the progression of liver fibrosis. Carbon tetrachloride (CCl4)-induced injury was performed to establish a mouse liver fibrosis model, and exogenous transforming growth factor-β1 was used to establish a hepatic stellate cell (HSC) activation model. Reverse transcription-quantitative PCR and western blot analyses were performed to detect mRNA and protein expression, respectively. RNA pull-down assay was performed to assess the interaction between microRNA (miR)-466g and lnc-MBI-52 or SMAD4. Dual-luciferase reporter assay was performed to verify the target of miR-466g. lnc-MBI-52 was overexpressed in CCl4-induced mouse liver fibrosis models and activated HSCs. lnc-MBI-52 knockdown suppressed liver fibrosis in vitro. Moreover, knockdown of lnc-MBI-52 downregulated α-smooth muscle actin and collagen type I expression. In addition, lnc-MBI-52 and SMAD4 were identified as targets of miR-466g. The effects of lnc-MBI-52 on HSC activation were reversed following transfection with miR-466g mimics or SMAD4 knockdown. lnc-MBI-52 miR-466g significantly decreased lnc-MBI-52 expression, while overexpression of lnc-MBI-52 suppressed miR-466g expression. The results of the RNA pull-down assay confirmed the interaction between miR-466g and lnc-MBI-52. Taken together, lnc-MBI-52 induced liver fibrosis by regulating the miR-466g/SMAD4 axis, which may provide a new possible strategy for liver fibrosis. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1), facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4) is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells) and in vivo (SOD1 G93A mutant mice) models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT) activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R) stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 113, 1621–1631. Increasing evidence suggests that glucagon-like peptide-1 (GLP-1), an incretin hormone of current interest in type 2 diabetes, is neuroprotective in both cell culture and animal models. To characterize the neuroprotective properties of GLP-1 and associated underlying mechanisms, we over-expressed the GLP-1 receptor (GLP-1R) on human neuroblastoma SH-SY5Y cells to generate a neuronal culture system featuring enhanced GLP-1R signaling. In GLP-1R over-expressing SH-SY5Y (SH-hGLP-1R#9) cells, GLP-1 and the long-acting agonist exendin-4 stimulated cell proliferation and increased cell viability by 2-fold at 24 h at physiologically relevant concentrations. This GLP-1R-dependent action was mediated via the protein kinase A and phosphoinositide 3-kinase signaling pathways, with the MAPK pathway playing a minor role. GLP-1 and exendin-4 pretreatment dose-dependently protected SH-hGLP-1R#9 cells from hydrogen peroxide (H2O2)- and 6-hydroxydopamine-induced cell death. This involved amelioration of elevated caspase 3 activity, down-regulation of pro-apoptotic Bax and up-regulation of anti-apoptotic Bcl-2 protein. In the presence of 6-hydroxydopamine, GLP-1’s ability to lower caspse-3 activity was abolished with the phosphoinositide 3-kinase inhibitor, LY2940002, and partly reduced with the protein kinase A inhibitor, H89. Hence, GLP-1R mediated neurotrophic and anti-apoptotic actions co-contribute to the neuroprotective property of GLP-1 in neuronal cell cultures, and reinforce the potential therapeutic value of GLP-1R agonists in neurodegenerative disorders involving oxidative stress. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) regulates energy intake, gastrointestinal motility, and nutrient disposal. The relative importance of the islet beta-cell for GLP-1 actions remains unclear. We determined the role of the islet beta-cell and the pancreatic duodenal homeobox-1 (Pdx1) transcription factor for GLP-1 receptor (GLP-1R)-dependent actions through analysis of mice with beta-cell-specific inactivation of the Pdx1 gene (beta-cell(Pdx1-/-) mice). The GLP-1R agonist exendin-4 (Ex-4) reduced glycemic excursion following intraperitoneal (i.p.) glucose challenge in control littermates (beta-cell(Pdx1+/+) mice) but not in beta-cell(Pdx1-/-) mice. Similarly, Ex-4 failed to increase levels of plasma insulin, pancreatic insulin content, and pancreatic insulin mRNA transcripts in beta-cell(Pdx1-/-) mice. Furthermore, Ex-4 significantly increased beta-cell proliferation and reduced beta-cell apoptosis in beta-cell(Pdx1+/+) mice but not in beta-cell(Pdx1-/-) mice. Moreover, Ex-4 increased the levels of insulin and amylin mRNA transcripts and augmented glucose-stimulated insulin secretion in islets from beta-cell(Pdx1+/+) mice but not in beta-cell(Pdx1-/-) islets. Surprisingly, Ex-4 failed to reduce levels of plasma glucagon in beta-cell(Pdx1-/-) mice. These findings demonstrate that Pdx1 expression is essential for integrating GLP-1R-dependent signals regulating alpha-cell glucagon secretion and for the growth, differentiated function, and survival of islet beta-cells. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) regulates energy intake, gastrointestinal motility, and nutrient disposal. The relative importance of the islet β-cell for GLP-1 actions remains unclear. We determined the role of the islet β-cell and the pancreatic duodenal homeobox-1 (Pdx1) transcription factor for GLP-1 receptor (GLP-1R)-dependent actions through analysis of mice with β-cell-specific inactivation of the Pdx1 gene (β-cellPdx-/- mice). The GLP-1R agonist exendin-4 (Ex-4) reduced glycemic excursion following intraperitoneal (i.p.) glucose challenge in control littermates (β-cell[sup Pdx1+/+] mice) but not in β-cellPdx1-/- mice. Similarly, Ex-4 failed to increase levels of plasma insulin, pancreatic insulin content, and pancreatic insulin mRNA transcripts in β-cellPdx1-/- mice. Furthermore, Ex-4 significantly increased β-cell proliferation and reduced β-cell apoptosis in β-cellPdx1+/+ mice but not in β-cell[Pdx1-/- mice. Moreover, Ex-4 increased the levels of insulin and amylin mRNA transcripts and augmented glucose-stimulated insulin secretion in islets from β-cellPdx1+/+ mice but not in β-cellPdx1-/- islets. Surprisingly, Ex-4 failed to reduce levels of plasma glucagon in β-cellPdx1-/- mice. These findings demonstrate that Pdx1 expression is essential for integrating GLP-1R-dependent signals regulating α-cell glucagon secretion and for the growth, differentiated function, and survival of islet β-cells. Diabetes 54:482-491, 2005 [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) receptor agonist-based drugs (incretin mimetics) have meaningfully impacted current treatment of type 2 diabetes mellitus (T2DM), and their actions on satiety and weight loss have led to their use as an obesity medication. With multiple pleotropic actions beyond their insulinotropic and weight loss ones, including anti-inflammatory and anti-insulin-resistant effects selectively mediated by their receptors present within numerous organs, this drug class offers potential efficacy for an increasing number of systemic and neurological disorders whose current treatment is inadequate. Among these are a host of neurodegenerative disorders that are prevalent in the elderly, such as Parkinson's and Alzheimer's disease, which have bucked previous therapeutic approaches. An increasing preclinical, clinical, and epidemiological literature suggests that select incretin mimetics may provide an effective treatment strategy, but 'which ones' for 'which disorders' and 'when' remain key open questions. • GLP-1 receptor agonists (RA) have become widely prescribed drugs (type 2 diabetes/weight loss). • GLP-1RA repurposing is being clinically evaluated in neurodegenerative disorders of the elderly. • Clinical trials of GLP-RAs are promising in Parkinson's disease – Alzheimer studies are ongoing. • GLP-1RAs with action on GIP and other receptors are available and may offer greater benefit. • Selection of the best GLP-1RAs, most likely patients to respond and best time to treat is critical. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to compare the different internal fixations between elastic stable intramedullary nailing and Kirschner wires in treatment of angulated radial neck fractures. Methods: We retrospectively reviewed the patients with radial neck fracture without associated injuries who underwent surgery approach in our department during April 2011–March 2020. There were 62 patients meeting all the criteria with complete clinical data, with median age of 7.5 (IQR 5.8–9.5) years, 34 males and 28 females. The preoperative fracture pattern was assessed according to the Judet classification system. Depending on the materials implanted and fixation strategy, the patients could be divided into a Kirschner wire group and an elastic stable intramedullary nailing group. Final functional outcomes of patients were assessed by the Mayo Elbow Performance Score and Tibone–Stoltz functional evaluation classification. Results: The Kirschner wire group included 37 patients, with 4.8 years median follow-up. The elastic stable intramedullary nailing group included 25 patients with 5.9 years median follow-up. There were no significant differences in gender, age, Judet classification, average operative time, Mayo Elbow Performance Score, Tibone–Stoltz classification, or length of hospital stay between groups. However, the time to union in the Kirschner wire group was significantly shorter than that in the elastic stable intramedullary nailing group (p < 0.05). Both groups achieved satisfactory functional and cosmetic results. Conclusion: In the management of pediatric radial neck fractures, both elastic stable intramedullary nailing and Kirschner wire internal fixation have shown equivalent therapeutic results, leading to satisfactory functional outcomes. The selection of the internal fixation approach can be influenced by the patient's fracture characteristics and the surgeon's preferences. Level of evidence: Level III; Retrospective Comparison; Treatment Study. [ABSTRACT FROM AUTHOR]

Background: Molasses is a wildly used feedstock for fermentation, but it also poses a severe wastewater-disposal problem worldwide. Recently, the wastewater from yeast molasses fermentation is being processed into fulvic acid (FA) powder as a fertilizer for crops, but it consequently induces a problem of soil acidification after being directly applied into soil. In this study, the low-cost FA powder was bioconverted into a value-added product of γ-PGA by a glutamate-independent producer of Bacillus velezensis GJ11. Results: FA power could partially substitute the high-cost substrates such as sodium glutamate and citrate sodium for producing γ-PGA. With FA powder in the fermentation medium, the amount of sodium glutamate and citrate sodium used for producing γ-PGA were both decreased around one-third. Moreover, FA powder could completely substitute Mg2+, Mn2+, Ca2+, and Fe3+ in the fermentation medium for producing γ-PGA. In the optimized medium with FA powder, the γ-PGA was produced at 42.55 g/L with a productivity of 1.15 g/(L·h), while only 2.87 g/L was produced in the medium without FA powder. Hydrolyzed γ-PGA could trigger induced systemic resistance (ISR), e.g., H2O2 accumulation and callose deposition, against the pathogen's infection in plants. Further investigations found that the ISR triggered by γ-PGA hydrolysates was dependent on the ethylene (ET) signaling and nonexpressor of pathogenesis-related proteins 1 (NPR1). Conclusions: To our knowledge, this is the first report to use the industry waste, FA powder, as a sustainable substrate for microbial synthesis of γ-PGA. This bioprocess can not only develop a new way to use FA powder as a cheap feedstock for producing γ-PGA, but also help to reduce pollution from the wastewater of yeast molasses fermentation. [ABSTRACT FROM AUTHOR]

As a useful equipment for ice sheet exploration, many Philberth thermal probe designs have been proposed for use on Earth or extraterrestrial planets. The classic method for calculating the power consumption of a Philberth thermal probe can be modified by assuming a reasonable thermal head efficiency. The influence of various parameters on the critical refreezing length and the power consumption of the thermal head and lateral heater are evaluated using the improved method. The power consumption of the thermal probe increases as the diameter, length, and penetration rate increase and decreases as the ice temperature increases. The efficiency of the thermal head has no influence on the total power consumption of the thermal probe. There exists an optimal diameter and efficiency of thermal head. While drilling an ice sheet, the power consumption of the lateral heater reduces gradually, and thus, moving the excess power of the lateral heater to the thermal head is a good method of increasing the penetration rate. Moreover, it is also suggested that the maximum working voltage of the thermal head should be as high as possible, and the lateral body of the thermal probe should be heated in sections. • The method for calculating power consumption of Phiberth thermal probe is improved. • Influence of various parameters on power consumption is evaluated. • Optimal diameter and thermal-head efficiency can be determined. • An optimal operation strategy of thermal probe during drilling is suggested. [ABSTRACT FROM AUTHOR]

A synthetic monomeric peptide triple receptor agonist, termed "Triagonist" that incorporates glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) actions, was previously developed to improve upon metabolic and glucose regulatory benefits of single and dual receptor agonists in rodent models of diet-induced obesity and type 2 diabetes. In the current study, the neurotrophic and neuroprotective actions of this Triagonist were probed in cellular and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in both the young and elderly. Triagonist dose- and time-dependently elevated cyclic AMP levels in cultured human SH-SY5Y neuronal cells, and induced neurotrophic and neuroprotective actions, mitigating oxidative stress and glutamate excitotoxicity. These actions were inhibited only by the co-administration of antagonists for all three receptor types, indicating the balanced co-involvement of GLP-1, GIP and Gcg receptors. To evaluate physiological relevance, a clinically translatable dose of Triagonist was administered subcutaneously, once daily for 7 days, to mice following a 30 g weight drop close head injury. Triagonist fully mitigated mTBI-induced visual and spatial memory deficits, evaluated at 7 and 30 days post injury. These results establish Triagonist as a novel neurotrophic/protective agent worthy of further evaluation as a TBI treatment strategy. Unlabelled Image • The GLP-1, GIP, Gcg Triagonist is neurotrophic in neuronal SH-SY5Y cultures. • Triagonist is neuroprotective against oxidative stress and glutamate excitotoxicity. • Triagonist neurotrophic/protective actions are balanced across receptors. • Triagonist reduces microglial cell inflammation. • Triagonist mitigates mild TBI-induced visual and spatial memory impairments. [ABSTRACT FROM AUTHOR]

The time-dependent (30 min - day 84) plasma profile of PT320, a sustained-release (SR)-Exenatide formulation under clinical development for treatment of neurodegenerative disorders, was evaluated in nonhuman primates after a single subcutaneous dose and was compared to Bydureon. Exenatide release from PT320 exhibited a triphasic pharmacokinetic profile. An initial peak occurred at 3 hr post-administration, a secondary peak at 5 days, and achievement of Exenatide steady-state plasma levels from day 10–28. Systemic exposure increased across PT320 doses, and Exenatide levels were maintained above the therapeutic threshold prior to achieving a steady-state. In contrast, Exenatide release from Bydureon exhibited a biphasic profile, with an initial plasma peak at 3 hr, followed by a rapid decline to a sub-therapeutic concentration, and a gradual elevation to provide a steady-state from day 35–49. Exenatide total exposure, evaluated from the area under the time-dependent Exenatide concentration curve, was similar for equivalent doses of PT320 and Bydureon. The former, however, reached and maintained steady-state plasma Exenatide levels more rapidly, without dipping to a sub-therapeutic concentration. Both SR-Exenatide formulations proved well-tolerated and, following a well-regulated initial release burst, generated steady-state plasma levels of Exenatide, but with PT320 producing continuous therapeutic Exenatide levels and more rapidly reaching a steady-state. [ABSTRACT FROM AUTHOR]

The spiroindolenine framework is a privileged heterocyclic motif and is widely present in numerous indole alkaloids. Herein, we develop a metal-free and environmentally friendly approach for the intramolecular cascade cyclization and dearomatization of indole derivatives to selectively afford iodinated and vinylic spiroindolenines by a substrate-controlled strategy. Simple operation, mild conditions, and high yield make this strategy a green and attractive pathway to construct functionalizable spiroindolenine scaffolds, which could be converted into diverse useful spiroindolenine derivatives. [ABSTRACT FROM AUTHOR]

Purpose: The primary aim of our study was to evaluate the comparative efficacy and safety profile of curettage and mixed bone grafting without instrument or with elastic intramedullary nailing in the treatment of humeral bone cyst in children. Methods: Our retrospective study included a total of 48 children harboring humeral bone cyst in our hospital from August 2012 to February 2019. The patients enrolled were divided into elastic nailing group with the application of elastic intramedullary nailing (n = 25) and control group without using instrument (n = 23) during the management of curettage and mixed bone grafting. The following medical outcomes of the two groups were monitored and recorded: the amount of intraoperative blood loss, operation time and postoperative full weight-bearing time, in addition to postoperative clinical effects after 1 year, the function and pain level of shoulder joint before and 1, 3, 6, 9, 12, and 16 months after operation. Follow-up radiographic outcomes were reviewed to observe bone healing, local recurrence and internal fixation loosening, and other postoperative complications. Results: The clinical curative effect of the elastic nailing group was higher than that of the control group 16 months after operation (96.00% > 73.91%, P < 0.05). The intraoperative blood loss and postoperative full weight-bearing time in the elastic nailing group were less than those in the control group (P < 0.05), but the operation time was statistically insignificant between the two groups (P > 0.05). Before operation, the shoulder joint function of the two groups was comparable (P > 0.05), while the function showed remarkably better outcome in the elastic nailing group than control group 1 to 16 months after operation (P < 0.05). Before operation, the pain level of the two groups was comparable (P > 0.05), while 1 to 16 months after operation, the pain level of the elastic nailing group was significantly lower than that of the control group (P < 0.05). Patients in both groups were followed up for 16 months. Mixed bone grafting fusion was indicated by imaging CT and X-ray during the follow-up period, with an average fusion time of 11.3 ± 1.2 months (range, 8–16 months). Three months after operation, there was 1 case of incomplete pathological fracture in the control group, while no related complications occurred in the elastic nailing group. Moreover, no tumor recurrence was observed in the two groups. The two groups were comparable in terms of the incidence of complications (P > 0.05). Conclusion: Children with humeral cyst treated with curettage and mixed bone grafting with the additional use of elastic intramedullary nailing exerted superior results to those without using instrument as there are beneficial outcomes and safety profile and no complications. [ABSTRACT FROM AUTHOR]

Invited for the cover of this issue are Xuewu Liang, Hong Liu and co‐workers at the Shanghai Institute of Materia Medica and Shenyang Pharmaceutical University. The image depicts how a rhodium‐catalyzed methodology leads to novel penta‐spiro/fused‐heterocyclic frameworks with potent antitumor activity through C−H activation/[4+1] and [4+2] annulation cascades. Read the full text of the article at 10.1002/chem. 202301553. [ABSTRACT FROM AUTHOR]

A 198.8 m deep borehole was drilled through ice to subglacial bedrock in the northwestern marginal part of Princess Elizabeth Land, ~12 km south of Zhongshan Station, in January–February 2019. Three years later, in February 2022, the borehole temperature profile was measured, and the geothermal heat flow (GHF) was estimated using a 1-D time-dependent energy-balance equation. For a depth corresponding to the base of the ice sheet, the GHF was calculated as 72.6 ± 2.3 mW m−2 and temperature −4.53 ± 0.27°C. The regional averages estimated for this area based, generally, on tectonic setting vary from 55 to 66 mW m−2. A higher GHF is interpreted to originate mostly from the occurrence of metamorphic complexes intruded by heat-producing elements in the subglacial bedrock below the drill site. [ABSTRACT FROM AUTHOR]

Background: Clinical studies suggest that immune checkpoint inhibitor (ICI) monotherapy has limited benefits in non-small cell lung cancer (NSCLC) patients after epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure. However, data about efficacy of ICI plus chemotherapy remain controversial, probably attributed to the heterogeneity among such population, and robust efficacy biomarkers are urgent to explore. Methods: A total of 60 eligible patients who received ICI plus chemotherapy after EGFR-TKI treatment failure were enrolled, 24 of whom peripheral blood mononuclear cell (PBMC) samples were collected at baseline and after 2 cycles of treatment. We have designed a 23-color-antibody panel to detect PBMC by full spectrum flow cytometry. Results: For EGFR-TKI resistant NSCLC patients: 1) ICI plus chemotherapy achieved an objective response rate (ORR) of 21.7% and a median progression-free survival (PFS) of 6.4 months. 2) clinical characteristics associated with worse efficacy included liver metastasis and platelet-to-lymphocyte ratio (PLR) > 200. 3) the proportion of immune cell subset associated with better efficacy was higher baseline effective CD4+T cells (E4). 4) the baseline expression of immune checkpoint proteins (ICPs) on cell subsets associated with better efficacy included: higher expression of CD25 on dendritic cells (DC) and central memory CD8+T cells (CM8), and higher expression of Lymphocyte activation gene 3 (LAG-3) on effective memory CD8+T cells (EM8). 5) the expression of ICPs after 2 cycles of treatment associated with better efficacy included: higher expression of CD25 on CD8+T/EM8 /natural killer (NK) cells. 6) the dynamic changes of ICPs expression associated with worse efficacy included: significantly decrease of T cell immunoglobulin and ITIM domain (TIGIT) expression on regular T cells (Tregs) and decrease of V-domain immunoglobulin suppressor of T cell activation (VISTA) expression on Th1. 7) a prediction model for the efficacy of ICI plus chemotherapy was successfully constructed with a sensitivity of 62.5%, specificity of 100%, and area under curve (AUC) = 0.817. Conclusions: Some EGFR-TKI-resistant NSCLC patients could indeed benefit from ICI plus chemotherapy, but most patients are primary resistant to immunotherapy. Comprehensive analysis of peripheral immune cells using full spectrum flow cytometry showed that compared to the proportion of cell subsets, the expression type and level of ICPs on immune cells, especially CD25, were significantly correlated with the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

Neuroinflammation is a unifying factor among all acute central nervous system (CNS) injuries and chronic neurodegenerative disorders. Here, we used immortalized microglial (IMG) cells and primary microglia (PMg) to understand the roles of the GTPase Ras homolog gene family member A (RhoA) and its downstream targets Rho-associated coiled-coil-containing protein kinases 1 and 2 (ROCK1 and ROCK2) in neuroinflammation. We used a pan-kinase inhibitor (Y27632) and a ROCK1- and ROCK2-specific inhibitor (RKI1447) to mitigate a lipopolysaccharide (LPS) challenge. In both the IMG cells and PMg, each drug significantly inhibited pro-inflammatory protein production detected in media (TNF-α, IL-6, KC/GRO, and IL-12p70). In the IMG cells, this resulted from the inhibition of NF-κB nuclear translocation and the blocking of neuroinflammatory gene transcription (iNOS, TNF-α, and IL-6). Additionally, we demonstrated the ability of both compounds to block the dephosphorylation and activation of cofilin. In the IMG cells, RhoA activation with Nogo-P4 or narciclasine (Narc) exacerbated the inflammatory response to the LPS challenge. We utilized a siRNA approach to differentiate ROCK1 and ROCK2 activity during the LPS challenges and showed that the blockade of both proteins may mediate the anti-inflammatory effects of Y27632 and RKI1447. Using previously published data, we show that genes in the RhoA/ROCK signaling cascade are highly upregulated in the neurodegenerative microglia (MGnD) from APP/PS-1 transgenic Alzheimer's disease (AD) mice. In addition to illuminating the specific roles of RhoA/ROCK signaling in neuroinflammation, we demonstrate the utility of using IMG cells as a model for primary microglia in cellular studies. [ABSTRACT FROM AUTHOR]

Therapeutics to reduce intracranial pressure are an unmet need. Preclinical data have demonstrated a novel strategy to lower intracranial pressure using glucagon-like peptide-1 (GLP-1) receptor signalling. Here, we translate these findings into patients by conducting a randomized, placebo-controlled, double-blind trial to assess the effect of exenatide, a GLP-1 receptor agonist, on intracranial pressure in idiopathic intracranial hypertension. Telemetric intracranial pressure catheters enabled long-term intracranial pressure monitoring. The trial enrolled adult women with active idiopathic intracranial hypertension (intracranial pressure >25 cmCSF and papilloedema) who receive subcutaneous exenatide or placebo. The three primary outcome measures were intracranial pressure at 2.5 h, 24 h and 12 weeks and alpha set a priori at less than 0.1. Among the 16 women recruited, 15 completed the study (mean age 28 ± 9, body mass index 38.1 ± 6.2 kg/m2, intracranial pressure 30.6 ± 5.1 cmCSF). Exenatide significantly and meaningfully lowered intracranial pressure at 2.5 h −5.7 ± 2.9 cmCSF (P = 0.048); 24 h −6.4 ± 2.9 cmCSF (P = 0.030); and 12 weeks −5.6 ± 3.0 cmCSF (P = 0.058). No serious safety signals were noted. These data provide confidence to proceed to a phase 3 trial in idiopathic intracranial hypertension and highlight the potential to utilize GLP-1 receptor agonist in other conditions characterized by raised intracranial pressure. [ABSTRACT FROM AUTHOR]

Legg-Calvé-Perthes disease (LCPD) commonly onsets in adolescents, and threatens their health. However, the potential mechanism underlying LCPD remains unclear. MicroRNA (miR)-206 and SRY-box 9 (SOX9) serve an important role in chondrocytes; however, their role in LCPD remains ambiguous. In the present study, whether miR-206 and SOX9 mediated cell apoptosis in dexamethasone (DEX)-induced LCPD was investigated. The chondrocytes of the LCPD and normal control group were isolated from clinical tissues. Reverse transcription-quantitative polymerase chain reaction was used to evaluate the expression of miR-206 and SOX9 mRNA. Western blotting was used to measure the protein level of SOX9. A combination of Annexin V-fluorescein isothiocyanate flow cytometry was used to assess cell apoptosis. The association between miR-206 and SOX9 was detected using a luciferase reporter assay. miR-206 was overexpressed while SOX9 was downregulated in chondrocytes treated with DEX obtained from patients with LCPD. miR-206 targeted SOX9 to regulate its expression. Overexpression of miR-206 promoted cell apoptosis in TC28, while it was reversed by SOX9 overexpression. TC28 cells pretreated with DEX significantly promoted cell apoptosis, while cells transfected with miR-206 inhibitor significantly reversed the effect; however, downregulated SOX9 abolished the effects of miR-206 inhibitor. SOX9 mediated by miR-206 possibly contributed to the pathogenesis of LCPD. The results of the present study suggest that miR-206 and SOX9 function as important therapeutic targets for the future of clinical therapy. [ABSTRACT FROM AUTHOR]

Traumatic brain injury represents a major public health issue that affects 1.7 million Americans each year and is a primary contributing factor (30.5%) of all injury-related deaths in the United States. The occurrence of traumatic brain injury is likely underestimated and thus has been termed “a silent epidemic”. Exendin-4 is a long-acting glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus that not only effectively induces glucose-dependent insulin secretion to regulate blood glucose levels but also reduces apoptotic cell death of pancreatic β-cells. Accumulating evidence also supports a neurotrophic and neuroprotective role of glucagon-like peptide-1 in an array of cellular and animal neurodegeneration models. In this study, we evaluated the neuroprotective effects of Exendin-4 using a glutamate toxicity model in vitro and fluid percussion injury in vivo. We found neuroprotective effects of Exendin-4 both in vitro, using markers of cell death, and in vivo, using markers of cognitive function, as assessed by Morris Water Maze. In combination with the reported benefits of ex-4 in other TBI models, these data support repositioning of Exendin-4 as a potential treatment for traumatic brain injury. [ABSTRACT FROM AUTHOR]

The newly developed RECoverable Autonomous Sonde (RECAS) allows sampling and analysis of subglacial water while the subglacial lake remains isolated from the surface. The sonde was successfully tested in East Antarctica during the 2021–2022 field season: it reached the ice-sheet base at a depth of 200.3 m, sampled basal meltwater and measured its pressure, temperature, pH and conductivity and returned to the ice surface. The average downward penetration rate was 1.85 m h -1 , and the average upward penetration rate was 2.94 m h -1. The successful test of a self-melting, recoverable probe in Antarctica marks further progress towards the clean exploration of subglacial water bodies. [ABSTRACT FROM AUTHOR]

The primary pump coast-down characteristics research is very important to ensure reactor safety during power failure events in the lead cooled fast reactor (LFR) design. The primary pump coast-down Flow Halving Time (FHT) effects on a 10 MW th lead-bismuth cooled research reactor with critical and sub-critical operation modes were analyzed under loss of flow transient in this paper. Comparison of different coast-down FHT effects on critical and sub-critical reactors was conducted. Moreover, other relevant parameters those may affect the coast-down FHT requirements (e.g. clad temperature limitation and temperature trigger threshold) were analyzed as well. The results showed that: Increasing the primary pump coast-down FHT can decrease the clad peak temperature in lead cooled fast reactor under LOF transient. Both unprotected and protected loss of flow (ULOF and PLOF) transients in critical reactor and ULOF transient in sub-critical reactor were insensitive to coast-down FHT, while PLOF transient in sub-critical reactor was found to be sensitive to the coast-down FHT. The coast-down FHT effects on sub-critical reactor was bigger than critical reactor in the early phase of LOF transient. The primary pump coast-down FHT had little effects on the critical reactor safety under LOF transients. The clad peak temperature of the sub-critical reactor under ULOF transient was the only one that exceeded the temperature limitation among these four transients. Raising the clad temperature limit of the sub-critical reactor contributes little to reactor safety under ULOF transient. Measures should be taken to avoid the happening of serious accident, such as ULOF transient in sub-critical reactor. Scram signal setup (e.g. core outlet temperature trigger threshold) would not enhance the safety of lead cooled critical and sub-critical reactors and would not change the coast-down FHT requirements under LOF transient. [ABSTRACT FROM AUTHOR]

Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed “twincretin,” was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism. [ABSTRACT FROM AUTHOR]

Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation. [Display omitted] [ABSTRACT FROM AUTHOR]

Cryopreservation can keep the bioactivity of biological specimens in long-term storage, but it is hard to retain the structural integrity due to serious thermomechanical stress during cooling and warming procedures, especially for complex living organisms. Few studies have reported on the thermomechanical stress of biological specimens in a pre-freezing supercooled state, which is a widespread phenomenon in slow-rate freezing cryopreservation. Here, we develop a thermomechanical coupling model to study transient thermal and mechanical fields of supercooled biological specimens experiencing freezing procedures. The results show that cryoprotectant accumulation in insects causes pronounced supercooled phenomena with severe deformation and thermomechanical stress in the initial state of phase transition. However, the loss of freezable water induced that final deformation and stress decrease, which is beneficial to organism survival after freezing. This numerical method is proved to be a guideline for optimizing slow-rate freezing cryopreservation protocols efficiently and economically. These results reveal survival mechanisms of insects with supercooled phenomena after freezing and assist researchers in exploring more valuable cryopreservation methods for biological specimens. • A thermo-mechanical coupling model is established for supercooled biological specimens during freezing processes. • Transient thermal distribution and thermo-mechanical stress of supercooled insects are studied. • Freezing at a high subzero temperature is not a unique requirement for freezing tolerance. • Cryoprotectant accumulation not only depresses supercooling points of body fluid but also assists organisms in dehydrating. [ABSTRACT FROM AUTHOR]

Introduction: Skin and soft tissue infections are common because of exposure to aquatic environment, while severe infections caused by Aeromonas veronii are rare. Case presentation: We report a case of severe skin and soft tissue infection of the left upper limb caused by Aeromonas veronii. A 50-year-old Chinese woman, who had a history of cardiac disease and type 2 diabetes mellitus, accidentally injured her left thumb while cutting a fish. Early antibiotic therapy and surgical debridement was performed before the result of bacterial culture came back. Whole-genome sequencing was further performed to confirm the pathogen and reveal the drug resistance and virulence genes. The wound was gradually repaired after 1 month of treatment, and the left hand recovered well in appearance and function after 3 months of rehabilitation. Conclusion: Early diagnosis, surgical intervention, and administration of appropriate antibiotics are crucial for patients who are suspected of having skin and soft tissue infection, or septicemia caused by Aeromonas veronii. [ABSTRACT FROM AUTHOR]

Very few studies have emphasized the effects of high-pressure sintering on snow density evolution, even though snow as a type of engineering material is widely used in construction engineering in cold regions for snow pavement, snow runway and polar infrastructure. This study presents new experimental results of snow densification under high pressures of up to 100 MPa for a temperature range from −3.5 to −17.3°C and uniaxial compression at the temperature of −10°C and constant strain rates from 5 × 10−4 to 10−1 s−1. Results reveal that density evolution of snow to ice under high-pressure sintering can be achieved in a wide temperature range within a duration as short as 5 min. The compressive strength of snow-sintered ice was ~1.2–2.2 times as large as that of water-frozen ice reported by previous work. The orthogonal experiment showed that pressure is a more significant factor affecting the final density in comparison with sintering temperature and time. The increased rates of ice fabrication, low limitations on temperature and reliable sintered snow strength indicate that snow-ice engineering, such as airport construction in Greenland and Antarctica, can be improved by high-pressure sintering of snow to overcome the harsh environment. [ABSTRACT FROM AUTHOR]

Objective. To investigate the effect of enteral and parenteral nutrition support (EPNS) on pulmonary function in elderly patients with chronic obstructive pulmonary disease (COPD) complicated by respiratory failure (RF). Methods. A total of 127 patients who underwent treatment for elderly patients with COPD complicated by RF in our hospital from February 2020 to May 2022 were collected for a retrospective analysis. There were 41 patients with enteral nutrition support (group A), 46 with parenteral nutrition support (group B), and 40 with EPNS (group C). The levels of serum albumin (ALB), prealbumin (PA), serum hemoglobin (Hb), and serum transferrin (TRF) were measured before and after nutritional support in the three groups, and the changes in pulmonary function of patients were compared. The changes in the levels of inflammatory factors and markers of oxidative stress (OS) in serum were also detected, and the incidence of adverse reactions and length of stay (LOS) were counted. Results. ALB, PA, Hb, and TRF levels were increased in all 3 groups after nutritional support, with the highest in group C (P < 0.05). Similarly, lung function was improved in all 3 groups and inflammatory factor levels and OS were suppressed, also most dramatically in group C (P < 0.05). There was no difference in the incidence of adverse reactions among the 3 groups, and the LOS in group C was shorter than those in groups A and B (P < 0.05). Conclusion. EPNS can effectively improve the lung function of patients with COPD combined with RF and reduce the inflammation and OS damage. It can effectively improve the therapeutic effect of patients and has great application prospects in the treatment of COPD combined with RH in the future. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress. Phenserine counteracted this by augmenting homeostatic mechanisms to mitigate oxidative stress, including superoxide dismutase [SOD] 1 and 2, and glutathione peroxidase [GPx], the activity and protein levels of which were measured by specific assays. Microarray analysis of hippocampal gene expression established that large numbers of genes were exclusively regulated by each individual treatment with a substantial number of them co-regulated between groups. Molecular pathways associated with lipid peroxidation were found to be regulated by mTBI, and treatment of mTBI animals with phenserine effectively reversed injury-induced regulations in the ‘Blalock Alzheimer’s Disease Up’ pathway. Together these data suggest that multiple phenserine-associated actions underpin this compound’s ability to ameliorate cognitive deficits caused by mTBI, and support the further evaluation of the compound as a therapeutic for TBI. [ABSTRACT FROM AUTHOR]