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Abstract Background Vitamin K‐dependent γ‐glutamic acid carboxylation (Gla) proteins are calcium‐binding and membrane‐associated, participating in coagulation, bone turnover, and cancer biology. The molecular function of transmembrane proline‐rich Gla proteins (PRRGs) remains unexplored. Methods Analysis of pancreatic ductal adenocarcinoma (PDAC) datasets, including transcription profiles, clinical data, and tissue microarrays, was conducted to evaluate PRRG1 expression and its clinical relevance. PDAC cell lines with overexpressed, knockdown, and mutated PRRG1 were developed to study biological functions and pathways using RNA‐seq, co‐immunoprecipitation with mass spectrometry, Western blotting, and immunofluorescence. In vivo xenograft and orthotopic models assessed PRRG1's impact on PDAC progression, with and without warfarin treatment. Results PRRG1 was significantly upregulated in PDAC compared to normal pancreas, correlating with poorer patient survival. PRRG1 knockdown reduced PDAC cell proliferation, anchorage‐independent growth in vitro, and tumor growth in vivo. PRRG1 localized at the plasma membrane, interacted with the HECT E3 ligase NEDD4 via the C‐terminal PPXY motif, and promoted NEDD4 self‐ubiquitination, reducing its protein levels. PRRG1 knockdown elevated NEDD4, destabilizing the oncoprotein KRAS and receptor EGFR, and attenuating downstream signaling and macropinocytosis under nutrient deprivation. The vitamin K‐dependent Gla modification of PRRG1 was crucial for its membrane localization and pro‐tumorigenic effects, and was inhibited by low‐dose warfarin, a clinical vitamin K antagonist. Conclusions This study identifies PRRG1 as a key regulator of pro‐tumorigenic signaling in PDAC, suggesting the potential of repurposing the anticoagulant warfarin as a therapeutic strategy. Key points PRRG1 is identified as the transmembrane Gla protein mediating PDAC malignancy. PRRG1 recruits and induces self‐ubiquitination of membrane‐anchoring E3 ligase NEDD4. PRRG1 exerts a protective role toward KRAS and EGFR by inhibiting NEDD4. The anticoagulant warfarin can be utilized to inhibit PRRG1 and PDAC advancement.

Abstract Object detection on fused images of visible and infrared modals is of great importance for many applications, for example, surveillance and rescue at low‐light conditions. However, current detectors have difficulty for robust fused image detection for mainly two reasons. First, objects are presented in various shapes and sizes, making some hard samples cannot be localized accurately. Second, the same object category in the fused images will have different appearance due to changing weather condition, temperature and intrinsic heat. Such a contradiction will degrade the classification task of a detection network, since it cannot merge commonalities and distinguish differences well. In this paper, we propose to reconstruct the detection pipeline of current detectors, and enhance the detection ability on difficult samples in fused images. Specifically, a Dilation Pyramid Network (DPN) is designed at the lateral connection to generate and aggregate features of various receptive field, without increasing pyramid layers. To strengthen the classification, a Semantic Category Attention Module (SCAM) is proposed to capture attention centers of semantics in fused images, rather than object centers. Abundant experiments on two fusion datasets show that the proposed method achieves a satisfying performance, and both modules can greatly improve current generic detectors on fused images.

Background. Da-Chuan-Xiong Decoction (DCXD) is an aqueous extract from a classic Chinese herbal formula composed of dried rhizomes of Ligusticum chuanxiong Hort and Gastrodia elata Bl. in the mass ratio of 4 : 1. It has been long used to treat chronic cardiovascular disease caused by blood stasis and wind pathogen in the clinic. This experimental study aimed to investigate the blood pressure (BP)-lowering effect of DCXD treatment on hypertension and underlying mechanisms. Methods. Male Sprague–Dawley rats were used in the experiment, and the hypertensive models were created by administering deoxycorticosterone acetate (DOCA) in conjunction with a high salt intake in uninephrectomized rats. DCXD was administered to hypertensive rats by oral gavage daily at a dose of 5 g/kg or 2.5 g/kg bodyweight for 28 days. The brain sodium sensitivity, ENaC function, superoxide anion level, NADPH oxidase activity, and expression of ENaC, p67phox, p47phox, and Rac1 in the paraventricular nucleus were assessed by using the appropriate methods. Results. The 28 days of DCXD (5 g/kg) treatment significantly reduced the increased BP effectively, inhibited the enhanced heart index, kidney index, and 24 h urinary protein, and improved the progressive pathological changes of heart and kidney, which was comparable to that of the positive control amlodipine. DCXD treatment also caused a marked reduction in plasma norepinephrine and induced a significant improvement in brain sodium sensitivity and ENaC function in DOCA-salt hypertensive rats. Rats in DCXD-treated groups also exhibited decreased superoxide anion levels and NADPH oxidase activity in the paraventricular nucleus. The level of ENaC, p67phox, and Rac1 protein expression in the paraventricular nucleus was significantly downregulated by DCXD treatment in DOCA-salt hypertensive rats. Conclusions. These findings indicate that the depressor action and sympathetic inhibition of DCXD on salt-sensitive hypertension may be by ameliorating brain sodium sensitivity, modulating ENaC function, and inhibiting the expression of ENaC and NADPH oxidase in the hypothalamic paraventricular nucleus.

Abstract KMT2C and KMT2D are the most frequently mutated epigenetic genes in human cancers. While KMT2C is identified as a tumor suppressor in acute myeloid leukemia (AML), the role of KMT2D remains unclear in this disease, though its loss promotes B cell lymphoma and various solid cancers. Here, it is reported that KMT2D is downregulated or mutated in AML and its deficiency, through shRNA knockdown or CRISPR/Cas9 editing, accelerates leukemogenesis in mice. Hematopoietic stem and progenitor cells and AML cells with Kmt2d loss have significantly enhanced ribosome biogenesis and consistently, enlarged nucleolus, increased rRNA and protein synthesis rates. Mechanistically, it is found that KMT2D deficiency leads to the activation of the mTOR pathway in both mouse and human AML cells. Kmt2d directly regulates the expression of Ddit4, a negative regulator of the mTOR pathway. Consistent with the abnormal ribosome biogenesis, it is shown that CX‐5461, an inhibitor of RNA polymerase I, significantly restrains the growth of AML with Kmt2d loss in vivo and extends the survival of leukemic mice. These studies validate KMT2D as a de facto tumor suppressor in AML and reveal an unprecedented vulnerability to ribosome biogenesis inhibition.

Abstract Sensitive and fast detection of neutrons and gamma rays is vital for homeland security, high‐energy physics, and proton therapy. Fast‐neutron detectors rely on light organic scintillators, and γ‐ray detectors use heavy inorganic scintillators and semiconductors. Efficient mixed‐field detection using a single material is highly challenging due to their contradictory requirements. Here we report hybrid perovskites (C8H12N)2Pb(Br1−xClx)4 that combine light organic cations and heavy inorganic skeletons at a molecular level to achieve unprecedented performance for mixed‐field radiation detection. High neutron absorption due to a high density of hydrogen, strong radiative recombination within the highly confined [PbX6]4− layer, and sub‐nanometer distance between absorption sites and radiative centers, enable a light yield of 41 000 photons/MeV, detection pulse width of 2.97 ns and extraordinary linearity response toward both fast neutrons and γ‐rays, outperforming commonly used fast‐neutron scintillators. Neutron energy spectrum, time‐of‐flight based fast‐neutron/γ‐ray discrimination and neutron yield monitoring were all successfully achieved using (C8H12N)2Pb(Br0.95Cl0.05)4 detectors. We further demonstrate the monitoring of reaction kinetics and total power of a nuclear fusion reaction. We envision that molecular hybridized scintillators open a new avenue for mixed‐field radiation detection and imaging.

Abstract Aims To explore the relationship between serum growth differentiation factor 15 (GDF15) and metabolic abnormalities in Chinese pregnant women. Materials and Methods We recruited 200 patients with gestational diabetes mellitus (GDM) and 211 matched normal control within 24–28 weeks of pregnancy. Enzyme‐linked immunosorbent assay (ELISA) was used to determine the serum GDF15 levels of all participants. Then we grouped participants according to the number of metabolic abnormalities (including blood glucose, blood lipids and blood pressure), divided them into a normal metabolic group, one metabolic abnormality group, two or more metabolic abnormalities group. Finally, multinomial logistic regression analysis was used to estimate the odds radio (OR) and 95% CIs expressing the association between GDF15 and metabolic abnormalities in pregnant women. Results Through bivariate correlation analysis, we found that serum GDF15 is linearly correlated with glucose metabolism indices, such as 1h‐PG, 2h‐PG, HbA1c (all P 1), and the risk of multiple metabolic abnormalities was higher. As the number of metabolic abnormalities increased, serum GDF15 levels also were elevated (P

The ability to predict responsiveness to drugs in individual patients is limited. We hypothesized that integrating molecular information from databases would yield predictions that could be experimentally tested to develop transcriptomic signatures for specific drugs. We analyzed lung adenocarcinoma patient data from The Cancer Genome Atlas and identified a subset of patients in which xanthine dehydrogenase (XDH) expression correlated with decreased survival. We tested allopurinol, an FDA‐approved drug that inhibits XDH, on human non‐small‐cell lung cancer (NSCLC) cell lines obtained from the Broad Institute Cancer Cell Line Encyclopedia and identified sensitive and resistant cell lines. We utilized the transcriptomic profiles of these cell lines to identify six‐gene signatures for allopurinol‐sensitive and allopurinol‐resistant cell lines. Transcriptomic networks identified JAK2 as an additional target in allopurinol‐resistant lines. Treatment of resistant cell lines with allopurinol and CEP‐33779 (a JAK2 inhibitor) resulted in cell death. The effectiveness of allopurinol alone or allopurinol and CEP‐33779 was verified in vivo using tumor formation in NCR‐nude mice. We utilized the six‐gene signatures to predict five additional allopurinol‐sensitive NSCLC cell lines and four allopurinol‐resistant cell lines susceptible to combination therapy. We searched the transcriptomic data from a library of patient‐derived NSCLC tumors from the Jackson Laboratory to identify tumors that would be predicted to be sensitive to allopurinol or allopurinol + CEP‐33779 treatment. Patient‐derived tumors showed the predicted drug sensitivity in vivo. These data indicate that we can use integrated molecular information from cancer databases to predict drug responsiveness in individual patients and thus enable precision medicine.

Abstract Aims/Introduction High plasma 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid (CMPF) levels are significantly associated with type 2 diabetes mellitus, which is usually accompanied by metabolic syndrome and non‐alcoholic fatty liver disease (NAFLD) with increased triglyceride levels. Thus, we hypothesized that elevated CMPF levels might be related to lipid metabolism and NAFLD risk. Materials and Methods Serum CMPF levels were determined using an enzyme‐linked immunosorbent assay in a total of 466 individuals, including 116 controls with no NAFLD or type 2 diabetes mellitus, 53 individuals with NAFLD but no type 2 diabetes mellitus, 151 individuals with type 2 diabetes mellitus but no NAFLD, and 146 individuals with both NAFLD and type 2 diabetes mellitus. The associations with age, blood pressure, lipid profiles, body mass index and liver injury marker levels were examined, and a meta‐analysis of non‐diabetic and diabetic groups was carried out to detect the combined effects. Results The CMPF concentration in NAFLD patients was significantly lower than individuals without NAFLD in both the non‐diabetic group (P

Abstract LiNi0.8Co0.1Mn0.1O2 cathodes suffer from severe bulk structural and interfacial degradation during battery operation. To address these issues, a three in one strategy using ZrB2 as the dopant is proposed for constructing a stable Ni‐rich cathode. In this strategy, Zr and B are doped into the bulk of LiNi0.8Co0.1Mn0.1O2, respectively, which is beneficial to stabilize the crystal structure and mitigate the microcracks. Meanwhile, during the high‐temperature calcination, some of the remaining Zr at the surface combined with the surface lithium source to form lithium zirconium coatings, which physically protect the surface and suppress the interfacial phase transition upon cycling. Thus, the 0.2 mol% ZrB2‐LiNi0.8Co0.1Mn0.1O2 cathode delivers a discharge capacity of 183.1 mAh g−1 after 100 cycles at 50 °C (1C, 3.0–4.3 V), with an outstanding capacity retention of 88.1%. The cycling stability improvement is more obvious when the cut‐off voltage increased to 4.4 V. Density functional theory confirms that the superior structural stability and excellent thermal stability are attributed to the higher exchange energy of Li/Ni exchange and the higher formation energy of oxygen vacancies by ZrB2 doping. The present work offers a three in one strategy to simultaneously stabilize the crystal structure and surface for the Ni‐rich cathode via a facile preparation process.

Abstract Mechanical signals such as pressure and strain reflect important psychological and physiological states of the human body. Body‐integrated sensors, including skin‐mounted and surgically implanted ones, allow personalized health monitoring for the general population as well as patients. However, the development of such measuring devices has been hindered by the strict requirements for human‐biocompatible materials and the need for high performance sensors; most existing devices or sensors do not meet all the desired specifications. Here, a set of flexible, stretchable, wearable, implantable, and degradable mechanical sensors is reported with excellent mechanical robustness and compliance, outstanding biocompatibility, remotely‐triggered degradation, and excellent sensing performance, using a conductive silk fibroin hydrogel (CSFH). They can detect multiple mechanical signals such as pressure, strain, and bending angles. Moreover, combined with a drug‐loaded silk‐based microneedle array, sensor‐equipped devices are shown to be effective for real‐time monitoring and in situ treatment of epilepsy in a rodent model. These sensors offer potential applications in custom health monitoring wearables, and in situ treatment of chronic clinical disorders.

Leiomyosarcoma with osteoclast‐like giant cells (LMS‐OGC) has seldom been reported clinically. LMS‐OGC of the breast is extremely rare according to the literature. Here, we report a case of LMS‐OGC leiomyosarcoma with osteoclast‐like giant cells of the breast. A 51‐year‐old female patient presented with a breast mass which was treated surgically and the pathological examination of the tumor indicated LMS‐OGC. Microscopically, the tumor was composed of spindle cells arranged in bundles or spokes with giant tumor cells and mitosis. Eosinophilic cytoplasm and morphologically benign osteoclast‐like cells were mixed together. Immunohistochemistry examination revealed SMA and desmin were positive with a Ki‐67 proliferation index of 40%. However, CK (AE1/AE3), E‐cadherin, ER, PR, CD34, S‐100 and CD10 were negatively expressed in the tumor tissue. LMS‐OGC is a soft tissue malignant tumor which develops extremely rarely in the breast. It should be differentiated and diagnosed according to the history, histological characteristics and immunohistochemical staining.

Abstract Suppressing the recombination of photogenerated charges is one of the most important routes for enhancing the catalytic performance of semiconductor photocatalysts. In addition to the built‐in field produced by semiconductor heterostructures and the photo‐electrocatalysis realized by applying an external electrical potential to photocatalysts assembled on electrodes, other strategies are waiting to be scientifically explored and understood. In this work, a Lorentz force–assisted charge carrier separation enhancement strategy is reported to improve the photocatalytic efficiency by applying a magnetic field to a photocatalytic system. The photocatalytic efficiency can be improved by 26% just by placing a permanent magnet beneath the normal photocatalytic system without any additional power supply. The mechanism by which the Lorentz force acts oppositely on the photogenerated electrons and holes is introduced, resulting in the suppression of the photoinduced charge recombination. This work provides insights into the specific role of the Lorentz force in suppressing the recombination of electron–hole pairs in their initial photogenerated states. This suppression would increase the population of charge carriers that would subsequently be transported in the semiconductor. It is believed that this strategy based on magnetic effects will initiate a new way of thinking about photoinduced charge separation.

Summary Transient expression of CRISPR/Cas9 is an effective approach for limiting its activities and improving its precision in genome editing. Here, we describe the heat‐shock‐inducible CRISPR/Cas9 for controlled genome editing, and demonstrate its efficiency in the model crop, rice. Using the soybean heat‐shock protein gene promoter and the rice U3 promoter to express Cas9 and sgRNA, respectively, we developed the heat‐shock (HS)‐inducible CRISPR/Cas9 system, and tested its efficacy in targeted mutagenesis. Two loci were targeted in rice, and the presence of targeted mutations was determined before and after the HS treatment. Only a low rate of targeted mutagenesis was detected before HS (~16%), but an increased rate of mutagenesis was observed after the HS treatment among the transgenic lines (50–63%). Analysis of regenerated plants harboring HS‐CRISPR/Cas9 revealed that targeted mutagenesis was suppressed in the plants but induced by HS, which was detectable by Sanger sequencing after a few weeks of HS treatments. Most importantly, the HS‐induced mutations were transmitted to the progeny at a high rate, generating monoallelic and biallelic mutations that independently segregated from the Cas9 gene. Additionally, off‐target mutations were either undetectable or found at a lower rate in HS‐CRISPR/Cas9 lines as compared to the constitutive‐overexpression CRISPR/Cas9 lines. Taken together, this work shows that HS‐CRISPR/Cas9 is a controlled and reasonably efficient platform for genome editing, and therefore, a promising tool for limiting genome‐wide off‐target effects and improving the precision of genome editing.

Abstract Flexible electronics can serve as powerful tools for biomedical diagnosis and therapies of neurological disorders, particularly for application cases with brain–machine interfaces (BMIs). Existing conformal soft bioelectrodes are applicable for basic electrocorticogram (ECoG) collecting/monitoring. Nevertheless, as an emerging and promising approach, further multidisciplinary efforts are still demanded for in‐depth exploitations with these conformal soft electronics toward their practical neurophysiological applications in both scientific research and real‐world clinical operation. Here, clinically‐friendly silk‐supported/delivered soft bioelectronics are developed, and multiple functions and features valuable for customizable intracranial applications (e.g., biocompatible and spontaneously conformal coupling with cortical surface, spatiotemporal ECoG detecting/monitoring, electro‐neurophysiological neural stimulating/decoding, controllable loading/delivery of therapeutic molecules, and parallel optical readouts of operating states) are integrated.

By far there is lack of research on different working conditions between rigid and flexible dynamics of truck mounted concrete pump booms. First a 3D model has been established by using virtual prototyping technology of a 37 m long boom in Pro/Engineering software. Then the rigid body simulation model has been built. Next modal superimposition method is adopted to change the 4 rigid body booms into flexible ones. Kinematics law and dynamic characteristics of 4 common working conditions had been studied then. Next tip displacement and the first boom hydraulic cylinder force of the 4 working conditions between rigid and flexible models have been researched. Furthermore the first natural frequencies of the structure have been calculated. The results show that the frequency of the horizontal condition has the lowest of all and the roof condition has the largest of all. Besides the cylinder forces of the flexible model are larger than the corresponding rigid ones because of the flexible boom vibration. Finally an experiment has been done on a boom test rig which proved that the established simulation model is reasonable and the frequency results are correct. All of these provide design reference to mechanical manipulator as well as reducing product development cost of such mechanism.

Type-2 fuzzy reasoning relations are the type-2 fuzzy relations obtained from a group of type-2 fuzzy reasonings by using extended t-(co)norm, which are essential for implementing type-2 fuzzy logic systems. In this paper an algorithm is provided for constructing type-2 fuzzy reasoning relations of SISO type-2 fuzzy logic systems. First, we give some properties of extended t-(co)norm and simplify the expression of type-2 fuzzy reasoning relations in accordance with different input subdomains under certain conditions. And then different techniques are discussed to solve the simplified expressions on the input subdomains by using the related methods on solving fuzzy relation equations. Besides, it is pointed out that the computation amount level of the proposed algorithm is the same as that of polynomials and the possibility of applying the proposed algorithm in the construction of type-2 fuzzy reasoning relations is illustrated on several examples. Finally, the calculation of an arbitrary extended continuous t-norm can be obtained as the special case of the proposed algorithm.

The ground and excited state properties of nT-C60 dyads and Por-nT-C60 triads (n=4, 8, and 12) have been theoretically investigated by using the time-dependent density functional theory together with a set of extensive multidimensional visualization techniques. The results reveal that the length of the nT moiety strongly influences the charge transfer characters of these systems. The charge transfer ability is largely strengthened by introducing the porphyrin group and decreases with the length of the nT moiety. Also the adjustment of the electron transport mode of Por-nT-C60 triads by the length of the nT moiety was visualized. It is found that Por*-4T-C60 shows predominantly the energy transfer process generating Por-4T-1C60* but the charge transfer becomes predominant for other triads, such as the direct formation of Por∙+-12T-C60∙− via Por*-12T-C60. Furthermore, the process of Por∙−-8T∙+-C60→Por-8T∙+-C60∙− via Por*-8T-C60 has been proved to be possible. Finally, the energetically most stable final charge transfer excited state is confirmed to be Por-nT∙+-C60∙−.