Search

Abstract Background Patients with Alzheimer’s disease (AD) are often co-morbid with unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release and suppress epileptogenesis, but its effects on cognition in AD are still controversial. Methods Four-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated. Results APP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV+ Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV+ Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice. Conclusion Our results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy.

Temporomandibular joint (TMJ) cartilage repair poses a considerable clinical challenge, and tissue engineering has emerged as a promising solution. In this study, we developed an injectable reactive oxygen species (ROS)-responsive multifunctional hydrogel (RDGel) to encapsulate dental pulp stem cells (DPSCs/RDGel in short) for the targeted repair of condylar cartilage defect. The DPSCs/RDGel composite exhibited a synergistic effect in the elimination of TMJ OA (osteoarthritis) inflammation via the interaction between the hydrogel component and the DPSCs. We first demonstrated the applicability and biocompatibility of RDGel. RDGel encapsulation could enhance the anti-apoptotic ability of DPSCs by inhibiting P38/P53 mitochondrial apoptotic signal in vitro. We also proved that the utilization of DPSCs/RDGel composite effectively enhanced the expression of TMJOA cartilage matrix and promoted subchondral bone structure in vivo. Subsequently, we observed the synergistic improvement of DPSCs/RDGel composite on the oxidative stress microenvironment of TMJOA and its regulation and promotion of M2 polarization, thereby confirmed that M2 macrophages further promoted the condylar cartilage repair of DPSCs. This is the first time application of DPSCs/RDGel composite for the targeted repair of TMJOA condylar cartilage defects, presenting a novel and promising avenue for cell-based therapy.

Renal cell carcinoma (RCC) is the most common renal tumor, with lung, bone, and liver being the primary sites of metastasis. Thyroid metastasis, on the other hand, is relatively uncommon. Metastatic tumors in the thyroid gland typically manifest as multiple or isolated nodules, which can be easily overlooked due to the lack of specific clinical and imaging features. However, the identification of thyroid metastasis suggests the presence of systemic metastasis and is indicative of a poor prognosis for patients. In this paper, we present two cases of thyroid metastasis following nephrectomy, with the objective of enhancing understanding among medical community regarding the diagnosis and treatment of thyroid metastasis originating from renal cell carcinoma. By raising awareness about this phenomenon, we emphasize the importance of early detection and diagnosis to improve patient prognoses. The implementation of standardized treatment protocols at the earliest possible stage is also emphasized. Through this research, we aim to contribute to the early identification and management of thyroid metastasis in patients with renal cell carcinoma, ultimately leading to improved outcomes.

Abstract Breast cancer, as a daunting global health threat, has driven an exponential growth in related research activity in recent decades. An area of research of paramount importance is protein synthesis, and the analysis of specific proteins inextricably linked to breast cancer. In this article, we undertake a bibliometric analysis of the literature on breast cancer and protein synthesis, aiming to provide crucial insights into this esoteric realm of investigation. Our approach was to scour the Web of Science database, between 2003 and 2022, for articles containing the keywords “breast cancer” and “protein synthesis” in their title, abstract, or keywords. We deployed bibliometric analysis software, exploring a range of measures such as publication output, citation counts, co-citation analysis, and keyword analysis. Our search yielded 2998 articles that met our inclusion criteria. The number of publications in this area has steadily increased, with a significant rise observed after 2003. Most of the articles were published in oncology or biology-related journals, with the most publications in Journal of Biological Chemistry, Cancer Research, Proceedings of the National Academy of Sciences of the United States of America, and Oncogene. Keyword analysis revealed that “breast cancer,” “expression,” “cancer,” “protein,” and “translation” were the most commonly researched topics. In conclusion, our bibliometric analysis of breast cancer and related protein synthesis literature underscores the burgeoning interest in this research. The focus of the research is primarily on the relationship between protein expression in breast cancer and the development and treatment of tumors. These studies have been instrumental in the diagnosis and treatment of breast cancer. Sustained research in this area will yield essential insights into the biology of breast cancer and the genesis of cutting-edge therapies.

BackgroundPrevious research has indicated that there may be a link between Crohn’s disease (CD) and breast cancer (BC), but the causality remains unclear. This study aimed to investigate the causal association between CD and BC using Mendelian randomization (MR) analysis.MethodsThe summary data for CD (5,956 cases/14,927 controls) was obtained from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). And the summary data for BC (122,977 cases/105,974 controls) was extracted from the Breast Cancer Association Consortium (BCAC). Based on the estrogen receptor status, the cases were classified into two subtypes: estrogen receptor-positive (ER+) BC and estrogen receptor-negative (ER−) BC. We used the inverse variance weighted method as the primary approach for two-sample MR. MR-PRESSO method was used to rule out outliers. Heterogeneity and pleiotropy tests were carried out to improve the accuracy of results. Additionally, multivariable MR was conducted by adjusting for possible confounders to ensure the stability of the results.ResultsThe two-sample MR indicated that CD increased the risks of overall (OR: 1.020; 95% CI: 1.010-1.031; p=0.000106), ER+ (OR: 1.019; 95%CI: 1.006-1.034; p=0.006) and ER− BC (OR: 1.019; 95%CI: 1.000-1.037; p=0.046) after removal of outliers by MR-PRESSO. This result was reliable in the sensitivity analysis, including Cochran’s Q and MR-Egger regression. In multivariate MR analyses, after adjusting for smoking and drinking separately or concurrently, the positive association between CD and the risks of overall and ER+ BC remained, but it disappeared in ER− BC. Furthermore, reverse MR analysis suggested that BC did not have a significant impact on CD risk.ConclusionOur findings provide evidence for a possible positive association between CD and the risk of BC. However, further studies are needed to fully understand the underlying mechanisms and establish a stronger causal relationship.

BackgroundPrevious studies have reported associations of Crohn’s disease (CD) and ulcerative colitis (UC) with the risks of extraintestinal cancers, but the causality remains unclear.MethodsUsing genetic variations robustly associated with CD and UC extracted from genome-wide association studies (GWAS) as instrumental variables. Nine types of extraintestinal cancers of European and Asian populations were selected as outcomes. We used the inverse variance weighted method as the primary approach for two-sample Mendelian randomization analysis. Sensitivity analyses were carried out to evaluate the reliability of our findings.ResultsIn the European population, we found that CD showed a potential causal relationship with pancreatic cancer (OR: 1.1042; 95% CI: 1.0087-1.2088; P=0.0318). Meanwhile, both CD (outliers excluded: OR: 1.0208; 95% CI: 1.0079-1.0339; P=0.0015) and UC (outliers excluded: OR: 1.0220; 95% CI: 1.0051-1.0393; P=0.0108) were associated with a slight increase in breast cancer risk. Additionally, UC exhibited a potential causal effect on cervical cancer (outliers excluded: OR: 1.1091; 95% CI: 1.0286-1.1960; P=0.0071). In the East Asian population, CD had significant causal effects on pancreatic cancer (OR: 1.1876; 95% CI: 1.0741-1.3132; P=0.0008) and breast cancer (outliers excluded: OR: 0.9452; 95% CI: 0.9096-0.9822; P=0.0040). For UC, it exhibited significant causal associations with gastric cancer (OR: 1.1240; 95% CI: 1.0624-1.1891; P=4.7359×10–5), bile duct cancer (OR: 1.3107; 95% CI: 1.0983-1.5641; P=0.0027), hepatocellular carcinoma (OR: 1.2365; 95% CI: 1.1235-1.3608; P=1.4007×10–5) and cervical cancer (OR: 1.3941; 95% CI: 1.1708-1.6599; P=0.0002), as well as a potential causal effect on lung cancer (outliers excluded: OR: 1.1313; 95% CI: 1.0280-1.2449; P=0.0116).ConclusionsOur study provided evidence that genetically predicted CD may be a risk factor for pancreatic and breast cancers in the European population, and for pancreatic cancer in the East Asian population. Regarding UC, it may be a risk factor for cervical and breast cancers in Europeans, and for gastric, bile duct, hepatocellular, lung, and cervical cancers in East Asians. Therefore, patients with CD and UC need to emphasize screening and prevention of site-specific extraintestinal cancers.

Measuring the obliquities of stars hosting giant planets may shed light on the dynamical history of planetary systems. Significant efforts have been made to measure the obliquities of FGK stars with hot Jupiters, mainly based on observations of the Rossiter–McLaughlin effect. In contrast, M dwarfs with hot Jupiters have hardly been explored because such systems are rare and often not favorable for such precise observations. Here, we report the first detection of the Rossiter–McLaughlin effect for an M dwarf with a hot Jupiter, TOI-4201, using the Gemini-North/MAROON-X spectrograph. We find TOI-4201 to be well aligned with its giant planet, with a sky-projected obliquity of $\lambda =-{3.0}_{-3.2}^{{+3.7}^{\circ}} $ and a true obliquity of $\psi ={21.3}_{-12.8}^{{+12.5}^{\circ}} $ with an upper limit of 40 ^◦ at a 95% confidence level. The result agrees with dynamically quiet formation or tidal obliquity damping that realigned the system. As the first hot Jupiter around an M dwarf with its obliquity measured, TOI-4201b joins the group of aligned giant planets around cool stars ( T _eff < 6250 K), as well as the small but growing sample of planets with relatively high planet-to-star mass ratio ( M _p / M _* ≳ 3 × 10 ^−3 ) that also appear to be mostly aligned.

Background: Previous studies have discovered an association between dietary factors and breast cancer. However, few studies have used Mendelian randomization (MR) to assess the potential causal relationship between dietary factors and breast cancer. Methods: The exposure datasets for fresh fruit intake, dried fruit intake, salad/raw vegetable intake, cooked vegetable intake, oily fish intake, non-oily fish intake, cheese intake, and bread intake were obtained from the UK Biobank. The outcome dataset was extracted from the Breast Cancer Association Consortium (BCAC). We used the inverse variance weighted (IVW) method as the primary approach for the two-sample MR analysis. To ensure the accuracy of the results, we conducted heterogeneity and horizontal pleiotropy analyses. Additionally, multivariable MR analysis was conducted to ensure the stability of the results. Results: Dried fruit intake was found to be a protective factor for overall breast cancer (outliers excluded: OR: 0.549; 95 % CI: 0.429–0.702; p = 1.75 × 10−6). Subtype analyses showed that dried fruit intake was inversely associated with both estrogen receptor-positive (ER+) breast cancer (outliers excluded: OR: 0.669; 95 % CI: 0.512–0.875; p = 0.003) and ER-negative (ER−) breast cancer (OR: 0.559; 95 % CI: 0.379–0.827; p = 0.004), while fresh fruit intake was inversely associated with ER− breast cancer (excluded outliers: OR: 0.510; 95 % CI: 0.308–0.846; p = 0.009). No significant causal relationship was found between other dietary intakes and breast cancer. After adjusting for the effects of possible confounders, the causal relationships found by the two-sample MR analysis remained. Conclusion: Our study provides evidence that dried fruit intake may reduce the risk of both ER+ and ER− breast cancer, and fresh fruit intake may reduce the risk of ER− breast cancer. Other factors included in this study were not linked to breast cancer.

Abstract Ischemic stroke leads to white matter damage and neurological deficits. However, the characteristics of white matter injury and repair after stroke are unclear. Additionally, the precise molecular communications between microglia and white matter repair during the stroke rehabilitation phase remain elusive. In this current study, MRI DTI scan and immunofluorescence staining were performed to trace white matter and microglia in the mouse transient middle cerebral artery occlusion (tMCAO) stroke model. We found that the most serious white matter damage was on Day 7 after the ischemic stroke, then it recovered gradually from Day 7 to Day 30. Parallel to white matter recovery, we observed that microglia centered around the damaged myelin sheath and swallowed myelin debris in the ischemic areas. Then, microglia of the ischemic hemisphere were sorted by flow cytometry for RNA sequencing and subpopulation analysis. We found that CD11c+ microglia increased from Day 7 to Day 30, demonstrating high phagocytotic capabilities, myelin-supportive genes, and lipid metabolism associated genes. CD11c+ microglia population was partly depleted by the stereotactic injecting of rAAV2/6M-taCasp3 (rAAV2/6M-CMV-DIO-taCasp3-TEVp) into CD11c-cre mice. Selective depletion of CD11c+ microglia disrupted white matter repair, oligodendrocyte maturation, and functional recovery after stroke by Rotarod test, Adhesive Removal test, and Morris Water Maze test. These findings suggest that spontaneous white matter repair occurs after ischemic stroke, while CD11c+ microglia play critical roles in this white matter restorative progress.

The No Free Lunch Theorem tells us that no algorithm can beat other algorithms on all types of problems. The algorithm selection structure is proposed to select the most suitable algorithm from a set of algorithms for an unknown optimization problem. This paper introduces an innovative algorithm selection approach called the CNN-HT, which is a two-stage algorithm selection framework. In the first stage, a Convolutional Neural Network (CNN) is employed to classify problems. In the second stage, the Hypothesis Testing (HT) technique is used to suggest the best-performing algorithm based on the statistical analysis of the performance metric of algorithms that address various problem categories. The two-stage approach can adapt to different algorithm combinations without the need to retrain the entire model, and modifications can be made in the second stage only, which is an improvement of one-stage approaches. To provide a more general structure for the classification model, we adopt Exploratory Landscape Analysis (ELA) features of the problem as input and utilize feature selection techniques to reduce the redundant ones. In problem classification, the average accuracy of classifying problems using CNN is 96%, which demonstrates the advantages of CNN compared to Random Forest and Support Vector Machines. After feature selection, the accuracy increases to 98.8%, further improving the classification performance while reducing the computational cost. This demonstrates the effectiveness of the first stage of the CNN-HT method, which provides a basis for algorithm selection. In the experiments, CNN-HT shows the advantages of the second stage algorithm as well as good performance with better average rankings in different algorithm combinations compared to the individual algorithms and another algorithm combination approach.

The chemical composition of an extrasolar planet is fundamental to its formation, evolution, and habitability. In this study, we explore a new way to measure the chemical composition of the building blocks of extrasolar planets by measuring the gas composition of the disrupted planetesimals around white dwarf stars. As a first attempt, we used the photoionization code Cloudy to model the circumstellar gas emission around white dwarf Gaia J0611−6931 under some simplified assumptions. We found that most of the emission lines are saturated, and the line ratios approach the ratios of thermal emission; therefore, only lower limits to the number density can be derived. Silicon is the best-constrained element in the circumstellar gas, and we derived a lower limit of 10 ^10.3 cm ^−3 . In addition, we placed a lower limit on the total amount of gas to be 1.8 × 10 ^19 g. Further study is needed to better constrain the parameters of the gas disk and connect it to other white dwarfs with circumstellar gas absorption.

ObjectiveTo explore the relationship between socioeconomic status (SES), illness perception, social functioning, and health-related quality of life (HRQoL) of young and middle-aged maintenance hemodialysis (MHD) patients and the internal mechanism of action.DesignA multicenter cross-sectional study.MethodsAn aggregate of 332 young and middle-aged MHD patients were enrolled from hemodialysis centers in four general hospitals in Guangzhou, Guangdong, China, from June to December 2022. The questionnaires used included one for general demographic data, the Brief Illness Perception Questionnaire (BIPQ), Social Dysfunction Screening Scale (SDSS), and the 12-item Short Form Health Survey (SF-12).ResultsBoth SES and HRQoL were negatively correlated with illness perception and social functioning, respectively. SES was positively correlated with HRQoL. Illness perception was positively correlated with social functioning. The indirect effects of illness perception and social functioning on the relationship between SES and HRQoL were 0.33 and 0.31, making up 41.06% and 38.91% of the sum. The chain indirect effect of illness perception and social functioning was 0.10, making up 12.59% of the total effect, while gender did not play a moderating role.ConclusionIllness perception and social functioning may independently and accumulatively mediate the association between SES and HRQoL. Nurses should consider developing individual intervention program for young and middle-aged MHD patients with low SES, focusing on establishing targeted counseling and health education strategies corresponding to illness perception and social functioning to help patients improve their HRQoL.

Oxidative stress plays an important role in the secondary neuronal damage after traumatic brain injury (TBI). Inhibition of histone deacetylases (HDACs) has been shown to reduce reactive oxygen species (ROS) production and NADPH oxidases (Nox) transcription. Vorinostat is an HDAC inhibitor. This study investigated the influence of vorinostat on neurological impairments in a rat model of TBI induced by lateral fluid percussion injury (LFPI). Different concentrations of vorinostat (5, 25, and 50 mg/kg) were administered via intraperitoneal injection. Neurological deficits were evaluated by modified neurological severity scoring (mNSS). Evans blue extravasation was performed to assess blood–brain barrier (BBB) permeability. Morris water maze assay was performed to evaluate cognitive impairments. Protein levels were evaluated through ELISA and Western blot. Vorinostat was found to attenuate TBI induced brain edema and BBB permeability in rats. Vorinostat also alleviated TBI-induced neurological impairments and anxiety-like behavior in rats. Vorinostat attenuated TBI induced apoptosis and oxidative stresses in ipsilateral injury cortical tissue. Vorinostat inhibited HDAC1, HDAC3, and Nox4 while activated AMPK signaling in ipsilateral injury cortical tissue. In conclusion, administration of vorinostat alleviates the secondary damage of TBI in rat model. The oxidative stress in the ipsilateral injury cortical tissues is decreased by the inhibition of Nox4 expression and the activation of AMPK.

The relationship between cancer and microorganisms has been extensively studied, with bacteria receiving more attention than fungi. However, fungi have been shown to play a significant role in cancer development and progression. Understanding the underlying mechanisms is crucial for identifying new avenues in prevention and treatment. To evaluate the current state of research on fungi and cancer, we conducted a comprehensive bibliometric analysis. Using the Web of Science Core Collection database, we searched for English-language articles published between 1998 and 2022. Analyzing the resulting publication data, we identified trends, patterns, and research gaps. Our analysis encompassed co-authorship networks, citation analysis, and keyword co-occurrence analysis. With 8283 publications identified, averaging 331.32 publications per year, our findings highlight China, the United States, India, Japan, and Germany as the top contributing countries. The Chinese Academy of Sciences, Sun Yat-Sen University, and University of São Paulo emerged as the most productive institutions. Key themes in the literature included “cancer,” “cytotoxicity,” “apoptosis,” “metabolites,” and “fungus.” Recent trends indicate increased interest in keywords such as “green synthesis,” “molecular docking,” “anticancer activity,” “antibacterial,” “anticancer,” and “silver nanoparticles.” Our study provides a comprehensive assessment of the current research landscape in the field of fungi and cancer, offering insights into collaborative networks, research directions, and emerging hotspots. The growing publication rate demonstrates the rising interest in the topic, while identifying leading countries, institutions, and research themes serves as a valuable resource for researchers, policymakers, and funders interested in supporting investigations on fungi-derived compounds as potential anti-cancer agents.

Abstract Background Selectively utilizing alternative mechanisms to repair damaged DNA in essential factors deficient cancer facilitates tumor genetic evolution and contributes to treatment resistance. Synthetic lethality strategies provide a novel scenario to anticancer therapy with DNA repair protein mutation, such as glioma with DNA-PKcs-deficiency, a core factor crucial for non-homologous end joining (NHEJ) mediated DNA damage repair. Nevertheless, the clinical significance and molecular mechanisms of synthetic lethality function by interfering tumor DNA replication remain largely unexplored. Methods Cancer clinic treatment resistance-related replication core factors were identified through bioinformatics analysis and RNA-sequencing and verified in clinical specimens by immunoblotting and in situ Proximity Ligation Analysis (PLA). Then, in vitro and in vivo experiments, including visible single molecular tracking system were performed to determine functional roles, the molecular mechanisms and clinical significance of synthetic lethality on glioma tumors. Results Hyperactive DNA replication and regulator Flap endonuclease 1 (FEN1) provides high efficiency DNA double strand breaks (DSB) repair abilities preventing replication forks collapse during DNA replication which facilitate adaptation to selective pressures. DNA-PKcs deficient glioma cells are highly dependent on FEN1/BRCA1/RAD51 to survival and counteract replication stress. FEN1 protects perturbed forks from erroneous over-resection by MRE11 through regulating of BRCA1-RAD51 and WRN helicase, uncovering an essential genetic interaction between FEN1 and DNA-PKcs in mitigating replication-stress induced tumor genomic instability. Therapeutically, genetic depletion or molecular inhibition of FEN1 and DNA-PKcs perturb glioma progression. Conclusions Our findings highlight an unanticipated synthetic interaction between FEN1/BRCA1/RAD51 and DNA-PKcs when dysfunction leads to incompatible with cell survival under conditions of interrupted replication progression by disrupting addictive alternative tumor evolution and demonstrate the applicability of combined FEN1 and DNA-PKcs targeting in the treatment of glioma.

While some exoplanets that once orbited Polluted white dwarfs are similar to Earth, most appear to have rock types that are exotic to our Solar System. We thus develop a new classification scheme to describe these new and novel lithologies that appear to be dominant among polluted white dwarfs.

ABSTRACT Increasing evidence indicates that interferon alpha (IFN-α) therapy is an effective treatment option for a subgroup of patients with chronic hepatitis B virus (HBV) infection. It has been confirmed that interferon-induced protein with tetratricopeptide repeats 3 (IFIT3), a member of the interferon-stimulated genes (ISGs), could inhibit the replication of various viruses. However, its effect on HBV replication is unclear. The present study sought to explore the role and mechanism of IFIT3 in IFN-α antiviral activities against HBV. IFIT3 mRNA levels in the peripheral blood of 108 treatment-naive patients and 70 healthy controls were analyzed first. The effect of IFIT3 on the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway under the dual intervention of IFN-α and HBV was also explored in vitro. Treatment-naive individuals exhibited elevated levels of IFIT3 mRNA compared to the controls (P

From the perspective of network attackers, finding attack sequences that can cause significant damage to network controllability is an important task, which also helps defenders improve robustness during network constructions. Therefore, developing effective attack strategies is a key aspect of research on network controllability and its robustness. In this paper, we propose a Leaf Node Neighbor-based Attack (LNNA) strategy that can effectively disrupt the controllability of undirected networks. The LNNA strategy targets the neighbors of leaf nodes, and when there are no leaf nodes in the network, the strategy attacks the neighbors of nodes with a higher degree to produce the leaf nodes. Results from simulations on synthetic and real-world networks demonstrate the effectiveness of the proposed method. In particular, our findings suggest that removing neighbors of low-degree nodes (i.e., nodes with degree 1 or 2) can significantly reduce the controllability robustness of networks. Thus, protecting such low-degree nodes and their neighbors during network construction can lead to networks with improved controllability robustness.

BackgroundDNA damage response (DDR) proficiency is the principal mechanism of temozolomide (TMZ) resistance in glioma. Accumulating evidence has also suggested the determining role of DDR in anticancer immunity. We propose that a comprehensive investigation of the DDR landscape can optimize glioma treatment.MethodsWe identified the pronounced enrichment of DDR in TMZ-resistant glioma cells by RNA sequencing. Nine differentially expressed genes between TMZ-sensitive/resistant glioma cells were selected to construct the DDR score through lasso regression analysis. Two glioma cohorts from TCGA and CGGA were interrogated to evaluate the predictive ability of DDR score. Multiple algorithms were applied to estimate the immunotherapeutic responses of two DDR phenotypes. Immunohistochemistry was used to determine the protein levels of PD-L1 and TGFβ in glioma specimens. The oncoPredict package was employed to predict the candidate chemotherapy agents.ResultsDDR score exhibited a robust prognostic capability in TCGA and CGGA cohorts and served as an independent predictive biomarker in glioma patients. Functional enrichment analyses revealed that high and low DDR score groups were characterized by distinct immune activity and metabolic processes. Elevated levels of infiltrating immune cells (including CD8+ T cells, CD4+ T cells, and dendritic cells) were observed in the high DDR score glioma. Further, high DDR scores correlated with increased mutation burden, up-regulated immune checkpoints, and tumor immunity activation, indicating a profound interplay between DDR score and glioma immunogenicity. In addition, PD-L1 and TGFβ were overexpressed in recurrent glioma specimens compared with primary ones. Finally, we estimated that PI3K inhibitors may serve as latent regimens for high DDR score patients.ConclusionOur study highlighted the promising prognostic role of DDR score in glioma. Individual assessment of DDR status for patients with glioma may provide new clues for developing immunotherapeutic strategies.

We report on a chemo-dynamical analysis of SPLUS J142445.34−254247.1 (SPLUS J1424−2542), an extremely metal-poor halo star enhanced in elements formed by the rapid neutron-capture process ( r -process). This star was first selected as a metal-poor candidate from its narrowband S-PLUS photometry and followed up spectroscopically in medium resolution with Gemini-South/GMOS, which confirmed its low-metallicity status. High-resolution spectroscopy was gathered with GHOST at Gemini-South, allowing for the determination of the chemical abundances for 36 elements, from carbon to thorium. At [Fe/H] = −3.39, SPLUS J1424−2542 is one of the lowest-metallicity stars with measured Th and has the highest $\mathrm{log}\epsilon (\mathrm{Th}/\mathrm{Eu})$ observed to date, making it part of the “actinide-boost” category of r -process–enhanced stars. The analysis presented here suggests that the gas cloud from which SPLUS J1424−2542 formed must have been enriched by at least two progenitor populations. The light-element ( Z ≤ 30) abundance pattern is consistent with the yields from a supernova explosion of metal-free stars with 11.3–13.4 M _⊙ , and the heavy-element ( Z ≥ 38) abundance pattern can be reproduced by the yields from a neutron star merger (1.66 M _⊙ and 1.27 M _⊙ ) event. A kinematical analysis also reveals that SPLUS J1424−2542 is a low-mass, old halo star with a likely in situ origin, not associated with any known early merger events in the Milky Way.

We present observations and analyses of eight white dwarf stars (WDs) that have accreted rocky material from their surrounding planetary systems. The spectra of these helium-atmosphere WDs contain detectable optical lines of all four major rock-forming elements (O, Mg, Si, and Fe). This work increases the sample of oxygen-bearing WDs with parent body composition analyses by roughly 33%. To first order, the parent bodies that have been accreted by the eight WDs are similar to those of chondritic meteorites in relative elemental abundances and oxidation states. Seventy-five percent of the WDs in this study have observed oxygen excesses implying volatiles in the parent bodies with abundances similar to those of chondritic meteorites. Three WDs have oxidation states that imply more reduced material than found in CI chondrites, indicating the possible detection of Mercury-like parent bodies, but are less constrained. These results contribute to the recurring conclusion that extrasolar rocky bodies closely resemble those in our solar system, and do not, as a whole, yield unusual or unique compositions.

Excess infrared flux from white dwarf stars is likely to arise from a dusty debris disk or a cool companion. In this work, we present near-infrared spectroscopic observations with Keck/MOSFIRE, Gemini/GNIRS, and Gemini/Flamingos-2 of seven white dwarfs with infrared excesses identified in previous studies. We confirmed the presence of dust disks around four white dwarfs (Gaia J0611–6931, Gaia J0006+2858, Gaia J2100+2122, and WD 0145+234) as well as two new white dwarf–brown dwarf pairs (Gaia J0052+4505 and Gaia J0603+4518). In three of the dust disk systems, we detected for the first time near-infrared metal emissions (Mg i , Si I, and possibly Fe I) from a gaseous component of the disk. We developed a new Markov Chain Monte Carlo framework to constrain the geometric properties of each dust disk. In three systems, the dust disk and the gas disk appear to coincide spatially. For the two brown dwarf–white dwarf pairs, we identified broad molecular absorption features typically seen in L dwarfs. The origin of the infrared excess around Gaia J0723+6301 remains a mystery. Our study underlines how near-infrared spectroscopy can be used to determine sources of infrared excess around white dwarfs, which has now been detected photometrically in hundreds of systems.

The accumulation of insoluble amyloid β (Aβ) peptides is one of the pathological changes in Alzheimer's disease (AD), which induced synaptic plasticity impairment and excitatory amino acid toxicity associated with decreased memory function. Xingnaojing (XNJ), a well-known prescription in traditional Chinese medicine, has been used for the treatment of stroke for many years in China. In this study, we aim to investigate the therapeutic effects of XNJ in a hippocampus of Aβ1–42 induced mouse model of AD which showed significant memory loss and impaired synaptic morphology and function. Treatment of XNJ could attenuate spatial and working memory dysfunction, increase dendritic spine density and improve long-term potential (LTP) induction. In addition, XNJ treatment significantly increased the level of N-methyl-d-aspartate receptors (NMDARs) and inhibit the NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) ratio in AD mice. XNJ treatment also activated the AKT/mechanistic target of rapamycin (mTOR) pathway, while inhibition of the mTOR pathway by rapamycin could reverse the protective effects of XNJ treatment. In conclusion, XNJ protected against synaptic plasticity and memory impairment in AD mice via the activation of AKT/mTOR signaling pathway, suggesting XNJ as an alternative treatment for AD.

Glioblastoma is the most common malignant primary brain tumor with poor prognosis and low long-term survival rate. Here we described the production of an iPSC line generated from peripheral blood mononuclear cells (PBMCs) of a 24-year-old female gliocytoma patient. The PBMCs were reprogrammed by the non-integrating Sendai Virus with human OKSM (OCT3/4, SOX2, KLF4, and c-MYC) transcription factors. The generated iPSCs were positive for pluripotent stem cell markers demonstrated by immunocytochemistry. Besides, they displayed a normal karyotype and had the potential to differentiate spontaneously three germ layers in vitro. Our model might be useful in studying the pathogenesis of gliocytoma patients.

Compared to the zenith hydrostatic delay (ZHD) obtained from the Saastamonien model based on in-situ measured meteorological (IMM) data and radiosonde-derived weighted mean temperature (Tm), the ZHD and Tm deviations of the GPT3 model have shown obvious periodic trends. This article analyzed the seasonal variations of GPT3-ZHD and GPT3-Tm during the 2016–2020 period in the Yangtze River Delta region, and the new improved ZHD and Tm models were established by the multi-order Fourier function. The precision of the improved-ZHD model was verified using IMM-ZHD products from 7 GNSS stations during the 2016–2020 period. Furthermore, the precisions of improved Tm and precipitable water vapor (PWV) were verified by radiosonde-derived Tm and PWV in the 2016–2019 period. Compared with the IMM-ZHD and GNSS-PWV products, the mean Bias and RMS of GPT3-ZHD are −0.5 mm and 2.1 mm, while those of GPT3-PWV are 2.7 mm and 11.1 mm. Compared to the radiosonde-derived Tm, the mean Bias and RMS of GPT3-Tm are −0.8 K and 3.2 K. The mean Bias and RMS of the improved-ZHD model from 2019 to 2020 are −0.1 mm and 0.5 mm, respectively, decreasing by 0.4 mm and 1.6 mm compared to the GPT3-ZHD, while those of the improved-Tm are −0.6 K and 2.7 K, respectively, decreasing by 0.2 K and 0.5 K compared to GPT3-Tm. The mean Bias and RMS of PWV calculated by GNSS-ZTD, improved-ZHD, and improved-Tm are 0.5 mm and 0.6 mm, respectively, compared to the GNSS-PWV, decreasing by 2.2 mm and 10.5 mm compared to the GPT3-PWV. It indicates that the improved ZHD and Tm models can be used to obtain the high-precision PWV. It can be applied effectively in the retrieval of high-precision PWV in real-time in the Yangtze River Delta region.

Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor, and patients with GBM have a median survival of 20 months. Clinical therapy resistance is a challenging barrier to overcome. Tumor genome stability maintenance during DNA replication, especially the ability to respond to replication stress, is highly correlated with drug resistance. Recently, we identified a protective role for RECQ1 under replication stress conditions. RECQ1 acts at replication forks, binds PCNA, inhibits single-strand DNA formation and nascent strand degradation in GBM cells. It is associated with the function of the PARP1 protein, promoting PARP1 recruitment to replication sites. RECQ1 is essential for DNA replication fork protection and tumor cell proliferation under replication stress conditions, and as a target of RECQ1, PARP1 effectively protects and restarts stalled replication forks, providing new insights into genomic stability maintenance and replication stress resistance. These findings indicate that tumor genome stability targeting RECQ1-PARP1 signaling may be a promising therapeutic intervention to overcome therapy resistance in GBM.

Capicua (Cic), a transcriptional repressor frequently mutated in brain cancer oligodendroglioma, is highly expressed in adult neurons. However, its function in the dendritic growth of neurons in the hippocampus remains poorly understood. Here, we confirmed that Cic was expressed in hippocampal neurons during the main period of dendritogenesis, suggesting that Cic has a function in dendrite growth. Loss-of-function and gain-of function assays indicated that Cic plays a central role in the inhibition of dendritic morphogenesis and dendritic spines in vitro. Further studies showed that overexpression of Cic reduced the expression of Ets in HT22 cells, while in vitro knockdown of Cic in hippocampal neurons significantly elevated the expression of Ets. These results suggest that Cic may negatively control dendrite growth through Ets, which was confirmed by ShRNA knockdown of either Etv4 or Etv5 abolishing the phenotype of Cic knockdown in cultured neurons. Taken together, our results suggest that Cic inhibits dendritic morphogenesis and the growth of dendritic spines through Ets.

Abstract MiRNAs have been widely reported as the therapeutic target for hepatocellular carcinoma (HCC). However, mirna clusters, as the more impressive tumor regulatory factors, have received little attention. By deeply digging the Cancer Genome Atlas (TCGA) database, we aimed to explore the vital mirna cluster that regulated the poor prognosis of HCC. The results showed that the upregulation of mirna cluster-767-105 in HCC was the most significant, compared with the non-tumor tissues. Besides, high expression of all three members of the cluster was positively correlated with poor prognosis of HCC and the resistance of sorafenib. Cox analysis proved that all the three mirnas were independent prognostic factors, while the mir-767 was the most compelling (HR value 8.388, 95%CI 2.524–27.897). The higher expression of the three-mirna signature also significantly indicated the worse prognosis. Through bioinformatics analysis, we screened their common potential target genes, which were highly correlated with tumor regulation. These results supported that the mirna cluster-767-105 promoted the poor outcome of HCC and could be a robust target for the therapy of HCC patients.

Abstract Long noncoding RNA (lncRNA) has played the important function in regulation of various biological processes and in diagnostic value has been widely appreciated. In the present study, we have found that LOC101928316 was significantly downregulated in gastric cancer (GC) tissues specimen, GC cell lines, and associated with the GC patients tumor, node, and metastasis (TNM) stage and degree of differentiation (P ＜ 0.05). LOC101928316 overexpression can significantly inhibit SGC‐7901 cell migration, invasion, and proliferation (P＜0.05). LOC101928316 molecular mechanism investigates suggested that LOC101928316 can regulate PI3K‐Akt‐mTOR signaling pathway and change the GC development progression in vivo and in vitro. In vivo experiment also revealed that LOC101928316‐Overexpression can inhibit the tumorigenicity of GC cells in tumor‐burdened experimental nude mice (P ＜ 0.05). LOC101928316 may function as anti‐oncogene and also plays an important role in GC tumorigenesis. Collectively, our data provided the key role of LOC101928316 in the tumorigenesis of GC. In addition, the present study elucidates LOC101928316 potential regulatory network, which may help us to lead a better knowing of the pathogenesis of GC and probe the lncRNA as a novel biomarker to diagnosis and therapy for this malignant tumor.

Body temperature provides an insight into the physiological state of a person, and body temperature changes reflect much information about human health. In this study, a garment for monitoring human body temperature based on fiber Bragg grating (FBG) sensors is reported. The FBG sensor was encapsulated with a PMMA tube and calibrated in the thermostatic water bath. The results showed that FBG sensors had good vibration resistance, and the wavelength changed about 0–1 pm at a 0.5–80 Hz vibration frequency. The bending path of the optical fiber after integration with clothing is discussed. When the bending radius is equal to or greater than 20 mm, a lower bending loss can be achieved even under the bending and stretching of the human body. The FBG sensor, the optical fiber, and the garment were integrated together using hot melt glue by the electric iron and the hot press machine. Through experiments of monitoring human body temperature, the sensor can reach the human armpit temperature in about 10–15 min with the upper arm close to the torso. Because it is immune to electromagnetic interferences, the smart garment can be used in some special environments such as ultrasonography, magnetic resonance (MR), and aerospace.

Abstract Background Traumatic brain injury (TBI) is a complex condition and remains a prominent public and medical health issue in individuals of all ages. A rapid increase in extracellular glutamate occurs after TBI, leading to glutamate-induced excitotoxicity, which causes neuronal damage and further functional impairments. Although inhibition of glutamate carboxypeptidase II (GCP II) is considered a potential approach for reducing glutamate-induced excitotoxicity after TBI, further detailed evidence regarding its efficacy is required. Therefore, in this study, we examined the differences in the metabolite status between wild-type (WT) and GCP II gene-knockout (KO) mice after TBI using proton magnetic resonance spectroscopy (1H-MRS) and T2-weighted magnetic resonance (MR) imaging with a 7-tesla imaging system, and brain water-content analysis. Results Evaluation of glutamate and N-acetylaspartate concentrations revealed a decrease in both levels in the ipsilateral hippocampus at 24 h post-TBI; however, the reduction in glutamate and N-acetylaspartate levels was less marked in GCP II-KO mice than in WT mice (p

Post-stroke inflammation is almost involved in the whole process of stroke pathogenesis, which serves as a prime target for developing new stroke therapies. Despite known sex differences in the incidence and outcome of stroke, few preclinical or clinical studies take into account sex bias in treatment. Recent evidence suggests that poly (ADP-ribose) polymerase (PARP)-1 inhibitor exerts sex-specific neuroprotection in the ischemic stroke. This study was aimed to investigate the effects of delayed PARP-1 inhibition on post-stroke inflammation and possible sexual dimorphism, and explore the possible relevant mediators. In male and female C57BL/6 mice subjected to transit middle cerebral artery occlusion (MCAO), we found that delayed treatment of PARP-1 inhibitor at 48 h following reperfusion could comparably alleviate neuro-inflammation at 72 h after stroke. Whereas, more remarkable reduction of iNOS and MMP9 induced by PARP-1 inhibition were found in male MCAO mice, and the improvement of behavioral outcomes was more prominent in male MCAO mice. In addition, we further identified that PARP-1 inhibitor might equivalently suppress microglial activation in males and females in vivo and in vitro. With proteomic analysis and western blotting assay, it was found that stroke-induced peroxiredoxin-1 (Prx1) expression was significantly affected by PARP-1 inhibition. Interestingly, injection of recombinant Prx1 into the ischemic core could block the anti-inflammatory effects of PARP-1 inhibitor in the experimental stroke. These findings suggest that PARP-1 inhibitor has effects on regulating microglial activation and post-stroke inflammation in males and females, and holds promise as a novel therapeutic agent for stroke with extended therapeutic time window. Efforts need to be made to delineate the actions of PARP-1 inhibition in stroke, and here we propose that Prx1 might be a critical mediator.

Abstract Accumulating evidence implies that long noncoding RNAs (lncRNAs) play a crucial role in predicting survival for Hepatocellular carcinoma (HCC) patients. This study aims to capture the current research hotspots of HCC, based on the analysis of publications related to HCC research from 2013 to 2017, and to identify a novel lncRNA signature for HCC prognosis through the data mining in The Cancer Genome Atlas (TCGA). “Prognosis” and “biomarker” were located in the core of the HCC research hotspot. Moreover, long noncoding RNA was the top one research frontier in HCC research. The associations between survival outcome and the expression of lncRNAs were evaluated by the univariate and multivariate Cox proportional hazards regression analyses. Four lncRNAs (LINC00261, TRELM3P, GBP1P1, and CDKN2B‐AS1) were identified as significantly correlated with overall survival (OS). These four lncRNAs were gathered as a single prognostic signature. There was a significant positive correlation between HCC patients with low‐risk scores and overall survival (HR = 1.802, 95%CI [1.224‐2.652], P = .003). Further analysis suggested that the prognostic value of this four‐lncRNA signature was independent in clinical features. The enrichment analysis of prognostic lncRNA‐related gene was performed to find out the related pathways. Our study indicates that this novel lncRNA expression signature may be a useful biomarker of the prognosis for HCC patients, based on bioinformatics analysis.

Abstract Cutaneous melanoma (CM) is the most malignant tumor of skin cancers because of its rapid development and high mortality rate. Long noncoding RNAs (lncRNAs), which play essential roles in the tumorigenesis and metastasis of CM and interplay with microRNAs (miRNAs) and mRNAs, are hopefully considered to be efficient biomarkers to detect deterioration during the progression of CM to improve the prognosis. Bioinformatics analysis was fully applied to predict the vital lncRNAs and the associated miRNAs and mRNAs, which eventually constructed the competing endogenous RNA (ceRNA) network to explain the RNA expression patterns in the progression of CM. Further statistical analysis emphasized the importance of these key genes, which were statistically significantly related to one or few clinical features from the ceRNA network. The results showed the lncRNAs MGC12926 and LINC00937 were verified to be strongly connected with the prognosis of CM patients.

Background Cervical cancer (CC) is a common gynecological malignancy in women worldwide. Evidence suggests that long non-coding RNAs (lncRNAs) can be used as biomarkers in patients with CC. However, prognostic biomarkers for CC are still lacking. The aim of our study was to find lncRNA biomarkers which are able to predict prognosis in CC based on the data from The Cancer Genome Atlas (TCGA). Methods The patients were divided into three groups according to FIGO stage. Differentially expressed lncRNAs were identified in CC tissue compared to adjacent normal tissues based on a fold change >2 and

With the large scale deployment of multihomed mobile computing devices in today’s Internet, the Multipath TCP (MPTCP) is being considered as a preferred data transmission technology in the future Internet due to its promising features of bandwidth aggregation and multipath transmission. However, MPTCP is more likely to be vulnerable to the transmission quality differences of multiple paths, which cause a “hot-potato” out-of-order arrival of packets at the receiver side, and in the absence of a related approach to fix this issue, serious application level performance degradations will occur. In this paper, we proposes MPTCP-LM 3 , a Lightweight path Management Mechanism to aid Multihomed MPTCP based mobile computing devices towards efficient multipath data transmission. The goals of MPTCP-LM 3 are: (i) to offer MPTCP a promising path management mechanism, (ii) to reduce out-of-order data reception and protect against receiver buffer blocking, and (iii) to increase the throughput of mobile computing devices in a multihomed wireless environment. Simulations show that MPTCP-LM 3 outperforms the current MPTCP schemes in terms of performance and quality of service.

We present new results on PHL 5038AB, a widely separated binary system composed of a white dwarf and a brown dwarf, refining the white and brown dwarf parameters and determining the binary separation to be |$66^{+12}_{-24}$| au. New spectra of the white dwarf show calcium absorption lines suggesting that the hydrogen-rich atmosphere is weakly polluted, inferring the presence of planetesimals in the system, which we determine are in an S-type orbit around the white dwarf in orbits closer than 17–32 au. We do not detect any infrared excess that would indicate the presence of a disc, suggesting that all dust present either has been totally accreted or is optically thin. In this system, we suggest that the metal pollution in the white dwarf atmosphere can be directly attributed to the presence of the brown dwarf companion disrupting the orbits of planetesimals within the system. [ABSTRACT FROM AUTHOR]

Over the past several decades, conventional spectral analysis techniques of polluted white dwarfs have become powerful tools to learn about the geology and chemistry of extrasolar bodies. Despite their proven capabilities and extensive legacy of scientific discoveries, these techniques are, however, still limited by their manual, time-intensive, and iterative nature. As a result, they are susceptible to human errors and are difficult to scale up to population-wide studies of metal pollution. This paper seeks to address this problem by presenting cecilia , the first machine learning (ML)-powered spectral modelling code designed to measure the metal abundances of intermediate-temperature (10 000 ≤ T eff ≤ 20 000 K), Helium-rich polluted white dwarfs. Trained with more than 22 000 randomly drawn atmosphere models and stellar parameters, our pipeline aims to overcome the limitations of classical methods by replacing the generation of synthetic spectra from computationally expensive codes and uniformly spaced model grids, with a fast, automated, and efficient neural-network-based interpolator. More specifically, cecilia combines state-of-the-art atmosphere models, powerful artificial intelligence tools, and robust statistical techniques to rapidly generate synthetic spectra of polluted white dwarfs in high-dimensional space, and enable accurate (≲0.1 dex) and simultaneous measurements of 14 stellar parameters – including 11 elemental abundances – from real spectroscopic observations. As massively multiplexed astronomical surveys begin scientific operations, cecilia 's performance has the potential to unlock large-scale studies of extrasolar geochemistry and propel the field of white dwarf science into the era of Big Data. In doing so, we aspire to uncover new statistical insights that were previously impractical with traditional white dwarf characterization techniques. [ABSTRACT FROM AUTHOR]

This work combines spectroscopic and photometric data of the polluted white dwarf WD 0141−675, which has a now retracted astrometric super-Jupiter candidate, and investigates the most promising ways to confirm Gaia astrometric planetary candidates and obtain follow-up data. Obtaining precise radial velocity measurements for white dwarfs is challenging due to their intrinsic faint magnitudes, lack of spectral absorption lines, and broad spectral features. However, dedicated radial velocity campaigns are capable of confirming close-in giant exoplanets (a few M Jup) around polluted white dwarfs, where additional metal lines aid radial velocity measurements. Infrared emission from these giant exoplanets is shown to be detectable with JWST Mid-Infrared Instrument (MIRI) and will provide constraints on the formation of the planet. Using the initial Gaia astrometric solution for WD 0141−675 as a case study, if there were a planet with a 33.65 d period or less with a nearly edge-on orbit, (1) ground-based radial velocity monitoring limits the mass to <15.4  M Jup, and (2) space-based infrared photometry shows a lack of infrared excess and in a cloud-free planetary cooling scenario, a substellar companion would have to be <16  M Jup and be older than 3.7 Gyr. These results demonstrate how radial velocities and infrared photometry can probe the mass of the objects producing some of the astrometric signals, and rule out parts of the brown dwarf and planet mass parameter space. Therefore, combining astrometric data with spectroscopic and photometric data is crucial to both confirm and characterize astrometric planet candidates around white dwarfs. [ABSTRACT FROM AUTHOR]