Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy.

The biological and functional heterogeneity between tumors-both across and within cancer types-poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy.

Disentanglement of Resting State Brain Networks for Localizing Epileptogenic Zone in Focal Epilepsy.

The objective of this study is to extract pathological brain networks from interictal period of E/MEG recordings to localize epileptic foci for presurgical evaluation. We proposed here a resting state E/MEG analysis framework, to disentangle brain functional networks represented by neural oscillations. By using an Embedded Hidden Markov Model, we constructed a state space for resting state recordings consisting of brain states with different spatiotemporal patterns. Functional connectivity analysis along with graph theory was applied on the extracted brain states to quantify the network features of the extracted brain states, based on which the source location of pathological states is determined. The method is evaluated by computer simulations and our simulation results revealed the proposed framework can extract brain states with high accuracy regarding both spatial and temporal profiles. We further evaluated the framework as compared with intracranial EEG defined seizure onset zone in 10 patients with drug-resistant focal epilepsy who underwent MEG recordings and were seizure free after surgical resection. The real patient data analysis showed very good localization results using the extracted pathological brain states in 6/10 patients, with localization error of about 15 mm as compared to the seizure onset zone. We show that the pathological brain networks can be disentangled from the resting-state electromagnetic recording and could be identified based on the connectivity features. The framework can serve as a useful tool in extracting brain functional networks from noninvasive resting state electromagnetic recordings, and promises to offer an alternative to aid presurgical evaluation guiding intracranial EEG electrodes implantation.

Noninvasive high-frequency oscillations riding spikes delineates epileptogenic sources.

High-frequency oscillations (HFOs) are a promising biomarker for localizing epileptogenic brain and guiding successful neurosurgery. However, the utility and translation of noninvasive HFOs, although highly desirable, is impeded by the difficulty in differentiating pathological HFOs from nonepileptiform high-frequency activities and localizing the epileptic tissue using noninvasive scalp recordings, which are typically contaminated with high noise levels. Here, we show that the consistent concurrence of HFOs with epileptiform spikes (pHFOs) provides a tractable means to identify pathological HFOs automatically, and this in turn demarks an epileptiform spike subgroup with higher epileptic relevance than the other spikes in a cohort of 25 temporal epilepsy patients (including a total of 2,967 interictal spikes and 1,477 HFO events). We found significant morphological distinctions of HFOs and spikes in the presence/absence of this concurrent status. We also demonstrated that the proposed pHFO source imaging enhanced localization of epileptogenic tissue by 162% (∼5.36 mm) for concordance with surgical resection and by 186% (∼12.48 mm) with seizure-onset zone determined by invasive studies, compared to conventional spike imaging, and demonstrated superior congruence with the surgical outcomes. Strikingly, the performance of spike imaging was selectively boosted by the presence of spikes with pHFOs, especially in patients with multitype spikes. Our findings suggest that concurrent HFOs and spikes reciprocally discriminate pathological activities, providing a translational tool for noninvasive presurgical diagnosis and postsurgical evaluation in vulnerable patients.

Possible genetic cross-talk between Down syndrome and obstructive sleep apnea revealed by transcriptomic analysis.

PURPOSE: Down syndrome (DS) is linked to a higher prevalence of obstructive sleep apnea (OSA) than in the general population, which in turn contributes to worse cognitive impairment in DS. However, the shared pathogenic mechanisms for DS and OSA remain incompletely illustrated. This study was designed to decipher the genetic cross-talk between DS and OSA by bioinformatics approach. METHODS: Transcriptomic datasets of DS (GSE59630) and OSA (GSE135917) were accessed from the Gene Expression Omnibus (GEO) repository. After screening out the common differentially expressed genes (DEGs) for DS and OSA, gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out. A protein-protein interaction (PPI) network was then constructed to determine essential modules and hub genes. Finally, based on hub genes, transcriptional factor (TF)-gene interaction and TF-miRNA regulatory networks were constructed. RESULTS: DS and OSA showed 229 DEGs. Functional analyses revealed how oxidative stress and inflammatory response were critical in the progression of DS and OSA. Ten significant hub genes were identified, including TLR4, SOD1, IGF1, FGF2, NFE2L2, PECAM1, S100A8, S100A9, FCGR3A, and KCNA1, which were candidate targets for DS and OSA. CONCLUSIONS: We found that DS and OSA display similarities in their pathogenesis. Key genes and signaling pathways revealed to be in common between the two conditions could lead us to new therapeutic targets for DS and OSA.

ReS2 Nanoflowers-Assisted Confined Growth of Gold Nanoparticles for Ultrasensitive and Reliable SERS Sensing.

ReS2, as a new member of transition metal dichalcogenides (TMDCs), has emerged as a promising substrate for semiconductor surface-enhanced Raman spectroscopy (SERS) due to its unique optoelectronic properties. Nevertheless, the sensitivity of the ReS2 SERS substrate poses a significant challenge to its widespread application in trace detection. In this work, we present a reliable approach for constructing a novel ReS2/AuNPs SERS composite substrate, enabling ultrasensitive detection of trace amounts of organic pesticides. We demonstrate that the porous structures of ReS2 nanoflowers can effectively confine the growth of AuNPs. By precisely controlling the size and distribution of AuNPs, numerous efficient and densely packed "hot spots" were created on the surface of ReS2 nanoflowers. As a result of the synergistic enhancement of the chemical and electromagnetic mechanisms, the ReS2/AuNPs SERS substrate demonstrates high sensitivity, good reproducibility, and superior stability in detecting typical organic dyes such as rhodamine 6G and crystalline violet. The ReS2/AuNPs SERS substrate shows an ultralow detection limit of 10-10 M and a linear detection of organic pesticide molecules within 10-6-10-10 M, which is significantly lower than the EU Environmental Protection Agency regulation standards. The strategy of constructing ReS2/AuNPs composites would contribute to the development of highly sensitive and reliable SERS sensing platforms for food safety monitoring.

Modified Frantz-Nodvik equation and numerical simulation of a high-power Innoslab picosecond laser amplifier.

A modified Frantz-Nodvik (F-N) equation and a simple one-dimensional unfolded slicing model for numerically simulating high-power Innoslab picosecond amplifier are developed for the first time. The anisotropic stimulated emission cross-section of laser crystal, the influence of the tilted optical path, the spatial overlap of the seed and pump laser, as well as the pump absorption saturation effect are considered. Based on the as-developed model, 4-, 6- and 8-pass schemes high-power Nd:YVO4 Innoslab picosecond amplifiers are designed with output powers of 76.2 W, 81.4 W, and 85.5 W, respectively. The experimental results agree well with that of numerical simulation, indicating that our model is a powerful tool and paves a new way for designing and optimizing high-power Innoslab picosecond laser amplifier.

Cascade MIR Ho:YLF laser at 2.1†µm and 2.9 µm.

Cascade transitions of Ho3+:5I6→5I7 and 5I7→5I8 provide a platform for a dual-wavelength mid-infrared (MIR) laser. In this paper, a continuous wave cascade MIR Ho:YLF laser operating at 2.1 and 2.9 µm is realized at room temperature. The total output power of 929 mW with 778 mW at 2.9 µm and 151 mW at 2.1 µm is obtained under the absorbed pump power of 5 W. Compared to the non-cascade mode, 2.9-µm lasing threshold is reduced by 10.3% and the slope efficiency is increased by 76.1% with the supports of cascade lasing at 2.1 µm. However, 2.9-µm lasing is the key population accumulation of the 5I7 level, which thus efficiently reduces the threshold and improves the output power of the 2.1-µm laser. Our results put forward a way for generating cascade dual-wavelength MIR lasing in Ho3+-doped crystals.

High-Performance Heterogeneous Thermocatalysis Caused by Catalyst Wettability Regulation.

Catalyst wettability regulation has emerged as an attractive approach for high catalytic performance for the past few years. By introducing appropriate wettability, the molecule diffusion of reactants and products can be enhanced, leading to high activity. Besides this, undesired molecules are isolated for high selectivity of target products and long-term stability of catalyst. Herein, we summarize wettability-induced high-performance heterogeneous thermocatalysis in recent years, including hydrophilicity, hydrophobicity, hybrid hydrophilicity-hydrophobicity, amphiphilicity, and superaerophilicity. Relevant reactions are further classified and described according to the reason for the performance improvement. It should be pointed out that studies of utilizing superaerophilicity to improve heterogeneous thermocatalytic performance have been included for the first time, so this is a comparatively comprehensive review in this field as yet.

Altered gut microbiota correlates with cognitive impairment in Chinese children with Down's syndrome.

Down's syndrome (DS), a common chromosomal disease caused by chromosome 21 trisomy, is the main cause of cognitive impairment in children worldwide. Emerging evidence suggests that the microbiota-gut-brain axis plays a potential role in cognitive impairment. However, data regarding gut microbiota alterations in DS patients remain scarce, especially data from children with DS. This case-control study was conducted to explore the gut microbiota composition in Chinese DS children. Additionally, the potential association between gut microbiota and cognitive function in DS was evaluated. Microbiota communities in the feces of 15 DS subjects and 15 matched controls were investigated using high-throughput Illumina Miseq sequencing targeting the V3-V4 region of 16S rRNA gene. The relationships between gut microbiota composition and DS cognitive function scores were analyzed. The structure and richness of the gut microbiota differed between DS patients and healthy controls. The abundance of Acidaminococcaceae was decreased in DS patients. Moreover, the Kyoto Encyclopedia of Genes and Genomes analysis showed increased modules related to peptidases and pyrimidine metabolism. Overall, we confirmed that gut microbiota alterations occurred in Chinese patients with DS. Additionally, the fecal microbiota was closely related to DS cognitive impairment. Larger cohorts are needed to confirm these findings and to clarify the mechanisms involved. Elucidating these novel findings in the field of microbiota-gut-brain axis will provide a promising strategy for future studies of DS cognitive impairment.

Fluorine-Nitrogen-Codoped Carbon Dots as Fluorescent Switch Probes for Selective Fe(III) and Ascorbic Acid Sensing in Living Cells.

High-quality fluorescent probes based on carbon dots (CDs) have promising applications in many fields owing to their good stability, low toxicity, high quantum yield, and low raw material price. The fluorine- and nitrogen-doped fluorescent CDs (NFCDs) with blue fluorescence was successfully synthesized using 3-aminophenol and 2,4-difluorobenzoic acid as the raw material by the hydrothermal method. The NFCDs as probe can be used to directly and indirectly detect Fe3+ (detection range: 0.1-150 µM and detection limit: 0.14 µM) and ascorbic acid (AA) (detection range: 10-80 µM and detection limit: 0.11 µM). The NFCDs-based probe shows exceptional selectivity and strong anti-interference for Fe3+ and ascorbic acid (AA). In addition, we examined the response of NFCDs to Fe3+ and AA in living cells, which showed that the timely use of AA can reduce the effects of iron poisoning. This has important biological significance. This means that using NFCDs as fluorescent probes is beneficial for Fe3+ and AA detection and observing their dynamic changes in living cells. Thus, this work may contribute to the study of Fe3+- and AA-related diseases.

Recent Advances in Perovskite Photodetectors for Image Sensing.

In recent years, metal halide perovskites have been widely investigated to fabricate photodetectors for image sensing due to the excellent photoelectric performance, tunable bandgap, and low-cost solution preparation process. In this review, a comprehensive overview of the recent advances in perovskite photodetectors for image sensing is provided. First, the key performance parameters and the basic device types of photodetectors are briefly introduced. Then, the recent developments of image sensors on the basis of different dimensional perovskite materials, including 0D, 1D, 2D, and 3D perovskite materials, are highlighted. Besides the device structures and photoelectric properties of perovskite image sensors, the preparation methods of perovskite photodetector arrays are also analyzed. Subsequently, the single-pixel imaging of perovskite photodetectors and the strategies to fabricate narrowband perovskite photodetectors for color discrimination are discussed. Finally, the potential challenges and possible solutions for the future development of perovskite image sensors are presented.

Brain-Heart Interactions Underlying Traditional Tibetan Buddhist Meditation.

Despite accumulating evidence suggesting improvement in one's well-being as a result of meditation, little is known about if or how the brain and the periphery interact to produce these behavioral and mental changes. We hypothesize that meditation reflects changes in the neural representations of visceral activity, such as cardiac behavior, and investigated the integration of neural and visceral systems and the spontaneous whole brain spatiotemporal dynamics underlying traditional Tibetan Buddhist meditation. In a large cohort of long-term Tibetan Buddhist monk meditation practitioners, we found distinct transient modulations of the neural response to heartbeats in the default mode network (DMN), along with large-scale network reconfigurations in the gamma and theta bands of electroencephalography (EEG) activity induced by meditation. Additionally, temporal-frontal network connectivity in the EEG theta band was negatively correlated with the duration of meditation experience, and gamma oscillations were uniquely, directionally coupled to theta oscillations during meditation. Overall, these data suggest that the neural representation of cardiac activity in the DMN and large-scale spatiotemporal network integrations underlie the fundamental neural mechanism of meditation and further imply that meditation may utilize cortical plasticity, inducing both immediate and long-lasting changes in the intrinsic organization and activity of brain networks.

Room temperature watt-level 3.87†µm MgO:PPLN optical parametric oscillator under pumping with a Tm:YAP laser.

A room-temperature highly efficient Tm:YAP laser pumped MgO:PPLN optical parametric oscillator operating at 3.87 µm near degeneracy is demonstrated. The pump source is an acousto-optical (AO) Q-switched Tm:YAP laser, which delivers a maximum output power of 6.17 W with a pulse duration of 45 ns and a repetition rate of 6 kHz. The temperature dependent wavelength tuning characteristics of the PPLN-OPO is investigated, and a maximum OPO output power of 1.2 W at around 3.87 µm is achieved at 35°C, corresponding to an optical-optical conversion efficiency of 19.4%. To the best of our knowledge, this is the maximum output power ever reported from 2 µm waveband laser pumped 3-5 µm MgO:PPLN OPOs.

Selective determination of 2,4,6-trinitrophenol by using a novel carbon nanoparticles as a fluorescent probe in real sample.

2,4,6-Trinitrophenol (TNP) is widely used in our daily life; however, excessive use of TNP can lead to a large number of diseases. Therefore, it is necessary to find an effective method to detect TNP. Herein, the rapid fluorescence quenching by TNP was developed for the fluorometric determination of TNP in aqueous medium based on the internal filter effect. Nitrogen-sulfur-codoped carbon nanoparticles (N,S-CNPs), synthesized by a one-pot solvothermal method with the precursors of L-cysteine and citric acid, were applied for the determination of TNP as a fluorescent probe. The excitation peak center of N,S-CNPs and the emission peak center are 340 nm and 423 nm, respectively. The probe can be used in a variety of conditions to detect TNP due to its relatively stable properties. Meanwhile, it has a fast response time (< 1 min), wide linear response range (0.1-40 µM), and low detection limit (43.0 nM). This probe still has excellent selectivity and high sensitivity. The method was also used to detect standard water samples with a satisfactory recovery rate, and it will be used in the application of pollutants and clinical diseases. Graphical abstract.

A Disintegrin and Metalloproteinase with Thrombospondin Motifs 18 Deficiency Leads to Visceral Adiposity and Associated Metabolic Syndrome in Mice.

Visceral adiposity is of greater risk than obesity in s.c. adipose tissue for diabetes and cardiovascular disease. Its pathogenesis remains unclear, but it is associated with extracellular matrix (ECM) remodeling. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are a family of secreted zinc-dependent metalloproteinases that play crucial roles in development and various diseases because of their ECM remodeling activity. ADAMTS18 is an orphan ADAMTS whose function and substrate remain unclear. Herein, we showed that Adamts18 mRNA was abundantly expressed in visceral (gonadal) white adipose tissue (vWAT) during the early stage of development after birth. Adamts18 knockout (KO) mice showed increased body fat percentage and larger adipocyte size in vWAT relative to wild-type littermates. These findings may be partly attributed to ECM remodeling, especially increased expression of laminin 1 and adipokine thrombospondin 1 in vWAT. Attenuated extracellular signal-regulated kinase 1 and 2 activity, along with increased expression of adipocyte-specific transcription factors peroxisome proliferator-activated receptor-γ, CCAAT/enhancer binding protein ß, and marker gene Fabp4, was detected in vWAT of Adamts18 KO mice. Furthermore, Adamts18 KO mice showed early metabolic syndrome, including hyperlipidemia, blood glucose metabolic disorder, and hypertension. ADAMTS18 deficiency promotes atherosclerosis in apolipoprotein E-deficient mice. These results indicate a novel function of ADAMTS18 in vWAT development and associated metabolic disorders.

MicroRNA-21-5p as a novel therapeutic target for osteoarthritis.

OBJECTIVE: Growing evidence indicates that microRNAs (miRNA) play a critical role in the pathogenesis of OA, and overexpressing or silencing miRNA expression in OA models can contribute to the development of miRNA-based therapeutics. The objective of this study was to determine whether intra-articular injection of miRNA can inhibit OA progression. METHODS: The miRNA expression profile was determined in OA cartilage tissues and controls. Functional analysis of the miRNAs on extracellular matrix degradation was performed after miRNA mimic or inhibitor transfection. Luciferase reporter assays and western blotting were employed to determine miRNA targets. To investigate the functional mechanism of miR-21-5p in OA development, miR-21-5pfl/flCol2a1-CreER and wild-type mice were subject to surgical destabilization of the medial meniscus. Therapeutically, wild-type mice undergoing surgical destabilization of the medial meniscus were treated with intra-articular injection of agomir- and antagomir-21-5p. RESULTS: We found that expression of miR-21-5p was significantly up-regulated in OA cartilage tissues. The articular cartilage degradation of miR-21-5p conditional knockout mice was significantly alleviated compared with that of wild-type mice in spontaneous and destabilization of the medial meniscus models. Through gain-of-function and loss-of-function studies, miR-21-5p was shown to significantly affect matrix synthesis genes expression, and chondrocyte proliferation and apoptosis. Further, fibroblast growth factor 18 (FGF18) was identified as a target of miR-21-5p. Intra-articular injection of antagomir-21-5p significantly attenuated the severity of experimental OA. Clinically, FGF18 expression level was correlated with miR-21-5p expression and a modified Mankin scale. CONCLUSION: Our findings reveal a miRNA functional pathway important for OA development, highlighting miRNA-21-5p silencing as an attractive therapeutic regimen in future clinical trials involving patients with OA.

Spark-Based Parallel Genetic Algorithm for Simulating a Solution of Optimal Deployment of an Underwater Sensor Network.

Underwater sensor networks have wide application prospects, but the large-scale sensing node deployment is severely hindered by problems like energy constraints, long delays, local disconnections, and heavy energy consumption. These problems can be solved effectively by optimizing sensing node deployment with a genetic algorithm. However, the genetic algorithm (GA) needs many iterations in solving the best location of underwater sensor deployment, which results in long running time delays and limited practical application when dealing with large-scale data. The classical parallel framework Hadoop can improve the GA running efficiency to some extent while the state-of-the-art parallel framework Spark can release much more parallel potential of GA by realizing parallel crossover, mutation, and other operations on each computing node. Giving full allowance for the working environment of the underwater sensor network and the characteristics of sensors, this paper proposes a Spark-based parallel GA to calculate the extremum of the Shubert multi-peak function, through which the optimal deployment of the underwater sensor network can be obtained. Experimental results show that while faced with a large-scale underwater sensor network, compared with single node and Hadoop framework, the Spark-based implementation not only significantly reduces the running time but also effectively avoids the problem of premature convergence because of its powerful randomness.

Solution-Phase Synthesis of Few-Layer Hexagonal Antimonene Nanosheets via Anisotropic Growth.

Antimonene, an emerging two-dimensional material, has garnered tremendous interest due to its intriguing structure and fascinating electronic properties. However, the synthesis of high-quality few-layer antimonene nanosheets, which can only be produced by exfoliation or epitaxial growth on exotic substrates, has greatly hindered the development of this new field. Herein, few-layer hexagonal and functionalized antimonene nanosheets were successfully prepared from SbCl3 solutions for the first time by exclusively promoting their anisotropic growth in a colloidal solution. Oleylamine was selected as the reducing agent, rather than oleic acid, and dodecylthiol was key to preventing the formation of antimony oxide. Additionally, halide ions adsorbed on the surface also influenced the anisotropic growth of hexagonal antimonene nanosheets. Atomic force microscopy (AFM) revealed that the sheets were ≈5 nm thick; Raman spectroscopy and X-ray diffraction (XRD) revealed a rhombohedral atomic structure (ß-Sb) with excellent stability.

The development of monoclonal anti-ADAMTS18 antibodies with precise validation of ADAMTS18 post-translational modification status in living organisms.

ADAMTS18 is a member of a secreted Zn-metalloproteinase ADAMTS family, and has been implicated in development, hemostasis, and various malignancies. It has thus far proven difficult to resolve its post-translational modification status, cleaved forms, and splice variants in living organisms due to the lack of specific antibodies available to characterize this enzyme. In this study, we develop six murine monoclonal antibodies (mAbs) against different functional regions of ADAMTS18 using hybridoma technology. These mAbs exhibit cross-recognition between ADAMTS18 and the homology domain of its family members. Using the tissues from Adamts18 knockout (KO) mice, we find that two of these mAbs (N-3 and C-5) precisely identify five significantly attenuated bands located at 180, 135, 95, 72, and 45 kDa. These bands represent the forms of ADAMTS18 that potentially exist in the tissues. These mAbs will provide a useful tool to investigate the ADAMTS18's biologic significance in the tissues.

Targeting the Hippo pathway: Clinical implications and therapeutics.

The Hippo pathway plays a critical role in tissue and organ size regulation by restraining cell proliferation and apoptosis under homeostatic conditions. Deregulation of this pathway can promote tumorigenesis in multiple malignant human tumor types, including sarcoma, breast, lung and liver cancers. In this review, we summarize the current understanding of Hippo pathway function, it's role in human cancer, and address the potential of Hippo pathway member proteins as therapeutic targets for a variety of tumors.