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The genus Pimoa Chamberlin & Ivie, 1943, is highly diverse and currently contains 85 species, of which 67 are distributed in Asia. In this study, a new species of Pimoa is described from Southwest China: P. shimian Wang, Yao & Zhang, sp. nov. (♂♀). This new species is closely related to P. bomi Zhang & Li, 2021, and P. reniformis Xu & Li, 2007. The taxonomic keys for distinguishing these three closely related species and a distribution map of all Asian pimoids are also provided.

ObjectivesIn this study, we constructed a model based on circadian rhythm associated genes (CRRGs) to predict prognosis and immune infiltration in patients with breast cancer (BC).Materials and methodsBy using TCGA and CGDB databases, we conducted a comprehensive analysis of circadian rhythm gene expression and clinicopathological data. Three different machine learning algorithms were used to screen out the characteristic circadian genes associated with BC prognosis. On this basis, a circadian gene prediction model about BC prognosis was constructed and validated. We also evaluated the association of the model’s risk score with immune cells and immune checkpoint genes, and analyzed prognostic genes and drug sensitivity in this model.ResultsWe screened 62 DEGs, including 30 upregulated genes and 32 downregulated genes, and performed GO and KEGG analysis on them. The above 62 DEGs were included in Cox analysis, LASSO regression, Random Forest and SVMV-RFE, respectively, and then the intersection was used to obtain 5 prognostic related characteristic genes (SUV39H2, OPN4, RORB, FBXL6 and SIAH2). The Risk Score of each sample was calculated according to the expression level and risk coefficient of 5 genes, Risk Score= (SUV39H2 expression level ×0.0436) + (OPN4 expression level ×1.4270) + (RORB expression level ×0.1917) + (FBXL6 expression level ×0.3190) + (SIAH2 expression level × -0.1984).ConclusionSUV39H2, OPN4, RORB and FBXL6 were positively correlated with Risk Score, while SIAH2 was negatively correlated with Risk Score. The above five circadian rhythm genes can construct a risk model for predicting the prognosis and immune invasion of BC.

China exhibits remarkable diversity of the spider genus Belisana Thorell, 1898, with 62 species recorded to date. However, the largest number of Belisana species was found in Yunnan Province (23 ssp.), while only seven species were found in Guizhou Province.In this paper, Belisana wangchengi sp. nov. as a new species is described from Guizhou Province, China.

Although oxidative stress is closely associated with tumor invasion and metastasis, its’ exact role and mechanism in the initial stage of oral cancer remain ambiguous. Glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) participates in glutathione synthesis to resolve oxidative stress. Currently, we firstly found that ASCT2 deletion caused oxidative stress in oral mucosa and promoted oral carcinogenesis induced by 4-Nitroquinoline-1-oxide (4-NQO) using transgenic mice of ASCT2 knockout in oral epithelium. Subsequently, we identified an upregulated gene Thbs1 linked to macrophage infiltration by mRNA sequencing and immunohistochemistry. Importantly, multiplex immunohistochemistry showed M1-like tumor-associated macrophages (TAMs) were enriched in cancerous area. Mechanically, targeted ASCT2 effectively curbed glutamine uptake and caused intracellular reactive oxygen species (ROS) accumulation, which upregulated Thbs1 in oral keratinocytes and then activated p38, Akt and SAPK/JNK signaling to polarize M1-like TAMs via exosome-transferred pathway. Moreover, we demonstrated M1-like TAMs promoted malignant progression of oral squamous cell carcinoma (OSCC) both in vitro and in vivo by a DOK transformed cell line induced by 4-NQO. All these results establish that oxidative stress triggered by ASCT2 deletion promotes oral carcinogenesis through Thbs1-mediated M1 polarization, and indicate that restore redox homeostasis is a new approach to prevent malignant progression of oral potentially malignant disorders.

Acute pancreatitis (AP) is a sudden-onset disease of the digestive system caused by abnormal activation of pancreatic enzymes. Dual oxidase 2 (DUOX2) has been found to be elevated in the progression of a variety of inflammatory diseases. Therefore, we analyzed the specific roles of DUOX2 in AP development. Blood samples were collected from of AP patients and healthy people, and the caerulein- stimulated human pancreatic duct cells (H6C7) were utilized to establish an AP cell model. Cell growth and apoptosis were measured using an MTT assay and TUNEL staining. Additionally, RT-qPCR and western blot assays were conducted to assess the RNA and protein expressions of the cells. ELISA kits were used to determine TNF-α, IL-6, IL-8, and IL-1β levels. The interaction between DUOX2 and miR-605-3p was predicted using the Targetscan database and confirmed by dual-luciferase report assay. We found that DUOX2 increased while miR-605-3p decreased in the blood of AP patients and caerulein-stimulated H6C7 cells. DUOX2 was targeted by miR-605-3p. Furthermore, DUOX2 knockdown or miR-605-3p overexpression promoted cell viability, decreased the TNF-α, IL-6, IL-8, and IL-1β levels, and inhibited apoptosis rate in caerulein-stimulated H6C7 cells. DUOX2 knockdown or miR-605-3p overexpression also increased the Bcl-2 protein levels and down-regulated Bax, cleaved-caspase-1, NLRP3 and p-p65. Interestingly, DUOX2 overexpression reversed the miR-605-3p mimic function in the caerulein-treated H6C7 cells. In conclusion, our research demonstrated that DUOX2 knockdown relieved the injury and inflammation in caerulein-stimulated H6C7 cells.

Abstract Background Circulating cell-free DNA (cfDNA) is a pool of short DNA fragments mainly released from apoptotic hematopoietic cells. Nevertheless, the precise physiological process governing the DNA fragmentation and molecular profile of cfDNA remains obscure. To dissect the DNA fragmentation process, we use a human leukemia cell line HL60 undergoing apoptosis to analyze the size distribution of DNA fragments by shallow whole-genome sequencing (sWGS). Meanwhile, we also scrutinize the size profile of plasma cfDNA in 901 healthy human subjects and 38 dogs, as well as 438 patients with six common cancer types by sWGS. Results Distinct size distribution profiles were observed in the HL60 cell pellet and supernatant, suggesting fragmentation is a stepwise process. Meanwhile, C-end preference was seen in both intracellular and extracellular cfDNA fragments. Moreover, the cfDNA profiles are characteristic and conserved across mammals. Compared with healthy subjects, distinct cfDNA profiles with a higher proportion of short fragments and lower C-end preference were found in cancer patients. Conclusions Our study provides new insight into fragmentomics of circulating cfDNA processing, which will be useful for early diagnosis of cancer and surveillance during cancer progression.

Abstract Background Intervertebral disc degeneration (IDD) naturally occurs during the aging process. Its occurrence is closely related to chronic inflammation; however, the causal relationship between them is controversial. This study aimed to investigate if inflammation would promote IDD incidence and explore the underlying mechanism. Methods A chronic inflammation mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS). Enzyme-linked immunosorbent assay was performed to determine proinflammatory cytokines in serum. Histological staining was used to evaluate the degeneration of IVDs. Immunoblots and RT-qPCR analyses were performed to measure protein and mRNA expression levels. Immunoprecipitation, mass spectrometry, and co-immunoprecipitation assays were used to determine the assembly of protein complex. Results We found that an inflammatory microenvironment activated p38 kinase, which phosphorylated the Runx2 transcription factor at the Ser28 site. The phosphorylated Runx2 (pRunx2) then recruited a deubiquitinase, ubiquitin-specific peptidase 24 (USP24), which stabilized pRunx2 and protected it from ubiquitin-dependent proteasomal degradation. The stabilized pRunx2 recruited histone acetyltransferase p300 and nuclear receptor coactivator 3 (NCOA3) to assemble a complex. This NCOA3-p300-pRunx2 complex then transactivated the expression of 13 ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) genes, thereby promoting the degradation of extracellular matrix (ECM) in intervertebral discs (IVDs) and causing IDD. Administration of either a p38 inhibitor (doramapimod), a NCOA3 inhibitor (bufalin), or a p300 inhibitor (EML425) significantly decreased the expression of the 13 ADAMTS genes and slowed the degeneration of IVDs. Conclusion In summary, our results demonstrate that USP24 protects pRunx2 from proteasomal degradation under chronic inflammation conditions, enabling pRunx2 to transactivate ADAMTS genes and degrade ECM. Our findings provide direct evidence that chronic inflammation triggers IDD and offer a therapeutic strategy for retarding IDD in patients with chronic inflammation.

Abstract Transient receptor potential (TRP) channels are sensors for a variety of cellular and environmental signals. Mammals express a total of 28 different TRP channel proteins, which can be divided into seven subfamilies based on amino acid sequence homology: TRPA (Ankyrin), TRPC (Canonical), TRPM (Melastatin), TRPML (Mucolipin), TRPN (NO-mechano-potential, NOMP), TRPP (Polycystin), TRPV (Vanilloid). They are a class of ion channels found in numerous tissues and cell types and are permeable to a wide range of cations such as Ca2+, Mg2+, Na+, K+, and others. TRP channels are responsible for various sensory responses including heat, cold, pain, stress, vision and taste and can be activated by a number of stimuli. Their predominantly location on the cell surface, their interaction with numerous physiological signaling pathways, and the unique crystal structure of TRP channels make TRPs attractive drug targets and implicate them in the treatment of a wide range of diseases. Here, we review the history of TRP channel discovery, summarize the structures and functions of the TRP ion channel family, and highlight the current understanding of the role of TRP channels in the pathogenesis of human disease. Most importantly, we describe TRP channel-related drug discovery, therapeutic interventions for diseases and the limitations of targeting TRP channels in potential clinical applications.

Text classification is not only a prerequisite for natural language processing work, such as sentiment analysis and natural language reasoning, but is also of great significance for screening massive amounts of information in daily life. However, the performance of classification algorithms is always affected due to the diversity of language expressions, inaccurate semantic information, colloquial information, and many other problems. We identify three clues in this study, namely, core relevance information, semantic location associations, and the mining characteristics of deep and shallow networks for different information, to cope with these challenges. Two key insights about the text are revealed based on these three clues: key information relationship and word group inline relationship. We propose a novel attention feature fusion network, Attention Pyramid Transformer (APTrans), which is capable of learning the core semantic and location information from sentences using the above-mentioned two key insights. Specially, a hierarchical feature fusion module, Feature Fusion Connection (FFCon), is proposed to merge the semantic features of higher layers with positional features of lower layers. Thereafter, a Transformer-based XLNet network is used as the backbone to initially extract the long dependencies from statements. Comprehensive experiments show that APTrans can achieve leading results on the THUCNews Chinese dataset, AG News, and TREC-QA English dataset, outperforming most excellent pre-trained models. Furthermore, extended experiments are carried out on a self-built Chinese dataset theme analysis of teachers’ classroom corpus. We also provide visualization work, further proving that APTrans has good potential in text classification work.

The physiological state of an insect can affect its olfactory system. However, the molecular mechanism underlying the effect of nutrition-dependent states on odour-guided behaviours in hoverflies remains unclear. In this study, comparative transcriptome analysis of the antenna and proboscis from Eupeodes corollae under different feeding states was conducted. Compared with the previously published antennal transcriptome, a total of 32 novel chemosensory genes were identified, including 4 ionotropic receptors, 17 gustatory receptors, 9 odorant binding proteins and 2 chemosensory proteins. Analysis of differences in gene expression between different feeding states in male and female antennae and proboscises revealed that the expression levels of chemosensory genes were impacted by feeding state. For instance, the expression levels of EcorOBP19 in female antennae, EcorOBP6 in female proboscis, and EcorOR6, EcorOR14, EcorIR5 and EcorIR84a in male antennae were significantly upregulated after feeding. On the other hand, the expression levels of EcorCSP7 in male proboscis and EcorOR40 in male antennae were significantly downregulated. These findings suggest that nutritional state plays a role in the adaptation of hoverflies' olfactory system to food availability. Overall, our study provides important insights into the plasticity and adaptation of chemosensory systems in hoverflies.

Amomum xanthioides, A. villosum and A. longiligulare are three medicinally important herbs that are widely cultivated in southeast Asia. The ripe fruits of all three species are not only used worldwide in treatments for gastrointestinal diseases, but are also popular condiments in cooked food. In this study, we determined and analyzed the complete chloroplast (cp) genome sequences of these three Amomum species. The sizes of the cp genomes of A. xanthioides, A. villosum and A. longiligulare were 161,889 bp, 162,355 bp, and 161,990 bp, respectively. The cp genomes of all three species displayed a typical quadripartite structure. The cp genomes of A. xanthioides, A. villosum, and A. longiligulare encoded a total of 139, 138, and 139 genes, respectively, of which 118, 117, and 118 genes were single-copy genes. These included 92 protein-coding genes, eight rRNAs, as well as 39, 38, and 39 tRNAs, respectively. A comparative analysis revealed that the cp genomes of the three Amomum species had similar characteristics and patterns of organization. However, they also varied in terms of gene content, the expansion of inverted repeats, codon usage, repeat sequences, and simple sequence repeats. A phylogenetic analysis strongly supported a sister relationship between A. xanthioides and A. villosum. Overall, the results advance understanding of the relationships among the three medicinally valuable Amomum species, and provide basic molecular information to aid conservation efforts as well as research in phylogenetics and systematics.

Nanoprobes that offer both fluorescence imaging (FI) and magnetic resonance imaging (MRI) can provide supplementary information and hold synergistic advantages. However, synthesis of such dual-modality imaging probes that simultaneously exhibit tunability of functional groups, high stability, great biocompatibility and desired dual-modality imaging results remains challenging. In this study, we used an amphiphilic block polymer from (ethylene glycol) methyl ether methacrylate (OEGMA) and N-(2-hydroxypropyl) methacrylamide (HPMA) derivatives as a carrier to conjugate a MR contrast agent, Gd-DOTA, and a two-photon fluorophore with an aggregation-induced emission (AIE) effect, TPBP, to construct a MR/two-photon fluorescence dual-modality contrast agent, Gd-DOTA-TPBP. Incorporation of gadolinium in the hydrophilic chain segment of the OEGMA-based carrier resulted in a high r1 value for Gd-DOTA-TPBP, revealing a great MR imaging resolution. The contrast agent specifically accumulated in the tumor region, allowing a long enhancement duration for vascular and tumor contrast-enhanced MR imaging. Meanwhile, coupling TPBP with AIE properties to the hydrophobic chain segment of the carrier not only improved its water solubility and reduced its cytotoxicity, but also significantly enhanced its imaging performance in an aqueous phase. Gd-DOTA-TPBP was also demonstrated to act as an excellent fluorescence probe for two-photon-excited bioimaging with higher resolution and greater sensitivity than MRI. Since high-resolution, complementary MRI/FI dual-modal images were acquired at both cellular and tissue levels in tumor-bearing mice after application of Gd-DOTA-TPBP, it has great potential in the early phase of disease diagnosis.

Although advances in single-cell technologies have enabled the characterization of multiple omics profiles in individual cells, extracting functional and mechanistic insights from such information remains a major challenge. Here, we present scapGNN, a graph neural network (GNN)-based framework that creatively transforms sparse single-cell profile data into the stable gene-cell association network for inferring single-cell pathway activity scores and identifying cell phenotype-associated gene modules from single-cell multi-omics data. Systematic benchmarking demonstrated that scapGNN was more accurate, robust, and scalable than state-of-the-art methods in various downstream single-cell analyses such as cell denoising, batch effect removal, cell clustering, cell trajectory inference, and pathway or gene module identification. scapGNN was developed as a systematic R package that can be flexibly extended and enhanced for existing analysis processes. It provides a new analytical platform for studying single cells at the pathway and network levels.

Adenosine promotes anti-tumor immune responses by modulating the functions of T-cells and natural killer (NK) cells in the tumor microenvironment; however, the role of adenosine receptors in the progression of oral squamous cell carcinoma (OSCC) and its effects on immune checkpoint therapy remain unclear. In this study, we obtained the tumor tissues from 80 OSCC patients admitted at the Shandong University Qilu Hospital between February 2014 and December 2016. Thereafter, we detected the expression of adenosine 2b receptor (A2BR) and programmed death-ligand 1 (PD-L1) using immunohistochemical staining and analyzed the association between their expression in different regions of the tumor tissues, such as tumor nest, border, and paracancer stroma. To determine the role of A2BR in PD-L1 expression, CAL-27 (an OSCC cell line) was treated with BAY60-6583 (an A2BR agonist), and PD-L1 expression was determined using western blot and flow cytometry. Furthermore, CAL-27 was treated with a nuclear transcription factor-kappa B (NF-κ B) inhibitor, PDTC, to determine whether A2BR regulates PD-L1 expression via the NF-κ B signaling pathway. Additionally, a transwell assay was performed to verify the effect of A2BR and PD-L1 on NK cell recruitment. The results of our study demonstrated that A2BR and PD-L1 are co-expressed in OSCC. Moreover, treatment with BAY60-6583 induced PD-L1 expression in the CAL-27 cells, which was partially reduced in cells pretreated with PDTC, suggesting that A2BR agonists induce PD-L1 expression via the induction of the NF-κ B signaling pathway. Furthermore, high A2BR expression in OSCC was associated with lower infiltration of NK cells. Additionally, our results demonstrated that treatment with MRS-1706 (an A2BR inverse agonist) and/or CD274 (a PD-L1-neutralizing antibody) promoted NK cell recruitment and cytotoxicity against OSCC cells. Altogether, our findings highlight the synergistic effect of co-inhibition of A2BR and PD-L1 in the treatment of OSCC via the modulation of NK cell recruitment and cytotoxicity.

Synechocystis sp. PCC 6803 (hereafter: Synechocystis) is a model organism for studying photosynthesis, energy metabolism, and environmental stress. Although known as the first fully sequenced phototrophic organism, Synechocystis still has almost half of its proteome without functional annotations. In this study, by using co-fractionation coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we define 291 multi-protein complexes, encompassing 24,092 protein–protein interactions (PPIs) among 2062 distinct gene products. This information not only reveals the roles of photosynthesis in metabolism, cell motility, DNA repair, cell division, and other physiological processes, but also shows how protein functions vary from bacteria to higher plants due to changes in interaction partners. It also allows us to uncover the functions of hypothetical proteins, such as Sll0445, Sll0446, and Sll0447 involved in photosynthesis and cell motility, and Sll1334 involved in regulation of fatty acid biogenesis. Here we present the most extensive PPI data for Synechocystis so far, which provide critical insights into fundamental molecular mechanisms in cyanobacteria.

To investigate the influence of external prestressing with carbon fiber-reinforced polymer (CFRP) tendons on the flexural and shear performance of reinforced concrete beams, a total of six simply supported beams with a length of 3.5 m and two two-span continuous beams with a length of 7 m were studied. The influences of the prestressing level of CFRP tendons, the pattern of straight-line and flexural reinforcement of externally prestressed CFRP tendons, and the existence of initial cracks in the beams on the flexural bearing capacity of the reinforced beams were explored through modeling tests. The calculating equation for anticipating the ultimate flexural bearing capacity of concrete beams reinforced with externally prestressed CFRP tendons was modified based on the test results. The findings indicate that the flexural bearing capacity of the test beams was significantly enhanced through both flexural and straight-line reinforcement. Specifically, the ultimate flexural bearing capacity of the simply supported beams exhibited improvements of approximately 160% and 170%, respectively, whereas the ultimate flexural bearing capacity of the continuous beams was enhanced by approximately 113% through the reinforcement of flexural arrangement. Additionally, the shear resistance capacity of the concrete beams was notably improved through the flexural arrangement reinforcement, and the shear resistance capacity of the beams exhibited a substantial increase as the prestressing level of the CFRP tendons increased. The flexural moments in the vicinity of the support point of the reinforced beam exhibited an increase ranging from 41.7% to 112.5% when the stirrup strains started to escalate rapidly. Additionally, the rigidity of the test beams showed a close correlation with both the prestressing level and the existence of initial cracks.

To investigate the reinforcing effect of externally prestressed carbon-fiber-reinforced polymer (CFRP) tendons on the shear performance of reinforced concrete beams, a set of model tests was designed. Static load comparative tests were conducted on one original beam and four reinforced beams to experimentally investigate the impacts of the prestress level and damage in the shear zone on the shear reinforcement effect and analyze the reinforcement mechanism of CFRP tendons. The results show that in the beams reinforced with CFRP, the CFRP tendons could work collaboratively with the stirrups to reduce the strain on the stirrups; the increasing rate in the yield load was 28–70%. After the stirrups yielded, the CFRP tendons did not yet reach their ultimate tensile strength and could still withstand increased shear forces, resulting in an increasing rate of the ultimate load for the reinforced beams with a CFRP content of 56–78%. The enhancements in both the yield load and the ultimate load were positively correlated with the level of prestress in the CFRP tendons. This reinforcement technique efficiently restricts the growth and delays the first appearance of diagonal cracks. The prestress can close the pre-existing diagonal cracks and provide a reserve of shear capacity for the beams. The initial damage in the shear zone decreases the initial shear stiffness and increases the width of the initial diagonal cracks. However, this effect gradually diminishes as the load increases and does not significantly impact the shear capacity. Prestressing can significantly improve the strength utilization rate of the CFRP reinforcement when the reinforced beams fail. The deformation of the CFRP tendon is directly related to the shear deformation. By combining this relationship with the truss–arch model, the shear capacity for the reinforced beam can be predicted. The predicted results exhibit an error of less than 10% when compared to the test results, offering valuable design guidance for reinforced engineering composites.

Rapid urbanization has triggered nutrient loading, which will inevitably lead to the eutrophication of water bodies and further affect the structure of aquatic populations. At present, eutrophication is a significant challenge for urban aquatic ecosystems. However, we still know little about the correlation between eutrophication in urban rivers and the composition of aquatic functional groups. The effects of urban river eutrophication on rotifer communities were investigated using an annual field survey of the Jinan section of the Xiaoqing River, a typical urban river in northern China. Using functional diversity (FD) and beta diversity, the spatiotemporal variation of the aquatic biological functional groups regime along stretches subject to different eutrophication was investigated. The functional evenness (FEve) and functional divergence (FDiv) decreased significantly with the increment of the trophic level index. Functional diversity exhibits an extremely low level across functional groups, with the richness difference (RichDiff) being an important component. The results indicate that eutrophication led to the homogenization of rotifer communities. This can be attributed to the functional homogenization of the rotifer community in the Jinan section of the Xiaoqing River. The observed homogenization may be due to widely distributed species complementing the ecological niche space. Our findings provide valuable information on the conservation of the urban river under the threat of eutrophication caused by high-intensity human activities.

Background With the improvement in diagnosis and treatment of gastric cancer (GC), the survival time of patients has been gradually prolonged. However, these survivors are at increased risk for other diseases, including second primary cancers (SPCs). Currently, there remain few central studies concerning double primary cancers with first gastric cancer (DPCFGC). Thus, this study aimed to investigate these patients’ clinical characteristics and perform prognostic nomogram analysis. Methods The clinical data of 78 DPCFGC patients were retrospectively collected and analyzed through the hospital electronic medical record system. Univariate and multivariate Cox regression analyses were performed to screen independent risk factors, based on which the prognostic nomogram was further constructed and validated using the R software package. Finally, Kaplan–Meier curves were plotted to explore the association of overall survival (OS) with prognostic factors and the model. Results The prevalence of DPCFGC was 0.86%, of which the proportions of synchronous and metachronous patients were 47.44% and 52.56% , respectively; 65.38% (51/78) and 34.62% (27/78) of patients were male and female, respectively. The median age at GC and SPC diagnosis was 63 and 65 years, respectively, and 52.57% of GC patients developed SPCs within 1 year. The top three SPCs were in the esophagus (19.24%), colon (16.67%), and rectum (15.39%). The most common features of GC and SPCs were adenocarcinoma, poorly and moderately differentiated histology, and pathological stages I and II. The radical resection rate of GC was significantly lower in synchronous patients than in metachronous patients (45.94% vs. 100.00%, P < 0.001), but no significant difference was noted in the radical resection rate of SPCs (35.13% vs. 46.34%, P = 0.315). The OS of DPCFGC patients was 31.03 ± 4.14 months. The pathological stage of GC and SPCs, whether to operate for GC, and diagnostic interval were independent risk factors. The predictive efficacy of the prognostic nomogram for 1-, 2- and 3-year OS in DPCFGC patients was 0.922, 0.935 and 0.796 , respectively, with good consistency and clinical applicability. The OS was significantly lower in the high-risk group than in the low-risk group. Conclusions During follow-up, clinicians should attach great importance to the screening of GC survivors, especially at early stage in older men within 1 year after diagnosis, and be alert to the possibility of occurrent digestive system malignancies. The nomogram constructed in this study can provide a theoretical basis for the early clinical development of individualized treatment plans.

Rock-inhabiting fungi (RIF) constitute an ecological group associated with terrestrial rocks. This association is generally restricted to the persistent colonisation of rocks and peculiar morphological features based on melanisation and slow growth, which endow RIF with significance in eukaryotic biology, special status in ecology, and exotic potential in biotechnology. There is a need to achieve a better understanding of the hidden biodiversity, antistress biology, origin and convergent evolution of RIF, which will facilitate cultural relic preservation, exploitation of the biogeochemical cycle of rock elements and biotechnology applications. This review focuses on summarising the current knowledge of rock-inhabiting fungi, with particular reference to terminology, biodiversity and geographic distribution, origin and evolution, and stress adaptation mechanisms. We especially teased out the definition through summing up the terms related to rock-inhabting fungi, and also provided a checklist of rock-inhabiting fungal taxa recorded following updated classification schemes.

Summary: The cerebellum is critical for motor coordination and learning. However, the role of feedback circuitry in this brain region has not been fully explored. Here, we characterize a nucleo-ponto-cortical feedback pathway in classical delayed eyeblink conditioning (dEBC) of rats. We find that the efference copy is conveyed from the interposed cerebellar nucleus (Int) to cerebellar cortex through pontine nucleus (PN). Inhibiting or exciting the projection from the Int to the PN can decelerate or speed up acquisition of dEBC, respectively. Importantly, we identify two subpopulations of PN neurons (PN1 and PN2) that convey and integrate the feedback signals with feedforward sensory signals. We also show that the feedforward and feedback pathways via different types of PN neurons contribute to the plastic changes and cooperate synergistically to the learning of dEBC. Our results suggest that this excitatory nucleo-ponto-cortical feedback plays a significant role in modulating associative motor learning in cerebellum.

Ice thickness is a critical parameter in single particle cryo-EM – too thin ice can break during imaging or exclude the sample of interest, while ice that is too thick contributes to more inelastic scattering that precludes obtaining high resolution reconstructions. Here we present the practical effects of ice thickness on resolution, and the influence of energy filters, accelerating voltage, or detector mode. We collected apoferritin data with a wide range of ice thicknesses on three microscopes with different instrumentation and settings. We show that on a 300 kV microscope, using a 20 eV energy filter slit has a greater effect on improving resolution in thicker ice; that operating at 300 kV instead of 200 kV accelerating voltage provides significant resolution improvements at an ice thickness above 150 nm; and that on a 200 kV microscope using a detector operating in super resolution mode enables good reconstructions for up to 200 nm ice thickness, while collecting in counting instead of linear mode leads to improvements in resolution for ice of 50–150 nm thickness. Our findings can serve as a guide for users seeking to optimize data collection or sample preparation routines for both single particle and in situ cryo-EM. We note that most in situ data collection is done on samples in a range of ice thickness above 150 nm so these results may be especially relevant to that community.

We perceived a trend in the study and practice of petroleum-contaminate sites. Monitored natural attenuation (MNA) can reduce the contaminant concentrations in the soil and groundwater, and it is a method that can remediate the petroleum-contaminated site effectively. MNA is becoming a research focus. This study evaluated MNA using a series of lab-based bench-scale experiments and a large amount of monitoring data from field samplings. Based on the in-site total petroleum hydrocarbon (TPH) results, we used statistical methods, the Mann-Kendall test, and mass fluxes in order to evaluate the MNA of petroleum-contaminated sites in groundwater. The results showed that the TPH concentrations were decreasing, and the plume became smaller. The attenuation rate was from 0.00876 mg/d to 0.10095 mg/d; remediating the petroleum contamination site would cost 1.3 years to 10.6 years. The plume reached a quasi-steady state, and mass flux declined. The most essential process of MNA was biodegradation, and the second was sorption. During the monitoring period, 393 g of TPH was attenuated, including 355 g of TPH gradated by microbes. Biodegradation upstream of the plume was more serious. Iron(Ⅲ) and manganese were the main electron acceptors utilized by microbes during the monitored period. MNA was in progress, and it can be an effective method to remediate the petroleum-contaminated site. Lab-based bench-scale experiments were performed with much monitoring data from the field samplings in order to understand the fate and transport mechanism of the petroleum contamination from the land surface to shallow groundwater according to site conditions.

Organic leafy vegetables face challenges related to potential substitution with non-organic products and vulnerability to dehydration and deterioration. To address these concerns, visible and near-infrared spectroscopy (VIS-NIR) combined with linear discriminant analysis (LDA) was employed in this study to rapidly distinguish between organic and non-organic leafy vegetables. The organic category includes organic water spinach (Ipomoea aquatica Forsskal), amaranth (Amaranthus tricolor L.), lettuce (Lactuca sativa var. ramosa Hort.), and pakchoi (Brassica rapa var. chinensis (Linnaeus) Kitamura), while the non-organic category consists of their four non-organic counterparts. Binary classification was performed on the reflectance spectra of these vegetables’ leaves and stems, respectively. Given the broad range of the VIS-NIR spectrum, stability selection (SS), random forest (RF), and analysis of variance (ANOVA) were used to evaluate the importance of the wavelengths selected by genetic algorithm (GA). According to the GA-selected wavelengths and their SS-evaluated values and locations, the significant bands for leaf spectra classification were identified as 550–910 nm and 1380–1500 nm, while 750–900 nm and 1700–1820 nm were important for stem spectra classification. Using these selected bands in the LDA classification, classification accuracies of over 95% were achieved, showcasing the effectiveness of utilizing the proposed method to rapidly identify organic leafy vegetables and the feasibility and potential of using a cost-effective spectrometer that only contains necessary bands for authenticating.

Abstract Background Optical maps record locations of specific enzyme recognition sites within long genome fragments. This long-distance information enables aligning genome assembly contigs onto optical maps and ordering contigs into scaffolds. The generated scaffolds, however, often contain a large amount of gaps. To fill these gaps, a feasible way is to search genome assembly graph for the best-matching contig paths that connect boundary contigs of gaps. The combination of searching and evaluation procedures might be “searching followed by evaluation”, which is infeasible for long gaps, or “searching by evaluation”, which heavily relies on heuristics and thus usually yields unreliable contig paths. Results We here report an accurate and efficient approach to filling gaps of genome scaffolds with aids of optical maps. Using simulated data from 12 species and real data from 3 species, we demonstrate the successful application of our approach in gap filling with improved accuracy and completeness of genome scaffolds. Conclusion Our approach applies a sequential Bayesian updating technique to measure the similarity between optical maps and candidate contig paths. Using this similarity to guide path searching, our approach achieves higher accuracy than the existing “searching by evaluation” strategy that relies on heuristics. Furthermore, unlike the “searching followed by evaluation” strategy enumerating all possible paths, our approach prunes the unlikely sub-paths and extends the highly-probable ones only, thus significantly increasing searching efficiency.

Purpose: In the present study, to achieve high paclitaxel (PTX) loading in a conjugated drug delivery system with minimal long-term side effects, we formulated a novel degradable stereocomplexed micelle-like particle with a core-shell structure. Materials and methods: In this system, methoxy polyethylene glycol (MPEG) acted as the hydrophilic shell, and the stereocomplex of polylactic acid with PTX (SCPLA-PTX) acted as the hydrophobic core. The MPEG-SCPLA-PTX micelle-like particles were synthesized via the self-assembly of a MPEG-poly l-lactic acid (PLLA) copolymer with a PTX-poly d-lactic acid-PTX copolymer. The resultant copolymers and their intermediates were characterized using 1H nuclear magnetic resonance and GPC. Micelle-like particles with different molecular weight ratios of MPEG and PLLA were synthesized to demonstrate the functions of both components. Results: PTX loading into MPEG2000Da-PLLA6000Da particles reached as high as 20.11%. At 216 h, the cumulative release from MPEG5000Da-PLLA6000Da, MPEG2000Da-PLLA6000Da, and MPEG5000Da-PLLA22000Da particles were 51.5%, 37.7%, and 52.0%, respectively. Conclusions: According to the cell uptake experiments, inhibition of tumor cell growth was satisfactory, indicating that the stereocomplexed particles developed in the present study can be employed as a promising nanocarrier for PTX delivery.

Ischemic stroke is still a serious threat to human life and health, but there are few therapeutic options available to treat stroke because of limited blood-brain penetration. The development of nanotechnology may overcome some of the problems related to traditional drug development. In this review, we focus on the potential applications of nanotechnology in stroke. First, we will discuss the main molecular pathological mechanisms of ischemic stroke to develop a targeted strategy. Second, considering the important role of the blood-brain barrier in stroke treatment, we also delve mechanisms by which the blood-brain barrier protects the brain, and the reasons why the therapeutics must pass through the blood-brain barrier to achieve efficacy. Lastly, we provide a comprehensive review related to the application of nanomaterials to treat stroke, including liposomes, polymers, metal nanoparticles, carbon nanotubes, graphene, black phosphorus, hydrogels and dendrimers. To conclude, we will summarize the challenges and future prospects of nanomedicine-based stroke treatments.

Lysyl-oxidase like-2 (LOXL2) regulates extracellular matrix remodeling and promotes tumor invasion and metastasis. Altered metabolism is a core hallmark of cancer, however, it remains unclear whether and how LOXL2 contributes to tumor metabolism. Here, we found that LOXL2 and its catalytically inactive L2Δ13 splice variant boost glucose metabolism of esophageal tumor cells, facilitate tumor cell proliferation and promote tumor development in vivo. Consistently, integrated transcriptomic and metabolomic analysis of a knock-in mouse model expressing L2Δ13 gene revealed that LOXL2/L2Δ13 overexpression perturbs glucose and lipid metabolism. Mechanistically, we identified aldolase A, glyceraldehyde-3-phosphate dehydrogenase and enolase as glycolytic proteins that interact physically with LOXL2 and L2Δ13. In the case of aldolase A, LOXL2/L2Δ13 stimulated its mobilization from the actin cytoskeleton to enhance aldolase activity during malignant transformation. Using stable isotope labeling of amino acids in cell culture (SILAC) followed by proteomic analysis, we identified LOXL2 and L2Δ13 as novel deacetylases that trigger metabolic reprogramming. Both LOXL2 and L2Δ13 directly catalyzed the deacetylation of aldolase A at K13, resulting in enhanced glycolysis which subsequently reprogramed tumor metabolism and promoted tumor progression. High level expression of LOXL2/L2Δ13 combined with decreased acetylation of aldolase-K13 predicted poor clinical outcome in patients with esophageal cancer. In summary, we have characterized a novel molecular mechanism that mediates the pro-tumorigenic activity of LOXL2 independently of its classical amine oxidase activity. These findings may enable the future development of therapeutic agents targeting the metabolic machinery via LOXL2 or L2Δ13. Highlight of the study: LOXL2 and its catalytically inactive isoform L2Δ13 function as new deacetylases to promote metabolic reprogramming and tumor progression in esophageal cancer by directly activating glycolytic enzymes such as aldolase A.

The coupled process of osteogenesis-angiogenesis plays a crucial role in periodontal tissue regeneration. Although various cytokines or chemokines have been widely applied in periodontal in situ tissue engineering, most of them are macromolecular proteins with the drawbacks of short effective half-life, poor stability and high cost, which constrain their clinical translation. Our study aimed to develop a difunctional structure for periodontal tissue regeneration by incorporating an angiogenic small molecule, dimethyloxalylglycine (DMOG), and an osteoinductive inorganic nanomaterial, nanosilicate (nSi) into poly (lactic-co-glycolic acid) (PLGA) fibers by electrospinning. The physiochemical properties of DMOG/nSi-PLGA fibrous membranes were characterized. Thereafter, the effect of DMOG/nSi-PLGA membranes on periodontal tissue regeneration was evaluated by detecting osteogenic and angiogenic differentiation potential of periodontal ligament stem cells (PDLSCs) in vitro. Additionally, the fibrous membranes were transplanted into rat periodontal defects, and tissue regeneration was assessed with histological evaluation, micro-computed tomography (micro-CT), and immunohistochemical analysis. DMOG/nSi-PLGA membranes possessed preferable mechanical property and biocompatibility. PDLSCs seeded on the DMOG/nSi-PLGA membranes showed up-regulated expression of osteogenic and angiogenic markers, higher alkaline phosphatase (ALP) activity, and more tube formation in comparison with single application. Further, in vivo study showed that the DMOG/nSi-PLGA membranes promoted recruitment of CD90+/CD34− stromal cells, induced angiogenesis and osteogenesis, and regenerated cementum-ligament-bone complex in periodontal defects. Consequently, the combination of DMOG and nSi exerted admirable effects on periodontal tissue regeneration. DMOG/nSi-PLGA fibrous membranes could enhance and orchestrate osteogenesis-angiogenesis, and may have the potential to be translated as an effective scaffold in periodontal tissue engineering.

Background: Target therapies play more and more important roles in gastrointestinal stromal tumors (GISTs) and melanoma with the advancement of clinical drugs that overcome the resistance caused by gene mutations. c-KIT gene mutations account for a large portion of GIST patients, which are known to be sensitive or resistant to tyrosine kinase inhibitors. However, the role rare mutations play in drug efficacy and progression-free duration remains elusive.Methods: Two rare mutations were identified using Sanger sequencing from the GIST and melanoma cases. Cell experiments were further carried out to demonstrate their role in the imatinib resistance.Results:c-KIT c.1926delA p.K642S*FS mutation in primary and recurrent GIST patients and c-KIT c.1936T>G p.Y646D point mutation in melanoma patients in exon 13 were first demonstrated to be novel targets resistant to imatinib agent.Conclusion:c-KIT mutations c.1926delA and c.1936T>G in exon 13 are clinically significant targets that exhibit resistance to imatinib. This study provides guidance to GIST and melanoma treatments.

Smart drug delivery nano-systems show significant changes in their physical or chemical properties in response to slight change in environmental physical and/or chemical signals, and further releasing drugs adjusted to the progression of the disease at the right target and rate intelligently. Two-dimensional materials possess dramatic status extend all over various scientific and technological disciplines by reason of their exceptional unique properties in application of smart drug delivery nano-systems. In this review, we summarized current progress to highlight various kinds of two-dimensional materials drug carriers which are widely explored in smart drug delivery systems as well as classification of stimuli responsive two-dimensional materials and the advantages and disadvantages of their applications. Consequently, we anticipate that this review might inspire the development of new two-dimensional materials with smart drug delivery systems, and deepen researchers’ understanding of smart nano-carries based on two-dimensional materials.

Background Bronchoalveolar lavage fluid (BALF) exosomes possess different properties in different diseases, which are mediated through microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), among others. By sequencing the differentially expressed lncRNAs in BALF exosomes, we seek potential targets for the diagnosis and treatment of acute lung injury (ALI). Methods Considering that human and rat genes are about 80% similar, ALI was induced using lipopolysaccharide in six male Wistar rats, with six rats as control (all weighing 200 ± 20 g and aged 6–8 weeks). BALF exosomes were obtained 24 h after ALI. The exosomes in BALF were extracted by ultracentrifugation. The differential expression of BALF exosomal lncRNAs in BALF was analyzed by RNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the functions of differentially expressed lncRNAs, which were confirmed by reverse transcription–polymerase chain reaction. Results Compared with the control group, the ALI group displayed a higher wet/dry ratio, tumor necrosis factor-α levels, and interleukin-6 levels (all P < 0.001). The airway injection of exosomes in rats led to significant infiltration by neutrophils. A total of 2,958 differentially expressed exosomal lncRNAs were identified, including 2,524 upregulated and 434 downregulated ones. Five lncRNAs confirmed the reliability of the sequencing data. The top three GO functions were phagocytic vesicle membrane, regulation of receptor biosynthesis process, and I-SMAD binding. Salmonella infection, Toll-like receptor signaling pathway, and osteoclast differentiation were the most enriched KEGG pathways. The lncRNA–miRNA interaction network of the five confirmed lncRNAs could be predicted using miRDB. Conclusions BALF-derived exosomes play an important role in ALI development and help identify potential therapeutic targets related to ALI.

In this paper, a novel fixed-time distributed optimization algorithm is proposed to solve the multi-agent collaborative optimization (MSCO) problem with local inequality constraints, global equation constraints and unknown disturbances. At first, a penalty function method is used to eliminate the local inequality constraints and transform the original problem into a problem without local constraints. Then, a novel three-stage control scheme is designed to achieve a robust fixed-time convergence. In the first stage, a fixed-time reaching law is given to completely eliminate the effect of unknown disturbances with the aid of the integral sliding mode control method; in the second stage, a suitable interaction strategy is provided such that the whole system could satisfy the global constraints in fixed-time; in the third stage, a fixed-time gradient optimization algorithm of the multi-agent system is presented, with which the states of all the agents will converge to the minimum value of the global objective in a fixed-time. Finally, the effectiveness of the proposed control strategy is verified in the problem of wind farm co-generation with 60 wind turbines.

(1) Background: Esophageal cancer (EC) is an important global health challenge. Due to the lack of necessary biomarkers and therapeutic targets, the survival of EC patients is poor. The EC proteomic data of 124 patients recently published by our group provides a database for research in this field. (2) Methods: Bioinformatics analysis was used to identify DNA replication and repair-related proteins in EC. Proximity ligation assay, colony formation assay, DNA fiber assay, and flow cytometry were used to study the effects of related proteins on EC cells. Kaplan–Meier survival analysis was used to evaluate the relationship between gene expression and the survival time of EC patients. (3) Results: Chromatin assembly factor 1 subunit A (CHAF1A) was highly correlated with proliferating cell nuclear antigen (PCNA) expression in EC. CHAF1A and PCNA colocalized in the nucleus of EC cells. Compared with the knockdown of CHAF1A or PCNA alone, the double knockdown of CHAF1A and PCNA could significantly inhibit EC cell proliferation. Mechanistically, CHAF1A and PCNA synergistically accelerated DNA replication and promoted S-phase progression. EC patients with high expression of both CHAF1A and PCNA had a worse survival rate. (4) Conclusion: we identify CHAF1A and PCNA as key cell cycle-related proteins leading to the malignant progression of EC, and these proteins could serve as important prognostic biomarkers and targets for EC.

In the MOOCs context, learners experience information overload. Thus, it is necessary to improve personalized recommendation algorithms for learners. The current recommendation algorithm focuses mainly on the learners’ course ratings. However, the choice of courses is not only based on the learners’ interests and preferences. It is also affected by learners’ knowledge domains and learning capabilities, all of which change dynamically over time. Therefore, this study proposes a personalized hybrid recommendation algorithm combining clustering with collaborative filtering. First, data on learners’ course rating preferences, course attribute preferences, and multidimensional capabilities that match course traits are used based on multidimensional item response theory. Second, considering that learners’ preferences and multidimensional capabilities change dynamically over time, the Ebbinghaus forgetting curve is introduced by integrating memory weights to improve the accuracy and interpretation of the proposed recommendation algorithm for MOOCs. Finally, the performance of the proposed recommendation algorithm is investigated using data from Coursera, an internationally renowned MOOCs platform. The experimental results show that the proposed recommendation algorithm is superior to the baseline algorithms. Accordingly, relevant suggestions are proposed for the development of MOOCs.

Concrete sandwich walls are commonly used as the exterior wall panels of a structure, in which the wall suffers out-of-plane bending under strong wind conditions. This paper aims to investigate the bending performance of concrete sandwich walls under actual boundary conditions through experimental and analytical methods. In total, four concrete sandwich walls were tested to detect the influence of openings and loading direction. Typical failure patterns were characterized and discussed. The load-displacement curves of four test specimens were analyzed. It was indicated that the bearing capacity of the walls under negative bending conditions was higher than that under positive bending conditions, owing to the additional constraints provided by the steel beams. Strain distributions of wall specimens were also discussed in order to obtain the composite action of the sandwich walls between the upper and lower layers of concrete. In addition, the finite element model (FEM) was developed by ABAQUS to provide insights into the bending performance of the sandwich walls. Through comparison with the test results, the FEM was verified with a good level of accuracy. Subsequently, the degree of composite action of the sandwich walls was assessed in terms of both the moment of inertia and bearing capacity. From the experimental and numerical results, it demonstrated that the bearing capacity of concrete sandwiched wall under negative direction was higher than that under positive direction owing to the constraints of steel beam. The derived composite action degree could be employed to evaluate the out-plane bending stiffness and strength of sandwiched concrete wall. Both the experimental and analytical results in this paper are beneficial for the design of sandwich walls under bending conditions.

Background: Long non-coding RNA (lncRNA) hypoxia inducible factor 1α-antisense RNA 1 (HIF1A-AS1) serves critical roles in cardiovascular diseases (CVDs). Vascular endothelial cells (VECs) are vulnerable to stimuli. Our previous study revealed that knockdown of HIF1A-AS1 reduces palmitic acid-induced apoptosis and promotes the proliferation of human VECs (HUVECs); however, the underlying mechanism remains unclear. Material and Methods: Cell Counting Kit-8, flow cytometry, transwell invasion, and wound healing were applied to detect the function of HUVECs. Moreover, miRNA sequencing (miRNA-seq) and RNA sequencing (RNA-seq) were conducted to uncover its underlying mechanism. Quantitative Polymerase Chain Reaction (qPCR) was implemented to assess the accuracy of miRNA-seq. A co-expression network was generated to determine the relationship between differentially expressed miRNAs (DEmiRNAs) and differentially expressed genes (DEGs). Results: Knockdown of HIF1A-AS1 promoted the proliferation, migration, and invasion but reduced the apoptosis of HUVECs, and the overexpression of this lncRNA had the opposite effect. Numerous DEmiRNAs and DEGs were identified, which might contribute to this phenomenon. Multiple target genes of DEmiRNAs were associated with cell proliferation and apoptosis, and overlapped with DEGs identified from RNA-seq. Finally, the network manifested that lncRNA HIF1A-AS1 moderated the function of HUVECs by not only regulating the expression of some genes directly but also by influencing a few miRNAs to indirectly mediate the expression of mRNAs. Conclusions: The results suggested that HIF1A-AS1 might regulate HUVEC function by not only regulating the expression of some genes directly but also by influencing some miRNAs to indirectly mediate the expression level of mRNA.

The disc cutter is a key tool in shield machines that come into direct contact with rock while participating in the removal of rock. Therefore, the reasonable design of the geometric configuration of disc cutters greatly determines the tunnelling efficiency of the shield machine. In this paper, the factors influencing the rock-breaking behaviour of disc cutters are studied. Firstly, to ensure the accuracy of the rock-breaking simulation, the parameters of the Holmquist–Johnson–Cook model of the diorite in the Jinan area were determined. Secondly, using ANSYS/LS-DYNA to simulate the rock-breaking process, the influence of the geometric configuration, including blade width and blade fillet, on rock-breaking behaviour was analysed. The results show that with increasing depth of penetration, the contact force increases approximately linearly. The contact force and the rock-breaking influence range gradually decrease with increasing number of blade fillets. In addition, with increasing number of blade fillets, the shape of the influence range gradually transitions from an approximate circle to a trapezoid, and finally to a triangle. With increasing blade width, the contact force and the rock-breaking influence range both increase, but the shape of the influence range remains largely unchanged as a trapezoid. On the basis of these research results, this paper gives some suggestions for the selection and configuration of disc cutters in different strata, which can give some guidance for practical engineering.

Immunotherapy is a novel clinical approach that has shown clinical efficacy in multiple cancers. However, only a fraction of patients respond well to immunotherapy. Immuno-oncological studies have identified the type of tumors that are sensitive to immunotherapy, the so-called hot tumors, while unresponsive tumors, known as “cold tumors,” have the potential to turn into hot ones. Therefore, the mechanisms underlying cold tumor formation must be elucidated, and efforts should be made to turn cold tumors into hot tumors. N6-methyladenosine (m6A) RNA modification affects the maturation and function of immune cells by controlling mRNA immunogenicity and innate immune components in the tumor microenvironment (TME), suggesting its predominant role in the development of tumors and its potential use as a target to improve cancer immunotherapy. In this review, we first describe the TME, cold and hot tumors, and m6A RNA modification. Then, we focus on the role of m6A RNA modification in cold tumor formation and regulation. Finally, we discuss the potential clinical implications and immunotherapeutic approaches of m6A RNA modification in cancer patients. In conclusion, m6A RNA modification is involved in cold tumor formation by regulating immunity, tumor-cell-intrinsic pathways, soluble inhibitory mediators in the TME, increasing metabolic competition, and affecting the tumor mutational burden. Furthermore, m6A RNA modification regulators may potentially be used as diagnostic and prognostic biomarkers for different types of cancer. In addition, targeting m6A RNA modification may sensitize cancers to immunotherapy, making it a promising immunotherapeutic approach for turning cold tumors into hot ones.

Abstract Background In recent years, lncRNAs (long-non-coding RNAs) have been proved to be closely related to the occurrence and development of many serious diseases that are seriously harmful to human health. However, most of the lncRNA-disease associations have not been found yet due to high costs and time complexity of traditional bio-experiments. Hence, it is quite urgent and necessary to establish efficient and reasonable computational models to predict potential associations between lncRNAs and diseases. Results In this manuscript, a novel prediction model called TCSRWRLD is proposed to predict potential lncRNA-disease associations based on improved random walk with restart. In TCSRWRLD, a heterogeneous lncRNA-disease network is constructed first by combining the integrated similarity of lncRNAs and the integrated similarity of diseases. And then, for each lncRNA/disease node in the newly constructed heterogeneous lncRNA-disease network, it will establish a node set called TCS (Target Convergence Set) consisting of top 100 disease/lncRNA nodes with minimum average network distances to these disease/lncRNA nodes having known associations with itself. Finally, an improved random walk with restart is implemented on the heterogeneous lncRNA-disease network to infer potential lncRNA-disease associations. The major contribution of this manuscript lies in the introduction of the concept of TCS, based on which, the velocity of convergence of TCSRWRLD can be quicken effectively, since the walker can stop its random walk while the walking probability vectors obtained by it at the nodes in TCS instead of all nodes in the whole network have reached stable state. And Simulation results show that TCSRWRLD can achieve a reliable AUC of 0.8712 in the Leave-One-Out Cross Validation (LOOCV), which outperforms previous state-of-the-art results apparently. Moreover, case studies of lung cancer and leukemia demonstrate the satisfactory prediction performance of TCSRWRLD as well. Conclusions Both comparative results and case studies have demonstrated that TCSRWRLD can achieve excellent performances in prediction of potential lncRNA-disease associations, which imply as well that TCSRWRLD may be a good addition to the research of bioinformatics in the future.

Abstract Background Accurate identification of potential interactions between drugs and protein targets is a critical step to accelerate drug discovery. Despite many relative experimental researches have been done in the past decades, detecting drug-target interactions (DTIs) remains to be extremely resource-intensive and time-consuming. Therefore, many computational approaches have been developed for predicting drug-target associations on a large scale. Results In this paper, we proposed an deep learning-based method to predict DTIs only using the information of drug structures and protein sequences. The final results showed that our method can achieve good performance with the accuracies up to 92.0%, 90.0%, 92.0% and 90.7% for the target families of enzymes, ion channels, GPCRs and nuclear receptors of our created dataset, respectively. Another dataset derived from DrugBank was used to further assess the generalization of the model, which yielded an accuracy of 0.9015 and an AUC value of 0.9557. Conclusion It was elucidated that our model shows improved performance in comparison with other state-of-the-art computational methods on the common benchmark datasets. Experimental results demonstrated that our model successfully extracted more nuanced yet useful features, and therefore can be used as a practical tool to discover new drugs. Availability http://deeplearner.ahu.edu.cn/web/CnnDTI.htm.

Abstract Background The occurrence of cotton pests and diseases has always been an important factor affecting the total cotton production. Cotton has a great dependence on environmental factors during its growth, especially climate change. In recent years, machine learning and especially deep learning methods have been widely used in many fields and have achieved good results. Methods First, this papaer used the common Aprioro algorithm to find the association rules between weather factors and the occurrence of cotton pests. Then, in this paper, the problem of predicting the occurrence of pests and diseases is formulated as time series prediction, and an LSTM-based method was developed to solve the problem. Results The association analysis reveals that moderate temperature, humid air, low wind spreed and rain fall in autumn and winter are more likely to occur cotton pests and diseases. The discovery was then used to predict the occurrence of pests and diseases. Experimental results showed that LSTM performs well on the prediction of occurrence of pests and diseases in cotton fields, and yields the Area Under the Curve (AUC) of 0.97. Conclusion Suitable temperature, humidity, low rainfall, low wind speed, suitable sunshine time and low evaporation are more likely to cause cotton pests and diseases. Based on these associations as well as historical weather and pest records, LSTM network is a good predictor for future pest and disease occurrences. Moreover, compared to the traditional machine learning models (i.e., SVM and Random Forest), the LSTM network performs the best.

Abstract Background The recognition of protein interaction sites is of great significance in many biological processes, signaling pathways and drug designs. However, most sites on protein sequences cannot be defined as interface or non-interface sites because only a small part of protein interactions had been identified, which will cause the lack of prediction accuracy and generalization ability of predictors in protein interaction sites prediction. Therefore, it is necessary to effectively improve prediction performance of protein interaction sites using large amounts of unlabeled data together with small amounts of labeled data and background knowledge today. Results In this work, three semi-supervised support vector machine–based methods are proposed to improve the performance in the protein interaction sites prediction, in which the information of unlabeled protein sites can be involved. Herein, five features related with the evolutionary conservation of amino acids are extracted from HSSP database and Consurf Sever, i.e., residue spatial sequence spectrum, residue sequence information entropy and relative entropy, residue sequence conserved weight and residual Base evolution rate, to represent the residues within the protein sequence. Then three predictors are built for identifying the interface residues from protein surface using three types of semi-supervised support vector machine algorithms. Conclusion The experimental results demonstrated that the semi-supervised approaches can effectively improve prediction performance of protein interaction sites when unlabeled information is involved into the predictors and one of them can achieve the best prediction performance, i.e., the accuracy of 70.7%, the sensitivity of 62.67% and the specificity of 78.72%, respectively. With comparison to the existing studies, the semi-supervised models show the improvement of the predication performance.

Summary: Here, we have used patient-derived induced pluripotent stem cell (iPSC) and gene-editing technology to study the cardiac-related molecular and functional consequences of mutations in GLA causing the lysosomal storage disorder Fabry disease (FD), for which heart dysfunction is a major cause of mortality. Our in vitro model recapitulated clinical data with FD cardiomyocytes accumulating GL-3 and displaying an increased excitability, with altered electrophysiology and calcium handling. Quantitative proteomics enabled the identification of >5,500 proteins in the cardiomyocyte proteome and secretome, and revealed accumulation of the lysosomal protein LIMP-2 and secretion of cathepsin F and HSPA2/HSP70-2 in FD. Genetic correction reversed these changes. Overexpression of LIMP-2 directly induced the secretion of cathepsin F and HSPA2/HSP70-2, implying causative relationship, and led to massive vacuole accumulation. In summary, our study has revealed potential new cardiac biomarkers for FD, and provides valuable mechanistic insight into the earliest pathological events in FD cardiomyocytes. : In this article, using an iPSC model, gene editing, and quantitative proteomics, Birket and colleagues gain unique insight into the molecular and functional consequences of heart disease-associated GLA mutations in human cardiomyocytes. They identified a panel of cell and secreted biomarkers, the discovery of which may have significant therapeutic relevance for Fabry disease and other lysosomal storage disorders. Key words: Fabry disease, iPSC, cardiomyocyte, heart, lysosome, proteomics, secretome, biomarkers, LIMP-2, maturation

The global bio-diversity of fungi has been extensively investigated and their species number has been estimated. Notably, the development of molecular phylogeny has revealed an unexpected fungal diversity and utilisation of culture-independent approaches including high-throughput amplicon sequencing has dramatically increased number of fungal operational taxonomic units. A number of novel taxa including new divisions, classes, orders and new families have been established in last decade. Many cryptic species were identified by molecular phylogeny. Based on recently generated data from culture-dependent and -independent survey on same samples, the fungal species on the earth were estimated to be 12 (11.7–13.2) million compared to 2.2–3.8 million species recently estimated by a variety of the estimation techniques. Moreover, it has been speculated that the current use of high-throughput sequencing techniques would reveal an even higher diversity than our current estimation. Recently, the formal classification of environmental sequences and permission of DNA sequence data as fungal names’ type were proposed but strongly objected by the mycologist community. Surveys on fungi in unusual niches have indicated that many previously regarded “unculturable fungi” could be cultured on certain substrates under specific conditions. Moreover, the high-throughput amplicon sequencing, shotgun metagenomics and a single-cell genomics could be a powerful means to detect novel taxa. Here, we propose to separate the fungal types into physical type based on specimen, genome DNA (gDNA) type based on complete genome sequence of culturable and uncluturable fungal specimen and digital type based on environmental DNA sequence data. The physical and gDNA type should have priority, while the digital type can be temporal supplementary before the physical type and gDNA type being available. The fungal name based on the “digital type” could be assigned as the “clade” name + species name. The “clade” name could be the name of genus, family or order, etc. which the sequence of digital type affiliates to. Facilitating future cultivation efforts should be encouraged. Also, with the advancement in knowledge of fungi inhabiting various environments mostly because of rapid development of new detection technologies, more information should be expected for fungal diversity on our planet.

Background: Oral cancer is one of the common malignant tumors of the head and neck. However, current treatments have numerous side effects, and drugs from natural sources may have better therapeutic potential. This research investigated the induction of apoptosis by α-hederin (α-HN), a constituent of Pulsatilla chinensis (Bunge) Regel, in the oral cancer cell line SCC-25 and its underlying mechanism. Results: SCC-25 cells were treated with 50, 100, and 200 μmol/L α-HN. Cell proliferation; extent of apoptosis; activities of caspases-3, 8, and 9; and the expression of Bcl-2, Bax, phosphorylated (p)-phosphoinositide 3-kinase (PI3K), p-Akt, and p-mammalian target of rapamycin (mTOR) proteins were determined using the 3-(4,5)-2-thiazole-(2,5)-diphenyl tetrazolium bromide, flow cytometry, caspase activity detection kits, and western blot assays, respectively. The results showed that the proliferation of SCC-25 cells in the α-HN-treated groups decreased significantly, and the inhibitory effect was time and concentration dependent. Compared with cells in the control group, the extent of apoptosis increased significantly, caspase-3 and -9 activities were significantly enhanced, and the Bcl-2 level was lowered and the Bax level was elevated significantly in SCC-25 cells treated with α-HN for 48 h (P

Background: T cell lymphoma is a complex and highly aggressive clinicopathological entity with a poor outcome. The angioimmunoblastic T-cell lymphoma (AITL) tumor immune microenvironment is poorly investigated. Methods: Here, to the best of our knowledge, spatial transcriptomics was applied for the first time to study AITL. Results: Using this method, we observed that AITL was surrounded by cells bearing immune-suppressive markers. CCL17 and CCL22, the dominant ligands for CCR4, were up-regulated, while the expression of natural killer (NK) cell and CD8+ cytotoxic T lymphocyte (CTL) markers decreased. Colocalization of Treg cells with the CD4+ TFH-GC region was also deduced from the bioinformatic analysis. The results obtained with spatial transcriptomics confirm that AITL has a suppressive immune environment. Chemotherapy based on the CHOP regimen (cyclophosphamide, doxorubicin, vincristine plus prednisone) induced complete remission (CR) in this AITL patient. However, the duration of remission (DoR) remains a concern. Conclusions: This study demonstrates that AITL has an immune suppressive environment and suggests that anti-CCR4 therapy could be a promising treatment for this lethal disease.

Brachiosauridae is a lineage of titanosauriform sauropods that includes some of the most iconic non-avian dinosaurs. Undisputed brachiosaurid fossils are known from the Late Jurassic through the Early Cretaceous of North America, Africa, and Europe, but proposed occurrences outside this range have proven controversial. Despite occasional suggestions that brachiosaurids dispersed into Asia, to date no fossils have provided convincing evidence for a pan-Laurasian distribution for the clade, and the failure to discover brachiosaurid fossils in the well-sampled sauropod-bearing horizons of the Early Cretaceous of Asia has been taken to evidence their genuine absence from the continent. Here we report on an isolated sauropod maxilla from the middle Cretaceous (Albian–Cenomanian) Longjing Formation of the Yanji basin of northeast China. Although the specimen preserves limited morphological information, it exhibits axially twisted dentition, a shared derived trait otherwise known only in brachiosaurids. Referral of the specimen to the Brachiosauridae receives support from phylogenetic analysis under both equal and implied weights parsimony, providing the most convincing evidence to date that brachiosaurids dispersed into Asia at some point in their evolutionary history. Inclusion in our phylogenetic analyses of an isolated sauropod dentary from the same site, for which an association with the maxilla is possible but uncertain, does not substantively alter these results. We consider several paleobiogeographic scenarios that could account for the occurrence of a middle Cretaceous Asian brachiosaurid, including dispersal from either North America or Europe during the Early Cretaceous. The identification of a brachiosaurid in the Longshan fauna, and the paleobiogeographic histories that could account for its presence there, are hypotheses that can be tested with continued study and excavation of fossils from the Longjing Formation.

Small open reading frame encoded peptides (SEPs), also called microproteins, play a vital role in biological processes. Plenty of their open reading frames are located within the non-coding RNA (ncRNA) range. Recent research has demonstrated that ncRNA-encoded polypeptides have essential functions and exist ubiquitously in various tissues. To better understand the role of microproteins, especially ncRNA-encoded proteins, expressed in different tissues, we profiled the proteomic characterization of five mouse tissues by mass spectrometry, including bottom-up, top-down, and de novo sequencing strategies. Bottom-up and top-down with database-dependent searches identified 811 microproteins in the OpenProt database. De novo sequencing identified 290 microproteins, including 12 ncRNA-encoded microproteins that were not found in current databases. In this study, we discovered 1,074 microproteins in total, including 270 ncRNA-encoded microproteins. From the annotation of these microproteins, we found that the brain contains the largest number of neuropeptides, while the spleen contains the most immunoassociated microproteins. This suggests that microproteins in different tissues have tissue-specific functions. These unannotated ncRNA-coded microproteins have predicted domains, such as the macrophage migration inhibitory factor domain and the Prefoldin domain. These results expand the mouse proteome and provide insight into the molecular biology of mouse tissues.

Synaptotagmin-7 (Syt7) plays direct or redundant Ca2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NMDARs that significantly contribute to mental illness. In mouse hippocampal neurons lacking Syt1/Doc2, Syt7 inactivation largely diminishes spontaneous release. Using 2 approaches, including measuring Ca2+ dose response and substituting extracellular Ca2+ with Sr2+, we detect that Syt7 directly triggers spontaneous release via its Ca2+ binding motif to activate GluN2B-NMDARs. Furthermore, modifying the localization of Syt7 in the active zone still allows Syt7 to drive spontaneous release, but the GluN2B-NMDAR activity is abolished. Finally, Syt7 SNPs identified in bipolar disorder patients destroy the function of Syt7 in spontaneous release in patient iPSC-derived and mouse hippocampal neurons. Therefore, Syt7 could contribute to neuropsychiatric disorders through driving spontaneous glutamate release.