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Abstract Detrital composition of sandstone is the most important data for siliciclastic studies including sandstone classification, provenance analysis, oil and gas exploration. A large amount of detrital composition data has accumulated over the past decades, however, they are scattered in publications without unified standards. Here we constructed a global dataset of detrital components of sandstones from 646 peer‐reviewed publications using Gazzi‐Dickinson method. A total of 19,861 samples from Precambrian to Quaternary are involved in this dataset. For each sample, we present details on reference information, geographic information, geological background, depositional age and the original data. It is a high‐quality dataset for the information on each sandstone sample from different studies which was standardized. The dataset can be used widely, such as for stratigraphic comparison, provenance analysis, exploring the general laws of the source‐to‐sink process and geological engineering.

IntroductionNitrogen (N) plays a pivotal role in the growth, development, and yield of maize. An optimal N application rate is crucial for enhancing N and carbohydrate (C) accumulation in waxy maize grains, which in turn synergistically improves grain weight.MethodsA 2-year field experiment was conducted to evaluate the impact of different N application rates on two waxy maize varieties, Jinnuo20 (JN20) and Jindannuo41 (JDN41), during various grain filling stages. The applied N rates were 0 (N0), 120 (N1), 240 (N2), and 360 (N3) kg N ha-1.ResultsThe study revealed that N application significantly influenced nitrogen accumulation, protein components (gliadin, albumin, globulin, and glutelin), carbohydrate contents (soluble sugars, amylose, and amylopectin), and activities of enzymes related to N and C metabolism in waxy maize grains. Notable varietal differences in these parameters were observed. In both varieties, the N2 treatment consistently resulted in the highest values for almost all measured traits compared to the other N treatments. Specifically, the N2 treatment yielded an average increase in grain dry matter of 21.78% for JN20 and 17.11% for JDN41 compared to N0. The application of N positively influenced the activities of enzymes involved in C and N metabolism, enhancing the biosynthesis of grain protein, amylose, and amylopectin while decreasing the accumulation of soluble sugars. This modulation of the C/N ratio in the grains directly contributed to an increase in grain dry weight.ConclusionCollectively, our findings underscore the critical role of N in regulating kernel N and C metabolism, thereby influencing dry matter accumulation in waxy maize grains during the grain filling stage.

The guided tissue regeneration (GTR) procedure has become an important process for the treatment of periodontal tissue regeneration, using the membrane as a mechanical barrier to generate a distance across the defect that subsequently allowing bone regeneration. Due to the complexity of periodontal microenvironment caused by bacterial infections, inflammation, and fibrous tissue penetration, the guided tissue regeneration membrane is required to have antibacterial and barrier functions. We developed a loaded methylene blue @ ZIF-8 and hydroxyapatite gradient thermoplastic polyurethane Janus membrane for antibacterial osteogenic and barrier. This Janus membrane with a porous gradient structure was prepared to use phase-conversion method. The rough layer facilitated cell growth and promoted periodontal bone regeneration, whereas the smooth layer isolated the growing fiber tissue.The rapid release of reactive oxygen species in the early stage and continuous release of zinc ions by methylene blue @ZIF-8 can achieve long-term synergistic antibacterial effect, with antibacterial rates of 84 % and 72 % against Escherichia coli and Staphylococcus aureus, respectively, which can effectively reduce the local inflammation caused by bacteria. In summary, we applied the Janus membrane to a rat periodontal bone defect model, and the membrane showed good surgical performance, barrier properties, osteogenic properties, and antibacterial effects, which could have broad application prospects in the treatment of periodontal bone defects.

Waxy corn is a special type of maize primarily consumed as a fresh vegetable by humans. Nitrogen (N) plays an essential role in regulating the growth progression, maturation, yield, and quality of waxy maize. A reasonable N application rate is vital for boosting the accumulation of both N and carbon (C) in the grains, thereby synergistically enhancing the grain quality. However, the impact of varying N levels on the dynamic changes in N metabolism, carbohydrate formation, and anthocyanin synthesis in purple waxy corn kernels, as well as the regulatory relationships among these processes, remains unclear. To explore the effects of varying N application rates on the N metabolism, carbohydrate formation, and anthocyanin synthesis in kernels during grain filling, a two-year field experiment was carried out using the purple waxy maize variety Jinnuo20 (JN20). This study examined the different N levels, specifically 0 (N0), 120 (N1), 240 (N2), and 360 (N3) kg N ha−1. The results of the analysis revealed that, for nearly all traits measured, the N application rate of N2 was the most suitable. Compared to the N0 treatment, the accumulation and content of anthocyanins, total nitrogen, soluble sugars, amylopectin, and C/N ratio in grains increased by an average of 35.62%, 11.49%, 12.84%, 23.74%, 13.00%, and 1.87% under N2 treatment over five filling stages within two years, respectively, while the harmful compound nitrite content only increased by an average of 30.2%. Correspondingly, the activities of related enzymes also significantly increased and were maintained under N2 treatment compared to N0 treatment. Regression and correlation analysis results revealed that the amount of anthocyanin accumulation was highly positively correlated with the activities of phenylalanine ammonia-lyase (PAL) and flavanone 3-hydroxylase (F3H), but negatively correlated with anthocyanidin synthase (ANS) and UDP-glycose: flavonoid-3-O-glycosyltransferase (UFGT) activity, nitrate reductase (NR), and glutamine synthetase (GS) showed significant positive correlations with the total nitrogen content and lysine content, and a significant negative correlation with nitrite, while soluble sugars were negatively with ADP-glucose pyrophosphorylase (AGPase) activity, and amylopectin content was positively correlated with the activities of soluble starch synthase (SSS), starch branching enzyme (SBE), and starch debranching enzyme (SDBE), respectively. Furthermore, there were positive or negative correlations among the detected traits. Hence, a reasonable N application rate improves purple waxy corn kernel nutritional quality by regulating N metabolism, as well as carbohydrate and anthocyanin biosynthesis.

Abstract Interferon-gamma (IFN-γ) signaling is necessary for the proinflammatory activation of macrophages but IFN-γ-independent pathways, for which the initiating stimuli and downstream mechanisms are lesser known, also contribute. Here we identify, by high-content screening, SEPTIN2 (SEPT2) as a negative regulation of IFN-γ-independent macrophage autoactivation. Mechanistically, endoplasmic reticulum (ER) stress induces the expression of SEPT2, which balances the competition between acetylation and ubiquitination of heat shock protein 5 at position Lysine 327, thereby alleviating ER stress and constraining M1-like polarization and proinflammatory cytokine release. Disruption of this negative feedback regulation leads to the accumulation of unfolded proteins, resulting in accelerated M1-like polarization, excessive inflammation and tissue damage. Our study thus uncovers an IFN-γ-independent macrophage proinflammatory autoactivation pathway and suggests that SEPT2 may play a role in the prevention or resolution of inflammation during infection.

Abstract Background Jian Yun Qing Hua Decoction (JYQHD), a traditional Chinese medicine decoction, which has been applied in the treatment of gastric cancer (GC). We attempt to confirm the anti-gastric cancer effect of JYQHD and explore the mechanism of JYQHD. Methods Acute toxicity test was used to understand the toxicity of JYQHD. We studied the expression and prognostic outcome of COL12A1 within GC tissues through the network databases. Using several web-based databases, we analyzed the major components and targets of JYQHD, as well as known therapeutic targets in gastric cancer. The Venn diagram was utilized to obtain the overlapped genes. Lentiviral vector, shRNAs and plasmids, were used to transfect GC cells. Cell counting kit-8 (CCK8), sphere formation, malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), Fe2+, transmission electron microscopy (TEM), quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), Western-Blot (WB), and immunohistochemical (IHC) assays were employed to investigate the role and mechanism of COL12A1 and JYQHD in GC. Results The results showed that JYQHD was non-toxic and safe. JYQHD inhibited growth and sphere formation ability through inducing the ferroptosis of GC cells, and suppressed the GC cells induced subcutaneous xenograft tumor growth. COL12A1 was highly expressed in gastric cancer tissues, indicating poor prognosis. COL12A1 specifically enhanced GC cell progression and stemness via suppressing ferroptosis. JYQHD down-regulated COL12A1 in order to suppress the stemness of GC cells via inducing ferroptosis. Conclusion COL12A1 inhibited ferroptosis and enhanced stemness in GC cells. JYQHD inhibited the development of GC cells by inhibiting cancer cell stemness via the ferroptosis pathway mediated by COL12A1.

Transplanting human neural progenitor cells is a promising method of replenishing the lost neurons after spinal cord injury (SCI), but differentiating neural progenitor cells into the diverse types of mature functional spinal cord neurons in vivo is challenging. In this study, engineered human embryonic spinal cord-like tissues with dorsal and ventral neuronal characters (DV-SC) were generated by inducing human neural progenitor cells (hscNPCs) to differentiate into various types of dorsal and ventral neuronal cells on collagen scaffold in vitro. Transplantation of DV-SC into complete SCI models in rats and monkeys showed better therapeutic effects than undifferentiated hscNPCs, including pronounced cell survival and maturation. DV-SC formed a targeted connection with the host's ascending and descending axons, partially restored interrupted neural circuits, and improved motor evoked potentials and the hindlimb function of animals with SCI. This suggests that the transplantation of pre-differentiated hscNPCs with spinal cord dorsal and ventral neuronal characteristics could be a promising strategy for SCI repair.

Seed vigor is a pivotal indicator of seed quality, and timely harvesting is essential for maize seed vigor. The seeds and embryos of maize inbred lines JNY6F and PH4CV at different maturity stages were selected as study materials, the phenotypic characteristics and seed vigor indexes of which were detected, and the soluble sugars, antioxidant enzyme activity, and pythormones [auxin (IAA), cytokinins (CTKs), gibberellins (GAs), and abscisic acid (ABA)] in fresh immature embryos were analyzed. The analysis results indicated that the seeds of JNY6F and PH4CV reached physiological maturity at 35 and 50 days after pollination, which were the optimal harvest times for JNY6F and PH4CV, respectively, as the embryonic morphology of which had been estabilished, and the seed vigor of which reached their peaks at these two stages. The seed vigor indexes showed significant negative correlations with the levels of soluble reducing sugar, total soluble sugar, and four pythormones in the immature embryos, but were highly positively correlated with catalase (CAT) and peroxidase (POD) enzyme activities. In summary, our findings offer valuable insights into the ideal harvest time and physiological mechanisms underlying the seed vigor of maize inbred lines, and contribute to the enhancement of seed quality and agricultural practices in maize inbred line production.

Microcantilever arrays are valuable tools for detecting minute physical and chemical changes. Traditional microcantilever array systems, including our previous work utilizing multiple laser arrays, frequently encounter high complexity, significant costs, and increased noise caused by laser switching. This study introduces a refraction-based laser scanning system that significantly mitigates these issues by employing a rotating glass optical block for multiplex scanning. This innovative approach not only simplifies the scanning process by eliminating the need to move the laser source or the microcantilever array but also enhances scanning speed and reduces noise, as demonstrated by our experiments. Overall, this research implements a new optical scanning strategy for microcantilever array systems, which is promising due to its direct application potential as it paves the way for more accurate, high-performing, and cost-effective sensing solutions.

In this paper, an innovative approach is introduced to address the noise issues associated with micro–cantilever array deflection measurement systems employing multiple lasers. Conventional systems are affected by laser mode hopping during switching, resulting in wavelength instability and beam spot fluctuations that take several hundred milliseconds to stabilize. To mitigate these limitations, a high–speed laser modulation technique is utilized, leveraging the averaging effect over multiple modulation cycles within the sampling window. By driving the lasers with a high–frequency carrier signal, a low–noise and stable output suitable for micro–cantilever beam deflection measurement is achieved. The effectiveness of this approach is demonstrated by simultaneously modulating the lasers and rapidly observing the spectral and centroid variations during high–speed switching using a custom–built high–speed spectrometer. The centroid fluctuations are also analyzed under different modulation frequencies. The experimental results confirm that the high–speed modulation method can reduce the standard deviation of beam spot fluctuations by more than 90%, leading to significant improvements in noise reduction compared to traditional laser switching methods. The proposed high–speed laser modulation approach offers a promising solution for enhancing the precision and stability of multi–laser micro–cantilever array deflection measurement systems.

Neural stem progenitor cell (NSPC) transplantation has been regarded as a promising therapeutic method for spinal cord injury (SCI) repair. However, different NSPCs may have different therapeutic effects, and it is therefore important to identify the optimal NSPC type. In our study, we compared the transcriptomes of human fetal brain-derived NSPCs (BNSPCs), spinal cord-derived NSPCs (SCNSPCs) and H9 embryonic stem-cell derived NSPCs (H9–NSPCs) in vitro and subsequently we transplanted each NSPC type on a collagen scaffold into a T8-9 complete SCI rat model in vivo. In vitro data showed that SCNSPCs had more highly expressed genes involved in nerve-related functions than the other two cell types. In vivo, compared with BNSPCs and H9–NSPCs, SCNSPCs exhibited the best therapeutic effects; in fact, SCNSPCs facilitated electrophysiological and hindlimb functional recovery. This study demonstrates that SCNSPCs may be an appropriate candidate cell type for SCI repair, which is of great clinical significance.

In this work, thermomechanical treatment (single-pass rolling at 800 °C and solution treatment) was applied to nuclear-grade hot-rolled austenitic stainless steel to eliminate the mixed grain induced by the uneven hot-rolled microstructure. By employing high-temperature laser scanning confocal microscopy, microstructure evolution during solution treatment was observed in situ, and the effect of single-pass rolling reduction on it was investigated. In uneven hot-rolled microstructure, the millimeter-grade elongated grains (MEGs) possessed an extremely large size and a high Schmid factor for slip compared to the fine grains, which led to greater plastic deformation and increased dislocation density and deformation energy storage during single-pass rolling. During subsequent solution treatment, there were fewer nucleation sites for the new grain, and the grain boundary (GB) was the main nucleation site in MEGs at a lower rolling reduction. In contrast, at a higher reduction, increased uniformly distributed rolling deformation and more nucleation sites were developed in MEGs. As the reduction increased, the number of in-grain nucleation sites gradually exceeded that of GB nucleation sites, and in-grain nucleation preferentially occurred. This was beneficial for promoting the refinement of new recrystallized grains and a reduction in the size difference of new grains during recrystallization. The single-pass rolling reduction of 15–20% can effectively increase the nucleation sites and improve the uniformity of rolling deformation distribution in the MEGs, promote in-grain nucleation, and finally refine the abnormally coarse elongated grain, and eliminate the mixed-grain structure after solution treatment.

Abstract The controversial history of Indian subduction beneath Asia is crucial to understand the Himalayan orogeny and more in general the geodynamic process of continental subduction. New key information is here presented from the Oligocene‐Pliocene Shiquanhe Basin located in the southwestern Tibetan Plateau. The alluvial‐fan, lacustrine, and braided‐river sediments of the Oligocene Rigongla Formation were non‐conformably deposited onto the Upper Cretaceous Gangdese granitoid rocks and fed from erosion of the batholith itself and of associated Paleogene Linzizong volcanic rocks. Stratigraphic evidence testifies to the development of an orogen‐parallel intracontinental rift along the retro‐side of the Gangdese arc in the Oligocene, at the same time as the Kailas basin formed along the pro‐side of the Gangdese arc. The subsidence of these twin basins may have been caused by steepening of the subducting Indian continental slab or by the passage of a wave of dynamic topography during continuing subduction.

For working out the approach of acquiring low planar anisotropy while achieving high ridging resistance and r-value, during two step cold rolling processes with different total reductions the texture evolution and corresponding mechanism were investigated for ferritic stainless steel. During cold rolling, the crystallites having orientations near {111} 〈112〉 and Goss were induced by shear bands and with further deformation Goss orientation tended to rotate towards more stable {111} 〈112〉. During subsequent annealing, these crystallites induced the recrystallized nuclei and {111} 〈112〉 nuclei consumed preferentially the adjacent matrixes, generating the γ-fiber recrystallization texture having the main component of {111} 〈112〉. With increasing total cold rolling reduction, the γ-fiber recrystallization textures were gradually intensified and band-like grain colonies having approximate r-value and those having variant with ε23 of same sign became more obvious and their distribution more uneven, the average r-value and ridging resistance exhibited a monotonous upward and downward trend, respectively, and the planar anisotropy of r-value first deteriorated and then improved and reached lowest value at 90 %. Considering acceptable ridging resistance in practical application, the excellent deep drawability can be acquired at the total reduction of 90 %.

Coronavirus disease 2019 is a respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence on the pathogenesis of SARS-CoV-2 is accumulating rapidly. In addition to structural proteins such as Spike and Envelope, the functional roles of non-structural and accessory proteins in regulating viral life cycle and host immune responses remain to be understood. Here, we show that open reading frame 8 (ORF8) acts as messenger for inter-cellular communication between alveolar epithelial cells and macrophages during SARS-CoV-2 infection. Mechanistically, ORF8 is a secretory protein that can be secreted by infected epithelial cells via both conventional and unconventional secretory pathways. Conventionally secreted ORF8 is glycosylated and loses the ability to recognize interleukin 17 receptor A of macrophages, possibly due to the steric hindrance imposed by N-glycosylation at Asn78. However, unconventionally secreted ORF8 does not undergo glycosylation without experiencing the ER-Golgi trafficking, thereby activating the downstream NF-κB signaling pathway and facilitating a burst of cytokine release. Furthermore, we show that ORF8 deletion in SARS-CoV-2 attenuates inflammation and yields less lung lesions in hamsters. Our data collectively highlights a role of ORF8 protein in the development of cytokine storms during SARS-CoV-2 infection.

Summary: The spinal cord possesses highly complex, finely organized cytoarchitecture guided by two dorsoventral morphogenic organizing centers. Thus, generation of human spinal cord tissue in vitro is challenging. Here, we demonstrated a novel method for generation of human dorsoventral spinal cord organoids using composite scaffolds. Specifically, the spinal cord ventralizing signaling Shh agonist (SAG) was loaded into a porous chitosan microsphere (PCSM), then thermosensitive Matrigel was coated on the surface to form composite microspheres with functional sustained-release SAG, termed as PCSM-Matrigel@SAG. Using PCSM-Matrigel@SAG as the core to induce 3D engineering of human spinal cord organoids from human pluripotent stem cells (ehSC-organoids), we found ehSC-organoids could form dorsoventral spinal cord-like cytoarchitecture with major domain-specific progenitors and neurons. Besides, these ehSC-organoids also showed functional calcium activity. In summary, these ehSC-organoids are of great significance for modeling spinal cord development, drug screening as 3D models for motor neuron diseases, and spinal cord injury repair.

Abstract Background Recently, neural stem cell (NSC) therapy has shown promise for the treatment of many neurological diseases. Enhancing the quality of implanted cells and improving therapeutic efficacy are currently research hotspots. It has been reported that collagen sponge material provided sufficient room for cell growth in all directions and promoted the absorption of nutrients and removal of wastes. And also, the Rotary Cell Culture System (RCCS), which mimics the microgravity environment, can be used to culture cells for tissue engineering. Materials and methods We performed the mRNA and miRNA sequencing to elucidate the regulatory mechanism of NSCs cultured on the collagen sponge in the RCCS system. The luciferase assay and Western blot revealed a direct regulatory role between let-7i-5p and neurotrophic receptor tyrosine kinase 3 (NTRK3; also called TrkC). And then, the neural differentiation markers Tuj1 and Map2 were detected by immunofluorescence staining. In the meantime, the migratory ability of NSCs was detected both in vitro and in spinal cord injury animals. Results In this study, we demonstrated that the expression of NTRK3 was elevated in NSCs cultured on collagen sponge in the RCCS system. Furthermore, increased NTRK3 expression was regulated by the downregulation of let-7i-5p. Compared to traditionally cultured NSCs, the NSCs cultured on collagen sponge in the RCCS system exhibited better neuronal differentiation and migratory ability, especially in the presence of NT-3. Conclusions As the biological properties and quality of transplanted cells are critical for therapeutic success, the RCCS system combined with the collagen sponge culture system shows promise for applications in clinical practice in the future.

Abstract Background Microtubule-stabilizing agents have been demonstrated to modulate axonal sprouting during neuronal disease. One such agent, Epothilone D, has been used to treat spinal cord injury (SCI) by promoting axonal sprouting at the lesion site after SCI. However, the role of Epothilone D in the differentiation of neural stem cells (NSCs) in SCI repair is unknown. In the present study, we mainly explored the effects and mechanisms of Epothilone D on the neuronal differentiation of NSCs and revealed a potential new SCI treatment. Methods In vitro differentiation assays, western blotting, and quantitative real-time polymerase chain reaction were used to detect the effects of Epothilone D on NSC differentiation. Retrograde tracing using a pseudotyped rabies virus was then used to detect neuronal circuit construction. RNA sequencing (RNA-Seq) was valuable for exploring the target gene involved in the neuronal differentiation stimulated by Epothilone D. In addition, lentivirus-induced overexpression and RNA interference technology were applied to demonstrate the function of the target gene. Last, an Apol8-NSC-linear ordered collagen scaffold (LOCS) graft was prepared to treat a mouse model of SCI, and functional and electrophysiological evaluations were performed. Results We first revealed that Epothilone D promoted the neuronal differentiation of cultured NSCs and facilitated neuronal relay formation in the injured site after SCI. Furthermore, the RNA-Seq results demonstrated that Apol8 was upregulated during Epothilone D-induced neuronal relay formation. Lentivirus-mediated Apol8 overexpression in NSCs (Apol8-NSCs) promoted NSC differentiation toward neurons, and an Apol8 interference assay showed that Apol8 had a role in promoting neuronal differentiation under the induction of Epothilone D. Last, Apol8-NSC transplantation with LOCS promoted the neuronal differentiation of transplanted NSCs in the lesion site as well as synapse formation, thus improving the motor function of mice with complete spinal cord transection. Conclusions Epothilone D can promote the neuronal differentiation of NSCs by upregulating Apol8, which may provide a promising therapeutic target for SCI repair.

With the merits of low cost, environmental friendliness and rich resources, manganese dioxide is considered to be a promising cathode material for aqueous zinc-ion batteries (AZIBs). However, its low ion diffusion and structural instability greatly limit its practical application. Hence, we developed an ion pre-intercalation strategy based on a simple water bath method to grow in situ δ-MnO2 nanosheets on flexible carbon cloth substrate (MnO2), while pre-intercalated Na+ in the interlayer of δ-MnO2 nanosheets (Na-MnO2), which effectively enlarges the layer spacing and enhances the conductivity of Na-MnO2. The prepared Na-MnO2//Zn battery obtained a fairly high capacity of 251 mAh g−1 at a current density of 2 A g−1, a satisfactory cycle life (62.5% of its initial capacity after 500 cycles) and favorable rate capability (96 mAh g−1 at 8 A g−1). Furthermore, this study revealed that the pre-intercalation engineering of alkaline cations is an effective method to boost the properties of δ-MnO2 zinc storage and provides new insights into the construction of high energy density flexible electrodes.

BackgroundThe long non-coding RNA (lncRNA) RP9 pseudogene (RP9P) is a pseudogene-derived lncRNA that has never been reported in cancer, and its function underlying tumorigenesis in colorectal cancer (CRC) remains unknown.MethodsRP9P and miR-133a-3p were filtered through bioinformatics analysis. The level of RP9P, miR-133a-3p, and FOXQ1 in CRC cell lines was detected by real-time PCR. Cell Counting Kit-8 and flow cytometric analyses were used to detect cell proliferation and apoptosis, respectively. Interactions between RP9P, miR-133a-3p, and FOXQ1 were confirmed by a dual-luciferase reporter assay.ResultsRP9P was overexpressed in CRC compared to normal control tissues and cells. Knockdown of RP9P inhibited CRC cell viability. RP9P directly interacted with miR-133a-3p, and miR-133a-3p downregulation abrogated the tumor-suppressing effect of RP9P knockdown. miR-133a-3p directly targeted FOXQ, which was positively regulated by RP9P. RP9P knockdown decreased FOXQ1 expression levels in CRC cells by directly targeting miR-133a-3p via a sponge mechanism. In addition, in vivo experiments in a xenograft model revealed that downregulated RP9P expression inhibited CRC cell tumorigenesis.ConclusionRP9P promotes colorectal cancer progression by regulating the miR-133a-3p/FOXQ1 axis.

Extracellular DNA (eDNA) is a critical component in the extracellular matrix (ECM) of bacterial biofilms, while little is known about the mechanisms underlying how eDNA integrates into the ECM through potential macromolecular interactions. Myxococcus xanthus biofilm was employed as a suitable model for the investigation due to the co-distribution of eDNA and exopolysaccharides (EPS) owing to their direct interactions in the ECM. DNA is able to combine with M. xanthus EPS to form a macromolecular conjugate, which is dominated by the electrostatic forces participating in the polymer-polymer interactions. Without intercalation binding, DNA-EPS interactions exhibit a certain degree of reversibility. Acting as a strong extracellular framework during biofilm formation process, the eDNA-EPS complex not only facilitates the initial cell adhesion and subsequent establishment of ECM architecture, but also renders cells within biofilms stress resistances that are relevant to the survival of M. xanthus in some hostile environments. Furthermore, the EPS protects the conjugated DNA from the degradation by nucleic acid hydrolases, which leads to the continuous and stable existence of eDNA in the native ECM of M. xanthus biofilms. These results will shed light on developing prevention and treatment strategies against biofilm-related risks.

A ring-shaped plasmonic nanostructure is established for realizing the plasmonic field enhancement and focusing through a radial vector beam incidence. The plasmonic light field of the proposed nanostructure is simulated by finite-difference time-domain (FDTD). The results show that the obvious plasmonic field enhancement and focusing spot can be observed when a ring-shaped Au nanostructure is placed on the gold layer. Especially, the maximum of intensity ratio for single ring-shaped nanostructure can reach up to 41, the minimum of the full width at half maximum (FWHM) of focusing spot closes to 60 nm, and spot size beyond the diffraction limit is as small as 0.19λ0. Moreover, the plasmonic field enhancement and focusing can not be realized in the cases of linear polarization, circular polarization, and angular vector polarization incidences. What’s more, the double ring-shaped nanostructure can further develop the intensity ratio to 109 caused by the interference enhancement of surface plasmons. These research results may pave the way for designing the ultra-strong plasmonic field and plasmonic focusing devices.

Excellent and wide-band absorption is of great benefit for lots of applications such as photoelectric conversions, photonics commutations as well as photovoltaic cells. Here, a simple MXene/Au-based metamaterial, consisting of a thick layer of Ti3C2Tx and Au-Nanorod, is studied through finite-difference time-domain (FDTD) method for realization of tunable strong absorption in the visible and near infrared. The results show that the enhanced wide-band absorption with AMAX = 0.99 can be realized for the proposed MXene/Au-based metamaterial. Moreover, the absorption can be effectively tuned by the structural parameters and polarization. These results may play an important role for designing plasmonic absorbers.

Diagenetic evolution is an important controlling factor of shale gas reservoirs. In this study, based on field outcrop and drilling core data, analytical techniques including X-ray diffraction (XRD), field emission scanning electron microscope combined with a focused ion beam (FIB-FESEM), and energy-dispersive spectroscopy (EDS) analyses were performed to determine the diagenetic evolution of the Longmaxi Formation shale and reveal the effect of diagenetic evolution on the shale gas exploration and development in the Sichuan Basin, Southwest China. The eodiagenesis phase was subdivided into two evolution stages, and the mesodiagenesis phase was subdivided into three evolution stages in the basin margin and center. Absorbed capacity and artificial fracturing effect of the Longmaxi Formation shale gas were related to mineral composition, which was influenced by sedimentary characteristics and diagenetic evolution. The diagenetic system in the basin margin was more open than that in the basin center due to a different burial history. The more open diagenetic system, with more micro-fractures and soluble constitute (e.g., feldspar), was in favor for the formation and preservation of secondary dissolved pores and organic pores in the basin margin. The relatively closed diagenetic system with stronger compaction resulted in deformation of pore space in the central basin.

Summary: Recently, COVID-19 caused by the novel coronavirus SARS-CoV-2 has brought great challenges to the world. More and more studies have shown that patients with severe COVID-19 may suffer from cytokine storm syndrome; however, there are few studies on its pathogenesis. Here we demonstrated that SARS-CoV-2 coding protein open reading frame 8 (ORF8) acted as a contributing factor to cytokine storm during COVID-19 infection. ORF8 could activate IL-17 signaling pathway and promote the expression of pro-inflammatory factors. Moreover, we demonstrated that treatment of IL17RA antibody protected mice from ORF8-induced inflammation. Our findings are helpful to understand the pathogenesis of cytokine storm caused by SARS-CoV-2 and provide a potential target for the development of COVID-19 therapeutic drugs.

Mesenchymal stemXin cells (MSCs) are a great cell source for bone regeneration. Although combining MSCs with growth factors and scaffolds provides a useful clinical strategy for bone tissue engineering, the efficiency of MSC osteogenic differentiation remains to be improved. Epigenetic modification is related to the differentiation ability of MSCs during osteogenic induction. In this study, we evaluate the effect of Chaetocin, an inhibitor of lysine-specific histone methyltransferases, on the differentiation of MSCs. We found that MSCs treated with Chaetocin demonstrated increased osteogenic ability and reduced adipogenic ability. The expression of osteogenic markers (Runx2 and OPN) was induced in MSCs by Chaetocin during osteogenic induction. Moveover, treatment of Chaetocin in MSCs improves Wnt/β-catenin signaling pathways and its downstream targets. Finally, we showed increased bone formation of MSC and Wnt/β-catenin signaling activity by treatment of Chaetocin using in vivo bone formation assays. Our data uncovered a critical role of Chaetocin in MSC osteogenic differentiation and provide new insights into bone tissue regeneration and repair.

The impact phenomena of solid micro-particles have gathered increasing interest across a wide range of fields, including space debris protection and cold-spray additive manufacturing of large, complicated structures. Effective motion monitoring is essential to understanding the impact behaviors of micro-particles. Consequently, a convenient and efficient micro-particle motion monitoring solution is proposed based on continuous single-frame multiple-exposure imaging technology. This method adopts a camera with excellent low-light performance coupled with high-frequency light-emitting diode (LED) flashes to generate short interval illumination. This technology can, in theory, achieve 1 million effective frames per second (fps) and monitor particles as small as 10 microns with speeds up to 12 km/s. The capabilities of the proposed method were validated by a series of micro-particle motion monitoring experiments with different particles sizes and materials under varying camera configurations. The study provides a feasible and economical solution for the velocity measurement and motion monitoring of high-speed micro-particles.

Tumor necrosis factor α (TNFα), an important clinical testing factor and drug target, can trigger serious autoimmune diseases and inflammation. Thus, the TNFα antibodies have great potential application in diagnostics and therapy fields. The variable binding domain of IgNAR (VNAR), the shark single domain antibody, has some excellent advantages in terms of size, solubility, and thermal and chemical stability, making them an ideal alternative to conventional antibodies. This study aims to obtain VNARs that are specific for mouse TNF (mTNF) from whitespotted bamboosharks. After immunization of whitespotted bamboosharks, the peripheral blood leukocytes (PBLs) were isolated from the sharks, then the VNAR phage display library was constructed. Through phage display panning against mTNFα, positive clones were validated through ELISA assay. The affinity of the VNAR and mTNFα was measured using ELISA and Bio-Layer Interferometry. The binding affinity of 3B11 VNAR reached 16.7 nM. Interestingly, one new type of VNAR targeting mTNF was identified that does not belong to any known VNAR type. To understand the binding mechanism of VNARs to mTNFα, the models of VNARs-mTNFα complexes were predicted by computational modeling combining HawkDock and RosettaDock. Our results showed that four VNARs’ epitopes overlapped in part with that of mTNFR. Furthermore, the ELISA assay shows that the 3B11 potently inhibited mTNFα binding to mTNFR. This study may provide the basis for the TNFα blockers and diagnostics applications.

ABSTRACT Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that poses threats to the public. M. tuberculosis survives in macrophages by escaping from immune surveillance and clearance, which exacerbates the bacterial proliferation. However, the molecular mechanisms of this immune escape have not yet been fully understood. Using multiple cell and mouse models, we found that microRNA-325-3p (miR-325-3p) is upregulated after M. tuberculosis infection and Mir325-deficient mice show resistance to M. tuberculosis. We demonstrated that miR-325-3p directly targets LNX1, an E3 ubiquitin ligase of NEK6, and that this hampers the proteasomal degradation of NEK6 in macrophages. The abnormal accumulation of NEK6 leads to the activation of STAT3 signaling, thus inhibiting the process of apoptosis and promoting the intracellular survival of M. tuberculosis. Our findings not only reveal a new immune escape pathway of M. tuberculosis but also may provide new insights into the development of therapeutic approaches for drug-resistant TB. IMPORTANCE Intracellular survival of Mycobacterium tuberculosis results in bacterial proliferation and the spread of infection in lungs, consequently deteriorating the conditions of tuberculosis (TB) patients. This research discovers a new immune escape pathway of M. tuberculosis by modulating host miR-325-3p expression, thus leading to the intracellular survival of M. tuberculosis. These findings make a contribution to the understanding of the immune escape of M. tuberculosis, and they provide a theoretical basis for the development of therapeutic approaches for drug-resistant TB.

We study spectral responses in a bright-dark mode ellipse-shaped resonators coupled waveguide. The results show that the plasmon-induced transparency (PIT) can be observed in the ellipse-shaped resonators coupled waveguide, and the symmetric line shape at the PIT window can be tuned by the radii of the long axis in ellipse-shaped resonators, the coupling distance, and the symmetry broken degree. Interestingly, the radii of the long axis for the bright mode and dark mode have opposite effect on the spectra of PIT. Our research results may pave the way for the understanding and tuning of PIT.

We study dual-Fano resonances and its sensing properties in a crossed ring-shaped metasurface by use of the finite-different time-domain (FDTD) simulation. The results show that the dual-Fano resonances in the proposed crossed ring-shaped metasurface are caused by the interaction among three local surface plasmon resonances (LSPRs), and spectra of the dual-Fano resonances can be tuned by the radius of the circular ring (CR) nanostructure, the distance between the center of the two CRs in x direction, and the polarization of the incident light. Interestingly, single Fano resonance splits into dual-Fano resonances in the case of the asymmetric ring structure arrangement or the non-y-axis polarized incident or the distance d

Therapeutics targeting cytokines such as the oncostatin M (OSM)-mediated inflammation represent a potential strategy for the treatment of inflammatory bowel disease (IBD). Despite the investigation of the specific role of the interactions between OSM and the receptor (OSMR) in IBD pathogenesis, the 3D structure of the OSM–OSMR complex remains elusive. In this work, the interaction mode between OSM and OSMR at atomic level was predicted by computational simulation approach. The interaction domain of the OSMR was built with the homology modeling method. The near-native structure of the OSM–OSMR complex was obtained by docking, and long-time scale molecular dynamics (MD) simulation in an explicit solvent was further performed to sample the conformations when OSM binds to the OSMR. After getting the equilibrated states of the simulation system, per-residue energy contribution was calculated to characterize the important residues for the OSM–OSMR complex formation. Based on these important residues, eight residues (OSM: Arg100, Leu103, Phe160, and Gln161; OSMR: Tyr214, Ser223, Asp262, and Trp267) were identified as the “hot spots” through computational alanine mutagenesis analysis and verified by additional MD simulation of R100A (one of the identified “hotspots”) mutant. Moreover, six cavities were detected at the OSM–OSMR interface through the FTMap analysis, and they were suggested as important binding sites. The predicted 3D structure of the OSM–OSMR complex and the identified “hot spots” constituting the core of the binding interface provide helpful information in understanding the OSM–OSMR interactions, and the detected sites serve as promising targets in designing small molecules to block the interactions.

Glioblastoma (GBM) is the most common and aggressive intracranial malignant brain tumor, and the abnormal expression of HDAC1 is closely correlated to the progression, recurrence and metastasis of GBM cells, making selective inhibition of HDAC1 a promising strategy for GBM treatments. Among all available selective HDAC1 inhibitors, the macrocyclic peptides have gained great attention due to their remarkable inhibitory selectivity on HDAC1. However, the binding mechanism underlying this selectivity is still elusive, which increases the difficulty of designing and synthesizing the macrocyclic peptide-based anti-GBM drug. Herein, multiple computational approaches were employed to explore the binding behaviors of a typical macrocyclic peptide FK228 in both HDAC1 and HDAC6. Starting from the docking conformations of FK228 in the binding pockets of HDAC1&6, relatively long MD simulation (500 ns) shown that the hydrophobic interaction and hydrogen bonding of E91 and D92 in the Loop2 of HDAC1 with the Cap had a certain traction effect on FK228, and the sub-pocket formed by Loop1 and Loop2 in HDAC1 could better accommodate the Cap group, which had a positive effect on maintaining the active conformation of FK228. While the weakening of the interactions between FK228 and the residues in the Loop2 of HDAC6 during the MD simulation led to the large deflection of FK228 in the binding site, which also resulted in the decrease in the interactions between the Linker region of FK228 and the previously identified key amino acids (H134, F143, H174, and F203). Therefore, the residues located in Loop1 and Loop2 contributed in maintaining the active conformation of FK228, which would provide valuable hints for the discovery and design of novel macrocyclic polypeptide HDAC inhibitors.

Multiple sclerosis (MS) is a chronic fatal central nervous system (CNS) disease involving in complex immunity dysfunction. Recently, long noncoding RNAs (lncRNAs) were discovered as the important regulatory factors for the pathogenesis of MS. However, these findings often cannot be repeated and confirmed by the subsequent studies. We considered that the small-scale samples or the heterogeneity among various tissues may result in the divergence of the results. Currently, RNA-seq has become a powerful approach to quantify the abundances of lncRNA transcripts. Therefore, we comprehensively collected the MS-related RNA-seq data from a variety of previous studies, and integrated these data using an expression-based meta-analysis to identify the differentially expressed lncRNA between MS patients and controls in whole samples and subgroups. Then, we performed the Jensen-Shannon (JS) divergence and cluster analysis to explore the heterogeneity and expression specificity among various tissues. Finally, we investigated the potential function of identified lncRNAs for MS using weighted gene co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA), and 5,420 MS-related lncRNAs specifically expressed in the brain tissue were identified. The subgroup analysis found a small heterogeneity of the lncRNA expression profiles between brain and blood tissues. The results of WGCNA and GSEA showed that a potential important function of lncRNAs in MS may be involved in the regulation of ribonucleoproteins and tumor necrosis factor cytokines receptors. In summary, this study provided a strategy to explore disease-related lncRNAs on genome-wide scale, and our findings will be benefit to improve the understanding of MS pathogenesis.

Because of the extended period of clinic data collection and huge size of analyzed samples, the long-term and large-scale pharmacometabonomics profiling is frequently encountered in the discovery of drug/target and the guidance of personalized medicine. So far, integration of the results (ReIn) from multiple experiments in a large-scale metabolomic profiling has become a widely used strategy for enhancing the reliability and robustness of analytical results, and the strategy of direct data merging (DiMe) among experiments is also proposed to increase statistical power, reduce experimental bias, enhance reproducibility and improve overall biological understanding. However, compared with the ReIn, the DiMe has not yet been widely adopted in current metabolomics studies, due to the difficulty in removing unwanted variations and the inexistence of prior knowledges on the performance of the available merging methods. It is therefore urgently needed to clarify whether DiMe can enhance the performance of metabolic profiling or not. Herein, the performance of DiMe on 4 pairs of benchmark datasets was comprehensively assessed by multiple criteria (classification capacity, robustness and false discovery rate). As a result, integration/merging-based strategies (ReIn and DiMe) were found to perform better under all criteria than those strategies based on single experiment. Moreover, DiMe was discovered to outperform ReIn in classification capacity and robustness, while the ReIn showed superior capacity in controlling false discovery rate. In conclusion, these findings provided valuable guidance to the selection of suitable analytical strategy for current metabolomics.

The unidirectional reflectionless (UR) light propagation is investigated in the waveguide coupled to gain and loss resonators by using a developed coupled mode-scattering matrix theory. The results show that there is almost no reflection in the case of the backward incidence, but total reflection in the case of the forward incidence under the condition of balancing gain and loss in the gain resonator for the proposed waveguide when the indirect coupling phase θ ranges from 0.8 rad to 2.3 rad and from 4 rad to 5.5 rad. Moreover, the coherent perfect absorption (CPA) can be observed at the same time. Especially, the UR light propagation appears when the absolute value of detuning δ is smaller than 1 × 10 ^13 rad s ^−1 . Based on the findings above, we propose a metal–insulator–metal non-parity-time symmetric plasmonic waveguide and obtain the UR plasmonic propagation and CPA. The theoretical results are in excellent agreement with the finite-difference time-domain simulations. These results will provide a new pathway for the realization of unidirectional propagation and absorption of light at the nanoscale.

We investigate Fano resonances and sensing enhancements in a simple Au/TiO2 hybrid metasurface through the finite-different time-domain (FDTD) simulation and coupled mode theory (CMT) analysis. The results show that the Fano resonance in the proposed simple metasurface is caused by the destructive interaction between the surface plasmon polaritons (SPPs) and the local surface plasmon resonances (LSPRs), the quality factor and dephasing time for the Fano resonance can be effectively tuned by the thickness of Au and TiO2 structures, the length of each unit in x and y directions, as well as the structural defect. In particular, single Fano resonance splits into multiple Fano resonances caused by a stub-shaped defect, and multiple Fano resonances can be tuned by the size and position of the stub-shaped defect. Moreover, we also find that the sensitivity in the Au/TiO2 hybrid metasurface with the stub-shaped defect can reach up to 330 nm/RIU and 535 nm/RIU at the Fano resonance 1 and Fano resonance 2, which is more than three times as sensitive in the Au/TiO2 hybrid metasurface without the stub-shaped defect, and also higher than that in the TiO2 metasurface reported before. These results may provide further understanding of Fano resonances and guidance for designing ultra-high sensitive refractive index sensors.

We develop a novel nonlinear radiation oscillator theory, which can describe nonlinear optical responses in symmetric and anti-symmetric damping graphene coupled metamaterials. An ultra-high quality factor of induced transparency can be realized in the proposed model. The results show that the spectral response and quality factor can be effectively tuned by the resonant detuning, the phase difference, the damping factor as well as the field intensity of the pump light. Moreover, the quality factor of induced transparency is increased by more than 60 times when the field intensity of the pump light and the damping factor are changed. Especially, the single induced transparency window splits into double induced transparency windows as the damping factors of dark mode and bright mode show anti-symmetric damping case. These results may pave the way for designing the high performance of nano-optical devices in terahertz.

One of the most challenging puzzles in drug discovery is the identification and characterization of candidate drug of well-balanced profile between efficacy and safety. So far, extensive efforts have been made to evaluate this balance by estimating the quantitative structure–therapeutic relationship and exploring target profile of adverse drug reaction. Particularly, the therapeutic index (TI) has emerged as a key indicator illustrating this delicate balance, and a clinically successful agent requires a sufficient TI suitable for it corresponding indication. However, the TI information are largely unknown for most drugs, and the mechanism underlying the drugs with narrow TI (NTI drugs) is still elusive. In this study, the collective effects of human protein–protein interaction (PPI) network and biological system profile on the drugs' efficacy–safety balance were systematically evaluated. First, a comprehensive literature review of the FDA approved drugs confirmed their NTI status. Second, a popular feature selection algorithm based on artificial intelligence (AI) was adopted to identify key factors differencing the target mechanism between NTI and non-NTI drugs. Finally, this work revealed that the targets of NTI drugs were highly centralized and connected in human PPI network, and the number of similarity proteins and affiliated signaling pathways of the corresponding targets was much higher than those of non-NTI drugs. These findings together with the newly discovered features or feature groups clarified the key factors indicating drug's narrow TI, and could thus provide a novel direction for determining the delicate drug efficacy-safety balance.

Sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) has emerged as one of the most popular techniques for label-free proteome quantification in current pharmacoproteomic research. It provides more comprehensive detection and more accurate quantitation of proteins comparing with the traditional techniques. The performance of SWATH-MS is highly susceptible to the selection of processing method. Till now, ≥27 methods (transformation, normalization, and missing-value imputation) are sequentially applied to construct numerous analysis chains for SWATH-MS, but it is still not clear which analysis chain gives the optimal quantification performance. Herein, the performances of 560 analysis chains for quantifying pharmacoproteomic data were comprehensively assessed. Firstly, the most complete set of the publicly available SWATH-MS based pharmacoproteomic data were collected by comprehensive literature review. Secondly, substantial variations among the performances of various analysis chains were observed, and the consistently well-performed analysis chains (CWPACs) across various datasets were for the first time generalized. Finally, the log and power transformations sequentially followed by the total ion current normalization were discovered as one of the best performed analysis chains for the quantification of SWATH-MS based pharmacoproteomic data. In sum, the CWPACs identified here provided important guidance to the quantification of proteomic data and could therefore facilitate the cutting-edge research in any pharmacoproteomic studies requiring SWATH-MS technique.

Natural resistance-associated macrophage protein 1 encoding gene (NRAMP1) plays an important role in immune response against intracellular pathogens. To evaluate the effects of NRAMP1 gene on immune capacity in pigs, tissue expression of NRAMP1 mRNA was observed by real time quantitative polymerase chain reaction (PCR), and the results revealed NRAMP1 expressed widely in nine tissues. One single nucleotide polymorphism (SNP) (ENSSSCG00000025058: g.130 C>T) in exon1 and one SNP (ENSSSCG00000025058: g.657 A>G) in intron1 region of porcine NRAMP1 gene were demonstrated by DNA sequencing and PCR-RFLP analysis. A further analysis of SNP genotypes associated with immune traits including contain of white blood cell (WBC), granulocyte, lymphocyte, monocyte (MO), rate of cytotoxin in monocyte (MC) and CD4/CD8 T lymphocyte subpopulations in blood was carried out in four pig populations including Large White and three Chinese indigenous breeds (Wannan Black, Huai pig and Wei pig). The results showed that the SNP (ENSSSCG00000025058: g.130 C>T) was significantly associated with level of WBC % (p = 0.031), MO% (p = 0.024), MC% (p = 0.013) and CD4−CD8+ T lymphocyte (p = 0.023). The other SNP (ENSSSCG00000025058: g.657 A>G) was significantly associated with the level of MO% (p = 0.012), MC% (p = 0.019) and CD4−CD8+ T lymphocyte (p = 0.037). These results indicate that the NRAMP1 gene can be regarded as a molecular marker for genetic selection of disease susceptibility in pig breeding.

The interaction of death-associated protein kinase 1 (DAPK1) with the 2B subunit (GluN2B) C-terminus of N-methyl-D-aspartate receptor (NMDAR) plays a critical role in the pathophysiology of depression and is considered a potential target for the structure-based discovery of new antidepressants. However, the 3D structures of C-terminus residues 1290⁻1310 of GluN2B (GluN2B-CT1290-1310) remain elusive and the interaction between GluN2B-CT1290-1310 and DAPK1 is unknown. In this study, the mechanism of interaction between DAPK1 and GluN2B-CT1290-1310 was predicted by computational simulation methods including protein⁻peptide docking and molecular dynamics (MD) simulation. Based on the equilibrated MD trajectory, the total binding free energy between GluN2B-CT1290-1310 and DAPK1 was computed by the mechanics generalized born surface area (MM/GBSA) approach. The simulation results showed that hydrophobic, van der Waals, and electrostatic interactions are responsible for the binding of GluN2B-CT1290⁻1310/DAPK1. Moreover, through per-residue free energy decomposition and in silico alanine scanning analysis, hotspot residues between GluN2B-CT1290-1310 and DAPK1 interface were identified. In conclusion, this work predicted the binding mode and quantitatively characterized the protein⁻peptide interface, which will aid in the discovery of novel drugs targeting the GluN2B-CT1290-1310 and DAPK1 interface.

HIV-1 integrase (IN) is essential for the integration of viral DNA into the host genome and an attractive therapeutic target for developing antiretroviral inhibitors. LEDGINs are a class of allosteric inhibitors targeting LEDGF/p75 binding site of HIV-1 IN. Yet, the detailed binding mode and allosteric inhibition mechanism of LEDGINs to HIV-1 IN is only partially understood, which hinders the structure-based design of more potent anti-HIV agents. A molecular modeling study combining molecular docking, molecular dynamics simulation, and binding free energy calculation were performed to investigate the interaction details of HIV-1 IN catalytic core domain (CCD) with two recently discovered LEDGINs BI-1001 and CX14442, as well as the LEDGF/p75 protein. Simulation results demonstrated the hydrophobic domain of BI-1001 and CX14442 engages one subunit of HIV-1 IN CCD dimer through hydrophobic interactions, and the hydrophilic group forms hydrogen bonds with HIV-1 IN CCD residues from other subunit. CX14442 has a larger tert-butyl group than the methyl of BI-1001, and forms better interactions with the highly hydrophobic binding pocket of HIV-1 IN CCD dimer interface, which can explain the stronger affinity of CX14442 than BI-1001. Analysis of the binding mode of LEDGF/p75 with HIV-1 IN CCD reveals that the LEDGF/p75 integrase binding domain residues Ile365, Asp366, Phe406 and Val408 have significant contributions to the binding of the LEDGF/p75 to HIV1-IN. Remarkably, we found that binding of BI-1001 and CX14442 to HIV-1 IN CCD induced the structural rearrangements of the 140 s loop and oration displacements of the side chains of the three conserved catalytic residues Asp64, Asp116, and Glu152 located at the active site. These results we obtained will be valuable not only for understanding the allosteric inhibition mechanism of LEDGINs but also for the rational design of allosteric inhibitors of HIV-1 IN targeting LEDGF/p75 binding site.

HCV NS3/4A protein is an attractive therapeutic target responsible for harboring serine protease and RNA helicase activities during the viral replication. Small molecules binding at the interface between the protease and helicase domains can stabilize the closed conformation of the protein and thus block the catalytic function of HCV NS3/4A protein via an allosteric regulation mechanism. But the detailed mechanism remains elusive. Here, we aimed to provide some insight into the inhibitor binding mode and allosteric regulation mechanism of HCV NS3/4A protein by using computational methods. Four simulation systems were investigated. They include: apo state of HCV NS3/4A protein, HCV NS3/4A protein in complex with an allosteric inhibitor and the truncated form of the above two systems. The molecular dynamics simulation results indicate HCV NS3/4A protein in complex with the allosteric inhibitor 4VA adopts a closed conformation (inactive state), while the truncated apo protein adopts an open conformation (active state). Further residue interaction network analysis suggests the communication of the domain-domain interface play an important role in the transition from closed to open conformation of HCV NS3/4A protein. However, the inhibitor stabilizes the closed conformation through interaction with several key residues from both the protease and helicase domains, including His57, Asp79, Asp81, Asp168, Met485, Cys525 and Asp527, which blocks the information communication between the functional domains interface. Finally, a dynamic model about the allosteric regulation and conformational changes of HCV NS3/4A protein was proposed and could provide fundamental insights into the allosteric mechanism of HCV NS3/4A protein function regulation and design of new potent inhibitors.