SAM-DTA: a sequence-agnostic model for drug-target binding affinity prediction.

Drug-target binding affinity prediction is a fundamental task for drug discovery and has been studied for decades. Most methods follow the canonical paradigm that processes the inputs of the protein (target) and the ligand (drug) separately and then combines them together. In this study we demonstrate, surprisingly, that a model is able to achieve even superior performance without access to any protein-sequence-related information. Instead, a protein is characterized completely by the ligands that it interacts. Specifically, we treat different proteins separately, which are jointly trained in a multi-head manner, so as to learn a robust and universal representation of ligands that is generalizable across proteins. Empirical evidences show that the novel paradigm outperforms its competitive sequence-based counterpart, with the Mean Squared Error (MSE) of 0.4261 versus 0.7612 and the R-Square of 0.7984 versus 0.6570 compared with DeepAffinity. We also investigate the transfer learning scenario where unseen proteins are encountered after the initial training, and the cross-dataset evaluation for prospective studies. The results reveals the robustness of the proposed model in generalizing to unseen proteins as well as in predicting future data. Source codes and data are available at https://github.com/huzqatpku/SAM-DTA.

Reconstruction Strategy for Upper Extremity Defects After Bone Tumor Resection Based on 3D Customized Bone Cement Mold.

BACKGROUND: Reconstructing bone defects in the upper extremities and restoring their functions poses a significant challenge. In this study, we describe a novel workflow for designing and manufacturing customized bone cement molds using 3D printing technology to reconstruct upper extremity defects after bone tumor resection. METHODS: Computer tomography data was acquired from the unaffected upper extremities to create a detachable mold, which can be customized to fit the joint precisely by shaping the bone cement accordingly. Fourteen patients who underwent reconstructive surgery following bone tumor resection in the proximal humerus (13 cases) or distal radius (1 case) between January 2014 and December 2022 were retrospectively evaluated. The medical records of this case series were reviewed for the demographic, radiological, and operative data. Metastasis, local recurrence, and complication were also reviewed. Additionally, Musculoskeletal Tumor Society Score (MSTS) and Visual Analogue Scale (VAS) were used to assess clinical outcomes. RESULTS: The mean follow-up period was 49.36 ± 15.18 months (range, 27-82 months). At the end of follow-up, there were no cases of metastasis or recurrence, and patients did not experience complications such as infection, dislocation, or implant loosening. Two cases complicated with subluxation (14.3%), and 1 case underwent revision surgery for prosthetic fracture (7.1%). The average MSTS score was 23.2 ± 1.76 (77.4%, range, 66.7%-86.7%), and the postoperative VAS score was 1.86 ± 1.03 (range, 1-4), which was significantly lower than that before surgery (average preoperative VAS score was 5.21 ± 2.00 (range, 2-8)) (P < .001). CONCLUSION: Customized 3D molds can be utilized to shape bone cement prostheses, which may serve as a potential alternative for reconstructing the proximal humerus and distal radius following en bloc resection of bone tumors. This reconstruction strategy offers apparent advantages, including precise matching of articular surfaces and comparatively reduced costs.

LS-MolGen: Ligand-and-Structure Dual-Driven Deep Reinforcement Learning for Target-Specific Molecular Generation Improves Binding Affinity and Novelty.

Deep learning-based molecular generative models have garnered considerable interest in the field of de novo drug design. However, most extant models focus on either ligand-based or structure-based strategies, thereby failing to effectively harness the combined knowledge derived from both ligands and the structure of the binding target. In this article, we introduce LS-MolGen, a novel ligand and structure-integrated molecular generative model. This model synergistically combines representation learning, transfer learning, and reinforcement learning. The targeted knowledge assimilation from transfer learning, coupled with an advanced exploration strategy in reinforcement learning, empowers LS-MolGen to efficiently generate novel and high-affinity molecules efficiently. The comparable performance of our model is affirmed through multiple evaluations, including EGFR, DRD3, CDK2, AA2AR, ADRB2, and a dedicated case study of inhibitor design for SARS-CoV-2 Mpro. The results indicate that LS-MolGen performs better than other ligand-based or structure-based generative models in de novo designing promising compounds with novel scaffolds and high binding affinity. This proof-of-concept study signifies the potential of our ligand- and structure-based generative model, LS-MolGen, as a promising new tool for target-specific molecular generation and drug design.

Education level has an effect on the recovery of total knee arthroplasty: a retrospective study.

OBJECTIVE: This study aimed to observe the relationship between education level and outcomes after total knee arthroplasty (TKA). METHODS: One thousand two hundred sixty four patients after TKA in our hospital from April 2016 to April 2020 were reviewed. These patients were divided into 4 groups (A who were illiterate, B who had elementary school degree, C who had junior high school degree, D who had senior high school degree or higher) by the educational level, which was blinded to the observers. The postoperative outcomes of KSS score, pain, joint extension and flexion function were observed 1 year after discharged from hospital. RESULTS: Among 1253 patients met the inclusion criteria, the average age was 68.63 years, the average body mass was 57.73 kg. There are no distinctions among 4 groups one day after the surgery. However, the outcomes of the follow up were that, the KSS score was: 77.84 ± 10.635; 80.70 ± 8.956; 87.92 ± 8.123;91.27 ± 8.262, with significant differences (P < 0.05). The mean VAS scores were: 1.97 ± 1.60; 2.07 ± 1.66; 1.197 ± 1.5265, 1.044 ± 1.4662. Patients in Group C and D had significantly less pain than that in Group A and B (P < 0.05). The knee flexion range of motion (ROM) was: 91.21 ± 11.69°; 91.77 ± 11.95°; 102.12 ± 11.38°; 109.96 ± 10.64°, Group D performed best, with significant differences (P < 0.05). The knee extension ROM were: - 2.41 ± 4.49°; - 0.91 ± 2.82°; - 0.83 ± 2.87°; - 0.35 ± 1.60°, with significant difference between Group D and the others (P < 0.05). CONCLUSION: Education level affects the outcomes such as VAS score, KSS score, the extension and flexion ROM of the knee after TKA. The patients with higher education level have better outcomes.

Comparative Study of Sargassum fusiforme Polysaccharides in Regulating Cecal and Fecal Microbiota of High-Fat Diet-Fed Mice.

Seaweed polysaccharides represent a kind of novel gut microbiota regulator. The advantages and disadvantages of using cecal and fecal microbiota to represent gut microbiota have been discussed, but the regulatory effects of seaweed polysaccharides on cecal and fecal microbiota, which would benefit the study of seaweed polysaccharide-based gut microbiota regulator, have not been compared. Here, the effects of two Sargassum fusiforme polysaccharides prepared by water extraction (SfW) and acid extraction (SfA) on the cecal and fecal microbiota of high-fat diet (HFD) fed mice were investigated by 16S rRNA gene sequencing. The results indicated that 16 weeks of HFD dramatically impaired the homeostasis of both the cecal and fecal microbiota, including the dominant phyla Bacteroidetes and Actinobacteria, and genera Coriobacteriaceae, S24-7, and Ruminococcus, but did not affect the relative abundance of Firmicutes, Clostridiales, Oscillospira, and Ruminococcaceae in cecal microbiota and the Simpson's index of fecal microbiota. Co-treatments with SfW and SfA exacerbated body weight gain and partially reversed HFD-induced alterations of Clostridiales and Ruminococcaceae. Moreover, the administration of SfW and SfA also altered the abundance of genes encoding monosaccharide-transporting ATPase, α-galactosidase, ß-fructofuranosidase, and ß-glucosidase with the latter showing more significant potency. Our findings revealed the difference of cecal and fecal microbiota in HFD-fed mice and demonstrated that SfW and SfA could more significantly regulate the cecal microbiota and lay important foundations for the study of seaweed polysaccharide-based gut microbiota regulators.

Sargassum fusiforme Polysaccharides Prevent High-Fat Diet-Induced Early Fasting Hypoglycemia and Regulate the Gut Microbiota Composition.

A low fasting blood glucose level is a common symptom in diabetes patients and can be induced by high-fat diet (HFD) feeding at an early stage, which may play important roles in the development of diabetes, but has received little attention. In this study, five polysaccharides were prepared from Sargassumfusiforme and their effects on HFD-induced fasting hypoglycemia and gut microbiota dysbiosis were investigated. The results indicated that C57BL/6J male mice fed an HFD for 4 weeks developed severe hypoglycemia and four Sargassumfusiforme polysaccharides (SFPs), consisting of Sf-2, Sf-3, Sf-3-1, and Sf-A, significantly prevented early fasting hypoglycemia without inducing hyperglycemia. Sf-1 and Sf-A could also significantly prevent HFD-induced weight gain. Sf-2, Sf-3, Sf-3-1, and Sf-A mainly attenuated the HFD-induced decrease in Bacteroidetes, and all five SFPs had a considerable influence on the relative abundance of Oscillospira, Mucispirillum, and Clostridiales. Correlation analysis revealed that the fasting blood glucose level was associated with the relative abundance of Mucispinllum and Oscillospira. Receiver operating characteristic analysis indicated that Mucispinllum and Oscillospira exhibited good discriminatory power (AUC = 0.745-0.833) in the prediction of fasting hypoglycemia. Our findings highlight the novel application of SFPs (especially Sf-A) in glucose homeostasis and the potential roles of Mucispinllum and Oscillospira in the biological activity of SFPs.

Does patient-specific instrumentation increase the risk of notching in the anterior femoral cortex in total knee arthroplasty? A comparative prospective trial.

PURPOSE: Patient-specific instrumentation (PSI) was usually applied in total knee arthroplasty (TKA) to acquire a favourable alignment. We hypothesized that using PSI had a potential risk of notching in the anterior femoral cortex, because the femoral component may be placed in an overextension position due to the distal femoral sagittal anteversion. The aim of this study was to figure out the relationship between the notch and the distal femoral sagittal anteversion in PSI-assisted TKA. METHODS: One hundred thirty-one patients who were to undergo total knee arthroplasty (TKA) were randomly divided into conventional instrumentation (CI) group and PSI group. The computed tomography (CT) data of lower extremities was collected and imported to the Mimics software to reconstruct the three-dimensional (3D) bone image of the femur. The angle between distal femoral anatomic axis (DFAA) and femoral mechanical axis (FMA) on sagittal plane was defined as distal femoral sagittal anteverted angle (DFSAA) and measured. The number of notch intra-operative and post-operative was recorded. Then, we calculated the incidence of the notch and analyzed its relationship with DFSAA. RESULTS: The average DFSAA of 262 femurs is 2.5° ± 1.5° (range, 0.0°-5.7°). When DFSAA ≥ 3°, the incidence of notch was 7.10% in CI group and 33.30% in PSI group, respectively, which shows significant statistical difference in the two groups (P = 0.016 < 0.05). When DFSAA < 3°, the incidence of notch was 6.50% in CI group and 5.30% in PSI group, respectively, which shows no significant statistical difference in the two groups (P = 0.667 > 0.05). CONCLUSION: DFSAA could be taken as an indicator to predict the notch when performing TKA assisted with PSI. Especially when the DFSAA ≥ 3°, the risk of notch could be markedly increased.

Role of the Interaction Motif in Maintaining the Open Gate of an Open Sodium Channel.

Voltage-gated sodium channels undergo transitions between open, closed, and inactivated states, enabling regulation of the translocation of sodium ions across membranes. A recently published crystal structure of the full-length prokaryotic NavMs crystal structure in the activated open conformation has revealed the presence of a novel motif consisting of an extensive network of salt bridges involving residues in the voltage sensor, S4-S5 linker, pore, and C-terminal domains. This motif has been proposed to be responsible for maintaining an open conformation that enables ion translocation through the channel. In this study, we have used long-time molecular dynamics calculations without artificial restraints to demonstrate that the interaction network of full-length NavMs indeed prevents a rapid collapse and closure of the gate, in marked difference to earlier studies of the pore-only construct in which the gate had to be restrained to remain open. Interestingly, a frequently discussed "hydrophobic gating" mechanism at nanoscopic level is also observed in our simulations, in which the discontinuous water wire close to the gate region leads to an energetic barrier for ion conduction. In addition, we demonstrate the effects of in silico mutations of several of the key residues in the motif on the open channel's stability and functioning, correlating them with existing functional studies on this channel and homologous disease-associated mutations in human sodium channels; we also examine the effects of truncating/removing the voltage sensor and C-terminal domains in maintaining an open gate.

Electrospun LiFePO4/C Composite Fiber Membrane as a Binder-Free, Self-Standing Cathode for Power Lithium-Ion Battery.

A LiFePO4/C composite fiber membrane was fabricated by the electrospinning method and subsequent thermal treatment. The thermal decomposition process was analyzed by TG/DSC, the morphology, microstructure and composition were studied using SEM, TEM, XRD, Raman, respectively. The results indicated that the prepared LiFePO4/C composite fibers were composed of nanosized LiFePO4 crystals and amorphous carbon coatings, which formed a three dimensional (3D) long-range networks, greatly enhanced the electronic conductivity of LiFePO4 electrode up to 3.59× 10-2 S · cm-2. The 3D LiFePO4/C fiber membrane could be directly used as a binder-free, self-standing cathode for lithium-ion battery, and exhibited an improved capacity and rate performance. The LiFePO4/C composite electrode delivered a discharge capacity of 116 mAh·g-1, 109 mAh·g-1, 103 mAh·g-1, 91 mAh·g-1, 80 mAh·g-1 at 0.1 C, 0.5 C, 1 C, 3 C, 5 C, respectively. And a stable cycling performance was also achieved that the specific capacity could retain 75 mA·g-1 after 500 cycles at 5 C. Therefore, this LiFePO4/C composite fiber membrane was promising to be used as a cathode for power lithium ion battery.

Exploring the structure of the voltage-gated Na+ channel by an engineered drug access pathway to the receptor site for local anesthetics.

Despite the availability of several crystal structures of bacterial voltage-gated Na(+) channels, the structure of eukaryotic Na(+) channels is still undefined. We used predictions from available homology models and crystal structures to modulate an external access pathway for the membrane-impermeant local anesthetic derivative QX-222 into the internal vestibule of the mammalian rNaV1.4 channel. Potassium channel-based homology models predict amino acid Ile-1575 in domain IV segment 6 to be in close proximity to Lys-1237 of the domain III pore-loop selectivity filter. The mutation K1237E has been shown previously to increase the diameter of the selectivity filter. We found that an access pathway for external QX-222 created by mutations of Ile-1575 was abolished by the additional mutation K1237E, supporting the notion of a close spatial relationship between sites 1237 and 1575. Crystal structures of bacterial voltage-gated Na(+) channels predict that the side chain of rNaV1.4 Trp-1531 of the domain IV pore-loop projects into the space between domain IV segment 6 and domain III pore-loop and, therefore, should obstruct the putative external access pathway. Indeed, mutations W1531A and W1531G allowed for exceptionally rapid access of QX-222. In addition, W1531G created a second non-selective ion-conducting pore, bypassing the outer vestibule but probably merging into the internal vestibule, allowing for control by the activation gate. These data suggest a strong structural similarity between bacterial and eukaryotic voltage-gated Na(+) channels.

Different inward and outward conduction mechanisms in NaVMs suggested by molecular dynamics simulations.

Rapid and selective ion transport is essential for the generation and regulation of electrical signaling pathways in living organisms. Here, we use molecular dynamics (MD) simulations with an applied membrane potential to investigate the ion flux of bacterial sodium channel NaVMs. 5.9 µs simulations with 500 mM NaCl suggest different mechanisms for inward and outward flux. The predicted inward conductance rate of ∼27±3 pS, agrees with experiment. The estimated outward conductance rate is 15±3 pS, which is considerably lower. Comparing inward and outward flux, the mean ion dwell time in the selectivity filter (SF) is prolonged from 13.5±0.6 ns to 20.1±1.1 ns. Analysis of the Na+ distribution revealed distinct patterns for influx and efflux events. In 32.0±5.9% of the simulation time, the E53 side chains adopted a flipped conformation during outward conduction, whereas this conformational change was rarely observed (2.7±0.5%) during influx. Further, simulations with dihedral restraints revealed that influx is less affected by the E53 conformational flexibility. In contrast, during outward conduction, our simulations indicate that the flipped E53 conformation provides direct coordination for Na+. The free energy profile (potential of mean force calculations) indicates that this conformational change lowers the putative barriers between sites SCEN and SHFS during outward conduction. We hypothesize that during an action potential, the increased Na+ outward transition propensities at depolarizing potentials might increase the probability of E53 conformational changes in the SF. Subsequently, this might be a first step towards initiating slow inactivation.

G protein-coupled estrogen receptor-protein kinase A-ERK-CREB signaling pathway is involved in the regulation of mouse gubernaculum testis cells by diethylstilbestrol.

The etiology of testicular dysgenesis syndrome is multifactorial and involves environmental factors, such as environmental estrogens. Several studies have shown that hormonal effects on the gubernaculum may affect testicular descent. Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that disrupts the morphology and proliferation of gubernacular cells, but the underlying mechanisms remain elusive. In this study, we aimed to determine whether DES may regulate the function of gubernaculum testis cells by way of nongenomic effects mediated by G protein-coupled estrogen receptor (GPER). We used cultured mouse gubernacular testis cells to demonstrate that GPER is expressed in gubernaculum testis cells. Erk1/2 inhibitor PD98059, PKA inhibitor H89, and Src inhibitor PP2 relieved DES-induced inhibition of gubernaculum testis cell proliferation, but ER inhibitor ICI 182780 had no effects on DES-induced inhibition of gubernaculum testis cell proliferation. In addition, we found that DES induced the activation of CREB downstream of PKA, Src, and ERK1/2 in these cells. These data suggest that the effects of DES on mouse gubernaculum testis cells are mediated at least partially by GPER-protein kinase A-ERK-CREB signaling pathway.

YY1-induced lncRNA00511 promotes melanoma progression via the miR-150-5p/ADAM19 axis.

Increasing evidence indicates that long noncoding RNAs (lncRNAs) are therapeutic targets and key regulators of tumors development and progression, including melanoma. Long intergenic non-protein-coding RNA 511 (LINC00511) has been demonstrated as an oncogenic molecule in breast, stomach, colorectal, and lung cancers. However, the precise role and functional mechanisms of LINC00511 in melanoma remain unknown. This study confirmed that LINC00511 was highly expressed in melanoma cells (A375 and SK-Mel-28 cells) and tissues, knockdown of LINC00511 could inhibit melanoma cell migration and invasion, as well as the growth of subcutaneous tumor xenografts in vivo. By using Chromatin immunoprecipitation (ChIP) assay, it was demonstrated that the transcription factor Yin Yang 1 (YY1) is capable of binding to the LINC00511 promoter and enhancing its expression in cis. Further mechanistic investigation showed that LINC00511 was mainly enriched in the cytoplasm of melanoma cells and interacted directly with microRNA-150-5p (miR-150-5p). Consistently, the knockdown of miR-150-5p could recover the effects of LINC00511 knockdown on melanoma cells. Furthermore, ADAM metallopeptidase domain expression 19 (ADAM19) was identified as a downstream target of miR-150-5p, and overexpression of ADAM19 could promote melanoma cell proliferation. Rescue assays indicated that LINC00511 acted as a competing endogenous RNA (ceRNA) to sponge miR-150-5p and increase the expression of ADAM19, thereby activating the PI3K/AKT pathway. In summary, we identified LINC00511 as an oncogenic lncRNA in melanoma and defined the LINC00511/miR-150-5p/ADAM19 axis, which might be considered a potential therapeutic target and novel molecular mechanism the treatment of patients with melanoma.

Distinct interactions of Na+ and Ca2+ ions with the selectivity filter of the bacterial sodium channel Na(V)Ab.

Rapid and selective ion transport is essential for the generation and regulation of electrical signaling pathways in living organisms. In this study, we use molecular dynamics simulations and free energy calculations to investigate how the bacterial sodium channel Na(V)Ab (Arcobacter butzleri) differentiates between Na(+) and Ca(2+) ions. Multiple nanosecond molecular dynamics simulations revealed distinct binding patterns for these two cations in the selectivity filter and suggested a high affinity calcium binding site formed by backbone atoms of residues Leu-176 and Thr-175 (S(CEN)) in the sodium channel selectivity filter.

The principles of health, illness and treatment - The key concepts from "The Yellow Emperor's Classic of Internal Medicine".

The Yellow Emperor's Classic of Internal Medicine is an important book in the study of Traditional Chinese Medicine (TCM) with the text presenting an integration of the essential TCM practices and philosophy in the use and application of Chinese medicine for healthcare. Within the Chinese Health System, TCM provides a balancing and integrating approach to health and the prevention of disease. The book provides the story of human existence, of our relationship to the environment and how 'balance' provides us with health and wellbeing in our daily lives. The role of the TCM practitioner is to look for wellness as a way of preventing disease. This paper discusses the key terms of the 'Dao', 'Qi', 'Yin' and 'Yang', 'Ben' and 'Biao' and the essence and role of the elements of fire, water, wood, metal and earth in health and disease prevention. TCM is an integrative approach to health and has many lessons for global health systems.

A Morphometric Study of the Distal Femoral Resected Surface In Osteoarthritis Knees of the Patients in Southwest China and a Comparison with Femoral Components in Six Total Knee Arthroplasty Systems.

OBJECTIVE: Mismatch between the femoral component and the resected surface is related to the postoperative clinical outcome. This study aimed to measure the morphometric features of the distal femoral resected surfaces in patients with osteoarthritis in southwestern China and to compare the measured morphometric data with six commonly used total knee arthroplasty (TKA) femoral components in China. METHOD: The computer tomography (CT) images of a total of 406 knees from 203 osteoarthritis patients who underwent TKA from January 2018 to December 2021 were imported into Mimics 21.0 software to reconstruct the three-dimensional (3D) model of the femur. Morphometric data of the distal femoral resected surfaces were measured after the completion of simulated bone resection in the software. The data included the medial-lateral (ML) dimension, anterior-posterior (AP) dimension, and the aspect ratio (AR) (AR = ML/AP), which were compared between genders with independent sample t-tests. In addition, we plotted the scatter diagram of those morphometric data in Origin software, and the linear fits of ML versus AP and AR versus AP were performed and compared for the six femoral components commonly used in enrolled patients in China. RESULTS: The mean ML dimension, the mean AP dimension, and the mean AR value measured for Chinese knees were 66.62 ± 4.57 mm, 58.10 ± 3.74 mm, and 1.15 ± 0.06 respectively. All dimensions were significantly larger in males than in females, including the calculated values for AR (P < 0.05). The fitted lines for males showed that the ML dimensions tended to be wider compared to femoral components of a given AP dimension. Females tended to have wider ML dimensions compared to small femoral components and, on the other hand, narrower ML dimensions compared to large femoral components. CONCLUSION: The femoral component of the current commonly used TKA prosthesis in China may not be perfectly matched to the distal femoral resected surface of patients in southwestern China. Male patients tended to underhang in all dimensions of the ML dimension. Female patients with shorter AP lengths are more likely to experience underhang, whereas those with longer AP lengths are more likely to develop overhangs. Therefore, we recommend multiple ML width options for a given AP length to more appropriately match the Chinese femoral anatomy.

Are there correlations between facet joint parameters and lumbar disk herniation laterality in young adults?

OBJECTIVE: We aimed to determine whether there is an association, in young adults, between the occurrence of lumbar disk herniation (LDH) at a given segment and the segment's facet joint parameters [facet orientation (FO) and tropism (FT)]. In addition, associations between facet joint parameters in the corresponding segment and LDH laterality were also investigated. METHODS: We retrospectively analyzed data from 529 patients who were between 18 and 35 years old, who had experienced single-level LDH (L4-5 or L5-S1) between June 2017 and December 2019, and with<2 years of clinical history. We included an additional 122 patients with no history of LDH as an age-matched control group. LDH were classified by laterality (left-sided, right-sided, or central herniation). At each level, we investigated the relationship between facet joint parameters and herniation laterality. RESULTS: FOA values at the L4-L5 level and the L5-S1 level were significantly lower and FT was higher for the LDH group compared with those for the control group. The level at which LDH occurred, FOL, FOR, and FT differed significantly among the three groups. There was a significant association between herniationlaterality and FO at the L4-L5 level but not at the L5-S1 level. CONCLUSIONS: Abnormal facet joint parameters are significantly associated with LDH. Young adults with higher FT should be paid more attention, to prevent the occurrence of LDH. Compared with L5-S1 level, intervertebral disk herniation at the L4-L5 level tended to occur ipsilateral to the side with a lower facet joint angle when FT was present.

Target fishing and docking studies of the novel derivatives of aryl-aminopyridines with potential anticancer activity.

A set of 16 previously synthesized aryl-aminopyridine and aryl-aminoquinoline derivatives have been evaluated for cytotoxic activity against three cancer cell lines (human cervical cancer-HeLa; human chronic myeloid leukemia-K562; human melanoma-Fem-x) and two types of normal peripheral blood mononuclear cells, with and without phytohemaglutinin (PBMC-PHA; PBMC+PHA). Twelve of the studied compounds showed moderate cytotoxicity, with selectivity against K562 but not the remaining two cancer cell lines. Four compounds were not active in cytotoxicity assays, presumably due to high predicted lipophilicity and low solubility. To rationalize the observed cytotoxic effects, structure-based virtual screening was carried out against a pool of potential targets constructed using the inverse docking program Tarfisdock and bibliographical references. The putative targets were identified on the basis of the best correlation between docking scores and in vitro cytotoxicity. It is proposed that the mechanism of action of the studied aminopyridines involves the disruption of signaling pathways and cancer cell cycle through the inhibition of cyclin-dependent kinases and several tyrosine kinases, namely Bcr-Abl kinase and KIT receptor kinase. The obtained results can guide further structural modifications of the studied compounds aimed at developing selective agents targeting proteins involved in cancer cell survival and proliferation.

The Antibacterial Activity Comparison between Novel Carbon-Based Nanofilm Coated Titanium Alloy and Co-Cr-Mo Alloy.

Objective: The purpose of this study was to reveal the antibacterial activity of carbon-based nanofilm titanium alloy. Methods: The experiments were performed both in vitro and in vivo of animals using two circular-piece test specimens of the same specification, which were made from carbon-based nanofilm coated titanium alloy and commonly used in artificial joints Co-Cr-Mo alloy, respectively. In the in vitro experiments, the two test specimens were cocultured with standard strains of Staphylococcus aureus and Escherichia coli, and the antibacterial properties of the two test specimens were evaluated via inhibition zone size, scanning electron microscopy, fluorescence staining, colony forming unit count, and others; the cytotoxicities of the two test specimens were evaluated by coculturing and them with rabbit bone marrow mesenchymal stem cells (BMSCs). In the in vivo experiments, the two test specimens were implanted in the muscle tissue of experimental rabbits to evaluate their histocompatibilities. Results: Both in vitro cocultures of the carbon-based nanofilm titanium alloy and the Co-Cr-Mo alloy with Staphylococcus aureus and Escherichia coli failed to form inhibition zone. However, some biofilms were observed on the surface of the Co-Cr-Mo alloy. Fewer bacteria adhered to the carbon-based nanofilm titanium alloy can be observed via scanning electron microscopy and fluorescence staining techniques. Meanwhile, the colony forming counts showed that, compared with the Co-Cr-Mo alloy, the carbon-based nanofilm titanium alloy had fewer bacteria adhered (P < 0.05). After coculture of the two test specimens with rabbit BMSCs, there was no significant difference in cell count, and both cell counts showed no cytotoxicity. In the in vivo experiment of animals, there are relatively fewer giant cells and better histocompatibility in tissues near the carbon-based nanofilm titanium alloy. Conclusion: Compared with Co-Cr-Mo alloy, the novel carbon-based nanofilm titanium alloy enjoys stronger in vitro antibacterial activity and better in vivo histocompatibility.

Saccharina japonica fucan suppresses high fat diet-induced obesity and enriches fucoidan-degrading gut bacteria.

Low molecular weight seaweed polysaccharides exhibit promising potential as novel therapeutics for the prevention of obesity and gut microbiota dysbiosis. The interplay between polysaccharides and gut microbiota may play crucial roles in their anti-obesity effects, but is largely unknown, including the impact of polysaccharides on the composition of the gut microbiota with polysaccharide-degrading capacity. The primary structure of a 5.1 kDa fucan (J2H) from Saccharina japonica was characterized and oral administration of J2H effectively suppressed high-fat diet-induced obesity, blood glucose metabolic dysfunction, dyslipidemia, and gut microbiota dysbiosis. Furthermore, the Jensen-Shannon divergence analysis demonstrated that J2H enriched at least four gut bacterial species with fucoidan-degrading potential, including Bacteroides sartorii and Bacteroides acidifaciens. Our findings suggest that the low molecular weight S. japonica fucan, J2H, is a promising potential agent for obesity prevention and its enrichment of gut bacteria with fucoidan-degrading potential may play a vital role in the anti-obesity effects.