Laminin-Augmented Decellularized Extracellular Matrix Ameliorating Neural Differentiation and Neuroinflammation in Human Mini-Brains.

Non-neural extracellular matrix (ECM) has limited application in humanized physiological neural modeling due to insufficient brain-specificity and safety concerns. Although brain-derived ECM contains enriched neural components, certain essential components are partially lost during the decellularization process, necessitating augmentation. Here, it is demonstrated that the laminin-augmented porcine brain-decellularized ECM (P-BdECM) is xenogeneic factor-depleted as well as favorable for the regulation of human neurons, astrocytes, and microglia. P-BdECM composition is comparable to human BdECM regarding brain-specificity through the matrisome and gene ontology-biological process analysis. As augmenting strategy, laminin 111 supplement promotes neural function by synergic effect with laminin 521 in P-BdECM. Annexin A1(ANXA1) and Peroxiredoxin(PRDX) in P-BdECM stabilized microglial and astrocytic behavior under normal while promoting active neuroinflammation in response to neuropathological factors. Further, supplementation of the brain-specific molecule to non-neural matrix also ameliorated glial cell inflammation as in P-BdECM. In conclusion, P-BdECM-augmentation strategy can be used to recapitulate humanized pathophysiological cerebral environments for neurological study.

Antioxidant, Collagenase Inhibitory, and Antibacterial Effects of Bioactive Peptides Derived from Enzymatic Hydrolysate of Ulva australis.

The protein extract of Ulva australis hydrolyzed with Alcalase and Flavourzyme was found to have multi-functional properties, including total antioxidant capacity (TAC), collagenase inhibitory, and antibacterial activities. The #5 fraction (SP5) and #7 fraction (SP7) of U. australis hydrolysate from cation-exchange chromatography displayed significantly high TAC, collagenase inhibitory, and antibacterial effects against Propionibacterium acnes, and only the Q3 fraction from anion-exchange chromatography displayed high multi-functional activities. Eight of 42 peptides identified by MALDI-TOF/MS and Q-TOF/MS/MS were selected from the results for screening with molecular docking on target proteins and were then synthesized. Thr-Gly-Thr-Trp (TGTW) displayed ABTS [2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)] radical scavenging activity. The effect of TAC as Trolox equivalence was dependent on the concentration of TGTW. Asn-Arg-Asp-Tyr (NRDY) and Arg-Asp-Arg-Phe (RDRF) exhibited collagenase inhibitory activity, which increased according to the increase in concentration, and their IC50 values were 0.95 mM and 0.84 mM, respectively. Peptides RDRF and His-Ala-Val-Tyr (HAVY) displayed anti-P. Acnes effects, with IC50 values of 8.57 mM and 13.23 mM, respectively. These results suggest that the U. australis hydrolysate could be a resource for the application of effective nutraceuticals and cosmetics.

Effect of cement space settings on the marginal and internal fit of 3D-printed definitive resin crowns.

STATEMENT OF PROBLEM: The cement gap setting affects the marginal and internal fits depending on the crown material and manufacturing method (subtractive or additive manufacturing). However, information on the effects of cement space settings in the computer-aided design (CAD) software program, which is used to aid the manufacturing with 3-dimensional (3D) printing-type resin material, is lacking, and recommendations for optimal marginal and internal fit are needed. PURPOSE: The purpose of this in vitro study was to evaluate how cement gap settings affect the marginal and internal fit of a 3D-printed definitive resin crown. MATERIAL AND METHODS: After scanning a prepared typodont left maxillary first molar, a crown was designed with cement spaces of 35, 50, 70, and 100 µm by using a CAD software program. A total of 14 specimens per group were 3D printed from definitive 3D-printing resin. By using the replica technique, the intaglio surface of the crown was duplicated, and the duplicated specimen was sectioned in the buccolingual and mesiodistal directions. Statistical analyses were performed using the Kruskal-Wallis and the Mann-Whitney post hoc tests (α=.05). RESULTS: Although the median values of the marginal gaps were within the clinically acceptable limit (<120 µm) for all the groups, the smallest marginal gaps were obtained with the 70-µm setting. For the axial gaps, there was no observed difference in the 35-, 50-, and 70-µm groups, and the 100-µm group showed the largest gap. The smallest axio-occlusal and occlusal gaps were obtained with the 70-µm setting. CONCLUSIONS: Based on the findings of this in vitro study, a 70-µm cement gap setting is recommended for optimal marginal and internal fit of 3D-printed resin crowns.

Comparison of the accuracy of a cone beam computed tomography-based virtual mounting technique with that of the conventional mounting technique using a facebow.

STATEMENT OF PROBLEM: The introduction of digital technology in dentistry has resulted in a shift from conventional methods to digital techniques. However, mounting a digitized dental cast on a virtual articulator is challenging. Several techniques have been suggested to resolve this problem, but in the absence of a standardized method, digitized dental casts are often mounted arbitrarily on a virtual articulator. PURPOSE: The purpose of this clinical study was to compare the accuracy of a novel virtual facebow transfer (VM) technique based on cone beam computed tomography (CBCT) with that of the conventional mounting (CM) technique using a facebow. MATERIAL AND METHODS: Five repeated mountings were performed with each technique for 15 participants. In the CM group, dental casts were mounted using a facebow record and scanned for transmission to the virtual dental space. In the VM group, digital dental casts were mounted on the standard tessellation language file of a reference articulator by reconstructing a file of the participant's skull from CBCT data. In this group, a virtual facebow, prepared by scanning the articulator and facebow complex, was used. After the CM and VM casts had been aligned, the coordinates of target points set on the maxillary right central incisor, maxillary right first molar, and maxillary left first molar were determined, and the mean ±standard deviation distance between the target points was calculated to compare the precision of the techniques. Additionally, vectors of the target point on the maxillary right central incisor were compared to analyze the spatial difference between the techniques. Finally, the occlusal plane angle was calculated. For the correlation analysis of repeated measured data, a 1-way repeated measures analysis of variance (ANOVA) was first performed. The Kolmogorov-Smirnov test was performed to determine normality, and a paired t test and the Wilcoxon signed rank test were performed for normally and nonnormally distributed variables, respectively (α=.05). RESULTS: The mean distance between target points was significantly greater in the CM group (4.72 ±1.45 to 5.17 ±1.54 mm) than in the VM group (2.14 ±0.58 to 2.35 ±0.60 mm) (P<.05). The standard deviation between target points was significantly greater in the CM group (1.60 ±0.64 to 2.30 ±0.87 mm) than in the VM group (0.74 ±0.23 to 1.12 ±0.45 mm) (P<.05). The maxillary right central incisor was located more anteriorly in the VM group than in the CM (100%, P<.05) group. The occlusal plane angle was significantly steeper in the CM group than in the VM group (8.14 degrees versus 2.13 degrees, P<.05). CONCLUSIONS: The VM technique was more precise than the CM technique. VM casts were positioned ahead of CM casts. Further, the occlusal plane angle tended to be steeper with the CM technique than with the VM technique.

Engineered Human Intervertebral Disc Model Inducing Degenerative Microglial Proinflammation.

Degeneration of the intervertebral disc (IVD) is a major contributor to low back pain (LBP). IVD degeneration is characterized by abnormal production of inflammatory cytokines secreted by IVD cells. Although the underlying molecular mechanisms of LBP have not been elucidated, increasing evidence suggests that LBP is associated particularly with microglia in IVD tissues and the peridiscal space, aggravating the cascade of degenerative events. In this study, we implemented our microfluidic chemotaxis platform to investigate microglial inflammation in response to our reconstituted degenerative IVD models. The IVD models were constructed by stimulating human nucleus pulposus (NP) cells with interleukin-1ß and producing interleukin-6 (129.93 folds), interleukin-8 (18.31 folds), C-C motif chemokine ligand-2 (CCL-2) (6.12 folds), and CCL-5 (5.68 folds). We measured microglial chemotaxis (p < 0.05) toward the conditioned media of the IVD models. In addition, we observed considerable activation of neurodegenerative and deactivation of protective microglia via upregulated expression of CD11b (p < 0.001) and down-regulation of CD206 protein (p < 0.001) by soluble factors from IVD models. This, in turn, enhances the inflammatory milieu in IVD tissues, causing matrix degradation and cellular damage. Our findings indicate that degenerative IVD may induce degenerative microglial proinflammation, leading to LBP development.

Comparative evaluation of digitally fabricated complete dentures versus conventional complete dentures: A randomized, single-blinded, cross-over clinical trial.

STATEMENT OF PROBLEM: Clinical trials comparing outcomes associated with digital complete dentures (CDs) fabricated from intraoral scan data with those of CDs fabricated by using the conventional workflow are lacking. PURPOSE: The purpose of this randomized clinical trial was to evaluate the clinical performance of and patient satisfaction associated with digitally versus conventionally fabricated CDs. MATERIAL AND METHODS: Eight participants requiring CDs were enrolled in this study. Two sets of CDs were fabricated for each participant. One set was fabricated by using a digital workflow, which involved digital scanning with an intraoral scanner, whereas the other set was made by using the conventional workflow. The participants were given 1 set of CDs for 1 month and another set for the next month. The order of placing CDs was randomly selected for each participant. The internal adaptation, masticatory force, and masticatory efficiency of the CDs in each group were evaluated for objective analysis. Additionally, a questionnaire was provided to the participants, and the responses were evaluated for subjective satisfaction analysis. All parameters were analyzed by using t tests (α=.05). RESULTS: The internal adaptation did not statistically significantly differ between the conventional and digital CDs with regard to the maxillary arches (P=.406) and mandibular arches (P=.412). The average masticatory force (P=.051) and maximum masticatory force (P=.110) likewise did not statistically significantly differ between the 2 types of CDs. Masticatory efficiency, expressed via the mixing ability index, was statistically better for conventional CDs than the digital CDs (P=.009). No statistically significant differences were observed between the 2 types of CDs in terms of overall patient satisfaction as assessed by using the study questionnaire (P=.172 for maxillary CD and P=.161 for mandibular CD). However, the conventional CDs were statistically significantly better than the digital CDs with regard to subjective satisfaction with pronunciation ability (P=.006). CONCLUSIONS: The digital CDs were inferior to the conventional CDs in terms of masticatory efficiency and pronunciation. However, internal adaptation and overall patient satisfaction were comparable between conventional and digital CDs. This finding suggests that intraoral scanning and additively manufactured CDs may be suitable for edentulous patients, at least for interim use.

[Randomized Controlled Trial of the Effects of Repetitive Transcranial Magnetic Stimulation and Mirror Therapy on Phantom Limb Pain in Amputees].

Objective: To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on phantom limb pain (PLP) in amputees, and to compare the therapeutic effect with that of mirror therapy (MT). Methods: The study was designed as a randomized controlled trial. The evaluators were blinded, while the subjects and the therapists were unblinded. Subjects were randomly assigned to either the rTMS group or the MT group with a computer-generated random number table. From June 2018 to December 2020, from out of 45 amputee patients screened for the study, 30 who met the inclusion criteria were recruited for the study. All patients were recruited from the Rehabilitation Medicine Center, West China Hospital, Sichuan University. In the end, 4 patients withdrew from the study and 26 patients (12 in the rTMS group and 14 in the MT group) completed the prescribed treatment and evaluation. The rTMS group was given rTMS (1 Hz, 15 min, 5 d/week) for 2 weeks in addition to conventional rehabilitation therapy, while the MT group received MT (corresponding movements of limbs, 15 min, 5 d/week) for 2 weeks in addition to conventional rehabilitation therapy. PLP was evaluated by the Visual Analogue Scale (VAS) and Douleur Neuropathique 4 Questions (DN-4). Subjects were assessed before treatment ( t 0), immediately after the completion of the treatment ( t 1) and 3 months after the completion of the treatment ( t 2). Results: The mean age of the 26 patients was 39.73±12.64. There were 15 males and 11 females. According to the reported description of the characteristics of the PLP by the patients, the characteristics with the highest incidence were tingling, stabbing, numbing, electric shocks and burning in descending order. There was no significant difference in the incidence of PLP characteristics between the two groups ( P>0.05). The two groups had comparable baseline data, showing no significant difference in VAS and DN-4 between the two groups at t 0 ( P>0.05). At t 1 and t 2, the VAS and DN-4 scores were decreased from those of t 0, showing statistically significant difference in both groups ( P<0.01 for both scores). In the rTMS group, there was no significant difference between VAS and DN-4 scores at t 1 and those at t 2 ( P>0.05). In the MT group, the VAS and DN-4 scores at t 2 were significantly lower than those of t 1 ( P<0.05). There was no statistically significant difference between the rTMS group and MT group in the changes in pain measurements, i.e., VAS and DN-4 scores, before and after the intervention ( P>0.05). The 26 patients who completed the experiment showed no dizziness, headache, or other abnormalities during the study. Conclusion: The results of this study indicate that repetitive transcranial magnetic stimulation could improve PLP in amputees, and the improvement effect was comparable to that of mirror therapy.

Oral Pathogenic Bacteria-Inducing Neurodegenerative Microgliosis in Human Neural Cell Platform.

Porphyromonas gingivalis is a gram-negative bacterium found in the human oral cavity and is responsible for the development of chronic periodontitis as well as neurological diseases, including Alzheimer's disease (AD). Given the significance of the roles of P. gingivalis in AD pathogenesis, it is critical to understand the underlying mechanisms of P. gingivalis-driven neuroinflammation and their contribution to neurodegeneration. Herein, we hypothesize that P. gingivalis produces secondary metabolites that may cause neurodegeneration through direct or indirect pathways mediated by microglia. To test our hypothesis, we treated human neural cells with bacterial conditioned media on our brain platforms and assessed microgliosis, astrogliosis and neurodegeneration. We found that bacteria-mediated microgliosis induced the production of nitric oxide, which causes neurodegeneration assessed with high pTau level. Our study demonstrated the elevation of detrimental protein mediators, CD86 and iNOS and the production of several pro-inflammatory markers from stimulated microglia. Through inhibition of LPS and succinate dehydrogenase in a bacterial conditioned medium, we showed a decrease in neurodegenerative microgliosis. In addition, we demonstrated the bidirectional effect of microgliosis and astrogliosis on each other exacerbating neurodegeneration. Overall, our study suggests that the mouth-brain axis may contribute to the pathogenesis of AD.

Influence of shoulder coverage difference of abutment on stress distribution and screw stability in tissue-level internal connection implants: A finite element analysis and in vitro study.

STATEMENT OF PROBLEM: Tissue-level internal connection implants are widely used, but the difference in abutment screw stability because of the shoulder coverage formed by the contact between the shoulder of the implant collar and the abutment remains unclear. PURPOSE: The purpose of this finite element analysis (FEA) and in vitro study was to investigate stress distribution and abutment screw stability as per the difference in shoulder coverage of the abutment in tissue-level internal connection implants. MATERIAL AND METHODS: Abutments were designed in 3 groups as per the shoulder coverage of the implant collar, yielding complete coverage (complete group), half coverage (half group), no coverage (no group) groups. In the FEA, a tightening torque of 30.0 Ncm was applied to the abutment screw, a force of 250 N was applied to the crown at a 30-degree angle, and the von Mises stresses and the stress distribution patterns were evaluated. In the in vitro study, the groups were tested (n=12). A total of 200 000 cyclic loads were applied at 250 N, 14 Hz, and at a 30-degree angle. Removal torque values and scanning electron microscopy (SEM) images were assessed. Removal torque values were analyzed by ANOVA and paired t tests. RESULTS: The maximum von Mises stress of the abutment screw was the lowest in the complete group, slightly higher in the half group, and highest in the no group. High stresses were concentrated in 1 location in the implant abutment connection area of the no group. The removal torque values after loading were significantly lower in the no group than in the complete group (P=.047). The SEM images revealed concentrated structural loss and wear in 1 location of the no group. CONCLUSIONS: FEA and in vitro studies confirmed that the shoulder coverage of the abutment in the tissue-level internal connection implant helped improve screw stability. Cyclic loading reduced the removal torque of the abutment screw.

Therapeutic Targeting Strategies for Early- to Late-Staged Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia, typically showing progressive neurodegeneration in aging brains. The key signatures of the AD progression are the deposition of amyloid-beta (Aß) peptides, the formation of tau tangles, and the induction of detrimental neuroinflammation leading to neuronal loss. However, conventional pharmacotherapeutic options are merely relying on the alleviation of symptoms that are limited to mild to moderate AD patients. Moreover, some of these medicines discontinued to use due to either the insignificant effectiveness in improving the cognitive impairment or the adverse side effects worsening essential bodily functions. One of the reasons for the failure is the lack of knowledge on the underlying mechanisms that can accurately explain the major causes of the AD progression correlating to the severity of AD. Therefore, there is an urgent need for the better understanding of AD pathogenesis and the development of the disease-modifying treatments, particularly for severe and late-onset AD, which have not been covered thoroughly. Here, we review the underlying mechanisms of AD progression, which have been employed for the currently established therapeutic strategies. We believe this will further spur the discovery of a novel disease-modifying treatment for mild to severe, as well as early- to late-onset, AD.

Accuracy of Scanned Stock Abutments Using Different Intraoral Scanners: An In Vitro Study.

PURPOSE: To determine the accuracy of a digital manufacturing method for dental implant restorations on stock abutments using intraoral scanners and prefabricated stock-abutment libraries. MATERIALS AND METHODS: Two dental implants with internal hexagonal connections were placed in the mandibular second premolar and second molar areas of a partially edentulous dentoform model; stock abutments with a diameter of 5 mm, abutment height of 5.5 mm, and gingival cuff height of 2 mm were connected. The study model was scanned 10 times using a reference tabletop scanner and 5 types of intraoral scanners (IOSs). The data collected by 5 types of IOSs were divided into 3 groups, based on the type and matching of stock abutment library data: no library, optical library, and contact library groups. A total of 160 data files were analyzed, including reference data. The resulting data were used to evaluate trueness and precision. RESULTS: Trueness and precision values in the group in which library data of the stock abutment were not used were 42.0 to 76.3 µm and 30.5 to 99.7 µm; corresponding values when the library data using an optical scanner were matched were 51.2 to 73.4 µm and 26.3 to 62.8 µm, and those when contact scanner library data were used were 30.1 to 62.4 µm and 15.5 to 55.9 µm. Thus, the accuracy of the contact library group was significantly higher than the accuracies of the no library (p < 0.001) and optical library groups (p < 0.001). CONCLUSION: The application of prefabricated library data of stock abutments using a contact scanner improved the accuracy of scan data. Scan accuracy of the stock abutments differed significantly based on the type of scanner.

Protective effects of guggulsterone against colitis are associated with the suppression of TREM-1 and modulation of macrophages.

Triggering receptor expressed on myeloid cells 1 (TREM-1)-expressing intestinal macrophages are significantly increased in the colons of patients with inflammatory bowel disease (IBD). We focused here on the effects of guggulsterone on macrophage modulation in colitis as a potential therapeutic molecule in human IBD and explore the underlying mechanisms. Gene expression in macrophages was examined and wound-healing assay using HT-29 cells was performed. Colitis in wild-type and IL-10-, Toll-like receptor 4 (TLR4)-, and myeloid differentiation primary response 88 (MyD88)-deficient mice was induced via the administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the colon. In both in vitro and in vivo experiments, guggulsterone suppressed intestinal inflammation amplified by TREM-1 stimulation, in which the suppression of NF-κB, activating protein-1, and proteasome pathways was involved. In the TNBS-induced colitis model, guggulsterone reduced disease activity index scores and TREM-1 expression, stimulated IL-10 production, and improved survival in wild-type mice. These effects were not observed in IL-10-, TLR4-, and MyD88-deficient mice. Guggulsterone also suppressed M1 polarization, yet induced the M2 phenotype in macrophages from IBD patients as well as from mice. These findings indicate that guggulsterone blocks the hyperactivation of macrophages via TREM-1 suppression and induces M2 polarization via IL-10 mediated by the TLR4 signaling pathway. Furthermore, this study provides a new rationale for the therapeutic potential of guggulsterone in the treatment of IBD. NEW & NOTEWORTHY We found that guggulsterone attenuates triggering receptor expressed on myeloid cells 1 (TREM-1)-mediated hyperactivation of macrophages and polarizes macrophages toward the M2 phenotype. This was mediated by IL-10 and partly Toll-like receptor 4 signaling pathways. Overall, these data support that guggulsterone as a natural plant sterol modulates macrophage phenotypes in colitis, which may be of novel therapeutic importance in inflammatory bowel disease treatment.

Highly permeable artificial water channels that can self-assemble into two-dimensional arrays.

Bioinspired artificial water channels aim to combine the high permeability and selectivity of biological aquaporin (AQP) water channels with chemical stability. Here, we carefully characterized a class of artificial water channels, peptide-appended pillar[5]arenes (PAPs). The average single-channel osmotic water permeability for PAPs is 1.0(± 0.3) × 10(-14) cm(3)/s or 3.5(± 1.0) × 10(8) water molecules per s, which is in the range of AQPs (3.4 ∼ 40.3 × 10(8) water molecules per s) and their current synthetic analogs, carbon nanotubes (CNTs, 9.0 × 10(8) water molecules per s). This permeability is an order of magnitude higher than first-generation artificial water channels (20 to ∼ 10(7) water molecules per s). Furthermore, within lipid bilayers, PAP channels can self-assemble into 2D arrays. Relevant to permeable membrane design, the pore density of PAP channel arrays (∼ 2.6 × 10(5) pores per µm(2)) is two orders of magnitude higher than that of CNT membranes (0.1 ∼ 2.5 × 10(3) pores per µm(2)). PAP channels thus combine the advantages of biological channels and CNTs and improve upon them through their relatively simple synthesis, chemical stability, and propensity to form arrays.

Reduced-Intensity Conditioning with Busulfan, Fludarabine, and Antithymocyte Globulin for Hematopoietic Cell Transplantation from Unrelated or Haploidentical Family Donors in Patients with Acute Myeloid Leukemia in Remission.

To investigate the role of antithymocyte globulin (ATG)-containing reduced-intensity conditioning (RIC) in hematopoietic cell transplantation (HCT) from unrelated (UD) or haploidentical family donors (HFD), we conducted a phase 2 trial of 237 patients (age range, 16 to 69 years) with acute myeloid leukemia (AML) in remission. Patients undergoing UD-HCT (n = 93) or HFD-HCT (n = 59) received RIC comprising busulfan, fludarabine, and ATG, 9 mg/kg, whereas those undergoing HCT from matched sibling donors (MSD, n = 85) received myeloablative busulfan and cyclophosphamide conditioning or aforementioned RIC with ATG, 4.5 mg/kg. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine and methotrexate were administered. The median follow-up period was 44.7 months after HCT for 161 survivors. For UD-HCT versus HFD-HCT, there were no significant differences in leukemia recurrence, nonrelapse mortality, relapse-free survival, grades 2 to 4 acute GVHD, and moderate-to-severe chronic GVHD. Furthermore, when the outcomes of UD-HCT and HFD-HCT were combined and compared with those of MSD-HCT, there were no significant differences in leukemia recurrence (3-year cumulative incidence, 30% versus 29%), nonrelapse mortality (3-year cumulative incidence, 7% versus 8%), relapse-free survival (3-year estimate, 63% versus 63%), and grades 2 to 4 acute GVHD (120-day cumulative incidence, 16% versus 13%). Moderate-to-severe chronic GVHD, however, occurred less frequently in UD/HFD-HCT (2-year cumulative incidence, 22% versus 40%; P = .006). The addition of ATG to conditioning regimen was a significant predictor for less chronic GVHD (subdistribution hazard ratio, .59). In AML in remission, UD/HFD-HCT after ATG-containing RIC achieved leukemia control equivalent to that of MSD-HCT. Despite HLA disparity in UD/HFD-HCT, chronic GVHD occurred less frequently after ATG-containing RIC, suggesting a strong GVHD-modulating effect of ATG.

Donor-Derived Natural Killer Cell Infusion after Human Leukocyte Antigen-Haploidentical Hematopoietic Cell Transplantation in Patients with Refractory Acute Leukemia.

The optimum method of donor natural killer cell infusion (DNKI) after allogeneic hematopoietic cell transplantation (HCT) remains unclear. Fifty-one patients (age range, 19 years to 67 years) with refractory acute leukemia underwent HLA-haploidentical HCT and underwent DNKI on days 6, 9, 13, and 20 of HCT. Median DNKI doses were .5, .5, 1.0, and 2.0 × 108/kg cells, respectively. During DNKI, 33 of the 45 evaluated patients (73%) developed fever (>38.3°C) along with weight gain (median, 13%; range, 2% to 31%) and/or hyperbilirubinemia (median, 6.2 mg/dL; range, 1.0 mg/dL to 35.1 mg/dL); the toxicity was reversible in 90% of patients. After transplantation, we observed cumulative incidences of neutrophil engraftment (≥500/µL), grade 2 to 4 acute graft-versus-host disease (GVHD), chronic GVHD, and nonrelapse mortality of 84%, 28%, 30%, and 16%, respectively. The leukemia complete remission rate was 57% at 1 month after HCT and 3-year cumulative incidence of leukemia progression was 75%. When analyzed together with our historical cohort of 40 patients with refractory acute leukemia who underwent haploidentical HCT and DNKI on days 14 and 21 only, higher expression of NKp30 (>90%) on donor NK cells was an independent predictor of higher complete remission (hazard ratio, 5.59) and less leukemia progression (hazard ratio, .57). Additional DNKI on days 6 and 9 was not associated with less leukemia progression (75% versus 55%).

D3R grand challenge 2015: Evaluation of protein-ligand pose and affinity predictions.

The Drug Design Data Resource (D3R) ran Grand Challenge 2015 between September 2015 and February 2016. Two targets served as the framework to test community docking and scoring methods: (1) HSP90, donated by AbbVie and the Community Structure Activity Resource (CSAR), and (2) MAP4K4, donated by Genentech. The challenges for both target datasets were conducted in two stages, with the first stage testing pose predictions and the capacity to rank compounds by affinity with minimal structural data; and the second stage testing methods for ranking compounds with knowledge of at least a subset of the ligand-protein poses. An additional sub-challenge provided small groups of chemically similar HSP90 compounds amenable to alchemical calculations of relative binding free energy. Unlike previous blinded Challenges, we did not provide cognate receptors or receptors prepared with hydrogens and likewise did not require a specified crystal structure to be used for pose or affinity prediction in Stage 1. Given the freedom to select from over 200 crystal structures of HSP90 in the PDB, participants employed workflows that tested not only core docking and scoring technologies, but also methods for addressing water-mediated ligand-protein interactions, binding pocket flexibility, and the optimal selection of protein structures for use in docking calculations. Nearly 40 participating groups submitted over 350 prediction sets for Grand Challenge 2015. This overview describes the datasets and the organization of the challenge components, summarizes the results across all submitted predictions, and considers broad conclusions that may be drawn from this collaborative community endeavor.

[Continuous XRF Element Characteristics and Significance of Sedimentary Facies Indication of the Quaternary Core from Fuzhou Basin].

This paper focuses on the study on continuous XRF (X-Ray Fluorescence) scanning elements of a 39 m core from Fuzhou Basin. The XRF scanning result is used to recognize the different sedimentary environment before the discussion of the element variation of different deposit in transitional zone between land and ocean. There are five sedimentary facies in the study area from the late Pleistocene: lacustrine-fluvial-estuary (mud tidal flat)-mixed tidal flat-fluvial. The XRF result from the 5 sedimentary stages shows that the high concentration of Co, Fe, Ti, Si are controlled largely by grain size. The average element intensity of layers with similar grain size indicates that Ca, Ti, Mn, Fe and Co from the marine (tidal flat) deposit is 3~10 times bigger than those from terrestrial (fluvial) deposit, with higher content of Si coinciding with terrestrial deposit. It is indicated that except grain size, the deposit environment is an important factor for element concentration. In this study, Ca, Ti, Mn, Fe and Co are relatively better indicator elements for marine sediments while Si is good and K, Rb and Sr have some indication for terrestrial sediments. The study result shows XRF continuous scanning can help to identify the subtle variation of elements, as to the determination of the sediment facies. Thus, XRF scanning is an important supplement to sediment facies identification. This study also provides an application example of XRF in a typical transitional zone between land and ocean.

Postbiotics in colorectal cancer: intervention mechanisms and perspectives.

Colorectal cancer (CRC) is a common malignancy affecting the gastrointestinal tract worldwide. The etiology and progression of CRC are related to factors such as environmental influences, dietary structure, and genetic susceptibility. Intestinal microbiota can influence the integrity of the intestinal mucosal barrier and modulate intestinal immunity by secreting various metabolites. Dysbiosis of the intestinal microbiota can affect the metabolites of the microbial, leading to the accumulation of toxic metabolites, which can trigger chronic inflammation or DNA damage and ultimately lead to cellular carcinogenesis and the development of CRC. Postbiotics are preparations of inanimate microorganisms or their components that are beneficial to the health of the host, with the main components including bacterial components (e.g., exopolysaccharides, teichoic acids, surface layer protein) and metabolites (e.g., short-chain fatty acids, tryptophan metabolite, bile acids, vitamins and enzymes). Compared with traditional probiotics, it has a more stable chemical structure and higher safety. In recent years, it has been demonstrated that postbiotics are involved in regulating intestinal microecology and improving the progression of CRC, which provides new ideas for the prevention and diagnosis of CRC. In this article, we review the changes in intestinal microbiota in different states of the gut and the mechanisms of anti-tumor activity of postbiotic-related components, and discuss the potential significance of postbiotics in the diagnosis and treatment of CRC. This reviews the changes and pathogenesis of intestinal microbiota in the development of CRC, and summarizes the relevant mechanisms of postbiotics in resisting the development of CRC in recent years, as well as the advantages and limitations of postbiotics in the treatment process of CRC.

Environmental aluminum oxide inducing neurodegeneration in human neurovascular unit with immunity.

Aluminum oxide nanoparticle (AlNP), a ubiquitous neurotoxin highly enriched in air pollution, is often produced as an inevitable byproduct in the manufacturing of industrial products such as cosmetics and metal materials. Meanwhile, ALNP has emerged as a significant public health concern due to its potential association with neurological diseases. However, the studies about the neurotoxic effects of AlNP are limited, partially due to the lack of physiologically relevant human neurovascular unit with innate immunity (hNVUI). Here, we employed our AlNP-treated hNVUI model to investigate the underlying mechanism of AlNP-driven neurodegeneration. First, we validated the penetration of AlNP across a blood-brain barrier (BBB) compartment and found AlNP-derived endothelial cellular senescence through the p16 and p53/p21 pathways. Our study showed that BBB-penetrating AlNP promoted reactive astrocytes, which produced a significant level of reactive oxygen species (ROS). The astrocytic neurotoxic factors caused neuronal damage, including the synaptic impairment, the accumulation of phosphoric-tau proteins, and even neuronal death. Our study suggests that AlNP could be a potential environmental risk factor of neurological disorders mediated by neuroinflammation.