Myelin sheath structure and regeneration in peripheral nerve injury repair.

Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of the myelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath.

FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing.

Free fatty acid receptors 2 and 3 (FFAR2/FFA2/GPR43 and FFAR3/FFA3/GPR41) are mammalian receptors for gut microbiota-derived short-chain fatty acids (SCFAs). These receptors are promising drug targets for obesity, colitis, colon cancer, asthma, and arthritis. Here, we demonstrate that FFAR2 and FFAR3 interact to form a heteromer in primary human monocytes and macrophages via proximity ligation assay, and during heterologous expression in HEK293 cells via bimolecular fluorescence complementation and fluorescence resonance energy transfer. The FFAR2-FFAR3 heteromer displayed enhanced cytosolic Ca2+ signaling (1.5-fold increase relative to homomeric FFAR2) and ß-arrestin-2 recruitment (30-fold increase relative to homomeric FFAR3). The enhanced heteromer signaling was attenuated by FFAR2 antagonism (CATPB), Gαq inhibition (YM254890), or Gαi inhibition (pertussis toxin). Unlike homomeric FFAR2/3, the heteromer lacked the ability to inhibit cAMP production but gained the ability to induce p38 phosphorylation in HEK293 and inflammatory monocytes via a CATPB- and YM254890-sensitive mechanism. Our data, taken together, reveal that FFAR2 and FFAR3 may interact to form a receptor heteromer with signaling that is distinct from the parent homomers-a novel pathway for drug targeting.-Ang, Z., Xiong, D., Wu, M., Ding, J. L. FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing.

Mitogen-activated protein kinase kinase 6 is involved in the immune response to bacterial di-/tripeptide challenge in grass carp Ctenopharyngodon idella.

Mitogen-activated protein kinase kinase 6 (MKK6) is an essential component of the p38MAPK signaling pathway, which is involved in the modulation of inflammation, cell apoptosis and survival responses in mammals. However, the function of MKK6s in teleosts is still unclear. In this study, a fish MKK6 homolog (CiMKK6) was first identified from the grass carp (Ctenopharyngodon idella), a freshwater fish. CiMKK6 cDNA encodes a putative protein of 357 amino acids that contains conserved structural characteristics of the MKK6 family, including the S_TKc domain, SVAKT motif and DVD site. The deduced CiMKK6 protein exhibits high sequence homology with other reported fish MKK6s and shares the closest relationship with MKK6 from Danio rerio. Quantitative real-time PCR (qRT-PCR) analysis revealed that CiMKK6 mRNA was widely expressed in all tested tissues and stages of embryonic development. Additionally, the transcript levels of CiMKK6 in the intestine were significantly upregulated in response to bacterial muramyl dipeptide (MDP) and L-Ala-γ-D-Glu-meso-diaminopimelic acid (Tri-DAP) stimulation. Moreover, subcellular localization analysis indicated that CiMKK6 was distributed in both the cytoplasm and the nucleus of HEK293T cells. Finally, overexpression of CiMKK6 significantly enhanced the transcriptional activity of the AP-1 reporter gene in HEK293T cells. Overall, these findings may help better clarify the immune function of teleost MKK6s and provide new insight into the immune defense mechanisms of grass carp.

Regain Strain-Hardening in High-Strength Metals by Nanofiller Incorporation at Grain Boundaries.

Grain refinement to the nano/ultrafine-grained regime can make metals several times stronger, but this process is usually accompanied by a dramatic loss of ductility. Such strength-ductility trade-off originates from a lack of strain-hardening capacity in tiny grains. Here, we present a strategy to regain the strain-hardening ability of high-strength metals by incorporation of extrinsic nanofillers at grain boundaries. We demonstrate that the dislocation storage ability in Cu grains can be considerably improved through this novel grain-boundary engineering approach, leading to a remarkably enhanced strain-hardening capacity and tensile ductility (uniform elongation). Experiments and large-scale atomistic simulations reveal that a key benefit of incorporated nanofillers is a reduction in the grain-boundary energy, enabling concurrent dislocation storage near the boundaries and in the Cu grain interior during straining. The strategy of grain-boundary engineering through nanofillers is easily controllable, generally applicable, and may open new avenues for producing nanostructured metals with extraordinary mechanical properties.

Frequency and amplitude control of cortical oscillations by phosphoinositide waves.

Rhythmicity is prevalent in the cortical dynamics of diverse single and multicellular systems. Current models of cortical oscillations focus primarily on cytoskeleton-based feedbacks, but information on signals upstream of the actin cytoskeleton is limited. In addition, inhibitory mechanisms--especially local inhibitory mechanisms, which ensure proper spatial and kinetic controls of activation--are not well understood. Here, we identified two phosphoinositide phosphatases, synaptojanin 2 and SHIP1, that function in periodic traveling waves of rat basophilic leukemia (RBL) mast cells. The local, phase-shifted activation of lipid phosphatases generates sequential waves of phosphoinositides. By acutely perturbing phosphoinositide composition using optogenetic methods, we showed that pulses of PtdIns(4,5)P2 regulate the amplitude of cyclic membrane waves while PtdIns(3,4)P2 sets the frequency. Collectively, these data suggest that the spatiotemporal dynamics of lipid metabolism have a key role in governing cortical oscillations and reveal how phosphatidylinositol 3-kinases (PI3K) activity could be frequency-encoded by a phosphatase-dependent inhibitory reaction.

Enhanced Mechanical Properties of Graphene (Reduced Graphene Oxide)/Aluminum Composites with a Bioinspired Nanolaminated Structure.

Bulk graphene (reduced graphene oxide)-reinforced Al matrix composites with a bioinspired nanolaminated microstructure were fabricated via a composite powder assembly approach. Compared with the unreinforced Al matrix, these composites were shown to possess significantly improved stiffness and tensile strength, and a similar or even slightly higher total elongation. These observations were interpreted by the facilitated load transfer between graphene and the Al matrix, and the extrinsic toughening effect as a result of the nanolaminated microstructure.

[Plus Tree Selection of Litsea mollis by Principal Component Analysis].

Objective: To establish a principal component analysis( PCA) method for selecting Litsea mollis,to determine the selection criteria, in order to provide a theoretical basis for the early excellenting, selective breeding of Litsea mollis. Methods: The seedling origin of Litsea mollis plantion in Wanzhou district of Chongqing province were used as the research object,72 plus trees were selected by using 5 dominant comparative method. Its growth and economic traits were observed and analyzed by variance analysis and PCA method. Results: The variatice analysis result showed that the traits existed rich genetic differences. The PCA analysis result showed that in rotated component matrix, tree height, crown area, east-west crown, north-south crown, diameter at breast height were used as the selection optimal criteria of Litsea mollis. Four plants with superior integrated economical were selected, which namely Y12-4,Y12,Y11-3and Y10. Conclusion: The rich variability of Litsea mollis provide the prerequisite condition for plus tree selection. The results conform to the phenotypic and indicate that the optimization methods are scientific and feasible.

Injectable Nanocomposite Hydrogels with Strong Antibacterial, Osteoinductive, and ROS-Scavenging Capabilities for Periodontitis Treatment.

Injectable antibacterial and osteoinductive hydrogels have received considerable attention for promoting bone regeneration owing to their versatile functionalities. However, a current hydrogel with antibacterial, osteoinductive, and antioxidant properties by a facile method for periodontitis treatment is still missing. To overcome this issue, we designed an injectable hydrogel system (GPM) composed of gelatin, Ti3C2Tx MXene nanosheets, and poly-l-lysine using a simple enzymatic cross-linking technique. Physicochemical characterization demonstrated that the GPM hydrogel matrix exhibited excellent stability, moderate tissue adhesion ability, and good mechanical behavior. The GPM hydrogels significantly inhibited the growth of Porphyromonas gingivalis, scavenged reactive oxygen species, attenuated inflammatory responses, and enhanced bone tissue regeneration. Intriguingly, the arrangement of the junctional epithelium, alveolar bone volume, and alveolar bone height in the GPM-treated periodontal disease group recovered to that of the healthy group. Therefore, our injectable hydrogel system with versatile functions may serve as an excellent tissue scaffold for the treatment of periodontitis.

Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated Mesenchymal Stem Cell Recruitment and Histone Acetylation-Mediated Osteogenesis.

Cranial bone defects remain a major clinical challenge, increasing patients' life burdens. Tricarboxylic acid (TCA) cycle metabolites play crucial roles in facilitating bone tissue regeneration. However, the development of TCA cycle metabolite-modified biomimetic grafts for skull bone regeneration still needs to be improved. The mechanism underlying the release of TCA cycle metabolites from biomaterials in regulating immune responses and mesenchymal stem cell (MSC) fate (migration and differentiation) remains unknown. Herein, this work constructs biomimetic hydrogels composed of gelatin and chitosan networks covalently cross-linked by genipin (CGG hydrogels). A series of TCA cycle metabolite-coordinated CGG hydrogels with strong mechanical and antiswelling performances are subsequently developed. Remarkably, the citrate (Na3Cit, Cit)-coordinated CGG hydrogels (CGG-Cit hydrogels) with the highest mechanical modulus and strength significantly promote skull bone regeneration in rat and murine cranial defects. Mechanistically, using a transgenic mouse model, bulk RNA sequencing, and single-cell RNA sequencing, this work demonstrates that CGG-Cit hydrogels promote Gli1+ MSC migration via neutrophil-secreted oncostatin M. Results also indicate that citrate improves osteogenesis via enhanced histone H3K9 acetylation on osteogenic master genes. Taken together, the immune microenvironment- and MSC fate-regulated CGG-Cit hydrogels represent a highly efficient and facile approach toward skull bone tissue regeneration with great potential for bench-to-bedside translation.

Prognostic factors of nivolumab in advanced hepatocellular carcinoma: a systematic review and meta-analysis.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, and a major unresolved medical issue. According to the guideline recommendations of the European Association for the Study of the Liver in 2018 and the American Society for Clinical Oncology (ASCO) Guideline, nivolumab is a reasonable option for appropriate advanced stage HCC. EVIDENCE ACQUISITION: We searched the PubMed, Embase and CNKI (China National Knowledge Infrastructure) databases for all articles within a range of published years from 2010 to 2020 of nivolumab in advanced hepatocellular carcinoma and carried out this meta-analysis on all published studies to estimate prognostic factors of nivolumab in advanced hepatocellular carcinoma. EVIDENCE SYNTHESIS: Finally, 6 studies with 627 advanced hepatocellular carcinoma patients treated with nivolumab met the inclusion criteria for this study. Our results indicated that α-fetoprotein (AFP), eastern Cooperative Oncology Group (ECOG) performance status, Child­Pugh Class, portal vein invasion, protein induced by vitamin K absence­II (PIVKA­II), and albumin­bilirubin (ALBI) score were prognostic factor of nivolumab in advanced hepatocellular carcinoma; however, hepatitis C virus (HBV) infection, Barcelona Clinic Liver Cancer (BCLC) stage, and extrahepatic metastasis were not significant prognostic factors. CONCLUSIONS: Our meta-analysis indicated the potential prognostic factor of nivolumab in advanced hepatocellular carcinoma. However, ongoing clinical and translational research may provide us a better understanding of the prognostic factor and mechanisms.

Optimal treatment strategy for recurrent hepatocellular carcinoma based on recurrence time and tumor size: A propensity score matching study.

BACKGROUND: Recurrent hepatocellular carcinoma (RHCC) is commonly treated with transcatheter arterial chemoembolization (TACE) combined with microwave ablation (MWA) or repeated hepatectomy(RH), but the optimal treatment strategy is still controversial. This study aimed to compare the efficacy and safety of TACE-MWA and RH in RHCC patients after initial radical hepatectomy. METHODS: A total of 210 RHCC patients were included between June 2014 and January 2021, with 126 patients in the TACE-MWA group and 84 patients in the RH group. The primary endpoints were median repeat recurrence-free survival (rRFS) and overall survival (OS), and the secondary endpoint was complications. Propensity-score matching (PSM) was conducted to minimize bias. Subgroup analysis based on recurrence patterns (recurrence time and tumor size) was performed, and prognostic factors were studied. RESULTS: Before PSM, the RH group had better median OS (37.0 vs 26.0 months, P<0.001) and rRFS (15.0 vs 14.0 months, P = 0.003). After PSM, the RH group also had a better median OS (33.5 vs 29.0 months, P = 0.038), but there was no significant difference in median rRFS between the two groups (14.0 vs 13.0 months, P = 0.099). Subgroup analysis showed that when RHCC diameter>5 cm, RH had a better median OS (33.5 vs 25.0 months, P = 0.013) and rRFS (14.0 vs 10.9 months, P = 0.030). When the RHCC diameter was≤5 cm, there was no significant difference in the median OS (37.0 vs 31.0 months, P = 0.338) and rRFS (15.0 vs 17.0 months, P = 0.758) between the two groups. When RHCC relapses in the early stage (≤2 years), there is no significant difference in the median OS (26.0 vs 26.0 months, P = 0.310) and rRFS (12.0 vs 10.5 months, P = 0.089) between the two groups. When RHCC relapses in the late stage (>2 years), the RH group has better median OS (41.0 vs 33.0 months, P<0.001) and rRFS (30.0 vs 20.0 months, P = 0.010). CONCLUSION: Individualized therapy is necessary for RHCC. TACE -MWA may be a good choice for RHCC with early recurrence or tumor diameter ≤5 cm. However, RH should be the first choice for RHCC with late recurrence or tumor diameter>5 cm.

Mitochondrial Dynamics: Working with the Cytoskeleton and Intracellular Organelles to Mediate Mechanotransduction.

Cells are constantly exposed to various mechanical environments; therefore, it is important that they are able to sense and adapt to changes. It is known that the cytoskeleton plays a critical role in mediating and generating extra- and intracellular forces and that mitochondrial dynamics are crucial for maintaining energy homeostasis. Nevertheless, the mechanisms by which cells integrate mechanosensing, mechanotransduction, and metabolic reprogramming remain poorly understood. In this review, we first discuss the interaction between mitochondrial dynamics and cytoskeletal components, followed by the annotation of membranous organelles intimately related to mitochondrial dynamic events. Finally, we discuss the evidence supporting the participation of mitochondria in mechanotransduction and corresponding alterations in cellular energy conditions. Notable advances in bioenergetics and biomechanics suggest that the mechanotransduction system composed of mitochondria, the cytoskeletal system, and membranous organelles is regulated through mitochondrial dynamics, which may be a promising target for further investigation and precision therapies.

Divalent Anion-Induced Biohydrogels with High Strength, Anti-swelling, and Bioactive Capability for Enhanced Skull Bone Regeneration.

Increased intracranial pressure after traumatic brain injury (TBI) is an urgent problem in clinical practice. A pliable hydrogel is preferred for cranioplasty applications after TBI since it can protect brain tissue and promote bone healing. Nevertheless, biohydrogels for cranial bone regeneration still face challenges of poor mechanical properties, large swelling ratios, and low osteogenesis activity. Herein, inspired by Hofmeister effects, biopolymer hydrogels composed of protein and polysaccharides were treated with a Hofmeister series including a series of monovalent and divalent anions. Our results reveal that the divalent anion-cross-linked biohydrogels exhibit stronger mechanical properties and lower swelling ratios compared with monovalent-anion treated gels. Intriguingly, the divalent HPO42- anion induced biohybrid hydrogels with excellent mechanical behaviors (3.7 ± 0.58 MPa, 484 ± 76.7 kPa, and 148.3 ± 6.85 kJ/m3), anti-swelling capability (16.7%), and gradual degradation ability, significantly stimulating osteogenic differentiation and in vivo cranial bone regeneration. Overall, this study may provide new insights into the design of biomimetic hydrogels for treating cranial bone defects after TBI.

Collective dynamics of actin and microtubule and its crosstalk mediated by FHDC1.

The coordination between actin and microtubule network is crucial, yet this remains a challenging problem to dissect and our understanding of the underlying mechanisms remains limited. In this study, we used travelling waves in the cell cortex to characterize the collective dynamics of cytoskeletal networks. Our findings show that Cdc42 and F-BAR-dependent actin waves in mast cells are mainly driven by formin-mediated actin polymerization, with the microtubule-binding formin FH2 domain-containing protein 1 (FHDC1) as an early regulator. Knocking down FHDC1 inhibits actin wave formation, and this inhibition require FHDC1's interaction with both microtubule and actin. The phase of microtubule depolymerization coincides with the nucleation of actin waves and microtubule stabilization inhibit actin waves, leading us to propose that microtubule shrinking and the concurrent release of FHDC1 locally regulate actin nucleation. Lastly, we show that FHDC1 is crucial for multiple cellular processes such as cell division and migration. Our data provided molecular insights into the nucleation mechanisms of actin waves and uncover an antagonistic interplay between microtubule and actin polymerization in their collective dynamics.

High-Tc ferromagnetic semiconductor-like behavior and unusual electrical properties in compounds with a 2×2×2 superstructure of the half-Heusler phase.

Heusler phases, including the full- and half-Heusler families, represent an outstanding class of multifunctional materials on account of their great tunability in compositions, valence electron counts (VEC), and properties. Here we demonstrate a systematic design of a series of new compounds with a 2×2×2 superstructure of the half-Heusler unit cell in X-Y-Z (X=Fe, Ru, Co, Rh, Ir; Y=Zn, Mn; Z=Sn, Sb) systems. Their structures were solved by using both powder and single-crystal X-ray diffraction, and also directly observed by using high-angle annular dark-field imaging in a scanning transmission electron microscope (HAADF-STEM). The VEC values of these new compounds span a wide and continuous range comparable to those for the full- and half-Heusler families, thereby implying tunability in compositions and physical properties in the superstructure. In fact, we observed abnormal electrical properties and a ferromagnetic semiconductor-like behavior with a high and tunable Curie temperature in these superstructures.

Planar symmetry incompatibility in Ru-Sn-Zn pseudo-decagonal approximants composed of novel pentagonal antiprisms.

Two new ternary compounds in the Ru-Sn-Zn system were synthesized by conventional high-temperature reactions, and their crystal structures were analyzed by means of the single crystal X-ray diffraction: Ru(2)Sn(2)Zn(3) (orthorhombic, Pnma, Pearson symbol oP28, a = 8.2219(16), b = 4.1925(8), c = 13.625(3) Å, V = 469.66(16) Å(3), Z = 4) and Ru(4.15)Sn(4.96)Zn(5.85) (orthorhombic, Pnma, Pearson symbol oP60-δ, a = 8.3394(17), b = 4.2914(9), c = 28.864(6) Å, V = 1032.98(40) Å(3), Z = 4). With the increase in the Sn content, the half-decagon structure unit with a triangle center in Ru(2)Sn(2)Zn(3) grows up to a symmetry incompatible decagonal unit with a central triangle in the common plane in Ru(4.15)Sn(4.96)Zn(5.85). Both structures can be described by hexagonal arrays of Sn-centered novel pentagonal antiprisms. In light of their pseudodecagonal diffraction in the h0l section and point group mmm, both phases are considered as new quasicrystal approximants in the Ru-Zn-Sn ternary system. The temperature dependences of the electrical resistivity for both compounds exhibit metallic behavior, but their Seebeck coefficients are of opposite sign.

Complex alloys containing double-Mackay clusters and (Sb(1-δ)Zn(δ))(24) snub cubes filled with highly disordered zinc aggregates: synthesis, structures, and physical properties of ruthenium zinc antimonides.

A series of cluster-based ruthenium zinc antimonides with a large unit cell were obtained. Their structures were solved by the single crystal X-ray diffraction methods. They crystallize in the cubic space group of Fm3̅c (No. 226) with cell dimensions of 25.098(3), 24.355(3), 24.307(3), and 24.376(3) Šfor Ru(26)Sb(24)Zn(67) (CA), Ru(13)Sb(12)Zn(83.4) (CB), Ru(13)Sb(6.29)Zn(91.56) (CC), and Ru(13)Sb(17.1)Zn(74.8) (CD), respectively. By all indications, compounds CA and CB are two phases showing pronounced distinctions regarding compositions, lattice parameters, thermal and transport properties, but they are not members of an extended solid solution. Compounds CB, CC, and CD are three members of a same solid solution. Topologically, these four compounds contain face-centered cubic packing of double-Mackay type clusters and (Sb(1-δ)Zn(δ))(24) snub cubes filled with highly disordered zinc aggregates, with or without glue atoms between them. Both phases CA and CB are diamagnetic. There is a difference of ∼170 K between their thermally stable temperatures. CA exhibits rather low thermal conductivity with the value of ∼0.9 W m(-1) K(-1) at room temperature, which is about one-third that of CB. The electrical resistivity of CB is almost temperature independent. The Seebeck coefficient of CB is small and negative, while that of CA exhibits a complicated temperature dependence and undergoes a transition from p- to n-type conduction around room temperature.

Ru9Zn7Sb8: a structure with a 2 × 2 × 2 supercell of the half-Heusler phase.

The title compound Ru(9)Zn(7)Sb(8) was synthesized via a high-temperature reaction from the elements in a stoichiometric ratio, and its structure was solved by a single-crystal X-ray diffraction method. The structure [cubic, space group Fm3m, Pearson symbol cF96, a = 11.9062(14) Å (293 K), and Z = 4] adopts a unique 2a(hh) × 2a(hh) × 2a(hh) supercell of a normal half-Heusler phase and shows abnormal features of atomic coordination against the Pauling rule. The formation of this superstructure was discussed in light of the valence electron concentration per unit cell. It is a metallic conductor [ρ(300 K) = 16 µΩ·m], and differential scanning calorimetry revealed that Ru(9)Zn(7)Sb(8) undergoes a transformation at 1356(1) K and melts, by all indications, congruently at 1386 K. At room temperature, its thermal conductivity is about 3 W/m·K, which is only one-quarter of that of most normal half-Heusler phases. Ru(9)Zn(7)Sb(8) as well as its analogues of iron-, cobalt-, rhodium-, and iridium-containing compounds are expected to serve as a new structure type for exploring new thermoelectric materials.

Genomic and functional assays demonstrate reduced gammaretroviral vector genotoxicity associated with use of the cHS4 chromatin insulator.

Interest in the use of recombinant retroviral vectors for clinical gene therapy has been tempered by evidence of vector-mediated genotoxicity involving the activation of cellular oncogenes flanking sites of vector integration. We report here that the rate of gammaretroviral vector genotoxicity can be significantly reduced by addition of the cHS4 chromatin insulator, based on two complementary approaches for assessing vector-mediated genotoxicity. One approach involves the direct, genomewide assessment of cellular gene dysregulation using panels of transduced cell clones and genomic microarrays, whereas the other involves the functional assessment of malignant transformation using a factor-dependent cell line. Both assays are robust and quantitative, and indicate the cHS4 chromatin insulator can reduce vector-mediated genotoxicity approximately sixfold (ranged three to eight fold). These approaches also provide a means for assessing various aspects of vector-mediated genotoxicity, including the overall rate of cellular gene dysregulation, the potential influence of vector provirus over large genomic distances, and the involvement of oncogenic pathways in vector-mediated malignant transformation.