Amino acid and protein specificity of protein fatty acylation in C. elegans.

Protein lipidation plays critical roles in regulating protein function and localization. However, the chemical diversity and specificity of fatty acyl group utilization have not been investigated using untargeted approaches, and it is unclear to what extent structures and biosynthetic origins of S-acyl moieties differ from N- and O-fatty acylation. Here, we show that fatty acylation patterns in Caenorhabditis elegans differ markedly between different amino acid residues. Hydroxylamine capture revealed predominant cysteine S-acylation with 15-methylhexadecanoic acid (isoC17:0), a monomethyl branched-chain fatty acid (mmBCFA) derived from endogenous leucine catabolism. In contrast, enzymatic protein hydrolysis showed that N-terminal glycine was acylated almost exclusively with straight-chain myristic acid, whereas lysine was acylated preferentially with two different mmBCFAs and serine was acylated promiscuously with a broad range of fatty acids, including eicosapentaenoic acid. Global profiling of fatty acylated proteins using a set of click chemistry-capable alkyne probes for branched- and straight-chain fatty acids uncovered 1,013 S-acylated proteins and 510 hydroxylamine-resistant N- or O-acylated proteins. Subsets of S-acylated proteins were labeled almost exclusively by either a branched-chain or a straight-chain probe, demonstrating acylation specificity at the protein level. Acylation specificity was confirmed for selected examples, including the S-acyltransferase DHHC-10. Last, homology searches for the identified acylated proteins revealed a high degree of conservation of acylation site patterns across metazoa. Our results show that protein fatty acylation patterns integrate distinct branches of lipid metabolism in a residue- and protein-specific manner, providing a basis for mechanistic studies at both the amino acid and protein levels.

The efficacy of acceptance and commitment therapy for chronic pain: A three-level meta-analysis and a trial sequential analysis of randomized controlled trials.

The current study included randomized controlled trials (RCTs) to assess the benefits of Acceptance and commitment therapy (ACT) for chronic pain. Searches were conducted in Web of Science, PsycINFO, PubMed, Scopus, Cochrane Library, and Embase from inception until September 30, 2022. Thirty-three RCTs, including 2293 participants, were included. Small to medium effect sizes for pain intensity/physical function favoring ACT were found both at post-treatment (pain intensity: g = 0.44; physical function: g = 0.59) and follow-up (pain intensity: g = 0.34; physical function: g = 0.56). The effect sizes on psychological outcomes were significant at post-treatment (depression: g = 0.43; anxiety: g = 0.43; quality of life: g = 0.45) and follow-up (depression: g = 0.43; anxiety: g = 0.35; quality of life: g = 0.43). The results of the trial sequential analyses indicated that pooled estimates were unlikely to be incidental findings, as effects of multiple testing were controlled and power was adequate. Face-to-face ACT yielded significantly larger effects on physical outcomes than internet-delivered ACT. Participants with chronic headache and fibromyalgia showed greater benefit from ACT compared to those with non-specific pain or mixed pain. In addition, the longer the follow-up duration, the smaller the effect sizes for pain intensity/physical function at follow-up. The present meta-analysis suggests sufficient evidence for the significant benefits of ACT for people with chronic pain.

Deep-Learning-Based Metal Artefact Reduction With Unsupervised Domain Adaptation Regularization for Practical CT Images.

CT metal artefact reduction (MAR) methods based on supervised deep learning are often troubled by domain gap between simulated training dataset and real-application dataset, i.e., methods trained on simulation cannot generalize well to practical data. Unsupervised MAR methods can be trained directly on practical data, but they learn MAR with indirect metrics and often perform unsatisfactorily. To tackle the domain gap problem, we propose a novel MAR method called UDAMAR based on unsupervised domain adaptation (UDA). Specifically, we introduce a UDA regularization loss into a typical image-domain supervised MAR method, which mitigates the domain discrepancy between simulated and practical artefacts by feature-space alignment. Our adversarial-based UDA focuses on a low-level feature space where the domain difference of metal artefacts mainly lies. UDAMAR can simultaneously learn MAR from simulated data with known labels and extract critical information from unlabeled practical data. Experiments on both clinical dental and torso datasets show the superiority of UDAMAR by outperforming its supervised backbone and two state-of-the-art unsupervised methods. We carefully analyze UDAMAR by both experiments on simulated metal artefacts and various ablation studies. On simulation, its close performance to the supervised methods and advantages over the unsupervised methods justify its efficacy. Ablation studies on the influence from the weight of UDA regularization loss, UDA feature layers, and the amount of practical data used for training further demonstrate the robustness of UDAMAR. UDAMAR provides a simple and clean design and is easy to implement. These advantages make it a very feasible solution for practical CT MAR.

Design and Evaluation of an Adjustable Compliant Constant-Force Microgripper.

Precise control of the manipulating force within an appropriate range is crucial to prevent potential damage to the operating object. However, achieving accurate force control through force feedback is challenging in micro-scale applications. This study presents the design of a quasi-zero stiffness-compliant constant-force microgripper with adjustable force output. The parameters of the constant-force mechanism are designed using a model-based optimization method. By utilizing this mechanism, a compliant microgripper capable of providing adjustable constant-force output is developed to overcome the limitation of traditional grippers that offer only a single constant force. Finite element analysis is performed to simulate the behavior and verify the stability of the constant-force output. Furthermore, an experimental platform is constructed to validate the mechanical properties of the developed microgripper. The experimental results demonstrate that the automatically optimized structural parameters enable the microgripper to achieve the desired constant-force value of 2 N with an adjustable range of 0.15 N. These findings provide a further basis for the application and promotion of compliant constant-force structures.

Application Perspectives of Nanomedicine in Cancer Treatment.

Cancer is a disease that seriously threatens human health. Based on the improvement of traditional treatment methods and the development of new treatment modes, the pattern of cancer treatment is constantly being optimized. Nanomedicine plays an important role in these evolving tumor treatment modalities. In this article, we outline the applications of nanomedicine in three important tumor-related fields: chemotherapy, gene therapy, and immunotherapy. According to the current common problems, such as poor targeting of first-line chemotherapy drugs, easy destruction of nucleic acid drugs, and common immune-related adverse events in immunotherapy, we discuss how nanomedicine can be combined with these treatment modalities, provide typical examples, and summarize the advantages brought by the application of nanomedicine.

Multistimulus-Responsive Graphene Oxide/Fe3O4/Starch Soft Actuators.

Soft actuators that respond to external stimuli like moisture, magnetism, light, and temperature have received tremendous attention owing to their promising potential in many frontier applications, including smart switches, soft robots, sensors, and artificial muscles. However, most of the conventional actuators can only be triggered by a solo stimulus and demand advanced manufacturing techniques that utilize expensive, hazardous, and synthetic raw materials. Herein, we design and fabricate a multiple stimuli-responsive actuator using graphene oxide, Fe3O4 nanoparticles, and tapioca starch via a water evaporation-induced self-assembly method. The resultant hybrid actuator exhibits a bending speed of ∼72° s-1 upon moisture exposure. Moreover, it can perform clockwise and counterclockwise rotations, linear motion, and magnetic object capture by regulating a magnetic field. As representative examples, the actuator is used to fabricate various smart devices such as smart curtains, biomimetic structures, and a smart gripper that undergo complex and consecutive motion under the influence of multiple stimuli.

High-Throughput Enzyme Assay for Screening Inhibitors of the ZDHHC3/7/20 Acyltransferases.

As enzymes that mediate the attachment of long-chain fatty acids to cysteine residues, ZDHHC proteins have been reported to be promising therapeutic targets for treating cancer and autoimmune diseases. Yet, due to the lack of potent selective inhibitors, scrutiny of the biological functions of ZDHHCs has been limited. The main hindrance for developing ZDHHC inhibitors is the lack of a facile high-throughput assay. Here, we developed a ZDHHC3/7/20 high-throughput assay based on the acylation-coupled lipophilic induction of polarization (Acyl-cLIP) method and screened several potential ZDHHC inhibitors. Furthermore, we demonstrated that in vitro results from the Acyl-cLIP assay are supported by the results from cell-based assays. We envision that this new ZDHHC3/7/20 Acyl-cLIP assay will accelerate the high-throughput screening of large compound libraries for improved ZDHHC inhibitors and provide therapeutic benefits for cancer and autoimmune diseases.

3D-Printing Damage-Tolerant Architected Metallic Materials with Shape Recoverability via Special Deformation Design of Constituent Material.

Architected metallic materials generally suffer from a serious engineering problem of mechanical instability manifested as the emergence of localized deformation bands and collapse of strength. They usually cannot exhibit satisfactory shape recoverability due to the little recoverable strain of metallic constituent material. After yielding, the metallic constituent material usually exhibits a continuous low strain-hardening capacity, giving the local yielded regions of architecture low load resistance and easily developing into excessive deformation bands, accompanied by the collapse of strength. Here, a novel constituent material deformation design strategy has been skillfully proposed, where the low load resistance of yielded regions of the architecture can be effectively compensated by the significant self-strengthening behavior of constituent material, thus avoiding the formation of localized deformation bands and collapse of strength. To substantiate this strategy, shape-memory alloys (SMAs) are considered as suitable constituent materials for possessing both self-strengthening behavior and shape-recovery function. A 3D-printing technique was adopted to prepare various NiTi SMA architected materials with different geometric structures. It is demonstrated that all of these architected metallic materials can be stably and uniformly compressed by up to 80% without the formation of localized bands, collapse of strength, and structural failure, exhibiting ultrahigh damage tolerance. Furthermore, these SMA architected materials can display more than 98% shape recovery even after 80% deformation and excellent cycle stability during 15 cycles. This work exploits the amazing impact of constituent materials on constructing supernormal properties of architected materials and will open new avenues for developing high-performance architected metallic materials.

Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative.

Hereditary cancer syndromes infer high cancer risks and require intensive surveillance. Identification of high-risk individuals among patients with colorectal cancer (CRC) needs improvement. METHODS: Three thousand three hundred ten unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016. Universal Tumor screening (UTS) for mismatch repair (MMR) deficiency was performed for all, and pathogenic germline variants (PGVs) were identified using multigene panel testing (MGPT) in those who met at least one inclusion criterion: MMR deficiency, diagnosed < 50 years, multiple primary tumors (CRC or endometrial cancer), or with a first-degree relative with CRC or endometrial cancer. RESULTS: Five hundred twenty-five patients (15.9%) had MMR deficiency. Two hundred thirty-four of 3,310 (7.1%; 16% of the 1,462 who received MGPT) had 248 PGVs in cancer susceptibility genes. One hundred forty-two (4.3%) had a PGV in an MMR gene, and 101 (3.1%) had a PGV in a non-MMR gene. Ten with Lynch syndrome (LS) also had a non-MMR PGV and were included in both groups. Two (0.06%) had constitutional MLH1 hypermethylation. Of unexplained MMR-deficient patients, 88.4% (76 of 86) had double somatic MMR mutations. Testing for only MMR genes in MMR-deficient patients would have missed 18 non-MMR gene PGVs (7.3% of total PGVs identified). Had UTS been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) would have been missed, including 6.3% (9 of 144) of those with LS. These results have treatment implications as 5.3% (175 of 3,310) had PGVs in genes with therapeutic targets. CONCLUSION: UTS alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with LS. At a minimum, 7.1% of individuals with CRC have a PGV and pan-cancer MGPT should be considered for all patients with CRC.

Grain Size Effect of the γ Phase Precipitation on Martensitic Transformation and Mechanical Properties of Ni-Mn-Sn-Fe Heusler Alloys.

Isothermal annealing of a eutectic dual phase Ni-Mn-Sn-Fe alloy was carried out to encourage grain growth and investigate the effects of grain size of the γ phase on the martensitic transformation behaviour and mechanical properties of the alloy. It is found that with the increase of the annealing time, the grain size and volume fraction of the γ phase both increased with the annealing time predominantly by the inter-diffusion of Fe and Sn elements between the γ phase and the Heusler matrix. The isothermal anneals resulted in the decrease of the e/a ratio and suppression of the martensitic transformation of the matrix phase. The fine γ phase microstructure with an average grain size of 0.31 µm showed higher fracture strength and ductility values by 28% and 77% compared to the coarse-grained counterpart with an average grain size of 3.31 µm. The fine dual phase microstructure shows a quasi-linear superelasticity of 4.2% and very small stress hysteresis during cyclic loading, while the coarse dual phase counterpart presents degraded superelasticity of 2.6% and large stress hysteresis. These findings indicate that grain size refinement of the γ phase is an effective approach in improving the mechanical and transformation properties of dual phase Heusler alloys.

Timely and atomic-resolved high-temperature mechanical investigation of ductile fracture and atomistic mechanisms of tungsten.

Revealing the atomistic mechanisms for the high-temperature mechanical behavior of materials is important for optimizing their properties for service at high-temperatures and their thermomechanical processing. However, due to materials microstructure's dynamic recovery and the absence of available in situ techniques, the high-temperature deformation behavior and atomistic mechanisms of materials are difficult to evaluate. Here, we report the development of a microelectromechanical systems-based thermomechanical testing apparatus that enables mechanical testing at temperatures reaching 1556 K inside a transmission electron microscope for in situ investigation with atomic-resolution. With this unique technique, we first uncovered that tungsten fractures at 973 K in a ductile manner via a strain-induced multi-step body-centered cubic (BCC)-to-face-centered cubic (FCC) transformation and dislocation activities within the strain-induced FCC phase. Both events reduce the stress concentration at the crack tip and retard crack propagation. Our research provides an approach for timely and atomic-resolved high-temperature mechanical investigation of materials at high-temperatures.

Investigation of failure mechanisms of nacre at macro and nano scales.

Nacre is a natural composite featuring exceptional mechanical properties such as high strength and high toughness. Its unique structure is now universally applied in engineering bioinspired materials. On the other hand, it is still a technical challenge to investigate its interfacial strength and fracture mechanisms at micro or nano-scale. In this work, the interfacial strength and fracture mechanism of the 'brick-mortar' structure in nacre are investigated using micro-sized cantilever beam and bend samples. As compared to previous works, a high aragonite/biopolymer interfacial strength is observed (~298 MPa). The crack propagation path is investigated via experiment and finite element modelling and compared with the fracture mechanics analysis. It is confirmed that crack deflection to the aragonite/biopolymer interface contributes to a high overall toughness. This work provides a better understanding of the toughening mechanism in nacre and other bioinspired composites.

Zinc is essential for the transcription function of the PGC-1α/Nrf2 signaling pathway in human primary endometrial stromal cells.

Zinc (Zn) has antioxidant effect in different types of organs and is closely associated with human health. Endometrial receptivity is one of the most important factors in the embryo implantation and development. However, the regulatory mechanism of Zn in endometrium tissue is still unclear. In the study, we found that plasma Zn level is significantly associated with female infertility, which severely affects female reproductive health. Primary endometrial stromal cells were isolated from female endometrium and cultured in the laboratory. Zn chelator TPEN treatment reduced the expression of stem cell markers CD73, CD90, and CD105 and generated reactive oxygen species in endometrial stromal cells. However, pretreatment of Zn (zinc sulfate) is able to prevent TPEN-induced oxidative stress in vitro. By transcriptional profiling and gene ontology analysis, we found that Zn increased the cellular pluripotency signaling and extracellular matrix-receptor interaction, but reduced autophagy, endocytosis, and the nitrogen metabolism pathway. We further discovered the antioxidant function of Zn through the peroxisome proliferator-activated receptor gamma coactivator 1α/nuclear factor erythroid-2-related factor signaling pathway in endometrial stromal cells. Zn supplementation may open up an effective therapeutic approach for patients with oxidative stress-related endometrial diseases.

"Lattice Strain Matching"-Enabled Nanocomposite Design to Harness the Exceptional Mechanical Properties of Nanomaterials in Bulk Forms.

Nanosized materials are known to have the ability to withstand ultralarge elastic strains (4-10%) and to have ultrahigh strengths approaching their theoretical limits. However, it is a long-standing challenge to harnessing their exceptional intrinsic mechanical properties in bulk forms. This is commonly known as "the valley of death" in nanocomposite design. In 2013, a breakthrough was made to overcome this challenge by using a martensitic phase transforming matrix to create a composite in which ultralarge elastic lattice strains up to 6.7% are achieved in Nb nanoribbons embedded in it. This breakthrough was enabled by a novel concept of phase transformation assisted lattice strain matching between the uniform ultralarge elastic strains (4-10%) of nanomaterials and the uniform crystallographic lattice distortion strains (4-10%) of the martensitic phase transformation of the matrix. This novel concept has opened new opportunities for developing materials of exceptional mechanical properties or enhanced functional properties that are not possible before. The work in progress in this research over the past six years is reported.

Experimental and numerical data for transformation propagation in NiTi shape memory structures.

This article provides experimental and numerical data for the propagation of stress-induced martensitic transformation within NiTi structures with uniform and nonuniform geometries. This article is related to the research paper entitled "Computational and experimental analyses of martensitic transformation propagation in shape memory alloys" [1]. The heterogeneous transformation evolutions within geometrically graded NiTi structures are presented by thermal images recorded by a high-resolution infrared camera during tensile loading. The modelling of transformation and deformation behaviours of those structures is presented by finite element computational method.

Spectral tracing of deuterium for imaging glucose metabolism.

Cells and tissues often display pronounced spatial and dynamical metabolic heterogeneity. Common glucose-imaging techniques report glucose uptake or catabolism activity, yet do not trace the functional utilization of glucose-derived anabolic products. Here we report a microscopy technique for the optical imaging, via the spectral tracing of deuterium (STRIDE), of diverse macromolecules derived from glucose. Based on stimulated Raman-scattering imaging, STRIDE visualizes the metabolic dynamics of newly synthesized macromolecules, such as DNA, protein, lipids and glycogen, via the enrichment and distinct spectra of carbon-deuterium bonds transferred from the deuterated glucose precursor. STRIDE can also use spectral differences derived from different glucose isotopologues to visualize temporally separated glucose populations using a pulse-chase protocol. We also show that STRIDE can be used to image glucose metabolism in many mouse tissues, including tumours, brain, intestine and liver, at a detection limit of 10 mM of carbon-deuterium bonds. STRIDE provides a high-resolution and chemically informative assessment of glucose anabolic utilization.

In vitro and in vivo studies of Mg-30Sc alloys with different phase structure for potential usage within bone.

Proper alloying magnesium with element scandium (Sc) could transform its microstructure from α phase with hexagonal closed-packed (hcp) structure into ß phase with body-cubic centered (bcc) structure. In the present work, the Mg-30 wt% Sc alloy with single α phase, dual phases (α + ß) or ß phase microstructure were developed by altering the heat-treatment routines and their suitability for usage within bone was comprehensively investigated. The ß phased Mg-30 wt% Sc alloy showed the best mechanical performance with ultimate compressive strength of 603 ±â€¯39 MPa and compressive strain of 31 ±â€¯3%. In vitro degradation test showed that element scandium could effectively incorporate into the surface corrosion product layer, form a double-layered structure, and further protect the alloy matrix. No cytotoxic effect was observed for both single α phased and ß phased Mg-30 wt% Sc alloys on MC3T3 cell line. Moreover, the ß phased Mg-30 wt%Sc alloy displayed acceptable corrosion resistance in vivo (0.06 mm y-1) and maintained mechanical integrity up to 24 weeks. The degradation process did not significantly influence the hematology indexes of inflammation, hepatic or renal functions. The bone-implant contact ratio of 75 ±â€¯10% after 24 weeks implied satisfactory integration between ß phased Mg-30 wt%Sc alloy and the surrounding bone. These findings indicate a potential usage of the bcc-structured Mg-Sc alloy within bone and might provide a new strategy for future biomedical magnesium alloy design. STATEMENT OF SIGNIFICANCE: Scandium is the only rare earth element that can transform the matrix of magnesium alloy into bcc structure, and Mg-30 wt%Sc alloy had been recently reported to exhibit shape memory effect. The aim of the present work is to study the feasibility of Mg-30 wt%Sc alloy with different constitutional phases (single α phase, single ß phase or dual phases (α + ß)) as biodegradable orthopedic implant by in vitro and in vivo testings. Our findings showed that ß phased Mg-30 wt%Sc alloy which is of bcc structure exhibited improved strength and superior in vivo degradation performance (0.06 mm y-1). No cytotoxicity and systematic toxicity were shown for ß phased Mg-30 wt%Sc alloy on MC3T3 cell model and rat organisms. Moreover, good osseointegration, limited hydrogen gas release and maintained mechanical integrity were observed after 24 weeks' implantation into the rat femur bone.

Fabrication of a silver nanoparticle-coated collagen membrane with anti-bacterial and anti-inflammatory activities for guided bone regeneration.

Alveolar bone loss is a common problem that affects dental implant placement. A barrier between the bone substitute and gingiva that can prevent fibro-tissue ingrowth, bacterial infection and induce bone formation is a key factor in improving the success of alveolar ridge reconstruction. This study aims to develop a bioactive collagen barrier material for guided bone regeneration, that is coupled with anti-bacterial and anti-inflammatory properties. We have evaluated two silver coating methods and found controllable and precise coating achieved by sonication compared with sputtering. The optimized AgNP-coated collagen membrane exhibited excellent anti-bacterial effects against Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) with limited cellular toxicity. It also displayed effective anti-inflammatory effects by reducing the expression and release of inflammatory cytokines including IL-6 and TNF-alpha. Additionally, AgNP-coated collagen membranes were able to induce osteogenic differentiation of mesenchymal stem cells that guide bone regeneration. These findings demonstrate the potential application of AgNP-coated collagen membranes to prevent infection after bone graft introduction in alveolar ridge reconstruction.

Dual Phase Synergy Enabled Large Elastic Strains of Nanoinclusions in a Dislocation Slip Matrix Composite.

Freestanding nanomaterials (such as nanowires, nanoribbons, and nanotubes) are known to exhibit ultralarge elastic strains and ultrahigh strengths. However, harnessing their superior intrinsic mechanical properties in bulk composites has proven to be difficult. A recent breakthrough has overcome this difficulty by using a martensitic phase transforming matrix in which ultralarge elastic strains approaching the theoretical limit is achieved in Nb nanowires embedded in the matrix. This discovery, breaking a long-standing challenge, still limits our ability of harnessing the exceptional properties of nanomaterials and developing ultrahigh strength bulk materials to a narrow selection of phase transforming alloy matrices. In this study, we investigated the possibility to harness the intrinsic mechanical properties of nanoinclusions in conventional dislocation slip matrix based on a principle of synergy between the inclusion and the matrix. The small spacing between the densely populated hard and dislocation-impenetrable nanoinclusions departmentalize the plastic matrix into small domains to effectively impede dislocation motion within the matrix, inducing significant strengthening and large local elastic strains of the matrix, which in turn induced large elastic strains in the nanoinclusions. This dual phase synergy is verified in a Ti3Sn inclusions/B2-NiTi(Fe) plastic matrix model materials system. The maximum elastic strain of Ti3Sn inclusion obtained in the dislocation slip matrix is comparable to that achieved in a phase transforming matrix. This finding opens new opportunities for the development of high-strength nanocomposites.