Idiopathic Isolated Adrenocorticotropic Hormone Deficiency: A Single-Center Retrospective Study.

Idiopathic isolated adrenocorticotrophic hormone deficiency (IIAD) is rare, with high clinical omission and misdiagnosis rates. This study retrospectively collected information on clinical presentation, laboratory findings, and treatment response of 17 patients with IIAD at Jining No. 1 People's Hospital from January 2014 to December 2022. The clinical characteristics were summarized, and the pertinent data were analyzed. As a result, most of the patients with IIAD were male (94.12%), with age at onset ranging from 13 to 80 years. The primary manifestations were anorexia (88.24%), nausea (70.59%), vomiting (47.06%), fatigue (64.71%), and neurological or psychiatric symptoms (88.24%). The median time to diagnosis was 2 months and the longest was 10 years. Laboratory tests mostly showed hyponatremia (88.24%) and hypoglycemia (70.59%). The symptoms and laboratory indicators returned to normal after supplementing patients with glucocorticoids. IIAD has an insidious onset and atypical symptoms; it was often misdiagnosed as gastrointestinal, neurological, or psychiatric disease. The aim of this study was to improve clinicians' understanding of IIAD, patients with unexplained gastrointestinal symptoms, neurological and psychiatric symptoms, hyponatremia, or hypoglycemia should be evaluated for IIAD and ensure early diagnosis and treatment.

Protein-level mutant p53 reporters identify druggable rare precancerous clones in noncancerous tissues.

Detecting and targeting precancerous cells in noncancerous tissues is a major challenge for cancer prevention. Massive stabilization of mutant p53 (mutp53) proteins is a cancer-specific event that could potentially mark precancerous cells, yet in vivo protein-level mutp53 reporters are lacking. Here we developed two transgenic protein-level mutp53 reporters, p53R172H-Akaluc and p53-mCherry, that faithfully mimic the dynamics and function of mutp53 proteins in vivo. Using these reporters, we identified and traced rare precancerous clones in deep noncancerous tissues in various cancer models. In classic mutp53-driven thymic lymphoma models, we found that precancerous clones exhibit broad chromosome number variations, upregulate precancerous stage-specific genes such as Ybx3 and enhance amino acid transport and metabolism. Inhibiting amino acid transporters downstream of Ybx3 at the early but not late stage effectively suppresses tumorigenesis and prolongs survival. Together, these protein-level mutp53 reporters reveal undercharacterized features and vulnerabilities of precancerous cells during early tumorigenesis, paving the way for precision cancer prevention.

Complex phase transitions and phase engineering in the aqueous solution of an isopolyoxometalate cluster.

Inorganic salts usually demonstrate simple phasal behaviors in dilute aqueous solution mainly involving soluble (homogeneous) and insoluble (macrophase separation) scenarios. Herein, we report the discovery of complex phase behavior involving multiple phase transitions of clear solution - macrophase separation - gelation - solution - macrophase separation in the dilute aqueous solutions of a structurally well-defined molecular cluster [Mo7O24]6- macroanions with the continuous addition of Fe3+. No chemical reaction was involved. The transitions are closely related to the strong electrostatic interaction between [Mo7O24]6- and their Fe3+ counterions, the counterion-mediated attraction and the consequent charge inversion, leading to the formation of linear/branched supramolecular structures, as confirmed by experimental results and molecular dynamics simulations. The rich phase behavior demonstrated by the inorganic cluster [Mo7O24]6- expands our understanding of nanoscale ions in solution.

The counterion-mediated controllable coacervation of nano-ions with polyelectrolytes.

Nano-ions can complex with polyelectrolytes for coacervates with hierarchical structures; however, the rational design of functional coacervations is still rare due to the poor understanding of their structure-property relationship from their complex interaction. Herein, 1 nm anionic metal oxide clusters, PW12O403-, with well-defined, mono-disperse structures are applied to complex with cationic polyelectrolyte and the system shows tunable coacervation via the alternation of counterions (H+ and Na+) of PW12O403-. Suggested from Fourier transform infrared spectroscopy (FT-IR) and isothermal titration studies, the interaction between PW12O403- and cationic polyelectrolytes can be modulated by the bridging effect of counterions via hydrogen bonding or ion-dipole interaction to carbonyl groups of polyelectrolytes. The condensed structures of the complexed coacervates are explored by small angle X-ray and neutron scattering techniques, respectively. The coacervate with H+ as counterions shows both crystallized and discrete PW12O403- clusters, with a loose polymer-cluster network in comparison to the system of Na+ which shows a dense packing structure with aggregated nano-ions filling the meshes of polyelectrolyte networks. The bridging effect of counterions helps understand the super-chaotropic effect observed in nano-ion system and provides avenues for the design of metal oxide cluster-based functional coacervates.

The design and evaluation of bionic porous bone scaffolds in fluid flow characteristics and mechanical properties.

BACKGROUND AND OBJECTIVE: At present, there is a lack of efficient modeling methods for bionic artificial bone scaffolds, and the tissue fluid/nutrient mass transport characteristics of bone scaffolds has not been evaluated sufficiently. This study aims to explore an effective and efficient modeling method for biomimetic porous bone scaffolds for biological three-dimensional printing based on the imitation of the histomorphological characteristics of human vertebral cancellous bone. The fluid mass transport and mechanical characteristics of the porous scaffolds were evaluated and compared with those of a human cancellous bone,and the relationship between the geometric parameters (e.g., the size, number, shape of pores and porosity) and the performence of biomimetic porous bone scaffolds are revealed. METHODS: The bionic modeling design method proposed in this study considers the biological characteristics of vertebral cancellous tissue and performs imitation and design of vertebrae-like two-dimensional slices images.It then reconstructs the slices layer-by-layer to form porous scaffolds with a three-dimensional reconstruction method, similar to computed tomography image reconstruction. By controlling the design parameters, this method can easily realize the formation of plate-like (femoral cancellous bone-like) or rod-like (vertebral cancellous bone-like) porous scaffolds. The flow characterization of porous structures was performed using the computational fluid simulation method. RESULTS: The flow characterization results showed that the permeability of the porous scaffolds and human bone was 10-8∼10-9m2,and when the porosity of the porous scaffolds was higher than 70%, the permeability was higher than that of human vertebrae with a porosity of 82%. The maximum shear stress of the designed porous scaffolds and human vertebra were less than 0.8Mpa, which was conducive to cell adhesion, cell migration, and cell differentiation. The results of 3D printing and mechanical testing showed good printability and reflected the relationship between the mechanical properties and design parameters. CONCLUSIONS: The design method proposed in this study has many controllable parameters, which can be adjusted to generate diversified functional porous structures to meet specific needs, increase the potential of bone scaffold design, and leave room for meeting the new requirements for bone scaffold characteristics in the future.

Success Factors of Additive Manufactured Root Analogue Implants.

Dental implantation is an effective method for the treatment of loose teeth, but the threaded dental implants used in the clinic cannot match with the tooth extraction socket. A root analogue implant (RAI) has the congruence shape, which reduces the damage to bone and soft tissue. Additive manufacturing (AM) technologies have the advantages of high precision, flexibility, and easy operation, becoming the main manufacturing method of RAI in basic research. The purpose of this systematic review is to summarize AM technologies used for RAI manufacturing as well as the factors affecting successful implantation. First, it introduces the AM technologies according to different operating principles and summarizes the advantages and disadvantages of each method. Then the influences of materials, structure design, surface characteristics, implant site, and positioning are discussed, providing reference for designers and dentists. Finally, it addresses the gap between basic research and clinical application for additive manufactured RAIs and discusses the current challenges and future research directions for this field.

A polymeric co-assembly of subunit vaccine with polyoxometalates induces enhanced immune responses.

Long-lasting protective immune responses are expected following vaccination. However, most vaccines alone are inability to evoke an efficient protection. The combinatory administration of adjuvants with vaccines is critical for generating the enhanced immune responses. Herein, with biocompatible poly(4-vinylpyridine) (P4VP) as template, 2.5 nm iron/molybdenum oxide cluster, {Mo72Fe30}, is applied as an adjuvant to co-assemble with antigens of Mycobacterium bovis via hydrogen bonding at molecular scale. Molecular scale integration of the antigens and {Mo72Fe30} and their full exposure to body fluid media contribute to the augmentation of both humoral and cellular immune responses of the vaccines after inoculation in mice. Anti-inflammatory factor IL-10 gradually increases after 2 weeks followed by a final back to normal level by the 5th week. The balance between proinflammatory cytokines and anti-inflammatory factors suggests that immune system can be activated in the early stage of infection by the antigens carried by the supra-particles and secrete acute inflammatory factors for host defense and antiinflammatory factors for immune protection. Electronic Supplementary Material: Supplementary material (further structural analysis and biological analsyis) is available in the online version of this article at 10.1007/s12274-021-4004-9.

Three-year observations on the effect of different cusp inclinations on the restoration of short maxillary first molar implants: A randomized controlled trial.

Objective: To investigate the effect of different cusp inclination on short implant prosthesis of maxillary first molar after 3 years of weight-bearing in biology and mechanics. Methods: The clinical patients were randomly selected from the database and divided into four groups A, B, C, and D according to the cusp inclination of the maxillary first molar short implant restoration (4.8 mm × 8 mm, Dentium). 20 cases in each group. The cusp inclination was 10 degrees-15 degrees, 15 degrees-20 degrees, 20 degrees-25 degrees, 25 degrees-30 degrees. After 3 years of weight-bearing, cone beam computed tomography (CBCT) and Florida probe were used to measure and observe the height of alveolar bone (H), periodontal probing depth (PD) and modified sulcus bleeding index (MBI). Visual analogue scale (VAS) was used to evaluate the overall satisfaction of patients, and the mechanical complications of each group within 3 years of implant weight-bearing were counted. Results: The H and PD of group D were 1.09 ± 0.23 and 2.19 ± 0.11 respectively, which were significantly higher than those of group A, B and C (p < 0.05). There was no significant difference in MBI between groups A-D (p > 0.05). The VAS scores of group B and group C were 88.36 ± 5.12 and 88.70 ± 4.52 respectively, which were higher than those of group A and group D (p < 0.05). The incidence of food impaction, porcelain collapse and abutment loosening in group D were 40.0%, 25.0% and 15.0% respectively, which were higher than those in group B and C (p < 0.05). Conclusion: The risk of biological and mechanical complications increases after long-term weight-bearing of maxillary first molar short implant prostheses with high cusp inclination. The cusp inclination of short implant prostheses should be designed as low as 25 degrees.

Design and Fabrication of Sodium Alginate/Carboxymethyl Cellulose Sodium Blend Hydrogel for Artificial Skin.

Tissue-engineered skin grafts have long been considered to be the most effective treatment for large skin defects. Especially with the advent of 3D printing technology, the manufacture of artificial skin scaffold with complex shape and structure is becoming more convenient. However, the matrix material used as the bio-ink for 3D printing artificial skin is still a challenge. To address this issue, sodium alginate (SA)/carboxymethyl cellulose (CMC-Na) blend hydrogel was proposed to be the bio-ink for artificial skin fabrication, and SA/CMC-Na (SC) composite hydrogels at different compositions were investigated in terms of morphology, thermal properties, mechanical properties, and biological properties, so as to screen out the optimal composition ratio of SC for 3D printing artificial skin. Moreover, the designed SC composite hydrogel skin membranes were used for rabbit wound defeat repairing to evaluate the repair effect. Results show that SC4:1 blend hydrogel possesses the best mechanical properties, good moisturizing ability, proper degradation rate, and good biocompatibility, which is most suitable for 3D printing artificial skin. This research provides a process guidance for the design and fabrication of SA/CMC-Na composite artificial skin.

Polymer-templated supramolecular co-assemblies of proteins and metal oxide clusters as versatile platform for chemo-enzymatic catalysis.

The hybridization of enzymes and inorganics in controlled manner is challenging, however, critical for the development of chemo-enzymatic cascade catalyst with high efficiency and selectivity. Here, proteins and metal oxide clusters can be facilely co-assembled on the surface of colloid of poly(4-vinylpyridine) (P4VP) via hydrogen bonding, due to their enriched surface hydrogen bonding donors. The co-assembly method can be generally applied for preparing chemo-enzymatic catalyst within the selected database of various proteins and metal oxide clusters while the assembly units retain their structures and activities. Typically, a 2.5 nm metal oxide cluster {Mo72Fe30}, with peroxidase-like activity, are complexed with glucose oxidase (GOX) on P4VP for the catalysis against the oxidization of o-dianisidine (ODA) with the existence of glucose. Due to the synergistic effects of chemical and enzymatic catalysis, the co-assemblies show even higher ODA oxidation activity compared to GOX/catalase bi-enzymatic system, confirming the effectiveness of the co-assembly protocol for cascade catalysis and enabling its applications in rapid glucose detection and biomass conversion.

Enhanced Immune Responses by Virus-Mimetic Polymeric Nanostructures Against Infectious Diseases.

Intermittent outbreaks of global pandemic disease have spurred new sensors and medicines development for the prevention of disease spread. This perspective specifically covers recent advances, challenges, and future directions in virus-mimetic polymeric nanostructures and their application in biological medicines with a special emphasis on subunit vaccine development. With tailorable compositions and properties, polymers facilitate the ingenious design of various polymeric nanostructures. As one type of polymeric nanostructures, virus-mimetic polymeric nanostructures have been developed as an attractive platform for enhanced immune responses, since they combine the merits of polymer nanocores with the biomimetic characteristic of virus which displays multivalent epitopes on their surfaces. This perspective also provides an applicative approach to rationally design virus-mimetic polymeric platforms based on nanostructures that are self-assembled by using polymers as templates and the antigens and metal oxide clusters loaded on their surface to mimic viruses in size and surface antigenicity. Sub-200 nm virus-mimetic polymeric nanostructures are in a relatively lower level of endotoxins and can promote the antigens to elicit potent humoral and cellular immune responses against pathogenic bacteria. The promising development of virus-mimetic polymeric nanostructures will continue to protect human health from common pathogens and emerging infectious threats.

Unexpected Elasticity in Assemblies of Glassy Supra-Nanoparticle Clusters.

Granular materials, composed of densely packed particles, are known to possess unique mechanical properties that are highly dependent on the surface structure of the particles. A microscopic understanding of the structure-property relationship in these systems remains unclear. Here, supra-nanoparticle clusters (SNPCs) with precise structures are developed as model systems to elucidate the unexpected elastic behaviors. SNPCs are prepared by coordination-driven assembly of polyhedral oligomeric silsesquioxane (POSS) with metal-organic polyhedron (MOP). Due to the disparity in sizes, the POSS-MOP assemblies, like their classic nanoparticles counterparts, ordering is suppressed, and the POSS-MOP mixtures will vitrify or jam as a function of decreasing temperature. An unexpected elasticity is observed for the SNPC assemblies with a high modulus that is maintained at temperatures far beyond the glass transition temperature. From studies on the dynamics of the hierarchical structures of SNPCs and molecular dynamic simulation, the elasticity has its origins in the interpenetration of POSS-ended arms. The physical molecular interpenetration and inter-locking phenomenon favors the convenient solution or pressing processing of the novel cluster-based elastomers.

Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM.

The extent of ribosomal heterogeneity has caught increasing interest over the past few years, as recent studies have highlighted the presence of structural variations of the ribosome. More precisely, the heterogeneity of the ribosome covers multiple scales, including the dynamical aspects of ribosomal motion at the single particle level, specialization at the cellular and subcellular scale, or evolutionary differences across species. Upon solving the ribosome atomic structure at medium to high resolution, cryogenic electron microscopy (cryo-EM) has enabled investigating all these forms of heterogeneity. In this review, we present some recent advances in quantifying ribosome heterogeneity, with a focus on the conformational and evolutionary variations of the ribosome and their functional implications. These efforts highlight the need for new computational methods and comparative tools, to comprehensively model the continuous conformational transition pathways of the ribosome, as well as its evolution. While developing these methods presents some important challenges, it also provides an opportunity to extend our interpretation and usage of cryo-EM data, which would more generally benefit the study of molecular dynamics and evolution of proteins and other complexes.

Layered double hydroxide/poly(vinylpyrrolidone) coated solid phase microextraction Arrow for the determination of volatile organic compounds in water.

Today, wide variety of adsorbents have been developed for sample pretreatment to concentrate and separate harmful substances. However, only a few solid phase microextraction Arrow adsorbents are commercially available. In this study, we developed a new solid phase microextraction Arrow coating, in which nanosheets layered double hydroxides and poly(vinylpyrrolidone) were utilized as the extraction phase and poly(vinyl chloride) as the adhesive. This new coating entailed higher extraction capacity for several volatile organic compounds (allyl methyl sulfide, methyl propyl sulfide, 3-pentanone, 2-butanone, and methyl isobutyl ketone) compared to the commercial Carboxen 1000/polydimethylsiloxane coating. Fabrication parameters for the coating were optimized and extraction and desorption conditions were investigated. The validation of the new solid phase microextraction Arrow coating was accomplished using water sample spiked with volatile organic compounds. Under the optimal conditions, the limits of quantification for the five volatile organic compounds by the new solid phase microextraction Arrow coating and developed gas chromatography with mass spectrometry method were in the range of 0.2-4.6 ng/mL. The proposed method was briefly applied for enrichment of volatile organic compounds in sludge.

Matrix solid-phase dispersion coupled with hollow fiber liquid phase microextraction for determination of triazine herbicides in peanuts.

Two extraction procedures, matrix solid-phase dispersion and hollow fiber liquid-phase microextraction, were combined and applied to determine triazine herbicides in peanut samples. The results showed that the established method has high extraction efficiency and could greatly eliminate the interferences from complex matrix samples. A series of important experimental parameters were all investigated in detail. Under the optimal conditions, the developed method has the limits of detection for triazine herbicides in the range of 0.05 to 1.71 µg/kg. Moreover, it has the recovery in the range of 80.4-120.0% with relative standard deviations of equal or lower than 8.9%. The established method may have a great potential in separation, enrichment, and purification of triazines from complex fatty solid samples.

Application of metal-organic framework MIL-101(Cr) to microextraction in packed syringe for determination of triazine herbicides in corn samples by liquid chromatography-tandem mass spectrometry.

In this work, a metal-organic framework material MIL-101(Cr) was prepared and used as the sorbent for a laboratory-made semi-automated microextraction in packed syringe (MEPS). Six triazine herbicides, including desmetryn, prometon, ametryn, prometryn, atraton, and dipropetryn, that are commonly found in corn samples, were extracted and determined by the MEPS method and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Key parameters affecting the extraction efficiencies, including type of extraction solvent, type and amount of sorbent, time of ultrasonic extraction and adsorption, and type, volume and flow rate of elution solvent, were investigated. The limits of detection (LODs, S/N = 3) and quantification (LOQs, S/N = 10) for all analytes obtained by the proposed method were in the ranges of 0.01-0.12 ng g-1 and 0.04-0.35 ng g-1, respectively, which were far lower than that of reported methods. The findings indicated that the proposed semi-automated MEPS method was easy and efficient for the extraction of triazine herbicides in corn samples.

Packed hybrids of gold nanoparticles and layered double hydroxide nanosheets for microextraction of triazine herbicides from maize.

This work describes a nanohybrid material consisting of gold nanoparticles (AuNPs) and nanosheets of layered double hydroxides (NLDHs) of Mg(II) and Al(III). Mono-disperse AuNPs were immobilized on the surface of the LDHs via Au-O bonding. The nanohybrid sorbent was packed in an organic filter along with a syringe and applied to the microextraction of triazine herbicides with the help of an injection pump. The collected hexane eluate was concentrated and directly injected into a HPLC column for quantification. The effects of the amount of Au/LDH nanohydrobrids, type, flow rate, volume of washing and eluting solvent were optimized. The method was validated by detecting four triazine herbicides (prometryn, atrazine, terbumeton and secbumeton) in spiked maize. The limits of detection range between 35 and 108 pg g-1. The relative standard deviations range from 1.0-6.9% for repeatability and 4.6-7.8% for reproducibility (for n = 5). Graphical abstract Schematic presentation of a nanohybrid material consisting of gold nanoparticles and nanosheets of layered double hydroxides of Mg(II) and Al(III) (Au/LDH) for use as an adsorbent for microextraction in a packed syringe. Organic filter heads were used as the container of Au/LDHs nanohybrids, and were connected with the syringes installed on the injection pump for the semi-automatic microextraction and preconcentration of triazines in maize.

Magnetic solid-phase extraction of triazine herbicides from rice using metal-organic framework MIL-101(Cr) functionalized magnetic particles.

The metal-organic framework (MOF) functionalized magnetic graphene oxide/mesoporous silica composites (Fe3O4@SiO2-GO/MIL-101(Cr)) were synthesized and utilized as magnetic solid-phase extraction (MSPE) adsorbent for the extraction of seven triazine herbicides (terbuthylazine, secbumeton, terbumeton, atraton, atrazine, prometon and trietazine) in rice samples. Several experimental parameters, including type and volume of extraction solvent, amount of MIL-101(Cr), extraction time, volume of desorption solvent and desorption time were investigated and optimized. The limits of detection (LODs) of seven triazine herbicides obtained by using the proposed MSPE method combined with high performance liquid chromatography (HPLC) were in the range of 0.010-0.080µgkg-1. The recoveries of the triazine herbicides in spiked rice samples ranged from of 83.9-103.5% with the relative standard deviations lower than 8.7%. The intra and inter-day (n = 6) precisions for all triazine herbicides at the spiked level of 100.0µgkg-1 were 1.4-5.9% and 2.6-7.8%, respectively.

Ionic-liquid-functionalized zinc oxide nanoparticles for the solid-phase extraction of triazine herbicides in corn prior to high-performance liquid chromatography analysis.

Zinc oxide nanoparticles have recently been used as effective adsorbent materials for sample pretreatment in analytical chemistry because of their excellent properties, such as high specific surface area, high effective porosity, non-toxicity, and ease of fabrication. In this study, the zinc oxide nanoparticles functionalized by an ionic liquid, 1-carboxyethyl-3-methylimidazolium chloride, were fabricated and used as the adsorbent for the solid phase extraction of five triazine herbicides in corn for the first time. High-performance liquid chromatography was employed for the determination of these triazine herbicides. Several experimental parameters affecting the extraction efficiency were investigated, including the volume of extraction solvent, the extraction time, the type of extraction solvent and elution solvent, the amount of absorbent, and the volume of elution solvent. By using the proposed method, low limits of detection and quantification for all the five triazine herbicides were obtained between 0.71-1.08 and 2.67-3.64 ng/g, respectively. Recoveries of the proposed method range from 89.05 to 100.33% with intra- and inter-day relative standard deviations lower than 8.45%. The calibration curves are linear in the concentration range of 0.005-1.00 µg/g with the correlation coefficient higher than 0.9954.

3D fabrication and characterization of phosphoric acid scaffold with a HA/ß-TCP weight ratio of 60:40 for bone tissue engineering applications.

A key requirement for three-dimensional printing (3-DP) at room temperature of medical implants depends on the availability of printable and biocompatible binder-powder systems. Different concentration polyvinyl alcohol (PVA) and phosphoric acid solutions were chosen as the binders to make the artificial stent biocompatible with sufficient compressive strength. In order to achieve an optimum balance between the bioceramic powder and binder solution, the biocompatibility and mechanical properties of these artificial stent samples were tested using two kinds of binder solutions. This study demonstrated the printable binder formulation at room temperature for the 3D artificial bone scaffolds. 0.6 wt% PVA solution was ejected easily via inkjet printing, with a supplementation of 0.25 wt% Tween 80 to reduce the surface tension of the polyvinyl alcohol solution. Compared with the polyvinyl alcohol scaffolds, the phosphoric acid scaffolds had better mechanical properties. Though both scaffolds supported the cell proliferation, the absorbance of the polyvinyl alcohol scaffolds was higher than that of the phosphoric acid scaffolds. The artificial stents with a hydroxyapatite/beta-tricalcium phosphate (HA/ß-TCP) weight ratios of 60:40 depicted good biocompatibility for both scaffolds. Considering the scaffolds' mechanical and biocompatible properties, the phosphoric acid scaffolds with a HA/ß-TCP weight ratio of 60:40 may be the best combination for bone tissue engineering applications.