[Genetic analysis of a child with Generalized arterial calcification of infancy due to variant of ABCC6 gene].

OBJECTIVE: To explore the clinical manifestations and genetic basis for a rare case of Generalized arterial calcification of infancy (GACI). METHODS: A 44-day-old female infant who was treated at Baoding Hospital of Beijing Children's Hospital Affiliated to Capital Medical University on August 26, 2022 was selected as the study subject. Clinical data of the child was collected, and Trio-whole exome sequencing (Trio-WES), whole genome copy number variation sequencing (CNV-seq) and minigene splicing assay were carried out to analyze the pathogenicity of the variants. RESULTS: The child had presented with fever and high inflammatory indicators, for which treatment with various antibiotics was ineffective. Ultrasound had revealed extensive arterial calcification and arterial wall thickening. The child was suspected for GACI with arteritis related to the primary disease. Her fever was relieved by treatment with glucocorticoid and biological agents. Trio-WES revealed that she has harbored compound heterozygous variants of the ABCC6 gene, namely c.4404-1G>A and c.4041+5G>T, for which the latter was unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics, the variants were classified as likely pathogenic (PVS1+PM2_Supporting) and variant of unknown significance (PM2_Supporting+PM3+PP3), respectively. The result of CNV-seq was negative. And the minigene splicing assay has further verified that both variants can result in alternative splicing. CONCLUSION: For pyrexia with unknown causes and refractory to conventional treatment, it is necessary to recommend early genetic testing to avoid missed diagnosis of GACI.

The lactate dehydrogenase gene is involved in the growth and metabolism of Lacticaseibacillus paracasei and the production of fermented milk flavor substances.

Objective: Lactate dehydrogenase (ldh) in lactic acid bacteria is an important enzyme that is involved in the process of milk fermentation. This study aimed to explore the changes and effects of fermented milk metabolites in mutant strains after knocking out the ldh gene of Lacticaseibacillus paracasei. Methods: The ldh mutant ΔAF91_07315 was obtained from L. paracasei using clustered regularly interspaced short palindromic repeats technology, and we determined fermented milk pH, titratable acidity, viable count, and differential metabolites in the different stages of milk fermentation that were identified using metabolomic analysis. Results: The results showed that the growth rate and acidification ability of the mutant strain were lower than those of the wild-type strain before the end of fermentation, and analysis of the differential metabolites showed that lactate, L-cysteine, proline, and intermediate metabolites of phenylalanine, tryptophan, and methionine were downregulated (P < 0.05), which affected the growth initiation rate and acidification ability of the strain. At the end of fermentation (pH 4.5), the fermentation time of the mutant strain was prolonged and all differential metabolites were upregulated (P < 0.05), including amino acids and precursors, acetyl coenzyme A, and other metabolites involved in amino acid and fatty acid synthesis, which are associated with the regulation of fermented milk flavors. In addition, riboflavin was upregulated to promote the growth of the strain and compensate for the growth defects caused by the mutation. Conclusion: Our data established a link between the AF91_07315 gene and strain growth and metabolism and provided a target for the regulation of fermented milk flavor substances.

A newborn with coffin-siris syndrome.

Coffin-Siris syndrome (CSS) is a rare congenital genetic syndrome, a multisystem disease related to congenital abnormalities, that manifests with abnormal features, causes repeated infections and is associated with developmental delays. Here, we report a newborn male with CSS from Baoding in the Hebei Province of China.

In vitro Intervention of Lactobacillus paracasei N1115 Can Alter Fecal Microbiota and Their SCFAs Metabolism of Pregnant Women with Constipation and Diarrhea.

In vitro fermentation was used to evaluate the possible effects of intervention with Lactobacillus paracasei N1115 (LP N1115) on gut microbiota and metabolite shortchain fatty acids (SCFAs) in pregnant women with constipation and diarrhea. Feces were collected from pregnant women and fermented by YCFA medium to profile the changes in the gut microbiota before and after intervention with LP N1115 using 16SrRNA sequencing. At the same time, the changes in several specific bacteria were detected using quantitative real-time PCR (qPCR) and the SCFAs in fermentation were detected using gas chromatography (GC) for each subject to determine the effect of the intervention. In vitro intervention with LP N1115 significantly increased the relative abundances of Lactobacillus, Faecalibacterium prausnitzii, and Bifidobacterium in constipated pregnant women and reduced the contents of acetic acid, propanoic acid. Moreover, 16S rRNA gene analysis showed that LP N1115 also reduced the relative abundance of Clostridium_XI. The results of this study suggest that LP N1115 might increase the content of beneficial bacteria and reduce the relative abundance of pathogenic bacteria, which might be beneficial to gut health in pregnant women.

Detection of viable Lacticaseibacillus paracasei in fermented milk using propidium monoazide combined with quantitative loop-mediated isothermal amplification.

To quantify viable probiotic Lacticaseibacillus paracasei (L. paracasei) in fermented milk accurately and quickly, propidium monoazide combined with quantitative loop-mediated isothermal amplification (PMA-qLAMP) was applied. The optimal PMA treatment conditions for treating a L. paracasei suspension were determined using an orthogonal test to eliminate the DNA amplification of 108 CFU/mL of dead L. paracasei. Primers were designed based on the species-specific gyrB gene of L. paracasei. A phylogenetic tree based on the gyrB gene showed that L. paracasei clustered on the same branch with 91% support. Compared with the 16 strains commonly found in fermented milk, three strains of L. paracasei showed positive PMA-qLAMP results, and the melting temperature was approximately 82.4°C. There was a linear relationship (R2 = 0.9983) between the Ct values and the logarithm of the concentration of viable bacteria. The PMA-qLAMP detection limit for the L. paracasei artificially added to fermented milk was 7.3 × 102 CFU/mL. There was no significant difference between the logarithm values of the concentration of viable L. paracasei of 50 fermented milk samples within shelf life using the PMA-qLAMP and plate count methods (P > 0.01). PMA-qLAMP is specific and accurate for obtaining reliable results faster than when using plate counts.

Composition Optimization and Microstructure Design in MOFs-Derived Magnetic Carbon-Based Microwave Absorbers: A Review.

Magnetic carbon-based composites are the most attractive candidates for electromagnetic (EM) absorption because they can terminate the propagation of surplus EM waves in space by interacting with both electric and magnetic branches. Metal-organic frameworks (MOFs) have demonstrated their great potential as sacrificing precursors of magnetic metals/carbon composites, because they provide a good platform to achieve high dispersion of magnetic nanoparticles in carbon matrix. Nevertheless, the chemical composition and microstructure of these composites are always highly dependent on their precursors and cannot promise an optimal EM state favorable for EM absorption, which more or less discount the superiority of MOFs-derived strategy. It is hence of great importance to develop some accompanied methods that can regulate EM properties of MOFs-derived magnetic carbon-based composites effectively. This review comprehensively introduces recent advancements on EM absorption enhancement in MOFs-derived magnetic carbon-based composites and some available strategies therein. In addition, some challenges and prospects are also proposed to indicate the pending issues on performance breakthrough and mechanism exploration in the related field.

Space-Confined Synthesis of Core-Shell BaTiO3@Carbon Microspheres as a High-Performance Binary Dielectric System for Microwave Absorption.

Binary dielectric composites are viewed as a kind of promising candidate for conventional magnetic materials in the field of microwave absorption. Herein, we demonstrate the successful fabrication of core-shell BaTiO3@carbon microspheres through a space-confined strategy. The electromagnetic properties of BaTiO3@carbon microspheres can be easily tailored by manipulating the relative content of carbon shells. It is confirmed that dielectric loss of these composites mainly benefits from conductivity loss, dipole orientation polarization, and interfacial polarization, and the core-shell configuration shows its positive contribution to the reinforcement of interfacial polarization. When the content of carbon shells is optimized, the as-obtained composite will display excellent microwave-absorption performance due to decent attenuation and well-matched impedance. The strongest reflection loss can reach up to -88.5 dB at 6.9 GHz with the absorber thickness of 3.0 mm, and the qualified bandwidth below -10.0 dB covers 9.0-12.0 GHz, when the thickness is designated at 2.0 mm. Such a performance in the X band is superior to those of most typical binary dielectric systems. More importantly, these BaTiO3@carbon microspheres maintain good performance after being treated under high-temperature and acidic conditions for a long time, manifesting their promising prospect for practical application. It is believed that these results may be helpful for the development of multicomponent dielectric systems as high-performance microwave absorbing materials.

Fe3O4@mSiO2 core-shell nanocomposite capped with disulfide gatekeepers for enzyme-sensitive controlled release of anti-cancer drugs.

Multifunctional nanocarriers based on the magnetic Fe3O4 nanoparticle core and bis-(3-carboxy-4-hydroxy phenyl) disulfide (R-S-S-R1) modified mesoporous silica shell (Fe3O4@mSiO2@R-S-S-R1) were synthesized for cancer treatment through passive targeting and enzyme-sensitive drug release. Anti-cancer drug doxorubicin (DOX) was used as the model cargo to reveal the release behavior of the system. The drug loading system (DOX-Fe3O4@mSiO2@R-S-S-R1) retains the drug until it reaches the tumor tissue where glutathione reductase (GSH) can degrade the disulfide bonds and release the drug. Furthermore, the grafting amount of R-S-S-R1 can be used to adjust the release performance. All the release behaviors fit the Higuchi model very well and the release kinetics are predominated by disulfide bond degradation and mesoporous structure. With good bioactivity and targeted release performance, the system could play an important role in the development of intracellular delivery nanodevices for cancer therapy.

NIR light responsive core-shell nanocontainers for drug delivery.

A novel near infrared (NIR)-triggered anticancer drug delivery system has been successfully constructed. Firstly, upconversion nanoparticles (UCNPs, NaYF4:Tm,Yb@NaYF4) were synthesized as a core and mesoporous silica (mSiO2) as a shell to assemble the core-shell nanostructure (UCNP@mSiO2) as the host. Supramolecular nanovalves based on α-cyclodextrin (α-CD) torus encircling a pimelic acid thread and being held in place by a cleavable stopper (nitrobenzyl alcohol) were used as nanoscopic caps to block the pore and inhibit drug diffusion. Upon irradiation with a 980 nm laser on the nanocomposites, the emitted ultraviolet light (UV, 360 nm) photocleaved the o-nitrobenzyl (ONB) photolabile group, causing these α-CD caps to dissociate from the stalk and release the drug. The "Ladder" pulsatile release-profiles, regulated by varying the intensity and time duration of NIR irradiation, further reveal the light-triggered release performance. In addition, without NIR irradiation, few immaturities ensure the high pharmacological efficacy. Moreover, the elaborate cell experiments, by using HeLa as model cancer cells, were also carried out to reveal the good biocompatibility, fast uptake and NIR light-sensitive toxicity. Therefore, the novel NIR light-triggered drug delivery system displays great potential for cancer therapy.

Simple way to obtain pH-sensitive drug release from functional mesoporous silica materials.

A novel pH-sensitive drug release system has been synthesised by functional mesoporous silica materials. SBA-15, calcium modified SBA-15 (Ca-SBA-15) and phosphate modified SBA-15 (PO4-SBA-15) were synthesised using solvent evaporation method. It is a simple and feasible way to prepare the doping mesoporous silica materials. They show the large surface are, high pore volume and uniform pore size. Metformin hydrochloride was used as the model drug, and the control release behaviour was investigated. The functional mesoporous silica materials show the pH sensitive drug release behaviour because of the adjustable interaction between the drug molecule and the host.

pH-responsive magnetic core-shell nanocomposites for drug delivery.

Polymer-modified nanoparticles, which can load anticancer drugs such as doxorubicin (DOX), showing the release in response to a specific trigger, have been paid much attention in cancer therapy. In our study, a pH-sensitive drug-delivery system consisting of Fe3O4@mSiO2 core-shell nanocomposite (about 65 nm) and a ß-thiopropionate-poly(ethylene glycol) "gatekeeper" (P2) has been successfully synthesized as a drug carrier (Fe3O4@mSiO2@P2). Because of the hydrolysis of the ß-thiopropionate linker under mildly acidic conditions, Fe3O4@mSiO2@P2 shows a pH-sensitive release performance based on the slight difference between a tumor (weakly acid) and normal tissue (weakly alkaline). And before reaching the tumor site, the drug-delivery system shows good drug retention. Notably, the nanocomposites are quickly taken up by HeLa cells due to their small particle size and the poly(ethylene glycol) modification, which is significant for increasing the drug efficiency as well as the cancer therapy of the drug vehicles. The excellent biocompatibility and selective release performance of the nanocomposites combined with the magnetic targeted ability are expected to be promising in the potential application of cancer treatment.

An enzyme-responsive controlled release system of mesoporous silica coated with Konjac oligosaccharide.

A simple and green method to fabricate an ingenious enzyme-responsive drug controlled release system was presented. Mesoporous silica material (mSiO2) 100 nm in size was used as the host, and Konjac oligosaccharide (KOGC) was employed to seal the nanopores of mSiO2 to inhibit the drug release. Rhodamine B was used as the model cargo to reveal the release behavior of the system. The KOGC-modified mSiO2 (mSiO2@KOGC) retains the drug until it reaches the colonic environment where bacteria secrete enzymes (ß-mannanase) can degrade KOGC and make drug release. The amount of KOGC and enzyme can be used to adjust the release performance. And all the release behaviors fit the two-step Higuchi model, which predominate by KOGC degradation and mesoporous structure, respectively. With well bioactivity and selectivity, the system has potential application as an oral medicine carrier for treating intestinal disease.

pH-responsive controlled-release system based on mesoporous bioglass materials capped with mineralized hydroxyapatite.

A controlled release system with pH-responsive ability has been presented. Mesoporous bioglass (MBG) was used as the drug carrier and a spontaneous mineralization method was adopted to cap the pores of the carrier with hydroxyapatite (HAp) and to restrict the drug release. It is a simple and green method to realize the ingenious pH-sensitive controlled release. The model drug, metformin hydrochloride (MH), was loaded simultaneously with the mineralization process. Due to the degradation of HAp at acid environments, the system shows well pH-sensitive drug release ability. The release kinetics can be easily adjusted by the mineralization time and the ion concentration of media. The system is recommended as a promising candidate as a pH-sensitive vehicle for drug controlled release to low pH tissues, such as inflammatory sites and tumors.