Gut virome and diabetes: discovering links, exploring therapies.

This review offers a comprehensive analysis of the intricate relationship between the gut virome and diabetes, elucidating the mechanisms by which the virome engages with both human cells and the intestinal bacteriome. By examining a decade of scientific literature, we provide a detailed account of the distinct viral variations observed in type 1 diabetes (T1D) and type 2 diabetes (T2D). Our synthesis reveals that the gut virome significantly influences the development of both diabetes types through its interactions, which indirectly modulate immune and inflammatory responses. In T1D, the focus is on eukaryotic viruses that stimulate the host's immune system, whereas T2D is characterized by a broader spectrum of altered phage diversities. Promisingly, in vitro and animal studies suggest fecal virome transplantation as a potential therapeutic strategy to alleviate symptoms of T2D and obesity. This study pioneers a holistic overview of the gut virome's role in T1D and T2D, its interplay with host immunity, and the innovative potential of fecal transplantation therapy in clinical diabetes management.

Peri-treatment adverse events of primary mediastinal non-seminomatous germ cell tumors.

Primary mediastinal non-seminomatous germ cell tumors (PMNSGCT) are rare but life-threatening thoracic cancers. We report our experience from eight patients with peri-treatment adverse events. By analyzing changes in tumor extent, serum tumor markers, and pathologies between diagnosis and transfer, those events could be attributed to postbiopsy respiratory insufficiency, growing teratoma syndrome, secondary histiocytic malignancy, and PMNSGCT progression. Subjecting patients to respiratory therapy, conventional or high-dose chemotherapy, and surgery controlled the disease, with five of the eight patients surviving disease free. These outcomes indicate that integrated appropriate and timely approaches are important in tackling peri-treatment adverse events.

Evolution of Graves' Disease during Immune Reconstitution following Nonmyeloablative Haploidentical Peripheral Blood Stem Cell Transplantation in a Boy Carrying Germline SAMD9L and FLT3 Variants.

Graves' disease, characterized by hyperthyroidism resulting from loss of immune tolerance to thyroid autoantigens, may be attributable to both genetic and environmental factors. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a means to induce immunotolerance via an artificial immune environment. We present a male patient with severe aplastic anemia arising from a germline SAMD9L missense mutation who successfully underwent HSCT from his HLA-haploidentical SAMD9L non-mutated father together with nonmyeloablative conditioning and post-transplant cyclophosphamide at 8 years of age. He did not suffer graft-versus-host disease, but Graves' disease evolved 10 months post-transplant when cyclosporine was discontinued for one month. Reconstitution of peripheral lymphocyte subsets was found to be transiently downregulated shortly after Graves' disease onset but recovered upon antithyroid treatment. Our investigation revealed the presence of genetic factors associated with Graves' disease, including HLA-B*46:01 and HLA-DRB1*09:01 haplotypes carried by the asymptomatic donor and germline FLT3 c.2500C>T mutation carried by both the patient and the donor. Given his current euthyroid state with normal hematopoiesis, the patient has returned to normal school life. This rare event of Graves' disease in a young boy arising from special HSCT circumstances indicates that both the genetic background and the HSCT environment can prompt the evolution of Graves' disease.

Wave front aberrations induced from biomechanical effects after customized myopic laser refractive surgery in finite element model.

PURPOSE: A customized myopic refractive surgery was simulated by establishing a finite element model of the human eye, after which we studied the wave front aberrations induced by biomechanical effects and ablation profile after wave front-guided LASIK surgery. METHODS: Thirty myopia patients (i.e., 60 eyes) without other eye diseases were selected. Their ages, preoperative spherical equivalent, astigmatism, and wave front aberration were then obtained, in addition to the mean spherical equivalent error range - 4 to - 8D. Afterward, wave front-guided customized LASIK surgery was simulated by establishing a finite element eye model, followed by the analysis of the wave front aberrations induced by the surface displacement from corneal biomechanical effects, as well as customized ablation profile. Finally, the preoperative and induced aberrations were statistically analyzed. RESULTS: Comatic aberrations were the main wave front abnormality induced by biomechanical effects, and the wave front aberrations induced by the ablation profile mainly included coma and secondary coma, as well as sphere and secondary-sphere aberrations. Overall, the total high-order aberrations (tHOAs), total coma (C31), and sphere ([Formula: see text]) increased after wave front-guided customized LASIK surgery. According to our correlation analyses, coma, sphere, and tHOAs were significantly correlated with decentration. Additionally, the material parameters of ocular tissue were found to affect the postoperative wave front aberrations. When the material parameters of the sclera remained constant but those of cornea increased, the induced wave front aberrations were reduced. CONCLUSION: All biomechanical effects of cornea and ablation profile had significant effects on postoperative wave front aberrations after customized LASIK refractive surgery; however, the effects of the ablation profile were more notorious. Additionally, the characteristics of biomechanical materials have influence on the clinical correction effect.

Identification of methylation-driven genes related to prognosis in clear-cell renal cell carcinoma.

With the participation of the existing treatment methods, the prognosis of advanced clear-cell renal cell carcinoma (ccRCC) is poor. More evidence indicates the presence of methylation in ccRCC cancer cells, but there is a lack of studies on methylation-driven genes in ccRCC. We analyzed the open data of ccRCC in The Cancer Genome Atlas database to obtain ccRCC-related methylation-driven genes, and then carried out pathway enrichment, survival, and joint survival analyses. More important, we deeply explored the correlation between differential methylation sites and the expression of these driving genes. Finally, we screened 29 methylation-driven genes via MethylMix, of which six were significantly associated with the survival of ccRCC patients. This study demonstrated that the effect of hypermethylation or hypomethylation on prognosis is different, and the level of methylation of key methylation sites is associated with gene expression. We identified methylation-driven genes independently predicting prognosis in ccRCC, which offers theoretical support in bioinformatics for the study of methylation in ccRCC and a new perspective for the epigenetic study of ccRCC.

Effects of the LASIK flap thickness on corneal biomechanical behavior: a finite element analysis.

BACKGROUND: It is well known that the biomechanical properties change after LASIK refractive surgery. One reason is the impact of flap creation on the residual stroma. The results have revealed that the change is closely related with the flap thickness in several studies. However, the quantitative relationships between the distributions of displacement and stress on the corneal surface and flap thickness have not been studied. The aim of the study was to quantify evaluate the biomechanical change caused by the LASIK flap. METHODS: By building a finite element model of the cornea, the displacement, the stress and the strain on the corneal surface were analyzed. RESULTS: The results showed that the corneal flap could obviously cause the deformation of the anterior corneal surface. For example, the displacement of the corneal vertex achieved 15 µm more than that without corneal flap, when the thickness of corneal flap was 120 µm thick. This displacement was enough to cause the change of aberrations in the human eyes. In the central part of the cornea, the stress on the anterior corneal surface increased with flap thickness. But the change in the stress on the posterior corneal surface was significantly less than that on the anterior surface. In addition, the stress in the central part of the anterior corneal surface increased significantly as the intra-ocular pressure (IOP) increase. Furthermore the increase of IOP had a clearly less effect on stress distribution at the edge of the cornea. Distributions of strain on the corneal surface were similar to those of stress. CONCLUSIONS: The changes in the biomechanical properties of cornea after refractive surgery should not be ignored.

Selective laser melting of titanium alloy enables osseointegration of porous multi-rooted implants in a rabbit model.

BACKGROUND: Osseointegration refers to the direct connection between living bone and the surface of a load-bearing artificial implant. Porous implants with well-controlled porosity and pore size can enhance osseointegration. However, until recently implants were produced by machining solid core titanium rods. The aim of this study was to develop a multi-rooted dental implant (MRI) with a connected porous surface structure to facilitate osseointegration. METHODS: MRIs manufactured by selective laser melting (SLM) and commercial implants with resorbable blasting media (RBM)-treated surfaces were inserted into the hind limbs of New Zealand white rabbits. Osseointegration was evaluated periodically over 12 weeks by micro-computerized tomography (CT) scanning, histological analysis, mechanical push-out tests, and torque tests. RESULTS: Bone volume densities were consistently higher in the MRI group than in the RBM group throughout the study period, ultimately resulting in a peak value of 48.41 % for the MRI group. Histological analysis revealed denser surrounding bone growth in the MRIs; after 4 and 8 weeks, bone tissue had grown into the pore structures and root bifurcation areas, respectively. Biomechanics tests indicated binding of the porous MRIs to the neobone tissues, as push-out forces strengthened from 294.7 to 446.5 N and maximum mean torque forces improved from 81.15 to 289.57 N (MRI), versus 34.79 to 87.8 N in the RBM group. CONCLUSIONS: MRIs manufactured by SLM possess a connected porous surface structure that improves the osteogenic characteristics of the implant surface.

Mechanical Fault Diagnosis of High Voltage Circuit Breakers Based on Variational Mode Decomposition and Multi-Layer Classifier.

Mechanical fault diagnosis of high-voltage circuit breakers (HVCBs) based on vibration signal analysis is one of the most significant issues in improving the reliability and reducing the outage cost for power systems. The limitation of training samples and types of machine faults in HVCBs causes the existing mechanical fault diagnostic methods to recognize new types of machine faults easily without training samples as either a normal condition or a wrong fault type. A new mechanical fault diagnosis method for HVCBs based on variational mode decomposition (VMD) and multi-layer classifier (MLC) is proposed to improve the accuracy of fault diagnosis. First, HVCB vibration signals during operation are measured using an acceleration sensor. Second, a VMD algorithm is used to decompose the vibration signals into several intrinsic mode functions (IMFs). The IMF matrix is divided into submatrices to compute the local singular values (LSV). The maximum singular values of each submatrix are selected as the feature vectors for fault diagnosis. Finally, a MLC composed of two one-class support vector machines (OCSVMs) and a support vector machine (SVM) is constructed to identify the fault type. Two layers of independent OCSVM are adopted to distinguish normal or fault conditions with known or unknown fault types, respectively. On this basis, SVM recognizes the specific fault type. Real diagnostic experiments are conducted with a real SF6 HVCB with normal and fault states. Three different faults (i.e., jam fault of the iron core, looseness of the base screw, and poor lubrication of the connecting lever) are simulated in a field experiment on a real HVCB to test the feasibility of the proposed method. Results show that the classification accuracy of the new method is superior to other traditional methods.

Effect of pupil size on residual wavefront aberration with transition zone after customized laser refractive surgery.

The analysis of the change in residual wavefront aberrations after laser refractive surgery is important for the development of visual correction technology. Based on the ablation profile for wavefront-guided refractive surgery including optical zone and transition zone, the effect of pupil size on residual wavefront aberrations was studied. The research revealed that the optical zone to pupil ratio had a significant influence on the residual wavefront aberrations. The residual spherical aberration and coma were obviously larger than other individual Zernike higher-order terms when pupil diameter was larger than the optical zone size, and they increased rapidly as the pupil size increased. In addition, when the ablation zone diameter was kept constant, the residual higher-order aberrations increased rapidly as the blend coefficient increased for a 6 mm or 7 mm pupil. Furthermore, the residual higher-order aberrations with treatment decentration were distinctly larger than those without decentration. In the achievement of the best postoperative visual performance, the design of ablation profile played a crucial role in decrease of the residual wavefront aberrations after refractive surgery, especially optical zone size and the ablation pattern of transition zone.

Wavefront aberrations caused by biomechanical effects after Small Incision Lenticule Extraction (SMILE) based on finite element analysis.

To examine wavefront aberrations induced by biomechanical effects after Small Incision Lenticule Extraction (SMILE) surgery. The three-dimensional (3D) finite element models of the human eye were established. By loading the intraocular pressure (IOP), the displacement of the anterior and posterior surface of the cornea was calculated. Then the displacement was converted into the wavefront aberrations by wave-surface fitting. The results showed that the induced wavefront aberrations were noticeable from biomechanical effects after SMILE surgery. The induced higher-order aberrations from the anterior corneal surface included spherical aberration, y-Trefoil, and x-Tetrafoil. Spherical aberration was positively correlated with corrected diopter (D), but x-Tetrafoil and y-Trefoil remained stable. The induced wavefront aberrations from the posterior corneal surface were smaller than those from the anterior corneal surface, and some of the aberrations compensated each other. With IOP increased, defocus and x-Tetrafoil from the anterior corneal surface increased, while y-Trefoil and spherical aberration decreased. The IOP only affected defocus from the posterior corneal surface. In addition, the incision size also had a distinct impact on primary x-astigmatism and x-Trefoil from the anterior corneal surface, and it had a smaller effect on the aberrations from the posterior corneal surface. Therefore, the biomechanical effects increased residual wavefront aberrations after SMILE refractive surgery.

Biomechanical Responses of Different Cap Thicknesses of Corneas After Small Incision Lenticule Extraction: Finite Element Analysis.

Purpose: This study analyzed the biomechanical responses of different corneal cap thicknesses after small incision lenticule extraction (SMILE). Methods: Individual finite element models of myopic eyes were constructed based on the clinical data. Then, four types of corneal cap thicknesses after SMILE were included for each model. The biomechanical effects of material parameters and intraocular pressure on corneas with different cap thicknesses were analyzed. Results: When the cap thickness increased, the vertex displacements of the anterior and posterior corneal surfaces decreased slightly. The corneal stress distributions demonstrated little change. Regarding wave-front aberrations caused by the displacements of the anterior surface, the absolute defocus value decreased slightly, but the magnitude of primary spherical aberration increased slightly. The horizontal coma increased, and the levels of other low-order and high-order aberrations were small and demonstrated little change. The corneal vertex displacement and wave-front aberration were significantly affected by elastic modulus and intraocular pressure, whereas the corneal stress distribution was greatly affected by intraocular pressure. There were obvious individual differences in the biomechanical responses of human eyes. Conclusions: The biomechanical difference of different corneal cap thicknesses after SMILE was small. The effect of corneal cap thickness was significantly less than that resulting from material parameters and intraocular pressure. Translational Relevance: Individual models were constructed based on the clinical data. The elastic modulus was controlled by programming to simulate its heterogeneous distribution in the actual human eye. The simulation was improved to bridge the gap between basic research and clinical care.

Thioredoxin A of Streptococcus suis Serotype 2 Contributes to Virulence by Inhibiting the Expression of Pentraxin 3 to Promote Survival Within Macrophages.

Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that can infect humans in contact with infected pigs or their byproducts. It can employ different types of genes to defend against oxidative stress and ensure its survival. The thioredoxin (Trx) system is a key antioxidant system that contributes adversity adaptation and pathogenicity. SS2 has been shown to encode putative thioredoxin genes, but the biological roles, coding sequence, and underlying mechanisms remains uncharacterized. Here, we demonstrated that SSU05_0237-ORF, from a clinical SS2 strain, ZJ081101, encodes a protein of 104 amino acids with a canonical CGPC active motif and an identity 70-85% similar to the thioredoxin A (TrxA) in other microorganisms. Recombinant TrxA efficiently catalyzed the thiol-disulfide oxidoreduction of insulin. The deletion of TrxA led to a significantly slow growth and markedly compromised tolerance of the pathogen to temperature stress, as well as impaired adhesion ability to pig intestinal epithelial cells (IPEC-J2). However, it was not involved in H2O2 and paraquat-induced oxidative stress. Compared with the wild-type strain, the ΔTrxA strain was more susceptible to killing by macrophages through increasing NO production. Treatment with TrxA mutant strain also significantly attenuated cytotoxic effects on RAW 264.7 cells by inhibiting inflammatory response and apoptosis. Knockdown of pentraxin 3 in RAW 264.7 cells was more vulnerable to phagocytic activity, and TrxA promoted SS2 survival in phagocytic cells depending on pentraxin 3 activity compared with the wild-type strain. Moreover, a co-inoculation experiment in mice revealed that TrxA mutant strain is far more easily cleared from the body than the wild type strain in the period from 8-24 h, and exhibits significantly attenuated oxidative stress and liver injury. In summary, we reveal the important role of TrxA in the pathogenesis of SS2.

Influence of Stiles-Crawford effect on visual performance after laser in situ keratomileusis.

We evaluated the impact of the Stiles-Crawford effect (SCE) on visual performance following laser in situ keratomileusis procedures. This prospective study included 71 eyes of 36 consecutive myopic patients (mean age, 20.94±3.69 years). Ocular aberrations and contrast sensitivity were measured one month after surgery. The SCE was modeled optically as a filter placed in front of the eye, and then the modulation transfer functions (MTFs) and the predicted log contrast sensitivity were calculated from the measured wavefront aberration data. Then the visual Strehl ratio for MTF (VSMTF) was calculated. The results indicated that the computed MTF with SCE were superior to that without SCE. The predicted contrast sensitivity functions were underestimated about 20% when the SCE was not taken into account for the scotopic pupil. Moreover, the measured contrast sensitivity was not significantly different from that with SCE at 6, 12, and 18 cycles/deg spatial frequencies. According to the obtained VSMTF ratio, optical qualities of all eyes were underestimated with the range from 5% (0.02 log unit) to 65% (0.22 log unit) without SCE, and the average value is 41% (0.15 log unit). When only taking higher-order aberrations into account, the predicted postoperative visual performance would be different from the real values. The evaluation of postoperative visual performance from wavefront aberrations should consider not only the compensation relationship between defocus and spherical aberration but also the SCE.

Comparison of higher-order aberration and optical quality after Epi-LASIK and LASIK for myopia.

BACKGROUND: Epipolis laser in keratomileusis (Epi-LASIK) and laser in situ keratomileusis (LASIK) are two main surgical techniques for myopia in refractive surgery at present. However, the visual outcome and optical quality after the two procedures are not clear. We conducted the current prospective study to compare ocular higher-order aberrations and evaluate optical quality after Epi-LASIK and LASIK. METHODS: Sixty-two eyes were included. Thirty-two eyes were treated using Epi-LASIK and thirty eyes using LASIK. Best-corrected visual acuity, uncorrected visual acuity, manifest refraction, and wavefront aberrations were measured and analyzed preoperatively and 4-6 months postoperatively. Wavefront aberrations were measured by Wavescan (VISX, Santa Clara, CA, USA) using a Hartmann-Shack sensor. RESULTS: The mean changes in RMS for the 5th order (S(5)) were 0.022 ± 0.009 µm and 0.050 ± 0.010 µm, which was significantly smaller in the Epi-LASIK group than in the LASIK group for a 6-mm pupil (P = 0.048, analysis of covariance). The mean changes in C (5) (-1) and C (5) (5) were significantly smaller in the Epi-LASIK group than in the LASIK group at both 3-mm and 6-mm pupil sizes (P = 0.027, 0.045 and 0.024, 0.027, analysis of covariance). Also, the changes in the contribution of coma-like and spherical-like aberration at 6-mm pupil size were statistically significantly different after both procedures (P = 0.000, randomized block design analysis of covariance). CONCLUSIONS: Both Epi-LASIK and LASIK show their own characteristics in increased higher-order aberration at smaller and larger pupil sizes, and may create different effects on optical quality for photopic (smaller pupil) and scotopic conditions (larger pupil). We speculate that the visual performance in the Epi-LASIK group may be better than in the LASIK group for the larger pupil size.

Biomechanical responses of the cornea after small incision lenticule extraction (SMILE) refractive surgery based on a finite element model of the human eye.

PURPOSE: To investigate the biomechanical responses of the human cornea after small incision lenticule extraction (SMILE) procedures, especially their effects of SMILE surgery on stress and strain. METHODS: Based on finite element analysis, a three-dimensional (3D) model of the human eye was established to simulate SMILE refractive surgery procedures. Stress and strain values were calculated by inputting the intraocular pressure (IOP). RESULTS: After SMILE refractive surgery procedures, the stress and strain of the anterior and posterior corneal surfaces were significantly increased. The equivalent stress and strain on the anterior and posterior corneal surfaces increased with increasing diopter and were concentrated in the central area, whereas the values of stress and strain at the incision site on the anterior surface of the cornea were approximately 0. Compared with the anterior corneal surface, the stress and strain of the posterior surface were larger. Increasing IOP caused an approximately linear change in stress and a nonlinear increase in corneal strain. In addition, we found that the incision sizes and direction had less of an influence on stress and strain. In summary, SMILE surgery increased the equivalent stress and strain on the human cornea. CONCLUSIONS: The equivalent stress and strain of the anterior and posterior human corneal surfaces increased after SMILE refractive surgery; these increases were particularly noticeable on the posterior surface of the cornea.

Simulated biomechanical effect of aspheric transition zone ablation profiles after conventional hyperopia refractive surgery.

We studied the effects of the aspheric transition zone on the optical wavefront aberrations, corneal surface displacement, and stress induced by the biomechanical properties of the cornea after conventional laser in situ keratomileusis (LASIK) refractive surgery. The findings in this study can help improve visual quality after refractive surgery. Hyperopia correction in 1-5D was simulated using five types of aspheric transition zones with finite element modeling. The algorithm for the simulations was designed according to the optical path difference. Wavefront aberrations were calculated from the displacements on the anterior and posterior corneal surfaces. The vertex displacements and stress on the corneal surface were also evaluated. The results showed that the aspheric transition zone has an effect on the postoperative visual quality. The main wavefront aberrations on the anterior corneal surface are defocus, y-primary astigmatism, x-coma, and spherical aberrations. The wavefront aberrations on the corneal posterior surface were relatively small and vertex displacements on the posterior corneal surface were not significantly affected by the aspheric transition zone. Stress analysis revealed that the stress on the cutting edge of the anterior corneal surface decreased with the number of aspheric transition zone increased, and profile #1 resulted in the maximum stress. The stress on the posterior surface of the cornea was more concentrated in the central region and was less than that on the anterior corneal surface overall. The results showed that the aspheric transition zone has an effect on postoperative aberrations, but wavefront aberrations cannot be eliminated. In addition, the aspheric transition zone influences the postoperative biomechanical properties of the cornea, which significantly affect the postoperative visual quality.

Therapeutic Drug Monitoring of Busulfan in Patients Undergoing Hematopoietic Cell Transplantation: A Pilot Single-Center Study in Taiwan.

(1) Background: Busulfan has been used as a conditioning regimen in allogeneic hematopoietic cell stem transplantation (HSCT). Owing to a large inter-individual variation in pharmacokinetics, therapeutic drug monitoring (TDM)-guided busulfan dosing is necessary to reduce graft failure and relapse rate. As there exists no TDM of busulfan administration for HCT in Taiwan, we conducted a pilot study to assess the TDM-dosing of busulfan in the Taiwanese population; (2) Methods: Seven patients with HCT from The Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan, received conditioning regimens consisting of intravenous busulfan and other chemotherapies. After the initial busulfan dose, blood samples were collected for busulfan TDM at 5 min, 1 h, 2 h, and 3 h. Busulfan was extracted and detected by performing stable-isotope dilution LC-MS/MS. Plasma busulfan concentration was quantified and used for dose adjustment. Potential adverse effects of busulfan, such as mucositis and hepatic veno-occlusive disease (VOD), were also evaluated; (3) Results: The LC-MS/MS method was validated with an analyte recovery of 88-99%, within-run and between-run precision of <15%, and linearity ranging from 10 to 10,000 ng/mL. Using TDM-guided busulfan dosing, dose adjustment was necessary and performed in six out of seven patients (86%) with successful engraftments in all patients (100%). Mild mucositis was observed, and VOD was diagnosed in only one patient; (4) Conclusions: This single-center study in Taiwan demonstrated the importance of busulfan TDM in increasing the success rate of HCT transplantation. It is also necessary to further investigate the optimal busulfan target value in the Taiwanese population in the future.

LncRNA CALML3-AS1 regulates chondrocyte apoptosis by acting as a sponge for miR-146a.

Chondrocyte apoptosis contributes to osteoarthritis, while miR-146a is a critical player in chondrocyte apoptosis. Our bioinformatics analysis showed that miR-146a may bind with long non-coding RNA (lncRNA) CALML3 antisense RNA 1 (CALML3-AS1). Our study was therefore carried out to investigate the interactions between lncRNA CALML3-AS1 and miR-146a in osteoarthritis. This study included 66 osteoarthritis patients who were admitted at Shanxi People's Hospital from July 2016 to June 2019. Transfections were performed to analyse gene interactions. RT-qPCR and Western blot were performed to determine the expression levels of gene and protein, respectively. Cell apoptosis of chondrocytes induced by lipopolysaccharide (LPS) was analysed by cell apoptosis assay. We found that CALML3-AS1 was downregulated, while miR-146a was upregulated in osteoarthritis. However, no significant correlation was found between them. In addition, overexpression of CALML3-AS1 or miR-146a did not affect the expression of each other. However, overexpression of CALML3-AS1 resulted in the upregulation of Smad family member 4 (Smad4), a downstream target of miR-146a. We also found that the expression of miR-146a and Smad4 were negatively correlated, while the correlation between CALML3-AS1 and smad4 was not significant. In cell apoptosis assay, overexpression of CALML3-AS1 and Smad4 resulted in decreased proliferation of chondrocytes. MiR-146a played an opposite role and reduced the effects of overexpression of CALML3-AS1 and Smad4. Therefore, CALML3-AS1 may regulate chondrocyte apoptosis by acting as a sponge for miR-146a to upregulate Smad4.

Effects of Allicin on Late Sodium Current Caused by ΔKPQ-SCN5A Mutation in HEK293 Cells.

AIM: The aim was to study the effect of Allitridum (Allicin) on the heterologous expression of the late sodium current on the ΔKPQ-SCN5A mutations in HEK293 cells, with a view to screening new drugs for the treatment of long QT syndrome type 3 (LQT3). METHODS AND RESULTS: The ΔKPQ-SCN5A plasmid was transiently transferred into HEK293 cells by liposome technology and administered by extracellular perfusion, and the sodium current was recorded by whole-cell patch-clamp technology. Application of Allicin 30 µM reduced the late sodium current (I Na,L ) of the Nav1.5 channel current encoded by ΔKPQ-SCN5A from 1.92 ± 0.12 to 0.65 ± 0.03 pA/pF (P < 0.01, n = 15), which resulted in the decrease of I Na,L /I Na,P (from 0.94% ± 0.04% to 0.32% ± 0.02%). Furthermore, treatment with Allicin could move the steady-state inactivation of the channel to a more negative direction, resulting in an increase in channel inactivation at the same voltage, which reduced the increase in the window current and further increased the inactivation of the channel intermediate state. However, it had no effect on channel steady-state activation (SSA), inactivation mechanics, and recovery dynamics after inactivation. What's more, the Nav1.5 channel protein levels of membrane in the ΔKPQ-SCN5A mutation were enhanced from 0.49% ± 0.04% to 0.76% ± 0.02% with the effect of 30 mM Allicin, close to 0.89% ± 0.02% of the WT. CONCLUSION: Allicin reduced the late sodium current of ΔKPQ-SCN5A, whose mechanism may be related to the increase of channel steady-state inactivation (SSI) and intermediate-state inactivation (ISI) by the drug, thus reducing the window current.

Whole genome sequencing of silver carp (Hypophthalmichthys molitrix) and bighead carp (Hypophthalmichthys nobilis) provide novel insights into their evolution and speciation.

The edible silver carp (Hypophthalmichthys molitrix) and bighead carp (H. nobilis), which are two of the "Four Domesticated Fish" of China, are cultivated intensively worldwide. Here, we constructed 837- and 845-Mb draft genome assemblies for the silver carp and the bighead carp, respectively, including 24,571 and 24,229 annotated protein-coding genes. Genetic maps, anchoring 71.7% and 83.8% of all scaffolds, were obtained for the silver and bighead carp, respectively. Phylogenetic analysis showed that the bighead carp formed a clade with the silver carp, with an estimated divergence time of 3.6 million years ago; the time of divergence between the silver carp and zebrafish was 50.7 million years ago. An East Asian cyprinid genome-specific chromosome fusion took place ~9.2 million years after this clade diverged from the clade containing the common carp and Sinocyclocheilus. KEGG and GO analyses indicated that the expanded gene families in the silver and bighead carp were associated with diseases, the immune system and environmental adaptations. Genomic regions differentiating the silver and bighead carp populations were detected based on the whole-genome sequences of 42 individuals. Genes associated with the divergent regions were associated with reproductive system development and the development of primary female sexual characteristics. Thus, our results provided a novel systematic genomic analysis of the East Asian cyprinids, as well as the evolution and speciation of the silver carp and bighead carp.