Perforating scleral vessels adjacent to myopic choroidal neovascularization achieved a poor outcome after intravitreal anti-VEGF therapy

BackgroundThis study aimed to summarize the features of perforating scleral vessels (PSVs) in patients with myopic choroidal neovascularization (CNV) (mCNV) using optical coherence tomography angiography (OCTA) and to identify the associations with the response after intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.MethodsA consecutive series of naïve patients who had mCNV and received intravitreal anti-VEGF therapy with a follow-up duration of 12 months or more were enrolled. The prevalence, location, and branches of PSVs were analyzed. Projection-resolved OCTA (PR-OCTA) was used to analyze the neovascular signals between CNV and PSVs. Best corrected visual acuity (BCVA) and central macular thickness (CMT) were measured. The proportion of CMT change relative to baseline was used to assess therapeutic response.ResultsA total of 44 eyes from 42 patients with mCNV were enrolled. PSVs were identified in 41 out of 44 eyes. Branches were identified in the PSVs of 24 eyes (57.14%), and 20 eyes did not have PSV branches (47.62%). In eight eyes (18.18%), PSVs were adjacent to mCNV, and in 36 eyes (81.82%), PSVs were not adjacent to mCNV. After anti-VEGF therapy for mCNV, BCVA increased (F = 6.119, p < 0.001) and CMT decreased (F = 7.664, p < 0.001). In the eyes where PSVs were adjacent to mCNV, BCVA improvements (F = 7.649, p = 0.009) were poor, and changes in CMT were small.ConclusionThe eyes with PSVs adjacent to mCNV showed poor therapeutic responses after intravitreal anti-VEGF therapy

Modeling the Influence of Nonclinic Visits on the Transmission of Respiratory Diseases

According to the information reflected by Anhui Center for Disease Control (Anhui CDC) in Hefei, Anhui province of China, some patients infected with respiratory diseases did not seek medical treatment (nonclinic visits) due to their strong resistance, and the influence of them on the spread of respiratory diseases has not been known. A SIS model with considering the nonclinic visits was established; a qualitative theory of the model was analyzed to obtain the basic reproduction number R0, disease-free equilibrium, endemic equilibrium, and stability of two equilibriums. Then, the model is combined with the daily number of respiratory diseases for parameter estimation and numerical simulation. Numerical simulation results showed that respiratory diseases were easy to break out in the autumn and winter and were relatively stable in the spring and summer. Through parameter estimation, the unknown parameter value was achieved and the result was obtained that the initial number of nonclinic visits is 10-11 times that of clinic visits. Finally, the result of sensitivity analysis displayed that the proportion of the number of nonclinic visits to the total number of patients has a significant influence on the final number of patients. If persons improve their resistance so that the number of nonclinic visits increases, the total number of patients will be reduced or even reduced to zero. Besides, reducing contact infection rate of disease and increasing the cure rate can also reduce the final total number of patients

Nysfungin Production Improvement by UV Mutagenesis in <i>Streptomyces noursei</i> D-3-14

Streptomyces noursei D-3-14 was taken as a starting strain and treated with UV (15 W, 30 cm) mutagenesis for 40 s for three consecutive rounds. High yielding strains were screened using chemical and biological potency determination, and the components of the fermentation products were detected using HPLC. Finally, the mutant strain Streptomyces noursei 72-22-1 with a chemical potency of 8912 (U/mL) and a biological potency of 5557 (U/mL) was obtained after the genetic stability evaluation. After optimization of the fermentation conditions, the chemical potency and biological potency of Streptomyces noursei 72-22-1 reached 14,082 U/mL and 10579 U/mL, respectively, which is 1.58 and 1.91 times those before optimization. HPLC analysis indicated that the mutant strain 72-22-1 displayed a higher content of polyfungin B. When equimolar nystatin A1, A3, and polyfungin B were tested for their fungicidal activities towards Saccharomyces cerevisiae ATCC 2061, polyfungin B exhibited a better efficacy than nystatin A1 and A3

Nysfungin Production Improvement by UV Mutagenesis in Streptomyces noursei D-3-14

Streptomyces noursei D-3-14 was taken as a starting strain and treated with UV (15 W, 30 cm) mutagenesis for 40 s for three consecutive rounds. High yielding strains were screened using chemical and biological potency determination, and the components of the fermentation products were detected using HPLC. Finally, the mutant strain Streptomyces noursei 72-22-1 with a chemical potency of 8912 (U/mL) and a biological potency of 5557 (U/mL) was obtained after the genetic stability evaluation. After optimization of the fermentation conditions, the chemical potency and biological potency of Streptomyces noursei 72-22-1 reached 14,082 U/mL and 10579 U/mL, respectively, which is 1.58 and 1.91 times those before optimization. HPLC analysis indicated that the mutant strain 72-22-1 displayed a higher content of polyfungin B. When equimolar nystatin A1, A3, and polyfungin B were tested for their fungicidal activities towards Saccharomyces cerevisiae ATCC 2061, polyfungin B exhibited a better efficacy than nystatin A1 and A3

7<i>α</i> and 7<i>β</i> Hydroxylation of Dehydroepiandrosterone by <i>Gibberella sp.</i> and <i>Absidia Coerulea</i> Biotransformation

The hydroxylation of dehydroepiandrosterone (DHEA) to 7α -hydroxy-5-androstene-17-one (7α-OH-DHEA) and 7β-hydroxy-5-androstene-17-one (7β-OH-DHEA) by Gibberella sp. CICC 2498 and Absidia coerulea CICC 41050 was investigated. The media ingredients were optimized. Single factors such as the DHEA concentration, culture time, medium volume, and inoculum rate were individually investigated to generate optimum biotransformation conditions. An orthogonal optimization process using a four-factor, three- level L9 (33) experiment was designed and performed. Finally, the maximum production of 7β-OH-DHEA from DHEA biotransformation by Absidia coerulea is 69.61%. This strategy would provide a possible way to enhance the 7β-OH-DHEA yield in the pharmaceutical industry

The crystal structure of Ac-AChBP in complex with α-conotoxin LvIA reveals the mechanism of its selectivity towards different nAChR subtypes

Abstract The α3* nAChRs, which are considered to be promising drug targets for problems such as pain, addiction, cardiovascular function, cognitive disorders etc., are found throughout the central and peripheral nervous system. The α-conotoxin (α-CTx) LvIA has been identified as the most selective inhibitor of α3β2 nAChRs known to date, and it can distinguish the α3β2 nAChR subtype from the α6/α3β2β3 and α3β4 nAChR subtypes. However, the mechanism of its selectivity towards α3β2, α6/α3β2β3, and α3β4 nAChRs remains elusive. Here we report the co-crystal structure of LvIA in complex with Aplysia californica acetylcholine binding protein (Ac-AChBP) at a resolution of 3.4 Å. Based on the structure of this complex, together with homology modeling based on other nAChR subtypes and binding affinity assays, we conclude that Asp-11 of LvIA plays an important role in the selectivity of LvIA towards α3β2 and α3/α6β2β3 nAChRs by making a salt bridge with Lys-155 of the rat α3 subunit. Asn-9 lies within a hydrophobic pocket that is formed by Met-36, Thr-59, and Phe-119 of the rat β2 subunit in the α3β2 nAChR model, revealing the reason for its more potent selectivity towards the α3β2 nAChR subtype. These results provide molecular insights that can be used to design ligands that selectively target α3β2 nAChRs, with significant implications for the design of new therapeutic α-CTxs

Development of a Radiolabeled Cyclin-Dependent Kinases 4 and 6 (CDK4/6) Inhibitor for Brain and Cancer PET Imaging

The synthesis, biochemical evaluation and radiosynthesis of a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and radioligand was performed. NT431, a newly synthesized 4-fluorobenzyl-abemaciclib, exhibited high potency to CDK4/6 and against four cancer cell lines with IC50 similar to that of the parent abemaciclib. We performed a two-step one-pot radiosynthesis to produce [18F]NT431 with good radiochemical yield (9.6 ± 3%, n = 3, decay uncorrected), high radiochemical purity (>95%), and high molar activity (>370 GBq/µmol (>10.0 Ci/µmol). In vitro autoradiography confirmed the specific binding of [18F]NT431 to CDK4/6 in brain tissues. Dynamic PET imaging supports that both [18F]NT431 and the parent abemaciclib crossed the BBB albeit with modest brain uptake. Therefore, we conclude that it is unlikely that NT431 or abemaciclib (FDA approved drug) can accumulate in the brain in sufficient concentrations to be potentially effective against breast cancer brain metastases or brain cancers. However, despite the modest BBB penetration, [18F]NT431 represents an important step towards the development and evaluation of a new generation of CDK4/6 inhibitors with superior BBB penetration for the treatment and visualization of CDK4/6 positive tumors in the CNS. Also, [18F]NT431 may have potential application in peripheral tumors such as breast cancer and other CDK4/6 positive tumors

Measurement and Analysis of Central Corneal Thickness at Different Postnatal Stages in Chinese Premature Infants

Purpose. The objective of this study was to evaluate central corneal thickness (CCT) in Chinese premature infants at different postnatal stages to study the peak point and analyze influential factors on CCT development. Methods. This was a cross-sectional study of premature infants. Initial CCT measurement was taken at 34 weeks of gestational age (GA) and at intervals until 88 weeks of postmenstrual age (PMA) was reached. The comparison and correlation analysis were carried out to access the association of CCT with gender, birth weight (BW), GA, and retinopathy of prematurity (ROP) for each PMA. The premature infants were divided into the thick CCT group and the thin CCT group according to the average CCT at 40 w. And the difference in CCT between the two groups at subsequent 52 w and 64 w was compared. Results. A total of 1726 premature infants (3463 measurements) with an average of 2.21 ± 1.57 measurements were included in this study. The CCT decreased from 34 w GA to 52 w PMA (R = 92.36, P<0.0001) and then reached a plateau (R = 2.541, P=0.3567). Male P<0.05, low BW P<0.05, and low GA P<0.05 were associated with thicker CCT at the early stage of PMA. The premature infants who had thick CCT at 40 w would have thick CCT at 52 w and 64 w accordingly. Conclusions. The CCT values of premature infants decreased over time and plateaued at 52 w PMA. Gender, BW, and GA were considered as the influential factors of CCT at the early stage of PMA. Moreover, CCT at 40 w could forecast its development trend at 52 w or 64 w after birth

From crystal structure of α-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for α3β2 nAChR

Acetylcholine binding proteins (AChBPs) are unique spatial homologs of the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), and they reproduce some pharmacological properties of nAChRs. X-ray crystal structures of AСhBP in complex with α-conotoxins provide important insights into the interactions of α-conotoxins with distinct nAChR subtypes. Although considerable efforts have been made to understand why α-conotoxin GIC is strongly selective for α3β2 nAChR, this question has not yet been solved. Here we present the structure of α-conotoxin GIC in complex with Aplysia californica AChBP (Ac-AChBP) at a resolution of 2.1 Å. Based on this co-crystal structure complemented with molecular docking data, we suggest the key residues of GIC in determining its high affinity and selectivity for human α3β2 vs α3β4 nAChRs. These suggestions were checked by radioligand and electrophysiology experiments, which confirmed the functional role of detected contacts for GIC interactions with Ac-AChBP and α3β2 nAChR subtypes. While GIC elements responsible for its high affinity binding with Ac-AChBP and α3β2 nAChR were identified, our study also showed the limitations of computer modelling in extending the data from the X-ray structures of the AChBP complexes to all nAChR subtypes