A novel amide alkaloid,bursatamide A(1),featuring an unprecedented propyl-hexahydronaphthalene carbon frame-work,was isolated from the infrequently studied sea hare Bursatella leachi,alongside a new 3-phenoxypropanenitrile alkaloid,bursatellin B(2),and twelve known compounds.The structures of 1 and 2 were elucidated through comprehensive spectroscopic data analyses,while their relative and absolute configurations(ACs)were established through total synthesis and a series of quantum chem-ical calculations,including calculated electronic circular dichroism(ECD)spectra,optical rotatory dispersion(ORD)methods,and DP4+probability analyses.Bursatamide A(1)demonstrated inhibitory effects against the human pathogenic bacteria Listeria monocyt-ogenes and Vibrio cholerae.Erythro-bursatellin B(21),a diastereoisomer of 2,exhibited notable antibacterial activity against the fish pathogenic bacterium Streptococcus parauberis FP KSP28,with an MIC90 value of 0.0472 μg·mL-1.

Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism. Notably, TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells (PBMCs) derived from SLE patients. Furthermore, TH-407b showed prominent efficacy in vivo, improved survival rate and ameliorated symptoms of SLE model mice. To obtain molecular insights into the TH-407b derivatives' inhibition mechanism, we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy (cryo-EM) method. As an atomistic resolution cryo-EM structure of the TLR family, it not only of value to facilitate structure-based drug design, but also shed light to methodology development of small proteins using EM. Significantly, TH-407b has unveiled an inhibition strategy for TLR7 via stabilizing its resting/inactivated state. Such a resting state could be generally applicable to all TLRs, rendering a useful method for targeting this group of important immunological receptors.

Since the occurrence of the first case of "egg freezing for single women" in China, it has aroused different discussions and thoughts from all walks of life. Through the ethical analysis of the four principles of bioethics, this paper found a reasonable ethical basis for single women’s egg freezing. From the perspective of favorable principle, egg freezing could temporarily preserve women’s fertility, which is conducive to women’s better realization of their own personal value and social values. From the perspective of no harm principle, no harm is relative, and the harm brought by egg freezing technology is within the acceptable and permissible range. From the perspective of justice principle, whether there is gender discriminatory in that men could freeze their sperm but women have many restrictions on egg freezing. From the principle of respect for autonomy, whether to choose egg freezing is a manifestation of women’s autonomy rights, which should be respected. This paper tried to propose corresponding solutions to the ethical and legal issues caused by the permission of egg freezing from the legal perspective, the medical ethics committee’s responsibilities, and the ethical level.

Aim To investigate the estrogenic activities of four components from pregnant mare’s urine extract. Methods The estrogenic activities of four components were assessed using two in vitro tests:the MCF-7 cell proliferation assay (E-screen test)and the luciferase transfected CHO cell gene reporter assay.In the lucifer-ase reporter gene assay,the reporter gene plasmids PGM-ERE-Luc and ERαor ERβand a control plasmid (pRL-cmv)were transiently co-transfected into CHO cells to establish an ERα-or ERβ-cell screening system which was used to measure estrogenic activity of four compounds.Results MCF-7 cells treated with HP, DHP,PT and HA significantly proliferated,thereby of-fering in vitro evidence for the estrogenic activities of HP,DHP,PT and HA,and they showed dose-depend-ent activities.Compared EC50 of PE and RPE with that of E2 ,HP,DHP,PT and HA exerted relatively weak estrogenic activities.The in vitro ER-mediated reporter gene assay revealed that HP,DHP,PT and HA dis-played estrogenic activities mediated by ERβor ERα. Compared with the EC50 of E2 ,HP,DHP,PT and HA exhibited lower estrogenic potencies.Conclusion HP, DHP,PT and HA possess weaker estrogenic activities than E2 .

Objective To explore the design of forehead flap pedicled with supratrochlear artery and shift way for aesthetic reconstruction of the nose without secondary operations for debulking.Methods Origin of blood supplies and the distributed situation of the vessel in the frontal region were studied through the internal carotid artery and the external carotid artery X-ray angiography.The frontal region existed polyphyletic blood supplies,the supratrochlear artery and the supraorbital artery set out many branches,respectively,in the level of frontal bone eyebrow plane.One constant,thicker horizontal branch from the superficial temporal artery obviously extended to the forehead median.The branches from three blood vessels mentioned above constituted the network of artery adequate in the muscle and the subcutaneous tissue level,assumed the three-dimensional distribution in the forchead region.The nasal reconstruction had been done for 9 patients with the oblique orientation designed forehead flap by using one side of supratrochlear artery as the pedicle and cutting skin paddle with the same or the opposite side of forehead flap.Results All flap survived completely with the restoration of nasal shape and functional satisfaction.Conclusion The forehead oblique orientation flap pedicled with one side supratrochlear artery is nourished by the rich blood supply.The flap can be split into two flaps:a myofascial flap and a skin flap in far part.Myofascial flap may be the good package of cartilage framework,and simultaneously split skin flap is favorable of the shape models.The flap may satisfy the demand of the nasal restoration.

Human tumor necrosis factor alpha (hTNFalpha), a pleiotropic cytokine with activities ranging from host defense mechanisms in infection and injury to severe toxicity in septic shock or other related diseases, is a promising target for drug screening. Using the SELEX (systematic evolution of ligands by exponential enrichment) process, we isolated oligonucleotide ligands (aptamers) with high affinities for hTNFalpha. Aptamers were selected from a starting pool of 40 randomized sequences composed of about 10(15) RNA molecules. Representative aptamers were truncated to the minimal length with high affinity for hTNFalpha and were further modified by replacement of 2'-OH with 2'-F and 2'-NH2 at all ribopurine positions. These modified RNA aptamers were resistant to nuclease. The specificity of these aptamers for hTNFalpha was confirmed, and their activity to inhibit the cytotoxicity of hTNFalpha on mouse L929 cells was determined. Results demonstrated that four 2'-NH2-modified aptamers bound to hTNFalpha with high affinity and blocked the binding of hTNFalpha to its receptor, thus protecting the L929 cells from the cytotoxicity of hTNFalpha. Oligonucleotide aptamers described here are potential therapeutics and diagnostics for hTNFalpha-related diseases.
Animals ; Base Pairing ; Base Sequence ; Binding Sites ; Cells, Cultured ; Humans ; Ligands ; Mice ; Oligonucleotides ; genetics ; pharmacology ; RNA ; genetics ; pharmacology ; Tumor Necrosis Factor-alpha ; antagonists & inhibitors ; genetics