The lactose carrier of Escherichia coli functionally incorporated in Rhodopseudomonas sphaeroides obeys the regulatory conditions of the phototrophic bacterium

Rhodopseudomonas sphaeroides was provided with the ability to transport lactose via conjugation with a strain of Escherichia coli bearing a plasmid containing the lactose operon (including the lac Y gene, coding for the lactose carrier or M protein) and subsequent expression of the lac operon in Rps. sphaeroides (Nano, F.E. and Kaplan, S. submitted). The initial rate of lactose transport in Rps. sphaeroides was studied as a function of the light intensity and the magnitude of the proton-motive force. The results demonstrate that lactose transport is regulated by the rate of cyclic electron transfer in the same way as the endogenous transport systems.     

Strong Visible‐Light Absorption and Hot‐Carrier Injection in TiO2/SrRuO3 Heterostructures

Correlated electron oxides prove a diverse landscape of exotic materials' phenomena and properties. One example of such a correlated oxide material is strontium ruthenate (SrRuO₃) which is known to be a metallic itinerant ferromagnet and for its widespread utility as a conducting electrode in oxide heterostructures. We observe that the complex electronic structure of SrRuO₃ is also responsible for unexpected optical properties including high absorption across the visible spectrum (commensurate with a low band gap semiconductor) and remarkably low reflection compared to traditional metals. By coupling this material to a wide band gap semiconductor (TiO₂) we demonstrate dramatically enhanced visible light absorption and large photocatalytic activities. The devices function by photo‐excited hot‐carrier injection from the SrRuO₃ to the TiO₂ and the effect is enhanced in thin films due to electronic structure changes. This observation provides an exciting new approach to the challenge of designing visible‐light photosensitive materials.     

Acoustic-based chemical tools for profiling the tumor microenvironment

Acoustic-based imaging modalities (e.g. ultrasonography and photoacoustic imaging) have emerged as powerful approaches to noninvasively visualize the interior of the body due to their biocompatibility and the ease of sound transmission in tissue. These technologies have recently been augmented with an array of chemical tools that enable the study and modulation of the tumor microenvironment at the molecular level. In addition, the application of ultrasound and ultrasound-responsive materials has been used for drug delivery with high spatiotemporal control. In this review, we highlight recent advances (in the last 2–3 years) in acoustic-based chemical tools and technologies suitable for furthering our understanding of molecular events in complex tumor microenvironments.     

Mechanisms underlying the regulation of intracellular and luminal pH in vaginal epithelium

The vagina provides a characteristic low-Na⁺ and low-pH fluid microenvironment that is considered generally protective. Previous studies have shown that various types of epithelial cells harbor the capacity of intracellular pH (pHi) regulation. However, it remains elusive whether vaginal epithelium could actively regulate pHi by transporting acid–base ions. In this study, we verified that after transient exposure to NH₄Cl, the pHi values could rapidly recover from acidification via Na⁺-H⁺ exchanger (NHE), Na⁺-HCO₃⁻ cotransporter (NBC), and carbonic anhydrase in human vaginal epithelial cell line VK2/E6E7. Positive expression of the main acid–base transporters including NHE1-2, NBCe1-2, and NBCn1 mRNA was also detected in VK2/E6E7 cells. Moreover, the in vivo study further showed that interfering with the function of V-type H⁺-ATPase, NHE or NBC expressed in vagina impaired vaginal luminal pH homeostasis in rats. Taken together, our study reveals the property of pH regulation in vaginal epithelial cells, which might provide novel insights into the potential role of vaginal epithelium in the formation of the vaginal acidic microenvironment.     

l-Type amino acid transporter 1 activity of 1,2,3-triazolyl analogs of l-histidine and l-tryptophan

A series of 1,2,3-triazole analogs of the amino acids l-histidine and l-tryptophan were modeled, synthesized and tested for l-type amino acid transporter 1 (LAT1; SLC7A5) activity to guide the design of amino acid-drug conjugates (prodrugs). These triazoles were conveniently prepared by the highly convergent Huisgen 1,3-dipolar cycloaddition (Click Chemistry). Despite comparable predicted binding modes, triazoles generally demonstrated reduced cell uptake and LAT1 binding potency relative to their natural amino acid counterparts. The structure-activity relationship (SAR) data for these triazoles has important ramifications for treating cancer and brain disorders using amino acid prodrugs or LAT1 inhibitors.     

The multi-xenobiotic resistance phenotype as a tool to biomonitor the environment

Organisms use a variety of cellular mechanisms to avoid the effects of toxins. These strategies include de-toxification of putative toxins, sequestration of the toxins or the utilization of transport mechanisms to actually prevent the entry and accumulation of toxins in the cells. These toxin avoidance mechanisms, which presumably evolved in response to natural toxins, can also be used to counter the effects of anthropogenic compounds introduced into the environment by the activities of our modern society. In this article we discuss (1) the use of transport mechanism strategies to protect against toxins and (2) the possible use of these mechanisms as biomarkers indicative of exposure to man-made toxins. We will first review the characteristics of these transport mechanisms, including their biology, genetics and molecular properties and then discuss their use as biomarkers.     

Effect of temperature on glucocorticoid uptake and glucocorticoidreceptor translocation in rat thymocytes

The temperature dependence of uptake of [³H]dexamethasone by rat thymocytes in suspension and of the intracellular distribution of the bound hormone was studied as a function of time of incubation. The transport of [³H]dexamethasone was found to obey a simple solubility-diffusion mechanism. The permeability coefficient for glucocorticoid transport corresponded to values reported for other nonelectrolytes of a similar size through biological membranes. At temperatures ranging from 0 to 42 °C, the permeability coefficient increased with temperature and no maximum was observed. However, the maximum cellular uptake of the hormone varied depending on the temperature and time of incubation. Maximal uptake of [³H]dexamethasone was observed at 30 min when the reaction mixture was incubated at 30 °C; when incubated at 20 °C, maximum uptake of [³H]dexamethasone was observed at 3 h. These data were interpreted to mean that there was competition between two temperature-dependent processes, namely steroid transport and inactivation of intracellular binding sites. Intracellular hormone was observed to bind to specific sites as well as to nonspecific, presumably membranal sites. Two independent methods, one of which is based on a linear plot of uptake versus extracellular hormone concentration, gave similar values for the amount of specifically bound hormone, estimated to be 3300 molecules per cell. The binding results are in accord with the sequence of events previously proposed for the interaction of glucocorticoids with thymocytes. These events include nonspecific uptake, specific cytoplasmic binding, a highly temperature-dependent translocation into the nucleus, intranuclear binding, as well as receptor inactivation and regeneration. The amount of intracellular bound hormone and its distribution between the cytoplasmic and nuclear fractions showed no equilibrium or steady-state phenomenon throughout extended periods of incubation up to 28 h. The experiments verified kinetic equations which predicted maximum nuclear binding of the hormone at a given time, followed by an appreciable and progressive reduction in the binding of the hormone to cytoplasmic and nuclear fractions.     

神经干细胞生物制剂治疗中枢神经系统恶性肿瘤的研究进展

中枢神经系统肿瘤是一类由于神经元、胶质细胞及神经系统中其它相关细胞异常增殖及恶性转化引发的、具有侵袭性的神经系统疾病。由于发病部位常危及控制机体重要功能的中枢,传统治疗方法对原发性神经系统肿瘤的治疗效果不佳,导致该类疾病患者的临床受益有限。因此,开发更为有效的治疗性药物是该领域亟待解决的重大科学问题。神经干细胞(NSCs)是一类具有自我更新和分化的神经系统来源的成体干细胞。已有大量研究报道,NSCs对神经系统来源的肿瘤具有特异的定向迁移及浸润能力,可以将具有肿瘤杀伤活性的药物定向传递到病灶部位。因此,这一特性使得NSCs成为一种具有良好临床转化潜力的生物治疗候选制剂,为中枢神经系统恶性肿瘤的新型药物研发提供了新思路。     

The use of genomic variants to drive drug repurposing for chronic hepatitis B

BackgroundOne of the main challenges in personalized medicine is to establish and apply a large number of variants from genomic databases into clinical diagnostics and further facilitate genome-driven drug repurposing. By utilizing biological chronic hepatitis B infection (CHB) risk genes, our study proposed a systematic approach to use genomic variants to drive drug repurposing for CHB.MethodThe genomic variants were retrieved from the Genome-Wide Association Study (GWAS) and Phenome-Wide Association Study (PheWAS) databases. Then, the biological CHB risk genes crucial for CHB progression were prioritized based on the scoring system devised with five strict functional annotation criteria. A score of ≥ 2 were categorized as the biological CHB risk genes and further shed light on drug target genes for CHB treatments. Overlapping druggable targets were identified using two drug databases (DrugBank and Drug-Gene Interaction Database (DGIdb)).ResultsA total of 44 biological CHB risk genes were screened based on the scoring system from five functional annotation criteria. Interestingly, we found 6 druggable targets that overlapped with 18 drugs with status of undergoing clinical trials for CHB, and 9 druggable targets that overlapped with 20 drugs undergoing preclinical investigations for CHB. Eight druggable targets were identified, overlapping with 25 drugs that can potentially be repurposed for CHB. Notably, CD40 and HLA-DPB1 were identified as promising targets for CHB drug repurposing based on the target scores.ConclusionThrough the integration of genomic variants and a bioinformatic approach, our findings suggested the plausibility of CHB genomic variant-driven drug repurposing for CHB.