Remote effects of kidney drug transporter OAT1 on gut microbiome composition and urate homeostasis.

The organic anion transporter OAT1 (SLC22A6, originally identified as NKT) is a multispecific transporter responsible for the elimination by the kidney of small organic anions that derive from the gut microbiome. Many are uremic toxins associated with chronic kidney disease (CKD). OAT1 is among a group of "drug" transporters that act as hubs in a large homeostatic network regulating interorgan and interorganismal communication via small molecules. The Remote Sensing and Signaling Theory predicts that genetic deletion of such a key hub in the network results in compensatory interorganismal communication (e.g., host-gut microbe dynamics). Recent metabolomics data from Oat1-KO mice indicate that some of the most highly affected metabolites derive from bacterial tyrosine, tryptophan, purine, and fatty acid metabolism. Functional metagenomic analysis of fecal 16S amplicon and whole-genome sequencing revealed that loss of OAT1 was impressively associated with microbial pathways regulating production of urate, gut-derived p-cresol, tryptophan derivatives, and fatty acids. Certain changes, such as alterations in gut microbiome urate metabolism, appear compensatory. Thus, Oat1 in the kidney appears to mediate remote interorganismal communication by regulating the gut microbiome composition and metabolic capability. Since OAT1 function in the proximal tubule is substantially affected in CKD, our results may shed light on the associated alterations in gut-microbiome dynamics.

The kidney drug transporter OAT1 regulates gut microbiome-dependent host metabolism.

Organic anion transporter 1 (OAT1/SLC22A6, NKT) is a multispecific drug transporter in the kidney with numerous substrates, including pharmaceuticals, endogenous metabolites, natural products, and uremic toxins. Here, we show that OAT1 regulates levels of gut microbiome-derived metabolites. We depleted the gut microbiome of Oat1-KO and WT mice and performed metabolomics to analyze the effects of genotype (KO versus WT) and microbiome depletion. OAT1 is an in vivo intermediary between the host and the microbes, with 40 of the 162 metabolites dependent on the gut microbiome also impacted by loss of Oat1. Chemoinformatic analysis revealed that the altered metabolites (e.g., indoxyl sulfate, p-cresol sulfate, deoxycholate) had more ring structures and sulfate groups. This indicates a pathway from gut microbes to liver phase II metabolism, to renal OAT1-mediated transport. The idea that multiple gut-derived metabolites directly interact with OAT1 was confirmed by in vitro transport and magnetic bead binding assays. We show that gut microbiome-derived metabolites dependent on OAT1 are impacted in a chronic kidney disease (CKD) model and human drug-metabolite interactions. Consistent with the Remote Sensing and Signaling Theory, our results support the view that drug transporters (e.g., OAT1, OAT3, OATP1B1, OATP1B3, MRP2, MRP4, ABCG2) play a central role in regulating gut microbe-dependent metabolism, as well as interorganismal communication between the host and microbiome.

Mars' plasma system. Scientific potential of coordinated multipoint missions: "The next generation".

The objective of this White Paper, submitted to ESA's Voyage 2050 call, is to get a more holistic knowledge of the dynamics of the Martian plasma system, from its surface up to the undisturbed solar wind outside of the induced magnetosphere. This can only be achieved with coordinated multi-point observations with high temporal resolution as they have the scientific potential to track the whole dynamics of the system (from small to large scales), and they constitute the next generation of the exploration of Mars analogous to what happened at Earth a few decades ago. This White Paper discusses the key science questions that are still open at Mars and how they could be addressed with coordinated multipoint missions. The main science questions are: (i) How does solar wind driving impact the dynamics of the magnetosphere and ionosphere? (ii) What is the structure and nature of the tail of Mars' magnetosphere at all scales? (iii) How does the lower atmosphere couple to the upper atmosphere? (iv) Why should we have a permanent in-situ Space Weather monitor at Mars? Each science question is devoted to a specific plasma region, and includes several specific scientific objectives to study in the coming decades. In addition, two mission concepts are also proposed based on coordinated multi-point science from a constellation of orbiting and ground-based platforms, which focus on understanding and solving the current science gaps.

A simple method for the preparation of pseudopure states in nuclear magnetic resonance quantum information processing.

The use of nuclear magnetic resonance (NMR) to carry out quantum information processing (QIP) often requires the preparation, transformation, and detection of pseudopure states. In our previous work, it was shown that the use of pairs of pseudopure states (POPS) as a basis for QIP is very convenient because of the simplicity in experimental execution. It is now further demonstrated that the product of the NMR spectra corresponding to two sets of POPS that share a common pseudopure state has the same peak frequencies as those of the common (single) pseudopure state. Examples of applying two different quantum logic gates to a 5-qubit system are given.

Selective excitation in spin systems with homogeneous broadening.

We have found that the application of a weak radio frequency (rf) pulse to a spin system with indirect spin-spin (J) couplings can produce a narrow inverted peak in spectral regions where there are many overlapping peaks. Examples of three compounds with (1)H-(1)H J couplings and one with (1)H-(13)C J couplings are given. The dependences of the signals on the frequency, duration, and amplitude of the weak rf irradiation have been studied. For an rf power of gammaB(1)/2pi=1.0 Hz, pulse widths longer than 0.25 s consistently produce inverted narrow peaks in spectral regions with unresolved peaks. An interpretation of the origin of this unusual result of selective excitation in spin systems with homogeneous broadening is given: the inverted signal observed can be considered as a cumulative effect of the weak rf irradiation acting on many uncorrelated transitions that are slightly off resonance on both sides of the irradiating frequency; the only role of the J couplings (or dipolar couplings in liquid crystals) is to produce a large number of closely spaced peaks that overlap with each other. Computer simulations of both coupled and noninteracting spin systems have been carried out, and the results support this interpretation.

The presence of long-lived spin states in organic solids with rapid molecular motions.

For organic solids with sufficiently mobile molecular segments, the application of a long and weak pulse (gammaB1/2pi approximately Hz) can yield inverted sharp peaks with linewidths of approximately 100 Hz in the 1H NMR spectra, and the use of multi-frequency weak pulses can excite multiple inverted sharp peaks. For these compounds, the normal 1H free induction decay (FID) of a static sample contains a slowly decaying part, which can be detected by acquisition delay up to about 2 ms. The presence of highly mobile molecular segments can also be identified by using a "dipolar filter."

A simple method for NMR photography.

The application of a multi-frequency weak pulse to a liquid crystal can excite narrow 1H NMR peaks at the applied frequencies. By using two-level amplitude coding, namely setting the amplitudes of some of the harmonics to zero, this method can be used to store up to 1024 bits of binary information in the liquid crystal molecules. When the information is retrieved in the form of a spectrum, which is plotted as an array of 32 or 16 segments, the stack of spectral segments reproduces a 2D input pattern quite well. This technique is called "NMR photography." The original method was a pseudo-2D technique that applies the 1024-frequency pulse in the first step, and reads the signal row-by-row in the second step. The present improvement involves subtracting two spectra obtained with the same 1024-frequency pulse but with different durations, so that the method becomes a 1D technique, with a tremendous saving of experimental time. Several examples are given to illustrate the results.

NMR implementation of a parallel search algorithm.

Recently it has been shown that the dynamics of a cluster of dipolar-coupled spins can be manipulated to store and process a large amount of information in a parallel way [Chem. Phys. Lett. 360, 161 (2002)]]. Here it is further demonstrated that it is possible to realize a cascade of parallel bitwise operations on a spin cluster so that an algorithm of parallel search can be experimentally implemented by means of nuclear magnetic resonance.