Solid-state 17O NMR study of α-d-glucose: exploring new frontiers in isotopic labeling, sensitivity enhancement, and NMR crystallography

We report synthesis and solid-state 17O NMR characterization of α-d-glucose for which all six oxygen atoms are site-specifically 17O-labeled. Solid-state 17O NMR spectra were recorded for α-d-glucose/NaCl/H2O (2/1/1) cocrystals under static and magic-angle-spinning (MAS) conditions at five moderate, high, and ultrahigh magnetic fields: 14.1, 16.4, 18.8, 21.1, and 35.2 T. Complete 17O chemical shift (CS) and quadrupolar coupling (QC) tensors were determined for each of the six oxygen-containing functional groups in α-d-glucose. Paramagnetic Cu(ii) doping was found to significantly shorten the spin–lattice relaxation times for both 1H and 17O nuclei in these compounds. A combination of the paramagnetic Cu(ii) doping, new CPMAS CryoProbe technology, and apodization weighted sampling led to a sensitivity boost for solid-state 17O NMR by a factor of 6–8, which made it possible to acquire high-quality 2D 17O multiple-quantum (MQ) MAS spectra for carbohydrate compounds. The unprecedented spectral resolution offered by 2D 17O MQMAS spectra permitted detection of a key structural difference for a single hydrogen bond between two types of crystallographically distinct α-d-glucose molecules. This work represents the first case where all oxygen-containing functional groups in a carbohydrate molecule are site-specifically 17O-labeled and fully characterized by solid-state 17O NMR. Gauge Including Projector Augmented Waves (GIPAW) DFT calculations were performed to aid 17O and 13C NMR signal assignments for a complex crystal structure where there are six crystallographically distinct α-d-glucose molecules in the asymmetric unit.


Introduction
The element of oxygen is a key constituent of organic and biological molecules. Oxygen-containing functional groups are oen directly involved in chemical reactions including biological transformation such as enzyme catalysis. While NMR spectroscopy is a powerful technique for structural elucidation of organic and biological molecules, most NMR studies are based on detection of signals from hydrogen, carbon, nitrogen, and phosphorus atoms. While it is highly desirable to add oxygen to the list of nuclear probes available for NMR studies, two major obstacles have made it difficult to characterize NMR signals from oxygen atoms. First, the NMR-active oxygen isotope, 17 O, has an exceedingly low natural abundance (0.037%). Thus, it is usually necessary to prepare 17 O-enriched molecular systems in order to boost NMR detectability. This 17 O-labeling process can be a difficult task. Second, 17 O has a quadrupolar nucleus (I ¼ 5/2), which oen gives rise to signicantly broader NMR signals than those commonly encountered from other more NMR-friendly spin-1/2 nuclei such as 1 H, 13 C and 15 N. This quadrupole line broadening is a major roadblock to 17 O NMR applications in terms of spectral resolution. Over the last two decades, however, signicant progress has been made in demonstrating 17 O NMR as a viable tool to study organic and biological molecules in both solution and the solid state. [1][2][3][4][5][6][7] For 17 O NMR studies of biological molecules, in particular, some important developments have occurred in recent years. Zhu et al. 8 showed that it is possible to obtain solid-state 17 O NMR spectra from protein-ligand complexes where the ligand molecules are site-specically 17 Olabeled. Tang et al. 9 applied this approach to study hydrogenbonding interactions around the "oxyanion hole" in several acyl-enzymes. Zhu et al. 10,11 demonstrated a technique known as quadrupole-central-transition (QCT) NMR in obtaining highresolution 17 O NMR spectra for biological macromolecules undergoing slow tumbling motion in aqueous solution. Young et al. 12 applied the 17 O QCT method to monitor the formation of enzymatic intermediates of tryptophan synthase under active catalysis. Recently, Paulino et al. 13 reported a comprehensive 17 O solid-state NMR study of the water-carbonyl interactions in gramicidin A ion channel. The latest advancement in the eld was the work by Lin et al. 14 where they demonstrated a general approach to incorporate 17 O isotopes into recombinant proteins and reported solid-state 17 O NMR spectra for yeast ubiquitin.
In addition to the abovementioned new applications, there have also been recent developments in solid-state 17 O NMR methodology. One particular area of interest is concerned with heteronuclear correlation solid-state NMR spectroscopy between 17 O and other nuclei such as 1 H, 13 C, and 15 N. [15][16][17][18][19] For example, Hung et al. 19 reported a new 3D D-RINEPT/DARR OCC experiment where overlapping 17 O NMR signals can be completely separated in the 13 C dimension. Another highly promising direction is to use dynamic nuclear polarization (DNP) to enhance 17 O NMR signals for organic and biological molecules. [20][21][22][23] Currently, most DNP-enhanced 17 O NMR studies were performed at low or moderate magnetic elds (#14.1 T) to study inorganic materials; it would be highly benecial for the study of organic and biological molecules if DNP for 17 O becomes feasible at higher magnetic elds. 24 While fundamental 17 O NMR data on chemical shi (CS) and electric-eld-gradient (EFG) tensors have been reported for many oxygen-containing organic functional groups, there are still many unexplored classes of organic compounds for which little is known about their 17 O NMR tensor properties. One notable example is concerned with carbohydrates. Carbohydrates are an important class of oxygen-rich organic molecules of biological signicance. However, solid-state 17  To further explore synthetic procedures and solid-state 17 O NMR for unprotected carbohydrate compounds, we selected Dglucose as an initial target (Scheme 1). In this work, we report synthesis of a total of six site-specically 17 O-labeled D-glucose compounds and their full solid-state 17 O NMR characterization. For the latter part, because crystallization of D-glucose into a pure anomeric form (a or b) oen encounters low yields, we decided to prepare all solid samples of D-glucose in the form of a D-glucose/NaCl/H 2 O (2/1/1) cocrystal. This cocrystal is known to contain exclusively a-D-glucose and can be readily prepared in crystalline form with near 100% yields. [29][30][31] Throughout this work, we will use "a-D-glucose" as a shorthand name for the a-Dglucose/NaCl/H 2 O (2/1/1) cocrystal.
Another objective of the present work is to demonstrate utilization of the current state-of-the-art solid-state 17 O NMR technologies achieving unprecedented sensitivity and spectral resolution for organic and biological molecules. To this end, we explore the following three areas. First, we perform solid-state 17 O NMR at multiple magnetic elds including an ultrahigh magnetic eld of 35.2 T. 28 Second, we investigate the effect of paramagnetic doping in shortening spin-relaxation times for 17   labeling of the O5 atom, we utilize a combined oxidation/ exchange/reduction method starting from 1,2-O-isopropylidene-D-glucofuranurono-6,3-lactone as illustrated in Scheme 2. Aer oxidation of the OH group by chromium trioxide, 37 17 O-labels are introduced onto the keto group from 17 O-water via an acid-catalyzed hydration/dehydration process (or keto/gem-diol exchange). Then, reduction with NaBH 4 converts the keto group back to the hydroxyl group. 38 Finally, removal of protecting groups allows the furanose/pyranose equilibrium to occur, producing [5-17 O]-D-glucose. 39 Full details of the synthetic procedures and compound characterization are provided in the ESI. †

Preparation of solid samples
As mentioned above, because crystallization of D-glucose into the pure a (or b) form is oen associated with low yields, we prepared all solid samples of 17 O-labeled D-glucose as a Dglucose/NaCl/H 2 O (2/1/1) cocrystal where all D-glucose molecules are in the a-form. 29 The D-glucose/NaCl/H 2 O (2/1/1) cocrystal was readily prepared by adding solid NaCl to aqueous solution of D-glucose followed by lyophilization. A solid sample was prepared as an equal molar mixture of   17 O chemical shi referencing (d ¼ 0 ppm). All spectral simulations were performed with DMt. 40 Solid-state 17 O NMR experiments at 35.2 T were carried out on the 36 T series-connected hybrid (SCH) magnet 28 at the National High Magnetic Field Laboratory (NHMFL, Tallahassee, Florida, USA) with a Bruker Avance NEO console. A singleresonance 3.2 mm MAS probe with an external eld regulation circuit designed and constructed at the NHMFL was used with pencil-type ZrO 2 rotors spinning at a MAS frequency of 16 kHz. A Hahn-echo sequence was used with 5 and 10 ms pulses (with 16.7 kHz rf eld) and a recycle delay of 0.1 s.
Solid-state 17 O and 13 C NMR experiments were also performed on a Bruker NEO-800 (18.8 T) at the Bruker application lab (Fällanden, Switzerland) with a broadband 3.2 mm CPMAS CryoProbe. The sample spinning was 15 kHz. The 17 O rf eld was about 64 kHz, which gave an effective 90 pulse of 1.3 ms for the CT. The 1 H decoupling eld was 83 kHz. An apodization weighted sampling (AWS) scheme 41 was used for collecting 2D 17 O shied-echo 3QMAS data. For the 13 C refocused INADE-QUATE experiment, the 13 C 90 pulse was 5.0 ms. The spectral width in the F 1 dimension was 7.5 kHz. A frequency swept TPPM 1 H decoupling (83 kHz) scheme was applied during data acquisition.

Computational details
All quantum chemical calculations were performed using the CASTEP code 42 (version 2019) together with BIOVIA's Materials Studio. CASTEP employs DFT using the plane-wave pseudopotential approach. The generalized gradient approximation with either the Perdew-Burke-Ernzerhof 43 or revised Perdew-Burke-Ernzerhof (rPBE) 44 exchange correlation functionals was chosen. First, geometry optimization was performed employing the Broyden-Fletcher-Goldfarb-Shanno (BFGS) algorithm together with OTFG on-the-y ultraso pseudopotentials (version 2017R2), a cut-off energy of 598.7 eV and a k-point grid with a maximum separation of 0.071Å À1 . We also tested the treatment of dispersion interactions by using the two-body force-eld method of Grimme (D2) (ref. 45) with a reparameterized damping function (s6 ¼ 1.0; d ¼ 3.25 or d ¼ 5.0) 46,47 in geometry optimizations. Subsequently, the NMR parameters were calculated using the Gauge Including Projector Augmented Waves (GIPAW) method implemented in the NMR module of CASTEP. [48][49][50] In this work, a total of four sets of GIPAW DFT computations were performed and they are denoted as: (1) PBE, (2) rPBE, (3) rPBE-D2 (d ¼ 3.25), and (4) rPBE-D2 (d ¼ 5.0). However, because these four methods produced essentially the same results, we will focus on the results obtained with the PBE method and report the complete results from all four methods in the ESI. †

Results and discussion
Determination of 17 O NMR tensors in a-D-glucose Fig. 1 shows the solid-state 17 O NMR spectra obtained for all six site-specically 17 O-labeled D-glucose compounds. In each 17 O MAS NMR spectrum, a well-dened powder line shape was observed, which is known to arise from the second-order quadrupole interaction. In general, second-order quadrupole interactions are inversely proportional to the applied magnetic eld. However, as seen from Fig. 1, even at 21.1 T, second-order quadrupole interactions cause a line broadening on the order of 100 ppm. This is because the oxygen-containing functional groups in D-glucose (hydroxyl and ether groups) are known to experience rather large 17 O nuclear quadrupole interactions. It is also immediately clear that the relatively small 17 O chemical shi variations among the six oxygen-containing groups in Dglucose can be easily obscured by such second-order quadrupole broadenings (vide infra). In each case, an analysis of the observed powder line shape obtained under MAS conditions allowed us to obtain three 17 O NMR parameters: d iso , C Q , and h Q . Complete experimental results are listed in Table 1.
When the solid-state 17 O NMR experiments are performed for stationary (non-spinning) powder samples, even broader powder line shapes are observed, as also seen from Fig. 1. At 14.1 T, each static powder line shape spans about 700 ppm, which is reduced to roughly 300 ppm at 21.1 T. This is because now both 17 O CS and QC tensors contribute to the static powder line shape. The interplay between the two NMR tensors is responsible for the observed eld dependence of the static 17 O NMR spectra. From an analysis of these static powder line shapes, we were able to obtain the principal components of the 17 O CS tensor and their relative orientations with respect to the 17 O QC tensor. All experimental 17 O NMR tensor parameters determined for the six oxygen atoms in a-D-glucose are summarized in Table 1. In general, the values of jC Q ( 17 O)j found in a-D-glucose are about 8-10 MHz with h Q close to 1. These parameters are similar to those previously reported for protected carbohydrate compounds, 25 D-glucosamine, 26 and several other related functional groups such as hemiacetal/hemiketal, 51,52 gem-diol, 53 hydroxyl, 54 and phenolic groups. [55][56][57] Because the six oxygen-containing functional groups in a-Dglucose are very similar, their 17  To aid the interpretation of experimentally determined 17 O NMR tensor parameters, we performed extensive GIPAW DFT computations. As mentioned earlier, the choice of making Dglucose/NaCl/H 2 O cocrystal for solid-state 17 O NMR experiments was based on the considerations for having a pure anomeric form and easy preparation of crystalline samples. Now this turns into a computational challenge, because the Dglucose/NaCl/H 2 O cocrystal has a very large unit cell (trigonal that contains six crystallographically distinct glucose molecules in the asymmetric unit. 29 Careful examination of the crystal structure reveals that the six crystallographically unique Dglucose molecules form three "dimers" via Na + chelation with the O1 and O2 atoms, as depicted in Fig. 2. Furthermore, the asymmetric unit contains three water molecules, each involved  Table 1. The same set of parameters were used for each compound to simulate spectra obtained at two magnetic fields. Detailed acquisition parameters are given in the ESI. † Table 1 Experimental 17 O NMR tensor parameters obtained for a-Dglucose from a spectral analysis of data presented in Fig. 1 29 displaying one of the three Na + -chelated glucose "dimers" in the asymmetric unit. While the two a-D-glucose molecules within each dimer, A and B, are crystallographically distinct, they are nonetheless related by an approximate two-fold axis perpendicular to the page plane. The two axial ligands to complete the octahedron geometry around the Na + ion are O4 atoms from neighboring glucose "dimers", but are omitted for clarity. in hydrogen bonding with both two symmetry-related D-glucose molecules and one Cl À ion. In the original crystal structure, 29 one of the water molecules was missing a single hydrogen atom, which was added back into the structure before the geometry was optimized using DFT. As a result, all three water molecules have a similar hydrogen-bonding environment (see Fig. S6 in the ESI †). The GIPAW DFT results obtained with the PBE method for 17 O NMR parameters are listed in Table 2; complete GIPAW DFT results from all four methods are given in the ESI. † It can be seen from Table 2 that all six crystallographically independent D-glucose molecules have similar 17 O NMR parameters (vide infra). Thus, within the spectral resolution limit of the 1D 17 O MAS spectra, we can assume just one 17 O NMR signal for each oxygen position. For this reason, Fig. 3 shows comparison between experimental 17 O CS tensor parameters and "averaged" GIPAW DFT results (averaged over the six crystallographically independent glucose molecules in the asymmetric unit). Because the 17 O chemical shi anisotropies are rather small in glucose, the agreement seen in Fig. 3 is clearly satisfactory. Since the 17 O QC tensor parameters do not show much variation, we will not examine them further, except to note that the GIPAW DFT calculations are consistent with the experimental results. GIPAW DFT computations also yielded further information about the 17 O NMR tensor orientations in the molecular frame. In Fig. 4, we used TensorView 65 to display the ovaloid representation of the 17 O CS and QC tensors for the six oxygen sites in a-D-glucose. Two general types of orientation were found for the 17 O CS tensors, as seen in Fig. 4(a). For O1, O2, and O3, the  orientations in the molecular frame, the two seemingly different orientations are essentially the same. This is because the largest QC tensor or EFG tensor component (V zz ) is dened according to its absolute value so that jV zz j $ jV yy j $ jV xx j. but because this component is always very small for h Q z 1, it is hardly seen in the ovaloid representation shown in Fig. 4 Fig. 4(b) are rather similar. The link between the tensor orientation and the sign of C Q ( 17 O) was recently explained with the concept of valence p-orbital population anisotropy (VPPA). 66 Since the 17 17 O QCT signals are signicantly narrower than the MAS signals. One additional benet for studying carbohydrates at ultrahigh magnetic elds is that the oxygen sites in carbohydrates exhibit rather small 17 O chemical shi anisotropies (CSAs). As seen from Fig. 5, no signicant spinning sidebands are observed at 35.2 T. In contrast, 17 O MAS NMR signals obtained at 35.2 T from protein backbone oxygen atoms display many spinning sidebands. 14 Because the cross-relaxation between CSA and second-order quadrupole interactions becomes more important at high magnetic elds, 17 O QCT spectra will display higher resolution for carbohydrates (with small CSAs) than for proteins (with large CSAs). 67

Combination of paramagnetic doping and CPMAS CryoProbe technology
Crystalline D-glucose is known for its exceedingly long T 1 ( 1 H) values. It was observed that T 1 ( 17 O) values are also long for Dglucose compounds, hindering rapid repetition of 17 O data acquisition. One common approach that has been widely employed in cross polarization (CP)-based solid-state 13 C NMR studies is to add paramagnetic Cu(II) dopants to shorten T 1 ( 1 H). [68][69][70] In this work, we hypothesized that the same paramagnetic doping approach might be useful for 17    further increase sensitivity, we combined the paramagnetic doping with new CPMAS CryoProbe technology. It has recently been shown that a CPMAS CryoProbe provides a 3-4 times higher sensitivity for detecting 13 C and 15 N nuclei compared to a conventional MAS probe. 32 Aer the submission of this work, we learned that Michaelis and co-workers 73 also obtained some preliminary solid-state 17 O NMR data using the CPMAS Cryo-Probe. For acquiring 17 O MAS spectra for the a-D-glucose compounds, we found that the combination of paramagnetic doping and CPMAS CryoProbe yielded a sensitivity gain by a factor of 6-8. Fig. 7 shows the 2D 17 Fig. 7 is quite remarkable. Interestingly, whereas each of the O3 and O6 signals appears to split into two signals, no signal splitting was observed for the O2 and O5 signals (vide infra). We were able to t the F2-slice spectra and obtained the following 17 These values are also conrmed by the signal positions in the isotropic dimension of the 17 O 3QMAS spectrum; see ESI. † As expected, the 17 O NMR parameters for O2 and O5 are identical to those extracted from 1D MAS spectra as listed in Table 1. For O3 and O6, in contrast, the unprecedented spectral resolution offered by 2D 17 O 3QMAS spectra revealed ner spectral details. We will further discuss these new details in the next section.

Further 17 O and 13 C NMR signal assignments
As mentioned earlier, there are six crystallographically independent glucose molecules in the asymmetric unit of D-glucose/ NaCl/H 2 O cocrystal. Thus, in principle, there should be six 17 O NMR signals for each oxygen atom in this compound. However, the six crystallographically independent glucose molecules form three Na + -chelated glucose "dimers" with very similar structures. For this reason, the two different signals observed for each of the O3 and O6 groups in the 2D 17 O 3QMAS spectrum shown in Fig. 7 can be attributed to the two types of a-Dglucose molecules, A and B, within each Na + -chelated glucose "dimer". This also implies that the difference among the three "dimers" cannot be detected with the current spectral resolution. The tentative signal assignments shown in Fig. 7 were based on the GIPAW DFT calculations listed in Table 2. To further conrm this hypothesis, we decided to fully assign the solid-state 13 C NMR signals for the same a-D-glucose sample. To this end, we obtained a 2D refocused INADEQUATE NMR spectrum at the 13 C natural-abundance isotope level for the same compound using the CPMAS CryoProbe. As seen from Fig. 8, a similar signal "doubling" was indeed observed for each carbon atom. Fig. 8 also shows the 13 C NMR signal assignment for Molecules A and B, based on GIPAW DFT results for 13 C chemical shis (provided in the ESI). In fact, in the 1D 13 C CPMAS spectrum shown in Fig. 8, there are also hints that smaller resonance splittings beyond the signal "doubling" are also present for C1, C2A, C3, C4, and C6B. Unfortunately, within the currently achievable spectral resolution, it is not possible to resolve all six 13 C NMR signals for each site. So, for now we focus on the chemical shi differences between Molecules A and B within the glucose "dimer". Clearly, for different carbon sites, the 13 C chemical shi differences between Molecules A and B show different patterns. We will further examine these patterns for all the carbon and oxygen atoms in a-D-glucose. Fig. 9 shows a comparison between experimental and GIPAW DFT results with the PBE method for both 13 C and 17 O chemical shis; complete GIPAW DFT results from all four methods are provided in the ESI. † The observed general agreement between experiment and computation suggests that the reported signal assignment is quite reasonable. Now we can understand why no "doubling" or "splitting" was observed for the O2 and O5 signals in the 17 O 3QMAS spectra shown in Fig. 7. As seen from Fig. 9, the GIPAW DFT calculations predict that the 17 O chemical shi difference between Molecules A and B is indeed rather small for O2 and O5 (<3 ppm). It is also evident from Fig. 9 that the 17 O chemical shi is a much more sensitive probe than the 13 C chemical shi to any structural variation. In practice, however, the generally lower spectral resolution encountered in 17 O NMR oen makes it difficult to fully utilize such sensitivity.
On the other hand, it is also not difficult to imagine that, in some cases, the superior sensitivity of 17 O NMR to molecular structure and chemical bonding can produce information that is unobtainable by 13 C NMR. Ideally, one should utilize all available magnetically-active nuclei in a molecular system as a general approach of "NMR crystallography". 74 Now, what are the reasons for the 17 O chemical shi differences between Molecules A and B to show the patterns displayed in Fig. 9? Why do the O2 and O5 atoms between Molecules A and B exhibit very similar 17 O chemical shis (within 2 ppm), but the O3 and O6 atoms have so different values (by more than 10 ppm)? To link the structural features to these spectral characteristics, we will need to further examine the crystal structure of the D-glucose/NaCl/H 2 O cocrystal. Fig. 10 summarizes the hydrogen-bonding and ion-coordination environments around the O2, O5, O3 and O6 atoms in Molecules A and B. Clearly, the O2 and O5 atoms have essentially the same hydrogen-bonding and ion-coordination environments between Molecules A and B. In both Molecules A and B, the O2 atom forms a hydrogen bond of the O-H/O type and is also coordinated to a Na + ion. In sharp contrast, the O3 and O6 atoms display quite different hydrogen-bonding environments between Molecules A and B. As seen from Fig. 10 Fig. 10. Thus, the unprecedented resolution in the 2D 17 O 3QMAS spectra allowed us to detect a subtle structural difference between the two crystallographically distinct molecules. More specically, we found that  Comparison between observed and GIPAW DFT calculated (a) 13 C and (b) 17 O chemical shift differences between Molecules A and B in a-D-glucose. In (b), because the line width observed in the 3Q isotropic dimension for the O2 and O5 3QMAS signals was about 5 ppm, the upper limit of any potential signal splittings for O2 and O5 was estimated to be 2 ppm.
replacement of a neutral O-H/O hydrogen bond by a stronger ionic O-H/Cl À hydrogen bond causes an increase in d( 17 O) by ca. 10-14 ppm. Once again, this nding illustrates the remarkable sensitivity of 17 O NMR parameters to hydrogen bonding interactions. Interestingly, the GIPAW DFT calculations showed that the protons attached to O3B and O6B are also signicantly deshielded by 2-3 ppm, due to the stronger hydrogen bonding, than the corresponding protons attached to O3A and O6A.

Conclusions
We have carried out a comprehensive solid-state 17 O NMR study for a-D-glucose. In this work, a total of six site-specically 17 Olabeled a-D-glucose compounds were synthesized. The 17 O CS and QC tensors were determined for each of the six oxygen sites in a-D-glucose from an analysis of solid-state 17 O NMR spectra obtained at multiple magnetic elds. This is the rst case where all oxygen-containing functional groups in a carbohydrate molecule are site-specically 17 O-labeled and have their 17 O NMR tensors fully characterized. We found that paramagnetic Cu(II) doping can signicantly shorten the T 1 ( 17 O) values for solid a-D-glucose samples, making it possible to rapidly collect 17 O NMR data. By combining the paramagnetic doping effect with the new CPMAS CryoProbe technology and apodization weighted sampling at high magnetic elds, we have achieved a signicant sensitivity boost that allowed us to obtain the rst set of 17 O 3QMAS spectra ever reported for carbohydrate compounds. The unprecedented resolution offered by 2D 17 O 3QMAS spectra permitted the detection of a subtle structural difference for a single hydrogen bond between two types of crystallographically distinct D-glucose molecules. With the aid of GIPAW DFT calculations, all observed 17 O and 13 C NMR signals were assigned to the two groups of crystallographically distinct a-D-glucose molecules. This combined 17 O and 13 C solid-state NMR approach adds a new dimension to the eld of "NMR crystallography". Successful synthesis of site-specically 17 O-labeled D-glucose also paves the way for researchers to consider 17 O NMR as a new spectroscopic tool in glucose-related research, which can range from glucose binding proteins to glucose metabolism of live cells. In a broader context, this work demonstrates that continuing advancement of solid-state 17

Conflicts of interest
There are no conicts to declare.