In this work, it is demonstrated how the correct combination of functional ligands and structural properties can form an ideal remediator for permanent Hg0 immobilization. The adsorption capacity of an amorphous molybdenum triselenide (MoSe3) nanosheet greater than 1000 mg g−1 is the highest recorded value compared to previously reported sorbents tested in a fixed‐bed reactor. Meanwhile, the uptake rate of 240 µg g−1 min−1 is also the highest recorded rate value. Mercury selenide as formed exhibits extremely low leachability when environmentally exposed. This impressive performance is primarily attributed to the appropriate layer space between the nanosheets that permeated Hg0 and the existence of diselenide (Se22−) ligands that exhibit excellent affinity toward Hg0. Thus, this work not only provides a promising trap for permanent Hg0 sequestration from industrial and domestic sources with minimum hazard but also provides a detailed illustration of using structural advantages to obtain an ideal sorbent as well as guidance for the further development of Hg0 decontamination techniques.The key challenge of vapor‐phase elemental mercury (Hg 3) sorbentAn amorphous molybdenum selenide  sequestration. After the rational design, the MoSe3 with increased interlayer space and abundant diselenide ligands shows the highest recorded performance for Hg0 capture. This work provides a new mindset for engineering a Hg0 trap using the appropriate combination of functional groups and structural properties. Moreover, the environmental stability of the final product is also an essential parameter to evaluate the feasibility of techniques. For a decent sorbent, it is important to take advantage of all of these requirements. For example, mineral sulfides (MSs) were recently found to very likely be potential sorbents for vapor‐phase Hg0 immobilization because they were capable of fully converting Hg0 into metabolically inactive and environmentally stable mercury sulfide (HgS).[qv: 6f] After adjusting the activity and accessibility of the sulfide species, molybdenum disulfide (MoS2) sheets exhibited an obvious enhanced Hg0 capture performance compared to bulky zinc monosulfide (ZnS). Recently, the uptake capacity was further increased using amorphous MoS3‐based sorbents with an abundant disulfide ligand (S22−) that exhibited a higher affinity toward Hg0 than the monosulfide (S2−) in MoS2.The techniques used for Hg0 remediator by combining different physical and chemical properties of the sorbent may derive an ideal material for permanent Hg0 sequestration. However, sorbents that include abundant functional groups exhibiting easy accessibility and high activity to simultaneously achieve a high capacity and rapid rate have rarely been realized. Even after the MSs were nanosized to achieve adequate exposure of the abundant sulfides (≥50% molar ratio), the Hg0 uptake capacity over the best MSs only reached less than 5% of its corresponding theoretical value, assuming that one mole of sulfide combines with one mole of Hg0.0, and it is imperative to develop new functional groups to break through this barrier.Previous studies have strongly indicated that the rational design of an Hg0 uptake performance, it was observed that the binding affinity constant between Hg and selenium is 106 times higher than the binding affinity constant between Hg and sulfur, but the solubility of mercury selenide (HgSe) is 103‐fold lower.2) is a promising candidate. However, MoSe2 has at least three drawbacks, i.e., the synthetic inconvenience of requiring a high temperature, relatively narrow layer spaces to exert its structural advantages to allow Hg0 in, and the lack of a diselenide ligand (Se22−) that is likely to exhibit higher affinity to Hg0 than monoselenide (Se2−).a, a>2) generally contain rich Se22− ligands.3, which is generally in an irregular phase,a can be spontaneously solidified into a nanosheet at a relatively low temperature as it is the precursor for MoSe2 and shares a similar morphology with MoSe2.a compared to the surface area of MoSe2a. Therefore, it is reasonable to speculate that MoSea would be a potential sorbent for Hg0 sequestration from industrial and domestic sources.When searching for alternatives to the previously reported groups to significantly enhance the Hga was demonstrated to be an efficient trap for permanent vapor‐phase Hg0 sequestration due to its morphologic and structural properties. The as‐derived adsorption performance reached more than 1000 mg g−1, the highest recorded value compared to previously developed sorbents tested in fixed‐bed reactors. This work not only presents a potential alternative to traditional selections as a Hg0 remediator with minimum environmental effects but also provides guidance for the future design of effective Hg0 sorbents from a new perspective.In this work, a rationally engineered amorphous MoSe22.1Figurea as synthesized. Only two weak and broad peaks were observed at 25–40o and 50–55o, which matches with the characteristic XRD peaks of amorphous MoSea reported in previous studies.a indicating its amorphism. The amorphous phase was further proven by high‐resolution transmission electronic microscopy (HRTEM) images showing that no characteristic lattice fringe was observed for MoSea, while TEM images clarified that MoSea existed in nanosheets  patterns of Mo 3d and Se 3d were recorded and are presented in Figure 4+ in MoSea, with negligible amounts of other valence states detected.a at 53.1 and 54.0 eV is designated as the Se 3d 5/2 and 3d 3/2 characteristic peaks of monoselenide (Se2−), while the Se 3d peaks at 54.2 and 55.0 eV are due to the presence of diselenide (Se22−).2− and Se22− in amorphous MoSea and that their molar ratio was nearly 1:1, giving a total charge of the Se species in MoSea of negative four (Sea4−), which matches with the total charge of the molybdenum species (Mo4+). The presence of Se22− was expected to exhibit superior affinity toward Hg0 over Se2−, similar to S22− that is superior to S2−.a was calculated based on the XPS results to be 1:3, which is helpful to derive its theoretical Hg0 adsorption capacity. Thus, amorphous MoSea is denoted as MoSe3 in the following context.2 are shown in Figure 2 (JCPD#29‐0914), which indicates that crystalline MoSe2 was successfully derived from amorphous MoSe3  planes (0.68 nm) . By contrast, the increased BET surface area of amorphous MoSe3 is probably attributed to its widened interlayer spaces (>0.6 nm), as the morphologies of the sorbents before and after annealing were negligibly changed. According to a previous study, an interlayer space of ≈0.3 nm was not adequate for Hg0 to form stable compounds, while an increased space of >0.6 nm was able to perform Hg0 chemisorption.[qv: 11b] Although the understanding of MoSe3 at the molecular level is still limited to date, its appropriate interlayer spaces may improve the accessibility of functional groups; hence, increasing its Hg0 sequestration performance.The Brunauer–Emmett–Teller (BET) surface areas of MoSe2.2Figure3 exhibited a twofold higher maximum Hg0 adsorption capacity  than that of well‐crystallized MoSe2 (740 mg g−1), although their theoretical values (QT) were not significantly different . The Qm of MoSe3 is equal to 93% of its corresponding QT, while MoSe2 only performs at a 46% ratio, further supporting our above assumptions that amorphous MoSe3 has a lattice space suitable for Hg0 permeation  surface with a binding energy of −56.9 kJ mol−1 (listed in Table S1 in the Supporting Information), while Hg0 adsorption over the MoSe3 (100) surface had a binding energy of −125.8 kJ mol−1. This difference indicates that the (100) edges are preferential for Hg0 adsorption over MoSe2, which is generally in line with the results of a previous study.0 capture between the interlayer spaces of MoSe2, which indicates that the active sites located in the space intervals are inaccessible to Hg0. This inaccessibility primarily caused the Qm of MoSe2 to be significantly inferior to its corresponding QT. On the contrary, although the molecular structure of MoSe3 remains unknown, the Qm of MoSe3 accounts for nearly 100% of its QT, indicating the interlayer spaces of amorphous MoSe3 are available for Hg0 immobilization  calculation was conducted for Hg2.3Figure3 exhibited an normalized outlet Hg0 concentration (to the inlet Hg0) concentration of less than 0.15, regardless of temperature, during the 6 h experiments. Only 1 mg of sorbent was used with a gas hourly space velocity (GHSV) of 7200 000 h−1, which is thousands of times higher than under real‐world conditions. These results indicate the superior fast kinetics of Hg0 adsorption over MoSe3. The optimal reaction temperature of 50 °C was probably because a relatively high temperature provided the reaction with more activation energy.0 sequestration.0 adsorption over crystalline MoSe2 , which was 5.5 times longer than the time required for MoSe2. From the slope of the breakthrough curves  of 0.9980, 0.9672, 0.8846, and 0.9779, respectively. Except for the pseudo‐first‐order kinetic model, the simulations by the other three models induced relatively high deviations from the experimental data. The Hg0 adsorption rate (Ra) as calculated by pseudo‐first‐order kinetics was 240 µg g−1 min−1.As shown in Figure 22− accounts for the increased Hg0 uptake rate of MoSe3 compared to MoSe2, Hg‐TPD was conducted to determine the adsorbate species on MoSe3 and MoSe2 ‐based sorbent, the adsorption capacity of MoSe3 was shown to be threefold greater, and its adsorption rate was improved by twofold. Even at 75 and 100 °C that are not the optimal operation temperature for MoSe3, MoSe3 still exhibited the highest adsorption capacities compared to the capacities of previously reported sorbents at their optimal temperatures . These improvements are mainly attributed to the rational design because: 1) the affinity between selenide/selenium and Hg0 is superior to the affinity between sulfide/sulfur and Hg0 and 3 compared to other selenide‐/selenium‐based sorbents. The excellent performance of MoSe3 for Hg0 sequestration indicates its great potential to be widely applied under real‐world conditions.The 2.53 for Hg0 adsorption, three typical flue gas atmospheres were chosen to simulate the real‐world conditions, i.e., N2 plus O2, simulated flue gas (SFG) from coal combustion flue gas and SFG from smelting flue gas. As shown in Figure2) had a negligible influence on Hg0 capture over MoSe3, which indicates that MoSe3 exhibits excellent resistance to oxidation at relatively low temperatures (50 °C). Its decent resistance toward oxidation also indicates that MoSe3 may be a promising trap for Hg0 decontamination from domestic sources.To quantitatively determine the potential of MoSe0 removal performance was slightly inhibited by coal combustion flue gas, possibly because: 2O) competed with Hg0 for active sites[qv: 27k] and/or 2 oxidized the active selenide sites into inert selenite species.0 capture from coal combustion flue gas. In an injection scenario, the sorbent is injected before the air pollution control devices with a residence time of less than 30 min.3 is still a potential sorbent for Hg0 capture from coal combustion flue gas because the Hg0 removal performance over MoSe3 was negligibly influenced by simulated SFG within 30 min with an extremely high GHSV of 7200 000 h−1.As shown in Figure 2 also had a negligible detrimental effect on Hg0 sequestration  as the adsorption liquor to transform vapor‐phase Hg0 into Hg2Cl2 solid, the performance of which is significantly inhibited by the presence of abundant SO2. This inhibitive effect is primarily attributed to SO2 being able to reduce HgCl2 and introduce redundant Hg0 into the flue gas.3 is also an ideal alternative to HgCl2 for Hg0 remediation in smelting flue gas.For simulated smelting flue gas, a high concentration of SO3 surface is ultrastable when environmentally exposed, which is manifested by its extremely low leachability  mandated by the United States Environmental Protection Agency (EPA) for classifying a material as hazardous waste.3 surface even meets the upper mercury content limit in drinking water (2.0 µg L−1) as imposed by the EPA,0 can be permanently sequestrated from a hypertoxic and volatile form into the most inert and stable form (HgSe) on MoSe3.More importantly, the as‐formed HgSe over the MoSe30 capture from various sources, the amorphous MoSe3 nanosheet synthesized by a one‐step hydrothermal method was used for the first time for permanent Hg0 sequestration. Compared to the well‐crystallized MoSe2 nanosheet, MoSe3 performed better primarily because of its abundant and accessible Se22− ligands, which exhibited excellent affinity toward Hg0. The adsorption capacity reached more than 1000 mg g−1, which is the highest recorded value compared to previously reported sorbents tested in a fixed‐bed reactor. The uptake rate reached high as 240 µg g−1 min−1 and was enhanced compared to traditional Hg0 traps by orders of magnitude. Moreover, the MoSe3 nanosheet showed excellent resistance to complicated gas atmospheres from various industrial/domestic sources, and the as‐formed adsorbate HgSe exhibited extremely low leachability when environmentally exposed. This work not only proposes an ideal sorbent for Hg0 decontamination from variable industrial and domestic sources but also provides guidance for the future design of efficient sorbents with a new mindset of morphologic and structural optimization.To realize a simultaneous high capacity and rapid rate of Hg4Sorbent Preparation: MoSe3 was prepared using a one‐step hydrothermal method. In a typical procedure, 2 mmol of sodium molybdate  was dissolved in deionized water. In a separate beaker, 6 mmol of selenium powder  was added to 15 mL of a hydrazine hydrate solution  and stirred for at least one day. Then, the Na2MoO4 solution was poured into the Se‐N2H4·H2O mixture, which was transferred into a Teflon‐lined autoclave and heated in an oven at 180 °C for 12 h. The as‐obtained black solid was separated by filtration, washed with deionized water and ethanol several times, and dried at 70 °C under vacuum for one night to produce amorphous MoSe3. For comparison, well‐crystallized MoSe2 was synthesized by annealing MoSe3 at 450 °C under pure argon (Ar) for 10 h.Sorbent Characterization: The crystallinity of the sorbents was measured by X‐ray diffraction  with two theta from 10° to 80° in Cuα (λ = 0.154 nm) radiation. A transmission electron microscope  was used to determine the morphologies of the as‐prepared sorbents. The fresh and spent sorbents were characterized by their X‐ray photoelectron spectroscopy  spectra with a C 1s binding energy value of 284.8 eV as the reference. Spent MoSe3 was obtained by pretreating fresh MoSe3 under 1.5 mg m−3 Hg0 for 120 h. The Brunauer–Emmett–Teller surface area of the sorbents was determined by the N2 adsorption and desorption method with a BET analyzer . Before BET testing, the prepared sorbents were purged in pure N2 for 4 h to obtain a clean surface.0 Adsorption Capacity and RateDetermination of the Hg: The maximum Hg0 adsorption capacities of MoSe3 and MoSe2 were determined by a nested tube reactor . The Hg0 source was placed in the bottom of the inner reactor without a lid, while the sorbent was settled on the top of the inner reactor and separated by a filter paper that was capable of permeating Hg0 but inert for Hg0 adsorption. Before the tests began, the sorbents without and with filter paper, which were denoted as Wsorbent and Win, respectively, were both weighed. Then, the Hg0 source in the sealed tube reactor was heated by an oil bath at 140 °C and held for 1 d. The Hg0 concentration reached a nearly infinite value in the sealed nested reactor and attacked every possible adsorption site on MoSe3 or MoSe2. Then, the filter paper with sorbents was taken out, and its weight (Wout) was determined again. The maximum Hg0 uptake capacity  of the sorbents was calculated by Equation 0 uptake rate must be derived by fitting breakthrough curves and requires in situ Hg0 concentration detection, a fixed‐bed reactor was used to test Hg0 capture  under pure N2. Under this condition, the temperature affected the Hg0 adsorption behavior since the temperature significantly affected the site activity (adsorption rate) and desorption behavior (desorption rate).Qe) with Qe < Qm. Thus, investigating the impact of temperature was the first step to properly define the corresponding adsorption rate. In the fixed‐bed reaction system, the total flow rate was precisely controlled by mass flow controllers (MFCs) to be 300 mL min−1. A Dynacal Hg0 permeation device (VICI Metronics) was used to produce a constant feed of Hg0 vapor. A fixed‐bed reactor made of Pyrex with an inner diameter of 1 cm was placed into a tubular furnace equipped with a temperature adjustment system to control the reaction temperature. The concentration of Hg0 was detected with a mercury analyzer  and continuously recorded by a connected computer. Before each test, the Hg0 carried by different carrier gases bypassed the reactor and was used to detect the inlet Hg0 concentration (Cin). Until the fluctuation of Cin was less than 10 µg m−3 within 30 min, Hg0 could pass through the sorbent. The as‐recorded Hg0 concentration was denoted as the outlet Hg0 concentration (Cout). Hence, the real‐time Hg0 adsorption capacity  was calculated by Equation f (m3 min−1) is the gas flow rate, m (g) is the mass of the sorbent, and t (min) is the adsorption process duration time. To obtain the equilibrium Hg0 capture capacity (Qe) in this case, t1 and t2 were denoted as zero and the time Cin = Cout (equilibrium time), respectively. Despite a relatively high Cin slightly enhances the Qe,Cin is also required for sorbents with different Qm to limit the total experimental time and avoid the flucturation of Cin. Based on the preliminary experiments, a Cin of 1.5 mg m−3 was used to significantly decrease the experimental errors resulted from dramatic Cin fluctuation in a lengthy test.As the Hg0 adsorption rate of MoSe3 was obtained by simulation with different kinetic models, i.e., a pseudo‐first‐order model, pseudo‐second‐order model, Elovich model, and Intra‐particle diffusion model. The optimal model with the highest coefficient factor (R2) was chosen to describe the kinetic behavior of Hg0 adsorption on the MoSe3 surface.Then, the Hg1) Pseudo‐first‐order modelThe pseudo‐first‐order kinetic model was based on the mass balance. The Hg adsorption rate was proportional to the difference between the equilibrium capacity and the adsorbed amount at any time, as described as followst = 0, Qt = 0k1, min−1) can be determined by fitting the adsorption breakthrough curve.Equation 2) Pseudo‐second‐order modelThe pseudo‐second‐order model considers that the surface diffusivity is inversely proportional to the square of the concentration variation on the sorbent surface, which could be described by Equation t = 0, tQ = 0k2, mg g−1 min−1) can be determined by fitting the adsorption breakthrough curve.Equation 3) Elovich model−1 min−1) represents the initial rate and β (min−1) is related to the extent of surface coverage and the activation energy for chemisorption. This equation can be modified intoThe Elovich model assumes that sorption takes place in two phases: 4) Intra‐particle diffusion modelkid (mg g−1 min−1/2) represents the intraparticle diffusion rate constant and C (mg g−1) is proportional to the boundary layer.The intraparticle diffusion model assumes that the intraparticle diffusivity is constant and that the diffusion direction is radial. The model can be interpreted by the following equationFirst Principle Calculation: Please refer to the Supporting Information, First Principle Calculation section.Mercury Temperature Programmed Desorption/Decomposition (Hg‐TPD): To identify the mercury species adsorbed on the surface of the sorbent, mercury temperature‐programmed desorption (Hg‐TPD) tests were conducted. Before the Hg‐TPD tests, MoSe3 and MoSe2 were pretreated with 1.5 mg m−3 Hg0 balanced in N2 at 50 °C for 30 min to assure that enough mercury was accumulated on the surface of the sorbent. Then, the Hg0 feed was cut off, and the Hg‐laden sorbents were purged by pure N2 at 50 °C until the outlet Hg0 concentration stably equaled zero. The Hg‐TPD tests were conducted from 50 to 450 °C with a heating rate of 10 °C min−1.0 Adsorption Activity Test under Simulated Real‐World ConditionsHg: For Hg0 removal under real‐world conditions, Hg0 generally exists in an open instead of a closed space, and the Hg0 adsorption capacity cannot reach its maximum value. Thus, the fixed‐bed reactor was selected to simulate the real‐world conditions in which the Hg0 feed continuously flows through the sorbents.2 plus 5% oxygen (O2), coal combustion flue gas, and nonferrous smelting flue gas, were adopted. The coal combustion flue gas contained 5% O2, 100 ppm nitrogen monoxide (NO), 300 ppm sulfur dioxide (SO2), 12% carbon dioxide (CO2), and 8% water vapor (H2O) carried by N2, and the smelting flue gas comprised 5% O2 plus 1.5% SO2. The different flue gas components were supplied by compressed gas cylinders containing N2, O2, SO2, CO2, and NO. Water vapor (H2O) was introduced into the reactor by a separate flow of N2. The total flow rate was precisely controlled by MFCs. Sorbent dosages of 1 mg were adopted in all experiments, which is much lower than a real‐world situation to avoid the possible influence of flue gas components being concealed by excessive sorbent used.Mercury Leaching Test: Please refer to the Supporting Information, Mercury Leaching Test section.The authors declare no conflict of interest.SupplementaryClick here for additional data file.


A growing body of evidence has suggested a protective effect on cognition of the ε2 allele of APOE. To determine if APOE ε2 is associated with protection against cognitive decline, we analyzed repeated measures of the Telephone Interview for Cognitive Status (TICS) from 2,933 Long Life Family Study subjects and 679 New England Centenarian Study subjects using a multivariable linear mixed effects model. The median age at first TICS administration was 73 . Subjects had a median of 3 TICS assessments  and a median follow-up time of 5.0 years . Carriers of the ε2/ε2 genotype had a significantly slower rate of decline in TICS score compared to the ε3/ε3 reference group . These results support a protective effect of the ε2 allele.


Antibiotics [1. We have found the error in the order of authors’ names and surnames in the article recently published in 1,2,*, Łoniewski Igor 3, Marlicz Wojciech 4Kamiński Mikołaj Which should be corrected to the following order in this paper :1,2,*, Igor Łoniewski 3 and Wojciech Marlicz 4Mikołaj Kamiński The authors would like to apologize for any inconvenience caused to the readers by these changes.


Ti3C2Tx MXenes possess a high dielectric loss tangent, which is correlated with this rapid heating under electromagnetic fields. Thermal imaging confirms that these structures are capable of extraordinary heating rates (as high as 303 K/s) that are frequency- and concentration-dependent. At high loading (and high conductivity), Ti3C2Tx MXene composites do not heat under RF fields due to reflection of electromagnetic waves, whereas composites with low conductivity do not heat due to the lack of an electrical percolating network. Composites with an intermediate loading and a conductivity between 10–1000 S m−1 rapidly generate heat under RF fields. This finding unlocks a new property of Ti3C2Tx MXenes and a new material for potential RF-based applications.Here we report for the first time that Ti MXenes are obtained by etching out the A layer from the parent Mn+1AXn phase, where M is an early transitional metal, A is a group 13 or 14 element, X is either carbon or nitrogen, and n can be integers 1, 2, or 3. Ti3C2Tx is the most studied MXene , derived from the etching and exfoliation of a parent Ti3AlC2 MAX phase. One of the compelling properties of Ti3C2Tx MXene is their high electrical conductivity, with reported values reaching 2.4 × 105 S m−1, similar to that reported for multi-layered graphene7. Based on our recent reports showing that carbon nanomaterials rapidly heat in response to RF fields, we hypothesized that Ti3C2Tx MXenes nanosheets would respond to RF fields as well8.MXenes are a family of 2D nanosheets discovered in 201120. Our group has recently reported that nanomaterials show extraordinary heating rates in response to RF fields; Sweeney et al.8 demonstrated rapid RF heating of multiwalled carbon nanotubes embedded in epoxy resin for curing industrial grade thermoset adhesives, for which RF-curing rate was localized, volumetric, and faster than conventional oven curing8.Radio frequencies (RF) lie between 3 kHz to 300 GHz on the electromagnetic spectrum. Successful use of RF has also been demonstrated for ablation of cancerous tumors, heating food (in lieu of microwaves), curing epoxy to weld and bond materials together, and testing quality of carbon nanotube (CNT) circuits3C2Tx MXenes and electromagnetic waves have focused on electromagnetic interference (EMI) shielding23. The high amount of charge carriers on the MXene surface causes the reflection of electromagnetic waves. The waves that are absorbed instead of reflected are weakened by internal attenuation between the MXene layers21. However, to the best of our knowledge, no one has attempted to examine the possible evolution of heat arising from Ti3C2Tx MXene nanosheets (in polymer composites or in a neat film) upon exposure to RF fields.Most prior reports concerning the relationship between Ti3C2Tx MXene/poly (PVA) composites in applied RF fields in the 1–150 MHz range. PVA is a commonly used commercial polymer that is also biodegradable and hydrophilic, making it easy to process24. PVA was selected because of its minimal response to the RF field. In prior literature, Ti3C2Tx/PVA composites demonstrated electrical conductivity, thermal stability, and mechanical strength25. We observed a high RF response for composites having conductivity in the range of 10–1000 S m−1 and a minimal response for composites with high and low conductivities. Using thermal imaging, we observed the heating responses of Ti3C2Tx/polymer composites of varying compositions under low power RF waves.Here we demonstrate for the first time the thermal response of Ti3C2Tx MXene nanosheets  were also prepared. Figure Tiets Fig.  were obt8. The frequency sweep was programmed such that the sample was exposed to 3 W RF fields for 2 seconds (power turned on) followed by 12 seconds of cooling time (power turned off) at each frequency from 1–150 MHz 8.RF heating rate varies with frequency because the impedance of the system is frequency-dependent. We utilize a frequency sweep to determine the resonant frequency has the highest resistive losses, and thus, the highest heating rate. The resonant frequency is the frequency at which the impedance of the source (RF generator) is closely matched to that of the sample, capacitor, and the connecting cables, leading to an efficient power transfer between the source and the sample). Additionally, neat PVA films were exposed to RF fields to determine if the matrix itself responded to RF waves, but they did not display any heating behavior , the samples were exposed to RF fields at their unique resonant frequency for a 12 second period to probe their heating profiles Figs  and S5. S1ior Fig. .27. The conductivity of the 1 wt.% composite was below the measurement threshold (<10−3 S m−1), but the 5 wt.% sample (2.41 ± 0.18 × 10−1 S m−1) was conductive as shown in Fig. 28.We first examine the connection between RF heating and the bulk conductivity of the samples. Conductive percolating networks in a polymer matrix are formed when the filler, in this case the nanosheets, are in close proximity to one another for the electron to transfer over (by hopping or tunneling) to the adjacent nanosheetamb) and the average temperature (Tave) reached are marked. The data demonstrates that a steady temperature is eventually reached upon RF exposure after about 3–4 seconds. The temperature rise (Tavg − Tamb) from RF heating of the samples as a function of composition and conductivity are shown in Fig. −1) exists for which the MXene composites will absorb RF waves and heat.The RF-induced heating of the samples are shown by the increase in the average temperature reached during the temperature vs. time experiments Figs  and S5. 3C2Tx nanosheets (1.26 ± 0.03 × 105 S m−1) did not heat under RF fields, which we attribute to reflection. As Shahzad et al.21 demonstrated, Ti3C2Tx surfaces possess a large number of charge carriers that are responsible for reflecting electromagnetic waves. Some of the waves that do get absorbed may experience energy loss due to attenuation within the MXene interlayer spacing21. Attenuation losses are also observed in the RF heating of bulk metals. This is consistent with the general observation that materials with high conductivity (>104 S m−1) show a poor RF heating response30. Our group has observed similar trends for carbon nanotubes (CNTs) embedded in polymers, with lower microwave and RF heating response at both low and high CNT loadings. Instead, CNT/polymer composites with an intermediate loading  showed the highest RF heating response; our results confirm a similar trend, where an intermediate loading  was the most responsive28.Interestingly, MXene buckypaper consisting of 100 wt.% Ti3C2Tx MXenes and other filler materials that have been shown to heat under RF fields. Ti3C2Tx MXenes possess a higher dielectric loss tangent (1.5 at 2.45 GHz) than other nanomaterials, indicating that it is a good material for heat generation from the dissipation of electromagnetic waves.Another important parameter to consider is the dielectric loss tangent (tan δ); this parameter represents the ratio of electromagnetic loss over the electromagnetic storage. In other words, it is the measure of dissipation of electromagnetic energy through heat for which a material with high tan δ will dissipate more heat. Table 3C2Tx MXenes are prone to oxidation in various media; as a result, their conductivity drops over time31. To observe the RF response of aged Ti3C2Tx MXene composites, we studied samples stored in ambient conditions for 30 days. The conductivities of all samples decreased over the period of 30 days , and the conductivity of the 5 wt.% composite sample by Day 30 was below the measurement threshold (<10−3 S m−1). Figure −1) where RF heating is optimal, regardless of power level. All of the Day 30 composites had a similar or lower heating value compared to the Day 0 composites. The only exception was the 75 wt.% composite. For both power values, the 75 wt.% composite experienced a jump in heating (from Day 0 to Day 30) even though the conductivity decreased. It is plausible that on Day 0, most of the RF waves reflected off the 75 wt.% sample but with a lower conductivity on Day 30, there was an increase in RF absorption leading to a higher amount of heating. There is also a significant drop in heating from the 25 wt.% sample at 3 W on Day 30, but the heating is still the highest compared to other samples; the heating trend between both power remain consistent. Our XPS results  were thermally cycled for 50 cycles on Day 0 at 3 W Fig. . Through3C2Tx MXene composites heat under RF fields. The main parameter of interest is the composite’s conductivity, which depends on Ti3C2Tx content. This is a new feature that can be exploited to induce remote heating using low power RF fields. This feature may provide alternative processing routes for heating, curing, and bonding materials. The heating of Ti3C2Tx MXene composites suggests of the possibility of RF field heating for other types of MXenes. With the theoretical existence of over >200 stable MXene phases, there is an immense range of MXenes that may demonstrate even a stronger response to RF. Our future work will include testing different type of MXenes for RF response and also in different polymer matrices.We have demonstrated that Ti3AlC2 MAX phase32. Commercial Ti , Al  and TiC powders , , were used as starting raw materials to produce the parent Ti3AlC2 MAX phase. Ti, Al and TiC powders were first weighed to achieve a ratio of Ti:Al:C = 3.0:1.2:1.8 and mixed together using ball milling with zirconia beads at the speed of 300 rpm for 24 hours. The bulk high-purity Ti3AlC2 samples were then sintered at temperature of 1510 °C for 15 mins with a loading of 50 MPa using the Pulsed Electric Current System (PECS). To fabricate high-purity Ti3AlC2 powder, the PECSed sample was first drill-milled and then sieved in order to obtain powder with particle sizes below 44 µm5.Our previously reported procedure was followed to synthesize the Ti3C2Tx MXene clay was synthesized by etching Al from the Ti3AlC2 phase using technique described by Ghidiu et al.33. Concentrated hydrochloric acid  was diluted with DI water to obtain 30 mL of 6 M HCl solution. This solution was transferred to a polypropylene beaker and 1.98 gm of lithium fluoride  was added to it. This dispersion was stirred for 5 minutes using a Polytetrafluoroethylene magnetic stirbar at room temperature. The Ti3AlC2 powder was slowly added to the HCl + LiF solution to prevent overheating as the reaction is exothermic. The beaker was capped to prevent evaporation of water and a hole was made in the cap to avoid buildup of hydrogen gas. The reaction mixture was stirred at 40 °C for ~45 hours. The slurry product was centrifuged and washed with deionized (DI) water to remove all of the unreacted HF and water-soluble salts. This washing process was repeated until the pH of the filtrate increased to ~5. The reaction product is collected at the bottom of the centrifuge tubes and is extracted as Ti3C2Tx MXene clay5. This is an established procedure in the prior literature32.Ti31. The Ti3C2Tx MXene clay was intercalated with dimethyl sulfoxide (DMSO) and bath sonicated to obtain an aqueous dispersion of delaminated Ti3C2Tx MXenes following procedure described in more detail by Mashtalir et al.34. DMSO  was added to Ti3C2Tx MXene to form a 60 mg/ml suspension followed by about 18 hours of stirring at room temperature. After intercalation, excess DMSO was removed by several cycles of washing with DI water and centrifugation at 5000 rpm for 4 hours. The intercalated Ti3C2Tx MXene clay suspension in deionized water was bath sonicated for 1 hour at room temperature followed by centrifugation at 3500 rpm for 1 hour to separate the heavier components5.A previously reported procedure was followed for intercalation and delaminationet al.31 Ti3C2Tx powder and polyvinyl alcohol  were bath sonicated for 15 minutes, then vacuum filtered on a polysulfone membrane (with pore size of 0.2 µm) to obtain a polymer composite film. All the composites were made with total mass of 10 mg; this ensure similar areal density for all composites. The composite films were vacuum dried overnight (room temperature) before their electrical conductivity was measured prior to RF experiments.The method to prepare such composites was described by Habib 36.The RF power source was a signal generator  and 500 W amplifier  measurements were obtained using Omnicron XPS. Malvern Zetasizer ZS90 was used to ascertain zeta potential of colloidal solutions. UV-vis measurements were obtained with Shimadzu UV-vis 2550. Scanning electron microscope (SEM) images were taken with JEOL JSM-7500 L.Supplementary Info


For respiratory motion compensation, a 2D fat‐iNAV was acquired before each 3D SASHA k‐space segment to correct for 2D translational motion in a beat‐to‐beat fashion. The effect of the fat‐iNAV on the 3D SASHA T1 estimation was evaluated on the T1 phantom. For 3 representative subjects, the proposed free‐breathing 3D SASHA with fat‐iNAV was compared to the original implementation with the diaphragmatic navigator. The 3D SASHA with fat‐iNAV was compared to the breath‐hold 2D SASHA sequence in terms of accuracy and precision.Data from T1 quantification of the 3D SASHA acquisition (0 ± 12.5 ms). For the in vivo study, the 2D fat‐iNAV permits to estimate the respiratory motion of the heart, while allowing for 100% scan efficiency, improving the precision of the T1 measurement compared to non‐motion‐corrected 3D SASHA. However, the image quality achieved with the proposed 3D SASHA with fat‐iNAV is lower compared to the original implementation, with reduced delineation of the myocardial borders and papillary muscles.In the phantom study, the Bland‐Altman plot shows that the 2D fat‐iNAVs does not affect the T1 mapping imaging sequence with a 2D fat‐iNAV for respiratory motion compensation, allowing 100% respiratory scan efficiency and predictable scan time.We demonstrate the feasibility to combine the 3D SASHA T Saturation recovery single‐shot acquisition (SASHA) sequence1 mapping sequences are typically performed as single‐shot 2D imaging techniques with a single slice being acquired per breath‐hold. A free‐breathing 3D whole‐heart technique would be preferable because it would enable complete volumetric coverage of the heart with potentially higher image resolution, allowing visualization of small myocardial structures and pathologies. A 3D SASHA1 accuracy to 2D SASHA, but with improved precision. In the approach described in Nordio et al.,1 mapping to assess diffuse fibrosis after contrast administration, which use the 1D NAV to minimize the respiratory motion.1‐weighted images, it has some limitations. The motion is estimated from the foot–head displacement of the lung–liver interface instead of the heart itself and therefore requires a motion model . In addition, the scan efficiency of the 1D NAV is typically 40–50% in healthy subjects, but can be considerably lower in patients with irregular breathing patterns. This prolonged and unpredictable scan time limits the applicability of this technique in very sick patients and precludes achieving the high spatial resolution necessary to visualize small focal fibrosis. Self‐navigation1 mapping because of the technical challenges of this technique that include: interference between the image navigator and the T1‐weighted images that can affect the accuracy and precision of the T1 measurement, low SNR of the navigators because of the effect of saturation pulses and the long T1 of blood, and change of contrast of the navigators during the acquisition of different T1‐weighted images.Several different imaging techniques have been devised and validated for myocardial T1 mapping with high spatial resolution in a clinically acceptable and predictable scan time. With the fat‐iNAV, epicardial fat is excited, and the navigator images are used to directly estimate the respiratory motion of the heart that has several theoretical advantages. First, with this approach the fat excitation pulses should not affect the (diagnostic) water signal and therefore not influence T1 quantification. Second, fat has a short T1 and therefore yields T1‐weighted navigator images with relatively high signal even for short saturation delays, whereas a water navigator would suffer from varying signal intensities for different saturation delays, potentially compromising image registration and motion estimation.In this work, we propose to address these challenges by combining the 3D SASHA imaging sequence with a fat image‐based navigator (fat‐iNAV)22.1Conventional image‐based navigator techniques excite both water and fat signals to obtain low‐resolution images of the heart at every heartbeat. Because fat magnetization recovers faster than that of water after the application of a saturation pulse, fat‐selective navigator measures a more constant signal at different saturation delays in contrast to water selective navigators, and therefore may improve motion estimation.1 map generation is shown in Figure 1‐weighted image acquisition in mid‐diastole. Foot–head and left–right displacements of the heart were estimated from the fat‐iNAV images using a normalized cross‐correlation registration algorithm and then used to correct the k‐space of each T1‐weighted image using the phase shift property of the Fourier transform.A schematic diagram of the framework used for image acquisition, motion estimation/correction using fat‐iNAV and T2 in plane image resolution, FOV = 300 × 300 mm2, slice thickness = 20 mm, 15° flip angle, TR/TE = 1.5 ms/7.2 ms, fat selective = 1331 binomial pulse,1 mapping reconstruction were performed offline using MATLAB . SENSE reconstruction was performed for both non‐motion‐corrected and motion‐corrected 3D SASHA data sets. A denoising method was applied to the T1‐weighted images of both the 2D and 3D SASHA acquisitions before parametric fitting to reduce the noise and improve both image quality and T1 precision of the T1 maps.1 maps offline for the 2 data sets with a pixel‐wise fitting approach.The acquisition parameters used for the fat‐iNAV acquisition were: 3 × 3 mm2.22 vials with T1 values ranging from 250–1500 ms was scanned using the proposed fat‐iNAV T1 mapping approach.1 phantom data was acquired with an inversion recovery spin‐echo (IRSE) acquisition, providing reference T1 values, and the 2D and 3D SASHA imaging sequences with fat‐iNAV for comparison purposes. Sequence parameters for IRSE were: FOV = 150 × 150 mm2, spatial resolution = 1.95 × 1.95 mm2, 10 mm slice thickness, TR between inversion pulses = 7000 ms, TE  =  6 ms, 20 inversion times varying from 50–5000 ms. The imaging parameters for the 2D SASHA sequence were: FOV = 300 × 280 mm2, spatial resolution = 1.7 × 2.1 × 10 mm3, flip angle = 70°, TR/TE = 2.4/1.2, SENSE factor of 2. The imaging parameters for the 3D SASHA technique were: FOV = 300 × 300 mm2, spatial resolution = 2 × 2 × 4 mm3, reconstructed image resolution = 2 × 2 × 2 mm3, flip angle = 35°, TR/TE = 3.2/1.6, SENSE factor of 2, balanced SSFP (bSSFP) acquisition, Cartesian trajectory with radial k‐space shutter, low‐high profile order, and coronal view. For the 3D SASHA, a total of 8 images were acquired, and 3 pause heart cycles were performed between the acquisitions of k‐space segments of the infinity image.A phantom with 9 agar/NiCl1 measurements were then obtained in the 2 slices and compared with the Bland‐Altman analysis and the Spearman test for correlation.To investigate potential interference between the fat‐iNAV and 3D SASHA acquisition, 2 different slices of the 3D SASHA acquisition were analyzed, 1 in the same slice location as the fat‐iNAV (slice with fat‐iNAV) and 1 parallel to the iNAV at a more distal location (16 mm) (slice without fat‐iNAV). T1 phantom and a phantom containing fat were scanned using the 3D SASHA imaging sequence with either of the 2 navigator acquisition approaches.1 phantom with a T1 value similar to that of blood.To compare the navigator signal between the fat‐iNAV and conventional non‐spectrally selective navigator excitation, the T2.32, spatial resolution = 2 × 2 × 4 mm3, reconstructed image resolution = 2 × 2 × 2 mm3, flip angle = 35˚, TR/TE = 3.2/1.6, SENSE factor of 2, bSSFP acquisition, Cartesian acquisition with radial k‐space shutter, low‐high profile order and coronal orientation. The 2D SASHA imaging sequence was acquired in short axis view, whereas the 3D SASHA and fat iNAV were acquired in a coronal orientation to mitigate through plane motion and facilitate retrospective in‐plane motion correction. Whole‐heart coverage in combination with coronal orientation and 4 mm slice thickness required the acquisition of a larger number of slices compared to the previously published short‐axis 3D SASHA that only covered the left‐ventricle and used 8‐mm slice thickness.The study was performed in accordance with the Declaration of Helsinki (2000). All subjects recruited in this study provided written informed consent with study approval from the Institutional Review Board 1/11/12). Ten healthy subjects  were imaged on a 1.5T Ingenia Philips MR system  with a 28‐channel coil array and using the 3D SASHA imaging sequence with the fat‐iNAV described in Figure /11/12. TFor 1 of the subjects, the 3D SASHA acquisition was performed twice, both using the fat‐iNAV and the conventional non‐spectrally selective excitation navigator, to compare the respiratory motion of the heart estimated using the 2 different navigators. In both cases, a normalized cross‐correlation registration algorithm was used for motion estimation.For 2 representative subjects, the proposed 3D SASHA imaging technique with the fat‐iNAV was compared with 3D SASHA using the diaphragmatic navigator with tracking only to evaluate the performance of the 2 different navigator techniques for motion estimation and correction.1 maps for both techniques.For 3 representative subjects, the proposed 3D SASHA imaging technique with the fat‐iNAV was also compared with the original implementation of the 3D SASHA with 1D NAV, gating, and tracking, to compare the image quality and quantitative values of the motion‐corrected T2.41 maps were reconstructed using a 3‐parameter fitting approach, both before and after translational motion correction. For the phantom study, a ROI was manually drawn in the 9 vials and the mean and SD of the T1 measurements were measured as an estimate of the accuracy and the precision of the T1 map, respectively. For statistical analysis, GraphPad Prism v5 for Windows  was used. The T1 values measured in the phantom in the 2 different slices (with and without fat‐iNAV) were compared using a Bland‐Altman plot and the correlation was calculated using a Spearman test. The mean percent difference was calculated to compare the T1 values estimated by the reference IRSE and the 2D and 3D SASHA sequences. For the in vivo study, a ROI was manually drawn in the myocardial septum and the mean and the SD of the T1 values were measured as an estimate of, respectively, the accuracy and precision. A Kruskal‐Wallis test was used to compare the accuracy and precision measured on the 2D and 3D SASHA T1 maps before and after motion correction. The in vivo data set, acquired in coronal view, were reformatted in the short axis view to the same slice as 2D SASHA for comparison using Horos software v1.1.7. An AHA segmentation was used to compare the accuracy and precision of the 3D SASHA with fat‐iNAV before and after motion correction and for a 3D visualization of the left ventricle. The cardiac volume was represented in 16 segments and 3 slices , with the segment 17 corresponding to the blood pool. The value in each segment was averaged within the 10 healthy subjects.T33.11 phantom using the IRSE, 2D SASHA, and 3D SASHA imaging sequences. For the 3D SASHA sequence, the T1 values were measured in 2 different slices (slice with and without fat‐iNAV). There was a good agreement between the IRSE and the 3D SASHA imaging sequence, for both slices. The correlation between the T1 measurements for the 2 different 3D SASHA slices is shown in Supporting Information Figure 2 = 0.99, P < 0.0001) was found. Supporting Information Figure 1 values measured in the 2 slices of the 3D SASHA acquisition. There is no bias between the 2 set of measurements, while the 95% limits of agreements are equal to 12.5 ms. Supporting Information Figure 1 maps of the 2D SASHA and 3D SASHA imaging sequences and the mean percent difference between the T1 values estimated by the reference IRSE and the 2D and 3D SASHA imaging sequences.Supporting Information Table Supporting Information Figure 3.21‐weighted images and T1 maps acquired with the 3D SASHA imaging sequence using fat‐iNAV or 1D diaphragmatic navigator with tracking  for 2 representative subjects. The fat‐iNAV resulted in improved delineation of the myocardium and higher quality T1 maps suggesting improved motion estimation and correction with fat‐iNAV compared to the 1D NAV.Supporting Information Figure 1‐weighting are reflected in the navigators with non‐spectrally selective excitation that causes a change in the trend of the translational motion estimated between the acquisition of the infinity images (green box) and the beginning of the acquisition of the saturated images (orange box). In addition, the change in contrast of the water image navigator makes it challenging to correct to a common reference iNAV used for the image registration, which causes errors in the motion estimation. Consequently, residual motion also affects the quality of the reconstructed T1 map, where the precision is lower compared to the T1 map reconstructed using the fat‐iNAV, as shown in Figure Figure 1‐weighted images and the 3D SASHA myocardial T1 map for 1 representative subject with no motion correction (NMC) and after 2D translational motion correction (MC). There was an improvement in the delineation of the myocardium and papillary muscle after motion correction both in the T1‐weighted images and the T1 map. The corresponding fat‐iNAVs are shown for the different saturation times with no visible change in image contrast. Figure 1 maps in short axis view for 3 representative subjects before and after respiratory motion correction, in comparison with the corresponding 2D SASHA T1 maps. After translational motion correction the delineation of the myocardial borders and the papillary muscles improves, as shown in Figure 1 measured in the septum of the myocardium between the 3D SASHA and 2D SASHA T1 maps, with an improvement in the precision for the 3D SASHA T1 map, because of the denoising method1 maps further improves after translational motion correction as shown in Supporting Information Figure 1 maps acquired with the proposed 3D SASHA with fat‐INAV, before and after motion correction, and with the original implementation of the 3D SASHA with 1D NAV for gating and tracking. After motion correction, the image quality achieved with the proposed 3D SASHA with fat‐iNAV is lower compared to the original implementation, with reduced delineation of the myocardial borders and papillary muscles.Figure 41 mapping. The fat‐iNAV has been combined with the previously proposed 3D SASHA myocardial T1 mapping technique,1 mapping acquisition and therefore does not introduce systematic bias of the T1 measurement. This has been demonstrated through the T1 phantom experiment, which shows good agreement between the T1 values measured in 2 different slices, 1 without fat‐iNAV and 1 corresponding with the fat‐iNAV  that experiences minimal motion in the through‐plane (anterior–posterior) direction during the binomial saturation pulse. In patients with significant amounts of epicardial fat, the image navigator will have more tissue from which to estimate respiratory motion, which may yield better respiratory motion correction. In the current work, fat suppression was used to minimize signal from subcutaneous and pericardial fat in the T1 maps, primarily to avoid motion artifacts arising from these tissues. Visualization of fat is of interest to detect fatty infiltration of the myocardium. Although fat‐iNAV RF‐pulses may cause saturation effects of the fat signal for the T1 maps, the use of low flip angles combined with few RF excitations and the short T1 of fat means more than 85% of the longitudinal magnetization remains immediately after the fat‐iNAV has been performed. Therefore, there is only a minor loss in fat SNR in the regions where the fat‐iNAV and T1 map overlap.The binomial fat excitation pulse of the iNAV should in theory only affect the fat signal. However, in practice some saturation of the water signal was observed, as shown in Supporting Information Figure 1 map, where residual motion affects the image quality and the delineation of the myocardium. In addition, the precision is lower on the T1 map motion‐corrected using the water iNAVs compared to the T1 map motion‐corrected using the fat‐iNAVs. The 2D fat‐iNAV also showed a better detection, and consequently motion correction, compared to the 1D diaphragmatic navigator and this results in improved myocardium delineation on the T1 maps as well as improved T1 accuracy and precision  yielded reduced image quality compared with the 3D SASHA T1 maps using a 1D diaphragmatic navigator with both gating and tracking  and 1 outside the area of excitation of the fat‐iNAV (slice without fat‐iNAV). The identity line is also indicated in the graphFIGURE S2 Bland‐Altman plot comparing the 3D SASHA acquired on the 2 different slices (without and with fat‐iNAV). The mean and the 95% limits of agreement are reported in the graphFIGURE S3 (A) T1 maps of the T1 phantom using the 2D and 3D SASHA sequences. (B) Mean percent difference between the T1 values estimated by the reference IRSE and the 2D (in blue) and 3D SASHA (in red) sequencesFIGURE S4 Comparison of the signal measured in the conventional (blue) and fat (red) image navigator, for each different T1‐weighted image of the T1 phantomFIGURE S5 T1‐weighted images and T1 maps of 2 representative subjects, acquired with the proposed 3D SASHA sequence with the fat‐iNAV and with the 3D SASHA sequence with the 1D diaphragmatic navigator with tracking only. The fat‐iNAV allows to improve myocardium delineation (white arrows), as well as to improve T1 accuracy and precisionFIGURE S6 Accuracy and precision measured on the non‐motion‐corrected , motion‐corrected  3D SASHA, and 2D SASHA (yellow) T1 maps for the 10 healthy subjects. The T1 values were measured in the septum of the myocardiumFIGURE S7 AHA plot of the left ventricle, shown for the non‐motion‐corrected (NMC) and motion‐corrected (MC) 3D SASHA (n = 10 subjects). The cardiac volume is represented in 16 segments and 3 slices , whereas the center represents the blood pool. The precision improves after motion correction, although low precision was found in the inferior wall after motion correction because of residual motion artefactsFIGURE S8 Transversal view of the T1‐weighted images and the reconstructed 3D SASHA T1 map of 3 subjects. The position of the fat‐iNAV is indicated by the pink box. Saturation effect of the blood pool are visible particularly in subjects 2 and 3TABLE S1 Mean and SDs measured in the 9 vials of the T1 phantom using the inversion recovery spin‐echo (IRSE), 2D SASHA, and 3D SASHA for 2 different slicesClick here for additional data file.


Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available materials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one‐step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput. HIV is a disease that currently affects around 37 million people.1  1 and its analogues.4 through rapid formation of the functionalized pyridone core 8 and subsequent cyclization with (S)‐alaninol 11 to synthesize the 5‐membered oxazine ring  13. Our first attempt at the analogous flow reaction proceeded with 60 % conversion to 14 when an equimolar ratio of the neat reactants 12 and 13 were streamed through a T‐mixer at 30 °C with a residence time (tR) of 10 min. Further optimization led to the discovery that an elevated reaction temperature of 85 °C and 1.6 equiv of DMF‐DMA 13 resulted in full conversion of 12 to 14 via HPLC with the same 10 min residence time.14, we next sought to telescope Steps 1 and 2 in continuous flow  to product 16 compared to N‐methylpyrrolidinone and MeOH (both 85 %); however the CH3CN condition suffered from poor solubility that led to clogging in flow.16 than LiOMe, which was utilized in the GSK synthesis.tR led to a 91 % isolated yield of 16  were utilized as check valves and Reactor III was used to facilitate premixing of solution 7 with the output from Reactor II prior to the addition of NaOMe. A 55 min residence time in Reactor IV was required for the reaction to reach completion. The three‐step telescoped synthesis of pyridone 16 led to a 56 % isolated yield in a total residence time of 74 min with a throughput of 3.4 g h−1.Next, we examined the synthesis of pyridone s Scheme . After m8 and subsequent amide coupling stood out as an opportunity. Specifically, in GSK's synthesis of Cabotegravir 4 (Scheme 16 was saponified to the 5‐carboxylic acid 8 and then treated with carbonyldiimidazole (CDI) and difluorobenzylamine 9 to form amide product 17. The process required a filtration and extraction, and took 17 h in total. We were encouraged by a similar direct amidation that was reported in the midst of our own studies.17 after 10 h . An ethyl ester substrate gave comparable yield and AcOH was found to be necessary for practical reaction time.When considering ways to shorten the reported GSK synthesis, the ester saponification to form 4 Scheme ,11e,11f 17 was obtained with the use of a 100 psi BPR albeit in low conversion of starting material 16. A systematic evaluation of temperature and residence time led to good conversion at 150 °C with a 1 h residence time and at 180 °C with a 30 min residence time.3CN were viable, but gave lower conversion than PhCH3 in the flow setup. DCE led to clogging in the system, and DMF and MeOH failed to produce any desired amide 17 after 1 h. Under the optimal conditions of 200 °C with a residence time of 124 min, we obtained 96 % isolated yield of amide 17 (2 % recovered 16) on a 3 mmol scale, which amounted to 3.5 g h−1 ‐3‐aminobutan‐1‐ol 18 in flow. Initial attempts were conducted on purified pyridone amide 17 with an acid additive and amino alcohol 18. Ultimately, we found that formic acid was required as a co‐solvent to observe any conversion of 17. Our best result afforded an 8 % yield of DTG‐OMe 19 as a 5:1 mix of diastereomers favoring the desired product .16 to reduce the step count, and separation of the acetal deprotection/oxazine formation flow reactors to attain high reactivity and selectivity for tricyclic product DTG‐OMe 19. Importantly, our synthesis should be adaptable to both Cabotegravir 4 and Bictegravir 5 by switching the benzylamine and amino alcohol used in the synthesis. Further studies will focus on the telescoping of all steps to achieve an end‐to‐end continuous flow synthesis as well as formulation of the final API as its sodium salt and to produce cGMP formulations in an engineered system without the use of silica gel chromatography.In conclusion, we have developed a continuous flow synthesis of the HIV integrase inhibitor Dolutegravir The authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


Here, we investigated the molecular function of REBELOTE (RBL), an Arabidopsis thaliana protein previously characterized as a regulator of floral meristem termination. We show that RBL displays a dual localization, in the nucleolus and nucleoplasm. Moreover, we used direct and global approaches to demonstrate that RBL interacts with nucleic acid‐binding proteins. It binds to the NOC proteins SWA2, AtNOC2 and AtNOC3 in both the nucleolus and nucleoplasm, and also to OBE1 and VFP3/ENAP1. Taking into account the identities of these RBL interactors, we hypothesize that RBL acts both in ribosomal biogenesis and in the regulation of gene expression.The nucleoplasm and nucleolus are the two main territories of the nucleus. While specific functions are associated with each of these territories (such as  BiFCbimolecular fluorescent complementationNOCnucleolar, complexRBLREBELOTEY2Hyeast two‐hybridThe nucleolus is known to be the initial site for ribosomal biogenesis. Processes occurring in the nucleolus include the transcription of ribosomal rDNA by RNA polymerase I and the maturation of ribosomal rRNAs, which are processed and assembled with 5S rRNA and ribosomal proteins to form ribonucleoproteins (RNPs), the precursors of the small and large ribosomal subunits Arabidopsis thaliana that some of these proteins, such as ALY4, are present in the nucleolus and in nuclear speckles, including those corresponding to exon junction complexes, that are involved in mRNA metabolism A. thalianaHowever, the functions of nucleolar proteins are not restricted to ribosomal biogenesis. Interestingly, several studies have shown the nucleolus to contain proteins unrelated to this process and which are known to be additionally present in other subcellular compartments Saccharomyces cerevisiae ScNoc2p, acts in two protein complexes, together with ScNoc1p and ScNoc3p, two proteins containing a CCAAT‐binding factor (CBF) domain, and acting for the transport of 60S large ribosomal subunits from the nucleolus to the cytoplasm Caenorhabditis elegans, loss of function of the NOC2 homolog causes defects in gonadogenesis A. thaliana, Prunet et al. Among the proteins involved in ribosomal biogenesis are the NOC2 proteins A. thaliana. Moreover, yeast two‐hybrid screens allowed us to show interactions of RBL with nucleic acid‐binding proteins, such as the nucleoplasmic OBE1 and VFP3/ENAP1 proteins, suggesting a role in the regulation of gene expression. In the present work, we have identified the molecular partners of RBL, thus paving the way for further studies to fully elucidate its developmental role.In this study, we provide insights on the molecular functions of RBL. We show that this protein is localized in the nucleoplasm and nucleolus, where it acts in NOC complexes similar to those found in yeast that involve the yeast RBL homolog Noc2p, together with the other Noc proteins Noc1p and Noc3p. We also show that NOC proteins from mammals are able to form complexes of similar composition to those in yeast and et al. et al. A. thaliana plants stably transformed with p35S::RBL‐GFP or pRBL::RBL‐mRFP constructs. As DNA is more abundant in the nucleoplasm than in the nucleolus, we used Hoechst's reagent as a marker of the nuclear compartments. Our data show that RBL is localized in the nucleolus of root cells in interphase, whereas it colocalized with DNA in dividing root cells Noc2p, called AtNOC2 and RBL, and a homolog of Noc3p, called AtNOC3.Given that RBL has a NOC2 domain and is localized in the nucleolus, we hypothesized that it might interact in nucleolar complexes similar to those in et al. SWA2 is a nucleolar protein of 1.043 amino acids A. thaliana root cells, in which we used DAPI to stain DNA  is able to bind the two NOC2‐domain‐containing proteins, AtNOC2 and RBL  experiments, we evaluated whether the yeast NOC complexes, formed from Noc1p, Noc2p, and Noc3p, are conserved in With the exception of the homodimerization of AtNOC2 proteins, all interactions found in the Y2H matrix were validated by bimolecular fluorescent complementation (BiFC) Fig. C. MoreovSaccharomyces cerevisiae noc mutant strains show temperature‐conditional lethality A. thaliana NOC protein was expressed in its respective noc mutant homolog strain. No complementation of lethality was observed at 37 °C  and VFP3/ENAP1 (VirF‐interacting Protein 3/EIN2 nuclear associated protein 1) as putative interactors in both screens. cDNAs encoding VFP3/ENAP1 and OBE1, respectively, represented 40% and 10% of selected diploids.OBE1 and VFP3/ENAP1 had been isolated. Confirmation of interactions involving RBL was performed using the Y2H approach. Negative controls using either an empty prey vector or a prey vector containing a cDNA partner inactivated by a frameshift mutation allowed us to confirm the observed interactions of RBL with VFP3/ENAP1 and OBE1  known to act in the regulation of chromatin states  known toAdditionally, to our search for RBL interactors, Y2H experiments were performed to investigate the importance of the NOC2 domain in protein–protein interactions. To that end, the N‐terminal RBL region, containing the NOC2 domain, and its C‐terminal region were used separately as bait in Y2H screens. We found that OBE2, the homolog and partner of OBE1, interacted with the NOC2 domain. No protein was found to interact with the C‐terminal region of RBL.A. thaliana and transient expression in Nicotiana benthamiana show that RBL is localized in the nucleolus and nucleoplasm and can also be observed in unidentified bodies of nucleoplasm . Infiltrations were performed on 3‐week‐old N. benthamiana leaves as previously described We used the previously described construction noc1‐1, noc2‐1, and noc3‐1 mutants and vectors expressing ScNoc were provided by H. Tchoschner Arabidopsis thaliana cDNAs were cloned in the YEplac195 Gateway expression vector, also provided by H. Tchoschner. Thermo‐sensitivity complementation was tested using nondiluted and diluted yeast colonies cultured at 37 °C on SD‐U medium.Yeast A. thaliana seedlings (Stock CD4‐22: https://www.arabidopsis.org/servlets/TairObject?type=stock%26id=88570) was initially screened using full‐length RBL cloned in pAS2.1 (Clontech). The cDNA library was cloned in the pADGAL4‐2.1 vector S. cerevisiae AH109 and Y187 strains and selection on triple  or quadruple (‐Ade) selective media sequencher  software.A cDNA library of etiolated The interaction of RBL with OBE1 and VFP3 were confirmed by mating between AH109  and Y187  A. thaliana proteins, full‐length cDNA were cloned into the pPC86‐ and pPC97‐based vectors. NIR was amplified from a human cDNA library obtained from the LBMC laboratory . CEBPZ was amplified from the pMT2‐CBF construct FAD24 cDNA was amplified from the pGFP‐c1‐mouseFAD24 plasmid For direct Y2H experiments using Imaging in subcellular localizations and in BiFC experiments was performed using Zeiss LSM‐510, Zeiss LSM‐700, or Leica SP5 confocal microscopes. A histone H2B‐mRFP marker was kindly provided by Frederic Berger We used online tools to study coexpression of AtNOC proteins and predict the presence of nuclear localization signal or specific protein domain. We respectively used ATTED‐II At3g55510), SWA2 (At1g72440), AtNOC2 (At2g18220), AtNOC3 (At1g79150), OBE1 (At3g07780), VFP3/ENAP1 (At3g11100)RBL  Localization of AtNOC2‐GFP and FIB‐mRFP in tobacco leaf cell. Arrowheads show the Cajal bodie. Scale bar: 10 μm. (B–D) Graphical representation of AtNOC co‐expression from micro‐array data using the ATTEDII and AtGenExpress tools. (B) Specific co‐expression using abiotic stressbased micro‐arrays. (C) Global co‐expression using developmental stage‐based micro‐arrays. (D) Co‐expression network of AtNOC genes.Fig. S2. Absence of complementation of yeast noc mutants by A. thaliana NOCs. Full‐length AtNOC, ScNOC and CRABS CLAW (CRC) were expressed in yeast mutants noc1‐1 (A), noc2‐1 (B) and noc3‐1 (C). Complementation of the lethal phenotype at 37°C is observed by yeast growth with or without dilution. CRC was used as negative control and yeast Noc proteins as positives controls for their respective mutants.Fig. S3. OBE1 interacts with MOM1 in yeast. Yeast two‐hybrid interaction matrix on SD‐AHTL selective media (10‐3 dilution). This is a confirmation of results of a yeast two‐hybrid screen using OBE1 as bait, in which we isolate MOM1 cDNA.Click here for additional data file.


Switching of the inclusion of guest molecules was realized by the crystallization induced self-assembly of a benzothiadiazole-type macrocyclic boronic ester. Selective inclusion of each of bicyclic and tricyclic aromatic guest molecules was realized utilizing the self-assembly of a crystalline benzothiadiazole-type macrocyclic boronic ester. The complete switching of the guest selectivity was achieved simply by changing the cosolvent used in the formation of the crystalline host–guest complexes. Both the association free energy of host–guest complexes and the stability of packing structure were found to play important roles for the determination of the guest selectivity in this system, and the critical role of solvent molecules in the crystalline state for the switching phenomena was clarified. Crystalline host materials are often capable of separating a single guest molecule from a mixture of analogous compounds, which is practically useful for isolation or removal of a specific molecule.et al.K) is generally utilized as an effective index to evaluate the relative affinity of different guest molecules for a host compound in the solution state. Although one can expect the selective inclusion of a guest molecule with a high K value into a crystalline host material, the relationship between the order of K values in solution and the solid-state separation of guest mixtures is not well documented as conventional crystalline host materials are often insoluble or dissociate into their components in solution. Herein, we demonstrate the selective guest separation by a self-assembled, crystalline macrocyclic boronic ester based on the K values of the discrete host boronic ester with guest molecules, and more importantly, a facile switching of guest selectivity in the crystalline state was achieved simply by changing the cosolvent used in the formation of the crystalline host–guest complexes  was chosen as a component for the construction of such a macrocyclic boronic ester since 2,1,3-benzothiadiazole unit is known as an efficient electron-accepting unit, which was expected to recognize the electronic state of guest molecules.3 composed of two molecules each of diboronic acid 1 and racemic bis 2 was obtained as a precipitate in 96% yield by the self-assembly of 1 with 2 in methanol/THF (NA) was added to a deuterated chloroform solution of 3, chemical shift values of 3 changed in 1H NMR spectrum of the mixture  in the solution state as expected. The binding stoichiometry of 3 with NA was estimated to be 1 : 1 by Job plot analysis  of NA with 3 was determined to be 104 M–1 by the 1H NMR experiment aromatic compounds were also evaluated by 1H NMR analyses . It should be noted that association constants of 3 for tricyclic compounds were higher than those for the corresponding bicyclic analogues .We already reported the self-assembly of macrocyclic boronic esters simply by mixing a di- or tri-boronic acid with the indacene-type bis anol/THF . When nae Fig. S2, indicats Fig. S1, and theperiment . Associa3 was carried out in the presence of naphthalene and anthracene aiming at the selective inclusion of one guest compound in 3 (K) of 3 with anthracene (218 M–1) than with naphthalene (104 M–1), anthracene was expected to be included in 3 preferentially. In fact, anthracene-included 3 (3·ANT·CH2Cl2) selectively precipitated out in 92% yield as dichloromethane solvate when equimolar amounts of 1, rac-2, naphthalene, and anthracene were mixed in methanol/dichloromethane (1 : 1) at room temperature for 24 h (ANT/NA ≥ 20 : 1 by 1H NMR). Powder X-ray diffraction (PXRD) analysis of the precipitate showed that the precipitate was an aggregate of microcrystals  were also applicable instead of dichloromethane for the selective inclusion of anthracene, suggesting the importance of the difference of the association constants of the two guest compounds rather than cosolvent used in the self-assembly of the host–guest complex (Table S323 (3·NA·4CHCl3) was selectively obtained as a crystalline precipitate in 96% yield when chloroform was used as cosolvent (NA/ANT ≥ 20 : 1 by 1H NMR).Next, the self-assembly of und in 3 . Conside Fig. S25, and rec Fig. S28.13 OtherTable S32. Interes3·NA·4CHCl3 suitable for X-ray analysis was prepared by vapor diffusion of hexane into a chloroform solution of 3·NA. As shown in 3·NA·4CHCl3 forms hydrogen bonds with two chloroform molecules by the oxygen atom of the boronic ester moiety and the nitrogen atom of the benzothiadiazole moiety, and thus each 3·NA is surrounded by four chloroform molecules . That is, two chloroform molecules, forming hydrogen bonds with neighboring 3·NA·4CHCl3, are additionally located just before and after the included naphthalene molecule  was obtained where each 3·ANT also formed hydrogen bonds with four chloroform molecules  than those of the corresponding bicyclic ones , tricyclic heterocyclic compounds are considered to be included in 3 when dichloromethane is used as cosolvent. When the self-assembly of 3 was carried out using dichloromethane, 3·DBT·CH2Cl2, 3·DBF·CH2Cl2, and 3·ACR·CH2Cl2 were selectively precipitated out in high yields in the presence of the corresponding bicyclic guest molecules, respectively (tricyclic/bicyclic ≥ 20 : 1 by 1H NMR). On the other hand, when the same experiments were carried out using chloroform as cosolvent, the reversal of the selectivity occurred and bicyclic compounds were selectively included in 3 as 3·BT·4CHCl3, 3·BF·4CHCl3, and 3·QU·4CHCl3, respectively (bicyclic/tricyclic ≥ 20 : 1 by 1H NMR). Single crystal X-ray diffraction analyses of 3·guest·4CHCl3 including these bicyclic heteroaromatic compounds revealed that the packing structures were identical to that of 3·NA·4CHCl3 (P21/c), indicating that the selective inclusion of the bicyclic compounds is attributed to the formation of the stable packing structure possessing the confined cavity created by 3 and chloroform molecules (Fig. S27 and S32–S3413We envisaged that the selective inclusion of each of the two guest compounds should also be applicable to several other combinations of bicyclic and tricyclic heteroaromatic compounds . Accordi3 containing benzothiadiazole moiety. The use of discrete self-assembled structure as crystalline host compound was found to have an advantage over extended porous frameworks such as MOFs in terms of the alteration of the guest selectivity. Although the crystalline-state guest selectivity generally coincided with the order of solution-state association energies of host–guest complexes when common organic solvents such as dichloromethane were used as the cosolvent, the guest selectivity was altered by using chloroform as the cosolvent, which could bind with host 3 by hydrogen bonding, thus forming the stable crystal structure with restricted space for guest inclusion. It should be noted that the solution-state association constant of a discrete self-assembled structure has not been utilized as an aid to understand the guest selectivity in crystalline-state to date. Moreover, the effective use of solvent effect for the switching of crystalline-state guest selectivity was demonstrated for the first time.In conclusion, the selective inclusion of each of two kinds of guest molecules was achieved by using the crystalline macrocyclic boronic ester Supplementary informationClick here for additional data file.Crystal structure dataClick here for additional data file.


Our work may guide rational design of electrocatalysts that work well at high current densities.Large-scale implementation of electrochemical hydrogen production requires several fundamental issues to be solved, including understanding the mechanism and developing inexpensive electrocatalysts that work well at high current densities. Here we address these challenges by exploring the roles of morphology and surface chemistry, and develop inexpensive and efficient electrocatalysts for hydrogen evolution. Three model electrocatalysts are flat platinum foil, molybdenum disulfide microspheres, and molybdenum disulfide microspheres modified by molybdenum carbide nanoparticles. The last catalyst is highly active for hydrogen evolution independent of pH, with low overpotentials of 227 mV in acidic medium and 220 mV in alkaline medium at a high current density of 1000 mA cm Hydrogen production from water provides one avenue toward harnessing renewable energy, although large-scale implementation remains a challenge. Here, authors explore roles of morphology and surface chemistry, and develop efficient catalysts for hydrogen evolution at high current densities. Unfortunately, there are several problems preventing the widespread use of Pt-based electrocatalysts, including limited reserves and high cost. Researchers have devoted a great deal of efforts to finding Pt-free electrocatalysts, including Ru2, transition metal disulfides6, metal carbides8, and metal phosphides10. For example, Mahmood et al. have reported an efficient electrocatalyst made of two-dimensional (2D) carbon decorated with Ru nanoparticles, which exhibits an activity for HER that is comparable to that of the commercial Pt/C catalyst with Tafel slopes of ~30 and ~38 mV dec−1 in acidic and alkaline media, respectively2. Although the cost of Ru is only 4% of Pt, its reserve is even lower than that of Pt, making its large-scale use questionable. Therefore, earth-abundant catalysts such as MoS2 have attracted intense research interest due to their low cost and high availability. Staszak-Jirkovský et al. have reported an HER electrocatalyst composed of CoMoSx chalcogels, which shows decent stability and catalytic performance with an overpotential of ~200 mV at 5 mA cm−2 in an acidic electrolyte (pH ~1)6. Despite the discovery of relatively cheap electrocatalysts for HER, they are currently not viable for water splitting because they exhibit either higher overpotentials or poorer stability than Pt-based catalysts6.The extensive use of fossil fuels has led to environmental pollution, and the need for sustainable energy storage is becoming more urgent. Electrochemical water splitting promises the production of clean hydrogen fuel from water, especially when the reaction is driven by electricity generated by wind, solar, or other renewable energy resources. However, water splitting is hindered by slow kinetics, resulting in the need for highly efficient and durable electrocatalysts. The hydrogen evolution reaction (HER) is usually initiated by the formation of adsorbed hydrogen intermediates (the Volmer step), followed by either a recombination step (the Tafel step) or an electrochemical desorption step (the Heyrovsky step) in acidic protonic media. Because of its fast kinetics in these steps−2, and can reach 1000 mA cm−2 in some cases11. For proton exchange membrane electrolyzers, the current densities are in the range of 1000–2000 mA cm−2. Unfortunately, these nonprecious catalysts, and even Pt/C, operate well only at low current densities , having fairly large overpotentials at high current densities13. In industry, Raney Ni is the currently-used electrocatalyst for alkaline HER and operates well at high current densities such as 500 mA cm−2. Although it has several advantages like low cost, large surface area, and good stability, it has overpotentials of ~300–500 mV at 500 mA cm−2 and Tafel slopes of ~90–120 dec−1 even in concentrated 30 wt% KOH solutions16. Therefore, developing electrocatalysts that perform well at high current densities is critical for large-scale use. To this end, Chen et al. have recently reported that α-MoB2 has decent catalytic activity for HER at very high hydrogen coverage, showing an overpotential less than 400 mV at 1000 mA cm−2 in an acid medium11. We note that these catalysts either have large overpotentials or are only suitable for a specific pH for HER at high current densities. Developing catalysts that work well in a wide pH range is important not only for an understanding of the different HER mechanisms in acidic and alkaline media, but also for use in different pH conditions based on specific needs. This is therefore another important issue to be addressed, especially when considering the slow water dissociation kinetics in an alkaline medium for most catalysts such as Pt and MoS2, which results in poorer catalytic activity in alkaline than in acidic media20. Many efforts have been devoted to improve the HER performance of electrocatalysts in alkaline media22. Subbaraman et al. have studied the HER activity of Pt in an alkaline medium by decorating Pt surfaces with Ni(OH)2 nanoclusters, and the resulting material shows an overpotential half that of pure Pt at 10 mA cm−217. Later, other metal hydroxides such as Co(OH)2 have also been shown to work as water dissociation promoters in alkaline media25. However, species that can work as kinetic promoters for water dissociation are few and are mainly limited to metal hydroxides and oxyhydroxides. Overall, the challenges in designing catalysts that work well over a range of pH values at high current densities stem from the fact that HER involves electron transfer and redistribution at liquid–solid–gas interfaces, which becomes complicated at large current densities and in different pH conditions26. Specifically, features of a catalyst may affect electron transfer rate, the amount and exposure of active sites, accessibility of catalytic surfaces to reactants, bonding strength with hydrogen, and water dissociation kinetics, and thus would influence their HER performance at high current densities.For practical industrial uses, the performance of electrocatalysts at large current densities is critical. For example, the current densities widely used in alkaline electrolyzers range from 200 to 500 mA cm2 microspheres made of MoS2 nanosheets, and MoS2 microspheres decorated by Mo2C nanoparticles (MoS2/Mo2C). Based on these studies, an efficient catalyst for HER at high current density over a range of pH values is synthesized. Microspheres are composed of radially aligned MoS2 nanosheets that are decorated by Mo2C nanoparticles at their edges  and 44 mV dec−1 , and good durability during a 24 h test in both media. Experimental and theoretical investigations show that Mo2C modified by surface oxygen groups formed during the HER not only promotes the interfacial mass transfer of reactants and hydrogen gas bubbles on MoS2, but also speeds up the water dissociation and hydrogen absorption kinetics, resulting in decent HER performance at high current densities.Here, we address these challenges by developing electrocatalysts with an optimized morphology and surface chemistry. Three model electrocatalysts with different morphologies or/and surface chemistry are used, i.e., a flat Pt foil, MoS2/Mo2C catalyst was synthesized by a two-step method. First, microspheres of radially aligned MoS2 nanosheets were grown on Ti foils by a hydrothermal method at 180 °C for 24 h. They were then loaded into a chemical vapor deposition (CVD) furnace and heated to 750 °C for the reaction with CH4 to prepare MoS2/Mo2C (see details in the “Methods” section). Scanning electron microscopy (SEM) images show that the MoS2/Mo2C has a rugged morphology derived from the spherical MoS2 , followed by carbonization in which CHx combines with the remaining Mo31. As a result, the MoS2 edges are converted into Mo2C nanoparticles as shown in Fig. 2   and 405 cm−1 (E2g1) as well as β-Mo2C peaks at 660, 812, and 987 cm−1, confirming the formation of β-Mo2C on the MoS2  or G bands (~1590 cm−1) associated with carbon materials, suggesting that there is no graphitic carbon formed after CVD. This is understandable because the reaction temperature is relatively low (750 °C) and no catalyst is added for the carbonization process, so that no graphitic carbon materials like graphene or carbon nanotubes are formed on the MoS2. The X-ray photoelectron spectroscopy (XPS) spectra of Mo 3d show two peaks located at 229.3 and 232.4 eV from Mo 3d5/2 and Mo 3d3/2 in Mo(IV), originating from MoS2. In addition, there are two peaks at 228.2 and 231.5 eV, from the Mo 3d5/2 and Mo 3d3/2 in Mo(II), suggesting the existence of Mo2C  and surface chemistry  on the performance of catalysts in a large current density HER. First, the HER performance of the three samples was tested in both acidic and alkaline media. All working electrodes were encapsulated  than Pt foil (567 @ 500 mA cm−2 and 822 mV @ 1000 mA cm−2) and MoS2 (589 @ 500 mA cm−2 and 788 mV @ 1000 mA cm−2), suggesting its superior performance at large current densities. As a control experiment, we sintered a MoS2 sample in Ar/H2 at the same conditions with the carbonization experiments, but without introducing CH4 (sample denoted as MoS2-H). We tested the HER performance of MoS2-H and found that though catalytic performance increases a little, it is much worse than the MoS2/Mo2C, indicating Mo2C plays an important role in the good HER performance of MoS2/Mo2C  transfers at interfaces are critical steps in the HER, especially at large current densities2 are strongly potential-dependent, but that of MoS2/Mo2C is not  is the rate-limiting step23. As the current density increases, mass transfer plays a key role in determining the current. Therefore, we summarized the ratios of ∆η/∆log|j|  of three samples at different current densities to evaluate how much overpotential is needed when current increases, which could be an indicator to evaluate the performance of a catalyst at high current densities and is meaningful for practical use , but that of the Pt foil increases to more than 120 mV dec−1 when increasing the current density. Moreover, when current density is very large , the performance of Pt and MoS2 is greatly affected by mass transfer at the interface, leading to much larger overpotentials needed to achieve a current density of 1000 mA cm−2 in Pt and MoS2 than in MoS2/Mo2C  in acidic media while Pt foil and MoS2 have large ratios (much larger than 40 mV dec−1) as current density increases  of a droplet of 1.0 M KOH on their surfaces. The CAs are 82.3°, 53.8°, and ~0° for Pt foil, MoS2, and MoS2/Mo2C, respectively, indicating the best wettability of MoS2/Mo2C by the electrolyte , but neither Pt nor MoS2 is good enough for practical use  in molybdenum oxides, Mo2C(OH)x (–OH terminated), Mo2COx (–O terminated), and Mo2C(OH)x–H2O (–OH terminated with strongly adsorbed water), respectively40. Note that after cycling in acidic or alkaline media, the surface of β-Mo2C is modified by terminating –OH and –O groups. This phenomenon was also found in other materials in previous studies, such as Mo2C and Ti3C2 in MXenes41. In contrast, neither Mo 3d nor S 2p peaks of the MoS2 show any observable changes, suggesting that there is no obvious change of MoS2, such as proton intercalation or surface oxygen modification during the above electrochemical process 43, it is reasonable to argue that Mo2C would serve as a better promoter and assist electrochemical hydrogen evolution.The MoS2C surface during HER, we used pure β-phase Mo2C as a model material, and the oxygen species formed on Mo2C surface were analyzed by high-resolution XPS. Figure 2C. It is evident that as the electrochemical potential increases, the main peak of surface oxygen changes from –OH terminated species to –O terminated species  and become –OH terminated at a potential of −1.5 V vs RHE. At pH = 0, the trend is similar. To further understand the relationship between electrochemical potential, pH, and oxygen species on Mo2C surface, we performed density functional theory (DFT) calculations and obtained a Pourbaix diagram, which shows the most stable oxygen species on Mo2C surfaces as a function of pH and electrochemical potential  surface at different potentials and pH values show good agreement with the experimental results in Fig. 2C (101) surfaces play a key role in determining the catalytic performance. In contrast, in alkaline media, –O terminated Mo2C (101) surfaces play a key role. To explain the catalytic performance of these surfaces in different media, Fig. 2O (OH and H) on an –O terminated surface as a function of the number of adsorbed H2O molecules. It can be seen that a hydrogen free energy of ~0.1 eV and a small energy barrier for water dissociation (~0.25 eV) are achieved, corresponding to fast hydrogen absorption/desorption and water dissociation kinetics. The relaxed structures of H on –OH terminated, and disassociated H2O on –O terminated Mo2C (101) are shown in Fig. 2/Mo2C compared to MoS2 in both acidic and alkaline media. These results are interesting for two reasons. First, the surface oxygen formed on β-Mo2C during HER changes the electron distribution on β-Mo2C surface, which highlights the importance of the interaction between the catalyst and the electrochemical conditions on its performance. Second, the oxygen-terminated β-Mo2C surface theoretically increases the interfacial mass transfer of the catalyst because oxygen terminates have a strong affinity to water and weak affinity to gas bubbles. It is possible that this could be further developed to design even better electrocatalysts than MoS2/Mo2C.To identify the oxygen species formed on Moies Fig. . For exa2 microspheres made of MoS2 nanosheets, and the same MoS2 microspheres decorated by Mo2C nanoparticles (MoS2/Mo2C). The MoS2/Mo2C electrocatalyst is highly active and stable, and is a catalyst for HER at all pH values, performing especially well at a large current density of 1000 mA cm−2. Experimental and theoretical investigations indicate that improved interfacial mass transfer and surface oxygen formed on β-Mo2C during HER are two crucial reasons for the good HER performance of MoS2/Mo2C. First, in addition to structures with both micro- and nanoscale roughness, surface chemistry at the atomic level is crucial for interfacial mass transfer at large current densities. This finding suggests that electrocatalysts should be modified with species with good water affinity at the atomic level. Second, the interactions between electrochemical conditions and Mo2C lead to self-optimized oxygen on Mo2C surface, where oxygen-terminated Mo2C (101) shows fast kinetics for both hydrogen absorption/desorption and water dissociation. These findings shine new light on the effect of morphology and surface chemistry on HER performance especially at large current densities, and pave the way to design good electrocatalysts for practical HER use. Furthermore, the discovery of oxygen-terminated β-Mo2C for promoting water dissociation can be used to design other HER electrocatalysts that work well in both acidic and alkaline media.We have explored the roles of the morphology and surface chemistry of catalysts on HER at large current densities using three model electrocatalysts, i.e., a flat Pt foil, MoS2 microspheres on a Ti foil by a hydrothermal method. First, a piece of Ti foil  was cleaned with concentrated HCl (37 wt%) for 30 min, then bath sonicated in deionized water and ethanol, each for 5 min. Second, amine molybdate ((NH4)6Mo7O24•4H2O, 0.1766 g) and thiocarbamide (CS(NH2)2, 0.484 g) were added to deionized water (36 mL) and stirred to form a clear solution. Finally, the aqueous solution contains the Mo and S precursors and the Ti foil were transferred to a Teflon-lined stainless-steel autoclave (50 mL), maintained at 180 °C for 24 h to grow MoS2 on the Ti foil33. The Ti foil with a black film on its surface was taken out of the autoclave and thoroughly rinsed with deionized water and ethanol, and then dried in vacuum at 60 °C for 6 h. We used the hydrothermal method to synthesize MoS2 because a little oxygen can be introduced into MoS2 during the synthesis, which would increase the HER performance of MoS244.We grew MoS2 grown on it was put into a 1.5 in. diameter horizontal quartz tube furnace that was heated to 750 °C with a mixture of Ar (100 standard cubic centimeter per minute (sccm)) and H2 (30 sccm) in 30 min. CH4 (10 sccm) was then introduced into the tube furnace and the CVD was performed at 750 °C for different times  to prepare the MoS2/Mo2C samples. After the reaction, the CH4 was turned off and the furnace was cooled to room temperature under Ar (100 sccm) and H2 (30 sccm).The Ti foil with MoSλ = 0.15418 nm, Bruker D8 Advance, Germany) and high-resolution XPS . The pass energy was 20 eV and energy step size was 0.1 eV. Oxygen species on the surface of the Mo2C were analyzed by high-resolution XPS after the samples had been collected and dried inside an Ar-filled glove box. The samples were exposed to air for less than 1 min before the XPS measurements to avoid oxidation in an ambient environment. XPS of each sample that experienced HER at a particular potential and pH was performed at least twice. The CAs of droplets on the sample surfaces were recorded by a contact angle measuring device . The droplet volume was the same in each case.The morphology of the samples was examined by SEM . TEM and HRTEM analyses were carried out at an electron acceleration voltage of 300 kV . Raman spectra were collected using 532 nm laser excitation with a beam size of ~1 μm . Structural and chemical analyses of the samples were performed by powder XRD  or H2SO4 solution (0.5 M) was used in all tests, with a saturated calomel electrode (SCE) and a graphite rod as the reference and counter electrodes, respectively. The scan rate was 5 mV s−1 for linear sweep voltammetry tests and 50 mV s−1 for long-term cyclic voltammetry tests. Before each test, the electrolyte was bubbled with Ar for 15 min to remove dissolved oxygen in the solution.The MoS46, all calculations were performed using the Perdew–Burke–Ernzerhof version47 of generalized gradient approximation for DFT. The ion–electron interaction was described by projector-augmented wave potentials49. A symmetric (2 × 3) Mo2C (101) slab consisting of five layers of Mo and four layers of C, and a symmetric (3 × 3) Mo2C (001) slab composed of three layers of Mo2C were constructed as our models. During structural relaxation, the bottom two layers of Mo and C for the (101) slab and the bottom Mo2C layer for the (001) slab were fixed. In the aperiodic direction, a vacuum layer larger than 10 Å was selected to keep spurious interactions negligible. The force convergence for structural relaxation was set to be 0.01 eV/Å. The thermodynamic free energies G = EDFT + EZPE − TS were determined following the computational hydrogen electrode model50. Here, EDFT and EZPE are the DFT ground state and zero-point energies. The molecular entropy was taken from the standard tables for gas-phase molecules50, and the vibrational entropy for adsorbed species was calculated as 51. For the Pourbaix diagram, the adsorption energies of O and OH were obtained taking H2O and H2 as references, based on equations (6) and (7) in ref. 50.Using the Vienna Ab-initio Simulation PackageSupplementary informationPeer Review FileDescription of Additional Supplementary InformationSupplementary Movie 1Supplementary Movie 2Source Data