Molecular architectures of iron complexes for oxygen reduction catalysis-Activity enhancement by hydroxide ions coupling.

Developing cost-effective and high-performance electrocatalysts for oxygen reduction reaction (ORR) is critical for clean energy generation. Here, we propose an approach to the synthesis of iron phthalocyanine nanotubes (FePc NTs) as a highly active and selective electrocatalyst for ORR. The performance is significantly superior to FePc in randomly aggregated and molecularly dispersed states, as well as the commercial Pt/C catalyst. When FePc NTs are anchored on graphene, the resulting architecture shifts the ORR potentials above the redox potentials of Fe2+/3+ sites. This does not obey the redox-mediated mechanism operative on conventional FePc with a Fe2+-N moiety serving as the active sites. Pourbaix analysis shows that the redox of Fe2+/3+ sites couples with HO- ions transfer, forming a HO-Fe3+-N moiety serving as the ORR active sites under the turnover condition. The chemisorption of ORR intermediates is appropriately weakened on the HO-Fe3+-N moiety compared to the Fe2+-N state and thus is intrinsically more ORR active.

Single-Molecule Discrimination of Saccharides Using Carbon Nitride Nanopores.

Structural complexity brings a huge challenge to the analysis of sugar chains. As a single-molecule sensor, nanopores have the potential to provide fingerprint information on saccharides. Traditionally, direct single-molecule saccharide detection with nanopores is hampered by their small size and weak affinity. Here, a carbon nitride nanopore device is developed to discern two types of trisaccharide molecules (LeApN and SLeCpN) with minor structural differences. The resolution of LeApN and SLeCpN in the mixture reaches 0.98, which has never been achieved in solid-state nanopores so far. Monosaccharide (GlcNAcpN) and disaccharide (LacNAcpN) can also be discriminated using this system, indicating that the versatile carbon nitride nanopores possess a monosaccharide-level resolution. This study demonstrates that the carbon nitride nanopores have the potential for conducting structure analysis on single-molecule saccharides.

Customizable Organic Charge-Transfer Cocrystals for the Dual-Mode Optoelectronics in the NIR (II) Window.

Organic molecules have been regarded as ideal candidates for near-infrared (NIR) optoelectronic active materials due to their customizability and ease of large-scale production. However, constrained by the intricate molecular design and severe energy gap law, the realization of optoelectronic devices in the second near-infrared (NIR (II)) region with required narrow band gaps presents more challenges. Herein, we have originally proposed a cocrystal strategy that utilizes intermolecular charge-transfer interaction to drive the redshift of absorption and emission spectra of a series BFXTQ (X = 0, 1, 2, 4) cocrystals, resulting in the spectra located at NIR (II) window and reducing the optical bandgap to ∼0.98 eV. Significantly, these BFXTQ-based optoelectronic devices can exhibit dual-mode optoelectronic characteristics. An investigation of a series of BFXTQ-based photodetectors exhibits detectivity (D*) surpassing 1013 Jones at 375 to 1064 nm with a maximum of 1.76 × 1014 Jones at 1064 nm. Moreover, the radiative transition of CT excitons within the cocrystals triggers NIR emission over 1000 nm with a photoluminescence quantum yield (PLQY) of ∼4.6% as well as optical waveguide behavior with a low optical-loss coefficient of 0.0097 dB/µm at 950 nm. These results promote the advancement of an emerging cocrystal approach in micro/nanoscale NIR multifunctional optoelectronics.

Mogroside Alleviates Diabetes Mellitus and Modulates Intestinal Microflora in Type 2 Diabetic Mice.

Mogroside, the main component of Siraitia grosvenorii (Swingle) C. Jeffrey (Cucurbitaceae) is a natural product with hypoglycemic and intestinal microbiota regulating properties. However, whether the alteration of intestinal microbiota is associated with the antidiabetic effect of mogroside remains poorly understood. This study investigated the mechanism underlying the hypoglycemic effect of mogroside in regulating intestinal flora and attenuating metabolic endotoxemia. Kunming mice with type 2 diabetes mellitus (T2DM) induced by high-fat diet and intraperitoneal injection of streptozotocin were randomly divided into model, pioglitazone (2.57 mg/kg) and mogroside (200, 100, and 50 mg/kg) groups. After 28 d of administration, molecular changes related to glucose metabolism and metabolic endotoxemia in mice were evaluated. The levels of insulin receptor substrate-1 (IRS-1), cluster of differentiation 14 (CD14) and toll-like receptor 4 (TLR4) mRNAs were measured, and the composition of intestinal microflora was determined by 16s ribosomal DNA (rDNA) sequencing. The results showed that mogroside treatment significantly improved hepatic glucose metabolism in T2DM mice. More importantly, mogroside treatment considerably reduced plasma endotoxin (inhibition rate 65.93%, high-dose group) and inflammatory factor levels, with a concomitant decrease in CD14 and TLR4 mRNA levels. Moreover, mogroside treatment reduced the relative abundance of Firmicutes and Proteobacteria (the inhibition rate of Proteobacteria was 85.17% in the low-dose group) and increased the relative abundance of Bacteroidetes (growth rate up to 40.57%, high-dose group) in the intestines of diabetic mice. This study reveals that mogroside can relieve T2DM, regulating intestinal flora and improving intestinal mucosal barrier, indicating that mogroside can be a potential therapeutic agent or intestinal microbiota regulator in the treatment of T2DM.

Polarization Conforms Performance Variability in Amorphous Electrodeposited Iridium Oxide pH Sensors: A Thorough Surface Chemistry Investigation.

Electrodeposited amorphous hydrated iridium oxide (IrOx) is a promising material for pH sensing due to its high sensitivity and the ease of fabrication. However, durability and variability continue to restrict the sensor's effectiveness. Variation in probe films can be seen in both performance and fabrication, but it has been found that performance variation can be controlled with potentiostatic conditioning (PC). To make proper use of this technique, the morphological and chemical changes affecting the conditioning process must be understood. Here, a thorough study of this material, after undergoing PC in a pH-sensing-relevant potential regime, was conducted by voltammetry, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Fitting of XPS data was performed, guided by raw trends in survey scans, core orbitals, and valence spectra, both XPS and UPS. The findings indicate that the PC process can repeatably control and conform performance and surface bonding to desired calibrations and distributions, respectively; PC was able to reduce sensitivity and offset ranges to as low as ±0.7 mV/pH and ±0.008 V, respectively, and repeat bonding distributions over ~2 months of sample preparation. Both Ir/O atomic ratios (shifting from 4:1 to over 4.5:1) and fitted components assigned hydroxide or oxide states based on the literature (low-voltage spectra being almost entirely with suggested hydroxide components, and high-voltage spectra almost entirely with suggested oxide components) trend across the polarization range. Self-consistent valence, core orbital, and survey quantitative trends point to a likely mechanism of ligand conversion from hydroxide to oxide, suggesting that the conditioning process enforces specific state mixtures that include both theoretical Ir(III) and Ir(IV) species, and raising the conditioning potential alters the surface species from an assumed mixture of Ir species to more oxidized Ir species.

Single Molecule Protein Segments Sequencing by a Plasmonic Nanopore.

Obtaining sequential and conformational information on proteins is vital to understand their functions. Although the nanopore-based electrical detection can sense single molecule (SM) protein and distinguish among different amino acids, this approach still faces difficulties in slowing down protein translocation and improving ionic current signal-to-noise ratio. Here, we observe the unfolding and multistep sequential translocation of SM cytochrome c (cyt c) through a surface enhanced Raman scattering (SERS) active conical gold nanopore. High bias voltage unfolds SM protein causing more exposure of amino acid residues to the nanopore, which slows down the protein translocation. Specific SERS traces of different SM cyt c segments are then recorded sequentially when they pass through the hotspot inside the gold nanopore. This study shows that the combination of SM SERS with a nanopore can provide a direct insight into protein segments and expedite the development of nanopore toward SM protein sequencing.

Unveiling the Solvent Effect in Plasmon Enhanced Electrochemistry via the Nanoparticle-Impact Technique.

Plasmon-enhanced electrochemistry (PEEC) has been observed to facilitate energy conversion systems by converting light energy to chemical energy. However, comprehensively understanding the PEEC mechanism remains challenging due to the predominant use of ensemble-based methodologies on macroscopic electrodes, which fails to measure electron-transfer kinetics due to constraints from mass transport and the averaging effect. In this study, we have employed nanoparticle impact electrochemistry (NIE), a newly developed electroanalytical technique capable of measuring electrochemical dynamics at a single-nanoparticle level under optimal mass transport conditions, along with microscopic electron-transfer theory for data interpretation. By investigating the plasmon enhanced hydrogen evolution reaction (HER) at individual silver nanoparticles (AgNPs), we have clearly revealed the previously unknown influence of solvent effects within the PEEC mechanism. This finding suggests an additional approach to optimize plasmon-assisted electrocatalysis and electrosynthesis systems.

Single-Molecule Electrical and Spectroscopic Profiling Protein Allostery Using a Gold Plasmonic Nanopore.

Direct structural and dynamic characterization of protein conformers in solution is highly desirable but currently impractical. Herein, we developed a single molecule gold plasmonic nanopore system for observation of protein allostery, enabling us to monitor translocation dynamics and conformation transition of proteins by ion current detection and SERS spectrum measurement, respectively. Allosteric transition of calmodulin (CaM) was elaborately probed by the nanopore system. Two conformers of CaM were well-resolved at a single-molecule level using both the ion current blockage signal and the SERS spectra. The collected SERS spectra provided structural evidence to confirm the interaction between CaM and the gold plasmonic nanopore, which was responsible for the different translocation behaviors of the two conformers. SERS spectra revealed the amino acid residues involved in the conformational change of CaM upon calcium binding. The results demonstrated that the excellent spectral characterization furnishes a single-molecule nanopore technique with an advanced capability of direct structure analysis.

Ultrasensitive Plasmon-Enhanced Infrared Spectroelectrochemistry.

IR spectroelectrochemistry (EC-IR) is a cutting-edge operando method for exploring electrochemical reaction mechanisms. However, detection of interfacial molecules is challenged by the limited sensitivity of existing EC-IR platforms due to the lack of high-enhancement substrates. Here, we propose an innovative plasmon-enhanced infrared spectroelectrochemistry (EC-PEIRS) platform to overcome this sensitivity limitation. Plasmonic antennae with ultrahigh IR signal enhancement are electrically connected via monolayer graphene while preserving optical path integrity, serving as both the electrode and IR substrate. The [Fe(CN)6 ]3- /[Fe(CN)6 ]4- redox reaction and electrochemical CO2 reduction reaction (CO2 RR) are investigated on the EC-PEIRS platform with a remarkable signal enhancement. Notably, the enhanced IR signals enable a reconstruction of the electrochemical curve of the redox reactions and unveil the CO2 RR mechanism. This study presents a promising technique for boosting the in-depth understanding of interfacial events across diverse applications.

Synergistic Al-Al Dual-Atomic Site for Efficient Artificial Nitrogen Fixation.

Synthesis of ammonia by electrochemical nitrogen reduction reaction (NRR) is a promising alternative to the Haber-Bosch process. However, it is commonly obstructed by the high activation energy. Here, we report the design and synthesis of an Al-Al bonded dual atomic catalyst stabilized within an amorphous nitrogen-doped porous carbon matrix (Al2NC) with high NRR performance. The dual atomic Al2-sites act synergistically to catalyze the complex multiple steps of NRR through adsorption and activation, enhancing the proton-coupled electron transfer. This Al2NC catalyst exhibits a high Faradaic efficiency of 16.56±0.3 % with a yield rate of 29.22±1.2 µg h-1 mgcat -1. The dual atomic Al2NC catalyst shows long-term repeatable, and stable NRR performance. This work presents an insight into the identification of synergistic dual atomic catalytic site and mechanistic pathway for the electrochemical conversion of N2 to NH3.

Design of Near-Infrared-Triggered Metallo-Photosensitizers via a Self-Assembly-Induced Vibronic Decoupling Strategy.

Development of highly efficient near-infrared (NIR)-excited photosensitizers is hampered by the fast nonradiative vibrational relaxation process regulated by the energy gap law. Here, from the fundamental perspective we propose that the intermolecular coupling of well-designed photosensitizers has the potential to facilitate exciton delocalization and hence reduce the exciton-vibration coupling, thereby boosting their phototherapeutic efficacy via inhibition of the vibrational relaxation pathway. Such conceived NIR-excited metallo-photosensitizers (IrHA1 and IrHA2) were prepared and studied for experimental validation. The resulting iridium complexes exhibited a little singlet oxygen (1O2) production in the monomeric state, but produced substantially enhanced 1O2 generation efficiency via benefiting from the exciton-vibration decoupling in the self-assembly state. Particularly, IrHA2 exhibits an unprecedented high 1O2 quantum yield of 54.9% (FDA-approved NIR dye indocyanine green: ΦΔ = 0.2%) under 808 nm laser irradiation with negligible heat generation, probably attributed to the suppression of vibronic couplings from the stretching mode of the acceptor ligand. In phototherapy, IrHA2-NPs with high biocompatibility and low dark toxicity can induce substantial tumor regression with 92.9% tumor volume reduction in vivo. This self-assembly-induced vibronic decoupling strategy would offer an effective approach to the design of high-performance NIR-excited photosensitizers.

Homochiral Zeolitic Imidazolate Framework with Defined Chiral Microenvironment for Electrochemical Enantioselective Recognition.

The recognition and separation of chiral molecules with similar structure are of great industrial and biological importance. Development of highly efficient chiral recognition systems is crucial for the precise application of these chiral molecules. Herein, a homochiral zeolitic imidazolate frameworks (c-ZIF) functionalized nanochannel device that exhibits an ideal platform for electrochemical enantioselective recognition is reported. Its distinct chiral binding cavity enables more sensitive discrimination of tryptophan (Trp) enantiomer pairs than other smaller chiral amino acids owing to its size matching to the target molecule. It is found that introducing neighboring aldehyde groups into the chiral cavity will result in an inferior chiral Trp recognition due to the decreased adsorption-energy difference of D- and L-Trp on the chiral sites. This study may provide an alternative strategy for designing efficient chiral recognition devices by utilizing the homochiral reticular materials and tailoring their chiral environments.

Closed Bipolar Electrode Array for Optical Reporting Reaction-Coupled Electrochemical Sensing and Imaging.

This review centers on a closed bipolar electrode (BPE) array using an electro-fluorochromism (EFC) or electro-chemiluminescence (ECL) reaction as the reporting reaction. Electrochemical signals at one pole of the closed BPE array can be transduced into the EFC or ECL signals at the opposite pole. Therefore, the current signal of a redox reaction can be easily detected and imaged by monitoring the luminescence signal. Recent developments in closed BPE array-based EFC and ECL sensing and imaging are summarized and discussed in detail. Finally, we consider the challenges and opportunities for improving the spatial resolution of closed BPE array-based electrochemical imaging, and emphasize the important application of this technique to the imaging of cellular activities at the single-cell level.

Organic Matter Counteracts the Enhancement of Cr(III) Extractability during the Fe(II)-Catalyzed Ferrihydrite Transformation: A Nanoscale- and Molecular-Level Investigation.

Phase transformation of ferrihydrite to more stable Fe (oxyhydr)oxides, catalyzed by iron(II) [Fe(II)], significantly influences the mobility of heavy metals [e.g., chromium (Cr)] associated with ferrihydrite. However, the impact of organic matter (OM) on the behavior of Cr(III) in the Fe(II)-catalyzed transformation of ferrihydrite and the underlying mechanisms are unclear. Here, the Fe(II)-catalyzed transformation of the coprecipitates of Fe(III), Cr(III), or rice straw-derived OM was studied at the nanoscale and molecular levels using Fe and Cr K-edge X-ray absorption spectroscopy and spherical aberration corrected scanning transmission electron microscopy (Cs-STEM). Batch extraction results suggested that the OM counteracted the enhancement of Cr(III) extractability during the Fe(II)-catalyzed transformation. Cs-STEM and XAS analysis suggested that Cr(III) could be incorporated into the goethite formed by Fe(II)-catalyzed ferrihydrite transformation, which, however, was inhibited by the OM. Furthermore, Cs-STEM analysis also provided direct nanoscale level evidence that residual ferrihydrite could re-immobilize the released Cr(III) during the Fe(II)-catalyzed transformation process. These results highlighted that the decreased extractability of Cr(III) mainly resulted from the inhibition of OM on the Fe(II)-catalyzed transformation of ferrihydrite to secondary Fe (oxyhydr)oxides, which facilitates insightful understanding and prediction of the geochemical cycling of Cr in soils with active redox dynamics.

Health outcomes of age at menarche in European women: a two-sample Mendelian randomization study.

BACKGROUND: Observational studies have shown an association between age at menarche (AAM) and the risk of gynecological diseases. However, the causality cannot be determined due to residual confounding. METHODS: We conducted a Mendelian randomization (MR) study to evaluate the causal effect of AAM on several gynecological diseases, including endometriosis, female infertility, pre-eclampsia or eclampsia, uterine fibroids, breast cancer, ovarian cancer, and endometrial cancer. Single nucleotide polymorphisms were used as genetic instruments. The inverse variance weighted method was used as the primary approach and several other MR models were conducted for comparison. Cochran's Q test, Egger's intercept test, and leave-one-out analysis were conducted for sensitivity analysis. Radial MR analysis was conducted when detecting the existence of heterogeneity. RESULTS: After Bonferroni correction and thorough sensitivity analysis, we observed a robust causal effect of AAM on endometrial cancer (odds ratio: 0.80; 95% confidence interval: 0.72-0.89; P = 4.61 × 10-5) and breast cancer (odds ratio: 0.94; 95% confidence interval: 0.90-0.98; P = .003). Sensitivity analysis found little evidence of horizontal pleiotropy. The inverse variance weighted method also detected weak evidence of associations of AAM with endometriosis and pre-eclampsia or eclampsia. CONCLUSIONS: This MR study demonstrated a causal effect of AAM on gynecological diseases, especially for breast cancer and endometrial cancer, which indicates AAM might be a promising index to use for disease screening and prevention in clinical practice. Key messages What is already known on this topic - Observational studies have reported associations between age at menarche (AAM) and a variety of gynecological diseases but the causality has not been determined. What this study adds - This Mendelian randomization study demonstrated that AAM causally affects the risk of breast cancer and endometrial cancer. How this study might affect research, practice, or policy - The findings of our study imply that AAM could be a candidate marker for early screening of populations at higher risk of breast cancer and endometrial cancer.

Evaluating the risk of sepsis attributing to obesity: a two-sample Mendelian randomization study.

BACKGROUND: Sepsis is a reaction to infection with high morbidity and mortality. It has been noted that patients with obesity were more likely to suffer from sepsis. However, the causality remains elucidating, as reverse causality and residual confounding could not be largely mitigated in conventional observational studies. OBJECTIVE: To evaluate the risk of sepsis attributed to obesity phenotypes including body mass index (BMI), waist circumstance (WC), and WC adjusted for BMI (WCadjBMI) in a causal way. METHODS: We conducted a two-sample Mendelian randomization (MR) study using large-scale genome-wide association study summary data with sample sizes ranging from 231 353 to 486 484. The inverse-weighted variance (IVW) was conducted as the primary approach. We also used the weighted median and MR-Egger for causal inference. A sensitivity analysis was conducted to evaluate the reliability of the MR estimates. RESULTS: IVW detected that genetic liability for increased BMI [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.20-1.63, P = 1.52 × 10-5] and WC (OR = 1.02, 95% CI = 1.01-1.03, P = 4.28 × 10-3) predicted a higher risk of sepsis. No evidence was observed for a causal effect of WCadjBMI on sepsis risk (OR = 1.01, 95% CI = 1.00-1.02, P = 0.08). Sensitivity analysis did not identify any bias in the MR results. CONCLUSION: This MR study showed that obesity contributed to an increased risk of sepsis, indicating that obesity management might be beneficial for reducing sepsis risk. Key messages What is already known on this topic-Observational studies have reported the association between obesity and sepsis, but the causality has not been determined. What this study adds-This Mendelian randomization study demonstrated that obesity-related phenotypes, including body mass index and Waist circumstance, causally increased the risk of sepsis. How this study might affect research, practice, or policy-The findings of our study might have an implication for clinicians that obesity management might be a promised strategy for reducing the risk of sepsis.

PNP Nanofluidic Transistor with Actively Tunable Current Response and Ionic Signal Amplification.

Inspired by electronic transistors, electric field gating has been adopted to manipulate ionic currents of smart nanofluidic devices. Here, we report a PNP nanofluidic bipolar junction transistor (nBJT) consisting of one polyaniline (PANI) layer sandwiched between two polyethylene terephthalate (PET) nanoporous membranes. The PNP nBJT exhibits three different responses of currents (quasi-linear, rectification, and sigmoid) due to the counterbalance between surface charge distribution and base voltage applied in the nanofluidic channels; thus, they can be switched by base voltage. Four operating modes (cutoff, active, saturation, and breakdown mode) occur in the collector response currents. Under optimal conditions, the PNP nBJT exhibits an average current gain of up to 95 in 100 mM KCl solution at a low base voltage of 0.2 V. The present nBJT is promising for fabrication of nanofluidic devices with logical-control functions for analysis of single molecules.

Single Molecule DNA Analysis Based on Atomic-Controllable Nanopores in Covalent Organic Frameworks.

We explored the application of two-dimensional covalent organic frameworks (2D COFs) in single molecule DNA analysis. Two ultrathin COF nanosheets were exfoliated with pore sizes of 1.1 nm (COF-1.1) and 1.3 nm (COF-1.3) and covered closely on a quartz nanopipette with an orifice of 20 ± 5 nm. COF nanopores exhibited high size selectivity for fluorescent dyes and DNA molecules. The transport of long (calf thymus DNA) and short (DNA-80) DNA molecules through the COF nanopores was studied. Because of the strong interaction between DNA bases and the organic backbones of COFs, the DNA-80 was transported through the COF-1.1 nanopore at a speed of 270 µs/base, which is the slowest speed ever observed compared with 2D inorganic nanomaterials. This study shows that the COF nanosheet can work individually as a nanopore monomer with controllable pore size like its biological counterparts.

A Novel Indole Derivative with Superior Photophysical Performance for Fluorescent Probe, pH-Sensing, and Logic Gates.

An indole-related molecules have been considered as the potential fluorescent probes for biological and electrochemical sensing. However, most of the indole probes have been usually used in a single detection mode. Indolium probes that enable accurate detection in complex environments are rarely reported. Here, four novel indole derivatives including the phenyl group substituted with different functional moieties were designed on the basis of the donor-π-acceptor (D-π-A) concept. These derivatives exhibit positive solvatochromism owing to their varied molecular conformations upon contacting to various solvents and the different HOMO-LUMO gaps caused by the difference in electronic push-pull capability of the substituents. Their solid-state fluorescence emissions and multiple chromisms are observed due to the inherent twisted geometries and aggregation modes. In addition, these derivatives show dramatic color and fluorescence responses due to the protonation of the nitrogen and oxygen containing groups, and thus novel colorimetric pH sensors, fluorescent papers and logic gates have been designed.

The impact of maize straw incorporation on arsenic and cadmium availability, transformation and microbial communities in alkaline-contaminated soils.

Increasing evidence of the uncertainty of crop straw returning in heavy metal-contaminated soil is a significant concern. The present study investigated the influence of 1 and 2% maize straws (MS) amendment on As and Cd bioavailability in two different alkaline soils (A-industrial and B-irrigation) after 56 days of ageing. Adding MS to the two soils decreased the pH by 1.28 (A soil) and 1.13 (B soil) and increased the concentration of dissolved organic carbon (DOC) by 54.40 mg/kg (A soil) and 100.00 mg/kg (B soil) during the study period. After 56 days of ageing, the overall NaHCO3-As and DTPA-Cd increased by 40% and 33% (A) and 39% and 41% (B) soils, respectively. The MS additions increased the alteration of As and Cd exchangeable and residual fractions, whereas advanced solid-state 13C nuclear magnetic resonance (NMR) revealed that alkyl C and alkyl O-C-O in A soil and alkyl C, Methoxy C/N-alkyl, and alkyl O-C-O in B soil significantly contributed to the As and Cd mobilisation. Collectively, 16 S rRNA analyses revealed Acidobacteria, Firmicutes, Chloroflexi, Actinobacteria and Bacillus promoted the As and Cd mobilisation following the MS addition, while principle component analysis (PCA) demonstrated that bacterial proliferation significantly influenced MS decomposition, resulting in As and Cd mobilisation in the two soils. Overall, the study highlights the implications of applying MS to As- and Cd-contaminated alkaline soil and offers the framework for conditions to be considered during As- and Cd-remediation efforts, especially when MS is the sole remediation component.