Effect of Lower Extremity Nerve Decompression in Patients With Painful Diabetic Peripheral Neuropathy: The Diabetic Neuropathy Nerve Decompression Randomized, Observation Group and Placebo Surgery-Controlled Clinical Trial.

OBJECTIVE: To evaluate the effect of nerve decompression on pain in patients with lower extremity painful diabetic peripheral neuropathy (DPN). BACKGROUND: Currently, no treatment provides lasting relief for patients with DPN. The benefits of nerve decompression remain inconclusive. METHODS: This double-blinded, observation and same-patient sham surgery-controlled randomized trial enrolled patients aged 18 to 80 years with lower extremity painful DPN who failed 1 year of medical treatment. Patients were randomized to nerve decompression or observation group (2:1). Decompression-group patients were further randomized and blinded to nerve decompression in either the right or left leg and sham surgery in the opposite leg. Pain (11-point Likert score) was compared between decompression and observation groups and between decompressed versus sham legs at 12 and 56 months. RESULTS: Of 2987 screened patients, 78 were randomized. At 12 months, compared with controls (n=37), both the right-decompression group (n=22) and left-decompression group (n=18) reported lower pain (mean difference for both: -4.46; 95% CI: -6.34 to -2.58 and -6.48 to -2.45, respectively; P < 0.0001). Decompressed and sham legs equally improved. At 56 months, compared with controls (n=m 14), pain was lower in both the right-decompression group (n=20; mean difference: -7.65; 95% CI: -9.87 to -5.44; P < 0.0001) and left-decompression group (n=16; mean difference: -7.26; 95% CI: -9.60 to -4.91; P < 0.0001). The mean pain score was lower in decompressed versus sham legs (mean difference: 1.57 95% CI: 0.46 to 2.67; P =0.0002). CONCLUSIONS: Although nerve decompression was associated with reduced pain, the benefit of surgical decompression needs further investigation as a placebo effect may be responsible for part or all of these effects.

Crebinostat facilitates memory formation.

Protein modifications importantly contribute to memory formation. Protein acetylation is a post-translational modification of proteins that regulates memory formation. Acetylation level is determined by the relative activities of acetylases and deacetylases. Crebinostat is a histone deacetylase inhibitor. Here we show that in an object recognition task, crebinostat facilitates memory formation by a weak training. Further, this compound enhances acetylation of α-tubulin, and reduces the level of histone deacetylase 6, an α-tubulin deacetylase. The results suggest that enhanced acetylation of α-tubulin by crebinostat contributes to its facilitatory effect on memory formation.

A Fluorescence-Based Assay for N5 -Carboxyaminoimidazole Ribonucleotide Mutase.

The enzyme N5 -carboxylaminoinidazole ribonucleotide (N5 -CAIR) mutase is found in microbial de novo purine biosynthesis but is absent in humans making it an attractive antimicrobial target. N5 -CAIR mutase catalyzes the synthesis of carboxyaminoimidazole ribonucleotide (CAIR) from N5 -CAIR which is itself prepared from aminoimidazole ribonucleotide (AIR) by the enzyme N5 -CAIR synthetase. During our research on identifying inhibitors of N5 -CAIR mutase, we developed an innovative, fluorescence-based assay to measure the activity of this enzyme. This assay relies upon our recent serendipitous observation that AIR reversibly reacts with the compound isatin. Reaction of a fluorescently-tagged isatin with AIR resulted in a large increase in fluorescence intensity allowing a measurement of the concentration of AIR in solution. From this observation, we developed a reproducible, non-continuous assay that can replicate the known kinetic parameters of the enzyme and can readily detect a recognized inhibitor of the enzyme. This assay should find utility in screening for inhibitors targeting N5 -CAIR mutase.

Sulfotransferase activity contributes to long-term potentiation and long-term memory.

A critical role of protein modifications such as phosphorylation and acetylation in synaptic plasticity and memory is well documented. Tyrosine sulfation plays important roles in several biological processes. However, its role in synaptic plasticity and memory is not well understood. Here, we show that sulfation contributes to long-term potentiation (LTP) in the hippocampal slices. In addition, inhibition of sulfation impairs long-term memory in a spatial memory task without affecting acquisition or short-term memory. Furthermore, LTP-inducing stimulus enhances protein tyrosine sulfation. These results suggest an important role for tyrosine sulfation in LTP and memory.

An Aniline-Substituted Bile Salt Analog Protects both Mice and Hamsters from Multiple Clostridioides difficile Strains.

Clostridioides difficile infection (CDI) is the major identifiable cause of antibiotic-associated diarrhea. The emergence of hypervirulent C. difficile strains has led to increases in both hospital- and community-acquired CDI. Furthermore, the rate of CDI relapse from hypervirulent strains can reach up to 25%. Thus, standard treatments are rendered less effective, making new methods of prevention and treatment more critical. Previously, the bile salt analog CamSA (cholic acid substituted with m-aminosulfonic acid) was shown to inhibit spore germination in vitro and protect mice and hamsters from C. difficile strain 630. Here, we show that CamSA was less active in preventing spore germination by other C. difficile ribotypes, including the hypervirulent strain R20291. The strain-specific in vitro germination activity of CamSA correlated with its ability to prevent CDI in mice. Additional bile salt analogs were screened for in vitro germination inhibition activity against strain R20291, and the most active compounds were tested against other strains. An aniline-substituted bile salt analog, CaPA (cholic acid substituted with phenylamine), was found to be a better antigerminant than CamSA against eight different C. difficile strains. In addition, CaPA was capable of reducing, delaying, or preventing murine CDI signs with all strains tested. CaPA-treated mice showed no obvious toxicity and showed minor effects on their gut microbiome. CaPA's efficacy was further confirmed by its ability to prevent CDI in hamsters infected with strain 630. These data suggest that C. difficile spores respond to germination inhibitors in a strain-dependent manner. However, careful screening can identify antigerminants with broad CDI prophylaxis activity.

Surface Chemistry Studies on the Formation of Mixed Stearic Acid/Phenylalanine Dehydrogenase Langmuir and Langmuir-Blodgett Films.

This work investigates the physicochemical properties of mixed stearic acid (HSt)/phenylalanine dehydrogenase enzyme (PheDH) Langmuir films and their immobilization onto solid supports as Langmuir-Blodgett (LB) films. PheDH from the aqueous subphase enters the surfactant matrix up to an exclusion surface pressure of 25.3 mN/m, leading to the formation of stable and highly condensed mixed Langmuir monolayers. Hydrophobic interactions between the enzyme and HSt nonpolar groups tuned the secondary structure of PheDH, evidenced by the presence of ß-sheet structures as demonstrated by infrared and circular dichroism spectra. The floating monolayers were successfully transferred to solid quartz supports, yielding Y-type LB films, and then characterized employing fluorescence, circular dichroism, and microscopic techniques, which indicated that PheDH was co-immobilized with HSt proportionally to the number of transferred layers. The enzyme fluidized the HSt monolayers, reducing their maximum dipoles when condensed to their maximum, and disorganized the alkyl chains of the fatty acid, as detected with infrared spectroscopy. The stability of the mixed floating monolayers enabled their transfer to solid supports as LB films, which is important for producing optical and electrochemical sensors for phenylalanine whose molecular architecture can be controlled with precision.

Studies on the Importance of the 7α-, and 12α- hydroxyl groups of N-Aryl-3α,7α,12α-trihydroxy-5ß-cholan-24-amides on their Antigermination Activity Against a Hypervirulent Strain of Clostridioides (Clostridium) difficile.

Chenodeoxycholic acid (CDCA) is a natural germination inhibitor for C. difficile spores. In our previous study (J. Med. Chem., 2018, 61, 6759-6778), we identified N-phenyl-3α,7α,12α-trihydroxy-5ß-cholan-24-amide as an inhibitor of C. difficile strain R20291 with an IC50 of 1.8 µM. Studies of bile salts on spore germination have shown that chenodeoxycholate, ursodeoxycholate and lithocholate are more potent inhibitors of germination compared to cholate. Given this, we created amide analogs of chenodeoxycholic, deoxycholic, lithocholic and ursodeoxycholic acids using amines identified from our previous studies. We found that chenodeoxy- and deoxycholate derivatives were active with potencies equivalent to those for cholanamides. This indicates that only 2 out of the 3 hydroxyl groups are needed for activity and that the alpha stereochemistry at position 7 is required for inhibition of spore germination.

OrganiCam: a lightweight time-resolved laser-induced luminescence imager and Raman spectrometer for planetary organic material characterization.

OrganiCam is a laser-induced luminescence imager and spectrometer designed for standoff organic and biosignature detection on planetary bodies. OrganiCam uses a diffused laser beam (12° cone) to cover a large area at several meters distance and records luminescence on half of its intensified detector. The diffuser can be removed to record Raman and fluorescence spectra from a small spot from 2 m standoff distance. OrganiCam's small size and light weight makes it ideal for surveying organics on planetary surfaces. We have designed and built a brassboard version of the OrganiCam instrument and performed initial tests of the system.

Activity- and memory training-induced acetylation of α-tubulin in the hippocampus.

Posttranslational modifications play crucial roles in synaptic plasticity and memory formation. The important role of histone acetylation is well established in these processes. However, activity-dependent regulation of acetylation of non-histone proteins is not well understood. We previously showed that α-tubulin is acetylated in an activity-dependent manner. Here, we show that cyclin-dependent kinase 5 (CDK5) plays an important role in α-tubulin acetylation induced by KCl depolarization or N-methyl-D-aspartate stimulation of the hippocampal slices. In addition, KCl depolarization inhibits the activity of SIRT2, an α-tubulin deacetylase. The inhibitory effect of KCl on SIRT2 activity requires CDK5 activity. Furthermore, α-tubulin acetylation is enhanced by memory training in object recognition task. These results suggest that memory formation may involve α-tubulin acetylation.

Mechanisms of protein kinase C-induced sustained activation of extracellular signal-regulated kinase in the hippocampus.

Protein Kinase C (PKC) and extracellular signal-regulated kinase (ERK) regulate synaptic plasticity and memory. PKC activation enhances long-term potentiation (LTP) in the hippocampal slices. In addition, activation of PKC by phorbol 12,13-diacetate (PDA) induces ERK activation. However, the mechanisms involved in PDA-induced activation of ERK are not well understood. Using hippocampal slices, we report that PDA induces a sustained activation of ERK. PDA-induced sustained ERK activation critically requires protein synthesis as well as transcription, the cellular processes that play crucial roles in long-lasting LTP and memory. In addition, the mammalian target of rapamycin activity is required for PDA-induced sustained ERK activation. Further, we show that growth factor signalling plays a critical role in PDA-induced sustained ERK activation. These results suggest that sustained ERK activation may have an important role in LTP.

Carbon Dots: Diverse Preparation, Application, and Perspective in Surface Chemistry.

Carbon dots (CDs) are a novel class of nanoparticles with excellent properties. The development of CDs involves versatile synthesis, characterization, and various applications. However, the importance of surface chemistry of CDs, especially in applications, is often underestimated. In fact, the study of the surface chemistry of CDs is of great significance in the explanation of the unique properties of CDs as well as the pursuit of potential applications. In this feature article, we do not only introduce the development of CDs in our group but also highlight their applications where surface chemistry plays a critical role.

Interfacial Behavior of Fumonisin B1 Toxin and Its Degradation on the Membrane.

Fumonisin B1 (FB1), the most abundant component of the fumonisin family, is highly responsible for fungal infections. In this paper, our main aim is to study the surface chemistry and spectroscopic properties of the FB1 molecule and observe the impact of green LED light on the FB1 Langmuir monolayer. From the surface chemistry and spectroscopic studies, we found that the FB1 molecule forms a self-assembled Langmuir monolayer which is sufficient to mimic its interaction with the corneal tissues. The irradiation of green LED light on the FB1 Langmuir monolayer showed the degradation of the FB1 when compared to that in the absence of light. This observation reveals that FB1 molecules lose their tendency to stay as a Langmuir monolayer. The degradation observed on the interface was compared with the bulk phase of FB1. The bulk phase observation also indicated the degradation tendency which reinforced the observed interfacial property of FB1.

Close-Packed Langmuir Monolayers of Saccharide-Based Carbon Dots at the Air-Subphase Interface.

Carbon dots (CDs) are zero-dimensional carbon-based spherical nanoparticles with diameters less than 10 nm. Here, we report for the first time CDs forming stable Langmuir monolayers at the air-subphase interface. Langmuir monolayers are of great interest both fundamentally to study the interactions at the interfaces and for many applications such as the development of sensors. However, CDs usually do not form Langmuir monolayers because of their highly hydrophilic nature. In this study, amphiphilic CDs were prepared through hydrothermal carbonization using saccharides as the precursors. The surface chemistry behavior and optical properties of CDs at the air-subphase interface were studied. CDs derived from saccharides consistently formed stable Langmuir monolayers which show all essential phases, namely, gas, liquid-expanded, liquid-condensed, and solid phases. The compression-decompression cycle method showed minimum hysteresis (4.3%), confirming the retaining capacity of the CDs as a monolayer. Limiting CD areas from surface pressure-area isotherm at the air-subphase interface were used to calculate the average diameter of the CDs at the air-subphase interface. UV/vis absorption spectra of CDs dispersed in water and in Langmuir monolayers had the same bands in the UV region. The intensity of the UV/vis absorption increases with increasing surface pressure at the air-subphase interface. Interestingly, photoluminescence (PL) of the Langmuir monolayer of CDs was excitation-independent, whereas the same CDs had excitation-dependent PL when dispersed in water.

Oxidation of a Levitated 1-Butyl-3-methylimidazolium Dicyanoborate Droplet by Nitrogen Dioxide.

To develop the next generation of hypergolic, ionic-liquid-based fuels, it is important to understand the fundamental reaction mechanisms for the oxidation of ionic liquids (ILs). We consequently studied the oxidation of a levitated 1-butyl-3-methylimidazolium dicyanoborate ([BMIM][DCBH]) droplet by nitrogen dioxide (NO2). The properties of [BMIM][DCBH], including short ignition-delay times, low viscosities, and a wide liquid temperature range, make the ionic liquid especially suitable as a component of a hypergolic fuel. The chemical modifications were monitored with Fourier-transform infrared (FTIR), Raman, and ultraviolet-visible spectroscopies. To identify changes induced by the oxidation, it was first necessary to assign vibrational modes to the FTIR and Raman spectra of unreacted [BMIM][DCBH]. The new features in the oxidized FTIR and Raman spectra could then be identified and assigned on the basis of the possible functional groups likely to form through addition with a nitrogen and an oxygen atom of nitrogen dioxide creating a new bond with the ionic liquid. The assignments suggest that organic nitro-compounds and boron-nitrogen and boron-oxygen containing compounds were produced. A large decrease in the intensity of some [DCBH]- fundamental modes suggests the nitrogen dioxide molecule prefers to react with the anion over the cation.

Remote Raman spectroscopy of natural rocks.

We report the remote Raman spectra of natural igneous, metamorphic, and sedimentary rock samples at a standoff distance of 5 m. High-quality remote Raman spectra of unprepared rocks are necessary for accurate and realistic analysis of future Raman measurements on planetary surfaces such as Mars. Our results display the ability of a portable compact remote Raman system (CRRS) to effectively detect and isolate various light- and dark-colored mineral phases in natural rocks. The CRRS easily detected plagioclase and potassium feldspar end members, quartz, and calcite in rocks with high fluorescence backgrounds. Intermediate feldspars and quartz, when found in rocks with complex mineralogies, exhibited band shifts and broadening in the ${504{-}510}\,\,{{\rm cm}^{ - 1}}$504-510cm-1 and ${600{-}1200}\,\,{{\rm cm}^{ - 1}}$600-1200cm-1 regions. A good approximation of intermediate plagioclase feldspars was possible by using overall Raman spectral shape and assigning other minor Raman peaks in addition to the $ 504{-}510\,\,{{\rm cm}^{ - 1}}$504-510cm-1 peaks. Detection of olivine and pyroxene in mafic rocks allowed for compositional characterization.

Conjugation of Carbon Dots with ß-Galactosidase Enzyme: Surface Chemistry and Use in Biosensing.

Nanoparticles have been conjugated to biological systems for numerous applications such as self-assembly, sensing, imaging, and therapy. Development of more reliable and robust biosensors that exhibit high response rate, increased detection limit, and enhanced useful lifetime is in high demand. We have developed a sensing platform by the conjugation of ß-galactosidase, a crucial enzyme, with lab-synthesized gel-like carbon dots (CDs) which have high luminescence, photostability, and easy surface functionalization. We found that the conjugated enzyme exhibited higher stability towards temperature and pH changes in comparison to the native enzyme. This enriched property of the enzyme was distinctly used to develop a stable, reliable, robust biosensor. The detection limit of the biosensor was found to be 2.9 × 10-4 M, whereas its sensitivity was 0.81 µA·mmol-1·cm-2. Further, we used the Langmuir monolayer technique to understand the surface properties of the conjugated enzyme. It was found that the conjugate was highly stable at the air/subphase interface which additionally reinforces the suitability of the use of the conjugated enzyme for the biosensing applications.

Surface Chemistry and Spectroscopic Study of a Cholera Toxin B Langmuir Monolayer.

In this article, we explored the surface chemistry properties of a cholera toxin B (CTB) monolayer at the air-subphase interface and investigated the change in interfacial properties through in situ spectroscopy. The study showed that the impact of the blue shift was negligible, suggesting that the CTB molecules were minimally affected by the subphase molecules. The stability of the CTB monolayer was studied by maintaining the constant surface pressure for a long time and also by using the compression-decompression cycle experiments. The high stability of the Langmuir monolayer of CTB clearly showed that the driving force of CTB going to the amphiphilic membrane was its amphiphilic nature. In addition, no major change was detected in the various in situ spectroscopy results (such as UV-vis, fluorescence, and IR ER) of the CTB Langmuir monolayer with the increase in surface pressure. This indicates that no aggregation occurs in the Langmuir monolayer of CTB.

Randomized Controlled Trial of the Clinical Efficacy of Multiport Versus Uniport Wire-Reinforced Flexible Catheters for Labor Epidural Analgesia.

BACKGROUND: The purpose of this prospective, randomized, controlled trial was to determine whether multiple ports improve the analgesic efficacy of wire-reinforced flexible catheters used for labor epidural analgesia (LEA). METHODS: Six hundred fifty laboring patients were randomized to receive epidural analgesia using either a multiport or uniport wire-reinforced flexible catheter. The primary outcome was analgesic success, defined as the incidence of adequate analgesia following the initial bolus given to initiate LEA. Secondary outcomes included the number of patients requiring clinician interventions during maintenance of LEA; anesthetic success, defined as the incidence of adequate anesthesia following the initial bolus given to establish surgical anesthesia for cesarean delivery; and maternal satisfaction with the overall quality of LEA. RESULTS: There was no significant difference in analgesic success at initiation of LEA between the uniport and the multiport wire-reinforced flexible catheter (93.6% vs 89.5%, respectively; difference of 4.1% [95% confidence interval, -0.4% to 8.5%]; P = .077). There was also no difference in the number of patients requiring clinician interventions during maintenance of LEA and in anesthetic success at the establishment of surgical anesthesia for cesarean delivery between the 2 catheter types. CONCLUSIONS: Multiple ports do not appear to improve the analgesic efficacy of wire-reinforced flexible catheters used for LEA.

Standoff ultracompact micro-Raman sensor for planetary surface explorations.

We report the development of an innovative standoff ultracompact micro-Raman instrument that would solve some of the limitations of traditional micro-Raman systems to provide a superior instrument for future NASA missions. This active remote sensor system, based on a 532 nm laser and a miniature spectrometer, is capable of inspection and identification of minerals, organics, and biogenic materials within several centimeters (2-20 cm) at a high 10 µm resolution. The sensor system is based on inelastic (Raman) light scattering and laser-induced fluorescence. We report on micro-Raman spectroscopy development and demonstration of the standoff Raman measurements by acquiring Raman spectra in daylight at a 10 cm target distance with a small line-shaped laser spot size of 17.3 µm (width) by 5 mm (height).

Biosensors based on ß-galactosidase enzyme: Recent advances and perspectives.

Many industries are striving for the development of more reliable and robust ß-galactosidase biosensors that exhibit high response rate, increased detection limit and enriched useful lifetime. In a newfangled technological atmosphere, a trivial advantage or disadvantage of the developed biosensor may escort to the survival and extinction of the industry. Several alternative strategies to immobilize ß-galactosidase enzyme for their utilization in biosensors have been developed in recent years in the quest of maximum utility by controlling the defects seen in the previous biosensors. The overwhelming call for on-line measurement of different sample constituents has directed science and industry to search for best practical solutions and biosensors are witnessed as the best prospect. The main objective of this paper is to serve as a narrow footbridge by comparing the literary works on the ß-galactosidase biosensors, critically analyze their use in the construction of best biosensor by showing the pros and cons of the predicted methods for the practical use of biosensors.