Azimuthal rotation-controlled nanoinscribing for continuous patterning of period- and shape-tunable asymmetric nanogratings.

We present an azimuthal-rotation-controlled dynamic nanoinscribing (ARC-DNI) process for continuous and scalable fabrication of asymmetric nanograting structures with tunable periods and shape profiles. A sliced edge of a nanograting mold, which typically has a rectangular grating profile, slides over a polymeric substrate to induce its burr-free plastic deformation into a linear nanopattern. During this continuous nanoinscribing process, the "azimuthal angle," that is, the angle between the moving direction of the polymeric substrate and the mold's grating line orientation, can be controlled to tailor the period, geometrical shape, and profile of the inscribed nanopatterns. By modulating the azimuthal angle, along with other important ARC-DNI parameters such as temperature, force, and inscribing speed, we demonstrate that the mold-opening profile and temperature- and time-dependent viscoelastic polymer reflow can be controlled to fabricate asymmetric, blazed, and slanted nanogratings that have diverse geometrical profiles such as trapezoidal, triangular, and parallelogrammatic. Finally, period- and profile-tunable ARC-DNI can be utilized for the practical fabrication of diverse optical devices, as is exemplified by asymmetric diffractive optical elements in this study.

Physicochemical Changes in Root-Canal Sealers under Thermal Challenge: A Comparative Analysis of Calcium Silicate- and Epoxy-Resin-Based Sealers.

INTRODUCTION: We compared the effects of heat on the physicochemical properties of recently developed calcium silicate-based sealers (CSBSs), including BioRoot Flow, BioRoot RCS, and AH Plus Bioceramic sealer, with those of the epoxy-resin-based sealer (ERBS) AH Plus. METHODS: The flow, film thickness, setting time, and solubility of sealers were evaluated at 37 °C and 100 °C using ISO 6876/2012. Furthermore, pH and calcium ion release were evaluated at these temperatures. In addition, the mass change in sealers at a high temperature was assessed via thermogravimetric analysis. Then, the chemical composition and components of the sealers were analyzed using a scanning electron microscope and Fourier-transform infrared spectroscopy (FTIR). RESULTS: BioRoot Flow, AH Plus Bioceramic, and AH Plus complied with ISO standards in terms of flow and film thickness, both before and after heat application. However, BioRoot RCS exhibited significantly increased film thickness at 100 °C. The setting times of all sealers were significantly reduced at 100 °C. The solubility of CSBS was >3%, exceeding the ISO 6876/2012 standard, both before and after heat exposure. Conversely, the solubility of AH Plus complied with the standard, regardless of the thermal condition. For 4 weeks, CSBS showed a significantly higher pH than AH Plus at both 37 °C and 100 °C. After heat treatment, calcium release decreased in Bioroot RCS and BioRoot Flow, while AH Plus showed no significant differences before and after treatment. However, CSBS consistently exhibited significantly higher calcium release than AH Plus at both temperatures. An FTIR analysis revealed that the chemical composition of the sealers did not change at the high temperature, whereas a thermogravimetric analysis demonstrated a >5% weight reduction in CSBS and a 0.005% weight reduction in AH Plus at 100 °C. CONCLUSIONS: BioRoot Flow, AH Plus Bioceramic, and AH Plus possess favorable physicochemical properties, which make them suitable for application under thermal conditions. At a high temperature, BioRoot RCS did not exhibit changes in its chemical composition. However, its film thickness was increased, and pH and solubility were reduced. Therefore, caution is needed when it is applied at high temperatures, such as during the warm obturation technique.

Lactobacillus Persisters Formation and Resuscitation.

Lactobacillus is a commonly used probiotic, and many researchers have focused on its stress response to improve its functionality and survival. However, studies on persister cells, dormant cells that aid bacteria in surviving general stress, have focused on pathogenic bacteria that cause infection, not Lactobacillus. Thus, understanding Lactobacillus persister cells will provide essential clues for understanding how Lactobacillus survives and maintains its function under various environmental conditions. We treated Lactobacillus strains with various antibiotics to determine the conditions required for persister formation using kill curves and transmission electron microscopy. In addition, we observed the resuscitation patterns of persister cells using single-cell analysis. Our results show that Lactobacillus creates a small population of persister cells (0.0001-1% of the bacterial population) in response to beta-lactam antibiotics such as ampicillin and amoxicillin. Moreover, only around 0.5-1% of persister cells are heterogeneously resuscitated by adding fresh media; the characteristics are typical of persister cells. This study provides a method for forming and verifying the persistence of Lactobacillus and demonstrates that antibiotic-induced Lactobacillus persister cells show characteristics of dormancy, sensitivity of antibiotics, same as exponential cells, multi-drug tolerance, and resuscitation, which are characteristics of general persister cells. This study suggests that the mechanisms of formation and resuscitation may vary depending on the characteristics, such as the membrane structure of the bacterial species.

Skin-Whitening Effect of a Callus Extract of Nelumbo nucifera Isolate Haman.

The sacred lotus (Nelumbo nucifera Gaertn. Isolate Haman, in the family Nelumbonaceae) used in this study originated from the Haman region of Korea, and lotus seeds dating back to the Goryeo Dynasty (650-760 years ago) were accidentally discovered. Lotus is known to possess antioxidant, anti-inflammatory, and soothing properties. Instead of using the lotus alone, we obtained extracts using Haman region lotus-derived callus (HLC), which allowed for a controlled, quantitative, and infinite supply. Based on the reported effects of the lotus, we formulated a hypothesis to investigate the skin-whitening effect of the HLC extract (HLCE). The HLCE was first obtained by extraction with distilled water and using 5% propanediol as a solvent and subsequently verified for the whitening effect (melanin content tests) using mammalian cells in vitro. Its efficacy at the molecular level was confirmed through real-time polymerase chain reaction (PCR) using melanin-related genes. Furthermore, clinical trials with 21 volunteers confirmed the significant whitening effect of cosmetics containing the HLCE. In conclusion, we found that the HLCE not only has anti-inflammatory, antioxidant, and skin-soothing properties but also plays an essential role in skin whitening. Therefore, we propose that the HLCE has the potential to become a new raw material for the cosmetic industry.

Estimation of Shape Error with Monitoring Signals.

Recently, extensive research has actively been conducted in relation to intelligent manufacturing systems. During the machining process, various factors, such as geometric errors, vibrations, and cutting force fluctuations, lead to shape errors. When a shape error exceeds the tolerance, it results in improper assembly or functionality issues in the assembled part. Predicting shape errors before or during the machining process helps increase production efficiency. In this paper, we propose a methodology that uses monitoring signals and on-machine measurement (OMM) results to predict machining quality in real time. We investigate the correlation between monitoring signals and OMM results and then construct a machine learning model for shape error estimation. The developed model implements a tool offset compensation strategy. The performance of the proposed method is evaluated under various sliding window sizes and the compensation weights. The experimental results confirmed that the proposed algorithm is effective for obtaining a uniform machining quality.

Leveraging the Fragment Molecular Orbital Method to Explore the PLK1 Kinase Binding Site and Polo-Box Domain for Potent Small-Molecule Drug Design.

Polo-like kinase 1 (PLK1) plays a pivotal role in cell division regulation and emerges as a promising therapeutic target for cancer treatment. Consequently, the development of small-molecule inhibitors targeting PLK1 has become a focal point in contemporary research. The adenosine triphosphate (ATP)-binding site and the polo-box domain in PLK1 present crucial interaction sites for these inhibitors, aiming to disrupt the protein's function. However, designing potent and selective small-molecule inhibitors can be challenging, requiring a deep understanding of protein-ligand interaction mechanisms at these binding sites. In this context, our study leverages the fragment molecular orbital (FMO) method to explore these site-specific interactions in depth. Using the FMO approach, we used the FMO method to elucidate the molecular mechanisms of small-molecule drugs binding to these sites to design PLK1 inhibitors that are both potent and selective. Our investigation further entailed a comparative analysis of various PLK1 inhibitors, each characterized by distinct structural attributes, helping us gain a better understanding of the relationship between molecular structure and biological activity. The FMO method was particularly effective in identifying key binding features and predicting binding modes for small-molecule ligands. Our research also highlighted specific "hot spot" residues that played a critical role in the selective and robust binding of PLK1. These findings provide valuable insights that can be used to design new and effective PLK1 inhibitors, which can have significant implications for developing anticancer therapeutics.

Electrostatics Control Nanoparticle Interactions with Model and Native Cell Walls of Plants and Algae.

A lack of mechanistic understanding of nanomaterial interactions with plants and algae cell walls limits the advancement of nanotechnology-based tools for sustainable agriculture. We systematically investigated the influence of nanoparticle charge on the interactions with model cell wall surfaces built with cellulose or pectin and performed a comparative analysis with native cell walls of Arabidopsis plants and green algae (Choleochaete). The high affinity of positively charged carbon dots (CDs) (46.0 ± 3.3 mV, 4.3 ± 1.5 nm) to both model and native cell walls was dominated by the strong ionic bonding between the surface amine groups of CDs and the carboxyl groups of pectin. In contrast, these CDs formed weaker hydrogen bonding with the hydroxyl groups of cellulose model surfaces. The CDs of similar size with negative (-46.2 ± 1.1 mV, 6.6 ± 3.8 nm) or neutral (-8.6 ± 1.3 mV, 4.3 ± 1.9 nm) ζ-potentials exhibited negligible interactions with cell walls. Real-time monitoring of CD interactions with model pectin cell walls indicated higher absorption efficiency (3.4 ± 1.3 10-9) and acoustic mass density (313.3 ± 63.3 ng cm-2) for the positively charged CDs than negative and neutral counterparts (p < 0.001 and p < 0.01, respectively). The surface charge density of the positively charged CDs significantly enhanced these electrostatic interactions with cell walls, pointing to approaches to control nanoparticle binding to plant biosurfaces. Ca2+-induced cross-linking of pectin affected the initial absorption efficiency of the positively charged CD on cell wall surfaces (∼3.75 times lower) but not the accumulation of the nanoparticles on cell wall surfaces. This study developed model biosurfaces for elucidating fundamental interactions of nanomaterials with cell walls, a main barrier for nanomaterial translocation in plants and algae in the environment, and for the advancement of nanoenabled agriculture with a reduced environmental impact.

Esophageal motility in systemic sclerosis before and after autologous hematopoietic cell transplantation.

INTRODUCTION: Systemic sclerosis (SSc) is associated with esophageal dysmotility. Autologous hematopoietic cell transplantation (HCT) results in improvement of skin tightness and lung function. Whether esophageal motility improves after HCT is unknown. METHODS: Esophageal motility was studied using high-resolution esophageal manometry in 21 SSc patients before and at multiple time points after autologous HCT. Median posttransplant follow-up was 2 years (range, 6 months to 5 years). RESULTS: Prior to HCT, all 21 patients had abnormal motility-10 (48%) had unmeasurable and 11 (52%) had measurable peristalsis. Manometric diagnosis in the former 10 patients was "absent contractility" and in the latter 11 patients "ineffective esophageal motility (IEM)." After HCT, among the 10 patients with absent contractility, 9 continued to have absent contractility and one demonstrated weak measurable peristalsis. Of the 11 patients with IEM, 5 experienced SSc relapse, and 2 out of these 5 patients developed absent contractility. Among the 6 non-relapsed patients, 4 continued to have IEM, and 2 developed normal motility. CONCLUSIONS: HCT appears to have no beneficial effect on motility in patients with unmeasurable peristalsis. In patients with measurable peristalsis, HCT appears to stabilize and in some normalize motility, unless relapse occurs. Key Points • In patients with systemic sclerosis, esophageal dysmotility is a significant contributor to morbidity and so far, there has been no data describing the effects of hematopoietic cell transplantation on esophageal motility. • Our work demonstrated that in patients with systemic sclerosis and unmeasurable esophageal peristalsis prehematopoietic cell transplantation, there was no measurable beneficial effect of transplantation on esophageal motility. • In patients with systemic sclerosis and measurable peristalsis prehematopoietic cell transplantation, esophageal motility stabilized, except in relapsed patients.

Spatial distribution of meiofaunal and macrofaunal assemblages in the tidal flats of the southern Korean coast in relation to natural and anthropogenic impacts.

We investigated the spatial variability of macrofaunal and meiofaunal assemblages in intertidal flats on the southern coast of Korea. Abiotic and biotic samples were collected at five stations. The species richness, density, and composition of the assemblages differed significantly among stations. Nematoda and Annelida were the most dominant meiofaunal and macrofaunal taxa, respectively, although taxon dominance differed among stations. Distance-based linear models showed that sediment-related variables and heavy metals were the main environmental factors determining the spatial variability of the assemblages. Macrofauna had only sediment-related variables and heavy metals as major environmental factors, but meiofauna were also influenced by other environmental factors such as sea surface temperature, dissolved oxygen-related variables, and salinity. This study can provide basic ecological data for understanding the spatial distribution of macro-meiofaunal assemblages and aid in the development of marine environmental management strategies on the western south coast of Korea.

Spatiotemporal variability on local-regional scale in subtidal meiofaunal assemblages along the southern coast of Korea.

This study was conducted to investigate the spatiotemporal variability in subtidal meiofaunal assemblages off the southern coast of Korea at local and regional scales. Abiotic and biotic samples were collected by site (three sites at least 10 km apart) within region (three coastal regions at least 50 km apart) over 7 years (2015-2021). The density and taxon richness of meiofaunal assemblages differed significantly among sites, but not among regions or years. The meiofaunal assemblage composition differed significantly among sites, regions, and years. A distance-based multivariate multiple regression analysis revealed that the mean sediment grain size and total nitrogen, lead, nickel, chromium, and aluminum concentrations were key environmental variables determining the variation of the meiofaunal assemblages. This study can provide basic ecological data for understanding the spatiotemporal distribution of meiofauna assemblages and aid in the development of management strategies to mitigate marine pollution on the southern coast of Korea.

Comparative Analysis of Water Extracts from Roselle (Hibiscus sabdariffa L.) Plants and Callus Cells: Constituents, Effects on Human Skin Cells, and Transcriptome Profiles.

Roselle (Hibiscus sabdariffa L.) is a plant that has traditionally been used in various food and beverage products. Here, we investigated the potential of water extracts derived from Roselle leaves and callus cells for cosmetic and pharmaceutical purposes. We generated calluses from Roselle leaves and produced two different water extracts through heat extraction, which we named Hibiscus sabdariffa plant extract (HSPE) and Hibiscus sabdariffa callus extract (HSCE). HPLC analysis showed that the two extracts have different components, with nucleic acids and metabolites such as phenylalanine and tryptophan being the most common components in both extracts. In vitro assays demonstrated that HSCE has strong anti-melanogenic effects and functions for skin barrier and antioxidant activity. Transcriptome profiling of human skin cells treated with HSPE and HSCE showed significant differences, with HSPE having more effects on human skin cells. Up-regulated genes by HSPE function in angiogenesis, the oxidation-reduction process, and glycolysis, while up-regulated genes by HSCE encode ribosome proteins and IFI6, functioning in the healing of radiation-injured skin cells. Therefore, we suggest that the two extracts from Roselle should be applied differently for cosmetics and pharmaceutical purposes. Our findings demonstrate the potential of Roselle extracts as a natural source for skincare products.

Demonstration of a roll-to-roll-configurable, all-solution-based progressive assembly of flexible transducer devices consisting of functional nanowires on micropatterned electrodes.

We demonstrate continuous fabrication of flexible transducer devices consisting of interdigitated (IDT) Ag microelectrodes interconnected by ZnO nanowires (ZNWs), created via serially connected solution-processable micro- and nanofabrication processes. On an Ag layer obtainable from the mild thermal reduction of an ionic Ag ink coating, the roll-to-roll-driven photolithography process [termed photo roll lithography (PRL)] followed by wet-etching can be applied to continuously define the IDT microelectrode structure. Conformal ZNWs can then be grown selectively on the Ag electrodes to interconnect them via an Ag-mediated hydrothermal ZNW growth that does not require high-temperature seed sintering. Given that all of these constitutive processes are vacuum-free and solution-processable at a low temperature, and are compatible with continuous processing onto flexible substrates, they can be eventually configured into the roll-to-roll-processable progressive assembly. Through parametric optimizations of processes consisting of the roll-to-roll-configurable, solution-based progressive assembly of nanostructures (ROLSPAN), a flexible transducer consisting of ZNW-interconnected, PRL-ed IDT Ag electrodes can be developed. This flexible architecture faithfully performs UV sensing as well as optoelectronic transduction. The ROLSPAN concept along with its specific applicability to flexible devices may inspire many diverse functional systems requiring high-throughput low-temperature fabrication over large-area flexible substrates.

Rapid Assembly of Pyrrole-Ligated 1,3,4-Oxadiazoles and Excellent Antibacterial Activity of Iodophenol Substituents.

Pyrrole-ligated 1,3,4-oxadiazole is a very important pharmacophore which exhibits broad therapeutic effects such as anti-tuberculosis, anti-epileptic, anti-HIV, anti-cancer, anti-inflammatory, antioxidant, and antibacterial activities. A one-pot Maillard reaction between D-Ribose and an L-amino methyl ester in DMSO with oxalic acid at 2.5 atm and 80 °C expeditiously produced pyrrole-2-carbaldehyde platform chemicals in reasonable yields, which were utilized for the synthesis of pyrrole-ligated 1,3,4-oxadiazoles. Benzohydrazide reacted with the formyl group of the pyrrole platforms to provide the corresponding imine intermediates, which underwent I2-mediated oxidative cyclization to the pyrrole-ligated 1,3,4-oxadiazole skeleton. The structure and activity relationship (SAR) of the target compounds with varying alkyl or aryl substituents of the amino acids and electron-withdrawing or electron-donating substituents on the phenyl ring of benzohydrazide were evaluated for antibacterial activity against Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii as representative Gram(-) and Gram(+) bacteria. Branched alkyl groups from the amino acid showed better antibacterial activities. Absolutely superior activities were observed for 5f-1 with an iodophenol substituent against A. baumannii (MIC < 2 µg/mL), a bacterial pathogen that displays a high resistance to commonly used antibiotics.

Modeling for the estimating the adsorption property of fruit waste-based biosorbents for the removal of organic micropollutants.

The enormous production of fruit waste and the generation of countless organic micropollutants are serious environmental problems. To solve the problems, the biowastes, i.e., orange, mandarin, and banana peels, were used as biosorbents to remove the organic pollutants. In this application, the difficult challenge is knowing the degree of adsorption affinity of biomass for each type of micropollutant. However, since there are numerous micropollutants, it requires enormous material consumption and labor to physically estimate the adsorbability of biomass. To address this limitation, quantitative structure-adsorption relationship (QSAR) models for the adsorption assessment were established. In this process, the surface properties of each adsorbent were measured with instrumental analyzers, their adsorption affinity values for several organic micropollutants were determined through isotherm experiments, and QSAR models for each adsorbent were developed. The results showed that the tested adsorbents had significant adsorption affinity for cationic and neutral micropollutants, while the anionic one had low adsorption. As a result of the modeling, it was found that the adsorption could be predicted for a modeling set with an R2 of 0.90-0.915, and the models were validated via the prediction of a test set that was not included in the modeling set. Also, using the models, the adsorption mechanisms were identified. It is speculated that these developed models can be used to rapidly estimate adsorption affinity values for other micropollutants.

A nurse-led mHealth intervention to alleviate depressive symptoms in older adults living alone in the community: A quasi-experimental study.

BACKGROUND: The prevalence of geriatric depression has increased worldwide, becoming a major contributor to the burden of health care costs. Geriatric depression is difficult to detect in daily life because of its atypical presentation for each person. Therefore, there is an emerging need to develop personalised mHealth interventions for older adults with depression based on data from an ecological momentary assessment. OBJECTIVE: To develop and evaluate the effect of a nurse-led mHealth intervention of geriatric depression in older adults living alone. DESIGN: A quasi-experimental research design was used, and the study followed the transparent reporting of evaluations with a nonrandomised design statement. SETTING: The nurse-led mHealth intervention was developed and evaluated in a community senior centre in Seoul, Korea. PARTICIPANTS: Sixty-four older adults living alone with depressive symptoms were recruited between 1 October 2018 and 1 October 2019. METHODS: Study participants were randomly assigned to the intervention or control groups by drawing lots. In the intervention group, nurses repeatedly assessed older adults' depressive symptoms using an ecological momentary assessment via a mobile tablet. The intervention consisted of weekly sessions, which included (1) standardised mHealth device training, (2) a nurse-led mHealth programme, and (3) art activities. The control group received care as usual. Intra- and inter-group differences were evaluated using paired t-tests and analysis of covariance was used to assess subjective depression symptoms. A linear mixed-model was used to analyse the relationship between groups and momentary scores over time. RESULTS: The average age of the final sample was 76.2 years (SD = 6.06), 63.6 % (28/44) of whom were female. Compared with the control group (n = 23), the intervention group (n = 21) showed a decreased depression score (t = 4.041, p = .027). There was no statistical difference between the intervention and control groups based on traditional scales and the ecological momentary assessment. However, our data from the ecological momentary assessment captures clear fluctuating patterns across the days during the study, which traditional scales could not measure. CONCLUSIONS: Most of the older adults successfully participated in a nurse-led mHealth intervention that included multiple components of a non-pharmacological approach to address depression. Mental health nurses should perform critical roles to personalise mHealth activities considering the older adult's autonomy and supportive decision-making, specifically when using high-technological intervention. Future research should maximise the methodological and clinical advantage of an ecological momentary assessment of geriatric depression. REGISTRATION: Clinical Research Information Service number KCT0005073.

Liquid Crystalline Systems from Nature and Interaction of Living Organisms with Liquid Crystals.

Biomaterials, which are substances interacting with biological systems, have been extensively explored to understand living organisms and obtain scientific inspiration (such as biomimetics). However, many aspects of biomaterials have yet to be fully understood. Because liquid crystalline phases are ubiquitously found in biomaterials (e.g., cholesterol, amphiphile, DNA, cellulose, bacteria), therefore, a wide range of research has made attempts to approach unresolved issues with the concept of liquid crystals (LCs). This review presents these studies that address the interactive correlation between biomaterials and LCs. Specifically, intrinsic LC behavior of various biomaterials such as DNA, cellulose nanocrystals, and bacteriaare first introduced. Second, the dynamics of bacteria in LC media are addressed, with focus on how bacteria interact with LCs, and how dynamics of bacteria can be controlled by exploiting the characteristics of LCs. Lastly, how the strong correlation between LCs and biomaterials has been leveraged to design a new class of biosensors with additional functionalities (e.g., self-regulated drug release) that are not available in previous systems is reviewed. Examples addressed in this review convey the message that the intersection between biomaterials and LCs offers deep insights into fundamental understanding of biomaterials, and provides resources for development of transformative technologies.

Creating reverse flow arteriovenous fistulas with a forearm cannulation target.

BACKGROUND: Establishing a forearm arteriovenous fistula (AVF) offers preferred cannulation sites and preserves proximal access opportunities. When a radiocephalic AVF at the wrist is not feasible and the upper arm cephalic and median cubital veins are inadequate, an AV graft or more complex access procedure is often required. Creating a retrograde flow forearm AVF (RF-AVF) is a valuable alternative where the mid-forearm median antebrachial or cephalic vein is adequate, offering forearm cannulation zones with AVF outflow through deep and superficial collaterals. We report our technique and results. METHODS: We retrospectively reviewed our vascular access data base of consecutive patients during an 11-year study period where a RF-AVF established the only available cannulation target in the forearm. In addition to physical examination, all patients had ultrasound vessel mapping. RESULTS: A forearm access was established with a RF-AVF as the only opportunity for cannulation in 48 patients. Ages were 14-86 years (median = 62 years). Forty-four percent female, 63% diabetic, 13% obese, and 29% had previous access operations. Inflow was proximal radial artery in 47 individuals and one proximal ulnar. Nine AVFs (19%) failed at 2-66 months (median 14 months). One RF-AVF was ligated due to arm edema. Follow-up was 2-111 months (median = 23.5 months). Primary and cumulative patency rates were 62% and 91% at 12 months, and 46% and 85% at 24 months. Five patients were lost to follow-up with functioning RF-AVFs (mean 41 months). Twenty-three patients (48%) died during F/U of causes unrelated to access procedures (mean 25 months). CONCLUSIONS: Establishing a reverse flow forearm AVF offers a successful autogenous access option in the forearm for selected patients with an inadequate distal radial artery and/or cephalic vein at the wrist, avoiding more complex or staged procedures and preserving upper arm sites for future use. A proximal radial artery inflow procedure is recommended.

Hematopoietic Cell Transplantation for Systemic Sclerosis-A Review.

Systemic sclerosis (SSc) is an autoimmune, multi-organ, connective tissue disease associated with significant morbidity and mortality. Conventional immunosuppressive therapies demonstrate limited efficacy. Autologous hematopoietic stem cell transplantation (HCT) is more efficacious but carries associated risks, including treatment-related mortality. Here, we review HCT as a treatment for SSc, its efficacy and toxicity in comparison to conventional therapies, and the proposed mechanisms of action. Furthermore, we discuss the importance of and recent developments in patient selection. Finally, we highlight the knowledge gaps and future work required to further improve patient outcomes.

Matching amino acids membrane preference profile to improve activity of antimicrobial peptides.

Antimicrobial peptides (AMPs) are cationic antibiotics that can kill multidrug-resistant bacteria via membrane insertion. However, their weak activity limits their clinical use. Ironically, the cationic charge of AMPs is essential for membrane binding, but it obstructs membrane insertion. In this study, we postulate that this problem can be overcome by locating cationic amino acids at the energetically preferred membrane surface. All amino acids have an energetically preferred or less preferred membrane position profile, and this profile is strongly related to membrane insertion. However, most AMPs do not follow this profile. One exception is protegrin-1, a powerful but neglected AMP. In the present study, we found that a potent AMP, WCopW5, strongly resembles protegrin-1 and that the match between its sequence and the preferred position profile closely correlates with its antimicrobial activity. One of its derivatives, WCopW43, has antimicrobial activity comparable to that of the most effective AMPs in clinical use.

Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.

Myasthenia gravis is an autoimmune disorder defined by muscle weakness and fatigability associated with antibodies against proteins of the neuromuscular junction (NMJ). The most common autoantibody target is the acetylcholine receptor (AChR). Three mechanisms have been postulated by which autoantibodies might interfere with neurotransmission: direct antagonism of the receptor, complement-mediated destruction of the postsynaptic membrane, and enhanced internalization of the receptor. It is very likely that more than one of these mechanisms act in parallel. Dissecting the mechanisms of autoantibody-mediated pathology requires patient-derived, monoclonal antibodies. Using membrane antigen capture activated cell sorting (MACACS), we isolated AChR-specific B cells from patients with myasthenia gravis, and produced six recombinant antibodies. All AChR-specific antibodies were hypermutated, including isotypes IgG1, IgG3, and IgG4, and recognized different subunits of the AChR. Despite clear binding, none of the individual antibodies showed significant antagonism of the AChR measured in an in vitro neuromuscular synapse model, or AChR-dependent complement activation, and they did not induce myasthenic signs in vivo. However, combinations of antibodies induced strong complement activation in vitro, and severe weakness in a passive transfer myasthenia gravis rat model, associated with NMJ destruction and complement activation in muscle. The strongest complement activation was mediated by combinations of antibodies targeting disparate subunits of the AChR, and such combinations also induced the formation of large clusters of AChR on the surface of live cells in vitro. We propose that synergy between antibodies of different epitope specificities is a fundamental feature of this disease, and possibly a general feature of complement-mediated autoimmune diseases. The importance of synergistic interaction between antibodies targeting different subunits of the receptor can explain the well-known discrepancy between serum anti-AChR titers and clinical severity, and has implications for therapeutic strategies currently under investigation.