Ultrahigh Sensitivity for Thermographic Human-Machine Interface via Precious Metals Atomic Layer Deposition on V-MXene: Computational and Experimental Exploration.

Global healthcare based on the Internet of Things system is rapidly transforming to measure precise physiological body parameters without visiting hospitals at remote patients and associated symptoms monitoring. 2D materials and the prevailing mood of current ever-expanding MXene-based sensing devices motivate to introduce first the novel iridium (Ir) precious metal incorporated vanadium (V)-MXene via industrially favored emerging atomic layer deposition (ALD) techniques. The current work contributes a precise control and delicate balance of Ir single atomic forms or clusters on the V-MXene to constitute a unique precious metal-MXene embedded heterostructure (Ir-ALD@V-MXene) in practical real-time sensing healthcare applications to thermography with human-machine interface for the first time. Ir-ALD@V-MXene delivers an ultrahigh durability and sensing performance of 2.4% °C-1 than pristine V-MXene (0.42% °C-1), outperforming several conventionally used MXenes, graphene, underscoring the importance of the Ir-ALD innovative process. Aberration-corrected advanced ultra-high-resolution transmission/scanning transmission electron microscopy confirms the presence of Ir atomic clusters on well-aligned 2D-layered V-MXene structure and their advanced heterostructure formation (Ir-ALD@V-MXene), enhanced sensing mechanism is investigated using density functional theory (DFT) computations. A rational design empowering the Ir-ALD process on least explored V-MXene can potentially unfold further precious metals ALD-process developments for next-generation wearable personal healthcare devices.

Stretchable and Skin-Mountable Temperature Sensor Array Using Reduction-Controlled Graphene Oxide for Dermatological Thermography.

Since thermometry of human skin is critical information that provides important aspects of human health and physiology, accurate and continuous temperature measurement is required for the observation of physical abnormalities. However, conventional thermometers are uncomfortable because of their bulky and heavy features. In this work, we fabricated a thin, stretchable array-type temperature sensor using graphene-based materials. Furthermore, we controlled the degree of graphene oxide reduction and enhanced the temperature sensitivity. The sensor exhibited an excellent sensitivity of 2.085% °C-1. The overall device was designed in a wavy meander shape to provide stretchability for the device so that precise detection of skin temperature could be performed. Furthermore, polyimide film was coated to secure the chemical and mechanical stabilities of the device. The array-type sensor enabled spatial heat mapping with high resolution. Finally, we introduced some practical applications of skin temperature sensing, suggesting the possibility of skin thermography and healthcare monitoring.

Chronic frontal neurobehavioural symptoms in combat-deployed military personnel with and without a history of blast-related mild traumatic brain injury.

OBJECTIVE: This study evaluated frontal behavioural symptoms, via the FrSBe self-report, in military personnel with and without a history of blast-related mild traumatic brain injury (mild TBI). METHODS: Prospective observational cohort study of combat-deployed service members leveraging 1-year and 5-year demographic and follow up clinical outcome data. RESULTS: The blast mild TBI group (n = 164) showed greater frontal behavioural symptoms, including clinically elevated apathy, disinhibition, and executive dysfunction, during a 5-year follow-up, compared to a group of combat-deployed controls (n = 107) without mild TBI history or history of blast exposure. We also explored changes inbehaviourall symptoms over a 4-year span, which showed clinically significant increases in disinhibition in the blast mild TBI group, whereas the control group did not show significant increases in symptoms over time. CONCLUSION: Our findings add to the growing evidence that a proportion of individuals who sustain mild TBI experience persistent behavioural symptoms. We also offer a demonstration of a novel use of the FrSBe as a tool for longitudinal symptom monitoring in a military mild TBI population.

Antibacterial application of covalently immobilized photosensitizers on a surface.

Singlet oxygen produced by irradiating photosensitizers (PSs) can be used to kill pathogens during water treatment. Chemical immobilization of the PSs on surfaces can maintain their disinfection function long-term. In this study, two model PSs (rose bengal (RB) and hematoporphyrin (HP)) were immobilized on a glass surface using a silane coupling agent with an epoxide group, and their antibacterial properties were analyzed. Fourier transform infrared spectroscopy demonstrated that a covalent bond formed between the epoxide group and hydroxyl group in the PSs. A large proportion of the immobilized PSs (approximately 50%) was active in singlet oxygen production, which was evidenced by a comparative analysis with free PSs. RB was more effective at producing singlet oxygen than HP. The immobilized PSs were durable in terms of repeated use. On the other hand, singlet oxygen produced by the PSs was effective at killing bacteria, mostly for Gram-positive bacteria (> 90% death for 2 h of irradiation), by damaging the cell membrane. The preferable antibacterial property against Gram-positive bacteria compared with that against Gram-negative bacteria suggested efficient penetrability of singlet oxygen across the cell membrane, which led to cell death. Taken together, it was concluded that immobilization of PSs on surfaces using the silane coupling agent proposed in this study was effective at killing Gram-positive bacteria by forming singlet oxygen.

Interaction of Individual Structural Domains of hnRNP LL with the BCL2 Promoter i-Motif DNA.

The recently discovered role of the BCL2 (B-cell lymphoma 2 gene) promoter i-motif DNA in modulation of gene expression via interaction with the ribonucleoprotein hnRNP L-like (hnRNP LL) has prompted a more detailed study of the nature of this protein-DNA interaction. The RNA recognition motifs (RRMs) of hnRNP LL were expressed individually, and both RRM1 and RRM2 were found to bind efficiently to the BCL2 i-motif DNA, as well as being critical for transcriptional activation, whereas RRM3-4 bound only weakly to this DNA. Binding was followed by unfolding of the DNA as monitored by changes in the CD spectrum. Mutational analysis of the i-motif DNA revealed that binding involved primarily the lateral loops of the i-motif. The kinetics of binding of the DNA with RRM1 was explored by recording CD spectra at predetermined times following admixture of the protein and DNA. The change in molar ellipticity was readily apparent after 30 s and largely complete within 1 min. A more detailed view of protein-DNA interaction was obtained by introducing the fluorescence donor 6-CNTrp in RRM1 at position 137, and the acceptor 4-aminobenzo[g]quinazoline-2-one (Cf) in lieu of cytidine22 in the i-motif DNA. The course of binding of the two species was monitored by FRET, which reflected a steady increase in energy transfer over a period of several minutes. The FRET signal could be diminished by the further addition of (unlabeled) RRM2, no doubt reflecting competition for binding to the i-motif DNA. These experiments using the individual RRM domains from hnRNP LL confirm the role of this transcription factor in activation of BCL2 transcription via the i-motif in the promoter element.

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters.

Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding sites that drive hTERT expression, but this model cannot fully account for differences in wild-type (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here, we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing. We show that promoter mutations exert a detrimental effect on the folding of one of these G-quadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression produces cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and induction of senescence by decreasing telomerase activity and telomere length. We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress hTERT.

In silico identification of novel ligands for G-quadruplex in the c-MYC promoter.

G-quadruplex DNA formed in NHEIII1 region of oncogene promoter inhibits transcription of the genes. In this study, virtual screening combining pharmacophore-based search and structure-based docking screening was conducted to discover ligands binding to G-quadruplex in promoter region of c-MYC. Several hit ligands showed the selective PCR-arresting effects for oligonucleotide containing c-MYC G-quadruplex forming sequence. Among them, three hits selectively inhibited cell proliferation and decreased c-MYC mRNA level in Ramos cells, where NHEIII1 is included in translocated c-MYC gene for overexpression. Promoter assay using two kinds of constructs with wild-type and mutant sequences showed that interaction of these ligands with the G-quadruplex resulted in turning-off of the reporter gene. In conclusion, combined virtual screening methods were successfully used for discovery of selective c-MYC promoter G-quadruplex binders with anticancer activity.

The transcriptional complex between the BCL2 i-motif and hnRNP LL is a molecular switch for control of gene expression that can be modulated by small molecules.

In a companion paper (DOI: 10.021/ja410934b) we demonstrate that the C-rich strand of the cis-regulatory element in the BCL2 promoter element is highly dynamic in nature and can form either an i-motif or a flexible hairpin. Under physiological conditions these two secondary DNA structures are found in an equilibrium mixture, which can be shifted by the addition of small molecules that trap out either the i-motif (IMC-48) or the flexible hairpin (IMC-76). In cellular experiments we demonstrate that the addition of these molecules has opposite effects on BCL2 gene expression and furthermore that these effects are antagonistic. In this contribution we have identified a transcriptional factor that recognizes and binds to the BCL2 i-motif to activate transcription. The molecular basis for the recognition of the i-motif by hnRNP LL is determined, and we demonstrate that the protein unfolds the i-motif structure to form a stable single-stranded complex. In subsequent experiments we show that IMC-48 and IMC-76 have opposite, antagonistic effects on the formation of the hnRNP LL-i-motif complex as well as on the transcription factor occupancy at the BCL2 promoter. For the first time we propose that the i-motif acts as a molecular switch that controls gene expression and that small molecules that target the dynamic equilibrium of the i-motif and the flexible hairpin can differentially modulate gene expression.

The dynamic character of the BCL2 promoter i-motif provides a mechanism for modulation of gene expression by compounds that bind selectively to the alternative DNA hairpin structure.

It is generally accepted that DNA predominantly exists in duplex form in cells. However, under torsional stress imposed by active transcription, DNA can assume nonduplex structures. The BCL2 promoter region forms two different secondary DNA structures on opposite strands called the G-quadruplex and the i-motif. The i-motif is a highly dynamic structure that exists in equilibrium with a flexible hairpin species. Here we identify a pregnanol derivative and a class of piperidine derivatives that differentially modulate gene expression by stabilizing either the i-motif or the flexible hairpin species. Stabilization of the i-motif structure results in significant upregulation of the BCL2 gene and associated protein expression; in contrast, stabilization of the flexible hairpin species lowers BCL2 levels. The BCL2 levels reduced by the hairpin-binding compound led to chemosensitization to etoposide in both in vitro and in vivo models. Furthermore, we show antagonism between the two classes of compounds in solution and in cells. For the first time, our results demonstrate the principle of small molecule targeting of i-motif structures in vitro and in vivo to modulate gene expression.

Differences in health-related quality of life and somatic symptoms in employed and unemployed patients with epilepsy.

This study compared overall and specific aspects of health-related quality of life (HRQOL) and self-report of somatic, anxiety, and depressive symptoms between employed (n = 71) and unemployed (n = 48) patients with epilepsy (PWE). The Quality of Life in Epilepsy (QOLIE-89) and the Personality Assessment Inventory (PAI) were examined. The unemployed group reported significantly worse overall HRQOL including aspects of HRQOL related to epilepsy, physical health, mental health, and cognitive function. Among these four, physical health related HRQOL revealed the most difference between groups. While there were no differences between the groups in the level of social support and social isolation, the unemployed group reported worse social function with respect to work and driving. The unemployed group reported significantly greater somatic symptoms, but not anxiety and depressive symptoms. When specifically examining the subscales of the Somatic Concerns scale, conversion and health concerns, but not somatization, were greater in the unemployed group. Among the Depression subscales, the unemployed group reported greater physiologically manifested depressive symptoms. These findings suggest that along with optimizing seizure control, identifying and addressing presence of physical limitations, dysfunction, and somatic symptoms are also of importance in the care of PWE, particularly for those who are unemployed.

Retinoic acid receptor-related orphan receptor α-induced activation of adenosine monophosphate-activated protein kinase results in attenuation of hepatic steatosis.

UNLABELLED: There is increasing evidence that the retinoic acid receptor-related orphan receptor α (RORα) plays an important role in the regulation of metabolic pathways, particularly of fatty acid and cholesterol metabolism; however, the role of RORα in the regulation of hepatic lipogenesis has not been studied. Here, we report that RORα attenuates hepatic steatosis, probably via activation of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) and repression of the liver X receptor α (LXRα). First, RORα and its activator, cholesterol sulfate (CS), induced phosphorylation of AMPK, which was accompanied by the activation of serine-threonine kinase liver kinase B1 (LKB1). Second, the activation of RORα, either by transient transfection or CS treatment, decreased the TO901317-induced transcriptional expression of LXRα and its downstream target genes, such as the sterol regulatory element binding protein-1 (SREBP-1) and fatty acid synthase. RORα interacted physically with LXRα and inhibited the LXRα response element in the promoter of LXRα, indicating that RORα interrupts the autoregulatory activation loop of LXRα. Third, infection with adenovirus encoding RORα suppressed the lipid accumulation that had been induced by a free-fatty-acid mixture in cultured cells. Furthermore, we observed that the level of expression of the RORα protein was decreased in the liver of mice that were fed a high-fat diet. Restoration of RORα via tail-vein injection of adenovirus (Ad)-RORα decreased the high-fat-diet-induced hepatic steatosis. Finally, we synthesized thiourea derivatives that activated RORα, thereby inducing activation of AMPK and repression of LXRα. These compounds decreased hepatic triglyceride levels and lipid droplets in the high-fat-diet-fed mice. CONCLUSION: We found that RORα induced activation of AMPK and inhibition of the lipogenic function of LXRα, which may be key phenomena that provide the beneficial effects of RORα against hepatic steatosis.

Specificity of performance validity tests in patients with confirmed epilepsy.

Objective: While assessment of performance validity is essential to neuropsychological evaluations, use of performance validity tests (PVTs) in an epilepsy population has raised concerns due to factors that may result in performance fluctuations. The current study assessed whether specificity was maintained at previously suggested cutoffs in a confirmed epilepsy population on the Warrington Recognition Memory Test (WRMT) - Words and Test of Memory Malingering (TOMM). Method: Eighty-two confirmed epilepsy patients were administered the WRMT-Words and TOMM as part of a standardized neuropsychological evaluation. Frequency tables were utilized to investigate specificity rates on these two PVTs. Results: The suggested WRMT-Words Accuracy Score cutoff of ≤42 was associated with a specificity rate of 90.2%. Five out of the 8 individuals falling below the Accuracy Score cutoff scored 42, suggesting specificity could be further improved by slightly lowering the cutoff. The WRMT-Words Total Time cutoff of ≥207 seconds was associated with 95.1% specificity. A TOMM Trial 1 cutoff of <40 was associated with 93.9% specificity, while the established cutoff of <45 on Trial 2 and the Retention Trial yielded specificity rates of 98.6% and 100.0%, respectively. Conclusions: Our findings demonstrate acceptable performance on two PVTs in a select confirmed epilepsy population without a history of brain surgery, active seizures during testing, and/or low IQ, irrespective of various factors such as seizure type, seizure lateralization/localization, and language lateralization. The possible presence of interictal discharges were not controlled for in the current study, which may have contributed to reduced PVT performances.

Rapid and sensitive detection of gram-negative bacteria using surface-immobilized polymyxin B.

Although detection of gram-negative bacteria (GNB) in body fluids is important for clinical purpose, traditional gram staining and other recently developed methods have inherent limitations in terms of accuracy, sensitivity, and convenience. To overcome the weakness, this study proposed a method detecting GNB based on specific binding of polymyxin B (PMB) to lipopolysaccharides (LPS) of GNB. Fluorescent microscopy demonstrated that surface immobilized PMB using a silane coupling agent was possible to detect fluorescent signal produced by a single Escherichia coli (a model GNB) cell. Furthermore, the signal was selective enough to differentiate between GNB and gram-positive bacteria. The proposed method could detect three cells per ml within one hour, indicating the method was very sensitive and the sensing was rapid. These results suggest that highly multifold PMB binding on each GNB cell occurred, as millions of LPS are present on cell wall of a GNB cell. Importantly, the principle used in this study was realized in a microfluidic chip for a sample containing E. coli cells suspended in porcine plasma, demonstrating its potential application to practical uses. In conclusion, the proposed method was accurate, sensitive, and convenient for detecting GNB, and could be applied clinically.

Monitoring bacterial community structure and variability in time scale in full-scale anaerobic digesters.

Using a high-throughput pyrosequencing technology, this study assessed bacterial community structure and time-scale variability in great detail in seven full-scale anaerobic digesters operated variously in terms of influent substrate, digestion temperature, and reactor configuration. Pyrosequencing generated a total of 83,774 sequence reads from 40 digester sludge samples collected monthly for six months. The highest number of sequence reads were detected within Proteobacteria (20.5%), followed by those within Bacteroidetes (19.7%), Firmicutes (17.8%), and Chloroflexi (4.8%). The relative composition of bacterial populations was varied within the digesters as well as between the digesters, and the bacterial community structures were mainly influenced by digestion temperature. Detailed bacterial community structures were assessed by analyzing the operational taxonomic units (OTUs) based on 97% sequence similarity, which resulted in a total of 9051 OTUs. Among these, a total of 31 core OTUs were analyzed and inferred phylogenetically, which enabled us to classify the sequences within an unclassified phylum. Unclassified sequences were mostly affiliated with the sequences within Spirochaetes and Firmicutes. Interestingly, numerically dominant novel phylotypes (18% of the total sequence reads) presumably involved in anaerobic digestion within Spirochaetes were identified. Temporal variability was further explored using a non-metric multidimensional scaling ordination which demonstrated that the variability of the bacterial community within the digesters was smaller than between digesters. Correlation analysis demonstrated that digester performance and operational conditions affected the pattern of bacterial community in the ordination. Additionally, a multi-response permutation procedure revealed that the bacterial communities within the digesters were more similar than those belonging to other digesters statistically, demonstrating a patchiness of the digesters in the distribution of bacterial populations. Overall, this study revealed the correlation of bacterial community structure and time-scale variability with digester performance and operating conditions.

Different contribution of exoelectrogens in methanogenesis via direct interspecies electron transfer (DIET) by the different substrate in continuous anaerobic bioreactor.

Direct interspecies electron transfer (DIET) is a syntrophic mechanism for electron transfer between exo- and endoelectrogens. Previous studies have demonstrated that methanogenesis performance was significantly improved via the DIET mechanism through conductive materials (CMs) under batch conditions with a single substrate, while that under continuous condition is still under investigation. To investigate how the DIET via CM on methanogenesis performance was changed in response to the different substrates (acetate versus glucose)-fed in continuous anaerobic bioreactors, continuous bioreactors were operated by cross-feeding with acetate and glucose. Acetate-fed conditions showed 0.40 day shorten lagtime, 1.88- and 1.22-folds higher methane production rate, and ultimate methane production than glucose-fed conditions, respectively. Burkholderiaceae- and Anaerolineaceae-related exo-electrogenic populations were enriched with low abundance of Geobacter species in batch reactors. Furthermore, influent substrates affected the distribution of the enriched populations. Taken together, the results suggested that different syntrophic associations contributed methane production by DIET in continuous bioreactors.

A Case of Linear Exacerbation of Atopic Dermatitis with Secondary Prurigo Nodularis.

Inflammatory acquired Blaschko-linear dermatoses (IABLD) are a continuous concept involving diseases such as lichen striatus, blaschkitis, and atopic dermatitis. However, atopic dermatitis that showed increase in severity along Blaschko lines is rarely reported on its own. Herein, we report a rare case of atopic dermatitis with secondary prurigo nodularis along Blaschko lines, which may be valuable in broadening the concept of IABLD. A 28-year-old male presented with multiple, pruritic, brownish nodules on the left lower extremity along Blaschko lines for 3 to 4 years. The patient had atopic dermatitis since childhood. Histopathologic findings revealed compact orthohyperkeratosis, hypergranulosis, spongiosis, and irregular acanthosis in the epidermis. Fibrosis with vertically arranged collagen fibers and perivascular lymphohistiocytic infiltration were shown in the upper dermis. We diagnosed the case as secondary prurigo nodularis along Blaschko lines, accompanied by the preceding atopic dermatitis. We hypothesized that the patient's underlying atopic dermatitis increased in severity along Blaschko lines, and prurigo nodularis occurred due to frequent scratching. The lesions improved with topical methylprednisolone cream, oral antihistamines and intralesional triamcinolone injection.

Effect of microbial community structure in inoculum on the stimulation of direct interspecies electron transfer for methanogenesis.

To investigate how the seed microbial community structure affects the improvement of methanogenesis efficiency through direct interspecies electron transfer (DIET), a biomethane potential (BMP) test was conducted using sludge collected from a total of six anaerobic digesters. DIET-stimulating microbial populations were investigated by 16S rRNA gene sequence analysis. Correlations between microbial community composition and methane production performance by DIET were analyzed. The methane production rate increased under all conditions when granular activated carbon (GAC) was injected regardless of the inoculum type. However, redundancy analysis indicated a significant correlation between the inoculum microbial community and lag time. In a network analysis, Methanolinea species distributed in the inocula formed a single modularity with lag time, suggesting that the methanogens in the inocula might reduce the lag time of methanogenesis through DIET. Overall, this study revealed that the inoculum microbial community composition is an important factor affecting methane production efficiency by DIET.

Recurrent Cellulitis Associated with Acupuncture with Migratory Gold Threads.

In Asian countries, acupuncture with gold threads has been widely used in the treatment of pain. However, several reports have suggested that the implanted gold threads can become fragmented and migrate to other parts of the body, damaging surrounding tissues. A 75-year-old female presented with diffuse erythematous edema with multiple vesicles on the right lower leg for 3 days. She had previously suffered from cellulitis on the same region twice for the last 1 year. Her past medical history included acupuncture with gold threads on the back due to lumbar herniated nucleus pulposus (HNP) about 10 years ago. Histopathological examination demonstrated marked subepithelial edema and diffuse perivascular infiltrate of inflammatory cells in the dermis. Simple radiography of the leg revealed numerous radiodense threads in the soft tissue. Since the patient did not receive acupuncture on any other sites except on the back, we hypothesized that the gold threads injected on the back may have migrated through the vessels to the leg. These metal fragments can cause inflammatory reaction and make the tissues more susceptible to secondary infections. The lesion gradually improved after treatment with systemic steroid and antibiotics for 1 week.

Recent advances in methanogenesis through direct interspecies electron transfer via conductive materials: A molecular microbiological perspective.

Conductive materials can serve as biocatalysts during direct interspecies electron transfer for methanogenesis in anaerobic reactors. However, the mechanism promoting direct interspecies electron transfer in anaerobic reactors, particularly under environments in which diverse substrates and microorganisms coexist, remains to be elucidated from a scientific or an engineering point of view. Currently, many molecular microbiological approaches are employed to understand the fundamentals of this phenomenon. Here, the direct interspecies electron transfer mechanisms and relevant microorganisms identified to date using molecular microbiological methods were critically reviewed. Moreover, molecular microbiological methods for direct interspecies electron transfer used in previous studies and important findings thus revealed were analyzed. This review will help us better understand the phenomena of direct interspecies electron transfer using conductive materials and offer a framework for future molecular microbiological studies.