Healthcare Utilization, Physical and Psychiatric Comorbidities Before Self-Injurious Behavior in Patients with Asthma: A Nested Case-Control Study.

Background: Patients with asthma experience more physical, psychological, and financial burdens; a link between asthma and suicidality has been reported in research. Purpose: This study analyzed the medical utilization and comorbidity before their self-injurious behavior in patients with asthma. Methods: We enrolled 186,862 patients newly diagnosed with asthma between 1999 and 2013 from the National Health Insurance Research Database in Taiwan. A total of 500 case subjects had ever conducted self-injurious behaviors during the study period. Based on a nested case-control study, each case was matched with 10 controls derived from the asthma cohort to analyze differences between them and their medical use models. Results: The results indicated that, compared to the control group, the cases presented higher frequencies of outpatient visits and hospitalizations. Regarding comorbidity, the cases had more cardiovascular diseases (adjusted odds ratio [aOR]=1.58; p<0.001), bipolar disorder (aOR=2.97; p<0.001), depression (aOR=4.44; p<0.001), and sleep disorder (aOR=1.83; p<0.001) than the controls. Conclusion: The evidence-based information serves as a reference for medical staff to reduce the occurrence of self-injurious behavior in patients with asthma.

Molecular interactions of tannic acid and matrix metalloproteinases 2 and 9.

Tannic acid (TA) has antibacterial, antioxidant, and anti-inflammatory properties and acts as an adhesive, hemostatic, and crosslinking agent in hydrogels. Matrix metalloproteinases (MMPs), a family of endopeptidase enzymes, play important roles in tissue remodeling and wound healing. TA has been reported to inhibit MMP-2/- 9 activities, thereby improving both tissue remodeling and wound healing. However, the mechanism of interaction of TA with MMP-2 and MMP-9 has not been fully elucidated. In this study, the full atomistic modeling approach was applied to explore the mechanisms and structures of TA binding with MMP-2 and MMP-9. Macromolecular models of the TA-MMP-2/- 9 complex were built by docking based on experimentally resolved MMP structures, and further equilibrium processes were examined by molecular dynamics (MD) simulations to investigate the binding mechanism and structural dynamics of the TA-MMP-2/- 9 complexes. The molecular interactions between TA and MMPs, including H-bond formation and hydrophobic and electrostatic interactions, were analyzed and decoupled to elucidate the dominant factors in TA-MMP binding. TA binds to MMPs mainly at two binding regions, residues 163-164 and 220-223 in MMP-2 and residues 179-190 and 228-248 in MMP-9. Two arms of TA participate in binding MMP-2 with 3.61 hydrogen bonds. On the other hand, TA binds MMP-9 with a distinct configuration involving four arms with 4.75 hydrogen bonds, resulting in a tighter binding conformation. Understanding the binding mechanism and structural dynamics of TA with these two MMPs provides crucial and fundamental knowledge regarding the inhibitory and stabilizing effects of TA on MMPs.

Calcium Imaging in Mouse Superior Colliculus.

The superior colliculus (SC), an evolutionarily conserved midbrain structure in all vertebrates, is the most sophisticated visual center before the emergence of the cerebral cortex. It receives direct inputs from ~30 types of retinal ganglion cells (RGCs), with each encoding a specific visual feature. It remains elusive whether the SC simply inherits retinal features or if additional and potentially de novo processing occurs in the SC. To reveal the neural coding of visual information in the SC, we provide here a detailed protocol to optically record visual responses with two complementary methods in awake mice. One method uses two-photon microscopy to image calcium activity at single-cell resolution without ablating the overlaying cortex, while the other uses wide-field microscopy to image the whole SC of a mutant mouse whose cortex is largely undeveloped. This protocol details these two methods, including animal preparation, viral injection, headplate implantation, plug implantation, data acquisition, and data analysis. The representative results show that the two-photon calcium imaging reveals visually evoked neuronal responses at single-cell resolution, and the wide-field calcium imaging reveals neural activity across the entire SC. By combining these two methods, one can reveal the neural coding in the SC at different scales, and such combination can also be applied to other brain regions.

Functional cell types in the mouse superior colliculus.

The superior colliculus (SC) represents a major visual processing station in the mammalian brain that receives input from many types of retinal ganglion cells (RGCs). How many parallel channels exist in the SC, and what information does each encode? Here, we recorded from mouse superficial SC neurons under a battery of visual stimuli including those used for classification of RGCs. An unsupervised clustering algorithm identified 24 functional types based on their visual responses. They fall into two groups: one that responds similarly to RGCs and another with more diverse and specialized stimulus selectivity. The second group is dominant at greater depths, consistent with a vertical progression of signal processing in the SC. Cells of the same functional type tend to cluster near each other in anatomical space. Compared to the retina, the visual representation in the SC has lower dimensionality, consistent with a sifting process along the visual pathway.

Conversion of Escherichia coli into Mixotrophic CO2 Assimilation with Malate and Hydrogen Based on Recombinant Expression of 2-Oxoglutarate:Ferredoxin Oxidoreductase Using Adaptive Laboratory Evolution.

We report the mixotrophic growth of Escherichia coli based on recombinant 2-oxoglutarate:ferredoxin oxidoreductase (OGOR) to assimilate CO2 using malate as an auxiliary carbon source and hydrogen as an energy source. We employ a long-term (~184 days) two-stage adaptive evolution to convert heterotrophic E. coli into mixotrophic E. coli. In the first stage of evolution with serine, diauxic growth emerges as a prominent feature. At the end of the second stage of evolution with malate, the strain exhibits mixotrophy with CO2 as an essential substrate for growth. We expect this work will open new possibilities in the utilization of OGOR for microbial CO2 assimilation and future hydrogen-based electro-microbial conversion.

Tough, Self-Healing, and Conductive Elastomer ─Ionic PEGgel.

Ionically conductive elastomers are necessary for realizing human-machine interfaces, bioelectronic applications, or durable wearable sensors. Current design strategies, however, often suffer from solvent leakage and evaporation, or from poor mechanical properties. Here, we report a strategy to fabricate ionic elastomers (IHPs) demonstrating high conductivity (0.04 S m-1), excellent electrochemical stability (>60,000 cycles), ultra-stretchability (up to 1400%), high toughness (7.16 MJ m-3), and fast self-healing properties, enabling the restoration of ionic conductivity within seconds, as well as no solvent leakage. The ionic elastomer is composed of in situ formed physically cross-linked poly(2-hydroxyethyl methacrylate) networks and poly(ethylene glycol) (PEG). The long molecular chains of PEG serve as a solvent for dissolving electrolytes, improve its long-term stability, reduce solvent leakage, and ensure the outstanding mechanical properties of the IHP. Surprisingly, the incorporation of ions into PEG simultaneously enhances the strength and toughness of the elastomer. The strengthening and toughening mechanisms were further revealed by molecular simulation. We demonstrate an application of the IHPs as (a) flexible sensors for strain or temperature sensing, (b) skin electrodes for recording electrocardiograms, and (c) a tough and sensing material for pneumatic artificial muscles. The proposed strategy is simple and easily scalable and can further inspire the design of novel ionic elastomers for ionotronics applications.

Streptococcus mutans PrsA mediates AtlA secretion contributing to extracellular DNA release and biofilm formation in the pathogenesis of infective endocarditis.

The role of secretion chaperone-regulated virulence proteins in the pathogenesis of infective endocarditis (IE) induced by viridans streptococci such as Streptococcus mutans is unclear. In this study, we investigated the contribution of the foldase protein PrsA, a putative parvulin-type peptidyl-prolyl isomerase, to the pathogenesis of S. mutans-induced IE. We found that a prsA-deficient strain had reduced virulence in terms of formation of vegetation on damaged heart valves, as well as reduced autolysis activity, eDNA release and biofilm formation capacity. The secretion and surface exposure of AtlA in vitro was reduced in the prsA-deficient mutant strain, and complementation of recombinant AtlA in the culture medium restored a wild type biofilm phenotype of the prsA-deficient mutant strain. This result suggests that secretion and surface localization of AtlA is regulated by PrsA during biofilm formation. Together, these results demonstrate that S. mutans PrsA could regulate AtlA-mediated eDNA release to contribute to biofilm formation in the pathogenesis of IE.

Balanced Enhancements of Synaptic Excitation and Inhibition Underlie Developmental Maturation of Receptive Fields in the Mouse Visual Cortex.

Neurons in the developing visual cortex undergo progressive functional maturation as indicated by the refinement of their visual feature selectivity. However, changes of the synaptic architecture underlying the maturation of spatial visual receptive fields (RFs) per se remain largely unclear. Here, loose-patch as well as single-unit recordings in layer 4 of mouse primary visual cortex (V1) of both sexes revealed that RF development following an eye-opening period is marked by an increased proportion of cortical neurons with spatially defined RFs, together with the increased signal-to-noise ratio of spiking responses. By exploring excitatory and inhibitory synaptic RFs with whole-cell voltage-clamp recordings, we observed a balanced enhancement of both synaptic excitation and inhibition, and while the excitatory subfield size remains relatively constant during development, the inhibitory subfield is broadened. This balanced developmental strengthening of excitatory and inhibitory synaptic inputs results in enhanced visual responses, and with a reduction of spontaneous firing rate, contributes to the maturation of visual cortical RFs. Visual deprivation by dark rearing impedes the normal strengthening of excitatory inputs but leaves the apparently normal enhancement of inhibition while preventing the broadening of the inhibitory subfield, leading to weakened RF responses and a reduced fraction of neurons exhibiting a clear RF, compared with normally reared animals. Our data demonstrate that an experience-dependent and coordinated maturation of excitatory and inhibitory circuits underlie the functional development of visual cortical RFs.SIGNIFICANCE STATEMENT The organization of synaptic RFs is a fundamental determinant of feature selectivity functions in the cortex. However, how changes of excitatory and inhibitory synaptic inputs lead to the functional maturation of visual RFs during cortical development remains not well understood. In layer 4 of mouse V1, we show that a coordinated, balanced enhancement of synaptic excitation and inhibition contributes to the developmental maturation of spatially defined visual RFs. Visual deprivation by dark rearing partially interferes with this process, resulting in a relatively more dominant inhibitory tone and a reduced fraction of neurons exhibiting clear RFs at the spike level. These data provide an unprecedented understanding of the functional development of visual cortical RFs at the synaptic level.

Hydrogen Bond Strength-Mediated Self-Assembly of Supramolecular Nanogels for Selective and Effective Cancer Treatment.

This study provides a significant contribution to the development of multiple hydrogen-bonded supramolecular nanocarrier systems by demonstrating that controlling the hydrogen bond strength within supramolecular polymers represents a crucial factor to tailor the drug delivery performance and enhance the effectiveness of cancer therapy. Herein, we successfully developed two kinds of poly(ethylene glycol)-based telechelic polymers Cy-PEG and UrCy-PEG having self-constituted double and quadruple hydrogen-bonding cytosine (Cy) and ureido-cytosine (UrCy) end-capped groups, respectively, which directly assemble into spherical nanogels with a number of interesting physical characteristics in aqueous solutions. The UrCy-PEG nanogels containing quadruple hydrogen-bonded UrCy dimers exhibited excellent long-term structural stability in a serum-containing biological medium, whereas the double hydrogen-bonded Cy moieties could not maintain the structural integrity of the Cy-PEG nanogels. More importantly, after the drug encapsulation process, a series of in vitro experiments clearly confirmed that drug-loaded UrCy-PEG nanogels induced selective apoptotic cell death in cancer cells without causing significant cytotoxicity to healthy cells, while drug-loaded Cy-PEG nanogels exerted nonselective cytotoxicity toward both cancer and normal cells, indicating that increasing the strength of hydrogen bonds in nanogels plays a key role in enhancing the selective cellular uptake and cytotoxicity of drugs and the subsequent induction of apoptosis in cancer cells.

Conquering the Tyranny of Number With Digital Microfluidics.

The development of large-scale integration based on soft lithography has ushered a new revolution in microfluidics. This technology, however, relies inherently on pneumatic control of micromechanical valves that require air pressure to operate, while digital microfluidics uses a purely electrical signal on an electrode for droplet manipulation. In this article, we discuss the prospect and current challenges of digital microfluidics to solve the problem of the tyranny of numbers in arbitrary fluidic manipulation. We distill the fundamental physics governing electrowetting and their implications for specifications of the control electronics. We survey existing control electronics in digital microfluidics and detail the improvements needed to realize a low-power, programmable digital microfluidic system. Such an instrument would attract wide interest in both professional and non-professional (hobbyist) communities.

A Versatile Kit Based on Digital Microfluidics Droplet Actuation for Science Education.

This paper describes an educational kit based on digital microfluidics. A protocol for luminol-based chemiluminescence experiment is reported as a specific example. It also has fluorescent imaging capability and closed humidified enclosure based on an ultrasonic atomizer to prevent evaporation. The kit can be assembled within a short period of time and with minimal training in electronics and soldering. The kit allows both undergraduate/graduate students and enthusiasts to obtain hands-on experience in microfluidics in an intuitive way and be trained to gain familiarity with digital microfluidics.

Functional Architecture of Motion Direction in the Mouse Superior Colliculus.

Motion vision is important in guiding animal behavior. Both the retina and the visual cortex process object motion in largely unbiased fashion: all directions are represented at all locations in the visual field. We investigate motion processing in the superior colliculus of the awake mouse by optically recording neural responses across both hemispheres. Within the retinotopic map, one finds large regions of ∼500 µm size where neurons prefer the same direction of motion. This preference is maintained in depth to ∼350 µm. The scale of these patches, ∼30 degrees of visual angle, is much coarser than the animal's visual resolution (∼2 degrees). A global map of motion direction shows approximate symmetry between the left and right hemispheres and a net bias for upward-nasal motion in the upper visual field.

Wireless bioreactor for anaerobic cultivation of bacteria.

Anaerobic cultivation methods of bacteria are indispensable in microbiology. One methodology is to cultivate the microbes in anaerobic enclosure with oxygen-adosrbing chemicals. Here, we report an electronic extension of such strategy for facultative anaerobic bacteria. The technique is based a bioreactor with entire operation including turbidity measurement, fluidic mixing, and gas delivery in an anaerobic enclosure. Wireless data transmission is employed and the anaerobic condition is achieved with gas pack. Although the technique is not meant to completely replace the anaerobic chamber for strict anaerobic bacteria, it provides a convenient way to bypass the cumbersome operation in anaerobic chamber for facultative anaerobic bacteria. Such a cultivation strategy is demonstrated with Escherichia coli with different carbon sources and hydrogen as energy source.

Detailed profiling of carbon fixation of in silico synthetic autotrophy with reductive tricarboxylic acid cycle and Calvin-Benson-Bassham cycle in Esherichia coli using hydrogen as an energy source.

Carbon fixation is the main route of inorganic carbon in the form of CO2 into the biosphere. In nature, RuBisCO is the most abundant protein that photosynthetic organisms use to fix CO2 from the atmosphere through the Calvin-Benson-Bassham (CBB) cycle. However, the CBB cycle is limited by its low catalytic rate and low energy efficiency. In this work, we attempt to integrate the reductive tricarboxylic acid and CBB cycles in silico to further improve carbon fixation capacity. Key heterologous enzymes, mostly carboxylating enzymes, are inserted into the Esherichia coli core metabolic network to assimilate CO2 into biomass using hydrogen as energy source. Overall, such a strain shows enhanced growth yield with simultaneous running of dual carbon fixation cycles. Our key results include the following. (i) We identified two main growth states: carbon-limited and hydrogen-limited; (ii) we identified a hierarchy of carbon fixation usage when hydrogen supply is limited; and (iii) we identified the alternative sub-optimal growth mode while performing genetic perturbation. The results and modeling approach can guide bioengineering projects toward optimal production using such a strain as a microbial cell factory.

H2 Reduction Annealing Induced Phase Transition and Improvements on Redox Durability of Pt Cluster-Decorated Cu@Pd Electrocatalysts in Oxygen Reduction Reaction.

Hierarchical structures in shell with transition metal underneath is a promising design for high-performance and low-cost heterogeneous nanocatalysts (NCs). Such a design enables the optimum extent of synergetic effects in NC surface. It facilitates intermediate reaction steps and, therefore, boosts activity of NC in oxygen reduction reaction (ORR). In this study, carbon nanotube (CNT)-supported ternary metallic NC comprising Cucluster-in-Pdcluster nanocrystal and surface decoration of atomic Pt clusters (14 wt %) is synthesized by using the wet chemical reduction method with sequence and reaction time controls. By annealing in H2 environment (H2/N2 = 9:1, 10 sccm) at 600 K for 2 h, specific activity of Cu@Pd/Pt is substantially improved by ∼2.0-fold as compared to that of the pristine sample and commercial Pt catalysts. By cross-referencing results of electron microscopic, X-ray spectroscopic, and electrochemical analyses, we demonstrated that reduction annealing turns ternary NC into complex of Cu3Pt alloy and Cu x Pd1-x alloy. Such a transition preserves Pt and Pd in metallic phases, therefore improving the activity by ∼29% and the stability of NC in an accelerated degradation test (ADT) as compared to those of pristine Cu@Pd/Pt in 36 000 cycles at 0.85 V (vs RHE). This study presents robust H2 annealing for structure stabilization of NC and systematic characterizations for rationalization of the corresponding mechanisms. These results provide promising scenarios for facilitation of heterogeneous NC in ORR applications.

Conformational Effects of Pt-Shells on Nanostructures and Corresponding Oxygen Reduction Reaction Activity of Au-Cluster-Decorated NiOx@Pt Nanocatalysts.

Herein, ternary metallic nanocatalysts (NCs) consisting of Au clusters decorated with a Pt shell and a Ni oxide core underneath (called NPA) on carbon nanotube (CNT) support were synthesized by combining adsorption, precipitation, and chemical reduction methods. By a retrospective investigation of the physical structure and electrochemical results, we elucidated the effects of Pt/Ni ratios (0.4 and 1.0) and Au contents (2 and 9 wt.%) on the nanostructure and corresponding oxygen reduction reaction (ORR) activity of the NPA NCs. We found that the ORR activity of NPA NCs was mainly dominated by the Pt-shell thickness which regulated the depth and size of the surface decorated with Au clusters. In the optimal case, NPA-1004006 (with a Pt/Ni of 0.4 and Au of ~2 wt.%) showed a kinetic current (JK) of 75.02 mA cm-2 which was nearly 17-times better than that (4.37 mA cm-2) of the commercial Johnson Matthey-Pt/C (20 wt.% Pt) catalyst at 0.85 V vs. the reference hydrogen electrode. Such a high JK value resulted in substantial improvements in both the specific activity (by ~53-fold) and mass activity (by nearly 10-fold) in the same benchmark target. Those scenarios rationalize that ORR activity can be substantially improved by a syngeneic effect at heterogeneous interfaces among nanometer-sized NiOx, Pt, and Au clusters on the NC surface.

"Do It Yourself" Microbial Cultivation Techniques for Synthetic and Systems Biology: Cheap, Fun, and Flexible.

With the emergence of inexpensive 3D printing technology, open-source platforms for electronic prototyping and single-board computers, "Do it Yourself" (DIY) approaches to the cultivation of microbial cultures are becoming more feasible, user-friendly, and thus wider spread. In this perspective, we survey some of these approaches, as well as add-on solutions to commercial instruments for synthetic and system biology applications. We discuss different cultivation designs, including capabilities and limitations. Our intention is to encourage the reader to consider the DIY solutions. Overall, custom cultivation devices offer controlled growth environments with in-line monitoring of, for example, optical density, fluorescence, pH, and dissolved oxygen, all at affordable prices. Moreover, they offer a great degree of flexibility for different applications and requirements and are fun to design and construct. We include several illustrative examples, such as gaining optogenetic control and adaptive laboratory evolution experiments.

Antipsychotic drugs and risk of newly diagnosed tuberculosis in schizophrenia.

AIM: Patients with schizophrenia have a higher incidence of tuberculosis than do people in the general population. Information is limited regarding the association between antipsychotic agents and the risk of tuberculosis in patients with schizophrenia. This exploratory study assessed the risk of tuberculosis among patients with schizophrenia on antipsychotic therapy. METHODS: Among a nationwide schizophrenia cohort derived from the National Health Insurance Research Database in Taiwan (n = 32 399), we identified 284 patients who had developed newly diagnosed tuberculosis after their first psychiatric admission. Ten or fewer matched controls were selected randomly from the cohort for each patient based on risk-set sampling. We categorized exposure to antipsychotic medications by type and defined daily dose. Using multivariate methods, we explored individual antipsychotic agents for the risk of tuberculosis and employed a propensity-scoring method in sensitivity analyses to validate any associations. RESULTS: Among the antipsychotic agents studied and after adjustment for covariates, current use of clozapine was the only antipsychotic agent associated with a 63% increased risk of tuberculosis (adjusted risk ratio = 1.63, P = 0.014). In addition, the association did not show a clear dose-dependent relationship. Clozapine combined with other antipsychotic agents showed a potential synergistic risk for tuberculosis (adjusted risk ratio = 2.30, P = 0.044). CONCLUSION: This exploratory study suggests the potential risk of clozapine on the risk of tuberculosis, especially for those on clozapine in combination with other antipsychotics. Future studies are needed to verify the association.