Discovery of a structural class of antibiotics with explainable deep learning.

The discovery of novel structural classes of antibiotics is urgently needed to address the ongoing antibiotic resistance crisis1-9. Deep learning approaches have aided in exploring chemical spaces1,10-15; these typically use black box models and do not provide chemical insights. Here we reasoned that the chemical substructures associated with antibiotic activity learned by neural network models can be identified and used to predict structural classes of antibiotics. We tested this hypothesis by developing an explainable, substructure-based approach for the efficient, deep learning-guided exploration of chemical spaces. We determined the antibiotic activities and human cell cytotoxicity profiles of 39,312 compounds and applied ensembles of graph neural networks to predict antibiotic activity and cytotoxicity for 12,076,365 compounds. Using explainable graph algorithms, we identified substructure-based rationales for compounds with high predicted antibiotic activity and low predicted cytotoxicity. We empirically tested 283 compounds and found that compounds exhibiting antibiotic activity against Staphylococcus aureus were enriched in putative structural classes arising from rationales. Of these structural classes of compounds, one is selective against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci, evades substantial resistance, and reduces bacterial titres in mouse models of MRSA skin and systemic thigh infection. Our approach enables the deep learning-guided discovery of structural classes of antibiotics and demonstrates that machine learning models in drug discovery can be explainable, providing insights into the chemical substructures that underlie selective antibiotic activity.

Entropic repulsion of cholesterol-containing layers counteracts bioadhesion.

Control of adhesion is a striking feature of living matter that is of particular interest regarding technological translation1-3. We discovered that entropic repulsion caused by interfacial orientational fluctuations of cholesterol layers restricts protein adsorption and bacterial adhesion. Moreover, we found that intrinsically adhesive wax ester layers become similarly antibioadhesive when containing small quantities (under 10 wt%) of cholesterol. Wetting, adsorption and adhesion experiments, as well as atomistic simulations, showed that repulsive characteristics depend on the specific molecular structure of cholesterol that encodes a finely balanced fluctuating reorientation at the interface of unconstrained supramolecular assemblies: layers of cholesterol analogues differing only in minute molecular variations showed markedly different interfacial mobility and no antiadhesive effects. Also, orientationally fixed cholesterol layers did not resist bioadhesion. Our insights provide a conceptually new physicochemical perspective on biointerfaces and may guide future material design in regulation of adhesion.

Multi-mode grounding and monophasic passive discharge stimulation avoid aberrant facial nerve stimulation following cochlear implantation.

We report on a case with severe facial nerve stimulation via a cochlea-facial nerve dehiscence that was most likely the result of prolonged occlusive hydrocephalus. The successful treatment of this adverse effect demonstrates for the first time its complete resolution using a multi-mode grounding and monophasic passive discharge stimulation.

Bioadhesion on Textured Interfaces in the Human Oral Cavity-An In Situ Study.

Extensive biofilm formation on materials used in restorative dentistry is a common reason for their failure and the development of oral diseases like peri-implantitis or secondary caries. Therefore, novel materials and strategies that result in reduced biofouling capacities are urgently sought. Previous research suggests that surface structures in the range of bacterial cell sizes seem to be a promising approach to modulate bacterial adhesion and biofilm formation. Here we investigated bioadhesion within the oral cavity on a low surface energy material (perfluorpolyether) with different texture types (line-, hole-, pillar-like), feature sizes in a range from 0.7-4.5 µm and graded distances (0.7-130.5 µm). As a model system, the materials were fixed on splints and exposed to the oral cavity. We analyzed the enzymatic activity of amylase and lysozyme, pellicle formation, and bacterial colonization after 8 h intraoral exposure. In opposite to in vitro experiments, these in situ experiments revealed no clear signs of altered bacterial surface colonization regarding structure dimensions and texture types compared to unstructured substrates or natural enamel. In part, there seemed to be a decreasing trend of adherent cells with increasing periodicities and structure sizes, but this pattern was weak and irregular. Pellicle formation took place on all substrates in an unaltered manner. However, pellicle formation was most pronounced within recessed areas thereby partially masking the three-dimensional character of the surfaces. As the natural pellicle layer is obviously the most dominant prerequisite for bacterial adhesion, colonization in the oral environment cannot be easily controlled by structural means.

Multicolor Patterning of 2D Semiconductor Nanoplatelets.

Nanocrystal micro/nanoarrays with multiplexed functionalities are of broad interest in the field of nanophotonics, cellular dynamics, and biosensing due to their tunable electrical and optical properties. This work focuses on the multicolor patterning of two-dimensional nanoplatelets (NPLs) via two sequential self-assembly and direct electron-beam lithography steps. By using scanning electron microscopy, atomic force microscopy, and fluorescence microscopy, we demonstrate the successful fabrication of fluorescent nanoarrays with a thickness of only two or three monolayers (7-11 nm) and a feature line width of ∼40 nm, which is three to four NPLs wide. To this end, first, large-area thin films of red-emitting CdSe/ZnyCd1-yS and green-emitting CdSe1-xSx/ZnyCd1-yS core/shell NPLs are fabricated based on Langmuir-type self-assembly at the liquid/air interface. By varying the concentration of ligands in the subphase, we investigate the effect of interaction potential on the film's final characteristics to prepare thin superlattices suitable for the patterning step. Equipped with the ability to fabricate a uniform superlattice with a controlled thickness, we next perform nanopatterning on a thin film of NPLs utilizing a direct electron-beam lithography (EBL) technique. The effect of acceleration voltage, aperture size, and e-beam dosage on the nanopattern's resolution and fidelity is investigated for both of the presented NPLs. After successfully optimizing EBL parameters to fabricate single-color nanopatterns, we finally focus on fabricating multicolor patterns. The obtained micro/nanoarrays provide us with an innovative experimental platform to investigate biological interactions as well as Förster resonance energy transfer.

Cochlear reimplantation from mid-scala to lateral wall electrode array: Surgical and hearing outcome.

A mid-scala cochlear implant electrode array, which was inserted with an atraumatic round window approach, could be replaced with longer lateral wall electrode array. Deeper electrode insertion seems to have beneficial influence on the hearing quality.

Understanding Beta-Lactam-Induced Lysis at the Single-Cell Level.

Mechanical rupture, or lysis, of the cytoplasmic membrane is a common cell death pathway in bacteria occurring in response to ß-lactam antibiotics. A better understanding of the cellular design principles governing the susceptibility and response of individual cells to lysis could indicate methods of potentiating ß-lactam antibiotics and clarify relevant aspects of cellular physiology. Here, we take a single-cell approach to bacterial cell lysis to examine three cellular features-turgor pressure, mechanosensitive channels, and cell shape changes-that are expected to modulate lysis. We develop a mechanical model of bacterial cell lysis and experimentally analyze the dynamics of lysis in hundreds of single Escherichia coli cells. We find that turgor pressure is the only factor, of these three cellular features, which robustly modulates lysis. We show that mechanosensitive channels do not modulate lysis due to insufficiently fast solute outflow, and that cell shape changes result in more severe cellular lesions but do not influence the dynamics of lysis. These results inform a single-cell view of bacterial cell lysis and underscore approaches of combatting antibiotic tolerance to ß-lactams aimed at targeting cellular turgor.

Controlling Surface Wettability for Automated In Situ Array Synthesis and Direct Bioscreening.

The in situ synthesis of biomolecules on glass surfaces for direct bioscreening can be a powerful tool in the fields of pharmaceutical sciences, biomaterials, and chemical biology. However, it is still challenging to 1) achieve this conventional multistep combinatorial synthesis on glass surfaces with small feature sizes and high yields and 2) develop a surface which is compatible with solid-phase syntheses, as well as the subsequent bioscreening. This work reports an amphiphilic coating of a glass surface on which small droplets of polar aprotic organic solvents can be deposited with an enhanced contact angle and inhibited motion to permit fully automated multiple rounds of the combinatorial synthesis of small-molecule compounds and peptides. This amphiphilic coating can be switched into a hydrophilic network for protein- and cell-based screening. Employing this in situ synthesis method, chemical space can be probed via array technology with unprecedented speed for various applications, such as lead discovery/optimization in medicinal chemistry and biomaterial development.

Bioadhesion in the oral cavity and approaches for biofilm management by surface modifications.

BACKGROUND: All soft and solid surface structures in the oral cavity are covered by the acquired pellicle followed by bacterial colonization. This applies for natural structures as well as for restorative or prosthetic materials; the adherent bacterial biofilm is associated among others with the development of caries, periodontal diseases, peri-implantitis, or denture-associated stomatitis. Accordingly, there is a considerable demand for novel materials and coatings that limit and modulate bacterial attachment and/or propagation of microorganisms. OBJECTIVES AND FINDINGS: The present paper depicts the current knowledge on the impact of different physicochemical surface characteristics on bioadsorption in the oral cavity. Furthermore, it was carved out which strategies were developed in dental research and general surface science to inhibit bacterial colonization and to delay biofilm formation by low-fouling or "easy-to-clean" surfaces. These include the modulation of physicochemical properties such as periodic topographies, roughness, surface free energy, or hardness. In recent years, a large emphasis was laid on micro- and nanostructured surfaces and on liquid repellent superhydrophic as well as superhydrophilic interfaces. Materials incorporating mobile or bound nanoparticles promoting bacteriostatic or bacteriotoxic properties were also used. Recently, chemically textured interfaces gained increasing interest and could represent promising solutions for innovative antibioadhesion interfaces. Due to the unique conditions in the oral cavity, mainly in vivo or in situ studies were considered in the review. CONCLUSION: Despite many promising approaches for modulation of biofilm formation in the oral cavity, the ubiquitous phenomenon of bioadsorption and adhesion pellicle formation in the challenging oral milieu masks surface properties and therewith hampers low-fouling strategies. CLINICAL RELEVANCE: Improved dental materials and surface coatings with easy-to-clean properties have the potential to improve oral health, but extensive and systematic research is required in this field to develop biocompatible and effective substances.

Fabrication of multifunctional titanium surfaces by producing hierarchical surface patterns using laser based ablation methods.

Textured implant surfaces with micrometer and sub-micrometer features can improve contact properties like cell adhesion and bacteria repellency. A critical point of these surfaces is their mechanical stability during implantation. Therefore, strategies capable to provide both biocompatibility for an improved implant healing and resistance to wear for protecting the functional surface are required. In this work, laser-based fabrication methods have been used to produce hierarchical patterns on titanium surfaces. Using Direct Laser Writing with a nanosecond pulsed laser, crater-like structures with a separation distance of 50 µm are produced on unpolished titanium surfaces. Directly on this texture, a hole-like pattern with 5 µm spatial period is generated using Direct Laser Interference Patterning with picosecond pulses. While the smaller features should reduce the bacterial adhesion, the larger geometry was designed to protect the smaller features from wear. On the multifunctional surface, the adherence of E. Coli bacteria is reduced by 30% compared to the untreated reference. In addition, wear test performed on the multiple-scale patterns demonstrated the possibility to protect the smaller features by the larger craters. Also, the influence of the laser treatment on the growth of a titanium oxide layer was evaluated using Energy Dispersive X-Ray Spectroscopy analysis.

Impact of the springtail's cuticle nanotopography on bioadhesion and biofilm formation in vitro and in the oral cavity.

Springtails (Collembola) have a nanostructured cuticle. To evaluate and to understand anti-biofouling properties of springtail cuticles' morphology under different conditions, springtails, shed cuticles and cuticle replicates were studied after incubation with protein solutions and bacterial cultures using common in vitro models. In a second step, they were exposed to human oral environment in situ in order to explore potential application in dentistry. In vitro, the cuticular structures were found to resist wetting by albumin solutions for up to 3 h and colonization by Staphylococcus epidermidis was inhibited. When exposed in the oral cavity, initial pellicle formation was of high heterogeneity: parts of the surface were coated by adsorbed proteins, others remained uncoated but exhibited locally attached, 'bridging', proteinaceous membranes spanning across cavities of the cuticle surface; this unique phenomenon was observed for the first time. Also the degree of bacterial colonization varied considerably. In conclusion, the springtail cuticle partially modulates bioadhesion in the oral cavity in a unique and specific manner, but it has no universal effect. Especially after longer exposure, the nanotextured surface of springtails is masked by the pellicle, resulting in subsequent bacterial colonization, and, thus, cannot effectively avoid bioadhesion in the oral cavity comprehensively. Nevertheless, the observed phenomena offer valuable information and new perspectives for the development of antifouling surfaces applicable in the oral cavity.

Influence of Floating-Mass Transducer Coupling Efficiency for Active Middle-Ear Implants on Speech Recognition.

OBJECTIVE: The efficiency of vibroplasty (coupler-floating mass transducer [FMT] assembly) can be monitored by direct stimulation of the inner ear through the active middle-ear implant system and comparison of the vibroplasty in vivo threshold and the postoperative bone-conduction pure-tone threshold. The aim of this study was to compare the vibroplasty in vivo threshold with the postoperative speech recognition in patients with a high preoperative maximum word recognition score. STUDY DESIGN: Retrospective cohort study of German-speaking patients implanted with a vibrating ossicular prosthesis (VORP) 502 or VORP 503 and high preoperative maximum word recognition score between the years of 2011 and 2015. SETTING: Multicenter study of four German centers. PATIENTS: Twenty-three active middle-ear implant users. INTERVENTION: Rehabilitative. MAIN OUTCOME MEASURES: Bone-conduction pure-tone and vibroplasty thresholds, postoperative aided word recognition score (WRS) at 65 dB SPL (sound pressure level) and preoperative maximum WRS with Freiburg monosyllabic words. RESULTS: The mean postoperative aided WRS at 65 dB SPL was 82%. An increasing difference between vibroplasty thresholds and bone-conduction thresholds was associated with a higher discrepancy between the unaided maximum WRS and the postoperative aided WRS. Only if this difference was less than 20 dB, an articulation index of 0.5 (WRS = 75%) or more was achieved. CONCLUSIONS: Audiological outcome after vibroplasty depends on the coupling efficiency reflected by the vibroplasty threshold.

The impact of structure dimensions on initial bacterial adhesion.

Substrate topography can have profound effects on initial bacterial adhesion during biofilm formation. We applied Staphylococcus epidermidis and Escherichia coli cells onto periodically structured substrates with different structure dimensions, structure types and wetting properties. We found a strong dependence of cell retention on the structure dimensions of the applied substrates. Periodicities in the range of the cell size increased, whereas smaller periodicities decreased cell retention, independent of contact time (minutes to hours) and hydrophobicity. These novel insights on the role of surface topography on bacterial retention might facilitate the development of non-fouling surfaces in the future.

Evaluation of Surface Microtopography Engineered by Direct Laser Interference for Bacterial Anti-Biofouling.

Modification of the biomaterial surface topography is a promising strategy to prevent bacterial adhesion and biofilm formation. In this study, we use direct laser interference patterning (DLIP) to modify polystyrene surface topography at sub-micrometer scale. The results revealed that three-dimensional micrometer structures have a profound impact on bacterial adhesion. Thus, line- and pillar-like patterns enhanced S. aureus adhesion, whereas complex lamella microtopography reduced S. aureus adhesion in static and continuous flow culture conditions. Interestingly, lamella-like textured surfaces retained the capacity to inhibit S. aureus adhesion both when the surface is coated with human serum proteins and when the material is implanted subcutaneously in a foreign-body associated infection model.

Horizontal VOR function shows frequency dynamics in vestibular schwannoma.

The objective of this retrospective study was to investigate the horizontal vestibulo-ocular reflex (hVOR) pathway with caloric test (low-frequency hVOR) and video head impulse test (vHIT) (high-frequency hVOR) in patients with sporadic vestibular schwannoma (69 patients, 27-86 years, mean age 58.1 years) and to compare both test methods in terms of their sensitivity and specificity to detect a retrocochlear lesion. Test results with a unilateral weakness (UWCaloric) >25 % (caloric test) or a Mean-GainvHIT <0.79/asymmetry ratio of Gain (AR-GainvHIT) >8.5 % and accompanied refixation saccades (vHIT) were considered abnormal. The overall sensitivity of the caloric test was 72 %. The evaluation of AR-GainvHIT detected more abnormal cases than did Mean-GainvHIT (44 vs. 36 %). In up to 4 %, a normal caloric test result was related to an abnormal vHIT. There was only a moderate correlation of UWCaloric and AR-GainvHIT (r = 0.54, p < 0.05) with a linear regression line intercept/slope of 32.2/0.9 (p < 0.05). Receiver operating characteristics curve analysis exhibited at a UWCaloric of 50 % a vHIT sensitivity/specificity/positive predictive value/negative predictive value of 0.45/0.9/0.94/0.42. Vestibular testing at varying frequencies provides deeper insights into hVOR function and is helpful in detecting a cerebello-pontine lesion. Whereas caloric test yields a high sensitivity for nerve dysfunction, vHIT test reveals a remaining function of hVOR in the high-frequency range.

In situ experiments to reveal the role of surface feature sidewalls in the Cassie-Wenzel transition.

Waterproof and self-cleaning surfaces continue to attract much attention as they can be instrumental in various different technologies. Such surfaces are typically rough, allowing liquids to contact only the outermost tops of their asperities, with air being entrapped underneath. The formed solid-liquid-air interface is metastable and, hence, can be forced into a completely wetted solid surface. A detailed understanding of the wetting barrier and the dynamics of this transition is critically important for the practical use of the related surfaces. Toward this aim, wetting transitions were studied in situ at a set of patterned perfluoropolyether dimethacrylate (PFPEdma) polymer surfaces exhibiting surface features with different types of sidewall profiles. PFPEdma is intrinsically hydrophobic and exhibits a refractive index very similar to water. Upon immersion of the patterned surfaces into water, incident light was differently scattered at the solid-liquid-air and solid-liquid interface, which allows for distinguishing between both wetting states by dark-field microscopy. The wetting transition observed with this methodology was found to be determined by the sidewall profiles of the patterned structures. Partial recovery of the wetting was demonstrated to be induced by abrupt and continuous pressure reductions. A theoretical model based on Laplace's law was developed and applied, allowing for the analytical calculation of the transition barrier and the potential to revert the wetting upon pressure reduction.

Biologically inspired omniphobic surfaces by reverse imprint lithography.

Springtail skin morphology is translated into robust omniphobic polymer membranes by reverse imprint lithography. The combination of overhanging cross-sections and their arrangement in a self-supporting comblike pattern are crucial for mechanically stable coatings that can be even applied to curved surfaces.

Wetting resistance at its topographical limit: the benefit of mushroom and serif T structures.

Springtails (Collembola) are wingless arthropods adapted to cutaneous respiration in temporarily rain-flooded habitats. They immediately form a plastron, protecting them against suffocation upon immersion into water and even low-surface-tension liquids such as alkanes. Recent experimental studies revealed a high-pressure resistance of such plastrons against collapse. In this work, skin sections of Orthonychiurus stachianus are studied by transmission electron microscopy. The micrographs reveal cavity side-wall profiles with characteristic overhangs. These were fitted by polynomials to allow access for analytical and numerical calculations of the breakthrough pressure, that is, the barrier against plastron collapse. Furthermore, model profiles with well-defined geometries were used to set the obtained results into context and to develop a general design principle for the most robust surface structures. Our results indicate the decisive role of the sectional profile of overhanging structures to form a robust heterogeneous wetting state for low-surface-tension liquids that enables the omniphobicity. Furthermore, the design principles of mushroom and serif T structures pave the way for omniphobic surfaces with a high-pressure resistance irrespective of solid surface chemistry.

Smart skin patterns protect springtails.

Springtails, arthropods who live in soil, in decaying material, and on plants, have adapted to demanding conditions by evolving extremely effective and robust anti-adhesive skin patterns. However, details of these unique properties and their structural basis are still unknown. Here we demonstrate that collembolan skin can resist wetting by many organic liquids and at elevated pressures. We show that the combination of bristles and a comb-like hexagonal or rhombic mesh of interconnected nanoscopic granules distinguish the skin of springtails from anti-adhesive plant surfaces. Furthermore, the negative overhang in the profile of the ridges and granules were revealed to be a highly effective, but as yet neglected, design principle of collembolan skin. We suggest an explanation for the non-wetting characteristics of surfaces consisting of such profiles irrespective of the chemical composition. Many valuable opportunities arise from the translation of the described comb-like patterns and overhanging profiles of collembolan skin into man-made surfaces that combine stability against wear and friction with superior non-wetting and anti-adhesive characteristics.