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Glucocorticoids are a major class of therapeutic anti-inflammatory and immunosuppressive drugs prescribed to patients with inflammatory diseases, to avoid transplant rejection, and as part of cancer chemotherapy. However, exposure to these drugs increases the risk of opportunistic infections such as with the fungus Aspergillus fumigatus, which causes mortality in >50% of infected patients. The mechanisms by which glucocorticoids increase susceptibility to A. fumigatus are poorly understood. In this article, we used a zebrafish larva Aspergillus infection model to identify innate immune mechanisms altered by glucocorticoid treatment. Infected larvae exposed to dexamethasone succumb to infection at a significantly higher rate than control larvae. However, both macrophages and neutrophils are still recruited to the site of infection, and dexamethasone treatment does not significantly affect fungal spore killing. Instead, the primary effect of dexamethasone manifests later in infection with treated larvae exhibiting increased invasive hyphal growth. In line with this, dexamethasone predominantly inhibits neutrophil function rather than macrophage function. Dexamethasone-induced mortality also depends on the glucocorticoid receptor. Dexamethasone partially suppresses NF-κB activation at the infection site by inducing the transcription of IκB via the glucocorticoid receptor. Independent CRISPR/Cas9 targeting of IKKγ to prevent NF-κB activation also increases invasive A. fumigatus growth and larval mortality. However, dexamethasone treatment of IKKγ crispant larvae further increases invasive hyphal growth and host mortality, suggesting that dexamethasone may suppress other pathways in addition to NF-κB to promote host susceptibility. Collectively, we find that dexamethasone acts through the glucocorticoid receptor to suppress NF-κB-mediated neutrophil control of A. fumigatus hyphae in zebrafish larvae., (Copyright © 2024 by The American Association of Immunologists, Inc.)

The availability of thin-film lithium niobate on insulator (LNOI) and advances in processing have led to the emergence of fully integrated LiNbO 3 electro-optic devices. Yet to date, LiNbO 3 photonic integrated circuits have mostly been fabricated using non-standard etching techniques and partially etched waveguides, that lack the reproducibility achieved in silicon photonics. Widespread application of thin-film LiNbO 3 requires a reliable solution with precise lithographic control. Here we demonstrate a heterogeneously integrated LiNbO 3 photonic platform employing wafer-scale bonding of thin-film LiNbO 3 to silicon nitride (Si 3 N 4 ) photonic integrated circuits. The platform maintains the low propagation loss (<0.1 dB/cm) and efficient fiber-to-chip coupling (<2.5 dB per facet) of the Si 3 N 4 waveguides and provides a link between passive Si 3 N 4 circuits and electro-optic components with adiabatic mode converters experiencing insertion losses below 0.1 dB. Using this approach we demonstrate several key applications, thus providing a scalable, foundry-ready solution to complex LiNbO 3 integrated photonic circuits., (© 2023. The Author(s).)

The Oak Ridge National Laboratory is planning to build the Second Target Station (STS) at the Spallation Neutron Source (SNS). STS will host a suite of novel instruments that complement the First Target Station's beamline capabilities by offering an increased flux for cold neutrons and a broader wavelength bandwidth. A novel neutron imaging beamline, named the Complex, Unique, and Powerful Imaging Instrument for Dynamics (CUPI2D), is among the first eight instruments that will be commissioned at STS as part of the construction project. CUPI2D is designed for a broad range of neutron imaging scientific applications, such as energy storage and conversion (batteries and fuel cells), materials science and engineering (additive manufacturing, superalloys, and archaeometry), nuclear materials (novel cladding materials, nuclear fuel, and moderators), cementitious materials, biology/medical/dental applications (regenerative medicine and cancer), and life sciences (plant-soil interactions and nutrient dynamics). The innovation of this instrument lies in the utilization of a high flux of wavelength-separated cold neutrons to perform real time in situ neutron grating interferometry and Bragg edge imaging-with a wavelength resolution of δλ/λ ≈ 0.3%-simultaneously when required, across a broad range of length and time scales. This manuscript briefly describes the science enabled at CUPI2D based on its unique capabilities. The preliminary beamline performance, a design concept, and future development requirements are also presented., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Affect is involved in many psychological phenomena, but a descriptive structure, long sought, has been elusive. Valence and arousal are fundamental, and a key question-the focus of the present study-is the relationship between them. Valence is sometimes thought to be independent of arousal, but, in some studies (representing too few societies in the world) arousal was found to vary with valence. One common finding is that arousal is lowest at neutral valence and increases with both positive and negative valence: a symmetric V-shaped relationship. In the study reported here of self-reported affect during a remembered moment ( N = 8,590), we tested the valence-arousal relationship in 33 societies with 25 different languages. The two most common hypotheses in the literature-independence and a symmetric V-shaped relationship-were not supported. With data of all samples pooled, arousal increased with positive but not negative valence. Valence accounted for between 5% (Finland) and 43% (China Beijing) of the variance in arousal. Although there is evidence for a structural relationship between the two, there is also a large amount of variability in this relation. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

We found that temperature-dependent infrared spectroscopy measurements (i.e., reflectance or transmittance) using a Fourier-transform spectrometer can have substantial errors, especially for elevated sample temperatures and collection using an objective lens. These errors can arise as a result of partial detector saturation due to thermal emission from the measured sample reaching the detector, resulting in nonphysical apparent reduction of reflectance or transmittance with increasing sample temperature. Here, we demonstrate that these temperature-dependent errors can be corrected by implementing several levels of optical attenuation that enable convergence testing of the measured reflectance or transmittance as the thermal-emission signal is reduced, or by applying correction factors that can be inferred by looking at the spectral regions where the sample is not expected to have a substantial temperature dependence.

Solitons are shape preserving waveforms that are ubiquitous across nonlinear dynamical systems from BEC to hydrodynamics, and fall into two separate classes: bright solitons existing in anomalous group velocity dispersion, and switching waves forming 'dark solitons' in normal dispersion. Bright solitons in particular have been relevant to chip-scale microresonator frequency combs, used in applications across communications, metrology, and spectroscopy. Both have been studied, yet the existence of a structure between this dichotomy has only been theoretically predicted. We report the observation of dissipative structures embodying a hybrid between switching waves and dissipative solitons, existing in the regime of vanishing group velocity dispersion where third-order dispersion is dominant, hence termed as 'zero-dispersion solitons'. They are observed to arise from the interlocking of two modulated switching waves, forming a stable solitary structure consisting of a quantized number of peaks. The switching waves form directly via synchronous pulse-driving of a Si 3 N 4 microresonator. The resulting comb spectrum spans 136 THz or 97% of an octave, further enhanced by higher-order dispersive wave formation. This dissipative structure expands the domain of Kerr cavity physics to the regime near to zero-dispersion and could present a superior alternative to conventional solitons for broadband comb generation., (© 2022. The Author(s).)

The past decade has witnessed major advances in the development and system-level applications of photonic integrated microcombs, that are coherent, broadband optical frequency combs with repetition rates in the millimeter-wave to terahertz domain. Most of these advances are based on harnessing of dissipative Kerr solitons (DKS) in microresonators with anomalous group velocity dispersion (GVD). However, microcombs can also be generated with normal GVD using localized structures that are referred to as dark pulses, switching waves or platicons. Compared with DKS microcombs that require specific designs and fabrication techniques for dispersion engineering, platicon microcombs can be readily built using CMOS-compatible platforms such as thin-film (i.e., thickness below 300 nm) silicon nitride with normal GVD. Here, we use laser self-injection locking to demonstrate a fully integrated platicon microcomb operating at a microwave K-band repetition rate. A distributed feedback (DFB) laser edge-coupled to a Si 3 N 4 chip is self-injection-locked to a high-Q ( > 10 7 ) microresonator with high confinement waveguides, and directly excites platicons without sophisticated active control. We demonstrate multi-platicon states and switching, perform optical feedback phase study and characterize the phase noise of the K-band platicon repetition rate and the pump laser. Laser self-injection-locked platicons could facilitate the wide adoption of microcombs as a building block in photonic integrated circuits via commercial foundry service., (© 2022. The Author(s).)

This study reports on state-level data in Rhode Island on employment and non-work activities of adults with intellectual and developmental disabilities receiving services between 2011 and 2017. The goal was to examine the complex patterns of change over time in individual-level employment outcomes and the potential short-term impacts of a consent decree entered into by the state of Rhode Island to address integrated employment outcomes. Findings suggest that policy initiatives such as the consent decree can lead to reductions in reliance on facility-based work, but also highlight the importance of planning for the transition to competitive, integrated employment and not simply a shift toward non-work activities. Further, the data support the notion that the best predictor of integrated employment over time is previous experiences in integrated employment (not facility-based or other work or non-work activities), suggesting the role of ongoing supported employment and transition services that create and support the maintenance of integrated employment., (©AAIDD.)

High-speed actuation of laser frequency 1 is critical in applications using lasers and frequency combs 2,3 , and is a prerequisite for phase locking, frequency stabilization and stability transfer among optical carriers. For example, high-bandwidth feedback control of frequency combs is used in optical-frequency synthesis 4 , frequency division 5 and optical clocks 6 . Soliton microcombs 7,8 have emerged as chip-scale frequency comb sources, and have been used in system-level demonstrations 9,10 . Yet integrated microcombs using thermal heaters have limited actuation bandwidths 11,12 of up to 10 kilohertz. Consequently, megahertz-bandwidth actuation and locking of microcombs have only been achieved with off-chip bulk component modulators. Here we demonstrate high-speed soliton microcomb actuation using integrated piezoelectric components 13 . By monolithically integrating AlN actuators 14 on ultralow-loss Si 3 N 4 photonic circuits 15 , we demonstrate voltage-controlled soliton initiation, tuning and stabilization with megahertz bandwidth. The AlN actuators use 300 nanowatts of power and feature bidirectional tuning, high linearity and low hysteresis. They exhibit a flat actuation response up to 1 megahertz-substantially exceeding bulk piezo tuning bandwidth-that is extendable to higher frequencies by overcoming coupling to acoustic contour modes of the chip. Via synchronous tuning of the laser and the microresonator, we exploit this ability to frequency-shift the optical comb spectrum (that is, to change the comb's carrier-envelope offset frequency) and make excursions beyond the soliton existence range. This enables a massively parallel frequency-modulated engine 16,17 for lidar (light detection and ranging), with increased frequency excursion, lower power and elimination of channel distortions resulting from the soliton Raman self-frequency shift. Moreover, by modulating at a rate matching the frequency of high-overtone bulk acoustic resonances 18 , resonant build-up of bulk acoustic energy allows a 14-fold reduction of the required driving voltage, making it compatible with CMOS (complementary metal-oxide-semiconductor) electronics. Our approach endows soliton microcombs with integrated, ultralow-power and fast actuation, expanding the repertoire of technological applications of microcombs.

The purpose of this study was to examine self-determination outcome data in the year following a one-year cluster randomized controlled trial (C-RCT) comparing the impacts of a Self-Determined Learning Model of Instruction (SDLMI) only condition to a SDLMI + Whose Future Is It? (SDLMI + WF) condition. Using multilevel B-spline model analysis with Bayesian estimation, we examined ongoing patterns of growth after the trial ended and all students were exposed to SDLMI + WF. The findings suggest that the inclusion of an additional year of outcome data provided additional insight into the impact of more intensive intervention conditions over time. Specifically, after the initial year of implementation, the SDLMI + WF condition predicted greater annual gains than the SDLMI only condition, unlike findings in the first year which reflected the opposite pattern. This evidence suggests a nonlinear growth pattern over multiple years of intervention with more intensive interventions. Implications for future research and practice are discussed.

The ability to drive is a highly valued freedom in the developed world. Sudden incapacitation while driving can result in injury or death for the driver and passengers or bystanders. Cardiovascular conditions are a primary cause for sudden incapacitation and regulations have long existed to restrict driving for patients with cardiac conditions at high risk of sudden incapacitation. Significant variation occurs between these rules in different countries and legislatures. Quantification of the potential risk of harm associated with various categories of drivers has attempted to make these regulations more objective. The assumptions on which these calculations are based are now old and less likely to reflect the reality of modern driving. Ultimately, a more individual assessment of risk with a combined assessment of the medical condition and the patient's driving behaviour may be appropriate. The development of driverless technologies may also have an impact on decision making in this field., Competing Interests: Disclosure: The authors have no conflicts of interest to declare.

The efficiency of generating electricity from heat using concentrated solar power plants (which use mirrors or lenses to concentrate sunlight in order to drive heat engines, usually involving turbines) may be appreciably increased by operating with higher turbine inlet temperatures, but this would require improved heat exchanger materials. By operating turbines with inlet temperatures above 1,023 kelvin using closed-cycle high-pressure supercritical carbon dioxide (sCO 2 ) recompression cycles, instead of using conventional (such as subcritical steam Rankine) cycles with inlet temperatures below 823 kelvin 1-3 , the relative heat-to-electricity conversion efficiency may be increased by more than 20 per cent. The resulting reduction in the cost of dispatchable electricity from concentrated solar power plants (coupled with thermal energy storage 4-6 ) would be an important step towards direct competition with fossil-fuel-based plants and a large reduction in greenhouse gas emissions 7 . However, the inlet temperatures of closed-cycle high-pressure sCO 2 turbine systems are limited 8 by the thermomechanical performance of the compact, metal-alloy-based, printed-circuit-type heat exchangers used to transfer heat to sCO 2 . Here we present a robust composite of ceramic (zirconium carbide, ZrC) and the refractory metal tungsten (W) for use in printed-circuit-type heat exchangers at temperatures above 1,023 kelvin 9 . This composite has attractive high-temperature thermal, mechanical and chemical properties and can be processed in a cost-effective manner. We fabricated ZrC/W-based heat exchanger plates with tunable channel patterns by the shape-and-size-preserving chemical conversion of porous tungsten carbide plates. The dense ZrC/W-based composites exhibited failure strengths of over 350 megapascals at 1,073 kelvin, and thermal conductivity values two to three times greater than those of iron- or nickel-based alloys at this temperature. Corrosion resistance to sCO 2 at 1,023 kelvin and 20 megapascals was achieved 10 by bonding a copper layer to the composite surface and adding 50 parts per million carbon monoxide to sCO 2 . Techno-economic analyses indicate that ZrC/W-based heat exchangers can strongly outperform nickel-superalloy-based printed-circuit heat exchangers at lower cost.

Contemporary hearing aids are markedlylimited in their most important role: improving speech perception in dynamic "cocktail party" environments with multiple, competing talkers. Here we describe an open-source, mobile assistive hearing platform entitled "Cochlearity" which uses eye gaze to guide an acoustic beamformer, so a listener will hear best wherever they look. Cochlearity runs on Android and its eight-channel microphone array can be worn comfortably on the head, e.g. mounted on eyeglasses. In this preliminary report, we examine the efficacy of both a static (delay-and-sum) and an adaptive (MVDR) beamformer in the task of separating an "attended" voice from an "unattended" voice in a two-talker scenario. We show that the different beamformers have the potential to complement each other to improve target speech SNR (signal to noise ratio), across the range of speech power, with tolerably low latency.

Solitons are waveforms that preserve their shape while propagating, as a result of a balance of dispersion and nonlinearity. Soliton-based data transmission schemes were investigated in the 1980s and showed promise as a way of overcoming the limitations imposed by dispersion of optical fibres. However, these approaches were later abandoned in favour of wavelength-division multiplexing schemes, which are easier to implement and offer improved scalability to higher data rates. Here we show that solitons could make a comeback in optical communications, not as a competitor but as a key element of massively parallel wavelength-division multiplexing. Instead of encoding data on the soliton pulse train itself, we use continuous-wave tones of the associated frequency comb as carriers for communication. Dissipative Kerr solitons (DKSs) (solitons that rely on a double balance of parametric gain and cavity loss, as well as dispersion and nonlinearity) are generated as continuously circulating pulses in an integrated silicon nitride microresonator via four-photon interactions mediated by the Kerr nonlinearity, leading to low-noise, spectrally smooth, broadband optical frequency combs. We use two interleaved DKS frequency combs to transmit a data stream of more than 50 terabits per second on 179 individual optical carriers that span the entire telecommunication C and L bands (centred around infrared telecommunication wavelengths of 1.55 micrometres). We also demonstrate coherent detection of a wavelength-division multiplexing data stream by using a pair of DKS frequency combs-one as a multi-wavelength light source at the transmitter and the other as the corresponding local oscillator at the receiver. This approach exploits the scalability of microresonator-based DKS frequency comb sources for massively parallel optical communications at both the transmitter and the receiver. Our results demonstrate the potential of these sources to replace the arrays of continuous-wave lasers that are currently used in high-speed communications. In combination with advanced spatial multiplexing schemes and highly integrated silicon photonic circuits, DKS frequency combs could bring chip-scale petabit-per-second transceivers into reach.

Background: The application of a clinical magnet over an implantable cardioverter defibrillator (ICD) can be used to suspend tachycardia therapies in patients receiving recurrent or inappropriate shocks. In our institution, they have been routinely issued to patients undergoing ICD implantation during the past 5 years. The purpose of this survey was to investigate how well information concerning their use had been retained, and in what circumstances the magnets had been used., Methods: We sent a questionnaire to 476 patients, and received a response from 343 (72%). Data was collated using 'Microsoft Excel', cross-referenced against our own pacing database, and analysed using basic statistical methods., Results: 256 (74.6%) patients recalled being issued with a magnet. 48% of these were still in possession of their written information leaflet at the time of survey; 62% felt that they were able to remember when and how to use the magnet-with patients who had received written instructions and verbal reinforcement demonstrating the best recall. 8% of patients had used their magnets and the most common reason for use was multiple or inappropriate shocks. In addition, almost half of the patients who had suffered inappropriate shocks had been able to successfully use their magnets. No cases of harm related to magnet use were identified., Conclusions: The results of our survey suggest that routinely issuing clinical magnets to ICD patients is a safe and effective practice, and a small but significant number of patients were able to utilise their magnets in clinically important situations.

We present the case of a 28-year-old female with Emery-Dreifuss muscular dystrophy and breast hypoplasia, who underwent implantation of a subpectoral defibrillator and bilateral breast augmentation during a single elective procedure at our institution.

Major depressive disorder (MDD) affects more than 10% of the population, although our understanding of the underlying aetiology of the disease and how antidepressant drugs act to remediate symptoms is limited. Major obstacles include the lack of availability of good animal models that replicate aspects of the phenotype and tests to assay depression-like behaviour in non-human species. To date, research in rodents has been dominated by two types of assays designed to test for depression-like behaviour: behavioural despair tests, such as the forced swim test, and measures of anhedonia, such as the sucrose preference test. These tests have shown relatively good predictive validity in terms of antidepressant efficacy, but have limited translational validity. Recent developments in clinical research have revealed that cognitive affective biases (CABs) are a key feature of MDD. Through the development of neuropsychological tests to provide objective measures of CAB in humans, we have the opportunity to use 'reverse translation' to develop and evaluate whether similar methods are suitable for research into MDD using animals. The first example of this approach was reported in 2004 where rodents in a putative negative affective state were shown to exhibit pessimistic choices in a judgement bias task. Subsequent work in both judgement bias tests and a novel affective bias task suggest that these types of assay may provide translational methods for studying MDD using animals. This review considers recent work in this area and the pharmacological and translational validity of these new animal models of CABs., (© 2014 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Rationale: Affective states are known to influence behaviour in humans resulting in cognitive affective biases, which may play an important role in the development and treatment of mood disorders. Similar biases have recently been shown in animals, including the rat, providing an opportunity to investigate these processes in non-human species., Objective: This study sought to investigate the psychopharmacology of cognitive affective bias in rats using systemic treatments with anxiolytic (diazepam) and antidepressant drugs (reboxetine or fluoxetine)., Methods: Lister hooded rats were trained to discriminate two distinct tones and respond on the appropriate lever to either obtain reward (food) or avoid punishment (mild foot shock). Cognitive affective bias, following acute or chronic drug treatment, was investigated using test sessions where both reference tones and intermediate ambiguous tones were included., Results: Rats exhibited a negative judgement bias under vehicle conditions which was not significantly attenuated by any of the acute drug treatments, diazepam (0.3, 1.0 mg/kg), reboxetine (0.3-3.0 mg/kg) or fluoxetine 0.1-1.0 mg/kg). Acute reboxetine induced a significant and dose-dependent decrease in the anticipation of reward. Chronic treatment with fluoxetine tended to reduce the negative bias observed in the rats after 1 week of treatment although no significant main effect of treatment was observed., Conclusions: The results from these initial psychopharmacological studies show that drug treatments can differentially affect motivation to respond to cues associated with reward versus punishment. Our data also suggest that cognitive affective bias, quantified using this method, may be sensitive to chronic but not acute antidepressant treatment.

Changes in the processing of emotional information are key features of affective disorders. Neuropsychological tests based on emotional faces or words are used to detect emotional/affective biases in humans, but these tests are not applicable to animal species. In the present study, we investigated whether a novel affective tone discrimination task (ATDT), developed to study emotion-related behaviour in rats, could also be used to quantify changes in affective states in humans. To date, the methods used in human neuropsychology have not been applicable to animal experiments. Participants completed a training session in which they learnt to discriminate specific tone frequencies and to correctly respond in order to gain emotionally valenced outcomes, to obtain rewards (money), or to avoid punishment (an aversive sound clip). During a subsequent test session, additional ambiguous probe tones were presented at frequencies intermediate between the reward and avoidance paired tones. At the end of the task, participants completed self-report questionnaires. All participants made more avoidance responses to the most ambiguous tone cues, suggesting a bias towards avoidance of punishment. Individual differences in the degrees of bias observed were correlated with anxiety measures, suggesting the task's sensitivity to differences in state anxiety within a healthy population. Further studies in clinical populations will be necessary to assess the task's sensitivity to pathological anxiety states. These data suggest that this affective tone discrimination task provides a novel method to study cognitive affective biases in different species, including humans, and offers a novel assessment to study anxiety.

Background/aims: Streptococcus mutans, the major etiological agent of dental caries, has a measurable impact on domestic and global health care costs. Though persistent in the oral cavity despite conventional oral hygiene, S. mutans can be excluded from intact oral biofilms through competitive exclusion by other microorganisms. This suggests that therapies capable of selectively eliminating S. mutans while limiting the damage to the normal oral flora might be effective long-term interventions to fight cariogenesis. To meet this challenge, we designed C16G2, a novel synthetic specifically targeted antimicrobial peptide with specificity for S. mutans. C16G2 consists of a S. mutans-selective 'targeting region' comprised of a fragment from S. mutans competence stimulation peptide (CSP) conjoined to a 'killing region' consisting of a broad-spectrum antimicrobial peptide (G2). In vitro studies have indicated that C16G2 has robust efficacy and selectivity for S. mutans, and not other oral bacteria, and affects targeted bacteria within seconds of contact., Methods: In the present study, we evaluated C16G2 for clinical utility in vitro, followed by a pilot efficacy study to examine the impact of a 0.04% (w/v) C16G2 rinse in an intra-oral remineralization/demineralization model., Results and Conclusions: C16G2 rinse usage was associated with reductions in plaque and salivary S. mutans, lactic acid production, and enamel demineralization. The impact on total plaque bacteria was minimal. These results suggest that C16G2 is effective against S. mutans in vivo and should be evaluated further in the clinic., (Copyright © 2011 S. Karger AG, Basel.)

Dental caries (tooth decay) is caused by a specific group of cariogenic bacteria, like Streptococcus mutans, which convert dietary sugars into acids that dissolve the mineral in tooth structure. Killing cariogenic bacteria is an effective way to control or prevent tooth decay. In a previous study, we discovered a novel compound (Glycyrrhizol A), from the extraction of licorice roots, with strong antimicrobial activity against cariogenic bacteria. In the current study, we developed a method to produce these specific herbal extracts in large quantities, and then used these extracts to develop a sugar-free lollipop that effectively kills cariogenic bacteria like Streptococcus mutans. Further studies showed that these sugar-free lollipops are safe and their antimicrobial activity is stable. Two pilot human studies indicate that a brief application of these lollipops (twice a day for ten days) led to a marked reduction of cariogenic bacteria in oral cavity among most human subjects tested. This herbal lollipop could be a novel tool to promote oral health through functional foods.

Finding unique peptides to target specific biological surfaces is crucial to basic research and technology development, though methods based on biological arrays or large libraries limit the speed and ease with which these necessary compounds can be found. We reasoned that because biological surfaces, such as cell surfaces, mineralized tissues, and various extracellular matrices have unique molecular compositions, they present unique physicochemical signatures to the surrounding medium which could be probed by peptides with appropriately corresponding physicochemical properties. To test this hypothesis, a naïve pilot library of 36 peptides, varying in their hydrophobicity and charge, was arranged in a two-dimensional matrix and screened against various biological surfaces. While the number of peptides in the matrix library was very small, we obtained "hits" against all biological surfaces probed. Sequence refinement of the "hits" led to peptides with markedly higher specificity and binding activity against screened biological surfaces. Genetic studies revealed that peptide binding to bacteria was mediated, at least in some cases, by specific cell-surface molecules, while examination of human tooth sections showed that this method can be used to derive peptides with highly specific binding to human tissue.

Two patients with the same model of single-coil active fix implantable defibrillator lead presented with evidence of lead malfunction, in one case with an abrupt rise in pacing impedance and threshold and in the other with evidence of over-sensing. In both cases, the chest radiograph showed separation of conductors in the defibrillation lead from the main body of the lead.

Previously we reported a novel strategy of "targeted killing" through the design of narrow-spectrum molecules known as specifically targeted antimicrobial peptides (STAMPs) (R. Eckert et al., Antimicrob. Agents Chemother. 50:3651-3657, 2006; R. Eckert et al., Antimicrob. Agents Chemother. 50:1480-1488, 2006). Construction of these molecules requires the identification and the subsequent utilization of two conjoined yet functionally independent peptide components: the targeting and killing regions. In this study, we sought to design and synthesize a large number of STAMPs targeting Streptococcus mutans, the primary etiologic agent of human dental caries, in order to identify candidate peptides with increased killing speed and selectivity compared with their unmodified precursor antimicrobial peptides (AMPs). We hypothesized that a combinatorial approach, utilizing a set number of AMP, targeting, and linker regions, would be an effective method for the identification of STAMPs with the desired level of activity. STAMPs composed of the Sm6 S. mutans binding peptide and the PL-135 AMP displayed selectivity at MICs after incubation for 18 to 24 h. A STAMP where PL-135 was replaced by the B-33 killing domain exhibited both selectivity and rapid killing within 1 min of exposure and displayed activity against multispecies biofilms grown in the presence of saliva. These results suggest that potent and selective STAMP molecules can be designed and improved via a tunable "building-block" approach.

Numerous reports have indicated the important role of human normal flora in the prevention of microbial pathogenesis and disease. Evidence suggests that infections at mucosal surfaces result from the outgrowth of subpopulations or clusters within a microbial community and are not linked to one pathogenic organism alone. To preserve the protective normal flora whilst treating the majority of infective bacteria in the community, a tuneable therapeutic is necessary that can discriminate between benign bystanders and multiple pathogenic organisms. Here we describe the proof-of-principle for such a multitargeted antimicrobial: a multiple-headed specifically targeted antimicrobial peptide (MH-STAMP). The completed MH-STAMP, M8(KH)-20, displays specific activity against targeted organisms in vitro (Pseudomonas aeruginosa and Streptococcus mutans) and can remove both species from a mixed planktonic culture with little impact against untargeted bacteria. These results demonstrate that a functional, dual-targeted molecule can be constructed from a wide-spectrum antimicrobial peptide precursor.

The cooling water of nuclear reactors undergoes radiolytic decomposition induced by gamma, fast electron, and neutron radiation in the core. To model the process, recombination reaction rates and radiolytic yields for the water radical fragments need to be measured at high temperature and pressure. Yields for the action of neutron radiation are particularly hard to determine independently because of the beta/gamma field also present in any reactor. In this paper we report the design of an apparatus intended to measure neutron radiolysis yields as a function of temperature and pressure. A new methodology for separation of neutron and beta/gamma radiolysis yields in a mixed radiation field is proposed and demonstrated.

While reductionism has greatly advanced microbiology in the past 400 years, assembly of smaller pieces just could not explain the whole! Modern microbiologists are learning "system thinking" and "holism." Such an approach is changing our understanding of microbial physiology and our ability to diagnose/treat microbial infections. This review uses oral microbial communities as a focal point to describe this new trend. With the common name "dental plaque," oral microbial communities are some of the most complex microbial floras in the human body, consisting of more than 700 different bacterial species. For a very long time, oral microbiologists endeavored to use reductionism to identify the key genes or key pathogens responsible for oral microbial pathogenesis. The limitations of reductionism forced scientists to begin adopting new strategies using emerging concepts such as interspecies interaction, microbial community, biofilms, polymicrobial disease, etc. These new research directions indicate that the whole is much more than the simple sum of its parts, since the interactions between different parts resulted in many new physiological functions which cannot be observed with individual components. This review describes some of these interesting interspecies-interaction scenarios.

G10KHc, a specifically targeted antimicrobial peptide developed in our laboratory, has shown rapid and selective killing activity against Pseudomonas aeruginosa in culture medium. Because of the major role played by this pathogen in cystic fibrosis, we sought to evaluate the utility of G10KHc under more physiologic conditions in vitro. In the current study, we found that robust G10KHc activity could be maintained in expectorated sputum if serine protease-dependent digestion associated with this fluid was inhibited, either by chemical antagonists or by the construction of a D-amino acid enantiomer of G10KHc. Further investigations revealed that specifically targeted antimicrobial peptide activity in sputum could be further enhanced when samples were treated with a combination of peptide and recombinant human DNase. Our results illustrate the importance of investigating combination therapy to treat cystic fibrosis, especially if protease-sensitive peptide-based agents, such as G10KHc, are to be developed as alternatives to, or in conjunction with, conventional small-molecule antibiotics.

This article is intended to stimulate dialogue within the intertwined dental practice and dental education communities about our evolving health care system and dentistry's role within this system as it reconfigures in response to a complex interplay of influences. The changing dental disease burden in the United States is analyzed with consideration of how evolution in disease prevalence influences societal need for dental services and the resulting potential impact on the types of services provided and the education of future dental practitioners. The article concludes with discussion of a potential future scenario for practice and education in which one or both of the two health abnormalities (dental caries and periodontal diseases) most closely associated with dentistry as an area of medical specialization go away as a consequence of transformational technologies.

Whether public or private dental insurance will provide benefits for caries management practices is a business decision. The foundation for this decision is multifactorial and continually changing as the values of the purchasers and health care consumers evolve. Understanding the dynamics involved in allocating finite health care resources will help those who advocate for caries management inform decision makers about the potential benefits of these strategies.

Streptococcus mutans, a common oral pathogen and the causative agent of dental caries, has persisted and even thrived on the tooth surface despite constant removal and eradication efforts. In this study, we generated a number of synthetic antimicrobial peptides against this bacterium via construction and screening of several structurally diverse peptide libraries where the hydrophobicity and charge within each library was varied incrementally in order to generate a collection of peptides with different biochemical characteristics. From these libraries, we identified multiple peptides with robust killing activity against S. mutans. To further improve their effectiveness, the most bactericidal peptides from each library were synthesized together as one molecule, in various combinations, with and without a flexible peptide linker between each antimicrobial region. Many of these "fusion" peptides had enhanced killing activities in comparison with those of the original nonconjoined molecules. The results presented here illustrate that small libraries of biochemically constrained peptides can be used to generate antimicrobial peptides against S. mutans, several of which may be likely candidates for the development of anticaries agents.

The aim of this study was to compare a recently developed monoclonal antibody (MAb)-based salivary Streptococcus mutans detection method with various selective media using polymerase chain reaction (PCR) as the gold standard. Salivary S. mutans cells were enumerated with a MAb-based method, along with three commonly used selective media, mitis-salivarius-bacitracin agar (MSB), trypticase yeast-extract cystine sucrose bacitracin agar (TYCSB), and glucose-sucrose-potassium tellurite-bacitracin (GSTB) agar. Statistical analysis showed no significant correlations between each method. With PCR as the standard, a MAb-based detection method was found to provide the highest sensitivity (91%) and specificity (96%) among these four methods. This study demonstrates that the MAb-based detection method may provide more accurate enumeration of salivary S. mutans than selective media.

Pseudomonas aeruginosa is a common opportunistic human pathogen that is associated with life-threatening acute infections and chronic airway colonization during cystic fibrosis. Previously, we converted the wide-spectrum antimicrobial peptide novispirin G10 into a selectively-targeted antimicrobial peptide (STAMP), G10KHc. Compared to novispirin G10, the STAMP had an enhanced ability to kill Pseudomonas mendocina. In this study, we explored the activity of G10KHc against P. aeruginosa. G10KHc was found to be highly active (as active as tobramycin) against P. aeruginosa clinical isolates. Most interestingly, we observed a synergistic-like enhancement in killing activity when biofilms and planktonic cultures of P. aeruginosa were cotreated with G10KHc and tobramycin. The data indicate that the mechanism of enhanced activity may involve increased tobramycin uptake due to G10KHc-mediated cell membrane disruption. These results suggest that G10KHc may be useful against P. aeruginosa during acute and chronic infection states, especially when it is coadministered with tobramycin.

Within the repertoire of antibiotics available to a prescribing clinician, the majority affect a broad range of microorganisms, including the normal flora. The ecological disruption resulting from antibiotic treatment frequently results in secondary infections or other negative clinical consequences. To address this problem, our laboratory has recently developed a new class of pathogen-selective molecules, called specifically (or selectively) targeted antimicrobial peptides (STAMPs), based on the fusion of a species-specific targeting peptide domain with a wide-spectrum antimicrobial peptide domain. In the current study, we focused on achieving targeted killing of Streptococcus mutans, a cavity-causing bacterium that resides in a multispecies microbial community (dental plaque). In particular, we explored the possibility of utilizing a pheromone produced by S. mutans, namely, the competence stimulating peptide (CSP), as a STAMP targeting domain to mediate S. mutans-specific delivery of an antimicrobial peptide domain. We discovered that STAMPs constructed with peptides derived from CSP were potent against S. mutans grown in liquid or biofilm states but did not affect other oral streptococci tested. Further studies showed that an 8-amino-acid region within the CSP sequence is sufficient for targeted delivery of the antimicrobial peptide domain to S. mutans. The STAMPs presented here are capable of eliminating S. mutans from multispecies biofilms without affecting closely related noncariogenic oral streptococci, indicating the potential of these molecules to be developed into "probiotic" antibiotics which could selectively eliminate pathogens while preserving the protective benefits of a healthy normal flora.

Despite major advances in therapy of hepatitis C over the past decade, nearly half of the patients treated with the currently available regimens do not clear the virus. Therefore, there is a large unmet need for more effective therapy for patients who have failed pegylated interferon plus ribavirin therapy. We describe a case of a HCV genotype 1b patient who had failed previous combination therapies of interferon plus ribavirin and pegylated interferon plus ribavirin and was subsequently successfully treated with a novel triple drug combination consisting of interferon-gamma plus interferon alfacon plus ribavirin with the outcome of a sustained virologic response. This triple drug therapy combination could be an option for patients who have failed therapies with currently available pegylated interferons plus ribavirin. Prospective randomized studies are required to evaluate the effectiveness and tolerability of this regimen in this patient population.

Currently available antimicrobials exhibit broad killing with regard to bacterial genera and species. Indiscriminate killing of microbes by these conventional antibiotics can disrupt the ecological balance of the indigenous microbial flora, often resulting in negative clinical consequences. Species-specific antimicrobials capable of precisely targeting pathogenic bacteria without damaging benign microorganisms provide a means of avoiding this problem. In this communication, we report the successful creation of the first synthetic, target-specific antimicrobial peptide, G10KHc, via addition of a rationally designed Pseudomonas-specific targeting moiety (KH) to a generally killing peptide (novispirin G10). The resulting chimeric peptide showed enhanced bactericidal activity and faster killing kinetics against Pseudomonas spp. than G10 alone. The enhanced killing activities are due to increased binding and penetration of the outer membrane of Pseudomonas sp. cells. These properties were not observed in tests of untargeted bacterial species, and this specificity allowed G10KHc to selectively eliminate Pseudomonas spp. from mixed cultures. This work lays a foundation for generating target-specific "smart" antimicrobials to complement currently available conventional antibiotics.

The surgical approach has been the predominate mode of caries management for the past 150 years. Dentistry has, however, in recent years moved toward an antibiotic/antimicrobial model of disease management. This approach, however, raises serious questions: (1) do the antibiotic/antimicrobial agents (chlorhexidine, povidone iodine, fluoride, etc) kill all offending organisms?; (2) if so, do the agents preclude the re-entry of the same organisms from external sources?; and (3) if the agents do kill all the offending organisms, do any remaining pathogenic organisms have selective advantage in repopulating the tooth surfaces? To overcome the problems inherent in an antibiotic/antimicrobial approach, probiotic methods are currently under study as means of caries management. This paper discusses probiotic approaches, such as genetically modified Streptococcus mutans and targeted antimicrobials in the management of dental caries. Implications for this approach in the management of other diseases are also presented.

Existing transformational leadership research has focused primarily on the behaviors of leaders and their effects on followers. The authors extended this research by examining the social networks of managers who exhibit transformational leadership behaviors. Their focus was on the network of relationships that managers develop and whether they hold key positions in the organization's informal social networks. In a field study using data from 39 managers and 130 nonmanagement employees of 6 organizations, the authors found that managers who score higher on transformational leadership tend to hold more central positions in organizational advice and influence networks. Furthermore, the direct reports of these leaders were also more central in informal organizational networks. These results illuminate one of the ways that managers who exhibit transformational leadership behaviors may exert influence in organizations., (((c) 2005 APA, all rights reserved).)

Noninvasive in situ detection of suspected cariogenic bacterial species within dental biofilms could facilitate monitoring of the dynamic change of oral microbial flora and assist in the assessment of the treatment efficacy of therapeutic agents. In this study, we explore the possibility to use three well-characterized monoclonal antibodies (MAbs) against Streptococcus mutans, Actinomyces naeslundii, and Lactobacillus casei to identify these three important members of the oral microbial community in the complex environment of oral biofilms. These MAbs, which were conjugated to different fluorescent labels and visualized with confocal laser scanning microscopy (CLSM), proved to be an useful tool to identify the three species of interest (S. mutans, A. naeslundii, and L. casei) under various experimental conditions including in vitro and in vivo derived oral biofilms. Manifold addition of the MAbs on consecutive days did not alter the biofilm structure thus allowing monitoring of the same biofilm over extended time periods. Using this MAb-based method the effect of sucrose challenge on the biofilm composition and the distribution of S. mutans, A. naeslundii, and L. casei were examined. S. mutans was found to be the predominant species under the various biofilm conditions tested. These studies indicate that MAbs based bacterial detection with CLSM is a versatile tool which permits new insights into the ecology of oral biofilm development.

Dentistry and dental payment systems as we know them today will continue to evolve. Dentistry as practiced today and the prepayment systems of dentistry are substantially different than they were fifty years ago when dental insurance as we know it was first developed. Dentistry has always changed with the development of our science and the expression of dentistry's diseases in the populations we serve. The changes that are likely to occur in the future will be focused on improving health outcomes across risk-analyzed populations with the goals of providing optimal health outcomes at reasonable costs. Dentists will increasingly become engaged in the whole health of their patients. Where sufficient correlations can be leveraged between dentistry and overall health, medical plans will play an increasing role in dentistry's future for two reasons. Given favorably altered therapeutic outcomes for medical systems that preserve scarce resources, it will be an economic imperative to engage the dental system. It will also be the right thing to do from a total health perspective. In the final analysis, this elevates the role of dentistry and empowers the dentist to participate in the total health of their patients.