Hypomineralised second primary molars: the Würzburg concept.

PURPOSE: In addition to molar incisor hypomineralisation, the occurrence of enamel hypomineralisation in the primary dentition has become increasingly important in recent years. Hypomineralised second primary molar (HSPM) is defined as hypomineralisation of systemic origin affecting from one to all four second primary molars. Some years ago, the "Würzburg concept" was introduced, which proposed a grading of MIH findings (MIH treatment need index) in combination with an appropriate treatment plan depending on the severity of the affected tooth. Recently, this concept was updated and new treatment approaches have been added. However, currently, the concept solely addresses the treatment plan for permanent teeth. As there is a need to expand its scope to encompass primary teeth and, consequently, HSPM, this paper seeks to develop the second component of the Würzburg concept, the treatment plan, for the primary dentition in response to the increased focus on the disease in recent years. Although the evidence base for the different treatment options is still weak, there is a need for guidance for clinicians in their day-to-day practice. METHODS: The authors conducted a comprehensive review of the literature, encompassing clinical and laboratory studies along with published guidelines. RESULTS: The treatment plan of the HSPM Würzburg concept contains prophylactic and regenerative aspects, non-invasive interventions, temporary and permanent restorative techniques, and extraction. CONCLUSIONS: The intention is to provide practical guidance to practitioners, acknowledging the necessity for further validation through clinical trials.

Ionic conduction in ammonia functionalised closo-dodecaborates MB12H11NH3 (M = Li and Na).

Metal hydroborates and their derivatives have been receiving attention as potential solid-state ion conductors for battery applications owing to their impressive electrochemical and mechanical characteristics. However, to date only a fraction of these compounds has been investigated as solid-state electrolytes. Here, MB12H11NH3 (M = Li and Na) hydroborates are synthesized and investigated as electrolyte materials for all-solid-state batteries. The room temperature α-NaB12H11NH3 was structurally solved in P212121 (a = 7.1972(3) Å, b = 9.9225(4) Å, and c = 14.5556(5) Å). It shows a polymorphic structural transition near 140 °C to cubic Fm3̄m. LiB12H11NH3 and NaB12H11NH3 exhibit cationic conductivities of σ(Li+) = 3.0 × 10-4 S cm-1 and σ(Na+) = 1.2 × 10-4 S cm-1 at 200 °C. Hydration is found to improve ionic conductivity of the hydroborates. It is presumed that modest ionic conductivities could be due to a lack of significant re-orientational dynamics in the crystal structure resulting from the presence of the bulky -NH3 group in the anion.

Breathing control of vocalization.

A crucial brainstem circuit for vocal-respiratory coordination of the larynx is revealed.

Dysfunction of specific auditory fibers impacts cortical oscillations, driving an autism phenotype despite near-normal hearing.

Autism spectrum disorder is discussed in the context of altered neural oscillations and imbalanced cortical excitation-inhibition of cortical origin. We studied here whether developmental changes in peripheral auditory processing, while preserving basic hearing function, lead to altered cortical oscillations. Local field potentials (LFPs) were recorded from auditory, visual, and prefrontal cortices and the hippocampus of BdnfPax2 KO mice. These mice develop an autism-like behavioral phenotype through deletion of BDNF in Pax2+ interneuron precursors, affecting lower brainstem functions, but not frontal brain regions directly. Evoked LFP responses to behaviorally relevant auditory stimuli were weaker in the auditory cortex of BdnfPax2 KOs, connected to maturation deficits of high-spontaneous rate auditory nerve fibers. This was correlated with enhanced spontaneous and induced LFP power, excitation-inhibition imbalance, and dendritic spine immaturity, mirroring autistic phenotypes. Thus, impairments in peripheral high-spontaneous rate fibers alter spike synchrony and subsequently cortical processing relevant for normal communication and behavior.

Update of the molar incisor hypomineralization: Würzburg concept.

PURPOSE: Molar incisor hypomineralization (MIH) is playing an increasingly important role in dental practice. MIH is defined as hypomineralization of systemic origin of one to four permanent first molars, often associated with affected incisors. Affected teeth are more susceptible to caries and post-eruptive enamel loss and should be diagnosed and treated as early as possible. In 2016, the Würzburg concept was developed for German-speaking countries including a classification index-the MIH Treatment Need Index (MIH-TNI)-and a treatment plan based on it for the use in daily practice. In the meantime, the concept has also gained international recognition. The aim of this paper is to update part 2 of the Würzburg concept, the treatment plan, as knowledge about MIH has increased and the disease has been studied more extensively in the last years. Other treatment approaches are now available and therefore need to be included in the concept. Although, the evidence of the different treatment options is still weak, practitioners need guidance in their daily practice. METHODS: The authors reviewed the available literature, including clinical and laboratory studies and published guidelines. RESULTS: The updated version of the Würzburg concept includes additional non-invasive strategies and temporary therapy options, as well as treatment approaches for incisors. It therefore covers currently available treatment modalities for MIH-affected teeth, ranging from prophylaxis, non-invasive treatment to restorative approaches and possibly even extraction. CONCLUSIONS: This is intended to help guide the practitioner and will need to be further validated by clinical trials.

Linguistic law-like compression strategies emerge to maximize coding efficiency in marmoset vocal communication.

Human language follows statistical regularities or linguistic laws. For instance, Zipf's law of brevity states that the more frequently a word is used, the shorter it tends to be. All human languages adhere to this word structure. However, it is unclear whether Zipf's law emerged de novo in humans or whether it also exists in the non-linguistic vocal systems of our primate ancestors. Using a vocal conditioning paradigm, we examined the capacity of marmoset monkeys to efficiently encode vocalizations. We observed that marmosets adopted vocal compression strategies at three levels: (i) increasing call rate, (ii) decreasing call duration and (iii) increasing the proportion of short calls. Our results demonstrate that marmosets, when able to freely choose what to vocalize, exhibit vocal statistical regularities consistent with Zipf's law of brevity that go beyond their context-specific natural vocal behaviour. This suggests that linguistic laws emerged in non-linguistic vocal systems in the primate lineage.

Neural representations of the content and production of human vocalization.

Speech, as the spoken form of language, is fundamental for human communication. The phenomenon of covert inner speech implies functional independence of speech content and motor production. However, it remains unclear how a flexible mapping between speech content and production is achieved on the neural level. To address this, we recorded magnetoencephalography in humans performing a rule-based vocalization task. On each trial, vocalization content (one of two vowels) and production form (overt or covert) were instructed independently. Using multivariate pattern analysis, we found robust neural information about vocalization content and production, mostly originating from speech areas of the left hemisphere. Production signals dynamically transformed upon presentation of the content cue, whereas content signals remained largely stable throughout the trial. In sum, our results show dissociable neural representations of vocalization content and production in the human brain and provide insights into the neural dynamics underlying human vocalization.

Identification and characterisation of the tegument-expressed aldehyde dehydrogenase SmALDH_312 of Schistosoma mansoni, a target of disulfiram.

Schistosomiasis is an infectious disease caused by blood flukes of the genus Schistosoma and affects approximately 200 million people worldwide. Since Praziquantel (PZQ) is the only drug for schistosomiasis, alternatives are needed. By a biochemical approach, we identified a tegumentally expressed aldehyde dehydrogenase (ALDH) of S. mansoni, SmALDH_312. Molecular analyses of adult parasites showed Smaldh_312 transcripts in both genders and different tissues. Physiological and cell-biological experiments exhibited detrimental effects of the drug disulfiram (DSF), a known ALDH inhibitor, on larval and adult schistosomes in vitro. DSF also reduced stem-cell proliferation and caused severe tegument damage in treated worms. In silico-modelling of SmALDH_312 and docking analyses predicted DSF binding, which we finally confirmed by enzyme assays with recombinant SmALDH_312. Furthermore, we identified compounds of the Medicine for Malaria Venture (MMV) pathogen box inhibiting SmALDH_312 activity. Our findings represent a promising starting point for further development towards new drugs for schistosomiasis.

Marmoset monkeys use different avoidance strategies to cope with ambient noise during vocal behavior.

Multiple strategies have evolved to compensate for masking noise, leading to changes in call features. One call adjustment is the Lombard effect, an increase in call amplitude in response to noise. Another strategy involves call production in periods where noise is absent. While mechanisms underlying vocal adjustments have been well studied, mechanisms underlying noise avoidance strategies remain largely unclear. We systematically perturbed ongoing phee calls of marmosets to investigate noise avoidance strategies. Marmosets canceled their calls after noise onset and produced longer calls after noise-phases ended. Additionally, the number of uttered syllables decreased during noise perturbation. This behavior persisted beyond the noise-phase. Using machine learning techniques, we found that a fraction of single phees were initially planned as double phees and became interrupted after the first syllable. Our findings indicate that marmosets use different noise avoidance strategies and suggest vocal flexibility at different complexity levels in the marmoset brain.

The impact of supportive leadership on employee outcomes during organizational mergers: An organizational-level field study.

Past merger and acquisition research has reported mixed findings on the impact of mergers on workforces. To address these ambiguities and advance merger research at the organizational level of analysis, we present a natural quasi-experiment focusing on mergers in the English National Health Service. Building on organizational support theory and conservation of resources theory, we propose that merger events represent environmental stressors, with negative implications for employees' subjective (job satisfaction) and objective (absenteeism) outcomes. However, extending previous theorizing, we argue that by increasing their supportive leadership, midlevel management can compensate for the resource losses incurred during mergers, and in doing so, minimize the adverse impact on their workforces. We test our predictions in the context of multiple primary care trust mergers, which took place in 2006. We analyzed the annual staff surveys, combined with objective information on employee absenteeism, and compared merging organizations with nonmerging organizations before (2005) and after (2007) the mergers. As expected, employees of merging (vs. not merging) organizations showed stronger decreases in job satisfaction, and these decreases in subjective outcomes were associated with increases in absenteeism over the course of the merger process. However, consistent with our propositions, we found that increases in supportive leadership during the merger period served to mitigate these negative outcomes. Our results highlight the organizational-level implications of mergers and the role that midlevel management can play in compensating for the losses experienced during (stressful) merger events. We discuss the implications for dynamic models of merger integration and leadership during change. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The impact of species-wide gene expression variation on Caenorhabditis elegans complex traits.

Phenotypic variation in organism-level traits has been studied in Caenorhabditis elegans wild strains, but the impacts of differences in gene expression and the underlying regulatory mechanisms are largely unknown. Here, we use natural variation in gene expression to connect genetic variants to differences in organismal-level traits, including drug and toxicant responses. We perform transcriptomic analyses on 207 genetically distinct C. elegans wild strains to study natural regulatory variation of gene expression. Using this massive dataset, we perform genome-wide association mappings to investigate the genetic basis underlying gene expression variation and reveal complex genetic architectures. We find a large collection of hotspots enriched for expression quantitative trait loci across the genome. We further use mediation analysis to understand how gene expression variation could underlie organism-level phenotypic variation for a variety of complex traits. These results reveal the natural diversity in gene expression and possible regulatory mechanisms in this keystone model organism, highlighting the promise of using gene expression variation to understand how phenotypic diversity is generated.

Cardiovascular mechanisms underlying vocal behavior in freely moving macaque monkeys.

Communication is a keystone of animal behavior. However, the physiological states underlying natural vocal signaling are still largely unknown. In this study, we investigated the correlation of affective vocal utterances with concomitant cardiorespiratory mechanisms. We telemetrically recorded electrocardiography, blood pressure, and physical activity in six freely moving and interacting cynomolgus monkeys (Macaca fascicularis). Our results demonstrate that vocal onsets are strengthened during states of sympathetic activation, and are phase locked to a slower Mayer wave and a faster heart rate signal at ∼2.5 Hz. Vocalizations are coupled with a distinct peri-vocal physiological signature based on which we were able to predict the onset of vocal output using three machine learning classification models. These findings emphasize the role of cardiorespiratory mechanisms correlated with vocal onsets to optimize arousal levels and minimize energy expenditure during natural vocal production.

Evaluation of the in vitro susceptibility of various filarial nematodes to emodepside.

Filariae are vector-borne nematodes responsible for an enormous burden of disease. Human lymphatic filariasis, caused by Wuchereria bancrofti, Brugia malayi, and Brugia timori, and onchocerciasis (caused by Onchocerca volvulus) are neglected parasitic diseases of major public health significance in tropical regions. To date, therapeutic efforts to eliminate human filariasis have been hampered by the lack of a drug with sufficient macrofilaricidal and/or long-term sterilizing effects that is suitable for use in mass drug administration (MDA) programs, particularly in areas co-endemic with Loa loa, the causative agent of loiasis. Emodepside, a semi-synthetic cyclooctadepsipeptide, has been shown to have broad-spectrum efficacy against gastrointestinal nematodes in a variety of mammalian hosts, and has been approved as an active ingredient in dewormers for cats and dogs. This paper evaluates, compares (where appropriate) and summarizes the in vitro effects of emodepside against a range of filarial nematodes at various developmental stages. Emodepside inhibited the motility of all tested stages of filariae frequently used as surrogate species for preclinical investigations (Acanthocheilonema viteae, Brugia pahangi, Litomosoides sigmodontis, Onchocerca gutturosa, and Onchocerca lienalis), human-pathogenic filariae (B. malayi) and filariae of veterinary importance (Dirofilaria immitis) in a concentration-dependent manner. While motility of all filariae was inhibited, both stage- and species-specific differences were observed. However, whether these differences were detected because of stage- and/or species-specific factors or as a consequence of variations in protocol parameters among the participating laboratories (such as purification of the parasites, read-out units, composition of media, incubation conditions, duration of incubation etc.) remains unclear. This study, however, clearly shows that emodepside demonstrates broad-spectrum in vitro activity against filarial nematode species across different genera and can therefore be validated as a promising candidate for the treatment of human filariases, including onchocerciasis and lymphatic filariasis.

Comparison of electrophysiological and motility assays to study anthelmintic effects in Caenorhabditis elegans.

Currently, only a few chemical drug classes are available to control the global burden of nematode infections in humans and animals. Most of these drugs exert their anthelmintic activity by interacting with proteins such as ion channels, and the nematode neuromuscular system remains a promising target for novel intervention strategies. Many commonly-used phenotypic readouts such as motility provide only indirect insight into neuromuscular function and the site(s) of action of chemical compounds. Electrophysiological recordings provide more specific information but are typically technically challenging and lack high throughput for drug discovery. Because drug discovery relies strongly on the evaluation and ranking of drug candidates, including closely related chemical derivatives, precise assays and assay combinations are needed for capturing and distinguishing subtle drug effects. Past studies show that nematode motility and pharyngeal pumping (feeding) are inhibited by most anthelmintic drugs. Here we compare two microfluidic devices ("chips") that record electrophysiological signals from the nematode pharynx (electropharyngeograms; EPGs) ─ the ScreenChip™ and the 8-channel EPG platform ─ to evaluate their respective utility for anthelmintic research. We additionally compared EPG data with whole-worm motility measurements obtained with the wMicroTracker instrument. As references, we used three macrocyclic lactones (ivermectin, moxidectin, and milbemycin oxime), and levamisole, which act on different ion channels. Drug potencies (IC50 and IC95 values) from concentration-response curves, and the time-course of drug effects, were compared across platforms and across drugs. Drug effects on pump timing and EPG waveforms were also investigated. These experiments confirmed drug-class specific effects of the tested anthelmintics and illustrated the relative strengths and limitations of the different assays for anthelmintic research.

Development of emodepside as a possible adulticidal treatment for human onchocerciasis-The fruit of a successful industrial-academic collaboration.

Current mass drug administration (MDA) programs for the treatment of human river blindness (onchocerciasis) caused by the filarial worm Onchocerca volvulus rely on ivermectin, an anthelmintic originally developed for animal health. These treatments are primarily directed against migrating microfilariae and also suppress fecundity for several months, but fail to eliminate adult O. volvulus. Therefore, elimination programs need time frames of decades, well exceeding the life span of adult worms. The situation is worsened by decreased ivermectin efficacy after long-term therapy. To improve treatment options against onchocerciasis, a drug development candidate should ideally kill or irreversibly sterilize adult worms. Emodepside is a broad-spectrum anthelmintic used for the treatment of parasitic nematodes in cats and dogs (Profender and Procox). Our current knowledge of the pharmacology of emodepside is the result of more than 2 decades of intensive collaborative research between academia and the pharmaceutical industry. Emodepside has a novel mode of action with a broad spectrum of activity, including against extraintestinal nematode stages such as migrating larvae or macrofilariae. Therefore, emodepside is considered to be among the most promising candidates for evaluation as an adulticide treatment against onchocerciasis. Consequently, in 2014, Bayer and the Drugs for Neglected Diseases initiative (DNDi) started a collaboration to develop emodepside for the treatment of patients suffering from the disease. Macrofilaricidal activity has been demonstrated in various models, including Onchocerca ochengi in cattle, the parasite most closely related to O. volvulus. Emodepside has now successfully passed Phase I clinical trials, and a Phase II study is planned. This Bayer-DNDi partnership is an outstanding example of "One World Health," in which experience gained in veterinary science and drug development is translated to human health and leads to improved tools to combat neglected tropical diseases (NTDs) and shorten development pathways and timelines in an otherwise neglected area.

Can the booster interval for the tick-borne encephalitis (TBE) vaccine 'FSME-IMMUN' be prolonged? - A systematic review.

Tick-borne encephalitis (TBE) vaccines are effective and well tolerated. However, their acceptance and use by the public in endemic areas are suboptimal. To some extent this is due to the complicated dosing schedule requiring frequent boosters at variable intervals that even change with age. Simplification of the dosing schedule has failed so far as it is debated if the persistence of TBE virus (TBEV) antibodies is the only relevant factor for protection or if immune memory plays a decisive role as well. The objective here is to present the available evidence to determine the need for boosters and their interval after a primary series of three doses of FSME-IMMUN. A systematic literature review was conducted with a focus on serology, particularly seropersistence, immune memory, effectiveness, and vaccine breakthroughs (VB) of FSME-IMMUN. While after a 3-dose primary series seropositivity persisted for more than 10 years in >90% of younger subjects, it dropped to 37.5% in those 60 years or older. In contrast, field effectiveness of FSME-IMMUN remains high in irregularly vaccinated subjects and thus does not correlate well with the percentage of subjects achieving an arbitrarily defined threshold of persisting antibodies. FSME-IMMUN booster doses led to increases in antibody responses within 7 days. VB are rare and remain poorly understood. VB did not increase, and vaccine effectiveness did not significantly decrease with time since completion of the primary vaccination series or with the time since administration of the last vaccine dose. For all these reasons, data identified from this systematic review suggest that seropersistence alone does not explain the high effectiveness of FSME-IMMUN irrespective of the time since the last vaccine dose was administered. Induction of immunological memory characterized by a rapid and sustained secondary immune response is proving to be an alternative mechanism of action for protection against TBE. In this context Switzerland and Finland have adopted a longer booster interval (i.e., 10 years) following the three-dose primary immunization schedule without any evidence of harm at a population level. Longer booster intervals will likely drive up vaccine uptake. There is a lack of data to base an interval recommendation beyond 10 years.

High plasticity in marmoset monkey vocal development from infancy to adulthood.

The vocal behavior of human infants undergoes marked changes across their first year while becoming increasingly speech-like. Conversely, vocal development in nonhuman primates has been assumed to be largely predetermined and completed within the first postnatal months. Contradicting this assumption, we found a dichotomy between the development of call features and vocal sequences in marmoset monkeys, suggestive of a role for experience. While changes in call features were related to physical maturation, sequences of and transitions between calls remained flexible until adulthood. As in humans, marmoset vocal behavior developed in stages correlated with motor and social development stages. These findings are evidence for a prolonged phase of plasticity during marmoset vocal development, a crucial primate evolutionary preadaptation for the emergence of vocal learning and speech.

Emodepside targets SLO-1 channels of Onchocerca ochengi and induces broad anthelmintic effects in a bovine model of onchocerciasis.

Onchocerciasis (river blindness), caused by the filarial worm Onchocerca volvulus, is a neglected tropical disease mostly affecting sub-Saharan Africa and is responsible for >1.3 million years lived with disability. Current control relies almost entirely on ivermectin, which suppresses symptoms caused by the first-stage larvae (microfilariae) but does not kill the long-lived adults. Here, we evaluated emodepside, a semi-synthetic cyclooctadepsipeptide registered for deworming applications in companion animals, for activity against adult filariae (i.e., as a macrofilaricide). We demonstrate the equivalence of emodepside activity on SLO-1 potassium channels in Onchocerca volvulus and Onchocerca ochengi, its sister species from cattle. Evaluation of emodepside in cattle as single or 7-day treatments at two doses (0.15 and 0.75 mg/kg) revealed rapid activity against microfilariae, prolonged suppression of female worm fecundity, and macrofilaricidal effects by 18 months post treatment. The drug was well tolerated, causing only transiently increased blood glucose. Female adult worms were mostly paralyzed; however, some retained metabolic activity even in the multiple high-dose group. These data support ongoing clinical development of emodepside to treat river blindness.