Search

Modeling the rate at which adaptive phenotypes appear in a population is a key to predicting evolutionary processes. Given random mutations, should this rate be modeled by a simple Poisson process, or is a more complex dynamics needed? Here we use analytic calculations and simulations of evolving populations on explicit genotype-phenotype maps to show that the introduction of novel phenotypes can be "bursty" or overdispersed. In other words, a novel phenotype either appears multiple times in quick succession or not at all for many generations. These bursts are fundamentally caused by statistical fluctuations and other structure in the map from genotypes to phenotypes. Their strength depends on population parameters, being highest for "monomorphic" populations with low mutation rates. They can also be enhanced by additional inhomogeneities in the mapping from genotypes to phenotypes. We mainly investigate the effect of bursts using the well-studied genotype-phenotype map for RNA secondary structure, but find similar behavior in a lattice protein model and in Richard Dawkins's biomorphs model of morphological development. Bursts can profoundly affect adaptive dynamics. Most notably, they imply that fitness differences play a smaller role in determining which phenotype fixes than would be the case for a Poisson process without bursts., Competing Interests: Conflict of interest statement None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Ixodid ticks are obligate blood-feeding arthropods and important vectors of pathogens. In Mallorca, almost no data on the tick fauna are available. Herein, we investigated ticks and tick-borne pathogens in ticks collected from dogs, a cat and humans in Mallorca as result of a citizen science project. A total of 91 ticks were received from German tourists and residents in Mallorca. Ticks were collected from March to October 2023 from dogs, cat and humans, morphologically and genetically identified and tested for pathogens by PCRs. Six tick species could be identified: Ixodes ricinus ( n = 2), Ixodes ventalloi ( n = 1), Hyalomma lusitanicum ( n = 7), Hyalomma marginatum ( n = 1), Rhipicephalus sanguineus s.l. ( n = 71) and Rhipicephalus pusillus ( n = 9). Rhipicephalus sanguineus s.l. adults were collected from dogs and four females from a cat and the 16S rDNA sequences identified it as Rh. sanguineus s.s. Hyalomma lusitanicum was collected from 1 human, 1 dog and 5 specimens were collected from the ground in the community of Santanyi, together with one H. marginatum male. This is the first report of Hyalomma marginatum in Mallorca. Both I. ricinus were collected from humans and I. ventalloi female was collected from a dog. All ticks tested negative for Anaplasma phagocytophilum , Coxiella spp., Francisella spp., and piroplasms. In 32/71 (45%) specimens of Rh. sanguineus s.s., Rickettsia spp. could be detected and in 18/32 (56.2%) sequenced tick DNAs R. massiliae was identified. Ixodes ventalloi female and both I. ricinus tested positive in the screening PCR, but the sequencing for the identification of the Rickettsia sp. failed.

Globally, food production for an ever-growing population is a well-known threat to the environment due to losses of excess reactive nitrogen (N) from agriculture. Since the 1980s, many countries of the Global North, such as Denmark, have successfully combatted N pollution in the aquatic environment by regulation and introduction of national agricultural one-size-fits-all mitigation measures. Despite this success, further reduction of the N load is required to meet the EU water directives demands, and implementation of additional targeted N regulation of agriculture has scientifically and politically been found to be a way forward. In this paper, we present a comprehensive concept to make future targeted N regulation successful environmentally and economically. The concept focus is on how and where to establish detailed maps of the groundwater denitrification potential (N retention) in areas, such as Denmark, covered by Quaternary deposits. Quaternary deposits are abundant in many parts of the world, and often feature very complex geological and geochemical architectures. We show that this subsurface complexity results in large local differences in groundwater N retention. Prioritization of the most complex areas for implementation of the new concept can be a cost-efficient way to achieve lower N impact on the aquatic environment., (© 2024. The Author(s).)

Background and Purpose: A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a comprehensive understanding of the proarrhythmic potential of drug candidates. While current computational methodologies focus on predicting the incidence of proarrhythmic events after drug administration, the objective of this study is to predict concentration-response relationships of QTc as a clinical endpoint., Experimental Approach: Full heart computational models reproducing human cardiac populations were created to predict the concentration-response relationship of changes in the QT interval as recommended for clinical trials. The concentration-response relationship of the QT-interval prolongation obtained from the computational cardiac population was compared against the relationship from clinical trial data for a set of well-characterized compounds: moxifloxacin, dofetilide, verapamil, and ondansetron., Key Results: Computationally derived concentration-response relationships of QT interval changes for three of the four drugs had slopes within the confidence interval of clinical trials (dofetilide, moxifloxacin and verapamil) when compared to placebo-corrected concentration-ΔQT and concentration-ΔQT regressions. Moxifloxacin showed a higher intercept, outside the confidence interval of the clinical data, demonstrating that in this example, the standard linear regression does not appropriately capture the concentration-response results at very low concentrations. The concentrations corresponding to a mean QTc prolongation of 10 ms were consistently lower in the computational model than in clinical data. The critical concentration varied within an approximate ratio of 0.5 (moxifloxacin and ondansetron) and 1 times (dofetilide, verapamil) the critical concentration observed in human clinical trials. Notably, no other in silico methodology can approximate the human critical concentration values for a QT interval prolongation of 10 ms., Conclusion and Implications: Computational concentration-response modelling of a virtual population of high-resolution, 3-dimensional cardiac models can provide comparable information to clinical data and could be used to complement pre-clinical and clinical safety packages. It provides access to an unlimited exposure range to support trial design and can improve the understanding of pre-clinical-clinical translation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elem Biotech owns the commercial rights to Alya, the computational finite element solver employed in this study. However, any other commercial or academic finite element solver could be employed to reproduce this work. Elem Biotech owns the commercial rights to Alya, the solver employed in this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We report the finding of five nymphs and three adult ticks attached to German tourists while traveling the American continents. All eight specimens were morphologically identified and confirmed genetically using the 16S rRNA gene and screened for Rickettsia spp. infections. Five tick species were identified: one Amblyomma mixtum nymph from Ecuador, one Amblyomma varium nymph from Colombia, three Amblyomma coelebs nymphs from Costa Rica, one Amblyomma americanum male from the USA, one Dermacentor andersoni female and one D. andersoni male from Canada. Tick-borne microorganisms screening using the pan-Rickettsia-PCR resulted in two positive and six negative ticks. The A. mixtum nymph was positive for Rickettsia amblyommatis, while the D. andersoni female was positive for Rickettsia peacockii., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Celiac disease (CeD) is an autoimmune disorder affecting the small intestine with gluten as disease trigger. Infections including Influenza A, increase the CeD risk. While gluten-specific CD4 + T-cells, recognizing HLA-DQ2/DQ8 presented gluten-peptides, initiate and sustain the celiac immune response, CD8 + α/β intraepithelial T-cells elicit mucosal damage. Here, we subjected TCRs from a cohort of 56 CeD patients and 22 controls to an analysis employing 749 published CeD-related TCRβ-rearrangements derived from gluten-specific CD4 + T-cells and gluten-triggered peripheral blood CD8 + T-cells. We show, that in addition to TCRs from gluten-specific CD4 + T-cells, TCRs of gluten-triggered CD8 + T-cells are significantly enriched in CeD duodenal tissue samples. TCRβ-rearrangements of gluten-triggered CD8 + T-cells were even more expanded in patients than TCRs from gluten-specific CD4 + T-cells (p < 0.0002) and highest in refractory CeD. Sequence alignments with TCR-antigen databases suggest that a subgroup of these most likely indirectly gluten-triggered TCRs recognize microbial, viral, and autoantigens., Competing Interests: Declaration of Competing Interest SH and VS are co-founders of HS Diagnomics. SS and AD are shareholders of HS Diagnomics, and VL holds the position of CS0 at HS Diagnomics. All other authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Secondary lissencephaly evolved in mice due to effects on neurogenesis and the tangential distribution of neurons. Signaling pathways that help maintain lissencephaly are still poorly understood. We show that inactivating Twist1 in the primitive meninges causes cortical folding in mice. Cell proliferation in the meninges is reduced, causing loss of arachnoid fibroblasts that express Raldh2, an enzyme required for retinoic acid synthesis. Regionalized loss of Raldh2 in the dorsolateral meninges is first detected when folding begins. The ventricular zone expands and the forebrain lengthens at this time due to expansion of apical radial glia. As the cortex expands, regionalized differences in the levels of neurogenesis are coupled with changes to the tangential distribution of neurons. Consequentially, cortical growth at and adjacent to the midline accelerates with respect to more dorsolateral regions, resulting in cortical buckling and folding. Maternal retinoic acid supplementation suppresses cortical folding by normalizing forebrain length, neurogenesis and the tangential distribution of neurons. These results suggest that Twist1 and balanced retinoic acid signaling from the meninges are required to maintain normal levels of neurogenesis and lissencephaly in mice., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Human genetic studies have associated Neuronatin gene variants with anorexia nervosa (AN) and obesity. Studies on the expression of the Neuronatin gene product, a proteolipid, are lacking. We investigated the relationship between circulating Neuronatin, body mass index (BMI), body composition (BC), physical activity (PA), and psychometric outcomes in patients with AN, normal weight, and obesity. Plasma Neuronatin was measured by ELISA in (1) 79 subjects of five BMI categories (AN/BMI < 17.5 kg/m 2 ; normal weight/BMI 18.5-25 kg/m 2 ; obesity/BMI 30-40 kg/m 2 ; obesity/BMI 40-50 kg/m 2 ; obesity/BMI > 50 kg/m 2 ) with assessment of BC (bioimpedance analysis; BIA); (2) 49 women with AN (BMI 14.5 ± 1.8 kg/m 2 ) with measurements of BC (BIA) and PA (accelerometry); (3) 79 women with obesity (BMI 48.8 ± 7.8 kg/m 2 ) with measurements of anxiety (GAD-7), stress (PSQ-20), depression (PHQ-9) and eating behavior (EDI-2). Overall, a positive correlation was found between Neuronatin and BMI ( p = 0.006) as well as total fat mass (FM; p = 0.036). In AN, Neuronatin did not correlate with BMI, FM, or PA ( p > 0.05); no correlations were found between Neuronatin and psychometric outcomes in obesity ( p > 0.05). The findings suggest an FM-dependent peripheral Neuronatin expression. The decreased Neuronatin expression in AN provides evidence that Neuronatin is implicated in the pathogenesis of eating disorders.

Questing ticks are usually collected by flagging or dragging. Mostly exophilic tick species are caught, such as Ixodes ricinus, the most common tick in Central Europe. In the present study, ticks collected from underground environments in the Grand Duchy of Luxembourg and in the Central German Uplands (Federal States of Hesse, Bavaria, Thuringia, Baden-Wuerttemberg, Rhineland-Palatinate, Saarland and Northrhine-Westphalia) were investigated. Six tick species were revealed among the 396 analyzed specimens: Ixodes ariadnae, Ixodes canisuga, Ixodes hexagonus, I. ricinus, Ixodes trianguliceps, and Dermacentor marginatus. Adults and immatures of I. hexagonus dominated the findings (57% of all specimens), especially in shelters acting as potential resting places of main hosts. Ixodes canisuga and I. trianguliceps were for the first time recorded in Luxembourg, and one nymph of the bat tick I. ariadnae represents only the second report for Germany. Collecting ticks in subterranean environments turned out to be a useful approach to increase knowledge about the occurrence of relatively rare tick species, including those that spend most of their lifetime on their hosts, but detach in such environmental settings., (© 2023. The Author(s).)

Electronic health records (EHRs) are used in hospitals to store diagnoses, clinician notes, examinations, lab results, and interventions for each patient. Grouping patients into distinct subsets, for example, via clustering, may enable the discovery of unknown disease patterns or comorbidities, which could eventually lead to better treatment through personalized medicine. Patient data derived from EHRs is heterogeneous and temporally irregular. Therefore, traditional machine learning methods like PCA are ill-suited for analysis of EHR-derived patient data. We propose to address these issues with a new methodology based on training a gated recurrent unit (GRU) autoencoder directly on health record data. Our method learns a low-dimensional feature space by training on patient data time series, where the time of each data point is expressed explicitly. We use positional encodings for time, allowing our model to better handle the temporal irregularity of the data. We apply our method to data from the Medical Information Mart for Intensive Care (MIMIC-III). Using our data-derived feature space, we can cluster patients into groups representing major classes of disease patterns. Additionally, we show that our feature space exhibits a rich substructure at multiple scales., (© 2023. The Author(s).)

Ticks are obligate blood-sucking parasites of wild animals and transmit many zoonotic microorganisms that can spread to domesticated animals and then to humans. In Cameroon, little is known about tick diversity among wildlife, especially for animals which are hunted for human consumption. Therefore, this survey was undertaken to investigate tick and Rickettsia species diversity parasitizing the wild animals sold in bush meat markets in Cameroon. In total, 686 ticks were collected and identified to the species level based on morphology, and some were genetically analyzed using the 16S rRNA gene. Eighteen tick species belonging to five genera were identified: Amblyomma spp. ( Amblyomma compressum , Amblyomma flavomaculatum , and Amblyomma variegatum ), Haemaphysalis spp. ( Haemaphysalis camicasi , Haemaphysalis houyi , Haemaphysalis leachi , and Haemaphysalis parmata ), Hyalomma spp. ( Hyalomma nitidum , Hyalomma rufipes , and Hyalomma truncatum ), Ixodes spp. ( Ixodes rasus and Ixodes moreli ), and Rhipicephalus spp. ( Rhipicephalus guilhoni , Rhipicephalus moucheti , Rhipicephalus muhsamae , Rhipicephalus microplus , Rhipicephalus camicasi , and Rhipicephalus linnaei ). In terms of Rickettsia important for public health, two Rickettsia spp., namely Rickettsia aeschlimannii and Rickettsia africae , were detected in Hyalomma spp. and Amblyomma spp., respectively. Distinct tick-pathogen patterns were present for divergent sequences of R. africae associated with exclusively A. variegatum vectors (type strain) versus vectors comprising A. compressum , A. flavomaculatum , and A. variegatum. This suggests possible effects of vector species population dynamics on pathogen population circulation dynamics. Furthermore, Candidatus Rickettsia africaustralis was detected for the first time in Cameroon in I. rasus . This study highlights the high diversity of ticks among wildlife sold in bush meat markets in Cameroon.

Epidemiology and distributions of canine tick-borne diseases as well as their veterinary and zoonotic significance are poorly understood in Algeria. The present study describes a molecular investigation of important tick-borne pathogens in Rhipicephalus sanguineus sensu stricto collected from domestic dogs in steppe and high plateau areas of central and eastern Algeria. In total, 1,043 ticks were collected from 147 dogs, including 756 ticks from 124 dogs in the steppe region of Djelfa and 287 ticks from 23 dogs in the high plateau area of Bordj Bou Arreridj. Ticks were divided into 384 pools (309 pools from Djelfa and 75 pools from Bordj Bou Arreridj) and tested for genomic materials of Crimean-Congo hemorrhagic fever virus (CCHFV) as well as DNA for Anaplasma phagocytophilum, Anaplasma platys, Ehrlichia canis, Rickettsia spp., Babesia spp., and Hepatozoon spp. using PCR, sequencing and phylogenetic analysis. Hepatozoon spp. was most prevalent, with 160 positive pools (41.7%), and 12 of these were sequenced and identified as Hepatozoon canis. Babesia spp. was detected in 50 samples (13.0%), of which 11 were sequenced and identified as Babesia vogeli. A. platys and E. canis were detected in 92 (24.0%) and 15 (3.9%) of tested samples, respectively. Rickettsia spp. were detected in 24 (6.3%) samples, including 11 samples identified as R. massiliae, 6 samples identified as R. conorii conorii, and 7 samples could not be identified to species level. All 384 pools tested negative for CCHFV and A. phagocytophilum. In addition to detection of R. conorii conorii, R. massiliae, and E. canis, the present study provides the first molecular data for occurrence of A. platys, B. vogeli, and H. canis in Rh. sanguineus s.s. infesting dogs in Algeria. Further large scale studies should be conducted to better understand the epidemiology, distributions, and importance of canine tick-borne pathogens in Algeria., (Copyright © 2022. Published by Elsevier B.V.)

Spexin (SPX) is a novel, widely expressed peptide, with anorexigenic effects demonstrated in animal models and negatively correlated with body mass index (BMI) in humans. It increases locomotor activity in rodents and is elevated in human plasma following exercise. Studies have also shown an effect of stress and anxiety on SPX’s expression in different brain structures in animals. The relationships between plasma SPX and physical activity, body composition, and patient-reported outcomes such as perceived stress, depressiveness, anxiety, and eating behaviors are unknown and were examined in this study over a wide BMI range. A total of 219 female (n = 68 with anorexia nervosa; n = 79 with obesity; n = 72 with normal weight) inpatients were enrolled. Perceived stress (PSQ 20), anxiety (GAD 7), depressiveness (PHQ 9), and eating disorder pathology (EDI 2), as well as BMI, bioimpedance analysis, and accelerometry, were measured cross-sectionally at the beginning of treatment and correlated with plasma SPX levels (measured by ELISA) obtained at the same time. Plasma SPX levels were negatively associated with BMI (r = −0.149, p = 0.027) and body fat mass (r = −0.149, p = 0.04), but did not correlate with perceived stress, anxiety, depressiveness, eating behavior, energy expenditure, and physical activity (p > 0.05). The results replicate the negative correlation of SPX with BMI and fat mass, but do not support the hypothesis that peripheral SPX plays a role in the regulation of stress, depressiveness, anxiety, eating behavior, or physical activity.

Tick-borne diseases are recognized as a growing public health concern and cause significant issues in humans and animals by serving as dispersal agents of ticks and their associated pathogens. Birds contribute to the spread of ticks and tick-borne diseases, with migratory birds playing a role in regional dispersal. Only a few studies have been carried out in Germany so far to investigate tick fauna on birds and the pathogens they harbour. In 2017 and 2018, we collected ticks from a total of 358 birds in the northern region of the Federal State of Hesse, Germany. Most ticks were Ixodes ricinus larvae and nymphs (95.4%). However, two ornithophilic species were also collected: Ixodes frontalis (larvae, nymphs and females) and Ixodes arboricola (larvae and nymphs). Ticks were tested individually or in pools, depending on the tick life stage and species for each bird host, in order to detect tick-borne encephalitis (TBE) virus and Rickettsia spp. All samples tested negative for TBE virus. Of 684 investigated tick pools, 162 tested positive for Rickettsia spp. by screening PCR. Of these, 117 carried Rickettsia helvetica detected by specific real-time PCR. The samples which were negative in the R. helvetica PCR were further investigated using five targets (gltA, 16S, ompA IV, ompB, 23S-5S intergenic spacer region) using multi locus sequence typing and phylogenetic analysis. The obtained sequences showed strong phylogenetic relationship to Candidatus Rickettsia vini, which is most closely related to R. japonica and R. heilongjiangensis, and occur in I. arboricola. Three more sequences were determined as R. helvetica in I. ricinus and I. frontalis. This is the first detection of Ca. R. vini in Germany and the first 23S-5S data published for Ca. R. vini, a useful target for Rickettsia species identification., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background & Aims: Decompensation is a hallmark of disease progression in cirrhotic patients. Early detection of a phase transition from compensated cirrhosis to decompensation would enable targeted therapeutic interventions potentially extending life expectancy. This study aims to (a) identify the predictors of decompensation in a large, multicentric cohort of patients with compensated cirrhosis, (b) to build a reliable prognostic score for decompensation and (c) to evaluate the score in independent cohorts., Methods: Decompensation was identified in electronic health records data from 6049 cirrhosis patients in the IBM Explorys database training cohort by diagnostic codes for variceal bleeding, encephalopathy, ascites, hepato-renal syndrome and/or jaundice. We identified predictors of clinical decompensation and developed a prognostic score using Cox regression analysis. The score was evaluated using the IBM Explorys database validation cohort (N = 17662), the Penn Medicine BioBank (N = 1326) and the UK Biobank (N = 317)., Results: The new Early Prediction of Decompensation (EPOD) score uses platelet count, albumin, and bilirubin concentration. It predicts decompensation during a 3-year follow-up in three validation cohorts with AUROCs of 0.69, 0.69 and 0.77, respectively, and outperforms the well-known MELD and Child-Pugh score in predicting decompensation. Furthermore, the EPOD score predicted the 3-year probability of decompensation., Conclusions: The EPOD score provides a prediction tool for the risk of decompensation in patients with cirrhosis that outperforms well-known cirrhosis scores. Since EPOD is based on three blood parameters, only, it provides maximal clinical feasibility at minimal costs., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6i) have significantly improved clinical outcomes in patients with advanced hormone receptor-positive (HR+) breast cancer and have demonstrated favourable antitumour immune responses in preclinical studies., Methods: Here, we investigated peripheral immune responses to ribociclib in patients with metastatic HR+ breast cancer as a preplanned exploratory subanalysis of the RIBECCA trial (NCT03096847). Peripheral blood mononuclear cells were subjected to immune cell profiling, gene expression analysis of immune-related signatures, and deep T cell receptor profiling before treatment started and after 12 weeks of treatment with ribociclib., Results: Gene expression analysis revealed an upregulation of signatures associated with an activated adaptive immune system and a decrease in immunosuppressive cytokine signalling during treatment with ribociclib. Profiling of peripheral immune cell subpopulations showed a decrease in Treg cell frequencies, which was associated with treatment response. Furthermore, induction of CD4+ naive T cells could be seen, whereas effector and memory T cell populations remained largely unchanged. Correspondingly, T cell repertoire diversity remained mostly unchanged during treatment, although an increase in clonality could be observed in single patients., Conclusions: We show that treatment with ribociclib has significant effects on the peripheral innate and adaptive immune response in patients with HR+ breast cancer. Our data suggest that these effects lead to an activation of an already existing immune response rather than a de novo induction and make a strong case for future combination strategies of CDK4/6i with immunotherapies to enhance the adaptive immune response in HR+ breast cancer., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SB, TD, PF, TF, WJ, SK, AS, MS and DL are members of the RIBECCA trial consortium and received speaker and advisory board honoraria from Novartis for work related to the RIBECCA study. CAP received speaker honoraria from Novartis for work unrelated to this manuscript. UK received speaker and advisory board honoraria from Novartis for work unrelated to this manuscript. The other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The impact of tick bites during holidays in tropical countries is seldom reported. Here, we describe long-term skin alterations and itching experienced by a German tourist following the bite of a nymph of Dermacentor auratus Supino, 1897 in Cambodia. Tick infestation may be neglected by travelers. Therefore, careful travel history is necessary when travelers report a tick bite after spending holiday in tropical and subtropical countries., (© The Author(s) 2021. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

For patients with dementia, dental care can pose a considerable challenge due to cognitive impairment, behavioral, and psychological symptoms, and (often subsequently) limited autonomous oral care. In this study, we aimed to assess the proficiency of dentists in general practice in the outpatient dental care of these patients. A total of 119 dentists from private practices in Lower Saxony, Germany, participated in this study. Concerning treatment of patients with dementia, they provided details about (1) practice equipment/consultation, (2) training/expertise, and (3) special circumstances of dental treatment. Participating dentists predominantly reported to use medical aids (e.g., positioning cushions) to improve the treatment situation for patients with dementia. Over two thirds (68.6%) offered consultations in nursing homes, and at the patients' homes (47.0%). The training rate was remarkably low in the field of gerodontology for dentists and their practice staff (<10%), however, 54.5% expressed interest in such training. The majority of dentists reportedly adapted their treatment strategy to the needs of patients with dementia (e.g., communication, inclusion of caregivers, time management). Furthermore, most participants adapted dental treatment adequately (e.g., strict indication for tooth extraction, simple design of dental prostheses). In summary, even though training in the field of gerodontology must be considered insufficient, most dentists in this study showed an adequate adaptation of their treatment strategy as well as consideration of dental characteristics in patients with dementia, along with interest in trainings. We conclude that dementia-specific training should be expanded in the field of dentistry, preferably already at university level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schaper, Meyer-Rötz, Bartels, Wiltfang, Rödig, Schott and Belz.)

Seasonal migration of birds between breeding and wintering areas can facilitate the spread of tick species and tick-borne diseases. In this study, 151 birds representing 10 different bird species were captured on Ponza Island, an important migratory stopover off the western coast of Italy and screened for tick infestation. Ticks were collected and identified morphologically. Morphological identification was supported through sequencing a fragment of the 16S mitochondrial gene. In total, 16 captured birds carried ticks from four tick species: Hyalomma rufipes (n = 14), Amblyomma variegatum (n = 1), Amblyomma sp. (n = 1), and Ixodes ventalloi (n = 2). All specimens were either larvae (n = 2) or nymphs (n = 16). All ticks were investigated for tick-borne pathogens using published molecular methods. Rickettsia aeschlimannii was detected in six of the 14 collected H. rufipes ticks. Additionally, the singular A. variegatum nymph tested positive for R. africae. In all 14 H. rufipes specimens (2 larvae and 12 nymphs), Francisella-like endosymbionts were detected. Four H. rufipes ticks tested positive for Borrelia burgdorferi sensu lato in a screening PCR but did not produce sufficient amplicon amounts for species identification. All ticks tested negative for tick-borne encephalitis virus, Crimean-Congo hemorrhagic fever virus, Coxiella burnetii, Coxiella-like organisms, Babesia spp., and Theileria spp. This study confirms the role of migratory birds in the spread and establishment of both exotic tick species and tick-borne pathogens outside their endemic range., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Ticks and tick-borne diseases (TBDs) have a major economic impact on animal production worldwide. In the present study, 2410 ticks were collected from January to August 2017 from livestock and other domestic animals in North Kordofan and Kassala, Sudan, for species identification and investigation of Rickettsia spp. and piroplasms, either individually or as pools containing up to 10 ticks by molecular methods. In total, 13 tick species were identified by morphology and 16S rDNA sequencing. The most frequent tick species were Hyalomma impeltatum (24.90%), Rhipicephalus evertsi evertsi (18.84%), Amblyomma lepidum (16.06%), and Rhipicephalus camicasi (12.49%). A pan- Rickettsia real-time PCR revealed an overall minimum infection rate (MIR) with Rickettsia spp. of 5.64% (136 positive tick pools/2410 total ticks). Rickettsia africae and Rickettsia aeschlimannii were the most frequently identified species by sequencing. Furthermore, the following highly pathogenic livestock parasites were detected: Theileria annulata , Theileria lestoquardi , Theileria equi , and Babesia caballi . The present study documented Rhipicephalus afranicus as well as Rickettsia conorii israelensis , Rickettsia massiliae , and Babesia pecorum for the first time in Sudan. These findings are significant for the animal production sector as well as in terms of One Health, as the detected Rickettsia spp. can cause serious illness in humans.

The importation of exotic ticks to Germany on infested humans is rarely reported. Here we describe the detection of an Amblyomma mixtum nymph harboring Rickettsia amblyommatis by a tourist returning from a holiday trip to Cuba. Tick infestation may be neglected by tourists. Therefore, careful anamnesis and diagnosis should be carried out when tourists return from tropical and subtropical countries suffering from nonspecific symptoms, such as fever and malaise., (© The Author(s) 2019. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ticks are important parasites from economic and public health points of view because of their ability to reduce farm animals' productivity and transmit zoonotic diseases. We conducted this cross-sectional study between January and March 2016 and between March and April 2017 to identify tick species in West Darfur, Al-Jazeera, and the River Nile states in the Sudan and to investigate whether these ticks carry Rickettsia spp. and Crimean-Congo hemorrhagic fever (CCHF) virus. In total, 1593 ticks were collected from 207 animals and identified based on morphology or 16S rRNA gene and tested for Rickettsia spp. and CCHF virus either individually or as pools containing 2 to 10 pooled ticks using molecular methods. Overall, 14 tick species belonging to three genera, namely Amblyomma, Hyalomma, and Rhipicephalus, were identified. Hyalomma anatolicum and Rhipicephalus evertsi evertsi were the most frequent ticks. A total of 561 tests comprised of individual or pooled ticks were conducted and 13.7% (77/561) were positive for Rickettsia spp. which were mostly Rickettsia aeschlimannii and R. africae. The highest positivity was noticed among H. rufipes collected from cattle and camels in West Darfur. However, none of the screened Hyalomma ticks harbored CCHF viral RNA. These findings suggest that there might be a risk of zoonotic transmission of Rickettsia spp. by ticks but zoonotic transmission of CCHF virus is apparently doubtful. An in-depth and a country-wide epidemiological study is needed to better understand the dynamic of Rickettsia spp. and CCHF virus in the Sudan.

An evidence for Crimean-Congo hemorrhagic fever virus (CCHFV) was found in Hyalomma impeltatum ticks collected from sheep in North Kordofan in the Sudan. Based on sequencing of the partial segment S, the detected virus belongs to lineage I with closest similarity to CCHFV strains from Senegal. So far, this lineage is unknown in the Sudan., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oral administration of drug products is a strict requirement in many medical indications. Therefore, bioavailability prediction models are of high importance for prioritization of compound candidates in the drug discovery process. However, oral exposure and bioavailability are difficult to predict, as they are the result of various highly complex factors and/or processes influenced by the physicochemical properties of a compound, such as solubility, lipophilicity, or charge state, as well as by interactions with the organism, for instance, metabolism or membrane permeation. In this study, we assess whether it is possible to predict intravenous (iv) or oral drug exposure and oral bioavailability in rats. As input parameters, we use (i) six experimentally determined in vitro and physicochemical endpoints, namely, membrane permeation, free fraction, metabolic stability, solubility, p K a value, and lipophilicity; (ii) the outputs of six in silico absorption, distribution, metabolism, and excretion models trained on the same endpoints, or (iii) the chemical structure encoded as fingerprints or simplified molecular input line entry system strings. The underlying data set for the models is an unprecedented collection of almost 1900 data points with high-quality in vivo experiments performed in rats. We find that drug exposure after iv administration can be predicted similarly well using hybrid models with in vitro- or in silico-predicted endpoints as inputs, with fold change errors (FCE) of 2.28 and 2.08, respectively. The FCEs for exposure after oral administration are higher, and here, the prediction from in vitro inputs performs significantly better in comparison to in silico-based models with FCEs of 3.49 and 2.40, respectively, most probably reflecting the higher complexity of oral bioavailability. Simplifying the prediction task to a binary alert for low oral bioavailability, based only on chemical structure, we achieve accuracy and precision close to 70%.

Background: Hyalomma marginatum and Hyalomma rufipes are two-host tick species, which are mainly distributed in southern Europe, Africa and middle-eastern Asia. They are well-known vectors of Crimean Congo hemorrhagic fever (CCHF) virus and other viruses as well as Rickettsia aeschlimannii. In recent years, these tick species have been found sporadically in Germany, but they do not belong to the autochthonous tick fauna in Germany., Methods: Ticks with unusual morphology were collected and sent from private persons or public health offices to involve institutions for morphological identification and further testing. All ticks identified as Hyalomma spp. were tested using molecular detection methods for CCHF virus, Rickettsia spp., Coxiella burnetii and Coxiella-like organisms, Babesia spp. and Theileria spp., Results: Thirty-five ticks with an unusual appearance or behaviour were reported to us during summer-autumn 2018. For 17 of them, the description or photos implied that they belong to the hard tick genus Hyalomma. The remaining 18 ticks were sent to us and were identified as adult Hyalomma marginatum (10 specimens) or adult Hyalomma rufipes (8 specimens). All ticks tested negative for CCHF virus, Coxiella burnetii, Coxiella-like organisms, Babesia spp. and Theileria spp. The screening for rickettsiae gave positive results in 9 specimens . The Rickettsia species in all cases was identified as R. aeschlimannii., Conclusions: These results show that exotic tick species imported into Germany were able to develop from the nymphal to the adult stage under appropriate weather conditions. Fifty percent of the ticks carried R. aeschlimannii, a human pathogen, while CCHF virus or other pathogens were not detected. Imported Hyalomma ticks may be the source of exotic diseases acquired in Germany.

Motivation: Mathematical models have become standard tools for the investigation of cellular processes and the unraveling of signal processing mechanisms. The parameters of these models are usually derived from the available data using optimization and sampling methods. However, the efficiency of these methods is limited by the properties of the mathematical model, e.g. non-identifiabilities, and the resulting posterior distribution. In particular, multi-modal distributions with long valleys or pronounced tails are difficult to optimize and sample. Thus, the developement or improvement of optimization and sampling methods is subject to ongoing research., Results: We suggest a region-based adaptive parallel tempering algorithm which adapts to the problem-specific posterior distributions, i.e. modes and valleys. The algorithm combines several established algorithms to overcome their individual shortcomings and to improve sampling efficiency. We assessed its properties for established benchmark problems and two ordinary differential equation models of biochemical reaction networks. The proposed algorithm outperformed state-of-the-art methods in terms of calculation efficiency and mixing. Since the algorithm does not rely on a specific problem structure, but adapts to the posterior distribution, it is suitable for a variety of model classes., Availability and Implementation: The code is available both as Supplementary Material and in a Git repository written in MATLAB., Supplementary Information: Supplementary data are available at Bioinformatics online.

Ticks are important vectors for Rickettsia spp. of the spotted fever group all around the world. Rickettsia conorii is the etiological agent of boutonneuse fever in the Mediterranean region and Africa. Tick identification was based on morphological features and further characterized using the 16S rRNA gene. The ticks were individually tested using pan-Rickettsia real-time-PCR for screening, and 23S-5S intergenic spacer region, 16S rDNA, gltA, sca4, ompB, and ompA genes were used to analyze the Rickettsia positive samples. Rickettsia conorii ssp. caspia was detected in tick collected in Zambia for the first time, thus demonstrating the possibility of the occurrence of human disease, namely Astrakhan fever, due to this Rickettsia ssp. in this region of Africa. The prevalence of R. conorii ssp. caspia was 0.06% (one positive tick out of 1465 tested ticks) and 0.07% (one positive tick out of 1254 tested Rh. sanguineus).

Mutational neighbourhoods in genotype-phenotype (GP) maps are widely believed to be more likely to share characteristics than expected from random chance. Such genetic correlations should strongly influence evolutionary dynamics. We explore and quantify these intuitions by comparing three GP maps-a model for RNA secondary structure, the HP model for protein tertiary structure, and the Polyomino model for protein quaternary structure-to a simple random null model that maintains the number of genotypes mapping to each phenotype, but assigns genotypes randomly. The mutational neighbourhood of a genotype in these GP maps is much more likely to contain genotypes mapping to the same phenotype than in the random null model. Such neutral correlations can be quantified by the robustness to mutations, which can be many orders of magnitude larger than that of the null model, and crucially, above the critical threshold for the formation of large neutral networks of mutationally connected genotypes which enhance the capacity for the exploration of phenotypic novelty. Thus neutral correlations increase evolvability. We also study non-neutral correlations: Compared to the null model, i) If a particular (non-neutral) phenotype is found once in the 1-mutation neighbourhood of a genotype, then the chance of finding that phenotype multiple times in this neighbourhood is larger than expected; ii) If two genotypes are connected by a single neutral mutation, then their respective non-neutral 1-mutation neighbourhoods are more likely to be similar; iii) If a genotype maps to a folding or self-assembling phenotype, then its non-neutral neighbours are less likely to be a potentially deleterious non-folding or non-assembling phenotype. Non-neutral correlations of type i) and ii) reduce the rate at which new phenotypes can be found by neutral exploration, and so may diminish evolvability, while non-neutral correlations of type iii) may instead facilitate evolutionary exploration and so increase evolvability.

The prevalence of neutral mutations implies that biological systems typically have many more genotypes than phenotypes. But, can the way that genotypes are distributed over phenotypes determine evolutionary outcomes? Answering such questions is difficult, in part because the number of genotypes can be hyper-astronomically large. By solving the genotype-phenotype (GP) map for RNA secondary structure (SS) for systems up to length L = 126 nucleotides (where the set of all possible RNA strands would weigh more than the mass of the visible universe), we show that the GP map strongly constrains the evolution of non-coding RNA (ncRNA). Simple random sampling over genotypes predicts the distribution of properties such as the mutational robustness or the number of stems per SS found in naturally occurring ncRNA with surprising accuracy. Because we ignore natural selection, this strikingly close correspondence with the mapping suggests that structures allowing for functionality are easily discovered, despite the enormous size of the genetic spaces. The mapping is extremely biased: the majority of genotypes map to an exponentially small portion of the morphospace of all biophysically possible structures. Such strong constraints provide a non-adaptive explanation for the convergent evolution of structures such as the hammerhead ribozyme. These results present a particularly clear example of bias in the arrival of variation strongly shaping evolutionary outcomes and may be relevant to Mayr's distinction between proximate and ultimate causes in evolutionary biology.

Two-step PCR procedures are an efficient and well established way to generate amplicon libraries for NGS sequencing. However, there is a high risk of cross-contamination by carry-over of amplicons from first to second amplification rounds, potentially leading to severe misinterpretation of results. Here we describe a new method able to prevent and/or to identify carry-over contaminations by introducing the K-box, a series of three synergistically acting short sequence elements. Our K-boxes are composed of (i) K1 sequences for suppression of contaminations, (ii) K2 sequences for detection of possible residual contaminations and (iii) S sequences acting as separators to avoid amplification bias. In order to demonstrate the effectiveness of our method we analyzed two-step PCR NGS libraries derived from a multiplex PCR system for detection of T-cell receptor beta gene rearrangements. We used this system since it is of high clinical relevance and may be affected by very low amounts of contaminations. Spike-in contaminations are effectively blocked by the K-box even at high rates as demonstrated by ultra-deep sequencing of the amplicons. Thus, we recommend implementation of the K-box in two-step PCR-based NGS systems for research and diagnostic applications demanding high sensitivity and accuracy., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)