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Mammalian innate-like T cells (ILTCs), including natural killer T (NKT), mucosal-associated invariant T (MAIT), and γδ T cells are tissue-resident unconventional T cells that share properties of innate and adaptive immunity. ILTC subsets can secrete cytotoxic effector molecules and cytokines to clear out abnormal hepatocytes, initiate effector cell recruitment and inflammation, and contribute to regulating homeostasis and tissue regeneration in liver diseases. ILTCs can contribute to both protective and pathogenic functions depending on the liver disease stage and tissue context. ILTCs can contribute to liver inflammation and injury in different pathological conditions including viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), cirrhosis, and others. Targeting ILTCs or modulating their functions may represent potential therapeutic strategies to help to treat liver diseases by aiming to restore immune balance and mitigating liver inflammation. As abundant tissue-resident lymphocytes, ILTCs play important roles in ensuring liver tissue integrity during homeostasis, infection, and non-infectious chronic perturbations. Pathological conditions, including viral infections, metabolic dysfunction, alcohol consumption, and others, can significantly influence the phenotype and function of ILTCs, further underscoring their dynamic role in liver immune responses across different disease contexts. Understanding the intricate interplay between ILTCs, other cells, and niches in liver diseases is essential for developing targeted therapeutic interventions to restore immune balance and mitigate pathology. Mammalian innate-like T cells (ILTCs), including mucosal-associated invariant T (MAIT), natural killer T (NKT), and γδ T cells, are abundant tissue-resident lymphocytes that have recently emerged as orchestrators of hepatic inflammation, tissue repair, and immune homeostasis. This review explores the involvement of different ILTC subsets in liver diseases. We explore the mechanisms underlying the pro- and anti-inflammatory effector functions of ILTCs in a context-dependent manner. We highlight latest findings regarding the dynamic interplay between ILTC functional subsets and other immune and parenchymal cells which may inform candidate immunomodulatory strategies to achieve improved clinical outcomes in liver diseases. We present new insights into how distinct gene expression programs in hepatic ILTCs are induced, maintained, and reprogrammed in a context- and disease stage-dependent manner. [ABSTRACT FROM AUTHOR]

Immunization through repeated direct venous inoculation of Plasmodium falciparum (Pf) sporozoites (PfSPZ) under chloroquine chemoprophylaxis, using the PfSPZ Chemoprophylaxis Vaccine (PfSPZ-CVac), induces high-level protection against controlled human malaria infection (CHMI). Humoral and cellular immunity contribute to vaccine efficacy but only limited information about the implicated Pf-specific antigens is available. Here, we examined Pf-specific antibody profiles, measured by protein arrays representing the full Pf proteome, of 40 placebo- and PfSPZ-immunized malaria-naïve volunteers from an earlier published PfSPZ-CVac dose-escalation trial. For this purpose, we both utilized and adapted supervised machine learning methods to identify predictive antibody profiles at two different time points: after immunization and before CHMI. We developed an adapted multitask support vector machine (SVM) approach and compared it to standard methods, i.e. single-task SVM, regularized logistic regression and random forests. Our results show, that the multitask SVM approach improved the classification performance to discriminate the protection status based on the underlying antibody-profiles while combining time- and dose-dependent data in the prediction model. Additionally, we developed the new fEature diStance exPlainabilitY (ESPY) method to quantify the impact of single antigens on the non-linear multitask SVM model and make it more interpretable. In conclusion, our multitask SVM model outperforms the studied standard approaches in regard of classification performance. Moreover, with our new explanation method ESPY, we were able to interpret the impact of Pf-specific antigen antibody responses that predict sterile protective immunity against CHMI after immunization. The identified Pf-specific antigens may contribute to a better understanding of immunity against human malaria and may foster vaccine development. Author summary: Developing an effective malaria vaccine is challenging. Malaria is a life-threatening disease caused by the plasmodium parasite, which has a complex multi-stage life-cycle and expresses several thousand proteins in a highly coordinated manner. To date, our understanding of the immune mechanisms mediating protection against Plasmodium falciparum (Pf) is incomplete. Proteome microarrays have been used earlier by our clinical collaboration partners to identify Pf-specific antibody profiles of malaria-naïve volunteers during immunization with attenuated Pf sporozoites (PfSPZ). We reused this data to compare the ability of three supervised machine learning methods to identify predictive antibody profiles after immunization and before controlled human malaria infection (CHMI). We adapted a multitask support vector machine (SVM) approach to analyze time-dependent Pf-induced antibody profiles from several time points in a single prediction model. Our multitask SVM approach outperforms the studied standard approaches in classification performance. Additionally, we developed a new explanation method, named fEature diStance exPlainabilitY (ESPY), to interpret the impact of Pf-specific antigens. We applied ESPY on the multitask SVM model and identified diverse Pf-specific antigen sets after immunization and before CHMI. Furthermore, we showed that the identified Pf-induced antibody profiles vary among protected and non-protected individuals who had been exposed to different doses of PfSPZ. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Are there subgroups among patients with cryptozoospermia pointing to distinct etiologies? SUMMARY ANSWER We reveal two distinct subgroups of cryptozoospermic (Crypto) patients based on testicular tissue composition, testicular volume, and FSH levels. WHAT IS KNOWN ALREADY Cryptozoospermic patients present with a sperm concentration below 0.1 million/ml. While the etiology of the severely impaired spermatogenesis remains largely unknown, alterations of the spermatogonial compartment have been reported including a reduction of the reserve stem cells in these patients. STUDY DESIGN, SIZE, DURATION To assess whether there are distinct subgroups among cryptozoospermic patients, we applied the statistical method of cluster analysis. For this, we retrospectively selected 132 cryptozoospermic patients from a clinical database who underwent a testicular biopsy in the frame of fertility treatment at a university hospital. As controls (Control), we selected 160 patients with obstructive azoospermia and full spermatogenesis. All 292 patients underwent routine evaluation for endocrine, semen, and histological parameters (i.e. the percentage of tubules with elongated spermatids). Moreover, outcome of medically assisted reproduction (MAR) was assessed for cryptozoospermic (n = 73) and Control patients (n = 87), respectively. For in-depth immunohistochemical and histomorphometrical analyses, representative tissue samples from cryptozoospermic (n = 27) and Control patients (n = 12) were selected based on cluster analysis results and histological parameters. PARTICIPANTS/MATERIALS, SETTING, METHODS This study included two parts: firstly using clinical parameters of the entire cohort of 292 patients, we performed principal component analysis (PCA) followed by hierarchical clustering on principal components (i.e. considering hormonal values, ejaculate parameters, and histological information). Secondly, for histological analyses seminiferous tubules were categorized according to the most advanced germ cell type present in sections stained with Periodic acid Schif. On the selected cohort of 39 patients (12 Control, 27 cryptozoospermic), we performed immunohistochemistry for spermatogonial markers melanoma-associated antigen 4 (MAGEA4) and piwi like RNA-mediated gene silencing 4 (PIWIL4) followed by quantitative analyses. Moreover, the morphologically defined Adark spermatogonia, which are considered to be the reserve stem cells, were quantified. MAIN RESULTS AND THE ROLE OF CHANCE The PCA and hierarchical clustering revealed three different clusters, one of them containing all Control samples. The main factors driving the sorting of patients to the clusters were the percentage of tubules with elongated spermatids (Cluster 1, all Control patients and two cryptozoospermic patients), the percentage of tubules with spermatocytes (Cluster 2, cryptozoospermic patients), and tubules showing a Sertoli cells only phenotype (Cluster 3, cryptozoospermic patients). Importantly, the percentage of tubules containing elongated spermatids was comparable between Clusters 2 and 3. Additional differences were higher FSH levels (P  < 0.001) and lower testicular volumes (P  < 0.001) in Cluster 3 compared to Cluster 2. In the spermatogonial compartment of both cryptozoospermic Clusters, we found lower numbers of MAGEA4+ and Adark spermatogonia but higher proportions of PIWIL4+ spermatogonia, which were significantly correlated with a lower percentage of tubules containing elongated spermatids. In line with this common alteration, the outcome of MAR was comparable between Controls as well as both cryptozoospermic Clusters. LIMITATIONS, REASONS FOR CAUTION While we have uncovered the existence of subgroups within the cohort of cryptozoospermic patients, comprehensive genetic analyses remain to be performed to unravel potentially distinct etiologies. WIDER IMPLICATIONS OF THE FINDINGS The novel insight that cryptozoospermic patients can be divided into two subgroups will facilitate the strategic search for underlying genetic etiologies. Moreover, the shared alterations of the spermatogonial stem cell compartment between the two cryptozoospermic subgroups could represent a general response mechanism to the reduced output of sperm, which may be associated with a progressive phenotype. This study therefore offers novel approaches towards the understanding of the etiology underlying the reduced sperm formation in cryptozoospermic patients. STUDY FUNDING/COMPETING INTEREST(S) German research foundation CRU 326 (grants to: SDP, NN). Moreover, we thank the Faculty of Medicine of the University of Münster for the financial support of Lena Charlotte Schülke through the MedK-program. We acknowledge support from the Open Access Publication Fund of the University of Münster. The authors have no potential conflicts of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

The specification of a particular type of effect (e.g., linear or non-linear) of a covariate in a regression model can be either based on graphical assessment, subject matter knowledge or also on data-driven model choice procedures. For the latter variant, we present a boosting approach that is available for a huge number of different model classes. Boosting is an indirect regularization technique that leads to variable selection and can easily incorporate also non-linear or smooth effects. Furthermore, the algorithm can be adapted in a way to automatically select whether to model a continuous variable with a smooth or a linear effect. We enhance this model choice procedure by trying to compensate the inherent bias towards the more complex effect by incorporating a pragmatic and simple deselection technique that was originally implemented for enhanced variable selection. We illustrate our approach in the analysis of T3 thyroid hormone levels from a larger Galician cohort and investigate its performance in a simulation study. [ABSTRACT FROM AUTHOR]

Motivation Machine learning methods can be used to support scientific discovery in healthcare-related research fields. However, these methods can only be reliably used if they can be trained on high-quality and curated datasets. Currently, no such dataset for the exploration of Plasmodium falciparum protein antigen candidates exists. The parasite P.falciparum causes the infectious disease malaria. Thus, identifying potential antigens is of utmost importance for the development of antimalarial drugs and vaccines. Since exploring antigen candidates experimentally is an expensive and time-consuming process, applying machine learning methods to support this process has the potential to accelerate the development of drugs and vaccines, which are needed for fighting and controlling malaria. Results We developed PlasmoFAB , a curated benchmark that can be used to train machine learning methods for the exploration of P.falciparum protein antigen candidates. We combined an extensive literature search with domain expertise to create high-quality labels for P.falciparum specific proteins that distinguish between antigen candidates and intracellular proteins. Additionally, we used our benchmark to compare different well-known prediction models and available protein localization prediction services on the task of identifying protein antigen candidates. We show that available general-purpose services are unable to provide sufficient performance on identifying protein antigen candidates and are outperformed by our models that were trained on this tailored data. Availability and implementation PlasmoFAB is publicly available on Zenodo with DOI 10.5281/zenodo.7433087. Furthermore, all scripts that were used in the creation of PlasmoFAB and the training and evaluation of machine learning models are open source and publicly available on GitHub here: https://github.com/msmdev/PlasmoFAB. [ABSTRACT FROM AUTHOR]

We consider a retrospective modelling approach for estimating effective reproduction numbers based on death counts during the first year of the COVID-19 pandemic in Germany. The proposed Bayesian hierarchical model incorporates splines to estimate reproduction numbers flexibly over time while adjusting for varying effective infection fatality rates. The approach also provides estimates of dark figures regarding undetected infections. Results for Germany illustrate that our estimates based on death counts are often similar to classical estimates based on confirmed cases; however, considering death counts allows to disentangle effects of adapted testing policies from transmission dynamics. In particular, during the second wave of infections, classical estimates suggest a flattening infection curve following the "lockdown light" in November 2020, while our results indicate that infections continued to rise until the "second lockdown" in December 2020. This observation is associated with more stringent testing criteria introduced concurrently with the "lockdown light", which is reflected in subsequently increasing dark figures of infections estimated by our model. In light of progressive vaccinations, shifting the focus from modelling confirmed cases to reported deaths with the possibility to incorporate effective infection fatality rates might be of increasing relevance for the future surveillance of the pandemic. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is a deadly disease. Over recent decades, a better understanding of the biological mechanisms implicated in its pathogenesis has led to the development of targeted therapies and immunotherapy, resulting in improvements in patient outcomes. To enhance our understanding of lung cancer tumor biology and advance towards precision oncology, we need a comprehensive tumor profile. In recent years, novel in situ spatial multiomics approaches have emerged, offering a more detailed view of the spatial location of tumor and tumor microenvironment cells. These advancements in in situ profiling may unveil further molecular and immune mechanisms in tumor biology that will lead to the discovery of biomarkers for treatment prediction and prognosis. In this review, we provide an overview of current and emerging pathology-based approaches for spatial immune profiling in lung cancer. Lung cancer is a deadly disease with the highest rates of mortality. Over recent decades, a better understanding of the biological mechanisms implicated in its pathogenesis has led to the development of targeted therapies and immunotherapy, resulting in improvements in patient outcomes. To better understand lung cancer tumor biology and advance towards precision oncology, a comprehensive tumor profile is necessary. In recent years, novel in situ spatial multiomics approaches have emerged offering a more detailed view of the spatial location of tumor and tumor microenvironment cells, identifying their unique composition and functional status. In this sense, novel multiomics platforms have been developed to evaluate tumor heterogeneity, gene expression, metabolic reprogramming, signaling pathway activation, cell–cell interactions, and immune cell programs. In lung cancer research, several studies have used these spatial technologies to locate cells and associated them with histological features that are relevant to the pathogenesis of lung adenocarcinoma. These advancements may unveil further molecular and immune mechanisms in tumor biology that will lead to the discovery of biomarkers for treatment prediction and prognosis. In this review, we provide an overview of more widely used and emerging pathology-based approaches for spatial immune profiling in lung cancer and how they enhance our understanding of tumor biology and immune response. [ABSTRACT FROM AUTHOR]

Little information is available on steroid hormone profiles in transwomen on the day of gender affirming surgery (GAS) after gender affirming hormone therapy (GAHT). We compared extended serum steroid hormone profiles of 77 transwomen with 3 different treatment regimens in order to get more insight on how GAHT changes the hormone system. Samples were obtained from 3 independent clinics. Individuals in clinic A (n = 13) and B (n = 51) discontinued GAHT 4–6 weeks and 2 weeks before GAS, individuals in clinic C (n = 13) continued treatment. Testicular tissue, blood samples and questionnaires on age, weight, height, and medication use were received from each patient. Steroid hormones were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), 6 sex hormones were determined by immunofluorometric assays, and ELISA. Spermatogenesis was scored using the Bergman/Kliesch score. Participants were not different with regard to age, BMI, treatment duration, and dosage. Feminized blood serum levels with low LH, low FSH and low testosterone, however, were achieved in persons taking GAHT until GAS. Significantly reduced cortisone levels were seen after stopping GAHT before GAS. GAHT had marked effects on the sex-steroid profile in each person. Factor analysis provided a model explaining 78% of the variance and interdependency of sex steroid levels. Stopping treatment was inversely associated with intactness of the corticosteroid-axis with adrenal steroidogenesis as well as it was inversely associated with pituitary-gonadal hormone production. Transwomen generally did not have elevated cortisone levels but differed significantly depending on and when GAHT was stopped. This is the first study examining the steroid hormone profiles of transgender persons on the day of GAS in a multi-center setting. Additional studies (including follow ups before and after GAS and stress questionnaires) will be necessary to assess these conflicting results about the possible psychological impact on persons undergoing GAS to improve care. Concerning feminized blood serum levels, continued GAHT seems the better alternative, however stopping treatment 4–6 weeks prior to surgery was associated with reduced cortisone levels. Schneider F, Wistuba J, Holterhus P-M, et al. New Insights Into Extended Steroid Hormone Profiles in Transwomen in a Multi-Center Setting in Germany. J Sex Med 2021;18:1807–1817. [ABSTRACT FROM AUTHOR]

Landslide protection and mitigation are critical issues in many regions worldwide, where lives and livelihoods depend on correctly determining landslide hazards. However, local differences in the response of landslide slopes to meteorological or seismic triggering factors can decrease the performance of landslide models and forecasts. Thus, recognising and understanding spatial patterns of landslide activity at a local scale should be one of the priorities of landslide research. In this study, we analyse the activity and triggering factors of two landslides in one mountain massif, <2 km apart, in the Western Carpathians, Poland. We analysed 61-year-long (1959–2019) records of the activity of study landslides, i.e. dendrochronological reconstruction based on ring eccentricity and compression wood dated in 65 specimens of European silver fir (Abies alba). We compared the dendrochronological proxy of landslide activity at two study slopes with precipitation and earthquakes in the study area. Based on statistical correlations with 560 precipitation indicators, we found that the similarities between the two study landslides include only the direct triggers in June–July and March. The Wiśnia landslide, unlike Hajdowska, can also be triggered by precipitation in October. However, the main difference between the study landslides lies in the preparatory precipitation. Hajdowska shows significant dependence from precipitation of the previous December and current February, while at the Wiśnia study site, the preparatory precipitation is less important and covers the previous October–November and current January. Our results show that although study landslides could be reactivated at one time by similar direct triggers of spring or summer, such simultaneous reactivation would require preconditions of antecedent precipitation of the previous winter half-year (October–March) different for each landslide. Suppose, the requirements of antecedent precipitation are fulfilled only for one of the landslides during the winter half-year. In that case, the other will remain inactive despite the later occurrence of a shared direct trigger in spring or summer. The example of Hajdowska and Wiśnia shows that significant differences in landslide activity, hazard and triggering factors can exist even at the local scale. We argue that omitting even such subtle, unevident differences in the conditions of landslide activity leads to errors in landslide modelling and forecasting. For example, linking Hajdowska and Wiśnia landslides with one precipitation threshold or model of slope instability based on their adjacent location would not be effective in predicting reactivations. The precision of landslide modelling and forecasting depends on the accuracy of preceding analyses of landslide activity and triggering factors. We argue that in the case of the two adjacent landslides studied the divergent patterns of their activity and triggers would not be revealed without analysing long-term (> 60 years long) data sets. • Landslides are linked with precipitation and earthquakes using dendrochronology. • Triggering factors of landslides are reconstructed for 1959–2019. • Similarities and differences are revealed in precipitation controls of two landslides. • Preparatory role of preceding winter precipitation differs between study landslides. • Revealed differences affect potential outcomes of landslide models and forecasts. [ABSTRACT FROM AUTHOR]

Background: The infection fatality rate (IFR) of the Coronavirus Disease 2019 (COVID-19) is one of the most discussed figures in the context of this pandemic. In contrast to the case fatality rate (CFR), the IFR depends on the total number of infected individuals - not just on the number of confirmed cases. In order to estimate the IFR, several seroprevalence studies have been or are currently conducted.Methods: Using German COVID-19 surveillance data and age-group specific IFR estimates from multiple international studies, this work investigates time-dependent variations in effective IFR over the course of the pandemic. Three different methods for estimating (effective) IFRs are presented: (a) population-averaged IFRs based on the assumption that the infection risk is independent of age and time, (b) effective IFRs based on the assumption that the age distribution of confirmed cases approximately reflects the age distribution of infected individuals, and (c) effective IFRs accounting for age- and time-dependent dark figures of infections.Results: Effective IFRs in Germany are estimated to vary over time, as the age distributions of confirmed cases and estimated infections are changing during the course of the pandemic. In particular during the first and second waves of infections in spring and autumn/winter 2020, there has been a pronounced shift in the age distribution of confirmed cases towards older age groups, resulting in larger effective IFR estimates. The temporary increase in effective IFR during the first wave is estimated to be smaller but still remains when adjusting for age- and time-dependent dark figures. A comparison of effective IFRs with observed CFRs indicates that a substantial fraction of the time-dependent variability in observed mortality can be explained by changes in the age distribution of infections. Furthermore, a vanishing gap between effective IFRs and observed CFRs is apparent after the first infection wave, while an increasing gap can be observed during the second wave.Conclusions: The development of estimated effective IFR and observed CFR reflects the changing age distribution of infections over the course of the COVID-19 pandemic in Germany. Further research is warranted to obtain timely age-stratified IFR estimates, particularly in light of new variants of the virus. [ABSTRACT FROM AUTHOR]

Warm mix asphalt (WMA) is gaining increased attention in the asphalt paving industry as an eco-friendly and sustainable technology. WMA technologies are favorable in producing asphalt mixtures at temperatures 20–60 °C lower in comparison to conventional hot mix asphalt. This saves non-renewable fossil fuels, reduces energy consumption, and minimizes vapors and greenhouse gas emissions in the production, placement and conservation processes of asphalt mixtures. At the same time, this temperature reduction must not reduce the performance of asphalt pavements in-field. Low aging resistance, high moisture susceptibility, and low durability are generally seen as substantial drawbacks of WMA, which can lead to inferior pavement performance, and increased maintenance costs. This is partly due to the fact that low production temperature may increase the amount of water molecules trapped in the asphalt mixture. As a potential remedy, here we use fumed silica nanoparticles (FSN) have shown excellent potential in enhancing moisture and aging susceptibility of asphalt binders. In this study, asphalt binder modification by means of FSN was investigated, considering the effects of short-term and long-term aging on the rheological, thermal, and microstructural binder properties. This research paves the way for optimizing WMA by nanoparticles to present enhanced green asphalt technology. [ABSTRACT FROM AUTHOR]

In this study, surface morphology, rheological and chemical properties were investigated of bitumen, which was modified by a composite of clay and fumed silica nanoparticles, and exposed to ultraviolet (UV) aging in laboratory. The volume fraction of the nanoparticles within the binder ranged from 1 to 3%, the temperature range considered was 30 to 70 °C. Surface morphology, rheological and chemical binder properties were analyzed using field emission scanning electron microscopy (FESEM), dynamic shear rheometer (DSR), and Fourier transform infrared (FT-IR) spectroscopy. It was found, that the bitumen modification through clay and fumed silica nanoparticles changed resulting binder properties significantly. The index of carbonyl and oxidation degree decreased, and the clay and fumed silica nanoparticles improved aging resistance to ultraviolet (UV) radiation considerably. The results indicate that the mechanical stability of the modified bitumen is very much driven by the specific concentration of clay and fumed silica nanoparticles. [ABSTRACT FROM AUTHOR]

The Pantanal, the world's largest wetland, is a biodiversity hotspot and home to several threatened species. The growth and transition of the local economy are a major threat to the ecosystem, and sustainable income sectors need to be established. The local economy is based mainly on cattle farming, while ecotourism has recently become important. Our study was conducted in two subregions of the Brazilian Pantanal, the northern subregion Poconé in Mato Grosso and the southern subregion Nhecolandia in Mato Grosso do Sul. Our results indicate that the two main economic sectors, cattle farming and ecotourism, can support sustainable development when operated at a small scale. Traditional cattle farming had no negative effect on mammalian wildlife richness or abundance in either of our study areas, whereas ecotourism did not affect species abundance but did affect species richness in a few cases. These results are derived from a ten-month camera-trap study (middle of July to middle of October 2010, end of December 2012 to beginning of March 2013, and middle of August to end of November 2013) conducted in both subregions. The habitats at both of our study sites consisted of a mix of forest and grassland savanna, the most important factor to support high species diversity. Our study is part of an ongoing long-term Pantanal mammal monitoring project aiming to introduce sustainable management practices. [ABSTRACT FROM AUTHOR]

Signalling pathways and cellular interactions defining initial processes of testis morphogenesis, i.e. cord formation, are poorly understood. In vitro cell-based systems modelling cord formation can be utilised as platforms to interrogate processes of tubulogenesis. We aimed at testing our established cord formation in vitro model using adult human testicular cells as a quantitative assay that can facilitate future studies on cord morphogenesis. We challenged the responsiveness of our system with a broad-spectrum protein kinase inhibitor, K252a. Cultured testicular cells were treated with various K252a concentrations under constant exposure and compound withdrawal. To quantify cell reaggregation changes, we performed computer-assisted phase-contrast image analysis of aggregate size and number. Cell reaggregation was analysed in detail by categorisation of aggregates into size groups and accounting for changes in aggregate number per size category. We found a dose-related disturbance of testicular cell reaggregation. K252a decreased aggregate size (IC50 of 203.3 nM) and reduced the large aggregate numbers. Video recordings revealed that treatment with K252a at a concentration above IC50 interfered with aggregate coalescence into cords. Short-term exposure and compound wash-out induced irreversible decrease in large aggregates. We propose our in vitro model as a functional platform to quantitatively investigate seminiferous tubulogenesis under pharmacological impact. [ABSTRACT FROM AUTHOR]

Human spermatogonia are target for exploration of adult stem cell characteristics and potential source for the development of therapeutic applications. Almost 50 years ago, Yves Clermont stated with regard to the nature of the true stem cells: 'there is the possibility that other classes of spermatogonia exist beside the three classes (Adark, Apale and type B)…; …we still know too little about the human spermatogonial stem cells'… This review seeks to provide current knowledge, focusing on different aspects of human spermatogonia, and novel information based on species comparisons with regard to the adaptation of their proliferative potential. Moreover, the objective is to provide an update on the state of the art concerning the potential use of human spermatogonia for clinical applications. Germ cell specification mechanisms and epigenetic as well as transcriptional features of primordial germ cells (PGC) and adult spermatogonia at the single-cell level are reviewed. Studies on single-cell analyses have been included as they provide hitherto unequaled resolution of the transcriptional profiles of unselected human testicular cells and, thereby, new insights into the molecular aspects of germ cell differentiation. Datasets on models of spermatogonial expansion were identified and spermatogonial turnover and lifetime sperm production rates in various species were calculated, based exclusively on studies employing the optical dissector approach. Finally, the state of the art concerning causes of impaired spermatogonial function and fertility preservation were comprehensively reviewed. RNA sequencing data from PGC and spermatogonia indicate that transcriptional heterogeneity is a feature of germ cells prior to differentiation. Based on these data as well as lineage-tracing studies it is now debated whether spermatogonia are a rather plastic population of undifferentiated germ cells with the stem cell niche being the regulatory unit for cell fate decisions. Based on our novel calculations we suggest that spermatogonia are adapted to the individual reproductive lifespan and that the life-long sperm output from a spermatogonium is balanced against the duration of a generation. Thereby, the risk of jeopardizing genome integrity is balanced against a maximized sperm output. With reference to Yves Clermont's statement, and based on recent datasets, we suggest that the question that needs to be answered is: 'Is there a true stem cell?' or better 'Is there a population of various cells with distinct features serving as a stem cell pool?'. This review provides an update including novel views on various aspects of spermatogonial biology (from embryonic to adult stages). We consider this review relevant for all research scientists and clinicians dealing with fertility, spermatogenesis and fertility preservation. [ABSTRACT FROM AUTHOR]

Purpose: Endograft infection is an infrequent but one of the most serious and challenging complications after endovascular aortic repair. The aim of this study was to assess the management of this complication in a tertiary center. Case Series: A retrospective analysis of a prospective database was performed including all patients who underwent elective endovascular abdominal aortic repair (EVAR) from 2003 to 2016 in a tertiary center. Seven cases of endograft infection were identified during the follow-up period from a total of 473 (1.48%) EVAR. Most frequent symptoms at presentation were fever (71.4%) and lumbar pain (57.1%). One case developed an early infection, while 6 cases were diagnosed as late infections. Mean time from endograft placement to symptom presentation was 28.3 months (2-91.5 months). Gram-positive cocci were the microorganisms most commonly isolated in blood cultures (66%). Two cases were managed with endograft removal and aortic reconstruction with a cryopreserved allograft, 2 cases with surgical drainage, and 2 cases exclusively with antibiotic therapy. In 1 case, the diagnosis was performed postoperatively based on intraoperative findings associated with positive graft cultures; and graft explantation was performed with "in situ" reconstruction using a Dacron graft. Perioperative mortality was 42.9%. One-year mortality was 57.1%. Mean follow-up was 21.5 months. Conclusion: Endograft explantation is the gold standard of treatment; however, given the overall high morbi–mortality rates of this pathology, a tailored approach should always be offered depending on the patient's overall condition. Conservative management can be an acceptable option in those patients with short life expectancy and high surgical risk. [ABSTRACT FROM AUTHOR]

PURPOSE: Circulating cell-free tumor DNA (ctDNA) reflects the heterogeneous spectrum of tumor-specific mutations, especially in systemic disease. We validated plasma-based assays that allow the dynamic quantitative detection of ctDNA as a prognostic biomarker for tumor load and prediction of therapy response in melanoma. MATERIALS and METHODS: We analyzed plasma-derived ctDNA from a large training cohort (n = 96) of patients with advanced-stage melanoma, with assays for the BRAF V600E and NRAS Q61 driver mutations as well as TERT C250T and TERT C228T promoter mutations. An independent patient cohort (n = 35) was used to validate the utility of ctDNA monitoring under mitogen-activated protein kinase–targeted or immune checkpoint therapies. RESULTS: Elevated plasma ctDNA level at baseline was an independent prognostic factor of disease progression when compared with serum S100 and lactate dehydrogenase levels in multivariable analyses (hazard ratio [HR], 7.43; 95% CI, 1.01 to 55.19; P =.05). The change in ctDNA levels during therapy correlated with treatment response, where increasing ctDNA was predictive for shorter progression-free survival (eg, for BRAF V600E ctDNA, HR, 3.70; 95% CI, 1.86 to 7.34; P <.001). Increasing ctDNA levels predicted disease progression significantly earlier than did routine radiologic scans (P <.05), with a mean lead time of 3.5 months. NRAS -mutant ctDNA was detected in a significant proportion of patients with BRAF -mutant tumors under therapy, but unexpectedly also at baseline. In vitro sensitivity studies suggested that this represents higher-than-expected intratumoral heterogeneity. The detection of NRAS Q61 ctDNA in baseline samples of patients with BRAF V600E mutation who were treated with mitogen-activated protein kinase inhibitors significantly correlated with shorter progression-free survival (HR, 3.18; 95% CI, 1.31 to 7.68; P =.03) and shorter overall survival (HR, 4.08; 95% CI, 1.57 to 10.58; P =.01). CONCLUSION: Our results show the potential role of ctDNA measurement as a sensitive monitoring and prediction tool for the early assessment of disease progression and therapeutic response in patients with metastatic melanoma. [ABSTRACT FROM AUTHOR]

Purpose: Endograft infection is an infrequent but one of the most serious and challenging complications after endovascular aortic repair. The aim of this study was to assess the management of this complication in a tertiary center. Case Series: A retrospective analysis of a prospective database was performed including all patients who underwent elective endovascular abdominal aortic repair (EVAR) from 2003 to 2016 in a tertiary center. Seven cases of endograft infection were identified during the follow-up period from a total of 473 (1.48%) EVAR. Most frequent symptoms at presentation were fever (71.4%) and lumbar pain (57.1%). One case developed an early infection, while 6 cases were diagnosed as late infections. Mean time from endograft placement to symptom presentation was 28.3 months (2-91.5 months). Gram-positive cocci were the microorganisms most commonly isolated in blood cultures (66%). Two cases were managed with endograft removal and aortic reconstruction with a cryopreserved allograft, 2 cases with surgical drainage, and 2 cases exclusively with antibiotic therapy. In 1 case, the diagnosis was performed postoperatively based on intraoperative findings associated with positive graft cultures; and graft explantation was performed with "in situ" reconstruction using a Dacron graft. Perioperative mortality was 42.9%. One-year mortality was 57.1%. Mean follow-up was 21.5 months. Conclusion: Endograft explantation is the gold standard of treatment; however, given the overall high morbi–mortality rates of this pathology, a tailored approach should always be offered depending on the patient's overall condition. Conservative management can be an acceptable option in those patients with short life expectancy and high surgical risk. [ABSTRACT FROM AUTHOR]

Abstract There are numerous examples of the impact of strong earthquakes on landslide activity. There is however very little information about the ability of low-magnitude earthquakes (M < 5.0) to affect the stability of pre-existing landslide slopes. Two landslides were studied (Hołowiec and Kamień, Western Carpathians, Poland). These are located 20–30 km from seismoactive zones where earthquakes of M ≤ 4.4 occur. We have used tree rings to date past landslide movements possibly caused by earthquakes. We have dated events of tree tilting by landslide activity, after which the trees developed eccentric rings and reaction wood, in a sample of 40 Norway spruces (Hołowiec) and 51 European silver firs (Kamień). The results of dendrochronological dating were compared with the occurrence of earthquakes in the study area (magnitudes, epicentral distance, etc.). We have also analysed precipitation data to help to disentangle the impact of rainfall and earthquakes as triggering factors. We were able to distinguish: earthquake-triggered landsliding with no impact of precipitation, precipitation-triggered landsliding with no seismic impact and landsliding triggered by the overlapping impact of precipitation and earthquakes. The results show that the combination of both triggering factors has the strongest influence on the stability of landslides under study. The study demonstrates the ability of low-magnitude (M < 5.0) earthquakes to trigger landslide activity, even at distances larger than appears from limiting curves published for co-seismic landslides. The results also suggest that the activity of the Kamień landslide can possibly be influenced by the long-distance (over 500 km) influence of strong earthquakes (M 6.8–7.4) from outside of the study area. The study demonstrates that the seismic factor, both local, low-magnitude earthquakes and distant, strong earthquakes, can be an important trigger of landslide activity. Their role may be underestimated in the study area and other areas considered as seismically non-active or of low seismic activity. Highlights • Earthquakes M < 5 can trigger activity of pre-existing landslides. • Earthquakes M < 5 can be responsible for 50% of landslide events on adjacent slopes. • The impact of M < 5 earthquakes is increased by co-occurrence of precipitation. • Earthquakes can be an underestimated landslide trigger in areas of low seismic activity. [ABSTRACT FROM AUTHOR]

This paper focuses on investigating the interface shear bonding properties of asphalt pavement structures using both monotonic and cyclic direct shear tests. Several pavement structures were considered, differing in the asphalt mixture type and tack coat type, and laboratory preparation of the double-layered asphalt specimens. Based on the results on bond materials used in this research, it was found that the resulting shear strength from monotonic shear test can be used only as a rough indicator for long term interface bonding performance, because not all research and field experience could be reflected in the test results. The cyclic shear test employed in this study can be used for evaluating the interface fatigue performance. Additionally, differentiation between particular bond materials with respect to interface shear bonding properties is assured. [ABSTRACT FROM AUTHOR]

The impact of the Wallachian settlement on small mountain catchments has been studied at the example of Škorňanský and Hartisov Streams (Moravskoslezské Beskydy Mts, Western Outer Carpathians). Between the 16th and the 19th centuries the Wallachian people introduced pastoral management originating from the woodless Balkans to the forested mid-altitude mountain area under study. This area was subjected to rapid settlement, intense grazing in forests and slash-and-burn deforestation. To assess the geomorphic effects of Wallachian activity in the catchments studied, grain size, structure, organic matter content, and the plant macrofossil composition of the alluvia forming terrace levels in the mouths of the Škorňanský and Hartisov Streams were analysed. Radiocarbon dating, 137 Cs and 210 Pb analyses and dendrochronological dating were also applied to determine the age of the alluvia studied. The results were compared with land-use and land-cover changes recorded on archival maps and pictures, and with population changes in the study area. It was found that the two successive trends of catchment settlement and later depopulation have led to the development of inset terraces on the outlet fans of the Škorňanský and Hartisov Streams. In the study catchments both settlement/deforestation and depopulation/land abandonment occurred very rapidly which also caused abrupt geomorphic changes. Before human disturbance, fluvial erosion and the redeposition of older Pleistocene deposits predominated. As a result coarse, gravel alluvia were deposited within stream channels. The stage of massive overbank accumulation of fine-grained alluvia was a reflection of intensified delivery of slope material into valley floors from catchments deforested by the Wallachians. The later stage of vertical incision of channels resulted from the decrease of sediment supply from hillslopes to river channels during catchment depopulation and afforestation. [ABSTRACT FROM AUTHOR]

Assessment and management of mass-movement hazard in developing mountain areas is a significant human problem. It can only be resolved through identifying the background behind the processes, including their magnitude and frequency. However, catchment monitoring is rare and historical records are often fragmentary or absent. In such cases dendrochronology can be one of the most precise methods for dating past mass-movement events. Our study is intended to provide a tree-ring based discussion of hazards caused by mass movements in a developing high-mountain area. The goal is to estimate the frequencies and magnitudes of mass movements of differing origin and scale: large and smaller debris flows, and rockfalls, typically endangering the population of the Moxi basin. On the terraces and slopes of the Xiaohezi gully the ages of 30 spruce trees were determined indicating the date of the last large debris flow moulding terrace levels. On the Daozhao debris cone we determined the dates of the events of smaller debris flows wounding the stems of 43 alder trees. On the Nimatuo Study Site the dates of rockfalls injuring the stems of a sample of 15 alder trees were determined. The results allowed the recurrence intervals of the mass movements observed in each study site to be calculated. During the last 55 years large debris flows originating in the vast, high-elevation and glaciated Xiaohezi catchment occurred every 18 years. During the last 20 years smaller debris flows fed from the mid-sized and medium elevation Daozhao catchment occurred every 7 years. Rockfalls, with a very small and steep source area (Nimatuo Site) occurred every 2.85 years. In general, the level of mass-movement activity in the study area is high. Based on the results from three study sites representing typical mass-movement hazards, the densely inhabited main valley of the Moxi basin is affected by 40 large debris flows, hundreds of smaller debris flows and thousands of single rockfalls per century. The hazard affects as much as 27.07% of developed area of the Moxi basin. However, thanks to sustainable land use, the majority is affected by manageable, high frequency, but middle-to low-magnitude phenomena. [ABSTRACT FROM AUTHOR]

This paper presents investigation on the recovery potential of hot mix asphalt (HMA) mixture using cyclic uniaxial tension-compression test in stress-controlled mode. The recovery potential and its dependence on rest period duration were investigated taking into consideration nonlinearity and self-heating effects observed during cyclic loading. In order to preserve the internal specimen’s structure a small-size temperature sensor was embedded into asphalt mixture during compaction. It is found, that the effect of nonlinearity on complex modulus recovery is relatively small and that it is not affected by increasing duration of the rest period. The effect of temperature variation in the core of the specimen occurring during cyclic excitation and rest periods has a significant influence on HMA recovery properties. Self-heating results in a much more rapid recovery of complex modulus than other eventual side effects, such as thixotropy, self-healing and strain relaxation. This effect vanishes when temperature reaches its original value, leaving to the other biasing phenomena dominant in terms of complex modulus recovery. [ABSTRACT FROM AUTHOR]

Germline and Somatic Smoothened Mutations in Non-Small-Cell Lung Cancer Are Potentially Responsive to Hedgehog Inhibitor Vismodegib Smoothened (SMO) is a seven-membrane spanning receptor involved in the hedgehog signaling pathway and is directly inhibited by Patched (PTCH).[1] In the absence of PTCH inhibition, SMO activates Gli family transcription factors and subsequently regulates stem- and progenitor-cell differentiation. Eight germline I SMO i P641A mutation cases (variant frequency, 0.11%) were identified in various cancer types, whereas none of the control germline cohort individuals had I SMO i P641A mutation. We hypothesized that PTCH1 may interact with SMO in the cytoplasmic domains and that I SMO i P641A mutation disrupts SMO/PTCH1 interactions and releases SMO suppression. [Extracted from the article]

The role of the assessment of peripheral T-cell phenotypes in predicting overall survival (OS) after ipilimumab treatment is unclear. Here, we analysed mononuclear cells in the blood before and at different time points during treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of baseline naïve and memory T-cells were measured by flow cytometry and correlated with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8 effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p = 0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1 cells and the M category had independent impacts on OS (hazard ratio = 1.5, p = 0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively associated with OS (p = 0.034) but did not correlate with clinical response. Following treatment, a decrease of CD8 cells from baseline to the time of the second drug dose and at later time points was strongly and consistently correlated with a high clinical response rate. Our observations thus suggest an important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for clinical response of ipilimumab. Further validation of these biomarker candidates is warranted. [ABSTRACT FROM AUTHOR]

The identification of blood-borne biomarkers correlating with melanoma patient survival remains elusive. Novel techniques such as mass cytometry could help to identify melanoma biomarkers, allowing simultaneous detection of up to 100 parameters. However, the evaluation of multiparametric data generated via time-of-flight mass cytometry requires novel analytical techniques because the application of conventional gating strategies currently used in polychromatic flow cytometry is not feasible. In this study, we have employed 38-channel time-of-flight mass cytometry analysis to generate comprehensive immune cell signatures using matrix boolean analysis in a cohort of 28 stage IV melanoma patients and 17 controls. Clusters of parameters were constructed from the abundance of cellular phenotypes significantly different between patients and controls. This approach identified patient-specific combinatorial immune signatures consisting of high-resolution subsets of the T cell, NK cell, B cell, and myeloid compartments. An association with superior survival was characterized by a balanced distribution of myeloid-derived suppressor cell-like and APC-like myeloid phenotypes and differentiated NK cells. The results of this study in a discovery cohort of melanoma patients suggest that multifactorial immune signatures have the potential to allow more accurate prediction of individual patient outcome. Further investigation of the identified immune signatures in a validation cohort is now warranted. [ABSTRACT FROM AUTHOR]

Currently, the amount of sequenced and classified MHC class I genes of the common marmoset is limited, in spite of the wide use of this species as an animal model for biomedical research. In this study, 480 clones of MHC class I G locus (Caja-G) cDNA sequences were obtained from 21 common marmosets. Up to 10 different alleles were detected in each common marmoset, leading to the assumption that the Caja-G loci duplicated in the marmoset genome. In the investigated population, four alleles occurred more often, giving evidence for higher immunological advantage of these alleles. In contrast to the human non-classical MHC class I genes, Caja-G shows high rates of polymorphism at the relevant peptide-binding sites, despite its phylogenetic relationship to the non-classical HLA-G. Our results provide information for better understanding of the immunological properties of the common marmoset and confirm the theory of a gene conversion of the Caja-G due to its detected plasticity and the absence of any known HLA-A equivalent. [ABSTRACT FROM AUTHOR]

Human γδ T-cells possess regulatory and cytotoxic capabilities, and could potentially influence the efficacy of immunotherapies. We analysed the frequencies of peripheral γδ T-cells, including their most prominent subsets (Vδ1+ and Vδ2+ cells) and differentiation states in 109 melanoma patients and 109 healthy controls. We additionally analysed the impact of γδ T-cells on overall survival (OS) calculated from the first dose of ipilimumab in melanoma patients. Higher median frequencies of Vδ1+ cells and lower median frequencies of Vδ2+ cells were identified in patients compared to healthy subjects (Vδ1+: 30% versus 15%, Vδ2+: 39% versus 64%, both p < 0.001). Patients with higher frequencies of Vδ1+ cells (≥30%) had poorer OS (p = 0.043) and a Vδ1+ differentiation signature dominated by late-differentiated phenotypes. In contrast, higher frequencies of Vδ2+ cells (≥39%) were associated with longer survival (p = 0.031) independent of the M category or lactate dehydrogenase level. Patients with decreasing frequencies of Vδ2+ cells under ipilimumab treatment had worse OS and a lower rate of clinical benefit than patients without such decreases. Therefore, we suggest frequencies of both Vδ1+ and Vδ2+ cells as candidate biomarkers for outcome in melanoma patients following ipilimumab. Further studies are needed to validate these results and to clarify whether they represent prognostic associations or whether γδ T-cells are specifically and/or functionally linked to the mode of action of ipilimumab. [ABSTRACT FROM AUTHOR]

We studied the abandoned mining field in southern Poland using high-resolution lidar images to distinguish the number of mining shaft remains and their morphological diversity. We identified 13,864 remains of mining shafts of various sizes (2–30 m in diameter) and diverse levels of denudation. This allowed us to select 13 mining shafts for detailed study. The radiocarbon dating of charcoal and peat from the shafts indicate three phases of exploitation in the study area: the Roman and early migration period (2nd century b.c.–6th century a.d.), the Middle Ages (6th–14th century a.d.), and the modern period (15th–17th century a.d.). The data on metal ore exploitation in the European Barbaricum is scarce and, in the study area itself, historical written sources indicate the onset of mining only in the 12th century a.d. Therefore, ore exploitation in the study area during the Roman period and early migration period, as well as in the early Middle Ages, is an unexpected result. [ABSTRACT FROM AUTHOR]

Out of the European methods, the steel roller method (EN 12697-33) is preferred in Germany. A segmented roller is used, as specified in the German Standards in detail (acc. to TP Asphalt-StB, part 33; in German only). It is appropriate for laboratory compaction of any hot rolled asphalt mix types (such as asphalt concrete AC, or stone mastic asphalt SMA) either manufactured in the laboratory or in a mixing plant. And it realizes properties that are similar to those of specimen taken from the road. The segmented roller compaction method as described in the German Standards has been developed in the frame of several studies conducted at the Braunschweig Pavement Engineering Centre (see, e.g. Arand & Renken, 1990, 1999; Renken, 2001, 2002). [ABSTRACT FROM AUTHOR]

For fundamental performance testing of asphalt mixtures, specimens have to be produced from an asphalt mixture that is compacted in laboratory. For this purpose, different laboratory compaction methods are available today, which are based on the effects of impact, kneading or rolling action and/or vibration. It is well known that the method used for compaction considerably influences the properties of the specimen, and in turn, the specimen properties significantly influence the outcome of fundamental asphalt mix testing. The choice of compaction method is therefore of utmost importance. Hence, there is general consensus among experts that high priority must be given to the harmonisation of laboratory methods for the production of specimens prior to mix testing. Asphalt mix requirements must not be specified independently from the detailed compaction requirements. In Europe, a harmonised quality assurance system for asphalt mix properties was established recently. In order to guarantee its practicability, also a harmonised approach for the fabrication of specimens for fundamental testing becomes indispensable. In this paper, an overview is given on how standardisation of specimen production has progressed in Europe so far, and the need for further harmonisation is pointed out from a European point of view. [ABSTRACT FROM AUTHOR]

In this study, the effect of various laboratory procedures for compacting hot-mix asphalt to form test specimens is investigated. Based on the triaxial cyclic compression test (TCCT) according to the European specification EN 12697-25, the resistance to permanent deformation of the specimen obtained from different types of laboratory compaction is studied. The deformation behaviour of the laboratory-compacted specimens is always compared with the deformation properties stated in TCCT for the asphalt mix specimen taken from on-site roller-compacted road pavement. As a result, the effect of the choice of laboratory compaction procedure on the resulting deformation behaviour in TCCT is assessed. [ABSTRACT FROM AUTHOR]

Background: Aging and latent infection with Cytomegalovirus (CMV) are thought to be major factors driving the immune system towards immunosenescence, primarily characterized by reduced amounts of naïve T-cells and increased memory T-cells, potentially associated with higher morbidity and mortality. The composition of both major compartments, γδ as well as αβ T-cells, is altered by age and CMV, but detailed knowledge of changes to the γδ subset is currently limited. Results: Here, we have surveyed a population of 73 younger (23-35 years) and 144 older (62-85 years) individuals drawn from the Berlin Aging Study II, investigating the distribution of detailed differentiation phenotypes of both γδ and αβ T-cells. Correlation of frequencies and absolute counts of the identified phenotypes with age and the presence of CMV revealed a lower abundance of Vδ2-positive and a higher amount of Vδ1-positive cells. We found higher frequencies of late-differentiated and lower frequencies of early-differentiated cells in the Vδ1+ and Vδ1-Vδ2-, but not in the Vδ2+ populations in elderly CMV-seropositive individuals confirming the association of these Vδ2-negative cells with CMV-immunosurveillance. We identified the highest Vδ1:Vδ2 ratios in the CMV-seropositive elderly. The observed increased CD4:CD8 ratios in the elderly were significantly lower in CMV-seropositive individuals, who also possessed a lower naïve and a larger late-differentiated compartment of CD8+ αβ T-cells, reflecting the consensus in the literature. Conclusions: Our findings illustrate in detail the strong influence of CMV on the abundance and differentiation pattern of γδ T-cells as well as αβ T-cells in older and younger people. Mechanisms responsible for the phenotypic alterations in the γδ T-cell compartment, associated both with the presence of CMV and with age require further clarification. [ABSTRACT FROM AUTHOR]

The Sertoli cell (SC)-specific knockout (KO) of connexin43 (Cx43) results in spermatogenic arrest at the level of spermatogonia and/or SC-only syndrome. Histology of the interstitial compartment suggests Leydig cell (LC) hyperplasia. Our aim has been to investigate possible effects of the SC-specific KO of Cx43 (SCCx43KO) on interstitial LC. We therefore counted LC via the optical dissector method (per microliter of testicular tissue and per testis) and found LC to be significantly increased in SCCx43KO compared with wild-type mice. Semiquantitative western blot together with Cx43 and 3β-hydroxysteroid dehydrogenase immunohistochemistry showed that Cx43 protein was significantly reduced and barely detectable in LC in adult SCCx43KO mice. This reduction of Cx43 protein was accompanied by a reduction of Cx43 mRNA as analyzed by laser-assisted microdissection of interstitial cells and subsequent quantitative real-time polymerase chain reaction (PCR). Interestingly, Cx45, another recently detected connexin in LC, was also downregulated. Preliminary qualitative data of LC differentiation markers ( Thb2, Hsd3b6) and a steroidogenic marker ( Hsd17b3) obtained by reverse transcription plus PCR revealed no obvious differences. Thus, the loss of Cx43 in SC also provokes the downregulation of connexins in interstitial LC at the transcriptional and translational levels. Moreover, SCCx43KO leads to alterations in LC numbers. Despite these alterations, steroidogenesis seems not to be impaired. Further studies, including ultrastructural analysis of the tissue as well as quantitative examination of additional LC markers and testosterone, and functional in vitro experiments, should provide more information about LC differentiation and function in SCCx43KO mice. [ABSTRACT FROM AUTHOR]

Time-series classification has attracted considerable research attention due to the various domains where time-series data are observed, ranging from medicine to econometrics. Traditionally, the focus of time-series classification has been on short time-series data composed of a few patterns exhibiting variabilities, while recently there have been attempts to focus on longer series composed of multiple local patrepeating with an arbitrary irregularity. The primary contribution of this paper relies on presenting a method which can detect local patterns in repetitive time-series via fitting local polynomial functions of a specified degree. We capture the repetitiveness degrees of time-series datasets via a new measure. Furthermore, our method approximates local polynomials in linear time and ensures an overall linear running time complexity. The coefficients of the polynomial functions are converted to symbolic words via equi-area discretizations of the coefficients’ distributions. The symbolic polynomial words enable the detection of similar local patterns by assigning the same word to similar polynomials. Moreover, a histogram of the frequencies of the words is constructed from each time-series’ bag of words. Each row of the histogram enables a new representation for the series and symbolizes the occurrence of local patterns and their frequencies. In an experimental comparison against state-of-the-art baselines on repetitive datasets, our method demonstrates significant improvements in terms of prediction accuracy. [ABSTRACT FROM AUTHOR]

Background: Several molecular changes, including loss of heterozygosity (i.e., deletion of one copy of allelic DNA sequences) and alterations in microsatellite DNA, have been detected early in the pathogenesis of lung cancer, even in histologically normal epithelium. In the bronchial epithelium of patients with lung cancer, we have determined the frequency, size, and patterns of molecularly abnormal clonal patches.Methods: We studied formalin-fixed, paraffin-embedded samples from 16 surgically resected lung carcinomas (five squamous cell carcinomas, four small-cell carcinomas, six adenocarcinomas, and one large-cell carcinoma). From each carcinoma, we microdissected foci (each containing about 200 cells) of tumor tissue and equivalent samples of histologically normal and abnormal epithelium. Furthermore, multiple discontinuous foci of bronchial epithelium were analyzed from methanol-fixed samples from three additional patients with lung cancer (two with squamous cell carcinoma and one with adenocarcinoma). We used two-step polymerase chain reaction-based assays involving 12 microsatellite markers at seven chromosomal regions frequently deleted in lung cancer.Results: Two hundred eighteen foci of nonmalignant bronchial epithelium (195 of histologically normal or slightly abnormal epithelium and 23 of dysplastic epithelium) were studied from the 19 surgically resected lobectomy specimens. Thirteen (68%) of the 19 specimens had at least one focus of bronchial epithelium with molecular changes. At least one molecular abnormality was detected in 32% of the 195 histologically normal or slightly abnormal foci and in 52% of the 23 dysplastic foci. Extrapolating from our two-dimensional analyses, we estimate that most clonal patches contain approximately 90 000 cells. Although, in a given individual, tumors appeared homogeneous with respect to molecular changes, the clonally altered patches of mildly abnormal epithelium were heterogeneous.Conclusions: Our findings indicate that multiple small clonal or subclonal patches containing molecular abnormalities are present in normal or slightly abnormal bronchial epithelium of patients with lung cancer. [ABSTRACT FROM AUTHOR]

Context: Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population.Objective: To investigate the molecular changes present in HIV-associated lung tumors and compare them with those present in lung carcinomas arising in HIV-indeterminate subjects ("sporadic tumors").Design: Convenience sample.Subjects: Archival tissues from 11 HIV-positive persons and from 35 persons of indeterminate HIV status.Setting: University-based medical centers and affiliated hospitals.Main Outcome Measures: Analysis of frequency of loss of heterozygosity (LOH) and microsatellite alteration (MA) using polymerase chain reaction and 16 polymorphic microsatellite markers at 8 chromosomal regions frequently deleted in lung cancer. Presence of HIV and human papillomavirus (HPV) sequences.Results: The overall frequency of LOH at all chromosomal regions tested and the frequencies at most of the individual regions were similar in the 2 groups. Frequency of MA present in the HIV-associated tumors (0.18) was 6-fold higher than in sporadic tumors (0.03) (P<.001). At least 1 MA was present in 10 (91%) of 11 HIV-associated tumors vs 17 (48%) of 35 sporadic tumors (P=.02). Molecular changes were independent of tumor stage and gender. HIV and HPV sequences were not detected in the HIV-associated lung carcinomas.Conclusions: Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated lung carcinomas. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated tumors. [ABSTRACT FROM AUTHOR]

The past decade has witnessed a revolution in cancer treatment by the shift from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based therapies, in particular the immune-checkpoint inhibitors (ICIs). These immunotherapies selectively release the host immune system against the tumour and have shown unprecedented durable remission for patients with cancers that were thought incurable such as advanced non-small cell lung cancer (aNSCLC). The prediction of therapy response is based since the first anti-PD-1/PD-L1 molecules FDA and EMA approvals on the level of PD-L1 tumour cells expression evaluated by immunohistochemistry, and recently more or less on tumour mutation burden in the USA. However, not all aNSCLC patients benefit from immunotherapy equally, since only around 30% of them received ICIs and among them 30% have an initial response to these treatments. Conversely, a few aNSCLC patients could have an efficacy ICIs response despite low PD-L1 tumour cells expression. In this context, there is an urgent need to look for additional robust predictive markers for ICIs efficacy in thoracic oncology. Understanding of the mechanisms that enable cancer cells to adapt to and eventually overcome therapy and identifying such mechanisms can help circumvent resistance and improve treatment. However, more than a unique universal marker, the evaluation of several molecules in the tumour at the same time, particularly by using multiplex immunostaining is a promising open room to optimise the selection of patients who benefit from ICIs. Therefore, urgent further efforts are needed to optimise to individualise immunotherapy based on both patient-specific and tumour-specific characteristics. This review aims to rethink the role of multiplex immunostaining in immuno-thoracic oncology, with the current advantages and limitations in the near-daily practice use. [ABSTRACT FROM AUTHOR]

The common marmoset (Callithrix jacchus) is a New World primate that exhibits a man-like adult testicular organization. Aims: this study examines the pubertal testicular development in the common marmoset. Material and methods: immature male common marmosets (n = 48) were monitored longitudinally for a period of 13 months. Body weight and testicular volume (TV) were recorded, and testosterone levels were analyzed by an in-house radioimmunoassay. After 13 months the testes were collected, fixed and embedded in paraffin (n = 48). Histological and morphometric data were determined. Results: the first 6 months exhibited a rapid rise in body weight but not in TV. At 7 months a threefold increase in testosterone levels was observed. After 7 months the first few animals displayed rapid testis growth (> 250 mm³ at 10 months), while others exhibited no or slow pubertal development (≤ 100 mm³ at 10 months). Histological features confirmed an individually variable pattern of testicular development. Parallel with the rise in serum testosterone levels, an increase in the diameter of seminiferous tubules and an appearance of a tubular lumen as well as meiotic germ cells were encountered. The onset and the kinetics of testicular development were highly variable between individual animals in the colony. Epididymal sperm were first observed at 12 months of age. The TV and seminiferous tubule diameter showed continued growth after 12 months of age, especially in the animals developing with a delay after 7 months. Conclusions: pubertal onset in the common marmosets occurs at the earliest at 6 months of age and is hallmarked by sudden threefold increase in serum testosterone levels and a significant rise in the TV. Pubertal testis growth is characterized by an appearance of a tubular lumen and of primary and secondary spermatocytes. Spermatogenesis is qualitatively accomplished at the earliest at 12 months of age. A very high individual difference in onset and kinetics of pubertal development renders the age a very poor prognostic factor to determine the pubertal status of individual marmosets. [ABSTRACT FROM AUTHOR]

The common marmoset (Callithrix jacchus) is a New World primate that exhibits a man-like adult testicular organization. Aims: this study examines the pubertal testicular development in the common marmoset. Material and methods: immature male common marmosets (n D 48) were monitored longitudinally for a period of 13 months. Body weight and testicular volume (TV) were recorded, and testosterone levels were analyzed by an in-house radioimmunoassay. After 13 months the testes were collected, fixed and embedded in paraffin (n D 48). Histological and morphometric data were determined. Results: the first 6 months exhibited a rapid rise in body weight but not in TV. At 7 months a threefold increase in testosterone levels was observed. After 7 months the first few animals displayed rapid testis growth (> 250mm³ at 10 months), while others exhibited no or slow pubertal development (≤ 100mm³ at 10 months). Histological features confirmed an individually variable pattern of testicular development. Parallel with the rise in serum testosterone levels, an increase in the diameter of seminiferous tubules and an appearance of a tubular lumen as well as meiotic germ cells were encountered. The onset and the kinetics of testicular development were highly variable between individual animals in the colony. Epididymal sperm were first observed at 12 months of age. The TV and seminiferous tubule diameter showed continued growth after 12 months of age, especially in the animals developing with a delay after 7 months. Conclusions: pubertal onset in the common marmosets occurs at the earliest at 6 months of age and is hallmarked by sudden threefold increase in serum testosterone levels and a significant rise in the TV. Pubertal testis growth is characterized by an appearance of a tubular lumen and of primary and secondary spermatocytes. Spermatogenesis is qualitatively accomplished at the earliest at 12 months of age. A very high individual difference in onset and kinetics of pubertal development renders the age a very poor prognostic factor to determine the pubertal status of individual marmosets. [ABSTRACT FROM AUTHOR]

Abstract: A method based on dendrochronology was developed to analyse the spatial and temporal variability of landslide activity as an alternative and complement to methods such as field monitoring of landslide relief, aerial-photography, and remote sensing. The method involves a feature of wood anatomy, tree-ring eccentricity, which is used in the dating procedure. The degree of eccentricity is used as an indicator of the intensity of the mechanical stress affecting a tree stem in a certain year. The objective was to develop a mathematical indicator of tree-ring eccentricity for dating the recent dynamics of landslides. A method presented in the paper is also designed for practical application in detecting initial landslide activity and allowing the determination of triggering factors. The index developed is dimensionless and for this reason is independent of the absolute ring variations of the single trees analysed. Using reference results (from stable slopes) as thresholds in dating an objective method for detecting landslide activity was developed. The method was used in the Carpathian and Sudeten Mountains on three landslides with different sizes and geological settings. It was found that the values of eccentricity index in trees growing on stable slopes rarely exceed at ±100%, while in trees growing on landslides they can reach hundreds to thousands per cent. A spatial analysis of the eccentricity values conducted for a single landslide has revealed that the method developed allows one to identify areas of landslide activation and to observe the down- or upslope propagation of instability. A comparison of the results obtained regarding the precipitation record has shown that, by using the method that has been developed, it is possible to detect past mass-movement episodes caused by heavy, long-term rainfall as well as by single, short-lasting but torrential downpours. [Copyright &y& Elsevier]

Dendrochronological datings of landslide activity on slopes and of fluvial erosion in adjacent channel were performed. Landsliding was dated from the tree-ring eccentricity. Erosion was dated using the wood anatomy of roots. The obtained results on the temporal occurrence of these geomorphic processes were compared and then confronted with the precipitation record. Analysis of the temporal relations between landsliding, erosion and rainfall has revealed that two types of repeating sequences occur in studied sites: (1) rainfall → landsliding → channel erosion, (2) rainfall → channel erosion → landsliding. In the first type landsliding triggered by rainfall delivers colluvium onto the valley floor and causes its narrowing, which in turn triggers increased channel erosion. In the second type channel erosion triggered by rainfall disturbs the slope equilibrium and causes landsliding. Coupling between landsliding and channel erosion was proved using dendrochronology but also its influence on the relief of the study sites was observed. Channel shifting, forced sinuosity and increased erosion of the slopes opposite the active landslides occurred. The results suggest that the repeating of the described sequences over longer periods of time can lead to a general widening of the valley floor at the expense of slopes and to a gradual change of the valley cross profile from narrow, V-shaped into a wide flat-bottomed one. [ABSTRACT FROM AUTHOR]

Abstract: The social environment plays an important role in modulating processes of the hormonal and behavioural profile of an animal in a variety of group-living species. In wild cavies for instance, unstable social environmental conditions during pregnancy and lactation lead to an infantilised biobehavioural profile of the male offspring. In the present study, the influence of the social environment during pregnancy and lactation on the male wild cavy offsprings' plasma testosterone development, reproductive capacity and stress system activity was investigated. To this purpose, 12 sons whose mothers had lived in an unstable social environment during pregnancy and lactation were compared with 12 sons whose mothers had lived in a stable social environment during the same time. Plasma testosterone (T) and plasma cortisol (C) concentrations were determined from days 20 to 107 of age. Adrenal tyrosine hydroxylase (TH) activity and different parameters of reproductive capacity (weights of testes, epididymides and accessory sex glands, cellular composition of the testes, DNA fragmentation indices and sperm motility parameters) were analysed at day 107 of age. TH activity and plasma C were unaffected by different social environmental conditions early in life. The developmental time course of T concentrations, however, was significantly different: Sons whose mothers had lived in an unstable social environment during pregnancy and lactation showed a delayed increase in T concentrations around adolescence compared to controls. In contrast, no reproduction-related parameters measured within this study differed significantly between the two groups. Thus, early social instability affects plasma testosterone development during adolescence in a significant way but does not alter reproductive capacity or measures of stress later in life. [Copyright &y& Elsevier]

Background: Despite the common perception that latent Cytomegalovirus (CMV) infection is usually symptom-free, emerging epidemiological evidence suggests that it may in fact be associated with higher mortality over extended follow-up. Mechanisms responsible for this potentially important effect are unclear. CMV infection is known to have a large impact on the distribution of T cell phenotypes, especially the accumulation of late-stage differentiated CD8+, as well as Vδ2- γδ T-cells, which are the main subset of γδ T-cells involved in anti-CMV immunity. Its impact on γδ T-cells in the aging context is less well-defined. Results: Here, we investigated a group of healthy individuals aged between 21 and 89 years, in order to correlate the frequency and differentiation status of γδ T-cells with age. We found that these parameters were only marginally influenced by age, but were marked in people with a latent CMV infection. Thus, we observed a significant age-associated accumulation of late-differentiated T-cells within the Vδ2- population, but only in CMV-seropositive donors. There was also a strong trend towards reduced frequency of early-differentiated cells within the Vδ2- phenotype. Older people had significantly higher anti-CMV IgG titers, which in turn correlated significantly with a lower Vδ2+/Vδ2- ratio and a shift from early- to a late-differentiated Vδ2- T-cell phenotype. Conclusions: Our findings demonstrate a strong influence of CMV on γδ T-cells during human ageing, similar to that observed for αβ T-cells. Differences between donors of different ages are more marked in CMV-infected individuals. The biological implications of this potent age-associated CMV-mediated immune-modulation require clarification. [ABSTRACT FROM AUTHOR]

The marmoset monkey is a valuable model in reproductive medicine. While previous studies have evaluated germ cell dynamics in the postnatal marmoset, the features of testicular somatic cells remain largely unknown. Therefore, the aim of this study was to establish marmoset-specific markers for Sertoli and peritubular cells (PTCs) and to compare protocols for the enrichment and culture of testicular cell types. Immunohistochemistry of Sertoli and PTC-specific markers - anti-müllerian hormone (AMH), vimentin (VIM), α-smooth muscle actin (SMA) - was performed and corresponding RNA expression profiles were established by quantitative PCR analysis (SOX9,AMH, FSHR,VIM, and SMA). For these analyses, testicular tissue from newborn (n = 4), 8-week-old (n = 4) and adult (n = 3) marmoset monkeys was used. Protocols for the enrichment and culture of testicular cell fractions from the 8-week-old marmoset monkeys (n = 3) were evaluated and cells were analyzed using germ cell- and somatic cell-specific markers. The expression of AMH, VIM and SMA reflects the proportion and differentiation status of Sertoli and PTCs at the RNA and the protein levels. While applied protocols did not support the propagation of germ cells in vitro, our analyses revealed that PTCs maintain their proliferative potential and constitute the dominant cell type after short- and long-term culture. Expression of functionally meaningful testicular somatic markers is similar in the human and the marmoset monkey, indicating that this primate can indeed be used as model for human testicular development. The PTC culture system established in this study will facilitate the identification of factors influencing male sex differentiation and spermatogenesis. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Thymic carcinomas are tumors of the anterior mediastinum derived from the epithelial cells of the thymic gland. Due to their low incidence they are often investigated in combination with thymomas under the rubric of “thymic epithelial neoplasms” and studies exclusively addressing thymic carcinomas are sparse. Thymic carcinomas are characterized by their histologic variability, often resembling tumors seen in other organ systems. This morphologic variation coupled with their rarity has prevented large scale research of these tumors and little is known about the etiology, biologic behavior or best treatment for thymic carcinoma. In recent years, attempts have been made to investigate the molecular characteristics of these tumors in the hope that molecular profiling can be used to predict the prognosis or lead to the development of new treatment strategies. Herein we provide an overview of the recent advances of the molecular analysis of thymic carcinoma with particular emphasis on the potential use for molecularly targeted therapies. [Copyright &y& Elsevier]