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Primary biological aerosols are transported over large distances, are traveling in various media such as dry air masses, clouds or fog, and eventually deposited with dry deposition, especially for larger particles, or precipitation like rain, hail or snow. To investigate relative abundance and diversity of airborne bacterial and fungal communities, samples have been collected with a liquid impinger (Coriolis µ) from the top of Mount Sonnblick (3106 m asl, Austrian Alps) from the respective sources under a temporal aspect over four seasons over the year to include all climatic conditions. Bacterial and fungal samples (16S rRNA and ITS) were sequenced using Illumina MiSeq paired-end sequencing, investigated for relative abundance by qPCR(16S rRNA and 18S rRNA) and ice nucleation activity. Results show that there is no stable free tropospheric air microbial community and air mass origin was different for the four sampling periods which exerted influence on the microbial composition of the atmosphere although a core microbiome could be identified consisting of 61 bacterial OTUs and eight fungal genera. Differentiation between seasons was stronger pronounced in air than in precipitation, with rain being most different and variable of precipitation types, indicating distinct forces driving microbial fate in the air. Microorganisms precipitated with snow, hail or rain or being transported by clouds differ in their species composition from free tropospheric air masses and do not mirror the air community structure. They were more diverse, distinct in composition, 16S:18S ratio and abundance from free-floating PBA. Hence, snow or cloud samples are not suitable proxies for free tropospheric air microbiome composition, since separation processes in aerosolization, transport and scavenging occur. The microbial composition of arriving precipitation or clouds represents only a part of the microbial air composition communities of the cumulative sources of origin. Relative abundance and composition of ice nucleation-active bacteria showed a higher share of relative % reads of known ice nucleation-active bacteria present in all wet phases compared to air. Results propose a separation of IN-active reads with higher shares occurring in precipitation. This study presents the first comparison of free tropospheric bacterial and fungal abundance and diversity in time series of air over several seasons in contrast to various precipitation forms in the free troposphere.

The atmosphere harbours a vast diversity of primary biological aerosols (PBAs) that are subjected to vertical and horizontal dispersal mechanisms that are not fully understood. In addition to size and weight constraints on PBAs to be lifted into the air column, local meteorological features dominate the fate of bioaerosols and their possible inclusion in long‐range transport. For organic particles to be included into long distant dispersal, they have to overcome surface vertical mixing of the planetary boundary layer (PBL) to reach levels of laminar air movement. Hence, the biogeography of PBAs along a vertical distribution through the PBL needed further study. To assess the microbial biodiversity along an altitudinal gradient, air samples were collected between 1,000 and 3,100 m above sea level at Mount Sonnblick in the Austrian Alps. 16S rRNA gene and internal transcribed spacer sequencing for bacteria and fungi, respectively, were used to define distinct microbial communities that were separated by the PBL. Up to the top of the PBL, plant‐associated bacteria and fungi were detected and were subjected to limited vertical dispersal due to size‐constraints. This indicates that those communities become aerosolised but were not lifted into higher altitudes. However, a variety of ubiquitous, thermophilic strains that are often identified with heavy dust events and high endurance towards extreme conditions were significantly increased (relative abundance) at higher elevations. The lack of information on vertical dispersal is due to reliance on ground‐based investigations that bias the interpretation of dispersal dynamics. Thus, to understand the mechanisms for near‐ground communities to become airborne and subsequently included in long‐range transport, we recommend investigating meteorological driving forces for an improved biogeographical assessment. Here, we show, for the first time, an assessment of the biogeography of bacterial and fungal assemblages along a vertical alpine air column transect. Knowledge about vertical bioaerosol occurences is crucial to understand global microbial atmospheric long range transport. Air samples were taken along a vertical transect out of an open cable car at a remote alpine site and analysed with molecular methods for fungal and bacterial abundance and diversity. Bacterial diversity above and below the planetary boundary layer (PBL) was significantly different, fungi were significantly less abundant above PBL. We identified Geobacillus, Planifilum and SM01A2 as indicator species for above PBL air. Below PBL bioaerosol community was more driven by ground emissions that above PBL.e00069

Sea spray aerosol particles are a recognised type of ice-nucleating particles under mixed-phase cloud conditions. Entities that are responsible for the heterogeneous ice nucleation ability include intact or fragmented cells of marine microorganisms as well as organic matter released by cell exudation. Only a small fraction of sea spray aerosol is transported to the upper troposphere, but there are indications from mass-spectrometric analyses of the residuals of sublimated cirrus particles that sea salt could also contribute to heterogeneous ice nucleation under cirrus conditions. Experimental studies on the heterogeneous ice nucleation ability of sea spray aerosol particles and their proxies at temperatures below 235 K are still scarce. In our article, we summarise previous measurements and present a new set of ice nucleation experiments at cirrus temperatures with particles generated from sea surface microlayer and surface seawater samples collected in three different regions of the Arctic and from a laboratory-grown diatom culture (Skeletonema marinoi). The particles were suspended in the Aerosol Interaction and Dynamics in the Atmosphere (AIDA) cloud chamber and ice formation was induced by expansion cooling. We confirmed that under cirrus conditions, apart from the ice-nucleating entities mentioned above, also crystalline inorganic salt constituents can contribute to heterogeneous ice formation. This takes place at temperatures below 220 K, where we observed in all experiments a strong immersion freezing mode due to the only partially deliquesced inorganic salts. The inferred ice nucleation active surface site densities for this nucleation mode reached a maximum of about 5×1010 m−2 at an ice saturation ratio of 1.3. Much smaller densities in the range of 108–109 m−2 were observed at temperatures between 220 and 235 K, where the inorganic salts fully deliquesced and only the organic matter and/or algal cells and cell debris could contribute to heterogeneous ice formation. These values are 2 orders of magnitude smaller than those previously reported for particles generated from microlayer suspensions collected in temperate and subtropical zones. While this difference might simply underline the strong variability of the number of ice-nucleating entities in the sea surface microlayer across different geographical regions, we also discuss how instrumental parameters like the aerosolisation method and the ice nucleation measurement technique might affect the comparability of the results amongst different studies.

Ice formation in the atmosphere is important for regulating cloud lifetime, Earth's radiative balance and initiating precipitation. Due to the difference in the saturation vapor pressure over ice and water, in mixed-phase clouds (MPCs), ice will grow at the expense of supercooled cloud droplets. As such, MPCs, which contain both supercooled liquid and ice, are particularly susceptible to ice formation. However, measuring and quantifying the concentration of ice-nucleating particles (INPs) responsible for ice formation at temperatures associated with MPCs is challenging due to their very low concentrations in the atmosphere (∼1 in 105 at −30 ∘C). Atmospheric INP concentrations vary over several orders of magnitude at a single temperature and strongly increase as temperature approaches the homogeneous freezing threshold of water. To further quantify the INP concentration in nature and perform systematic laboratory studies to increase the understanding of the properties responsible for ice nucleation, a new drop-freezing instrument, the DRoplet Ice Nuclei Counter Zurich), is developed. The instrument is based on the design of previous drop-freezing assays and uses a USB camera to automatically detect freezing in a 96-well tray cooled in an ethanol chilled bath with a user-friendly and fully automated analysis procedure. Based on an in-depth characterization of DRINCZ, we develop a new method for quantifying and correcting temperature biases across drop-freezing assays. DRINCZ is further validated performing NX-illite experiments, which compare well with the literature. The temperature uncertainty in DRINCZ was determined to be ±0.9 ∘C. Furthermore, we demonstrate the applicability of DRINCZ by measuring and analyzing field-collected snow samples during an evolving synoptic situation in the Austrian Alps. The field samples fall within previously observed ranges for cumulative INP concentrations and show a dependence on air mass origin and upstream precipitation amount.

Atmospheric dispersal of bacteria is increasingly acknowledged as an important factor influencing bacterial community biodiversity, biogeography and bacteria–human interactions, including those linked to human health. However, knowledge about patterns in microbial aerobiology is still relatively scarce, and this can be attributed, in part, to a lack of consensus on appropriate sampling and analytical methodology. In this study, three different methods were used to investigate aerial biodiversity over Svalbard: impaction, membrane filtration and drop plates. Sites around Svalbard were selected due to their relatively remote location, low human population, geographical location with respect to air movement and the tradition and history of scientific investigation on the archipelago, ensuring the presence of existing research infrastructure. The aerial bacterial biodiversity found was similar to that described in other aerobiological studies from both polar and non-polar environments, with Proteobacteria, Actinobacteria, and Firmicutes being the predominant groups. Twelve different phyla were detected in the air collected above Svalbard, although the diversity was considerably lower than in urban environments elsewhere. However, only 58 of 196 bacterial genera detected were consistently present, suggesting potentially higher levels of heterogeneity. Viable bacteria were present at all sampling locations, showing that living bacteria are ubiquitous in the air around Svalbard. Sampling location influenced the results obtained, as did sampling method. Specifically, impaction with a Sartorius MD8 produced a significantly higher number of viable colony forming units (CFUs) than drop plates alone.

Background While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Preclinical data suggest that stereotactic body radiotherapy (SBRT) could work synergistically with CPIs by acting as an in situ cancer vaccine, thus potentially increasing response rates and prolonging disease control. Though SBRT administered concurrently with CPIs has been shown to be safe, evidence of its efficacy from large randomized trials is still lacking. The aim of this multicenter randomized phase II trial is to assess whether SBRT administered concurrently with CPIs could prolong progression-free survival as compared to standard of care in patients with advanced solid tumors. Methods/design Ninety-eight patients with locally advanced or metastatic disease will be randomized in a 1:1 fashion to receive CPI treatment combined with SBRT (Arm A) or CPI monotherapy (Arm B). Randomization will be stratified according to tumor histology (melanoma, renal, urothelial, head and neck squamous cell or non-small cell lung carcinoma) and disease burden (≤ or > 3 cancer lesions). The recommended SBRT dose is 24Gy in 3 fractions, which will be administered to a maximum of 3 lesions and is to be completed prior to the second or third CPI cycle (depending on CPI treatment schedule). The study’s primary endpoint is progression-free survival as per iRECIST. Secondary endpoints include overall survival, objective response, local control, quality of life and toxicity. Translational analyses will be performed using blood, fecal and tissue samples. Discussion: The CHEERS trial will provide further insights into the clinical and immunological impact of SBRT when combined with CPIs in patients with advanced solid tumors. Furthermore, study results will inform the design of future immuno-radiotherapy trials. Trial registration Clinicaltrials.gov identifier: NCT03511391 . Registered 17 April 2018.

Background The primary objective was to determine maximum tolerated radiation dose in patients with metastatic renal cell carcinoma on pazopanib treatment. Methods Treatment-naïve patients received pazopanib according to standard of care. Stereotactic body radiotherapy (SBRT) was delivered concurrently to the largest metastatic lesion at day 8, 10 and 12. SBRT doses were escalated in 3 dose levels (24 Gy/3, 30 Gy/3 and 36 Gy/3). Dose level was assigned using Time-to-Event Continual Reassessment Method with the target dose-limiting toxicity rate set to 0.25. Results Thirteen patients were included. One patient experienced dose limiting toxicity (DLT) at dose level 3 (grade 4 hypoglycemia). Maximum tolerated dose was not reached with a recommended dose of 36 Gy/3 having a probability of DLT of 11%. One-year local control was 83% (95% confidence interval 61–100) and 1-year progression-free survival was 28% (95% confidence interval 1–55). Conclusions SBRT in combination with pazopanib is well tolerated with good local control and response rates outside the radiation field. Trial registration This trial was retrospectively registered on clinicaltrials.gov( NCT02334709 ) on January 6th, 2015.

Background Current first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates. Methods The phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon’s two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment. Discussion The progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy. Trial registration this trial is registered on clinicaltrials.gov (NCT02826564).

Despite uncontested evidence for fossils belonging to the early hominin genus Australopithecus in East Africa from at least 4.2 million years ago (Ma), and from Chad by 3.5 Ma, thus far there has been no convincing evidence of Australopithecus, Paranthropus or early Homo from the western (Albertine) branch of the Rift Valley. Here we report the discovery of an isolated upper molar (#Ish25) from the Western Rift Valley site of Ishango in Central Africa in a derived context, overlying beds dated to between ca. 2.6 to 2.0 Ma. We used µCT imaging to compare its external and internal macro-morphology to upper molars of australopiths, and fossil and recent Homo. We show that the size and shape of the enamel-dentine junction (EDJ) surface discriminate between Plio-Pleistocene and post-Lower Pleistocene hominins, and that the Ishango molar clusters with australopiths and early Homo from East and southern Africa. A reassessment of the archaeological context of the specimen is consistent with the morphological evidence and suggest that early hominins were occupying this region by at least 2 Ma.

The incidence of tick-borne diseases caused by Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum and Rickettsia spp. has been rising in Europe in recent decades. Early pre-assessment of acarological hazard still represents a complex challenge. The aim of this study was to model Ixodes ricinus questing nymph density and its infection rate with B. burgdorferi s.l., A. phagocytophilum and Rickettsia spp. in five European countries (Italy, Germany, Czech Republic, Slovakia, Hungary) in various land cover types differing in use and anthropisation (agricultural, urban and natural) with climatic and environmental factors (Normalized Difference Vegetation Index (NDVI), Normalized Difference Water Index (NDWI), Land Surface Temperature (LST) and precipitation). We show that the relative abundance of questing nymphs was significantly associated with climatic conditions, such as higher values of NDVI recorded in the sampling period, while no differences were observed among land use categories. However, the density of infected nymphs (DIN) also depended on the pathogen considered and land use. These results contribute to a better understanding of the variation in acarological hazard for Ixodes ricinus transmitted pathogens in Central Europe and provide the basis for more focused ecological studies aimed at assessing the effect of land use in different sites on tick–host pathogens interaction.