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Institute
- Theodor-Boveri-Institut für Biowissenschaften (130) (remove)
Sonstige beteiligte Institutionen
Invasive fungal infections (IFIs) are difficult to diagnose and to treat and, despite several available antifungal drugs, cause high mortality rates. In the past decades, the incidence of IFIs has continuously increased. More recently, SARS-CoV-2-associated lethal IFIs have been reported worldwide in critically ill patients. Combating IFIs requires a more profound understanding of fungal pathogenicity to facilitate the development of novel antifungal strategies. Animal models are indispensable for studying fungal infections and to develop new antifungals. However, using mammalian animal models faces various hurdles including ethical issues and high costs, which makes large-scale infection experiments extremely challenging. To overcome these limitations, we optimized an invertebrate model and introduced a simple calcofluor white (CW) staining protocol to macroscopically and microscopically monitor disease progression in silkworms (Bombyx mori) infected with the human pathogenic filamentous fungi Aspergillus fumigatus and Lichtheimia corymbifera. This advanced silkworm A. fumigatus infection model could validate knockout mutants with either attenuated, strongly attenuated or unchanged virulence. Finally, CW staining allowed us to efficiently visualize antifungal treatment outcomes in infected silkworms. Conclusively, we here present a powerful animal model combined with a straightforward staining protocol to expedite large-scale in vivo research of fungal pathogenicity and to investigate novel antifungal candidates.
Stable cell lines are widely used in laboratory research and pharmaceutical industry. They are mainly applied in recombinant protein and antibody productions, gene function studies, drug screens, toxicity assessments, and for cancer therapy investigation. There are two types of cell lines, polyclonal and monoclonal origin, that differ regarding their homogeneity and heterogeneity. Generating a high-quality stable cell line, which can grow continuously and carry a stable genetic modification without alteration is very important for most studies, because polyclonal cell lines of multicellular origin can be highly variable and unstable and lead to inconclusive experimental results. The most commonly used technologies of single cell originate monoclonal stable cell isolation in laboratory are fluorescence-activated cell sorting (FACS) sorting and limiting dilution cloning. Here, we describe a modified limiting dilution method of monoclonal stable cell line selection using the real-time fluorescence imaging system IncuCyte\(^®\)S3.
Engineered vaccinia virus (VACV) strains are used extensively as vectors for the development of novel cancer vaccines and cancer therapeutics. In this study, we describe for the first time a high-throughput approach for both fluorescent rVACV generation and rapid viral titer measurement with the multi-well plate imaging system, IncuCyte\(^®\)S3. The isolation of a single, well-defined plaque is critical for the generation of novel recombinant vaccinia virus (rVACV) strains. Unfortunately, current methods of rVACV engineering via plaque isolation are time-consuming and laborious. Here, we present a modified fluorescent viral plaque screening and selection strategy that allows one to generally obtain novel fluorescent rVACV strains in six days, with a minimum of just four days. The standard plaque assay requires chemicals for fixing and staining cells. Manual plaque counting based on visual inspection of the cell culture plates is time-consuming. Here, we developed a fluorescence-based plaque assay for quantifying the vaccinia virus that does not require a cell staining step. This approach is less toxic to researchers and is reproducible; it is thus an improvement over the traditional assay. Lastly, plaque counting by virtue of a fluorescence-based image is very convenient, as it can be performed directly on the computer.
To ask students what a species is always has something rhetorical about it. Too quickly comes the rote answer, often learned by heart without ever thinking about it: “A species is a reproductive community of populations (reproductively isolated from others), which occupies a specific niche in nature” (Mayr 1982). However, do two people look alike because they are twins or are they twins because they look alike? “Two organisms do not belong to the same species because they mate and reproduce, but they only are able to do so because they belong to the same species” (Mahner and Bunge 1997). Unfortunately, most biology (pre-university) teachers have no opinion on whether species are real or conceptual, simply because they have never been taught the question themselves, but rather one answer they still pass on to their students today, learned by heart without ever thinking about it. Species are either real or conceptual and, in my opinion, it is this “or” that we should teach about. Only then can we discuss those fundamental questions such as who or what is selected, who or what evolves and, finally, what is biodiversity and phylogenetics all about? Individuals related to each other by the tree of life.
Anthropogenic and environmental drivers shape diversity of naturalized plants across the Pacific
(2021)
Aim
The Pacific exhibits an exceptional number of naturalized plant species, but the drivers of this high diversity and the associated compositional patterns remain largely unknown. Here, we aim to (a) improve our understanding of introduction and establishment processes and (b) evaluate whether this information is sufficient to create scientific conservation tools, such as watchlists.
Location
Islands in the Pacific Ocean, excluding larger islands such as New Zealand, Japan, the Philippines and Indonesia.
Methods
We combined information from the most up‐to‐date data sources to quantify naturalized plant species richness and turnover across island groups and investigate the effects of anthropogenic, biogeographic and climate drivers on these patterns. In total, we found 2,672 naturalized plant species across 481 islands and 50 island groups, with a total of 11,074 records.
Results
Most naturalized species were restricted to few island groups, and most island groups have a low number of naturalized species. Island groups with few naturalized species were characterized by a set of widespread naturalized species. Several plant families that contributed many naturalized species globally also did so in the Pacific, particularly Fabaceae and Poaceae. However, many families were significantly over‐ or under‐represented in the Pacific naturalized flora compared to other regions of the world. Naturalized species richness increased primarily with increased human activity and island altitude/area, whereas similarity between island groups in temperature along with richness differences was most important for beta diversity.
Main conclusions
The distribution and richness of naturalized species can be explained by a small set of drivers. The Pacific region contains many naturalized plant species also naturalized in other regions in the world, but our results highlight key differences such as a stronger role of anthropogenic drivers in shaping diversity patterns. Our results establish a basis for predicting and preventing future naturalizations in a threatened biodiversity hotspot.
(1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1%), isolated hemihypertrophy (IHH, N = 29, 1.0%), Denys-Drash syndrome (DDS, N = 24, 0.8%) and WAGR syndrome (N = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.
A new innovative real-time tracking method for flying insects applicable under natural conditions
(2021)
Background
Sixty percent of all species are insects, yet despite global efforts to monitor animal movement patterns, insects are continuously underrepresented. This striking difference between species richness and the number of species monitored is not due to a lack of interest but rather to the lack of technical solutions. Often the accuracy and speed of established tracking methods is not high enough to record behavior and react to it experimentally in real-time, which applies in particular to small flying animals.
Results
Our new method of real-time tracking relates to frequencies of solar radiation which are almost completely absorbed by traveling through the atmosphere. For tracking, photoluminescent tags with a peak emission (1400 nm), which lays in such a region of strong absorption through the atmosphere, were attached to the animals. The photoluminescent properties of passivated lead sulphide quantum dots were responsible for the emission of light by the tags and provide a superb signal-to noise ratio. We developed prototype markers with a weight of 12.5 mg and a diameter of 5 mm. Furthermore, we developed a short wave infrared detection system which can record and determine the position of an animal in a heterogeneous environment with a delay smaller than 10 ms. With this method we were able to track tagged bumblebees as well as hawk moths in a flight arena that was placed outside on a natural meadow.
Conclusion
Our new method eliminates the necessity of a constant or predictable environment for many experimental setups. Furthermore, we postulate that the developed matrix-detector mounted to a multicopter will enable tracking of small flying insects, over medium range distances (>1000m) in the near future because: a) the matrix-detector equipped with an 70 mm interchangeable lens weighs less than 380 g, b) it evaluates the position of an animal in real-time and c) it can directly control and communicate with electronic devices.
Strains of the food-borne pathogen Listeria (L.) monocytogenes have diverse virulence potential. This study focused on the virulence of three outbreak strains: the CC1 strain PF49 (serovar 4b) from a cheese-associated outbreak in Switzerland, the clinical CC2 strain F80594 (serovar 4b), and strain G6006 (CC3, serovar 1/2a), responsible for a large gastroenteritis outbreak in the USA due to chocolate milk. We analysed the genomes and characterized the virulence in vitro and in vivo. Whole-genome sequencing revealed a high conservation of the major virulence genes. Minor deviations of the gene contents were found in the autolysins Ami, Auto, and IspC. Moreover, different ActA variants were present. Strain PF49 and F80594 showed prolonged survival in the liver of infected mice. Invasion and intracellular proliferation were similar for all strains, but the CC1 and CC2 strains showed increased spreading in intestinal epithelial Caco2 cells compared to strain G6006. Overall, this study revealed long-term survival of serovar 4b strains F80594 and PF49 in the liver of mice. Future work will be needed to determine the genes and molecular mechanism behind the long-term survival of L. monocytogenes strains in organs.
Most parasites and parasitoids are adapted to overcome defense mechanisms of their specific hosts and hence colonize a narrow range of host species. Accordingly, an increase in host functional or phylogenetic dissimilarity is expected to increase the species diversity of parasitoids. However, the local diversity of parasitoids may be driven by the accessibility and detectability of hosts, both increasing with increasing host abundance. Yet, the relative importance of these two mechanisms remains unclear. We parallelly reared communities of saproxylic beetle as potential hosts and associated parasitoid Hymenoptera from experimentally felled trees. The dissimilarity of beetle communities was inferred from distances in seven functional traits and from their evolutionary ancestry. We tested the effect of host abundance, species richness, functional, and phylogenetic dissimilarities on the abundance, species richness, and Shannon diversity of parasitoids. Our results showed an increase of abundance, species richness, and Shannon diversity of parasitoids with increasing beetle abundance. Additionally, abundance of parasitoids increased with increasing species richness of beetles. However, functional and phylogenetic dissimilarity showed no effect on the diversity of parasitoids. Our results suggest that the local diversity of parasitoids, of ephemeral and hidden resources like saproxylic beetles, is highest when resources are abundant and thereby detectable and accessible. Hence, in some cases, resources do not need to be diverse to promote parasitoid diversity.
Tree species diversity is important to maintain saproxylic beetle diversity in managed forests. Yet, knowledge about the conservational importance of single tree species and implications for forest management and conservation practices are lacking.
We exposed freshly cut branch‐bundles of 42 tree species, representing tree species native and non‐native to Europe, under sun‐exposed and shaded conditions for 1 year. Afterwards, communities of saproxylic beetles were reared ex situ for 2 years. We tested for the impact of tree species and sun exposure on alpha‐, beta‐, and gamma‐diversity as well as composition of saproxylic beetle communities. Furthermore, the number of colonised tree species by each saproxylic beetle species was determined.
Tree species had a lower impact on saproxylic beetle communities compared to sun exposure. The diversity of saproxylic beetles varied strongly among tree species, with highest alpha‐ and gamma‐diversity found in Quercus petraea. Red‐listed saproxylic beetle species occurred ubiquitously among tree species. We found distinct differences in the community composition of broadleaved and coniferous tree species, native and non‐native tree species as well as sun‐exposed and shaded deadwood.
Our study enhances the understanding of the importance of previously understudied and non‐native tree species for the diversity of saproxylic beetles. To improve conservation practices for saproxylic beetles and especially red‐listed species, we suggest a stronger incorporation of tree species diversity and sun exposure of into forest management strategies, including the enrichment of deadwood from native and with a specific focus on locally rare or silviculturally less important tree species.
Background
Landscape composition is known to affect both beneficial insect and pest communities on crop fields. Landscape composition therefore can impact ecosystem (dis)services provided by insects to crops. Though landscape effects on ecosystem service providers have been studied in large-scale agriculture in temperate regions, there is a lack of representation of tropical smallholder agriculture within this field of study, especially in sub-Sahara Africa. Legume crops can provide important food security and soil improvement benefits to vulnerable agriculturalists. However, legumes are dependent on pollinating insects, particularly bees (Hymenoptera: Apiformes) for production and are vulnerable to pests. We selected 10 pigeon pea (Fabaceae: Cajunus cajan (L.)) fields in Malawi with varying proportions of semi-natural habitat and agricultural area within a 1 km radius to study: (1) how the proportion of semi-natural habitat and agricultural area affects the abundance and richness of bees and abundance of florivorous blister beetles (Coleoptera: Melloidae), (2) if the proportion of flowers damaged and fruit set difference between open and bagged flowers are correlated with the proportion of semi-natural habitat or agricultural area and (3) if pigeon pea fruit set difference between open and bagged flowers in these landscapes was constrained by pest damage or improved by bee visitation.
Methods
We performed three, ten-minute, 15 m, transects per field to assess blister beetle abundance and bee abundance and richness. Bees were captured and identified to (morpho)species. We assessed the proportion of flowers damaged by beetles during the flowering period. We performed a pollinator and pest exclusion experiment on 15 plants per field to assess whether fruit set was pollinator limited or constrained by pests.
Results
In our study, bee abundance was higher in areas with proportionally more agricultural area surrounding the fields. This effect was mostly driven by an increase in honeybees. Bee richness and beetle abundances were not affected by landscape characteristics, nor was flower damage or fruit set difference between bagged and open flowers. We did not observe a positive effect of bee density or richness, nor a negative effect of florivory, on fruit set difference.
Discussion
In our study area, pigeon pea flowers relatively late—well into the dry season. This could explain why we observe higher densities of bees in areas dominated by agriculture rather than in areas with more semi-natural habitat where resources for bees during this time of the year are scarce. Therefore, late flowering legumes may be an important food resource for bees during a period of scarcity in the seasonal tropics. The differences in patterns between our study and those conducted in temperate regions highlight the need for landscape-scale studies in areas outside the temperate region.
Temperature and photoperiod are important Zeitgebers for plants and pollinators to synchronize growth and reproduction with suitable environmental conditions and their mutualistic interaction partners. Global warming can disturb this temporal synchronization since interacting species may respond differently to new combinations of photoperiod and temperature under future climates, but experimental studies on the potential phenological responses of plants and pollinators are lacking. We simulated current and future combinations of temperature and photoperiod to assess effects on the overwintering and spring phenology of an early flowering plant species (Crocus sieberi) and the Western honey bee (Apis mellifera). We could show that increased mean temperatures in winter and early spring advanced the flowering phenology of C. sieberi and intensified brood rearing activity of A. mellifera but did not advance their brood rearing activity. Flowering phenology of C. sieberi also relied on photoperiod, while brood rearing activity of A. mellifera did not. The results confirm that increases in temperature can induce changes in phenological responses and suggest that photoperiod can also play a critical role in these responses, with currently unknown consequences for real-world ecosystems in a warming climate.
Contemporary climate change leads to earlier spring phenological events in Europe. In forests, in which overstory strongly regulates the microclimate beneath, it is not clear if further change equally shifts the timing of leaf unfolding for the over- and understory of main deciduous forest species, such as Fagus sylvatica L. (European beech). Furthermore, it is not known yet how this vertical phenological (mis)match — the phenological difference between overstory and understory — affects the remotely sensed satellite signal. To investigate this, we disentangled the start of season (SOS) of overstory F.sylvatica foliage from understory F. sylvatica foliage in forests, within nine quadrants of 5.8 × 5.8 km, stratified over a temperature gradient of 2.5 °C in Bavaria, southeast Germany, in the spring seasons of 2019 and 2020 using time lapse cameras and visual ground observations. We explained SOS dates and vertical phenological (mis)match by canopy temperature and compared these to Sentinel-2 derived SOS in response to canopy temperature. We found that overstory SOS advanced with higher mean April canopy temperature (visual ground observations: −2.86 days per °C; cameras: −2.57 days per °C). However, understory SOS was not significantly affected by canopy temperature. This led to an increase of vertical phenological mismatch with increased canopy temperature (visual ground observations: +3.90 days per °C; cameras: +2.52 days per °C). These results matched Sentinel-2-derived SOS responses, as pixels of higher canopy height advanced more by increased canopy temperature than pixels of lower canopy height. The results may indicate that, with further climate change, spring phenology of F. sylvatica overstory will advance more than F. sylvatica understory, leading to increased vertical phenological mismatch in temperate deciduous forests. This may have major ecological effects, but also methodological consequences for the field of remote sensing, as what the signal senses highly depends on the pixel mean canopy height and the vertical (mis)match.
Recently reported insect declines have raised both political and social concern. Although the declines have been attributed to land use and climate change, supporting evidence suffers from low taxonomic resolution, short time series, a focus on local scales, and the collinearity of the identified drivers. In this study, we conducted a systematic assessment of insect populations in southern Germany, which showed that differences in insect biomass and richness are highly context dependent. We found the largest difference in biomass between semi-natural and urban environments (-42%), whereas differences in total richness (-29%) and the richness of threatened species (-56%) were largest from semi-natural to agricultural environments. These results point to urbanization and agriculture as major drivers of decline. We also found that richness and biomass increase monotonously with increasing temperature, independent of habitat. The contrasting patterns of insect biomass and richness question the use of these indicators as mutual surrogates. Our study provides support for the implementation of more comprehensive measures aimed at habitat restoration in order to halt insect declines.
Expansion microscopy (ExM) enables super-resolution fluorescence imaging on standard microscopes by physical expansion of the sample. However, the investigation of interactions between different organisms such as mammalian and fungal cells by ExM remains challenging because different cell types require different expansion protocols to ensure identical, ideally isotropic expansion of both partners. Here, we introduce an ExM method that enables super-resolved visualization of the interaction between NK cells and Aspergillus fumigatus hyphae. 4-fold expansion in combination with confocal fluorescence imaging allows us to resolve details of cytoskeleton rearrangement as well as NK cells' lytic granules triggered by contact with an RFP-expressing A. fumigatus strain. In particular, subdiffraction-resolution images show polarized degranulation upon contact formation and the presence of LAMP1 surrounding perforin at the NK cell-surface post degranulation. Our data demonstrate that optimized ExM protocols enable the investigation of immunological synapse formation between two different species with so far unmatched spatial resolution.
Staphylococcus aureus is a major human pathogen, which can invade and survive in non-professional and professional phagocytes. Uptake by host cells is thought to contribute to pathogenicity and persistence of the bacterium. Upon internalization by epithelial cells, cytotoxic S. aureus strains can escape from the phagosome, replicate in the cytosol and induce host cell death. Here, we identified a staphylococcal cysteine protease to induce cell death after translocation of intracellular S. aureus into the host cell cytoplasm. We demonstrated that loss of staphopain A function leads to delayed onset of host cell death and prolonged intracellular replication of S. aureus in epithelial cells. Overexpression of staphopain A in a non-cytotoxic strain facilitated intracellular killing of the host cell even in the absence of detectable intracellular replication. Moreover, staphopain A contributed to efficient colonization of the lung in a mouse pneumonia model. In phagocytic cells, where intracellular S. aureus is exclusively localized in the phagosome, staphopain A did not contribute to cytotoxicity. Our study suggests that staphopain A is utilized by S. aureus to exit the epithelial host cell and thus contributes to tissue destruction and dissemination of infection.
Author summary Staphylococcus aureus is an antibiotic-resistant pathogen that emerges in hospital and community settings and can cause a variety of diseases ranging from skin abscesses to lung inflammation and blood poisoning. The bacterium can asymptomatically colonize the upper respiratory tract and skin of humans and take advantage of opportune conditions, like immunodeficiency or breached barriers, to cause infection. Although S. aureus was not regarded as intracellular bacterium, it can be internalized by human cells and subsequently exit the host cells by induction of cell death, which is considered to cause tissue destruction and spread of infection. The bacterial virulence factors and underlying molecular mechanisms involved in the intracellular lifestyle of S. aureus remain largely unknown. We identified a bacterial cysteine protease to contribute to host cell death of epithelial cells mediated by intracellular S. aureus. Staphopain A induced killing of the host cell after translocation of the pathogen into the cell cytosol, while bacterial proliferation was not required. Further, the protease enhanced survival of the pathogen during lung infection. These findings reveal a novel, intracellular role for the bacterial protease staphopain A.
1. The potential for competition is highest among species in close association. Despite net benefits for both parties, mutualisms can involve costs, including food competition. This might be true for the two neotropical ants Camponotus femoratus and Crematogaster levior, which share the same nest in a presumably mutualistic association (parabiosis).
2. While each nest involves one Crematogaster and one Camponotus partner, both taxa were recently found to comprise two cryptic species that show no partner preferences and seem ecologically similar. Since these cryptic species often occur in close sympatry, they might need to partition their niches to avoid competitive exclusion.
3. Here, we investigated first, is there interference competition between parabiotic Camponotus and Crematogaster, and do they prefer different food sources under competition? And second, is there trophic niche partitioning between the cryptic species of either genus?
4. Using cafeteria experiments, neutral lipid fatty acid and stable isotope analyses, we found evidence for interference competition, but also trophic niche partitioning between Camponotus and Crematogaster. Both preferred protein‐ and carbohydrate‐rich baits, but at protein‐rich baits Ca. femoratus displaced Cr. levior over time, suggesting a potential discovery‐dominance trade‐off between parabiotic partners. Only limited evidence was found for trophic differentiation between the cryptic species of each genus.
5. Although we cannot exclude differentiation in other niche dimensions, we argue that neutral dynamics might mediate the coexistence of cryptic species. This model system is highly suitable for further studies of the maintenance of species diversity and the role of mutualisms in promoting species coexistence.
The term ‘urban beekeeping’ connotes a host of meanings—sociopolitical, commercial, ecological and personal—beyond the mere description of where bees and beekeepers happen to coincide. Yet, these meanings are seldom articulated explicitly or brought into critical engagement with the relevant fields of urban ecology and political ecology.
Beginning with a brief account of the history of urban beekeeping in the United States, we draw upon urban ecological theory to construct a conceptual model of urban beekeeping that distinguishes beekeeping in, of and for the city. In our model, beekeeping in the city describes the mere importation of the traditionally rural practice of beekeeping into urban spaces for the private reasons of the individual beekeeper, whereas beekeeping of the city describes beekeeping that is consciously tailored to the urban context, often accompanied by (semi)professionalization of beekeepers and the formation of local expert communities (i.e. beekeeping associations). Beekeeping for the city describes a shift in mindset in which beekeeping is directed to civic ends beyond the boundaries of the beekeeping community per se.
Using this framework, we identify and discuss specific socioecological assets and liabilities of urban beekeeping, and how these relate to beekeeping in, of and for the city. We then formulate actionable guidelines for maturing the practice of urban beekeeping into a beneficent and self‐critical form of urban ecological citizenship; these include fostering self‐regulation within the beekeeping community, harnessing beekeeping as a ‘gateway’ experience for a broader rapprochement between urban residents and nature, and recognizing the political‐ecological context of beekeeping with respect to matters of socioecological justice.
To study the interaction of human pathogens with their host target structures, human tissue models based on primary cells are considered suitable. Complex tissue models of the human airways have been used as infection models for various viral and bacterial pathogens. The Gram-negative bacterium Bordetella pertussis is of relevant clinical interest since whooping cough has developed into a resurgent infectious disease. In the present study, we created three-dimensional tissue models of the human ciliated nasal and tracheo-bronchial mucosa. We compared the innate immune response of these models towards the B. pertussis virulence factor adenylate cyclase toxin (CyaA) and its enzymatically inactive but fully pore-forming toxoid CyaA-AC\(^-\). Applying molecular biological, histological, and microbiological assays, we found that 1 µg/ml CyaA elevated the intracellular cAMP level but did not disturb the epithelial barrier integrity of nasal and tracheo-bronchial airway mucosa tissue models. Interestingly, CyaA significantly increased interleukin 6, interleukin 8, and human beta defensin 2 secretion in nasal tissue models, whereas tracheo-bronchial tissue models were not significantly affected compared to the controls. Subsequently, we investigated the interaction of B. pertussis with both differentiated primary nasal and tracheo-bronchial tissue models and demonstrated bacterial adherence and invasion without observing host cell type-specific significant differences. Even though the nasal and the tracheo-bronchial mucosa appear similar from a histological perspective, they are differentially susceptible to B. pertussis CyaA in vitro. Our finding that nasal tissue models showed an increased innate immune response towards the B. pertussis virulence factor CyaA compared to tracheo-bronchial tissue models may reflect the key role of the nasal airway mucosa as the first line of defense against airborne pathogens.
Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have consumed a significant amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or Worldwide for another indication is a more rapid and less expensive option. Therefore, we apply the scaffold searching approach based on known amyloid-beta (Aβ) inhibitor tramiprosate to screen the DrugCentral database (n = 4,642) of clinically tested drugs. As a result, menadione bisulfite and camphotamide substances with protrombogenic and neurostimulation/cardioprotection effects were identified as promising Aβ inhibitors with an improved binding affinity (ΔGbind) and blood-brain barrier permeation (logBB). Finally, the data was also confirmed by molecular dynamics simulations using implicit solvation, in particular as Molecular Mechanics Generalized Born Surface Area (MM-GBSA) model. Overall, the proposed in silico pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated in vitro and in vivo, and, finally, in a clinical trial.
Reports of major losses in insect biodiversity have stimulated an increasing interest in temporal population changes. Existing datasets are often limited to a small number of study sites, few points in time, a narrow range of land‐use intensities and only some taxonomic groups, or they lack standardised sampling. While new monitoring programs have been initiated, they still cover rather short time periods.
Daskalova et al. 2021 (Insect Conservation and Diversity, 14, 1‐18) argue that temporal trends of insect populations derived from short time series are biased towards extreme trends, while their own analysis of an assembly of shorter‐ and longer‐term time series does not support an overall insect decline. With respect to the results of Seibold et al. 2019 (Nature, 574, 671–674) based on a 10‐year multi‐site time series, they claim that the analysis suffers from not accounting for temporal pseudoreplication.
Here, we explain why the criticism of missing statistical rigour in the analysis of Seibold et al. (2019) is not warranted. Models that include ‘year’ as random effect, as suggested by Daskalova et al. (2021), fail to detect non‐linear trends and assume that consecutive years are independent samples which is questionable for insect time‐series data.
We agree with Daskalova et al. (2021) that the assembly and analysis of larger datasets is urgently needed, but it will take time until such datasets are available. Thus, short‐term datasets are highly valuable, should be extended and analysed continually to provide a more detailed understanding of insect population changes under the influence of global change, and to trigger immediate conservation actions.
African trypanosomes cause sleeping sickness in humans and nagana in cattle. These unicellular parasites are transmitted by the bloodsucking tsetse fly. In the mammalian host’s circulation, proliferating slender stage cells differentiate into cell cycle-arrested stumpy stage cells when they reach high population densities. This stage transition is thought to fulfil two main functions: first, it auto-regulates the parasite load in the host; second, the stumpy stage is regarded as the only stage capable of successful vector transmission. Here, we show that proliferating slender stage trypanosomes express the mRNA and protein of a known stumpy stage marker, complete the complex life cycle in the fly as successfully as the stumpy stage, and require only a single parasite for productive infection. These findings suggest a reassessment of the traditional view of the trypanosome life cycle. They may also provide a solution to a long-lasting paradox, namely the successful transmission of parasites in chronic infections, despite low parasitemia.
Many proteins are molecular machines, whose function is dependent on multiple conformational changes that are initiated and tightly controlled through biochemical stimuli. Their mechanistic understanding calls for spectroscopy that can probe simultaneously such structural coordinates. Here we present two-colour fluorescence microscopy in combination with photoinduced electron transfer (PET) probes as a method that simultaneously detects two structural coordinates in single protein molecules, one colour per coordinate. This contrasts with the commonly applied resonance energy transfer (FRET) technique that requires two colours per coordinate. We demonstrate the technique by directly and simultaneously observing three critical structural changes within the Hsp90 molecular chaperone machinery. Our results reveal synchronicity of conformational motions at remote sites during ATPase-driven closure of the Hsp90 molecular clamp, providing evidence for a cooperativity mechanism in the chaperone’s catalytic cycle. Single-molecule PET fluorescence microscopy opens up avenues in the multi-dimensional exploration of protein dynamics and allosteric mechanisms.
As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions are initiated by uptake of viral particles and subsequent trafficking to intracellular compartments to access their replication compartments which provide a spatially confined environment concentrating viral and cellular components, and subsequently, employ cellular membranes for assembly and exit of viral progeny. The ability of viruses to actively modulate lipid composition such as sphingolipids (SLs) is essential for successful completion of the viral life cycle. In addition to their structural and biophysical properties of cellular membranes, some sphingolipid (SL) species are bioactive and as such, take part in cellular signaling processes involved in regulating viral replication. It is especially due to the progress made in tools to study accumulation and dynamics of SLs, which visualize their compartmentalization and identify interaction partners at a cellular level, as well as the availability of genetic knockout systems, that the role of particular SL species in the viral replication process can be analyzed and, most importantly, be explored as targets for therapeutic intervention.
Methionine restriction (MetR) is an efficient method of amino acid restriction (AR) in cells and organisms that induces low energy metabolism (LEM) similar to caloric restriction (CR). The implementation of MetR as a therapy for cancer or other diseases is not simple since the elimination of a single amino acid in the diet is difficult. However, the in vivo turnover rate of cysteine is usually higher than the rate of intake through food. For this reason, every cell can enzymatically synthesize cysteine from methionine, which enables the use of specific enzymatic inhibitors. In this work, we analysed the potential of cysteine restriction (CysR) in the murine cell line L929. This study determined metabolic fingerprints using mass spectrometry (LC/MS). The profiles were compared with profiles created in an earlier work under MetR. The study was supplemented by proliferation studies using D-amino acid analogues and inhibitors of intracellular cysteine synthesis. CysR showed a proliferation inhibition potential comparable to that of MetR. However, the metabolic footprints differed significantly and showed that CysR does not induce classic LEM at the metabolic level. Nevertheless, CysR offers great potential as an alternative for decisive interventions in general and tumour metabolism at the metabolic level.
Since Otto Warburg reported in 1924 that cancer cells address their increased energy requirement through a massive intake of glucose, the cellular energy level has offered a therapeutic anticancer strategy. Methionine restriction (MetR) is one of the most effective approaches for inducing low-energy metabolism (LEM) due to the central position in metabolism of this amino acid. However, no simple in vitro system for the rapid analysis of MetR is currently available, and this study establishes the murine cell line L929 as such a model system. L929 cells react rapidly and efficiently to MetR, and the analysis of more than 150 different metabolites belonging to different classes (amino acids, urea and tricarboxylic acid cycle (TCA) cycles, carbohydrates, etc.) by liquid chromatography/mass spectrometry (LC/MS) defines a metabolic fingerprint and enables the identification of specific metabolites representing normal or MetR conditions. The system facilitates the rapid and efficient testing of potential cancer therapeutic metabolic targets. To date, MS studies of MetR have been performed using organisms and yeast, and the current LC/MS analysis of the intra- and extracellular metabolites in the murine cell line L929 over a period of 5 days thus provides new insights into the effects of MetR at the cellular metabolic level.
The biogenic amines octopamine and tyramine are important neurotransmitters in insects and other protostomes. They play a pivotal role in the sensory responses, learning and memory and social organisation of honeybees. Generally, octopamine and tyramine are believed to fulfil similar roles as their deuterostome counterparts epinephrine and norepinephrine. In some cases opposing functions of both amines have been observed. In this study, we examined the functions of tyramine and octopamine in honeybee responses to light. As a first step, electroretinography was used to analyse the effect of both amines on sensory sensitivity at the photoreceptor level. Here, the maximum receptor response was increased by octopamine and decreased by tyramine. As a second step, phototaxis experiments were performed to quantify the behavioural responses to light following treatment with either amine. Octopamine increased the walking speed towards different light sources while tyramine decreased it. This was independent of locomotor activity. Our results indicate that tyramine and octopamine act as functional opposites in processing responses to light.
In vitro rearing of honeybee larvae is an established method that enables exact control and monitoring of developmental factors and allows controlled application of pesticides or pathogens. However, only a few studies have investigated how the rearing method itself affects the behavior of the resulting adult honeybees. We raised honeybees in vitro according to a standardized protocol: marking the emerging honeybees individually and inserting them into established colonies. Subsequently, we investigated the behavioral performance of nurse bees and foragers and quantified the physiological factors underlying the social organization. Adult honeybees raised in vitro differed from naturally reared honeybees in their probability of performing social tasks. Further, in vitro-reared bees foraged for a shorter duration in their life and performed fewer foraging trips. Nursing behavior appeared to be unaffected by rearing condition. Weight was also unaffected by rearing condition. Interestingly, juvenile hormone titers, which normally increase strongly around the time when a honeybee becomes a forager, were significantly lower in three- and four-week-old in vitro bees. The effects of the rearing environment on individual sucrose responsiveness and lipid levels were rather minor. These data suggest that larval rearing conditions can affect the task performance and physiology of adult bees despite equal weight, pointing to an important role of the colony environment for these factors. Our observations of behavior and metabolic pathways offer important novel insight into how the rearing environment affects adult honeybees.
To enable a sustainable supply of chemicals, novel biotechnological solutions are required that replace the reliance on fossil resources. One potential solution is to utilize tailored biosynthetic modules for the metabolic conversion of CO2 or organic waste to chemicals and fuel by microorganisms. Currently, it is challenging to commercialize biotechnological processes for renewable chemical biomanufacturing because of a lack of highly active and specific biocatalysts. As experimental methods to engineer biocatalysts are time- and cost-intensive, it is important to establish efficient and reliable computational tools that can speed up the identification or optimization of selective, highly active, and stable enzyme variants for utilization in the biotechnological industry. Here, we review and suggest combinations of effective state-of-the-art software and online tools available for computational enzyme engineering pipelines to optimize metabolic pathways for the biosynthesis of renewable chemicals. Using examples relevant for biotechnology, we explain the underlying principles of enzyme engineering and design and illuminate future directions for automated optimization of biocatalysts for the assembly of synthetic metabolic pathways.
Comparing the appetitive learning performance of six European honeybee subspecies in a common apiary
(2021)
The Western honeybee (Apis mellifera L.) is one of the most widespread insects with numerous subspecies in its native range. How far adaptation to local habitats has affected the cognitive skills of the different subspecies is an intriguing question that we investigate in this study. Naturally mated queens of the following five subspecies from different parts of Europe were transferred to Southern Germany: A. m. iberiensis from Portugal, A. m. mellifera from Belgium, A. m. macedonica from Greece, A. m. ligustica from Italy, and A. m. ruttneri from Malta. We also included the local subspecies A. m. carnica in our study. New colonies were built up in a common apiary where the respective queens were introduced. Worker offspring from the different subspecies were compared in classical olfactory learning performance using the proboscis extension response. Prior to conditioning, we measured individual sucrose responsiveness to investigate whether possible differences in learning performances were due to differential responsiveness to the sugar water reward. Most subspecies did not differ in their appetitive learning performance. However, foragers of the Iberian honeybee, A. m. iberiensis, performed significantly more poorly, despite having a similar sucrose responsiveness. We discuss possible causes for the poor performance of the Iberian honeybees, which may have been shaped by adaptation to the local habitat.
In recent years, bumblebees have become a prominent insect model organism for a variety of biological disciplines, particularly to investigate learning behaviors as well as visual performance. Understanding these behaviors and their underlying neurobiological principles requires a clear understanding of brain anatomy. Furthermore, to be able to compare neuronal branching patterns across individuals, a common framework is required, which has led to the development of 3D standard brain atlases in most of the neurobiological insect model species. Yet, no bumblebee 3D standard brain atlas has been generated. Here we present a brain atlas for the buff-tailed bumblebee Bombus terrestris using micro-computed tomography (micro-CT) scans as a source for the raw data sets, rather than traditional confocal microscopy, to produce the first ever micro-CT-based insect brain atlas. We illustrate the advantages of the micro-CT technique, namely, identical native resolution in the three cardinal planes and 3D structure being better preserved. Our Bombus terrestris brain atlas consists of 30 neuropils reconstructed from ten individual worker bees, with micro-CT allowing us to segment neuropils completely intact, including the lamina, which is a tissue structure often damaged when dissecting for immunolabeling. Our brain atlas can serve as a platform to facilitate future neuroscience studies in bumblebees and illustrates the advantages of micro-CT for specific applications in insect neuroanatomy.
The high diversity of insects has limited the volume of long-term community data with a high taxonomic resolution and considerable geographic replications, especially in forests. Therefore, trends and causes of changes are poorly understood. Here we analyse trends in species richness, abundance and biomass of nocturnal macro moths in three quantitative data sets collected over four decades in forests in southern Germany. Two local data sets, one from coppiced oak forests and one from high oak forests included 125K and 48K specimens from 559 and 532 species, respectively. A third regional data set, representing all forest types in the temperate zone of central Europe comprised 735K specimens from 848 species. Generalized additive mixed models revealed temporal declines in species richness (−38%), abundance (−53%) and biomass (−57%) at the regional scale. These were more pronounced in plant host specialists and in dark coloured species. In contrast, the local coppiced oak forests showed an increase, in species richness (+62%), while the high oak forests showed no clear trends. Left and right censoring as well as cross validation confirmed the robustness of the analyses, which led to four conclusions. First, the decline in insects appears in hyper diverse insect groups in forests and affects species richness, abundance and biomass. Second, the pronounced decline in host specialists suggests habitat loss as an important driver of the observed decline. Third, the more severe decline in dark species might be an indication of global warming as a potential driver. Fourth, the trends in coppiced oak forests indicate that maintaining complex and diverse forest ecosystems through active management may be a promising conservation strategy in order to counteract negative trends in biodiversity, alongside rewilding approaches.
Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89%). Most patients were diagnosed with localized disease, whereas 23% had metastasis at primary diagnosis. Only 72% of the patients achieved complete resection. In 334 children (23%), recurrent disease was reported: 81% — local recurrence, 19% (n = 65) — distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.
Input‐driven, modern agriculture is commonly associated with large‐scale threats to biodiversity, the disruption of ecosystem services and long‐term risks to food security and human health. A switch to more sustainable yet highly productive farming practices seems unavoidable. However, an integrative evaluation of targeted management schemes at field and landscape scales is currently lacking. Furthermore, the often‐disproportionate influence of soil conditions and agrochemicals on yields may mask the benefits of biodiversity‐driven ecosystem services.
Here, we used a real‐world ecosystem approach to identify sustainable management practices for enhanced functional biodiversity and yield on 28 temperate wheat fields. Using path analysis, we assessed direct and indirect links between soil, crop and landscape management with natural enemies and pests, as well as follow‐on effects on yield quantity and quality. A paired‐field design with a crossed insecticide‐fertilizer experiment allowed us to control for the relative influence of soil characteristics and agrochemical inputs.
We demonstrate that biodiversity‐enhancing management options such as reduced tillage, crop rotation diversity and small field size can enhance natural enemies without relying on agrochemical inputs. Similarly, we show that in this system controlling pests and weeds by agrochemical means is less relevant than expected for final crop productivity.
Synthesis and applications. Our study highlights soil, crop and landscape management practices that can enhance beneficial biodiversity while reducing agrochemical usage and negative environmental impacts of conventional agriculture. The diversification of cropping systems and conservation tillage are practical measures most farmers can implement without productivity losses. Combining local measures with improved landscape management may also strengthen the sustainability and resilience of cropping systems in light of future global change.
Ionotropic glutamate receptors (iGluRs) mediate signal transmission in the brain and are important drug targets. Structural studies show snapshots of iGluRs, which provide a mechanistic understanding of gating, yet the rapid motions driving the receptor machinery are largely elusive. Here we detect kinetics of conformational change of isolated clamshell-shaped ligand-binding domains (LBDs) from the three major iGluR sub-types, which initiate gating upon binding of agonists. We design fluorescence probes to measure domain motions through nanosecond fluorescence correlation spectroscopy. We observe a broad kinetic spectrum of LBD dynamics that underlie activation of iGluRs. Microsecond clamshell motions slow upon dimerization and freeze upon binding of full and partial agonists. We uncover allosteric coupling within NMDA LBD hetero-dimers, where binding of L-glutamate to the GluN2A LBD stalls clamshell motions of the glycine-binding GluN1 LBD. Our results reveal rapid LBD dynamics across iGluRs and suggest a mechanism of negative allosteric cooperativity in NMDA receptors.
Parkinson's disease (PD) provokes bradykinesia, resting tremor, rigidity and postural instability, and also non-motor symptoms such as depression, anxiety, sleep and cognitive impairments. Similar phenotypes can be induced in Drosophila melanogaster through modification of PD-relevant genes or the administration of PD inducing toxins. Recent studies correlated deregulation of human p21-activated kinase 4 (PAK4) with PD, leaving open the question of a causative relationship of mutations in this gene for manifestation of PD symptoms. To determine whether flies lacking the PAK4 homolog Mushroom bodies tiny (Mbt) show PD-like phenotypes, we tested for a variety of PD criteria. Here, we demonstrate that mbt mutant flies show PD-like phenotypes including age-dependent movement deficits, reduced life expectancy and fragmented sleep. They also react to a stressful situation with higher immobility, indicating an influence of Mbt on emotional behavior. Loss of Mbt function has a negative effect on the number of dopaminergic protocerebral anterior medial (PAM) neurons, most likely caused by a proliferation defect of neural progenitors. The age-dependent movement deficits are not accompanied by a corresponding further loss of PAM neurons. Previous studies highlighted the importance of a small PAM subgroup for age-dependent PD motor impairments. We show that impaired motor skills are caused by a lack of Mbt in this PAM subgroup. In addition, a broader re-expression of Mbt in PAM neurons improves life expectancy. Conversely, selective Mbt knockout in the same cells shortens lifespan. We conclude that mutations in Mbt/PAK4 can play a causative role in the development of PD phenotypes.
Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors.
Sphingolipids, including ceramides, are a diverse group of structurally related lipids composed of a sphingoid base backbone coupled to a fatty acid side chain and modified terminal hydroxyl group. Recently, it has been shown that sphingolipids show antimicrobial activity against a broad range of pathogenic microorganisms. The antimicrobial mechanism, however, remains so far elusive. Here, we introduce 'click-AT-CLEM', a labeling technique for correlated light and electron microscopy (CLEM) based on the super-resolution array tomography (srAT) approach and bio-orthogonal click chemistry for imaging of azido-tagged sphingolipids to directly visualize their interaction with the model Gram-negative bacterium Neisseria meningitidis at subcellular level. We observed ultrastructural damage of bacteria and disruption of the bacterial outer membrane induced by two azido-modified sphingolipids by scanning electron microscopy and transmission electron microscopy. Click-AT-CLEM imaging and mass spectrometry clearly revealed efficient incorporation of azido-tagged sphingolipids into the outer membrane of Gram-negative bacteria as underlying cause of their antimicrobial activity.
Altered metabolic processes contribute to carcinogenesis by modulating proliferation, survival and differentiation. Tumours are composed of different cell populations, with cancer stem-like cells being one of the most prominent examples. This specific pool of cells is thought to be responsible for cancer growth and recurrence and plays a particularly relevant role in glioblastoma (GBM), the most lethal form of primary brain tumours. Here, we have analysed the transcriptome and metabolome of an established GBM cell line (U87) and a patient-derived GBM stem-like cell line (NCH644) exposed to neurosphere or monolayer culture conditions. By integrating transcriptome and metabolome data, we identified key metabolic pathways and gene signatures that are associated with stem-like and differentiated states in GBM cells, and demonstrated that neurospheres and monolayer cells differ substantially in their metabolism and gene regulation. Furthermore, arginine biosynthesis was identified as the most significantly regulated pathway in neurospheres, although individual nodes of this pathway were distinctly regulated in the two cellular systems. Neurosphere conditions, as opposed to monolayer conditions, cause a transcriptomic and metabolic rewiring that may be crucial for the regulation of stem-like features, where arginine biosynthesis may be a key metabolic pathway. Additionally, TCGA data from GBM patients showed significant regulation of specific components of the arginine biosynthesis pathway, providing further evidence for the importance of this metabolic pathway in GBM.
Revealing the molecular organization of anatomically precisely defined brain regions is necessary for refined understanding of synaptic plasticity. Although three-dimensional (3D) single-molecule localization microscopy can provide the required resolution, imaging more than a few micrometers deep into tissue remains challenging. To quantify presynaptic active zones (AZ) of entire, large, conditional detonator hippocampal mossy fiber (MF) boutons with diameters as large as 10 mu m, we developed a method for targeted volumetric direct stochastic optical reconstruction microscopy (dSTORM). An optimized protocol for fast repeated axial scanning and efficient sequential labeling of the AZ scaffold Bassoon and membrane bound GFP with Alexa Fluor 647 enabled 3D-dSTORM imaging of 25 mu m thick mouse brain sections and assignment of AZs to specific neuronal substructures. Quantitative data analysis revealed large differences in Bassoon cluster size and density for distinct hippocampal regions with largest clusters in MF boutons. Pauli et al. develop targeted volumetric dSTORM in order to image large hippocampal mossy fiber boutons (MFBs) in brain slices. They can identify synaptic targets of individual MFBs and measured size and density of Bassoon clusters within individual untruncated MFBs at nanoscopic resolution.
Aureobasidium pullulans is a black fungus that can adapt to various stressful conditions like hypersaline, acidic, and alkaline environments. The genome of A. pullulans exhibits three genes coding for putative opsins ApOps1, ApOps2, and ApOps3. We heterologously expressed these genes in mammalian cells and Xenopus oocytes. Localization in the plasma membrane was greatly improved by introducing additional membrane trafficking signals at the N-terminus and the C-terminus. In patch-clamp and two-electrode-voltage clamp experiments, all three proteins showed proton pump activity with maximal activity in green light. Among them, ApOps2 exhibited the most pronounced proton pump activity with current amplitudes occasionally extending 10 pA/pF at 0 mV. Proton pump activity was further supported in the presence of extracellular weak organic acids. Furthermore, we used site-directed mutagenesis to reshape protein functions and thereby implemented light-gated proton channels. We discuss the difference to other well-known proton pumps and the potential of these rhodopsins for optogenetic applications.
Plant hormones are small regulatory molecules that exert pharmacological actions in mammalian cells such as anti-oxidative and pro-metabolic effects. Kinetin belongs to the group of plant hormones cytokinin and has been associated with modulatory functions in mammalian cells. The mammalian adenosine receptor (A2a-R) is known to modulate multiple physiological responses in animal cells. Here, we describe that kinetin binds to the adenosine receptor (A2a-R) through the Asn253 residue in an adenosine dependent manner. To harness the beneficial effects of kinetin for future human use, we assess its acute toxicity by analyzing different biochemical and histological markers in rats. Kinetin at a dose below 1 mg/kg had no adverse effects on the serum level of glucose or on the activity of serum alanine transaminase (ALT) or aspartate aminotransferase (AST) enzymes in the kinetin treated rats. Whereas, creatinine levels increased after a kinetin treatment at a dose of 0.5 mg/kg. Furthermore, 5 mg/kg treated kinetin rats showed normal renal corpuscles, but a mild degeneration was observed in the renal glomeruli and renal tubules, as well as few degenerated hepatocytes were also observed in the liver. Kinetin doses below 5 mg/kg did not show any localized toxicity in the liver and kidney tissues. In addition to unraveling the binding interaction between kinetin and A2a-R, our findings suggest safe dose limits for the future use of kinetin as a therapeutic and modulatory agent against various pathophysiological conditions.
The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC50 values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells.
Synthetically designed alternative photorespiratory pathways increase the biomass of tobacco and rice plants. Likewise, some in planta–tested synthetic carbon-concentrating cycles (CCCs) hold promise to increase plant biomass while diminishing atmospheric carbon dioxide burden. Taking these individual contributions into account, we hypothesize that the integration of bypasses and CCCs will further increase plant productivity. To test this in silico, we reconstructed a metabolic model by integrating photorespiration and photosynthesis with the synthetically designed alternative pathway 3 (AP3) enzymes and transporters. We calculated fluxes of the native plant system and those of AP3 combined with the inhibition of the glycolate/glycerate transporter by using the YANAsquare package. The activity values corresponding to each enzyme in photosynthesis, photorespiration, and for synthetically designed alternative pathways were estimated. Next, we modeled the effect of the crotonyl-CoA/ethylmalonyl-CoA/hydroxybutyryl-CoA cycle (CETCH), which is a set of natural and synthetically designed enzymes that fix CO₂ manifold more than the native Calvin–Benson–Bassham (CBB) cycle. We compared estimated fluxes across various pathways in the native model and under an introduced CETCH cycle. Moreover, we combined CETCH and AP3-w/plgg1RNAi, and calculated the fluxes. We anticipate higher carbon dioxide–harvesting potential in plants with an AP3 bypass and CETCH–AP3 combination. We discuss the in vivo implementation of these strategies for the improvement of C3 plants and in natural high carbon harvesters.
Plant traits mediate the effects of climate on phytophagous beetle diversity on Mt. Kilimanjaro
(2021)
Patterns of insect diversity along elevational gradients are well described in ecology. However, it remains little tested how variation in the quantity, quality, and diversity of food resources influence these patterns. Here we analyzed the direct and indirect effects of climate, food quantity (estimated by net primary productivity), quality (variation in the specific leaf area index, leaf nitrogen to phosphorus and leaf carbon to nitrogen ratio), and food diversity (diversity of leaf traits) on the species richness of phytophagous beetles along the broad elevation and land use gradients of Mt. Kilimanjaro, Tanzania. We sampled beetles at 65 study sites located in both natural and anthropogenic habitats, ranging from 866 to 4,550 m asl. We used path analysis to unravel the direct and indirect effects of predictor variables on species richness. In total, 3,154 phytophagous beetles representing 19 families and 304 morphospecies were collected. We found that the species richness of phytophagous beetles was bimodally distributed along the elevation gradient with peaks at the lowest (˜866 m asl) and upper mid-elevations (˜3,200 m asl) and sharply declined at higher elevations. Path analysis revealed temperature- and climate-driven changes in primary productivity and leaf trait diversity to be the best predictors of changes in the species richness of phytophagous beetles. Species richness increased with increases in mean annual temperature, primary productivity, and with increases in the diversity of leaf traits of local ecosystems. Our study demonstrates that, apart from temperature, the quantity and diversity of food resources play a major role in shaping diversity gradients of phytophagous insects. Drivers of global change, leading to a change of leaf traits and causing reductions in plant diversity and productivity, may consequently reduce the diversity of herbivore assemblages.
Colorectal cancer (CRC) is the third most common malignancy worldwide. Most patients with metastatic CRC develop liver or lung metastases, while a minority suffer from brain metastases. There is little information available regarding the presentation, treatment, and overall survival of brain metastases (BM) from CRC. This systematic review and meta-analysis includes data collected from three major databases (PubMed, Cochrane, and Embase) based on the key words “brain”, “metastas*”, “tumor”, “colorectal”, “cancer”, and “malignancy”. In total, 1318 articles were identified in the search and 86 studies matched the inclusion criteria. The incidence of BM varied between 0.1% and 11.5%. Most patients developed metastases at other sites prior to developing BM. Lung metastases and KRAS mutations were described as risk factors for additional BM. Patients with BM suffered from various symptoms, but up to 96.8% of BM patients were asymptomatic at the time of BM diagnosis. Median survival time ranged from 2 to 9.6 months, and overall survival (OS) increased up to 41.1 months in patients on a multimodal therapy regimen. Several factors including age, blood levels of carcinoembryonic antigen (CEA), multiple metastases sites, number of brain lesions, and presence of the KRAS mutation were predictors of OS. For BM diagnosis, MRI was considered to be state of the art. Treatment consisted of a combination of surgery, radiation, or systemic treatment.
Neurotransmitter release is stabilized by homeostatic plasticity. Presynaptic homeostatic potentiation (PHP) operates on timescales ranging from minute- to life-long adaptations and likely involves reorganization of presynaptic active zones (AZs). At Drosophila melanogaster neuromuscular junctions, earlier work ascribed AZ enlargement by incorporating more Bruchpilot (Brp) scaffold protein a role in PHP. We use localization microscopy (direct stochastic optical reconstruction microscopy [dSTORM]) and hierarchical density-based spatial clustering of applications with noise (HDBSCAN) to study AZ plasticity during PHP at the synaptic mesoscale. We find compaction of individual AZs in acute philanthotoxin-induced and chronic genetically induced PHP but unchanged copy numbers of AZ proteins. Compaction even occurs at the level of Brp subclusters, which move toward AZ centers, and in Rab3 interacting molecule (RIM)-binding protein (RBP) subclusters. Furthermore, correlative confocal and dSTORM imaging reveals how AZ compaction in PHP translates into apparent increases in AZ area and Brp protein content, as implied earlier.
The mason wasp Odynerus spinipes shows an exceptional case of intrasexual cuticular hydrocarbon (CHC) profile dimorphism. Females of this species display one of two CHC profiles (chemotypes) that differ qualitatively and quantitatively from each other. The ratio of the two chemotypes was previously shown to be close to 1:1 at three sites in Southern Germany, which might not be representative given the Palearctic distribution of the species. To infer the frequency of the two chemotypes across the entire distributional range of the species, we analyzed with GC–MS the CHC profile of 1042 dry-mounted specimens stored in private and museum collections. We complemented our sampling by including 324 samples collected and preserved specifically for studying their CHCs. We were capable of reliably identifying the chemotypes in 91% of dry-mounted samples, some of which collected almost 200 years ago. We found both chemotypes to occur in the Far East, the presumed glacial refuge of the species, and their frequency to differ considerably between sites and geographic regions. The geographic structure in the chemotype frequencies could be the result of differential selection regimes and/or different dispersal routes during the colonization of the Western Palearctic. The presented data pave the route for disentangling these factors by providing information where to geographically sample O. spinipes for population genetic analyses. They also form the much-needed basis for future studies aiming to understand the evolutionary and geographic origin as well as the genetics of the astounding CHC profile dimorphism that O. spinipes females exhibit.
Enteric glial cells (EGCs) of the enteric nervous system are critically involved in the maintenance of intestinal epithelial barrier function (IEB). The underlying mechanisms remain undefined. Glial cell line-derived neurotrophic factor (GDNF) contributes to IEB maturation and may therefore be the predominant mediator of this process by EGCs. Using GFAP\(^{cre}\) x Ai14\(^{floxed}\) mice to isolate EGCs by Fluorescence-activated cell sorting (FACS), we confirmed that they synthesize GDNF in vivo as well as in primary cultures demonstrating that EGCs are a rich source of GDNF in vivo and in vitro. Co-culture of EGCs with Caco2 cells resulted in IEB maturation which was abrogated when GDNF was either depleted from EGC supernatants, or knocked down in EGCs or when the GDNF receptor RET was blocked. Further, TNFα-induced loss of IEB function in Caco2 cells and in organoids was attenuated by EGC supernatants or by recombinant GDNF. These barrier-protective effects were blunted when using supernatants from GDNF-deficient EGCs or by RET receptor blockade. Together, our data show that EGCs produce GDNF to maintain IEB function in vitro through the RET receptor.