Germline antibodies, the initial set of antibodies produced by the immune system, are critical for host defense, and information about their binding properties can be useful for designing vaccines, ...understanding the origins of autoantibodies, and developing monoclonal antibodies. Numerous studies have found that germline antibodies are polyreactive with malleable, flexible binding pockets. While insightful, it remains unclear how broadly this model applies, as there are many families of antibodies that have not yet been studied. In addition, the methods used to obtain germline antibodies typically rely on assumptions and do not work well for many antibodies. Herein, we present a distinct approach for isolating germline antibodies that involves immunizing activation-induced cytidine deaminase (AID) knockout mice. This strategy amplifies antigen-specific B cells, but somatic hypermutation does not occur because AID is absent. Using synthetic haptens, glycoproteins, and whole cells, we obtained germline antibodies to an assortment of clinically important tumor-associated carbohydrate antigens, including Lewis Y, the Tn antigen, sialyl Lewis C, and Lewis X (CD15/SSEA-1). Through glycan microarray profiling and cell binding, we demonstrate that all but one of these germline antibodies had high selectivity for their glycan targets. Using molecular dynamics simulations, we provide insights into the structural basis of glycan recognition. The results have important implications for designing carbohydrate-based vaccines, developing anti-glycan monoclonal antibodies, and understanding antibody evolution within the immune system.
Landslides are a major category of natural disasters, causing loss of lives, livelihoods and property. The critical roles played by triggering (such as extreme rainfall and earthquakes), and ...intrinsic factors (such as slope steepness, soil properties and lithology) have previously successfully been recognized and quantified using a variety of qualitative, quantitative and hybrid methods in a wide range of study sites. However, available data typically do not allow to investigate the effect that earlier landslides have on intrinsic factors and hence on follow-up landslides. Therefore, existing methods cannot account for the potentially complex susceptibility changes caused by landslide events. In this study, we used a substantially different alternative approach to shed light on the potential effect of earlier landslides using a multi-temporal dataset of landslide occurrence containing 17 time slices. Spatial overlap and the time interval between landslides play key roles in our work. We quantified the degree to which landslides preferentially occur in locations where landslides occurred previously, how long such an effect is noticeable, and how landslides are spatially associated over time. We also investigated whether overlap with previous landslides causes differences in landslide geometric properties. We found that overlap among landslides demonstrates a clear legacy effect (path dependency) that has influence on the landslide affected area. Landslides appear to cause greater susceptibility for follow-up landslides over a period of about 10 years. Follow-up landslides are on average larger and rounder than landslides that do not follow earlier slides. The effect of earlier landslides on follow-up landslides has implications for understanding of the landslides evolution and the assessment of landslide susceptibility.
Landslide susceptibility modelling—a crucial step towards the assessment of landslide hazard and risk—has hitherto not included the local, transient effects of previous landslides on susceptibility. ...In this contribution, we implement such transient effects, which we term “landslide path dependency”, for the first time. Two landslide path dependency variables are used to characterise transient effects: a variable reflecting how likely it is that an earlier landslide will have a follow-up landslide and a variable reflecting the decay of transient effects over time. These two landslide path dependency variables are considered in addition to a large set of conditioning attributes conventionally used in landslide susceptibility. Three logistic regression models were trained and tested fitted to landslide occurrence data from a multi-temporal landslide inventory: (1) a model with only conventional variables, (2) a model with conventional plus landslide path dependency variables, and (3) a model with only landslide path dependency variables. We compare the model performances, differences in the number, coefficient and significance of the selected variables, and the differences in the resulting susceptibility maps. Although the landslide path dependency variables are highly significant and have impacts on the importance of other variables, the performance of the models and the susceptibility maps do not substantially differ between conventional and conventional plus path dependent models. The path dependent landslide susceptibility model, with only two explanatory variables, has lower model performance, and differently patterned susceptibility map than the two other models. A simple landslide susceptibility model using only DEM-derived variables and landslide path dependency variables performs better than the path dependent landslide susceptibility model, and almost as well as the model with conventional plus landslide path dependency variables—while avoiding the need for hard-to-measure variables such as land use or lithology. Although the predictive power of landslide path dependency variables is lower than those of the most important conventional variables, our findings provide a clear incentive to further explore landslide path dependency effects and their potential role in landslide susceptibility modelling.
Urinary incontinence, defined as involuntary leakage of urine, is often considered a disorder of post-partum and post-menopausal women. However, this disorder is not exclusive to older women, as ...recent research has demonstrated a high prevalence of urinary incontinence among young, nulliparous female athletes. In fact, females participating in repetitive, high-impact sports are at the highest risk for urinary incontinence. In these athletes, the absence of sufficient pelvic floor strength and coordination to withstand sport related increases in intra-abdominal pressure results in physical activity related urinary incontinence, and may be a predictor of urinary incontinence in later adulthood. Pelvic floor dysfunction and urinary incontinence in this population is under-reported and consequently under-diagnosed and under-treated. Therefore, the prevalence is higher than one might expect, and the effects can include decreased performance, change in sport and avoidance of physical activity all together. This manuscript highlights the prevalence of pelvic floor dysfunction and outlines its pathophysiology, diagnosis, treatment, and rehabilitation. We discuss how greater recognition of this disorder by health care providers and routinely querying active females is a critical step in addressing this issue. Identification, education and appropriate rehabilitation can positively affect outcomes in regards to urinary incontinence symptoms and maintain physical activity participation in these athletes.
Purpose
Three previously published datasets of high-mountain soil variation in proglacial valleys in the Swiss Alps (80 soils) and a new dataset of high-mountain soil variation in a formerly ...glaciated valley in the Colorado Rocky Mountains (9 soils) are used to test the validity of the chronosequence approach and to study divergence and convergence of soil properties.
Materials and methods
Standard field-based soil observations were done, complemented with simple laboratory measurements of pH and soil organic matter.
Results and discussion
The mean values of soil properties change over time, as well as their standard deviations and coefficients of variation. Variation in soil properties between soils of the same age is significant. Although sampling was performed at locations that are assumed to be geomorphically stable, the observed variation in properties casts doubt on this assumption. Depending on the valley and the soil property, standard deviations and coefficients of variation increase over time whereas in other cases, they decrease. This indicates divergence and convergence of soil properties over centennial and Holocene timescales, respectively. Both dynamics are explored quantitatively.
Conclusions
Divergence is observed in settings that are unaffected by outside (hillslope) influences and presumably caused by vegetation differences and small-scale (diffusive) redistribution of the fine earth fraction. Convergence is observed in settings where soil formation is disturbed by outside influences. In the Swiss Alps, this influence is the provision of material from surrounding hillslopes. Chronosequence studies should sample and average multiple soils per age group, to characterize soil variation and minimize the uncertainty in the estimation of soil properties.
Up to ∼20% of HIV-infected individuals eventually develop broadly neutralizing antibodies (bnAbs), and many of these antibodies (∼40%) target a region of dense high-mannose glycosylation on gp120 of ...the HIV envelope protein, known as the “high-mannose patch” (HMP). Thus, there have been numerous attempts to develop glycoconjugate vaccine immunogens that structurally mimic the HMP and might elicit bnAbs targeting this conserved neutralization epitope. Herein, we report on the immunogenicity of glycopeptides, designed by in vitro selection, that bind tightly to anti-HMP antibody 2G12. By analyzing the fine carbohydrate specificity of rabbit antibodies elicited by these immunogens, we found that they differ from some natural human bnAbs, such as 2G12 and PGT128, in that they bind primarily to the core structures within the glycan, rather than to the Manα1 → 2Man termini (2G12) or to the whole glycan (PGT128). Antibody specificity for the glycan core may result from extensive serum mannosidase trimming of the immunogen in the vaccinated animals. This finding has broad implications for vaccine design aiming to target glycan-dependent HIV neutralizing antibodies.
Evolutionary adaptation to variation in resource supply has resulted in plant strategies that are based on trade‐offs in functional traits. Here, we investigate, for the first time across multiple ...species, whether such trade‐offs are also apparent in growth and morphology responses to past low, current ambient, and future high CO2 concentrations. We grew freshly germinated seedlings of up to 28 C3 species (16 forbs, 6 woody, and 6 grasses) in climate chambers at 160 ppm, 450 ppm, and 750 ppm CO2. We determined biomass, allocation, SLA (specific leaf area), LAR (leaf area ratio), and RGR (relative growth rate), thereby doubling the available data on these plant responses to low CO2. High CO2 increased RGR by 8%; low CO2 decreased RGR by 23%. Fast growers at ambient CO2 had the greatest reduction in RGR at low CO2 as they lost the benefits of a fast‐growth morphology (decoupling of RGR and LAR leaf area ratio). Despite these shifts species ranking on biomass and RGR was unaffected by CO2, winners continued to win, regardless of CO2. Unlike for other plant resources we found no trade‐offs in morphological and growth responses to CO2 variation, changes in morphological traits were unrelated to changes in growth at low or high CO2. Thus, changes in physiology may be more important than morphological changes in response to CO2 variation.
Evolutionary adaptation to variation in resource supply has resulted in plant strategies that are based on trade‐offs in functional traits. For up to 28 C3 species (16 forbs, 6 woody and 6 grasses) we analysed if such trade‐offs are apparent in growth and morphology responses to past low, current ambient and future high CO2 concentrations. We found no trade‐offs in morphological and growth responses to CO2 variation. Winners continued to win, regardless of CO2.
Prognosis for patients suffering from malignant glioma has not substantially improved. Specific immunotherapy as a novel treatment concept critically depends on target antigens, which are highly ...overexpressed in the majority of gliomas, but the number of such antigens is still very limited. SOX2 was identified by screening an expression database for transcripts that are overexpressed in malignant glioma, but display minimal expression in normal tissues. Expression of SOX2 mRNA was further investigated in tumour and normal tissues by real-time PCR. Compared to cDNA from pooled normal brain, SOX2 was overexpressed in almost all (9 out of 10) malignant glioma samples, whereas expression in other, non-malignant tissues was almost negligible. SOX2 protein expression in glioma cell lines and tumour tissues was verified by Western blot and immunofluorescence. Immunohistochemistry demonstrated SOX2 protein expression in all malignant glioma tissues investigated ranging from 6 to 66% stained tumour cells. Human leucocyte antigen-A(*)0201-restricted SOX2-derived peptides were tested for the activation of glioma-reactive CD8+ cytotoxic T lymphocytes (CTLs). Specific CTLs were raised against the peptide TLMKKDKYTL and were capable of lysing glioma cells. The abundant and glioma-restricted overexpression of SOX2 and the generation of SOX2-specific and tumour-reactive CTLs may recommend this antigen as target for T-cell-based immunotherapy of glioma.
Primary dysmenorrhea (PD; menstrual pain without an identified organic cause) has been proposed as a possible risk factor for the development of chronic pelvic pain, but the mechanism through which ...this process occurs is unknown. One possible mechanism is central sensitization - alterations in the central nervous system that increase responsiveness to pain leading to hypersensitivity. Repeated episodes of pain, such as those experienced over time with PD, may alter how the brain processes pain. Ecological momentary assessment (EMA; collection of data in real time in participants' natural environments) is a novel data collection method that may help elucidate pain occurring during non-menstrual cycle phases.
The current observational study assessed the feasibility and acceptability of using EMA via text messages to collect pelvic pain data during menstrual and non-menstrual cycle phases in a community sample of adolescents and young adults (AYA) aged 16-24 years with and without PD and explored occurrence rates and intensity of non-menstrual pelvic pain (NMPP) in each of these groups.
Thirty-nine AYA with PD and 53 healthy controls reported pelvic pain level via nightly text message. Global response rate was 98.5%, and all participants reported that the EMA protocol was acceptable. AYA with PD reported higher intensity (2.0 vs 1.6 on 0-10 numeric rating scale; p=0.003) and frequency (8.7% vs 3.1% of days; p=0.004) of NMPP compared to healthy controls.
The EMA protocol was feasible and acceptable. Though both the intensity and frequency of NMPP were low and at levels that would not typically warrant clinical assessment or intervention, these repeated nociceptive events may represent a potential mechanism contributing to the transition from cyclical to chronic pelvic pain in some individuals.
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