Land management: data availability and process understanding for global change studies

In the light of daunting global sustainability challenges such as climate change, biodiversity loss and food security, improving our understanding of the complex dynamics of the Earth system is crucial. However, large knowledge gaps related to the effects of land management persist, in particular those human‐induced changes in terrestrial ecosystems that do not result in land‐cover conversions. Here, we review the current state of knowledge of ten common land management activities for their biogeochemical and biophysical impacts, the level of process understanding and data availability. Our review shows that ca. one‐tenth of the ice‐free land surface is under intense human management, half under medium and one‐fifth under extensive management. Based on our review, we cluster these ten management activities into three groups: (i) management activities for which data sets are available, and for which a good knowledge base exists (cropland harvest and irrigation); (ii) management activities for which sufficient knowledge on biogeochemical and biophysical effects exists but robust global data sets are lacking (forest harvest, tree species selection, grazing and mowing harvest, N fertilization); and (iii) land management practices with severe data gaps concomitant with an unsatisfactory level of process understanding (crop species selection, artificial wetland drainage, tillage and fire management and crop residue management, an element of crop harvest). Although we identify multiple impediments to progress, we conclude that the current status of process understanding and data availability is sufficient to advance with incorporating management in, for example, Earth system or dynamic vegetation models in order to provide a systematic assessment of their role in the Earth system. This review contributes to a strategic prioritization of research efforts across multiple disciplines, including land system research, ecological research and Earth system modelling.     

What makes bacterial pathogens so sticky?

Pathogenic bacteria use a variety of cell surface adhesins to promote binding to host tissues and protein-coated biomaterials, as well as cell–cell aggregation. These cellular interactions represent the first essential step that leads to host colonization and infection. Atomic force microscopy (AFM) has greatly contributed to increase our understanding of the specific interactions at play during microbial adhesion, down to the single-molecule level. A key asset of AFM is that adhesive interactions are studied under mechanical force, which is highly relevant as surface-attached pathogens are often exposed to physical stresses in the human body. These studies have identified sophisticated binding mechanisms in adhesins, which represent promising new targets for antiadhesion therapy.     

Poaching lowers elephant path tortuosity: implications for conservation

Poaching is the most immediate threat to African elephants (Loxodonta africana). Several continental-wide surges in poaching have occurred since the latter half of the twentieth century, and the latest surge occurred from 2007 to 2012. The behavioral responses of elephants to poaching risk has not been studied widely because of a lack of high-resolution movement data collected simultaneously with verified causes of mortality. We managed to collate 2 such datasets from 2004 to 2013. We studied the spatial-temporal changes in movement behavior of 11 elephants in their core areas. Past studies have focused on elephant movement along corridors. We tested for the effect of poaching risk on their path straightness (i.e., tortuosity) while controlling for other environmental and human activities in the landscape using a set of generalized linear mixed models. To test for temporal variation of tortuosity, we used a time-series linear model. Elephants turned less frequently while they were in poaching locations and at times with a high level of poaching activity, even though their speed did not change. The variation of tortuosity is a good indicator of differences in poaching risk as perceived by the elephants, which could complement patrol-based anti-poaching efforts by wildlife managers, especially in remote, inaccessible landscapes. © 2019 The Authors. The Journal of Wildlife Management published by Wiley Periodicals, Inc. on behalf of The Wildlife Society     

Human papillomavirus persistence in young unscreened women, a prospective cohort study

Objective

To evaluate hr-HPV persistence and associated risk factors in a prospective cohort of young unscreened women. Additionally, the relation between hr-HPV status and cytology/histology results is examined.

Methods and Principal Findings

Two year follow-up of 235 out of 2065 young women (18–29 years), participating in a large, one year epidemiological study, with questionnaires, self-collected cervico-vaginal samples (Vibabrush), and SPF₁₀LiPA for HPV detection. Only women hr-HPV positive at sample month 12 were invited for a second year of follow-up. After study follow-up, available cytology/histology data were requested from PALGA (the national network and registry of histo- and cytopathology in The Netherlands). These data were compared with available cytology/histology data of the month 12 hr-HPV negative women from the same cohort. 44.1% of the hr-HPV types detected at study month 12, persisted during follow-up. HPV types 45, 31, 16 and 18 were most likely to persist with percentages of 60.0%, 56.8%, 54.4%,and 50.0%, respectively. Compared to newly detected infections at month 12, infections present since 6 months or baseline had an increased risk to persist (OR 3.09 [95% CI: 1.74–5.51] and OR 4.99 [95% CI: 2.67–9.32], respectively). Other co-factors influencing persistence were, multiple HPV infections, smoking and multiple lifetime sexual partners. The percentage of women with a HSIL/CIN2+ (12.1%) in the persistent HPV group, was not significantly different (p = 0.107) from the 5.3% of the women who cleared the hr-HPV infection, but was significantly (p 0.000) higher than to the 1.6% of women in the hr-HPV negative control group.

Conclusion

We showed that HPV genotype, multiple infections, smoking, and multiple lifetime sexual partners are co-factors that increase the risk of hr-HPV persistency. Most importantly, we showed that hr-HPV infections are more likely to persist the longer they have been present and that women with a persistent hr-HPV infection have a high risk of HSIL/CIN2+ development.     

Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases

Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission. We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease. Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates. Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.     

A new piperidinol derivative targeting mycolic acid transport in Mycobacterium abscessus

The natural resistance of Mycobacterium abscessus to most commonly available antibiotics seriously limits chemotherapeutic treatment options, which is particularly challenging for cystic fibrosis patients infected with this rapid‐growing mycobacterium. New drugs with novel molecular targets are urgently needed against this emerging pathogen. However, the discovery of such new chemotypes has not been appropriately performed. Here, we demonstrate the utility of a phenotypic screen for bactericidal compounds against M. abscessus using a library of compounds previously validated for activity against M. tuberculosis. We identified a new piperidinol‐based molecule, PIPD1, exhibiting potent activity against clinical M. abscessus strains in vitro and in infected macrophages. Treatment of infected zebrafish with PIPD1 correlated with increased embryo survival and decreased bacterial burden. Whole genome analysis of M. abscessus strains resistant to PIPD1 identified several mutations in MAB_4508, encoding a protein homologous to MmpL3. Biochemical analyses demonstrated that while de novo mycolic acid synthesis was unaffected, PIPD1 strongly inhibited the transport of trehalose monomycolate, thereby abrogating mycolylation of arabinogalactan. Mapping the mutations conferring resistance to PIPD1 on a MAB_4508 tridimensional homology model defined a potential PIPD1‐binding pocket. Our data emphasize a yet unexploited chemical structure class against M. abscessus infections with promising translational development possibilities.     

Infarct-related chronic total coronary occlusion and the risk of ventricular tachyarrhythmic events in out-of-hospital cardiac arrest survivors

IntroductionChronic total coronary occlusion (CTO) has been identified as a risk factor for ventricular arrhythmias, especially a CTO in an infarct-related artery (IRA). This study aimed to evaluate the effect of an IRA-CTO on the occurrence of ventricular tachyarrhythmic events (VTEs) in out-of-hospital cardiac arrest survivors without ST-segment elevation.MethodsWe conducted a post hoc analysis of the COACT trial, a multicentre randomised controlled trial. Patients were included when they survived index hospitalisation after cardiac arrest and demonstrated coronary artery disease on coronary angiography. The primary endpoint was the occurrence of a VTE, defined as appropriate implantable cardioverter-defibrillator (ICD) therapy, sustained ventricular tachyarrhythmia or sudden cardiac death.ResultsA total of 163 patients from ten centres were included. Unrevascularised IRA-CTO in a main vessel was present in 43 patients (26%). Overall, 61% of the study population received an ICD for secondary prevention. During a follow-up of 1 year, 12 patients (7.4%) experienced at least one VTE. The cumulative incidence rate of VTEs was higher in patients with an IRA-CTO compared to patients without an IRA-CTO (17.4% vs 5.6%, log-rank p = 0.03). However, multivariable analysis only identified left ventricular ejection fraction < 35% as an independent factor associated with VTEs (adjusted hazard ratio 8.7, 95% confidence interval 2.2–35.4). A subanalysis focusing on CTO, with or without an infarct in the CTO territory, did not change the results.ConclusionIn out-of-hospital cardiac arrest survivors with coronary artery disease without ST-segment elevation, an IRA-CTO was not an independent factor associated with VTEs in the 1st year after the index event.Supplementary InformationThe online version of this article (10.1007/s12471-021-01578-3) contains supplementary material, which is available to authorized users.     

Inhibition of the transforming growth factor beta (TGFbeta) pathway by interleukin-1beta is mediated through TGFbeta-activated kinase 1 phosphorylation of SMAD3

Transforming growth factor β is the prototype of a large family of secreted factors that regulate multiple biological processes. In the immune system, TGFβ acts as an anti-inflammatory and immunosuppressive molecule, whereas the cytokine interleukin (IL)-1β is a crucial mediator of inflammatory responses and induces proinflammatory genes and acute phase proteins. Here, we present evidence for the existence of a direct inhibitory interaction between the IL-1β and TGFβ signaling cascades that is not dependent on IL-1β–induced SMAD7 expression. IL-1β and its downstream mediator TAK1 inhibit SMAD3-mediated TGFβ target gene activation, whereas SMAD3 nuclear translocation and DNA binding in response to TGFβ are not affected. IL-1β transiently induces association between TAK1 and the MAD homology 2 domain of SMAD3, resulting in SMAD3 phosphorylation. Furthermore, IL-1β alleviates the inhibitory effect of TGFβ on in vitro hematopoietic myeloid colony formation. In conclusion, our data provide evidence for the existence of a direct inhibitory effect of the IL-1β-TAK1 pathway on SMAD3-mediated TGFβ signaling, resulting in reduced TGFβ target gene activation and restored proliferation of hematopoietic progenitors.