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River-valley morphology preserves information on tectonic and climatic conditions that shape landscapes. Observations suggest that river discharge and valley-wall lithology are the main controls on valley width. Yet, current models based on these observations fail to explain the full range of cross-sectional valley shapes in nature, suggesting hitherto unquantified controls on valley width. In particular, current models cannot explain the existence of paired terrace sequences that form under cyclic climate forcing. Paired river terraces are staircases of abandoned floodplains on both valley sides, and hence preserve past valley widths. Their formation requires alternating phases of predominantly river incision and predominantly lateral planation, plus progressive valley narrowing. While cyclic Quaternary climate changes can explain shifts between incision and lateral erosion, the driving mechanism of valley narrowing is unknown. Here, we extract valley geometries from climatically formed, alluvial river-terrace sequences and show that across our dataset, the total cumulative terrace height (here: total valley height) explains 90%–99% of the variance in valley width at the terrace sites. This finding suggests that valley height, or a parameter that scales linearly with valley height, controls valley width in addition to river discharge and lithology. To explain this valley-width-height relationship, we reformulate existing valley-width models and suggest that, when adjusting to new boundary conditions, alluvial valleys evolve to a width at which sediment removal from valley walls matches lateral sediment supply from hillslope erosion. Such a hillslope-channel coupling is not captured in current valley-evolution models. Our model can explain the existence of paired terrace sequences under cyclic climate forcing and relates valley width to measurable field parameters. Therefore, it facilitates the reconstruction of past climatic and tectonic conditions from valley topography.
Background: Network models are useful tools for researchers to simplify and understand investigated systems. Yet, the assessment of methods for network construction is often uncertain. Random resampling simulations can aid to assess methods, provided synthetic data exists for reliable network construction.
Objectives: We implemented a new Monte Carlo algorithm to create simulated data for network reconstruction, tested the influence of adjusted parameters and used simulations to select a method for network model estimation based on real-world data. We hypothesized, that reconstructs based on Monte Carlo data are scored at least as good compared to a benchmark.
Methods: Simulated data was generated in R using the Monte Carlo algorithm of the mcgraph package. Benchmark data was created by the huge package. Networks were reconstructed using six estimator functions and scored by four classification metrics. For compatibility tests of mean score differences, Welch’s t-test was used. Network model estimation based on real-world data was done by stepwise selection.
Samples: Simulated data was generated based on 640 input graphs of various types and sizes. The real-world dataset consisted of 67 medieval skeletons of females and males from the region of Refshale (Lolland) and Nordby (Jutland) in Denmark.
Results: Results after t-tests and determining confidence intervals (CI95%) show, that evaluation scores for network reconstructs based on the mcgraph package were at least as good compared to the benchmark huge. The results even indicate slightly better scores on average for the mcgraph package.
Conclusion: The results confirmed our objective and suggested that Monte Carlo data can keep up with the benchmark in the applied test framework. The algorithm offers the feature to use (weighted) un- and directed graphs and might be useful for assessing methods for network construction.
Background: Clinicians often refer anthropometric measures of a child to so-called “growth standards” and “growth references. Over 140 countries have meanwhile adopted WHO growth standards.
Objectives: The present study was conducted to thoroughly examine the idea of growth standards as a common yardstick for all populations. Weight depends on height. We became interested in whether also weight-for-height depends on height. First, we studied the age-group effect on weight-for-height. Thereafter, we tested the applicability of weight-for-height references in short and in historic populations.
Sample and Methods: We analyzed body height and body weight and weight-for-height of 3795 healthy boys and 3726 healthy girls aged 2 to 5 years measured in East-Germany between 1986 and 1990.
We chose contemporary height and weight charts from Germany, the UK, and the WHO growth chart and compared these with three geographically commensurable growth charts from the end of the 19th century.
Results: We analyzed body height and body weight and weight-for-height of 3795 healthy boys and 3726 healthy girls aged 2 to 5 years measured in East-Germany between 1986 and 1990.
We chose contemporary height and weight charts from Germany, the UK, and the WHO growth chart and compared these with three geographically commensurable growth charts of the end of the 19th century.
Conclusion: Weight-for-height depends on age and sex and apart from the nutritional state, reflects body proportion and body built particularly during infancy and early childhood. Populations with a relatively short average height are prone to high values of weight-for-height for arithmetic reasons independent of the nutritional state.
Background: Biological age markers are a crucial indicator whether children are decelerated in growth tempo. Skeletal maturation is the standard measure. Yet, it relies on exposing children to x-radiation. Dental eruption is a potential, but highly debated, radiation free alternative.
Objectives: We assess the interrelationship between dental eruption and other maturational markers. We hypothesize that dental age correlates with body height and skeletal age. We further evaluate how the three different variables behave in cohorts from differing social backgrounds.
Sample and Method: Dental, skeletal and height data from the 1970s to 1990s from Guatemalan boys were converted into standard deviation scores, using external references for each measurement. The boys, aged between 7 and 12, derived from different social backgrounds (middle SES (N = 6529), low-middle SES (N = 736), low SES Ladino (N = 3653) and low SES Maya (N = 4587).
Results: Dental age shows only a weak correlation with skeletal age (0.18) and height (0.2). The distinction between cohorts differs according to each of the three measurements. All cohorts differ significantly in height. In skeletal maturation, the middle SES cohort is significantly advanced compared to all other cohorts. The periodically malnourished cohorts of low SES Mayas and Ladinos are significantly delayed in dental maturation compared to the well-nourished low-middle and middle class Ladino children.
Conclusion: Dental development is an independent system, that is regulated by different mechanisms than skeletal development and growth. Tooth eruption is sensitive to nutritional status, whereas skeletal age is more sensitive to socioeconomic background.
Students learn by repetition. Repetition is essential, but repetition needs questioning, and questioning the repertoire belongs to the essential tasks of student education. Guiding students to questioning was and is our prime motive to offer our International Student Summer Schools. The data were critically discussed among the students, in the twilight of Just So Stories, common knowledge, and prompted questioning of contemporary solutions. For these schools, the students bring their own data, carry their preliminary concepts, and in group discussions, they may have to challenge these concepts. Catch-up growth is known to affect long bone growth, but different opinions exist to what extent it also affects body proportions. Skeletal age and dental development are considered appropriate measures of maturation, but it appears that both system develop independently and are regulated by different mechanisms. Body weight distributions are assumed to be skewed, yet, historic data disproved this assumption. Many discussions focused on current ideas of global growth standards as a common yardstick for all populations world-wide, with new statistical tools being developed including network reconstruction and evaluation of the reconstructs to determine the confidence of graph prediction methods.
125 years ago, European infants grew differently from modern infants. We show weight gains of 20 healthy children weighed longitudinally from birth to age 1 year, published by Camerer in 1882. The data illustrate the historically prevalent concepts of infant nutrition practiced by German civil servants, lawyers, merchants, university professors, physicians, foresters and farmers. Breastfeeding by the mother was not truly appreciated in those days; children were often breastfed by wet nurses or received bottled milk. Bottle feeding mainly used diluted cow’s milk with some added carbohydrates, without evidence that appropriate amounts of oil, butter or other fatty components were added. French children from 1914 showed similar weight gain patterns suggesting similar feeding practices. The historical data suggest that energy deficient infant formula was fed regularly in the late 19th and early 20th century Europe, regardless of wealth and social class. The data question current concerns that temporarily feeding energy deficient infant formula may warrant serious anxieties regarding long-term cognitive, social and emotional behavioral development.
Background: Child growth is a dynamic process. When measured at short intervals, children’s growth shows characteristic patterns that can be of great importance for clinical purposes.
Objective: To study whether measuring height on a daily basis using an APP is practicable and user-friendly.
Methods: Recruitment took place via Snowball Sampling. Thirteen out of 14 contacted families signed up for a study period of 12 weeks with altogether 22 healthy children aged 3 to 13 years (response rate 93%). The study started with a visit to the family home for the setup of the measurement site, conventional height measuring and initial training of the new measurement process. Follow-up appointments were made at four, eight and 12 weeks. The children’s height was measured at daily intervals at their family homes over a period of three months.
Results: The parents altogether recorded 1704 height measurements and meticulously documented practicability and problems when using the device.
A 93% response rate in recruitment was achieved by maintaining a high motivation within the families. Contact with the principal investigator was permanently available, including open communication, personal training and attendance during the appointments at the family homes.
Conclusion: Measuring height by photographic display is interesting for children and parents and can be used for height measurements at home. A positive response rate of 13 out of 14 families with altogether 22 children highlights feasible recruitment and the high convenience and user-friendliness of daily APP-supported height measurements. Daily APP measurements appear to be a promising new tool for longitudinal growth studies.
Stimuli-promoted in situ formation of hydrogels with thiol/thioester containing peptide precursors
(2022)
Hydrogels are potential synthetic ECM-like substitutes since they provide functional and structural similarities compared to soft tissues. They can be prepared by crosslinking of macromolecules or by polymerizing suitable precursors. The crosslinks are not necessarily covalent bonds, but could also be formed by physical interactions such as π-π interactions, hydrophobic interactions, or H-bonding. On demand in situ forming hydrogels have garnered increased interest especially for biomedical applications over preformed gels due to the relative ease of in vivo delivery and filling of cavities. The thiol-Michael addition reaction provides a straightforward and robust strategy for in situ gel formation with its fast reaction kinetics and ability to proceed under physiological conditions. The incorporation of a trigger function into a crosslinking system becomes even more interesting since gelling can be controlled with stimulus of choice. The use of small molar mass crosslinker precursors with active groups orthogonal to thiol-Michael reaction type electrophile provides the opportunity to implement an on-demand in situ crosslinking without compromising the fast reaction kinetics.
It was postulated that short peptide sequences due to the broad range structural-function relations available with the different constituent amino acids, can be exploited for the realisation of stimuli-promoted in situ covalent crosslinking and gelation applications. The advantages of this system over conventional polymer-polymer hydrogel systems are the ability tune and predict material property at the molecular level.
The main aim of this work was to develop a simplified and biologically-friendly stimuli-promoted in situ crosslinking and hydrogelation system using peptide mimetics as latent crosslinkers. The approach aims at using a single thiodepsipeptide sequence to achieve separate pH- and enzyme-promoted gelation systems with little modification to the thiodepsipeptide sequence. The realization of this aim required the completion of three milestones.
In the first place, after deciding on the thiol-Michael reaction as an effective in situ crosslinking strategy, a thiodepsipeptide, Ac-Pro-Leu-Gly-SLeu-Leu-Gly-NEtSH (TDP) with expected propensity towards pH-dependent thiol-thioester exchange (TTE) activation, was proposed as a suitable crosslinker precursor for pH-promoted gelation system. Prior to the synthesis of the proposed peptide-mimetic, knowledge of the thiol-Michael reactivity of the would-be activated thiol moiety SH-Leu, which is internally embedded in the thiodepsipeptide was required. In line with pKa requirements for a successful TTE, the reactivity of a more acidic thiol, SH-Phe was also investigated to aid the selection of the best thiol to be incorporated in the thioester bearing peptide based crosslinker precursor. Using ‘pseudo’ 2D-NMR investigations, it was found that only reactions involving SH-Leu yielded the expected thiol-Michael product, an observation that was attributed to the steric hindrance of the bulkier nature of SH-Phe. The fast reaction rates and complete acrylate/maleimide conversion obtained with SH-Leu at pH 7.2 and higher aided the direct elimination of SH-Phe as a potential thiol for the synthesis of the peptide mimetic.
Based on the initial studies, for the pH-promoted gelation system, the proposed Ac-Pro-Leu-Gly-SLeu-Leu-Gly-NEtSH was kept unmodified. The subtle difference in pKa values between SH-Leu (thioester thiol) and the terminal cysteamine thiol from theoretical conditions should be enough to effect a ‘pseudo’ intramolecular TTE. In polar protic solvents and under basic aqueous conditions, TDP successfully undergoes a ‘pseudo’ intramolecular TTE reaction to yield an α,ω-dithiol tripeptide, HSLeu-Leu-Gly-NEtSH. The pH dependence of thiolate ion generation by the cysteamine thiol aided the incorporation of the needed stimulus (pH) for the overall success of TTE (activation step) – thiol-Michael addition (crosslinking) strategy.
Secondly, with potential biomedical applications in focus, the susceptibility of TDP, like other thioesters, to intermolecular TTE reaction was probed with a group of thiols of varying thiol pKa values, since biological milieu characteristically contain peptide/protein thiols. L-cysteine, which is a biologically relevant thiol, and a small molecular weight thiol, methylthioglycolate both with relatively similar thiol pKa, values, led to an increase concentration of the dithiol crosslinker when reacted with TDP. In the presence of acidic thiols (p-NTP and 4MBA), a decrease in the dithiol concentration was observed, an observation that can be attributed to the inability of the TTE tetrahedral intermediate to dissociate into exchange products and is in line with pKa requirements for successful TTE reaction. These results additionally makes TDP more attractive and the potentially the first crosslinker precursor for applications in biologically relevant media.
Finally, the ability of TDP to promote pH-sensitive in situ gel formation was probed with maleimide functionalized 4-arm polyethylene glycol polymers in tris-buffered media of varying pHs. When a 1:1 thiol: maleimide molar ratio was used, TDP-PEG4MAL hydrogels formed within 3, 12 and 24 hours at pH values of 8.5, 8.0 and 7.5 respectively. However, gelation times of 3, 5 and 30 mins were observed for the same pH trend when the thiol: maleimide molar was increased to 2:1.
A direct correlation of thiol content with G’ of the gels at each pH could also be drawn by comparing gels with thiol: maleimide ratios of 1:1 to those with 2:1 thiol: maleimide mole ratios. This is supported by the fact that the storage modulus (G') is linearly dependent on the crosslinking density of the polymer. The values of initial G′ for all gels ranged between (200 – 5000 Pa), which falls in the range of elasticities of certain tissue microenvironments for example brain tissue 200 – 1000 Pa and adipose tissue (2500 – 3500 Pa).
Knowledge so far gained from the study on the ability to design and tune the exchange reaction of thioester containing peptide mimetic will give those working in the field further insight into the development of new sequences tailored towards specific applications.
TTE substrate design using peptide mimetic as presented in this work has revealed interesting new insights considering the state-of-the-art. Using the results obtained as reference, the strategy provides a possibility to extend the concept to the controlled delivery of active molecules needed for other robust and high yielding crosslinking reactions for biomedical applications. Application for this sequentially coupled functional system could be seen e.g. in the treatment of inflamed tissues associated with urinary tract like bladder infections for which pH levels above 7 were reported. By the inclusion of cell adhesion peptide motifs, the hydrogel network formed at this pH could act as a new support layer for the healing of damage epithelium as shown in interfacial gel formation experiments using TDP and PEG4MAL droplets.
The versatility of the thiodepsipeptide sequence, Ac-Pro-Leu-Gly-SLeu-Leu-Gly-(TDPo) was extended for the design and synthesis of a MMP-sensitive 4-arm PEG-TDPo conjugate. The purported cleavage of TDPo at the Gly-SLeu bond yields active thiol units for subsequent reaction of orthogonal Michael acceptor moieties. One of the advantages of stimuli-promoted in situ crosslinking systems using short peptides should be the ease of design of required peptide molecules due to the predictability of peptide functions their sequence structure. Consequently the functionalisation of a 4-arm PEG core with the collagenase active TDPo sequence yielded an MMP-sensitive 4-arm thiodepsipeptide-PEG conjugate (PEG4TDPo) substrate.
Cleavage studies using thiol flourometric assay in the presence of MMPs -2 and -9 confirmed the susceptibility of PEG4TDPo towards these enzymes. The resulting time-dependent increase in fluorescence intensity in the presence of thiol assay signifies the successful cleavage of TDPo at the Gly-SLeu bond as expected. It was observed that the cleavage studies with thiol flourometric assay introduces a sigmoid non-Michaelis-Menten type kinetic profile, hence making it difficult to accurately determine the enzyme cycling parameters, kcat and KM .
Gelation studies with PEG4MAL at 10 % wt. concentrations revealed faster gelation with MMP-2 than MMP-9 with 28 and 40 min gelation times respectively. Possible contributions by hydrolytic cleavage of PEG4TDPo has resulted in the gelation of PEG4MAL blank samples but only after 60 minutes of reaction. From theoretical considerations, the simultaneous gelation reaction would be expected to more negatively impact the enzymatic than hydrolytic cleavage. The exact contributions from hydrolytic cleavage of PEG4TDPo would however require additional studies.
In summary this new and simplified in situ crosslinking system using peptide-based crosslinker precursors with tuneable properties exhibited in situ crosslinking gelation kinetics on similar levels with already active dithiols reported. The advantageous on-demand functionality associated with its pH-sensitivity and physiological compatibility makes it a strong candidate worth further research as biomedical applications in general and on-demand material synthesis is concerned.
Results from MMP-promoted gelation system unveils a simple but unexplored approach for in situ synthesis of covalently crosslinked soft materials, that could lead to the development of an alternative pathway in addressing cancer metastasis by making use of MMP overexpression as a trigger. This goal has so far not being reach with MMP inhibitors despite the extensive work this regard.
Urban pollution
(2022)
We use worldwide satellite data to analyse how population size and density affect urban pollution. We find that density significantly increases pollution exposure. Looking only at urban areas, we find that population size affects exposure more than density. Moreover, the effect is driven mostly by population commuting to core cities rather than the core city population itself. We analyse heterogeneity by geography and income levels. By and large, the influence of population on pollution is greatest in Asia and middle-income countries. A counterfactual simulation shows that PM2.5 exposure would fall by up to 36% and NO2 exposure up to 53% if within countries population size were equalized across all cities.
Background: There is evidence that fully recovered COVID-19 patients usually resume physical exercise, but do not perform at the same intensity level performed prior to infection. The aim of this study was to evaluate the impact of COVID-19 infection and recovery as well as muscle fatigue on cardiorespiratory fitness and running biomechanics in female recreational runners.
Methods: Twenty-eight females were divided into a group of hospitalized and recovered COVID-19 patients (COV, n = 14, at least 14 days following recovery) and a group of healthy age-matched controls (CTR, n = 14). Ground reaction forces from stepping on a force plate while barefoot overground running at 3.3 m/s was measured before and after a fatiguing protocol. The fatigue protocol consisted of incrementally increasing running speed until reaching a score of 13 on the 6–20 Borg scale, followed by steady-state running until exhaustion. The effects of group and fatigue were assessed for steady-state running duration, steady-state running speed, ground contact time, vertical instantaneous loading rate and peak propulsion force.
Results: COV runners completed only 56% of the running time achieved by the CTR (p < 0.0001), and at a 26% slower steady-state running speed (p < 0.0001). There were fatigue-related reductions in loading rate (p = 0.004) without group differences. Increased ground contact time (p = 0.002) and reduced peak propulsion force (p = 0.005) were found for COV when compared to CTR.
Conclusion: Our results suggest that female runners who recovered from COVID-19 showed compromised running endurance and altered running kinetics in the form of longer stance periods and weaker propulsion forces. More research is needed in this area using larger sample sizes to confirm our study findings.