A document by Laura Vergani. Click on the document to view its contents.

Establishing dose response relationships in targeted patients is foundational in the development of therapeutic drugs including gene therapy products. Enlightened by interspecies normalization of plasma drug concentration-time curves using Dedrick plot, the author of this manuscript first demonstrated the feasibility of normalizing dose-response relationship of adeno-associated virus (AAV)-mediated hemophilia gene therapy products in multiple species to a species-invariant scale. Preclinical dose-response relationships of eight AAV vectors were normalized using an exponent of 0.25 and applied to first-in-human (FIH) dose prediction. The performance of this dose-response normalization approach for FIH dose prediction was compared to that of direct body weight-based dose conversion and allometric scaling approaches. The study results suggested that in addition to hemophilia dogs and non-human primates, inclusion of larger animal models (e.g., swine and cattle) in preclinical dose-finding studies of AAV vectors might improve the performance of interspecies dose-response normalization approach. Furthermore, it was found that AAV capsid-specific T cell responses in hemophilia patients might cause underprediction of FIH dose while novel bioengineered capsids with a high transduction efficiency specifically in human hepatocytes might cause overprediction of FIH dose. These factors should be considered when dose-response is extrapolated from preclinical species to patients.

： The problem of grassland degradation resulting from livestock production at the expense of local grasses has become a serious environmental problem worldwide. To maintain livestock production and sustainable grassland development, a better grasp of the extent and intensity of grassland utilization needs to be realized. We developed a model to monitor the intensity of grazing in a typical grazing area (Selinco basin) of the Qinghai-Tibet Plateau. Based on combining the number of livestock at the township scale with their matching livestock habitat area and location, the biomass consumed by livestock was then assigned to the productivity supply map (NPP) by a mathematical iterative algorithm from the perspective of different foraging habits of different livestock. The objective is to more accurately measure the overall grazing pressure on the pasture as well as to estimate livestock pasture utilization. The model has confirmed that there are obvious spatial differences in the intensity of grassland utilization in the Selinco basin, which is significantly lower except in the southwestern region. Overall grazing area derived from the statistics on the pixel is 150, thousands km 2. Among them, the area of moderate grazing area is 130, thousands km 2, accounting for 87% of the total grazing area, and the area of overgrazing area is 20, thousands km 2, accounting for 13% of the total grazing area. Our model can quantify human activities spatially and provide a reliable and accurate scientific basis for livestock production development and ecological environment management.

Bladder cancer treatment remains a challenge to every oncologist. We report the case of a 57-year-old man with BCG-refractory bladder cancer, who had a complete response to the intravesical Gemcitabine to shine the light on the role of Gemcitabine as a bladder sparing treatment in BCG-failure patients.

This case report describes a unique approach in the treatment of a patient with severe crowding by an orthopaedic widening of the dental arches using a skeletally anchored rapid palatal expander. This approach can serve as a robust alternative to extractions and can be effective in a variety of situations.

Group VII Ethylene Response Factors (ERF-VII) are plant-specific transcription factors (TFs) known for their role in the activation of hypoxia-responsive genes under low oxygen stress but also in plant endogenous hypoxic niches. However, their function in the microaerophilic nitrogen-fixing nodules of legumes has not yet been investigated. We investigated regulation and the function of the two Medicago truncatula ERF-VII TFs ( MtERF74 and MtERF75) in roots and nodules, MtERF74 and MtERF75 in response to hypoxia stress and during the nodulation process using an RNA interference strategy and targeted proteolysis of MtERF75. Knockdown of MtERF74 and MtERF75 partially blocked the induction of hypoxia-responsive genes in roots exposed to hypoxia stress. In addition, a significant reduction in nodulation capacity and nitrogen fixation activity was observed in mature nodules of double knockdown transgenic roots. Overall, the results indicate that MtERF74 and MtERF75 are involved in the induction of MtNR1 and Pgb1.1 expression for efficient Phytogb-NO respiration in the nodule.

The modulation of the leaf energy budget components to maintain optimal leaf temperature are fundamental aspects of plant functioning and survival. Better understanding these aspects becomes increasingly important under a drying and warming climate when cooling through evapotranspiration (ET) is suppressed. Combining novel measurements and theoretical estimates, we obtained unusually comprehensive twig-scale leaf energy budgets under extreme field conditions in droughted (suppressed ET) and non-droughted (enhanced ET) plots of a semi-arid pine forest. Under the same high mid-summer radiative load, leaf cooling shifted from relying on nearly equal contributions of sensible ( H) and latent ( LE) energy fluxes in non-droughted trees to relying almost exclusively on H in droughted ones, with no change in leaf temperature. Relying on our detailed leaf energy budget, we could demonstrate that this is due to a 2× reduction in leaf aerodynamic resistance. This capability for LE-to-H shift in leaves of mature Aleppo pine trees under droughted field conditions without increasing leaf temperature is likely a critical factor in the resilience and relatively high productivity of this important Mediterranean tree species under drying conditions.

Oriana Sanchez-Mahecha1* , Sophia Klink2* , Robin Heinen1 , Michael Rothballer2 , Sharon Zytynska1,31Technical University of Munich, Terrestrial Ecology Research Group, Department of Ecology and Ecosystem Management, School of Life Sciences Weihenstephan, Hans-Carl-von-Carlowitz-Platz, 85354 Freising, Germany.2German Research Center for Environmental Health, Institute of Network Biology, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.3 University of Liverpool, Department of Evolution, Ecology, and Behaviour, Institute of Infection, Veterinary and Ecological Sciences, Crown Street, L69 7ZB, Liverpool, United Kingdom.*These authors contributed equally to this workAuthor for correspondence:Sharon ZytynskaEmail: Sharon.Zytynska@liverpool.ac.uk

Background and Purpose: Verapamil, a drug widely used in certain cardiac pathologies, exert its therapeutic effect mainly through the blockade of cardiac L-type calcium channels. However, we also know that both voltage-dependent and certain potassium channels are blocked by verapamil. Because sympathetic neurons of the superior cervical ganglion (SCG) are known to express a good variety of potassium currents, and to finely tune cardiac activity, we speculated that the effect of verapamil on these SCG potassium channels could explain part of the therapeutic action of this drug. To address this question, we decided to study, the effects of verapamil on three different potassium currents observed in SCG neurons: delayed rectifier, A-type and TREK (a subfamily of K2P channels) currents. We also investigated the effect of verapamil on the electrical behavior of sympathetic SCG neurons. Experimental Approach: We employed the Patch-Clamp technique to mouse SCG neurons in culture. Key Results: We found that verapamil depolarizes of the resting membrane potential of SCG neurons. Moreover, we demonstrated that this drug also inhibits A-type potassium currents. Finally, and most importantly, we revealed that the current driven through TREK channels is also inhibited in the presence of verapamil. Conclusion and Implications: We have shown that verapamil causes a clear alteration of excitability in sympathetic cells. This fact undoubtedly leads to an alteration of the sympathetic-parasympathetic balance which may affect cardiac function. Therefore, we propose that these possible peripheral alterations in the autonomic system should be taken into consideration in the prescription of this drug.

A 65-year-old patient with LAD ostial stenosis proved by coronary angiography is presented. LAD ostial stenosis is an uncommon condition whose etiology is unknown. The patient also had a CABG 13 years ago after which complications occurred. The clinical and angiographic profile of the patient are discussed here supported by literature.

Il problema della contaminazione ambientale da parte di prodotti farmaceutici e prodotti per la cura della persona (PPCP) è centrale nello sviluppo di nuove tecniche per il trattamento delle acque reflue. I rischi per la salute e l'ambiente non sono trascurabili e i trattamenti delle acque reflue non adeguati alla loro rimozione. L'efficacia ormai accertata degli ultrasuoni nella rimozione di numerosi contaminanti organici ha aperto la strada alla valutazione dei possibili effetti nel trattamento dei prodotti farmaceutici. Di particolare interesse le applicazioni al trattamento del Diclofenac (DCF)). Sono stati analizzati, con varie prove sperimentali, i parametri che influenzano la degradazione del DCF e da questi è emerso che a consentire il processo non sono le reazioni pirolitiche ma piuttosto le reazioni di ossidazione dei radicali idrossilici. Altro fattore di notevole interesse è dato dall'aumento del rapporto BOD5/COD che evidenzia la formazione di sottoprodotti organici biodegradabili. Il trattamento non consente una completa mineralizzazione del campione né l'eliminazione completa tossicità. L'irradiazione ad ultrasuoni può connotarsi quindi come un pre-trattamento a cui associare un trattamento biologico per la completa rimozione del contaminante. 

Radar-based dynamic gesture recognition has great potential in human-computer interaction (HCI) applications. With the development of wideband radar, the radar signal of hand gestures is often represented by the three-dimensional (3D) range-Doppler-time cube, which is mainly processed by multichannel two-dimensional (2D) CNNs and 3D CNNs. However, the utilization and fusion of different kinds of features in existing networks is simple and not well optimized. In this paper, an efficient attention method named three-dimensional united attention (3D-UA) module in 3D space is proposed. The 3D-UA module applies a multi-scale pyramid convolution spatially, extracts channel attention weights on feature maps and captures the global temporal cues simultaneously. Furthermore, a network named 3D-UANet is proposed by replacing the 3x3x3 convolution with the 3D-UA module in the 3D-ResNet. 3D-UANet can efficiently extract the range-Doppler-time features of gestures. Experimental results show that the proposed method has good generalization performance on data from subjects in complex scenes.

–Title:Pediatric Colon Cancer - When Enemies Band Together.

A 69-year-old man presented with bloody pleural fluid effusion with elevated human chorionic gonadotropin (hCG) levels obtained by thoracentesis. The patient’s condition rapidly declined, and he died. An autopsy revealed primary lung choriocarcinoma. The early diagnosis of choriocarcinoma based on β-hCG levels in pleural fluid may be possible.

The origin of tetrapod has been one of intense debating open questions for decades between coelacanth(Latimeria chalumnae) and lungfish (Protopterus annectens). For resolving this incongruence in phylogenies, a genome-wide data mining approach is used to retrieve 43 shared genes of seven taxa from GenBank and further 1001 orthologous genes of ten taxa from the Ensembl and NCBI. We used the maximum gene-support tree approach and the majority-rule branch approach to analyze 43 nuclear genes encoding amino acid residues and compared these results to those inferred with the concatenation approach. Our results successfully provide strong evidence in favor of the lungfish-tetrapod hypothesis, but rejecting the coelacanth-tetrapod hypothesis based on significantly fewer gene supports and lower taxon jackknife probabilities for the coelacanth-tetrapod clade than the lungfish-tetrapod one with the maximum gene-support tree approach and the jackknife method for taxon subsampling. When more and more genomic data become available in recent years, sequence data of 1001 shared genes was mined. We used the maximum gene-support approach with this larger dataset successfully to infer that lungfish is the closest relative of land vertebrates with a significant difference at p < 0.01 (Chi-Square test) in gene support values between a maximum gene-support tree and the second most gene support tree with ML methods. The second most support to the maximum (SM ratio), a relative value, is a better support index than a single absolute value of support to show the insight of the phylogenetic support. Our results also show increasing the number of shared genes is much more effective than increasing the number of taxa.

Environmental heterogeneity is an important driver of ecological communities. Here, we assessed the effects of local and landscape spatial environmental heterogeneity on ant community structure in temperate semi-natural upland grasslands of Central Germany. We surveyed 33 grassland sites representing a gradient in elevation and landscape composition. Local environmental heterogeneity was measured in terms of variability of temperature and moisture within and between grasslands sites. Grassland management type (pasture vs. meadows) was additionally included as a local environmental heterogeneity measure. The complexity of habitat types in the surroundings of grassland sites were used as a measure of landscape environmental heterogeneity. As descriptors of ant community structure, we considered species composition, community evenness, and functional response traits. We found that extensively grazed pastures and within-site heterogeneity in soil moisture at local scale, and a high diversity of land cover types at the landscape scale affected ant species composition by promoting nest densities. Ant community evenness was high in wetter grasslands with low within-site variability in soil moisture and surrounded by a less diverse landscape. Fourth-corner models revealed that ant community structure response to environmental heterogeneity was mediated mainly by worker size, colony size, and life history traits related with colony reproduction and foundation. We discuss how within-site local variability in soil moisture and low intensity grazing promote ant species densities, and highlight the role of habitat temperature and humidity affecting on community evenness. We hypothesize that a higher diversity of land cover types in a forest-dominated landscape buffers less favorable environmental conditions for ant species establishment and dispersal between grasslands. We conclude that spatial environmental heterogeneity at local and landscape scale plays an important role as deterministic force in filtering ant species and, along with neutral processes (e.g. stochastic colonization), in shaping ant community structure in temperate semi-natural upland grasslands.

The predicted temperature increase caused by climate change is a threat to biodiversity. Male reproduction is particularly sensitive to elevated temperatures resulting in sterility. Here we investigate temperature induced changes in reproductive tissues and the fertility reduction in male Drosophila melanogaster. We challenged males during development and either allowed them to recover or not in early adulthood, while measuring several determinants of male reproductive success. We found significant differences in recovery rate, organ sizes, sperm production and other key reproductive traits among males from our different temperature treatments. Spermatogenesis and hence sperm maturation was impaired before reaching the upper thermal sterility threshold. While some effects were reversible, this did not compensate the earlier damage imposed. Surprisingly, developmental heat stress was damaging to accessory gland growth and female post mating responses mediated by seminal fluid proteins were impaired regardless of the possibility of recovery. We suggest that sub-lethal thermal sterility and the subsequent fertility reduction is caused by a combination of malfunctioning reproductive traits: inefficient functionality of the accessory gland and alteration of spermatogenesis.

A parameter-uniform numerical scheme for a system of weakly coupled singularly perturbed reaction-diffusion equations of arbitrary size with appropriate boundary conditions is investigated. More precisely, quadratic $B$-spline basis functions with an exponentially graded mesh are used to solve a $\ell\times\ell$ system whose solution exhibits parabolic (or exponential) boundary layers at both endpoints of the domain. A suitable mesh generating function is used to generate the exponentially graded mesh. The decomposition of the solution into regular and singular components is obtained to provide error estimates. A convergence analysis is addressed, which shows a uniform convergence of the second order. To validate the theoretical findings, two test problems are solved numerically.

Pollination is a key step of plant reproduction, allowing individual plants to produce offspring as father, mother or both. However, few studies exist that consider together male and female pollination success. This implies studying both mating system, through paternity analyses, and seed set, by measuring the percentage of flowers giving a seed. Studying these two processes together is needed as they are not independent: gaining fitness advantage through one sex can incur fitness costs through the other due to various tradeoffs including direct sexual interference. Hence, we developed the first spatially explicit mixed-mating model integrating these two interactive processes, by coupling a mating model with a fruit set model, therefore jointly exploring pollen export and import. We used as model an insect-pollinated tree species, chestnut. We carried out a paternity analysis based on nearly exhaustive sampling of potential pollen donors in an intensively studied plot of 273 trees belonging to three interfertile chestnut species and including both male-fertile and male-sterile individuals. We collected a large dataset of 1924 mating events. We further performed fruit set measurements for 216 trees. Our process-based model predicts fruit set with great accuracy, but only if we account for self-pollen interference and associated ovule discounting, a form of sexual interference. This model represents an important step forward for fundamental pollination studies aiming at comprehensively exploring pollen emission, transport and reception in a single study, thus clarifying the consequences of pollination on male and female fitness.

Evolutionary divergence and speciation often occur at a slower rate in the marine realm due to the higher potential for long-distance reproductive interaction through larval dispersal. One common evolutionary pattern in the Indo-Pacific, is divergence of populations and species at the peripheries of widely-distributed organisms. However, the evolutionary and demographic histories of such divergence are yet to be well understood. Here we address these issues by coupling genome-wide SNP data with mitochondrial DNA sequences to test the patterns of genetic divergence and possible secondary contact among geographically distant populations of the highly valuable spiny lobster Panulirus homarus species complex, distributed widely through the Indo-Pacific, from South Africa to the Marquesas Islands. After stringent filtering, 2020 SNPs were used for population genetic and demographic analyses, revealing strong regional structure (FST = 0.148, P<0001), superficially in accordance with previous analyses. However, detailed demographic analyses supported a much more complex evolutionary history of these populations, including a hybrid origin of a North-West Indian Ocean (NWIO) population, which has previously been discriminated morphologically, but not genetically. The best-supported demographic models suggested that the current genetic relationships among populations were due to a complex series of past divergences followed by asymmetric migration in more recent times. Overall, this study suggests that alternating periods of marine divergence and gene flow have driven the current genetic patterns observed in this lobster and may help explain the observed wider patterns of marine species diversity in the Indo-Pacific.

Sequence covariation in multiple sequence alignments of homologous proteins has been used extensively to obtain insights into protein structure. However, global statistical inference is required in order to ascertain direct relationships between amino acid positions in these sequences that are not simply secondary correlations induced by interactions with a third residue. Methods for statistical inference of such covariation have been developed to exploit the growing availability of sequence data. These hints about the folded protein structure provide critical a priori information for more detailed 3D predictions by neural networks. We present a novel method for protein structure inference using an iterative parameter-free model estimator which uses the formalism of statistical physics. With no tunable learning rate, our method scales to large system sizes while providing improved performance in the regime of small sample sizes. We apply this method to 40974 PDB structures and compare its performance to that of other methods. Our method outperforms existing methods for 76% of analysed proteins.

Abstract: Background: Telemedicine can be used to meet several objectives: reduce the time needed to obtain a diagnosis, monitor patients at home, reduce the risk of intra-hospital infection, inform citizens and train health professionals. In Morocco, this technology is currently being tested. Objective: Health professionals are the main users of telemedicine systems, and their acceptance will contribute to the successful implementation of this technology. The objective of this study is to provide a better understanding of the issues surrounding the acceptance of telemedicine technology by Moroccan health professionals in the public sector, for a possible generalization of this technology in Morocco. Method: Following a literature review, we mobilized a modified version of the unified model of technology acceptance and use, to explain and understand the determinants of health professionals’ intention to accept telemedicine technology. In order to confirm the proposed model, a hybrid exploratory qualitative approach via the method of semi-directive interviews was used, with a sample of doctors and nurses who constitute, in our opinion, the main actors towards an acceptance of this technology within Moroccan hospitals

Factors shaping the interspecific variations in herbivory have puzzled ecologists for decades and several hypotheses have been proposed. In a tropical rain forest in Yunnan Province, China, we collected 6,732 leaves from 129 species with canopy heights ranging from 1.6 m to 65.0 m above the ground. We tested the role of plant apparency, leaf traits and the diversity, composition and structural heterogeneity of neighbors in shaping the interspecific variations in herbivory. Results show that leaf herbivory decreased with canopy height and specific leaf area and increased with leaf size. However, neighboring species' diversity, composition, and structural heterogeneity showed no association with herbivory. Therefore, neither the plant apparency hypothesis nor the associational resistance hypothesis was supported in this hyper-diverse tropical rainforest. Our results highlight the importance of vertical structures and organic sizes in shaping herbivory patterns in natural communities.

A common conversion factor of 6.25 has been used worldwide to estimate crude protein content. However, many researchers especially Jones (1931) has extensively researched and did not agree with using the same factor for every food ingredient as it resulted in misleading estimation of crude protein content. ICMR/NIN and FAO/WHO/UNU recommendations over decades for protein and amino acid requirements using various techniques are used to state Estimated Average Requirement (EAR) and Recommended Daily Allowance (RDA) as accurate as possible. In the present manuscript, nitrogen: protein conversion factor has been reworked using NDpCal%.