The dengue-specific immune response and antibody identification with machine learning.

Dengue virus poses a serious threat to global health and there is no specific therapeutic for it. Broadly neutralizing antibodies recognizing all serotypes may be an effective treatment. High-throughput adaptive immune receptor repertoire sequencing (AIRR-seq) and bioinformatic analysis enable in-depth understanding of the B-cell immune response. Here, we investigate the dengue antibody response with these technologies and apply machine learning to identify rare and underrepresented broadly neutralizing antibody sequences. Dengue immunization elicited the following signatures on the antibody repertoire: (i) an increase of CDR3 and germline gene diversity; (ii) a change in the antibody repertoire architecture by eliciting power-law network distributions and CDR3 enrichment in polar amino acids; (iii) an increase in the expression of JNK/Fos transcription factors and ribosomal proteins. Furthermore, we demonstrate the applicability of computational methods and machine learning to AIRR-seq datasets for neutralizing antibody candidate sequence identification. Antibody expression and functional assays have validated the obtained results.

[Physiotherapeutic Scar Therapy for Large Scars]. / Physiotherapeutische Narbentherapie bei grossflächigen Narben.

Physiotherapeutic Scar Therapy for Large Scars Abstract. Deep dermal defects can result from burns, necrotizing fasciitis, and severe soft tissue trauma. Physiological scar restriction during wound healing becomes increasingly relevant in proportion to the area affected. It is massively restrictive for the general mobility of patients. External mechanical influences (activity or immobilization in everyday life) can cause pronounced scar strands and adhesions to form. Overloading ends in a renewed inflammatory reaction and thus in further restriction. Adequate mechanical stimuli can positively influence the scar tissue. The current state of research does not allow a direct transfer to the clinical treatment of large-area scars. However, the continuous clinical implementation of study results regarding the mechanosensitivity of isolated fibroblasts and the constant adaptation of manual techniques have resulted in an evidence-based foundation for manual scar therapy. Early manual treatment in combination with appropriate compression therapy is important.

Tidal stream to mainstream: mechanical testing of composite tidal stream blades to de-risk operational design life.

Tidal energy has seen a surge of interest in recent years with several companies developing technology to harness the power of the world's oceans where the operational capacity in Europe was over 11 MW in 2020. One such developer is the partnership of SCHOTTEL Hydro (Germany) and Sustainable Marine (UK) who have developed a scalable multi-turbine device equipped with 70 kW turbines and capable of operating in arrays at sites around the world. The technology to harness tidal energy is still at a relatively early stage of development; hence, de-risking of component parts plays a vital role on the road to commercialisation. Despite this, the number of tidal energy blades undergoing test programmes remains small. Two different rotor diameters have been developed for the aforementioned device such that it can be optimised for sites of varying potential. In this paper, a blade from each of the 4.0 m and 6.3 m diameter devices was tested for their responses in natural frequency, static loading and fatigue loading under test standards IEC 62600-3:2020 and DNVGL-ST-0164. Testing saw the survival of a blade in fatigue at a lifetime-equivalent load and the generation of natural frequency, strain and displacement results for both blades. Data generated from the testing as a whole will contribute to the modelling and validation of future tidal blades.

Machine Learning Detects Anti-DENV Signatures in Antibody Repertoire Sequences.

Dengue infection is a global threat. As of today, there is no universal dengue fever treatment or vaccines unreservedly recommended by the World Health Organization. The investigation of the specific immune response to dengue virus would support antibody discovery as therapeutics for passive immunization and vaccine design. High-throughput sequencing enables the identification of the multitude of antibodies elicited in response to dengue infection at the sequence level. Artificial intelligence can mine the complex data generated and has the potential to uncover patterns in entire antibody repertoires and detect signatures distinctive of single virus-binding antibodies. However, these machine learning have not been harnessed to determine the immune response to dengue virus. In order to enable the application of machine learning, we have benchmarked existing methods for encoding biological and chemical knowledge as inputs and have investigated novel encoding techniques. We have applied different machine learning methods such as neural networks, random forests, and support vector machines and have investigated the parameter space to determine best performing algorithms for the detection and prediction of antibody patterns at the repertoire and antibody sequence levels in dengue-infected individuals. Our results show that immune response signatures to dengue are detectable both at the antibody repertoire and at the antibody sequence levels. By combining machine learning with phylogenies and network analysis, we generated novel sequences that present dengue-binding specific signatures. These results might aid further antibody discovery and support vaccine design.

An investigation of a passive opened top-end pipe as an alternative solution for passive soil depressurisation systems for indoor radon mitigation.

This study carried out a series of large-scale experimental tests and numerical simulations to investigate the performance of a passive opened top-end pipe as an alternative solution for passive soil depressurisation systems for indoor radon mitigation. Measurements were conducted in terms of wind velocity, extracted air velocity and negative pressure at the sump-end inside the pipe. Investigations were performed with controlled and natural wind conditions. Test results confirmed that the passive opened top-end pipe can be used as an alternative solution for indoor radon concentration mitigation at low additional construction cost. However, the extracted air velocity and negative pressure were found to fluctuate when tested under natural wind conditions. This fluctuation would reduce the effectiveness of the performance of the passive pipe. To reduce this fluctuation, a novel static ventilator has been developed and can be added on the top-end of the pipe.

Accuracy of 3D-planned patient specific instrumentation in high tibial open wedge valgisation osteotomy.

PURPOSE: High tibial osteotomy (HTO) is an effective treatment option in early osteoarthritis. However, preoperative planning and surgical execution can be challenging. Computer assisted three-dimensional (3D) planning and patient-specific instruments (PSI) might be helpful tools in achieving successful outcomes. Goal of this study was to assess the accuracy of HTO using PSI. METHODS: All medial open wedge PSI-HTO between 2014 and 2016 were reviewed. Using pre- and postoperative radiographs, hip-knee-ankle angle (HKA) and posterior tibial slope (PTS) were determined two-dimensionally (2D) to calculate 2D accuracy. Using postoperative CT-data, 3D surface models of the tibias were reconstructed and superimposed with the planning to calculate 3D accuracy. RESULTS: Twenty-three patients could be included. A mean correction of HKA of 9.7° ± 2.6° was planned. Postoperative assessment of HKA correction showed a mean correction of 8.9° ± 3.2°, resulting in a 2D accuracy for HKA correction of 0.8° ± 1.5°. The postoperative PTS changed by 1.7° ± 2.2°. 3D accuracy showed average 3D rotational differences of - 0.1° ± 2.3° in coronal plane, - 0.2° ± 2.3° in transversal plane, and 1.3° ± 2.1° in sagittal plane, whereby 3D translational differences were calculated as 0.1 mm ± 1.3 mm in coronal plane, - 0.1 ± 0.6 mm in transversal plane, and - 0.1 ± 0.6 mm in sagittal plane. CONCLUSION: The use of PSI in HTO results in accurate correction of mechanical leg axis. In contrast to the known problem of unintended PTS changes in conventional HTO, just slight changes of PTS could be observed using PSI. The use of PSI in HTO might be preferable to obtain desired correction of HKA and to maintain PTS.

Single-Cell Approach to Monitor the Unfolded Protein Response During Biotechnological Processes With Pichia pastoris.

Pichia pastoris (Komagataella sp.) is broadly used for the production of secreted recombinant proteins. Due to the high rate of protein production, incorrectly folded proteins may accumulate in the endoplasmic reticulum (ER). To restore their proper folding, the cell triggers the unfolded protein response (UPR); however, if the proteins cannot be repaired, they are degraded, which impairs process productivity. Moreover, a non-producing/non-secreting subpopulation of cells might occur, which also decreases overall productivity. Therefore, an in depth understanding of intracellular protein fluxes and population heterogeneity is needed to improve productivity. Under industrially relevant cultivation conditions in bioreactors, we cultured P. pastoris strains producing three different recombinant proteins: penicillin G acylase from Escherichia coli (EcPGA), lipase B from Candida antarctica (CaLB) and xylanase A from Thermomyces lanuginosus (TlXynA). Extracellular and intracellular product concentrations were determined, along with flow cytometry-based single-cell measurements of cell viability and the up-regulation of UPR. The cell population was distributed into four clusters, two of which were viable cells with no UPR up-regulation, differing in cell size and complexity. The other two clusters were cells with impaired viability, and cells with up-regulated UPR. Over the time course of cultivation, the distribution of the population into these four clusters changed. After 30 h of production, 60% of the cells producing EcPGA, which accumulated in the cells (50-70% of the product), had up-regulated UPR, but only 13% of the cells had impaired viability. A higher proportion of cells with decreased viability was observed in strains producing CaLB (20%) and TlXynA (27%). The proportion of cells with up-regulated UPR in CaLB-producing (35%) and TlXynA-producing (30%) strains was lower in comparison to the EcPGA-producing strain, and a smaller proportion of CaLB and TlXynA (<10%) accumulated in the cells. These data provide an insight into the development of heterogeneity in a recombinant P. pastoris population during a biotechnological process. A deeper understanding of the relationship between protein production/secretion and the regulation of the UPR might be utilized in bioprocess control and optimization with respect to secretion and population heterogeneity.

Urine Biomarkers of Tubular Renal Cell Damage for the Prediction of Acute Kidney Injury After Cardiac Surgery-A Pilot Study.

OBJECTIVE: To evaluate the perioperative course of urine levels of the renal damage biomarkers tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) and to evaluate the predictive value of elevated TIMP-2 × IGFBP7 concentrations to predict acute kidney injury (AKI) early after cardiac on-pump surgery. DESIGN: Prospective, observational cohort study. SETTING: University hospital. PARTICIPANTS: The study comprised 110 consecutive patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) between January and March 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Urinary TIMP-2 × IGFBP7 levels were quantified using a commercially available kit at the following measurement points: before surgery, 1 hour after starting CPB, 4 hours after weaning from CPB, and 24 hours after weaning from CPB (time points 1-4). Postoperative AKI was defined according to Kidney Disease Improving Global Outcomes criteria. AKI after cardiac surgery was diagnosed in 9 patients (8%). The perioperative course of TIMP-2 × IGFBP7 was significantly different in patients with and without postoperative AKI (p < 0.001). TIMP-2 × IGFBP7 levels were significantly higher in patients with AKI 1 hour after CPB start and 24 hours after weaning from CPB (p < 0.05). TIMP-2 × IGFBP7 levels >0.40 (ng/mL)2/1,000 measured at 1 hour after starting CPB were found to be the optimal cut-off, with a sensitivity of 0.778 and a specificity of 0.641. The negative predictive value was 0.972. CONCLUSIONS: Urine levels of TIMP-2 × IGFBP7 are predictive for AKI at an early time point (1 hour after starting CPB). Renal damage biomarkers such as TIMP-2 and IGFBP7 might be recommended as a supplement to traditionally used criteria of AKI prediction.

Combining Human Computing and Machine Learning to Make Sense of Big (Aerial) Data for Disaster Response.

Aerial imagery captured via unmanned aerial vehicles (UAVs) is playing an increasingly important role in disaster response. Unlike satellite imagery, aerial imagery can be captured and processed within hours rather than days. In addition, the spatial resolution of aerial imagery is an order of magnitude higher than the imagery produced by the most sophisticated commercial satellites today. Both the United States Federal Emergency Management Agency (FEMA) and the European Commission's Joint Research Center (JRC) have noted that aerial imagery will inevitably present a big data challenge. The purpose of this article is to get ahead of this future challenge by proposing a hybrid crowdsourcing and real-time machine learning solution to rapidly process large volumes of aerial data for disaster response in a time-sensitive manner. Crowdsourcing can be used to annotate features of interest in aerial images (such as damaged shelters and roads blocked by debris). These human-annotated features can then be used to train a supervised machine learning system to learn to recognize such features in new unseen images. In this article, we describe how this hybrid solution for image analysis can be implemented as a module (i.e., Aerial Clicker) to extend an existing platform called Artificial Intelligence for Disaster Response (AIDR), which has already been deployed to classify microblog messages during disasters using its Text Clicker module and in response to Cyclone Pam, a category 5 cyclone that devastated Vanuatu in March 2015. The hybrid solution we present can be applied to both aerial and satellite imagery and has applications beyond disaster response such as wildlife protection, human rights, and archeological exploration. As a proof of concept, we recently piloted this solution using very high-resolution aerial photographs of a wildlife reserve in Namibia to support rangers with their wildlife conservation efforts (SAVMAP project, http://lasig.epfl.ch/savmap ). The results suggest that the platform we have developed to combine crowdsourcing and machine learning to make sense of large volumes of aerial images can be used for disaster response.

Towards an automated and efficient calculation of resonating vibrational states based on state-averaged multiconfigurational approaches.

Resonating vibrational states cannot consistently be described by single-reference vibrational self-consistent field methods but request the use of multiconfigurational approaches. Strategies are presented to accelerate vibrational multiconfiguration self-consistent field theory and subsequent multireference configuration interaction calculations in order to allow for routine calculations at this enhanced level of theory. State-averaged vibrational complete active space self-consistent field calculations using mode-specific and state-tailored active spaces were found to be very fast and superior to state-specific calculations or calculations with a uniform active space. Benchmark calculations are presented for trans-diazene and bromoform, which show strong resonances in their vibrational spectra.

Usefulness of SNPs as Supplementary Markers in a Paternity Case with 3 Genetic Incompatibilities at Autosomal and Y Chromosomal Loci.

BACKGROUND: In kinship testing, investigation of 15 short tandem repeats (STRs) usually provides decisive genetic information for resolving relationship cases. However, in complex deficiency cases, in cases with more than 2 mutations at different STR loci or when close (untested) relatives of the alleged father are suggested to be the biological father of the child, STR typing alone may not be sufficient. In these cases, the application of supplementary markers such as single nucleotide polymorphisms (SNPs) is recommended. METHODS: We describe a paternity case with 3 genetic incompatibilities (Penta D, VWA, and DYS385) between the alleged father and the child after analyzing 23 autosomal and 16 Y chromosomal STR loci. The question arose as to whether the alleged father could be excluded and a related person could be the biological father of the child, or whether the observed genetic incompatibilities were mutations. Interestingly, the 2 excluded full brothers of the alleged father possessed identical genetic incompatibilities at locus VWA and DYS385 as the alleged father. RESULTS AND CONCLUSIONS: Additional performance of a 50-plex SNP assay demonstrated that the observed mismatches were indeed mutations and the alleged father was the biological father of the child. The results show the usefulness of SNPs as supplementary markers in relationship testing when STR analyses show ambiguous results.

Transformation of potential energy surfaces for estimating isotopic shifts in anharmonic vibrational frequency calculations.

A transformation of potential energy surfaces (PES) being represented by multi-mode expansions is introduced, which allows for the calculation of anharmonic vibrational spectra of any isotopologue from a single PES. This simplifies the analysis of infrared spectra due to significant CPU-time savings. An investigation of remaining deviations due to truncations and the so-called multi-level approximation is provided. The importance of vibrational-rotational couplings for small molecules is discussed in detail. In addition, an analysis is proposed, which provides information about the quality of the transformation prior to its execution. Benchmark calculations are provided for a set of small molecules.

Modeling of high-order terms in potential energy surface expansions using the reference-geometry Harris-Foulkes method.

The reference-geometry Harris-Foulkes (RGHF) approach has been used to model high-order terms within the expansion of multi-dimensional potential energy surfaces (PES) as needed within the calculation of accurate vibrational frequencies beyond the harmonic approximation. The key step of this method is a localization of the electron density to the atoms of the molecule at a given reference structure and a subsequent transfer of these atom-centered partial densities to the atom positions of distorted structures. This concept has been used to evaluate the 3-mode coupling terms of a multi-mode expansion of the PES as arising in the Watson Hamiltonian. Systematic benchmark calculations for vibrational frequencies obtained from vibrational configuration interaction (VCI) theory have been performed in order to study the effects of this approximation on the fundamental modes of a test suite of 28 molecules.

The impact of antioxidant supplements and endurance exercise on genes of the carbohydrate and lipid metabolism in skeletal muscle of mice.

To ascertain whether reactive oxygen species (ROS) contribute to training-induced adaptation of skeletal muscle, we administered ROS-scavenging antioxidants (AOX; 140 mg/l of ascorbic acid, 12 mg/l of coenzyme Q10 and 1% N-acetyl-cysteine) via drinking water to 16 C57BL/6 mice. Sixteen other mice received unadulterated tap water (CON). One cohort of both groups (CON(EXE) and AOX(EXE) ) was subjected to treadmill exercise for 4 weeks (16-26 m/min, incline of 5°-10°). The other two cohorts (CON(SED) and AOX(SED) ) remained sedentary. In skeletal muscles of the AOX(EXE) mice, GSSG and the expression levels of SOD-1 and PRDX-6 were significantly lower than those in the CON(EXE) mice after training, suggesting disturbance of ROS levels. The peak power related to the body weight and citrate synthase activity was not significantly influenced in mice receiving AOX. Supplementation with AOX significantly altered the mRNA levels of the exercise-sensitive genes HK-II, GLUT-4 and SREBF-1c and the regulator gene PGC-1alpha but not G6PDH, glycogenin, FABP-3, MCAD and CD36 in skeletal muscle. Although the administration of AOX during endurance exercise alters the expression of particular genes of the ROS metabolism, it does not influence peak power or generally shift the metabolism, but it modulates the expression of specific genes of the carbohydrate and lipid metabolism and PGC-1alpha within murine skeletal muscle.

Cooperative Al(salen)-pyridinium catalysts for the asymmetric synthesis of trans-configured ß-lactones by [2+2]-cyclocondensation of acylbromides and aldehydes: investigation of pyridinium substituent effects.

The trans-selective catalytic asymmetric formation of ß-lactones constitutes an attractive surrogate for anti-aldol additions. Recently, we have reported the first catalyst which is capable of forming trans-ß-lactones with high enantioselectivity from aliphatic (and aromatic) aldehyde substrates by cyclocondensation with acyl bromides. In that previous study the concepts of Lewis acid and organic aprotic ion pair catalysis were combined in a salen-type catalyst molecule. Since a pyridinium residue on the salen periphery is essential for high trans- and enantioselectivity, we were interested in the question of whether substituents on the pyridinium rings could be used to further improve the catalyst efficiency, as they might have a significant impact on the effective charges within the heterocycles. In the present study we have thus compared a small library of aluminum salen/bispyridinium catalysts mainly differing in the substituents on the pyridinium residues. As one result of these studies a new catalyst was identified which offers slightly superior stereoselectivity as compared to the previously reported best catalyst. NBO calculations have revealed that the higher stereoselectivity can arguably not be explained by the variation of the effective charge.

Accurate Vibrational Frequencies of Borane and Its Isotopologues.

Vibrational transitions of borane and its isotopologues ((11)BH3, (11)BD3, (10)BH3, and (10)BD3) have been obtained from state-specific vibrational configuration interaction calculations. Explicitly correlated coupled-cluster calculations, CCSD(T)-F12a, with additional corrections for high-order terms of the coupled-cluster expansion, i.e., CCSDT(Q), were used to determine multidimensional potential energy surfaces. Additional contributions due to core-valence interactions, scalar relativistic effects, and such arising from the diagonal Born-Oppenheimer correction were accounted for in the one-dimensional terms within the expansion of the potential energy surface. From these, anharmonic vibrational spectra were obtained, which are in excellent agreement with experimental data. Mean absolute deviations from gas phase measurements were found to be in the sub-wavenumber regime.

Age, alcohol metabolism and liver disease.

PURPOSE OF REVIEW: Alcohol consumption among the elderly has increased. Alcohol metabolism changes with age and the elderly are more sensitive to the toxic effects; this increased consumption is therefore of great clinical relevance. RECENT FINDINGS: Metabolism of ethanol changes with advancing age because activity of the enzymes involved, such as alcohol and acetaldehyde dehydrogenase and cytochrome P-4502E1, diminish with age. The water distribution volume also decreases with age. Both lead to increased blood concentrations of ethanol. Also, elderly people take more drugs, and ethanol and these drugs may interact; therefore, alcohol consumption can modify serum drug concentrations and their toxicity. Finally, elderly people may suffer more frequently from other types of liver disease, and alcohol may exacerbate these. SUMMARY: Over recent decades alcohol consumption has increased among those who are older than 65 years. Alcohol is more toxic in the ageing organism because of changes in its metabolism, distribution and elimination, which lead to central nervous system effects at lower levels of intake; also, ageing organs such as brain and liver are more sensitive to the toxicity of alcohol. For these reasons, alcohol should be used in moderation, especially among those of older age.

Genetic subtraction profiling identifies genes essential for Arabidopsis reproduction and reveals interaction between the female gametophyte and the maternal sporophyte.

BACKGROUND: The embryo sac contains the haploid maternal cell types necessary for double fertilization and subsequent seed development in plants. Large-scale identification of genes expressed in the embryo sac remains cumbersome because of its inherent microscopic and inaccessible nature. We used genetic subtraction and comparative profiling by microarray between the Arabidopsis thaliana wild-type and a sporophytic mutant lacking an embryo sac in order to identify embryo sac expressed genes in this model organism. The influences of the embryo sac on the surrounding sporophytic tissues were previously thought to be negligible or nonexistent; we investigated the extent of these interactions by transcriptome analysis. RESULTS: We identified 1,260 genes as embryo sac expressed by analyzing both our dataset and a recently reported dataset, obtained by a similar approach, using three statistical procedures. Spatial expression of nine genes (for instance a central cell expressed trithorax-like gene, an egg cell expressed gene encoding a kinase, and a synergid expressed gene encoding a permease) validated our approach. We analyzed mutants in five of the newly identified genes that exhibited developmental anomalies during reproductive development. A total of 527 genes were identified for their expression in ovules of mutants lacking an embryo sac, at levels that were twofold higher than in the wild type. CONCLUSION: Identification of embryo sac expressed genes establishes a basis for the functional dissection of embryo sac development and function. Sporophytic gain of expression in mutants lacking an embryo sac suggests that a substantial portion of the sporophytic transcriptome involved in carpel and ovule development is, unexpectedly, under the indirect influence of the embryo sac.

The role of acetaldehyde in upper digestive tract cancer in alcoholics.

Chronic excessive alcohol consumption is the strongest risk factor for upper aerodigestive tract (UADT) cancer. Multiple mechanisms are involved in alcohol-associated cancer development of the UADT, including acetaldehyde (AA) effects. AA is toxic, mutagenic, and carcinogenic. Evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics. Polymorphism or mutation in genes coding for AA generation or detoxification enzymes are associated with increased cancer risk. It has been clearly shown in Asians that individuals carrying the acetaldehyde dehydrogenase 2*2 (ALDH2*2) allele have a significantly increased cancer risk when they consume alcohol. In Caucasians, alcohol dehydrogenase 1*1 (ADH1C*1) allele encodes for an alcohol dehydrogenase (ADH) isoenzyme, which produces 2.5 times more AA than the corresponding allele ADH1C*2. The authors found that the ADH1C*1 allele frequency and rate of homozygosity was significantly associated with an increased risk for alcohol-related cancer. AA seems to be an important factor in alcohol-associated carcinogenesis of the UADT.