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Developments in computational omics technologies have provided new means to access the hidden diversity of natural products, unearthing new potential for drug discovery. In parallel, artificial intelligence approaches such as machine learning have led to exciting developments in the computational drug design field, facilitating biological activity prediction and de novo drug design for molecular targets of interest. Here, we describe current and future synergies between these developments to effectively identify drug candidates from the plethora of molecules produced by nature. We also discuss how to address key challenges in realizing the potential of these synergies, such as the need for high-quality datasets to train deep learning algorithms and appropriate strategies for algorithm validation.

Existing computational methods for estimating pKavalues in proteins rely on theoretical approximations and lengthy computations. In this work, we use a data set of 6 million theoretically determined pKashifts to train deep learning models, which are shown to rival the physics-based predictors. These neural networks managed to infer the electrostatic contributions of different chemical groups and learned the importance of solvent exposure and close interactions, including hydrogen bonds. Although trained only using theoretical data, our pKAI+ model displayed the best accuracy in a test set of ∼750 experimental values. Inference times allow speedups of more than 1000× compared to physics-based methods. By combining speed, accuracy, and a reasonable understanding of the underlying physics, our models provide a game-changing solution for fast estimations of macroscopic pKavalues from ensembles of microscopic values as well as for many downstream applications such as molecular docking and constant-pH molecular dynamics simulations.

Wild animals in general, birds in particular, play a key role in transporting ticks and propagating tick-borne pathogens. Several studies have confirmed the infection of birds with Anaplasma phagocytophilum, with overall prevalence varying widely from country to country and/or study to study. This zoonotic bacterium, transmitted mainly by ticks of the genus Ixodes, is responsible for granulocytic anaplasmosis in humans (HGA) and domestic animals (cats, dogs, horses). The disease is also called tick-borne fever (TBF) in ruminants. Extremely rare in the USA, TBF is very common in Europe, where it causes economic losses in livestock. Conversely, HGA is well established in the USA whereas only a few less severe cases have been observed in Europe. Current typing techniques support the existence of multiple variants with differences in virulence/pathogenicity and tropism for certain tick and host species. However, epidemiological cycles remain difficult to characterize in Europe. Several studies describe a cycle apparently involving only birds in Europe, but no such study has been conducted in mainland France. Our objectives were to search for A. phagocytophilumin passerine birds in the Ile-de-France region and to explore their diversity using groELand ankAgene typing and multilocus sequence typing (MLST). Various tissues (spleen, liver, and skin) were collected from cadavers of 680 passerines between March and December 2021. The presence of A. phagocytophilumwas detected by qPCR Taqman targeting the msp2gene. Three blackbirds (Turdus merula) were found positive, representing detection rates of 0.4 % in all birds tested and 3.3 % in blackbirds. The higher frequency of detection in blackbirds could be at least partially explained by their lifestyle, as they feed on the ground. Analysis of the results of groELand ankAtyping and MLST from positive blackbirds support the hypothesis that the avian A. phagocytophilumstrains in Ile-de-France are distinct from those found in mammals, and that they form their own cluster in Europe.

Les complications des tatouages sont multiples et connues depuis de nombreuses années. Cependant, leur succès explique leur multiplication exponentielle dans tous les pays. Cela a permis de confirmer l’apparition de deux nouvelles complications : une réaction de type sarcoïdose cutanée, localisée ou à distance, ainsi que l’apparition d’uvéites cliniques et histologiques. Ceci dans le cadre d’une réaction d’hypersensibilité retardée, et/ou bien d’une réaction granulomateuse. Leur prévention reste assez mal connue. Elle impose de réaliser chez chaque sujet porteur d’un tatouage un bilan de sarcoïdose systémique ainsi qu’une enquête ophtalmologique à la recherche d’une éventuelle uvéite. Si elle se confirme, seront aussitôt réalisés en urgence des mesures préventives et thérapeutiques afin d’éviter une cécité. Ces nouvelles complications confirment l’extrême gravité de l’utilisation d’encres non contrôlées, véritables mélanges toxiques et sensibilisants, notablement lors de tatouages colorés étendus. Ces encres colorées particulièrement agressives libèrent dans l’organisme de multiples substances et nanoparticules dont on ne mesure pas toutes les conséquences néfastes, à moyen et long terme.

Cataract surgery is one of the most common operations in health care. Femtosecond laser-assisted cataract surgery (FLACS) enables more precise ocular incisions and lens fragmentation than does phacoemulsification cataract surgery (PCS). We hypothesised that FLACS might improve outcomes in cataract surgery compared with PCS despite having higher costs.

Predicting the outcome of biological assays based on high-throughput imaging data is a highly promising task in drug discovery since it can tremendously increase hit rates and suggest novel chemical scaffolds. However, end-to-end learning with convolutional neural networks (CNNs) has not been assessed for the task biological assay prediction despite the success of these networks at visual recognition. We compared several CNNs trained directly on high-throughput imaging data to a) CNNs trained on cell-centric crops and to b) the current state-of-the-art: fully connected networks trained on precalculated morphological cell features. The comparison was performed on the Cell Painting data set, the largest publicly available data set of microscopic images of cells with approximately 30,000 compound treatments. We found that CNNs perform significantly better at predicting the outcome of assays than fully connected networks operating on precomputed morphological features of cells. Surprisingly, the best performing method could predict 32% of the 209 biological assays at high predictive performance (AUC > 0.9) indicating that the cell morphology changes contain a large amount of information about compound activities. Our results suggest that many biological assays could be replaced by high-throughput imaging together with convolutional neural networks and that the costly cell segmentation and feature extraction step can be replaced by convolutional neural networks.

Myopathies and muscular dystrophies (M-MDs) are genetically heterogeneous diseases, with >100 identified genes, including the giant and complex titin (TTN) and nebulin (NEB) genes. Next-generation sequencing technology revolutionized M-MD diagnosis and revealed high frequency of TTNand NEBvariants. We developed a next-generation sequencing diagnostic strategy targeted to the coding sequences of 135 M-MD genes. Comparison of two targeted capture technologies (SeqCap EZ Choice library capture kit and Nextera Rapid Capture Custom Enrichment kit) and of two whole-exome sequencing kits (SureSelect V5 and TruSeq RapidExome capture) revealed best coverage with the SeqCap EZ Choice protocol. A marked decrease in coverage was observed with the other kits, affecting mostly the first exons of genes and the repeated regions of TTNand NEB. Bioinformatics analysis strategy was fine-tuned to achieve optimal detection of variants, including small insertions/deletions (INDELs) and copy number variants (CNVs). Analysis of a cohort of 128 patients allowed the detection of 52 substitutions, 13 INDELs (including a trinucleotide repeat expansion), and 3 CNVs. Two INDELs were localized in the repeated regions of NEB, suggesting that these mutations may be frequent but underestimated. A large deletion was also identified in TTNthat is, to our knowledge, the first published CNV in this gene.

Predictive modeling of toxicity is a crucial step in the drug discovery pipeline. It can help filter out molecules with a high probability of failing in the early stages of de novo drug design. Thus, several machine learning (ML) models have been developed to predict the toxicity of molecules by combining classical ML techniques or deep neural networks with well-known molecular representations such as fingerprints or 2D graphs. But the more natural, accurate representation of molecules is expected to be defined in physical 3D space like in ab initio methods. Recent studies successfully used equivariant graph neural networks (EGNNs) for representation learning based on 3D structures to predict quantum-mechanical properties of molecules. Inspired by this, we investigated the performance of EGNNs to construct reliable ML models for toxicity prediction. We used the equivariant transformer (ET) model in TorchMD-NET for this. Eleven toxicity data sets taken from MoleculeNet, TDCommons, and ToxBenchmark have been considered to evaluate the capability of ET for toxicity prediction. Our results show that ET adequately learns 3D representations of molecules that can successfully correlate with toxicity activity, achieving good accuracies on most data sets comparable to state-of-the-art models. We also test a physicochemical property, namely, the total energy of a molecule, to inform the toxicity prediction with a physical prior. However, our work suggests that these two properties can not be related. We also provide an attention weight analysis for helping to understand the toxicity prediction in 3D space and thus increase the explainability of the ML model. In summary, our findings offer promising insights considering 3D geometry information via EGNNs and provide a straightforward way to integrate molecular conformers into ML-based pipelines for predicting and investigating toxicity prediction in physical space. We expect that in the future, especially for larger, more diverse data sets, EGNNs will be an essential tool in this domain.

Federated multipartner machine learning has been touted as an appealing and efficient method to increase the effective training data volume and thereby the predictivity of models, particularly when the generation of training data is resource-intensive. In the landmark MELLODDY project, indeed, each of ten pharmaceutical companies realized aggregated improvements on its own classification or regression models through federated learning. To this end, they leveraged a novel implementation extending multitask learning across partners, on a platform audited for privacy and security. The experiments involved an unprecedented cross-pharma data set of 2.6+ billion confidential experimental activity data points, documenting 21+ million physical small molecules and 40+ thousand assays in on-target and secondary pharmacodynamics and pharmacokinetics. Appropriate complementary metrics were developed to evaluate the predictive performance in the federated setting. In addition to predictive performance increases in labeled space, the results point toward an extended applicability domain in federated learning. Increases in collective training data volume, including by means of auxiliary data resulting from single concentration high-throughput and imaging assays, continued to boost predictive performance, albeit with a saturating return. Markedly higher improvements were observed for the pharmacokinetics and safety panel assay-based task subsets.

Motivation: Current clinical and biological studies apply different biotechnologies and subsequently combine the resulting -omics data to test biological hypotheses. The plethora of -omics data and their combination generates a large number of hypotheses and apparently increases the study power. Contrary to these expectations, the wealth of -omics data may even reduce the statistical power of a study because of a large correction factor for multiple testing. Typically, this loss of power in analyzing -omics data are caused by an increased false detection rate (FDR) in measurements, like falsely detected DNA copy number changes, or falsely identified differentially expressed genes. The false detections are random and, therefore, not related to the tested conditions. Thus, a high FDR considerably decreases the discovery power of studies, especially if different -omics data are involved.Results: On a HapMap data set, where known CNVs have to be re-detected, I/NI call filtering was much more efficient than variance-based filtering. In particular, the I/NI call filter outperforms variance-based filters on data with rare events like the CNVs in the HapMap data set. We assessed the efficiency of the I/NI call filter in reducing the FDR on two different cancer cell lines where it reduced the FDR 18- to 22-fold.Materials and Methods: A mitigation strategy for too high FDRs is to filter out putative false detections. We suggest using probabilistic latent variable models to identify putative false detections which may be found via such models by high estimated noise or by model-based measurement inconsistencies across samples. To select such a model, a Bayesian approach starts with the maximum a priori model that assumes no detection and selects the maximum a posteriori model. Hence detection results in a deviation of the maximal posterior from the maximal prior model measured by the information gain obtained by the data. If this information gain exceeds a threshold then the selected model obtains an Informative/Non-Informative (I/NI) call that indicates a detection. I/NI call filtering has been successfully applied in different projects, but it has so far not been shown that correction for multiple testing after I/NI call filtering still controls the type-I error rate. We prove this important property of the I/NI call and show that it is independent of commonly used test statistics for null hypotheses. We apply the I/NI call to transcriptomics (gene expression), where the prior model corresponds to a constant gene expression level across compared samples, and to genomics, analyzing copy number variation (CNV) data, where the prior model corresponds to a constant DNA copy number of 2 across compared samples.

ABSTRACTScreening of extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacteria in companion animals living in the Paris area in France identified a high rate of CTX-M-15-producing Klebsiella pneumoniae. Those isolates were recovered during the 2010-2011 period from both infections and asymptomatic colonizations. Sequence typing revealed that most of these isolates belonged to sequence type ST274. Interestingly, the blaCTX-M-15gene was located on a specific and novel plasmid scaffold. These findings highlight that companion animals may be reservoirs for CTX-M-15-producing K. pneumoniaeevolving separately from the human reservoir of CTX-M-15 producers.

In chickens, colibacillosis is caused by avian pathogenic Escherichia coli (APEC) via respiratory tract infection. Many virulence factors, including type 1 (F1A) and P (F11) fimbriae, curli, aerobactin, K1 capsule, and temperature-sensitive hemagglutinin (Tsh) and plasmid DNA regions have been associated with APEC. A strong correlation between serum resistance and virulence has been demonstrated, but roles of virulence factors in serum resistance have not been well elucidated. By using mutants of APEC strains TK3, MT78, and chi7122, which belong to serogroups O1, O2, and O78, respectively, we investigated the role of virulence factors in resistance to serum and pathogenicity in chickens. Our results showed that serum resistance is one of the pathogenicity mechanisms of APEC strains. Virulence factors that increased bacterial resistance to serum and colonization of internal organs of infected chickens were O78 lipopolysaccharide of E. coli chi7122 and the K1 capsule of E. coli MT78. In contrast, curli, type 1, and P fimbriae did not appear to contribute to serum resistance. We also showed that the iss gene, which was previously demonstrated to increase resistance to serum in certain E. coli strains, is located on plasmid pAPEC-1 of E. coli chi7122 but does not play a major role in resistance to serum for strain chi7122.

ABSTRACTIn chickens, colibacillosis is caused by avian pathogenic Escherichia coli(APEC) via respiratory tract infection. Many virulence factors, including type 1 (F1A) and P (F11) fimbriae, curli, aerobactin, K1 capsule, and temperature-sensitive hemagglutinin (Tsh) and plasmid DNA regions have been associated with APEC. A strong correlation between serum resistance and virulence has been demonstrated, but roles of virulence factors in serum resistance have not been well elucidated. By using mutants of APEC strains TK3, MT78, and χ7122, which belong to serogroups O1, O2, and O78, respectively, we investigated the role of virulence factors in resistance to serum and pathogenicity in chickens. Our results showed that serum resistance is one of the pathogenicity mechanisms of APEC strains. Virulence factors that increased bacterial resistance to serum and colonization of internal organs of infected chickens were O78 lipopolysaccharide of E. coliχ7122 and the K1 capsule of E. coliMT78. In contrast, curli, type 1, and P fimbriae did not appear to contribute to serum resistance. We also showed that the issgene, which was previously demonstrated to increase resistance to serum in certain E. colistrains, is located on plasmid pAPEC-1 of E. coliχ7122 but does not play a major role in resistance to serum for strain χ7122.

Leg tremor during standing is a rare feature in idiopathic Parkinson's disease (PD). Tremor during standing usually has a low frequency (range, 4–6 Hz), similar to PD rest tremor frequency, and is improved by levodopa. We describe three cases of fast orthostatic tremor (FoT) of legs and trunk mimicking primary orthostatic tremor (OT) in patients treated with levodopa for PD. Asymmetrical akinetorigid syndrome was accompanied by a rest tremor in two cases. We obtained electrophysiological parameters by electromyographic (EMG) polygraphic recording after 16 hours withdrawal of antiparkinsonian treatment and at the maximal effect of levodopa in order to investigate the effect of dopaminergic stimulation upon such cases of orthostatic tremor in PD. Electrophysiological parameters of orthostatic tremor, especially frequency (range 14–18 Hz), were similar to that seen in POT. Severity of tremor was independent of seriousness and duration of PD. Levodopa had no effect either on the handicap due to OT or on the amplitude and frequency of the EMG OT activity. In contrast, mild improvement of OT was obtained with benzodiazepines in two cases and parkinsonian syndrome was levodopa‐sensitive. These findings suggest that FoT in PD would not be directly controlled by the dopaminergic system. However, increased rhythmicities in basal ganglia or in cerebello‐thalamic loops at the rapid frequencies range seen in PD could favor the emergence of a primary orthostatic tremor‐like tremor in PD patients. © 2001 Movement Disorder Society.

This paper gathers and critically analyses the results of 26 published epidemiological surveys on the prevalence of contamination of cattle with verocytotoxin-producing E. coli (VTEC) serogroup O157 : H7. These surveys have been conducted since 1986 on farms in North America (10 studies), on farms in Europe (6 studies) and at slaughterhouses prior to or just after slaughter (7 studies) or after skinning and evisceration (3 studies). The purpose of this review is to understand the first stages of the epidemiology of the infection in animals and humans (the infection process being obscure in many points) and to prepare herd-based control measures to reduce the risk of O157 : H7 human infection.

AimTo assess the efficacy and safety of an intraoperative intracameral injection of mepivacaine, administered when patients experienced pain during the course of cataract surgery under topical anaesthesia. MethodsThis is a prospective placebo controlled double masked randomised clinical trial. 50 eyes were included; 25 receiving the active compound and 25 receiving placebo. Mepivacaine (2%, 0.4 ml) or placebo was administered intraoperatively under the iris of the patients who experienced pain during the course of phacoemulsification in spite of previous topical anaesthesia. Efficacy was evaluated by the patients themselves using a five point subjective pain rating scale, the Keele verbal pain chart. Safety was measured by assessing intraocular inflammation (clinical evaluation and laser flare meter), intraocular pressure, and endothelial cell count. ResultsThe pain rating score significantly diminished after intracameral injection in the mepivacaine group (mean 3.0 (95% CI 2.6-3.4) v 0.8 (0.3-1.3), p<10^-4)) while remaining unchanged in the placebo group (2.9 (2.6-3.2) v 2.9 (2.5-3.3)), the mean reduction in pain score being significantly different between the two groups (p<10^-4). There was no indication of increased postoperative ocular inflammation, intraocular pressure change, or endothelial cell loss. ConclusionsThese results suggest that it may not be necessary to systematically add intracameral anaesthesia with topical anaesthesia for cataract surgery. An intraoperative intracameral injection, performed only in patients who happen to suffer during surgery, is safe and effective.

Purpose:To assess whether annexin V—coated poly(methyl methacrylate) (PMMA) intraocular lenses (IOLs) prevent postoperative inflammation in rabbit eyes.

Aims To determine functional results after unilateral and bilateral cataract surgery in children with different aphakic optical correction. Methods In this retrospective study, we evaluated visual acuity and binocular vision in 107 children who underwent cataract surgery during the 10 year period from 1985 to 1995. Aphakia was corrected by an intracapsular intraocular lens (IOL), spectacles or contact lenses. Results Mean visual acuity was >20/40 (<0.3 log MAR) with normal binocular vision in 58 children over 7 months of age operated on for bilateral cataracts. Pseudophakic eyes regained visual acuity >20/63 (<0.5 log MAR) more often (90%) than aphakic eyes (46%) (p<0.001). Binocular vision was also achieved more often after IOL implantation (p<0.001). Visual outcome of early bilateral cataracts was less satisfactory in children with abnormal foveolar function. For 49 children who had surgery for unilateral cataracts, prognosis was poor when surgery was performed before the age of 7 months. For cataract surgery in older children (≥7 months) mean visual acuities were better with IOL implantation (p<0.05). Conclusion Cataract surgery with unilateral and bilateral IOL implantation can provide a beneficial effect on final visual outcome in children who are operated on before abnormal foveolar function develops.

Regional cerebral blood flow (CBF) was studied in 51 young schizophrenics. A significant decrease of CBF was seen in frontal and prefrontal regions (hypofrontal pattern) in chronic patients whose disease had evolved for more than 2 years and who were in remission. This hypofrontal pattern was reversible, as it disappeared during exacerbation of the disease. In 10 patients who had not been treated with neuroleptics for several weeks, we found a dopaminergic hypersensitivity in the frontal lobes, as a weak dose of piribedil restored near-normal frontality. This may reflect either the role of neuroleptic washout or a primitive dopaminergic depletion, as proposed by some authors in the chronic form of schizophrenia.

The pathogenesis of proliferative vitreoretinopathy (PVR) membranes remains poorly understood. We have studied the presence of acidic fibroblast growth factor (aFGF), a potent mitogen for many cells, within these membranes. We have used affinity purified monospecific anti-aFGF polyclonal antibodies, in conjunction with highly sensitive immunofluorescence techniques. The labelling was exclusively localized to cell bodies and was absent from the extracellular matrix. Double labelling techniques revealed that all cytokeratin positive cells (probably pigmented epithelial cells) and macrophages contained aFGF-like immunoreactivity, whilst glial cells were unlabelled. Appropriate controls indicated the specificity of the antibodies. Hence, the presence of this mitogenic molecule within certain cell types constituting PVR membranes may contribute to the pathogenesis.

In baboons, the intravenous administration of piribedil, a dopaminergic agonist, was associated with marked dose dependent increases in CBF and cerebral oxygen consumption. We have studied the effects of piribedil on CBF in 20 normal, human volunteers of comparable ages. Ten received 0.1 mg/kg piribedil intravenously for 30 min; the other ten received 0.2 mg/kg. In the first group, CBF did not vary significantly, in the second group, there was a mean increase in CBF of 21.8% (p ≤ 0.005). In man, as in animals, piribedil provokes an increase of CBF.

• The mechanism of uveitis following cataract surgery, which is mediated in part by the cyclooxygenase pathway, is complex, the complexity of which is likely to be due to several factors. We investigated the possible local involvement of interleukin 6 (IL-6) in this response. Using a specific bioassay, we showed a dramatic increase of IL-6 levels (>4 × 103 times) in all of the aqueous humors of 12 patients following cataract surgery. The IL-6 levels in serum samples were below detection limits, indicating a local production of this cytokine. In addition, the injection of highly purified recombinant interleukin 6 in the anterior chamber of the eye in rabbits resulted in an inflammatory response. These observations suggest that IL-6 may play a crucial role in the occurrence of inflammation after cataract surgery, and it may lead to new therapeutic approaches to this problem.

PIPO, a readily prepared polymer immobilised TEMPO, can be employed as an efficient recyclable heterogeneous catalyst for the chlorinated hydrocarbon solvent-free and bromide-free bleach oxidation of a variety of alcohols and polyols.

The combination of RuCl2(PPh3)3 and TEMPO affords an efficient catalytic system for the aerobic oxidation of a broad range of primary and secondary (aliphatic) alcohols at 100 °C, giving the corresponding aldehydes and ketones, respectively, in >99% selectivity in all cases.

L’acouphène peut retentir sévèrement sur la qualité de vie. L’objectif de l’étude est d’évaluer l’efficacité de la stimulation électrique épidurale chronique exercée au niveau du cortex auditif.

Motivation: We propose a new model-based technique for summarizing high-density oligonucleotide array data at probe level for Affymetrix GeneChips. The new summarization method is based on a factor analysis model for which a Bayesian maximum a posteriori method optimizes the model parameters under the assumption of Gaussian measurement noise. Thereafter, the RNA concentration is estimated from the model. In contrast to previous methods our new method called ‘Factor Analysis for Robust Microarray Summarization (FARMS)’ supplies both P-values indicating interesting information and signal intensity values. Results: We compare FARMS on Affymetrix's spike-in and Gene Logic's dilution data to established algorithms like Affymetrix Microarray Suite (MAS) 5.0, Model Based Expression Index (MBEI), Robust Multi-array Average (RMA). Further, we compared FARMS with 43 other methods via the ‘Affycomp II’ competition. The experimental results show that FARMS with default parameters outperforms previous methods if both sensitivity and specificity are simultaneously considered by the area under the receiver operating curve (AUC). We measured two quantities through the AUC: correctly detected expression changes versus wrongly detected (fold change) and correctly detected significantly different expressed genes in two sets of arrays versus wrongly detected (P-value). Furthermore FARMS is computationally less expensive then RMA, MAS and MBEI. Availability: The FARMS R package is available from http://www.bioinf.jku.at/software/farms/farms.html Contact: hochreit@bioinf.jku.at Supplementary information: http://www.bioinf.jku.at/publications/papers/farms/supplementary.ps

Several clinical multifactorial indexes have been described for predicting difficult laryngoscopy or intubation, or both, mostly in general surgery, and less frequently in ENT surgery. The objective of this study was to develop and validate a single clinical index for prediction of difficulty in tracheal intubation in both ENT and general surgery. We studied a population of 1200 consecutive ENT and general surgical patients. Clinical criteria were tested using univariate and multivariate analysis. Difficult intubation was defined as requiring unusual techniques. Logistic regression identified seven criteria as independent predictors of difficult tracheal intubation; previous history of difficult intubation; pathologies associated with difficult intubation; clinical symptoms of pathological airway; inter-incisor gap and mandible luxation; thyromental distance; head and neck movement; and Mallampati's modified test. Point values were assigned to each of these factors in proportion to regression coefficients representing the relative weight of each predictive intubation difficulty factor, the sum comprising the score. The best predictive threshold was chosen using a receiver operating characteristic curve. We then prospectively studied and validated the score in a population of 1090 consecutive ENT and general surgery patients. The sensitivity and specificity of the predictions were 94% and 96% in general surgery, 90% and 93% in non-cancer ENT surgery, and 92% and 66% in ENT cancer surgery, respectively.