COSMIC: Molecular Conformation Space Modeling in Internal Coordinates with an Adversarial Framework.

The fast and accurate conformation space modeling is an essential part of computational approaches for solving ligand and structure-based drug discovery problems. Recent state-of-the-art diffusion models for molecular conformation generation show promising distribution coverage and physical plausibility metrics but suffer from a slow sampling procedure. We propose a novel adversarial generative framework, COSMIC, that shows comparable generative performance but provides a time-efficient sampling and training procedure. Given a molecular graph and random noise, the generator produces a conformation in two stages. First, it constructs a conformation in a rotation and translation invariant representation─internal coordinates. In the second step, the model predicts the distances between neighboring atoms and performs a few fast optimization steps to refine the initial conformation. The proposed model considers conformation energy, achieving comparable space coverage, and diversity metrics results.

Medical students in Russia evaluate the training during the COVID-19 pandemic: a student survey.

BACKGROUND: The aim of the study was to obtain feedback from medical students in Russia regarding their e-learning experience during COVID-19 Pandemic. METHODS: Thirteen thousand forty students from 46 Medical Schools in Russia completed an original evaluation form validated by 6 experts. Criterion and construct validity were determined in a pilot study (n = 46). The study design was based on the use of Google Forms. Participants used the Visual Analog Scale from 1 to 10 to assess the level of knowledge acquired. RESULTS: 95.31% of medical schools in Russia switched to e-learning during the Pandemic. 39.8% of the students stated that the time to prepare for the class has doubled. For 19.9% of them, it increased by one third, while 26.6% did not report any changes. 38,4% of the participants are satisfied with particular elements of e-learning, 27.5% like such a format, 22.9% do not like it, and 11.2% could not answer the question. The average scores for the knowledge assessment were 5.9 for the humanities, 6.1 for fundamental science, and 6.0 for clinical training. CONCLUSIONS: The most important findings are increased self-instruction time, insufficient knowledge gained and territorial and socio-economic inequalities within the country. Meanwhile, most students favor distance learning or its particular elements. Consequently, medical education leaders in Russia should consider the implementation of blended training in medicine taking into account specific regional factors, ensuring its effectiveness at all stages.

Preventive Triple Gene Therapy Reduces the Negative Consequences of Ischemia-Induced Brain Injury after Modelling Stroke in a Rat.

Currently, the main fundamental and clinical interest for stroke therapy is focused on developing a neuroprotective treatment of a penumbra region within the therapeutic window. The development of treatments for ischemic stroke in at-risk patients is of particular interest. Preventive gene therapy may significantly reduce the negative consequences of ischemia-induced brain injury. In the present study, we suggest the approach of preventive gene therapy for stroke. Adenoviral vectors carrying genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF) and neural cell adhesion molecule (NCAM) or gene engineered umbilical cord blood mononuclear cells (UCB-MC) overexpressing recombinant VEGF, GDNF, and NCAM were intrathecally injected before distal occlusion of the middle cerebral artery in rats. Post-ischemic brain recovery was investigated 21 days after stroke modelling. Morphometric and immunofluorescent analysis revealed a reduction of infarction volume accompanied with a lower number of apoptotic cells and decreased expression of Hsp70 in the peri-infarct region in gene-treated animals. The lower immunopositive areas for astrocytes and microglial cells markers, higher number of oligodendrocytes and increased expression of synaptic proteins suggest the inhibition of astrogliosis, supporting the corresponding myelination and functional recovery of neurons in animals receiving preventive gene therapy. In this study, for the first time, we provide evidence of the beneficial effects of preventive triple gene therapy by an adenoviral- or UCB-MC-mediated intrathecal simultaneous delivery combination of vegf165, gdnf, and ncam1 on the preservation and recovery of the brain in rats with subsequent modelling of stroke.

Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment.

The translation of new therapies for spinal cord injury to clinical trials can be facilitated with large animal models close in morpho-physiological scale to humans. Here, we report functional restoration and morphological reorganization after spinal contusion in pigs, following a combined treatment of locomotor training facilitated with epidural electrical stimulation (EES) and cell-mediated triple gene therapy with umbilical cord blood mononuclear cells overexpressing recombinant vascular endothelial growth factor, glial-derived neurotrophic factor, and neural cell adhesion molecule. Preliminary results obtained on a small sample of pigs 2 months after spinal contusion revealed the difference in post-traumatic spinal cord outcomes in control and treated animals. In treated pigs, motor performance was enabled by EES and the corresponding morpho-functional changes in hind limb skeletal muscles were accompanied by the reorganization of the glial cell, the reaction of stress cell, and synaptic proteins. Our data demonstrate effects of combined EES-facilitated motor training and cell-mediated triple gene therapy after spinal contusion in large animals, informing a background for further animal studies and clinical translation.

nach0: multimodal natural and chemical languages foundation model.

Large Language Models (LLMs) have substantially driven scientific progress in various domains, and many papers have demonstrated their ability to tackle complex problems with creative solutions. Our paper introduces a new foundation model, nach0, capable of solving various chemical and biological tasks: biomedical question answering, named entity recognition, molecular generation, molecular synthesis, attributes prediction, and others. nach0 is a multi-domain and multi-task encoder-decoder LLM pre-trained on unlabeled text from scientific literature, patents, and molecule strings to incorporate a range of chemical and linguistic knowledge. We employed instruction tuning, where specific task-related instructions are utilized to fine-tune nach0 for the final set of tasks. To train nach0 effectively, we leverage the NeMo framework, enabling efficient parallel optimization of both base and large model versions. Extensive experiments demonstrate that our model outperforms state-of-the-art baselines on single-domain and cross-domain tasks. Furthermore, it can generate high-quality outputs in molecular and textual formats, showcasing its effectiveness in multi-domain setups.

Fibrin Sealant TISSEEL Lyo as a haemostatic agent in vascular surgery: Results of randomized, controlled, patient-blinded, multicentre clinical study in the Russian population.

BACKGROUND: This phase III, controlled, patient-blinded, multicentre study in two parallel, equal-sized treatment groups compared the efficacy and safety of TISSEEL Lyo, fibrin sealant versus Manual Compression (MC) with surgical gauze pads for use as a haemostatic agent in patients who underwent vascular surgery in Russia. METHODS: Adult patients, both genders, who received peripheral vascular expanded polytetrafluoroethylene conduits and had suture line bleeding after surgical haemostasis were enrolled. Patients were randomized to be treated with TISSEEL Lyo or MC. The bleeding needed additional treatment and had to be assessed as grade 1 or 2 bleeding according to the Validated Intraoperative Bleeding scale. The primary efficacy endpoint was the proportion of patients achieving haemostasis at 4 min after treatment application (T4) at the study suture line, which was maintained until the closure of the surgical wound. The secondary efficacy endpoints included the proportion of patients achieving haemostasis at 6 min (T6) and 10 min (T10) after treatment application at the study suture line, which was maintained until closure of the surgical wound, as well as the proportion of patients with intraoperative and postoperative rebleeding. Safety outcomes included incidence of adverse events (AEs), surgical site infections and graft occlusions. RESULTS: A total of 110 patients were screened; 104 patients were randomized: (TISSEEL Lyo: 51 [49%] patients; MC: 53 [51%] patients). T4 haemostasis was achieved in 43 (84.3%) patients in the TISSEEL Lyo group and in 11 (20.8%) patients in the MC group (p < 0.001). Significantly more patients in TISSEEL Lyo group achieved the haemostasis at T6 (relative risk (RR) of achieving haemostasis 1.74 [95% confidence interval (CI) 1.37; 2.35]) and T10 (RR 1.18 [95% CI 1.05; 1.38]) versus MC. No one had intraoperative rebleeding. Postoperative rebleeding was reported only in one patient in the MC group. No treatment-emergent serious AEs (TESAEs) related to TISSEEL Lyo/MC, TESAEs leading to withdrawal and TESAEs leading to death were reported in patients during the study. CONCLUSIONS: Data demonstrated TISSEEL Lyo had clinically and statistically significant superiority to MC as a haemostatic agent in vascular surgery at all measured time points including 4, 6 and 10 min and had proven to be safe.

HIF-1α as a Target Molecule in the Use of Triazino-Indole Derivative on the Acoustic Trauma Model.

The effect of triazino-indole derivative (Trisan) on hypoxia-inducible factor (HIF) expression level in the organ of Corti, when administering it for therapeutic and preventive purposes, was investigated using an acoustic trauma model in experimental animals (female F1 hybrids of CBA and C57BL/6 lines). Cytoflavin was used as a comparator product. Study product Trisan (1% solution) was injected intravenously, intramuscularly and intraperitoneally, in the dose of 5, 7 and 10 mg/kg 2 h after the acoustic trauma for therapeutic purposes and in the dose of 5, 7 and 10 mg/kg for 3 days before the acoustic trauma for preventive purposes. IHC methods were used to investigate the organ of Corti. Trisan was observed to increase HIF expression in hair cells and neurons of the spiral ganglion in case of acoustic trauma. Depending on the dose, the increased HIF-1 expression in hair cells and spiral ganglion occurred both after therapeutic and preventive use of Trisan. Maximum HIF expression in hair cells and ganglion was noted at the therapeutic and preventive drug dose of 10 mg/kg. Following experimental results, we conclude that the otoprotective effect of triazino-indole derivative is realized via its effect on HIF metabolism, which makes it a target molecule for the drug.

Erratum: Addendum: Molecular Generation for Desired Transcriptome Changes With Adversarial Autoencoders.

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Molecular Generation for Desired Transcriptome Changes With Adversarial Autoencoders.

Gene expression profiles are useful for assessing the efficacy and side effects of drugs. In this paper, we propose a new generative model that infers drug molecules that could induce a desired change in gene expression. Our model-the Bidirectional Adversarial Autoencoder-explicitly separates cellular processes captured in gene expression changes into two feature sets: those related and unrelated to the drug incubation. The model uses related features to produce a drug hypothesis. We have validated our model on the LINCS L1000 dataset by generating molecular structures in the SMILES format for the desired transcriptional response. In the experiments, we have shown that the proposed model can generate novel molecular structures that could induce a given gene expression change or predict a gene expression difference after incubation of a given molecular structure. The code of the model is available at https://github.com/insilicomedicine/BiAAE.

Bioinformatic Study of Transcriptome Changes in the Mice Lumbar Spinal Cord After the 30-Day Spaceflight and Subsequent 7-Day Readaptation on Earth: New Insights Into Molecular Mechanisms of the Hypogravity Motor Syndrome.

The hypogravity motor syndrome (HMS) is one of the deleterious impacts of weightlessness on the human body in orbital space missions. There is a hypothesis that disorders of musculoskeletal system as part of HMS arise in consequence of changes in spinal motor neurons. The study was aimed at bioinformatic analysis of transcriptome changes in lumbar spinal cords of mice after a 30-day spaceflight aboard biosatellite Bion-M1 (space group, S) and subsequent 7-day readaptation to the Earth's gravity (recovery group, R) when compared with control mice (C group) housed in simulated biosatellite conditions on the Earth. Gene ontology and human phenotype ontology databases were used to detect biological processes, molecular functions, cellular components, and human phenotypes associated with HMS. Our results suggest resemblance of molecular changes developing in space orbit and during the postflight recovery to terrestrial neuromuscular disorders. Remarkably, more prominent transcriptome changes were revealed in R vs. S and R vs. C comparisons that are possibly related to the 7-day recovery period in the Earth's gravity condition. These data may assist with establishment of HMS pathogenesis and proposing effective preventive and therapeutic options.

Deep learning enables rapid identification of potent DDR1 kinase inhibitors.

We have developed a deep generative model, generative tensorial reinforcement learning (GENTRL), for de novo small-molecule design. GENTRL optimizes synthetic feasibility, novelty, and biological activity. We used GENTRL to discover potent inhibitors of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, in 21 days. Four compounds were active in biochemical assays, and two were validated in cell-based assays. One lead candidate was tested and demonstrated favorable pharmacokinetics in mice.