ITMO University

Abstract Gene set enrichment analysis (GSEA) is an ubiquitously used tool for evaluating pathway enrichment in transcriptional data. Typical experimental design consists in comparing two conditions with several replicates using a differential gene expression test followed by preranked GSEA performed against a collection of hundreds and thousands of pathways. However, the reference implementation of this method cannot accurately estimate small P-values, which significantly limits its sensitivity due to multiple hypotheses correction procedure. Here we present FGSEA (Fast Gene Set Enrichment Analysis) method that is able to estimate arbitrarily low GSEA P-values with a high accuracy in a matter of minutes or even seconds. To confirm the accuracy of the method, we also developed an exact algorithm for GSEA P-values calculation for integer gene-level statistics. Using the exact algorithm as a reference we show that FGSEA is able to routinely estimate P-values up to 10 −100 with a small and predictable estimation error. We systematically evaluate FGSEA on a collection of 605 datasets and show that FGSEA recovers much more statistically significant pathways compared to other implementations. FGSEA is open source and available as an R package in Bioconductor ( http://bioconductor.org/packages/fgsea/ ) and on GitHub ( https://github.com/ctlab/fgsea/ ).

Abstract High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species 1–4 . To address this issue, the international Genome 10K (G10K) consortium 5,6 has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences.

We reveal that metasurfaces created by seemingly different lattices of (dielectric or metallic) meta-atoms with broken in-plane symmetry can support sharp high-Q resonances arising from a distortion of symmetry-protected bound states in the continuum. We develop a rigorous theory of such asymmetric periodic structures and demonstrate a link between the bound states in the continuum and Fano resonances. Our results suggest the way for smart engineering of resonances in metasurfaces for many applications in nanophotonics and metaoptics.

In this framework, the demonstration of planar high-Q resonators, compatible with silicon technology Indeed, it is well acknowledged by the electronics industry that future generations of computer processing chips will inevitably require an extremely high density of copper-based interconnections, significantly increasing the chip power dissipation to beyond practical levels On-chip optical networks, or optical interconnects, can offer high speed and low energy pertransferred-bit, and micro-resonators are widely seen as a key component to interface the electronic world with photonics.

Subwavelength optical resonators made of high-index dielectric materials provide efficient ways to manipulate light at the nanoscale through mode interferences and enhancement of both electric and magnetic fields. Such Mie-resonant dielectric structures have low absorption, and their functionalities are limited predominantly by radiative losses. We implement a new physical mechanism for suppressing radiative losses of individual nanoscale resonators to engineer special modes with high quality factors: optical bound states in the continuum (BICs). We demonstrate that an individual subwavelength dielectric resonator hosting a BIC mode can boost nonlinear effects increasing second-harmonic generation efficiency. Our work suggests a route to use subwavelength high-index dielectric resonators for a strong enhancement of light-matter interactions with applications to nonlinear optics, nanoscale lasers, quantum photonics, and sensors.

Digital technologies have already become an internal part of our life. They change the way we are looking for information, how we communicate with each other, even how we behave. This transformation applies to many areas, including education. The main objective of this article is to identify prospective impact of artificial technologies to the study process and to predict possible changes in educational landscape. In presented literature review we considered four categories: customized educational content, innovative teaching methods, technology enhanced assessment, communication between student and lecturer. Having reviewed publications on the subject we present here a possible picture of how the Artificial Intelligence (AI) will reshape education landscape.

In this study, the ripple effect in the supply chain is analysed. Ripple effect describes the impact of a disruption propagation on supply chain performance and disruption-based scope of changes in supply chain structural design and planning parameters. We delineate major features of the ripple effect as compared to the bullwhip effect. Subsequently, we review recent quantitative literature that tackled the ripple effect explicitly or implicitly and give our vision of the state of the art and perspectives. The literature is classified into mathematical optimisation, simulation, control theoretic and complexity and reliability research. We observe the reasons and mitigation strategies for the ripple effect in the supply chain and present the ripple effect control framework that includes redundancy, flexibility and resilience analysis. Even though a variety of valuable insights has been developed in the said area in recent years, some crucial research avenues have been identified for the near future.

BACKGROUND: The process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly. RESULTS: In Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies. CONCLUSIONS: Many current genome assemblers produced useful assemblies, containing a significant representation of their genes and overall genome structure. However, the high degree of variability between the entries suggests that there is still much room for improvement in the field of genome assembly and that approaches which work well in assembling the genome of one species may not necessarily work well for another.

Recent progress in nanoscale optical physics is associated with the development of a new branch of nanophotonics exploring strong Mie resonances in dielectric nanoparticles with a high refractive index. The high-index resonant dielectric nanostructures form building blocks for novel photonic metadevices with low losses and advanced functionalities. However, unlike extensively studied cavities in photonic crystals, such dielectric resonators demonstrate low quality factors (Q factors). Here, we uncover a novel mechanism for achieving giant Q factors of subwavelength nanoscale resonators by realizing the regime of bound states in the continuum. In contrast to the previously suggested multilayer structures with zero permittivity, we reveal strong mode coupling and Fano resonances in homogeneous high-index dielectric finite-length nanorods resulting in high-Q factors at the nanoscale. Thus, high-index dielectric resonators represent the simplest example of nanophotonic supercavities, expanding substantially the range of applications of all-dielectric resonant nanophotonics and meta-optics.

Catalytic hydrogenation and dehydrogenation reactions form the core of the modern chemical industry. This vast class of reactions is found in any part of chemical synthesis starting from the milligram-scale exploratory organic chemistry to the multi-ton base chemicals production. Noble metal catalysis has long been the key driving force in enabling these transformations with carbonyl substrates and their nitrogen-containing counterparts. This review is aimed at introducing the reader to the remarkable progress made in the last three years in the development of base metal catalysts for hydrogenations and dehydrogenative transformations.

Scattering of electromagnetic waves by subwavelength objects is accompanied by the excitation of electric and magnetic Mie resonances that may modify substantially the scattering intensity and radiation pattern. Scattered fields can be decomposed into electric and magnetic multipoles, and the magnetic multipoles define magnetic response of structured materials underpinning the new field of all-dielectric resonant meta-optics. Here we review the recent developments in meta-optics and nanophotonics and demonstrate that the Mie resonances can play a crucial role offering novel ways for the enhancement of many optical effects near magnetic and electric multipolar resonances, as well as driving a variety of interference phenomena which govern recently discovered novel effects in nanophotonics. We further discuss the frontiers of all-dielectric meta-optics for flexible and advanced control of light with full phase and amplitude engineering, including nonlinear nanophotonics, anapole nanolasers, quantum optics, and topological photonics.

Over the past decade, optical frequency combs generated by high-Q microresonators, or optical microcombs, which feature compact device footprints, low power consumption, and high repetition rates in broad optical bandwidths, have led to a revolution in a wide range of fields including metrology, telecommunications, radio frequency (RF) photonics, spectroscopy, sensing, and quantum optics. Among these, an application that has attracted great interest is the use of optical microcombs for RF photonics, where they offer enhanced functionalities as well as reduced size and power consumption over other approaches. This paper reviews the recent advances in this emerging field. We provide an overview of the main achievements that have been obtained to date, and highlight the strong potential of optical microcombs for RF photonics applications. We also discuss some of the open challenges and limitations that need to be addressed for practical applications.

Ossification is a tightly regulated process, performed by specialized cells called osteoblasts. Dysregulation of this process may cause inadequate or excessive mineralization of bones or ectopic calcification, all of which have grave consequences for human health. Understanding osteoblast biology may help to treat diseases such as osteogenesis imperfecta, calcific heart valve disease, osteoporosis, and many others. Osteoblasts are bone-building cells of mesenchymal origin; they differentiate from mesenchymal progenitors, either directly or via an osteochondroprogenitor. The direct pathway is typical for intramembranous ossification of the skull and clavicles, while the latter is a hallmark of endochondral ossification of the axial skeleton and limbs. The pathways merge at the level of preosteoblasts, which progress through 3 stages: proliferation, matrix maturation, and mineralization. Osteoblasts can also differentiate into osteocytes, which are stellate cells populating narrow interconnecting passages within the bone matrix. The key molecular switch in the commitment of mesenchymal progenitors to osteoblast lineage is the transcription factor cbfa/runx2, which has multiple upstream regulators and a wide variety of targets. Upstream is the Wnt/Notch system, Sox9, Msx2, and hedgehog signaling. Cofactors of Runx2 include Osx, Atf4, and others. A few paracrine and endocrine factors serve as coactivators, in particular, bone morphogenetic proteins and parathyroid hormone. The process is further fine-tuned by vitamin D and histone deacetylases. Osteoblast differentiation is subject to regulation by physical stimuli to ensure the formation of bone adequate for structural and dynamic support of the body. Here, we provide a brief description of the various stimuli that influence osteogenesis: shear stress, compression, stretch, micro- and macrogravity, and ultrasound. A complex understanding of factors necessary for osteoblast differentiation paves a way to introduction of artificial bone matrices.

Toll-Like Receptor 4 (TLR4) signal pathway plays an important role in initiating the innate immune response and its activation by bacterial endotoxin is responsible for chronic and acute inflammatory disorders that are becoming more and more frequent in developed countries. Modulation of the TLR4 pathway is a potential strategy to specifically target these pathologies. Among the diseases caused by TLR4 abnormal activation by bacterial endotoxin, sepsis is the most dangerous one because it is a life-threatening acute system inflammatory condition that still lacks specific pharmacological treatment. Here, we review molecules at a preclinical or clinical phase of development, that are active in inhibiting the TLR4-MyD88 and TLR4-TRIF pathways in animal models. These are low-molecular weight compounds of natural and synthetic origin that can be considered leads for drug development. The results of in vivo studies in the sepsis model and the mechanisms of action of drug leads are presented and critically discussed, evidencing the differences in treatment results from rodents to humans.

We demonstrate advanced transversal radio frequency (RF) and microwave functions based on a Kerr optical comb source generated by an integrated micro-ring resonator. We achieve extremely high performance for an optical true time delay aimed at tunable phased array antenna applications, as well as reconfigurable microwave photonic filters. Our results agree well with theory. We show that our true time delay would yield a phased array antenna with features that include high angular resolution and a wide range of beam steering angles, while the microwave photonic filters feature high Q factors, wideband tunability, and highly reconfigurable filtering shapes. These results show that our approach is a competitive solution to implementing reconfigurable, high performance and potentially low cost RF and microwave signal processing functions for applications including radar and communication systems.

Smart factories Industry 4.0 on the basis of collaborative cyber-physical systems represents a future form of industrial networks. Supply chains in such networks have dynamic structures which evolve over time. In these settings, short-term supply chain scheduling in smart factories Industry 4.0 is challenged by temporal machine structures, different processing speed at parallel machines and dynamic job arrivals. In this study, for the first time, a dynamic model and algorithm for short-term supply chain scheduling in smart factories Industry 4.0 is presented. The peculiarity of the considered problem is the simultaneous consideration of both machine structure selection and job assignments. The scheduling approach is based on a dynamic non-stationary interpretation of the execution of the jobs and a temporal decomposition of the scheduling problem. The algorithmic realisation is based on a modified form of the continuous maximum principle blended with mathematical optimisation. A detailed theoretical analysis of the temporal decomposition and computational complexity is performed. The optimality conditions as well as the structural properties of the model and the algorithm are investigated. Advantages and limitations of the proposed approach are discussed.

Nonlinear nanostructured surfaces provide a paradigm shift in nonlinear optics with new ways to control and manipulate frequency conversion processes at the nanoscale, also offering novel opportunities for applications in photonics, chemistry, material science, and biosensing. Here, we develop a general approach to employ sharp resonances in metasurfaces originated from the physics of bound states in the continuum for both engineering and enhancing the nonlinear response. We study experimentally the third-harmonic generation from metasurfaces composed of symmetry-broken silicon meta-atoms and reveal that the harmonic generation intensity depends critically on the asymmetry parameter. We employ the concept of the critical coupling of light to the metasurface resonances to uncover the effect of radiative and nonradiative losses on the nonlinear conversion efficiency.

We study in detail a novel type of optical nanoantennas made of high-permittivity low-loss dielectric particles. In addition to the electric resonances, the dielectric particles exhibit very strong magnetic resonances at the nanoscale, that can be employed in the Yagi-Uda geometry for creating highly efficient optical nanoantennas. By comparing plasmonic and dielectric nanoantennas, we demonstrate that all-dielectric nanoantennas may exhibit better radiation efficiency also allowing more compact design.

Hyaluronic acid, as a natural linear polysaccharide, has attracted researchers' attention from its initial detection and isolation from tissues in 1934 until the present day. Due to biocompatibility and a high biodegradation of hyaluronic acid, it finds wide application in bioengineering and biomedicine: from biorevitalizing skin cosmetics and endoprostheses of joint fluid to polymeric scaffolds and wound dressings. However, the main properties of aqueous polysaccharide solutions with different molecular weights are different. Moreover, the therapeutic effect of hyaluronic acid-based preparations directly depends on the molecular weight of the biopolymer. The present review collects the information about relations between the molecular weight of hyaluronic acid and its original properties. Particular emphasis is placed on the structural, physical and physico-chemical properties of hyaluronic acid in water solutions, as well as their degradability.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.