Essential Role Research Articles

Using artificial intelligence to improve human performance: efficient retinal disease detection training with synthetic images

BackgroundArtificial intelligence (AI) in medical imaging diagnostics has huge potential, but human judgement is still indispensable. We propose an AI-aided teaching method that leverages generative AI to train students on...

Computational study on the inhibition mechanism of cyclodextran against GTF-SI from Streptococcus mutans focusing on the glucan-binding domain

Glucosyltransferases (GTFs) from Streptococcus mutans (S. mutans) are enzymes that synthesize glucan, a polymer that forms a biofilm causing dental caries. Cyclodextran (CI), which contains a ring structure formed from D-glucose by α-1,6 glycoside linkage, has been reported to strongly inhibit GTFs. In contrast, cyclodextrin, formed by α-1,4 glycoside linkage, has almost no inhibitory activity. In this study, we examined the inhibition mechanism of CI through computational chemistry, focusing on the glucan-binding domain of GTF-SI, which is one of GTFs produced by S. mutans. Analysis using molecular dynamics simulation and fragment molecular orbital method demonstrated a clear difference in the molecular interaction mechanism between α-1,6- and α-1,4-linked oligosaccharides. The calculated affinity of α-1,6-linked oligosaccharides was higher than that of α-1,4-linked oligosaccharides. Additionally, geometry optimization based on density functional theory revealed that three amino acids—Q1282, K1284, and S1302—play an essential role in the binding with α-1,6-linked oligosaccharides. These results successfully explain the inhibition mechanism of CI.

Salmonella Enteritidis antitoxin DinJ inhibits NLRP3-dependent canonical inflammasome activation in macrophages.

The inflammasome is a pivotal component of the innate immune system, acting as a multiprotein complex that plays an essential role in detecting and responding to microbial infections. Salmonella Enteritidis have evolved multiple mechanisms to regulate inflammasome activation and evade host immune system clearance. Through screening S. Enteritidis C50336ΔfliC transposon mutant library, we found that the insertion mutant of dinJ increased inflammasome activation. In this study, we demonstrated the genetic connection between the antitoxin DinJ and the toxin YafQ in S. Enteritidis, confirming their co-transcription. The deletion mutant ΔfliCΔdinJ increased cell death and IL-1β secretion in J774A.1 cells. Western blotting analysis further showed elevated cleaved Caspase-1 product (p10 subunits) and IL-1β secretion in cells infected with ΔfliCΔdinJ compared to cells infected with ΔfliC. DinJ was found to inhibit canonical inflammasome activation using primary bone marrow-derived macrophages (BMDMs) from Casp-/- C57BL/6 mice. Furthermore, DinJ specifically inhibited NLRP3 inflammasome activation, as demonstrated in BMDMs from Nlrp3-/- and Nlrc4-/- mice. Fluorescence resonance energy transfer (FRET) experiments confirmed the translocation of DinJ into host cells during infection. Finally, we revealed that DinJ could inhibit the secretion of IL-1β and IL-18 in vivo, contributing to S. Enteritidis evading host immune clearance. In summary, our findings provide insights into the role of DinJ in modulating the inflammasome response during S. Enteritidis infection, highlighting its impact on inhibiting inflammasome activation and immune evasion.

Land-use change interacts with island biogeography to alter bird community assembly.

Anthropogenic activities have reshaped biodiversity on islands worldwide. However, it remains unclear how island attributes and land-use change interactively shape multiple facets of island biodiversity through community assembly processes. To answer this, we conducted bird surveys in various land-use types (mainly forest and farmland) using transects on 34 oceanic land-bridge islands in the largest archipelago of China. We found that bird species richness increased with island area and decreased with isolation, regardless of the intensity of land-use change. However, forest-dominated habitats exhibited lower richness than farmland-dominated habitats. Island bird assemblages generally comprised species that share more similar traits or evolutionary histories (i.e. functional and/or phylogenetic clustering) than expected if assemblages were randomly assembled. Contrary to our expectations, we observed that bird assemblages in forest-dominated habitats were more clustered on large and close islands, whereas assemblages in farmland-dominated habitats were more clustered on small islands. These contrasting results indicate that land-use change interacts with island biogeography to alter the community assembly of birds on inhabited islands. Our findings emphasize the importance of incorporating human-modified habitats when examining the community assembly of island biota, and further suggest that agricultural landscapes on large islands may play essential roles in protecting countryside island biodiversity.

Cystic Echinococcosis of the Liver: Correlation Between Intra-Operative Ultrasound and Pre-Operative Imaging.

Background: Imaging plays an essential role in the management of hepatic hydatid cysts (HCE). The objective of our study was to determine the correlation between pre-operative ultrasound, computed tomography (CT), and intra-operative ultrasound (IOUS) in studying the characteristics and complications of HCE. Patients and Methods: This was a prospective, descriptive, and analytical study conducted in the General Surgery Department of Habib Bourguiba Hospital in Sfax. The study included patients with HCE who underwent conservative surgery between April 2017 and June 2022. Results: We enrolled 49 patients with 94 cysts. At the end of our study, IOUS allowed for better detection of HCE (98.8%) regardless of the number of cysts per patient. IOUS and CT were accurate in studying the location of cysts (κ = 1), whereas pre-operative abdominal ultrasound was less efficient (κ = 0.870). IOUS was the best examination for detecting exocysts (κ = 0.961), studying daughter cysts (κ = 0.823), and exploring vascular relations, but it was less effective (κ = 0.523) in detecting calcifications. Regarding classifications, ultrasound and CT had similar results. However, IOUS was most reliable in differentiating between CE3b and CE4 types (κ = 0.653). Ultrasound, CT, and IOUS were not sensitive in detecting latent HCE suppurations and cystobiliary fistulas. Conclusions: Performing IOUS is essential to prevent recurrences and reduce post-operative morbidity.

Functionality of IAV packaging signals depends on site-specific charges within the viral nucleoprotein.

Influenza A viruses (IAVs) have a segmented viral RNA (vRNA) genome encapsidated by multiple copies of the viral nucleoprotein (NP) and organized into eight distinct viral ribonucleoprotein complexes. Although genome segmentation contributes significantly to viral evolution and adaptation, it requires a highly sophisticated genome-packaging mechanism. How eight distinct genome complexes are incorporated into the virion is poorly understood, but previous research suggests an essential role for both vRNA packaging signals and highly conserved NP amino acids. By demonstrating that the packaging process is controlled by charge-dependent interactions of highly conserved lysine residues in NP and vRNA packaging signals, our study provides new insights into the sophisticated packaging mechanism of IAVs.

RISMiCal: A software package to perform fast RISM/3D-RISM calculations.

Solvent plays an essential role in a variety of chemical, physical, and biological processes that occur in the solution phase. The reference interaction site model (RISM) and its three-dimensional extension (3D-RISM) serve as powerful computational tools for modeling solvation effects in chemical reactions, biological functions, and structure formations. We present the RISM integrated calculator (RISMiCal) program package, which is based on RISM and 3D-RISM theories with fast GPU code. RISMiCal has been developed as an integrated RISM/3D-RISM program that has interfaces with external programs such as Gaussian16, GAMESS, and Tinker. Fast 3D-RISM programs for single- and multi-GPU codes written in CUDA would enhance the availability of these hybrid methods because they require the performance of many computationally expensive 3D-RISM calculations. We expect that our package can be widely applied for chemical and biological processes in solvent. The RISMiCal package is available at https://rismical-dev.github.io.

Virulence genes, antimicrobial resistance profile, phylotyping and pathotyping of diarrheagenic Escherichia coli isolated from children in Southwest Mexico.

Diarrheagenic E. coli (DEC) strains are one of the most important etiology factors causing diarrhea in children worldwide, especially in developing countries. DEC strains have characteristic virulence factors; however, other supplemental virulence genes (SVG) may contribute to the development of diarrhea in children. Therefore, this study aimed to determine the prevalence of DEC in children with diarrhea in southwestern Mexico and to associate childhood symptoms, SVG, and pathotypes with diarrhea-causing DEC strains. DEC strains were isolated from 230 children with diarrhea aged 0-60 months from the state of Oaxaca, southwestern Mexico; clinical data were collected, and PCR was used to identify SVG and pathotypes. Antibiotic resistance profiling was performed on DEC strains. 63% of samples were DEC positive, single or combined infections (two (21%) or three strains (1.3%)) of aEPEC (51%), EAEC (10.2%), tEPEC (5.4%), DAEC (4.8%), ETEC (4.1%), EIEC (1.4%), or EHEC (0.7%) were found. Children aged ≤ 12 and 49-60 months and symptoms (e.g., fever and blood) were associated with DEC strains. SVG related to colonization (nleB-EHEC), cytotoxicity (sat-DAEC and espC-tEPEC), and proteolysis (pic-aEPEC) were associated with DECs strains. E. coli phylogroup A was the most frequent, and some pathotypes (aEPEC-A, DAEC-B), and SVG (espC-B2, and sat-D) were associated with the phylogroups. Over 79% of the DEC strains were resistant to antibiotics, and 40% were MDR and XDR, respectively. In conclusion aEPEC was the most prevalent pathotype in children with diarrhea in this region. SVG related to colonization, cytotoxicity, and proteolysis were associated with diarrhea-producing DEC strains, which may play an essential role in the development of diarrhea in children in southwestern Mexico.

Advances in the co-signal molecular function of Mtb-specific T lymphocytes

Costimulatory and co-inhibitory receptors on T lymphocytes play an essential role in the immune response. There is increasing evidence that the expression of co-signal molecules on T cells is altered in infection, tumor, autoimmunity, and other diseases, and that intervention of co-signal molecules can be used in the immunotherapy. This paper reviewed the costimulatory and coinhibitory receptors on Mtb-specific T lymphocytes and further explained the mechanism of co-signal molecules in the progression of tuberculosis, to provide a reference for future research and clinical application.

A novel Knowledge Graph recommendation algorithm based on Graph Convolutional Network

Knowledge Graphs (KGs) are widely used in many fields of application, and especially play an essential role in recommendation systems. KGs often need to be complete, missing relationships between users and items, data sparsity, weak associations, and difficulties in knowledge inference, resulting in low credibility of recommendation results. Therefore, we propose a novel Knowledge Graph (KG) recommendation algorithms. Due to the availability of interaction data across numerous events, KGs also exhibit dynamics over time. By taking into account the temporal variable, it is possible to organise well-structured external information to connect users and items, thereby expanding user preferences to a certain extent. The proposed algorithm employs GCNs to encode the heterogeneous graph, which includes user-item interactions and the KG. It addresses the challenge of high-dimensional data by using the inner product of users and items. The algorithm uncovers potential alignment relationships and learns the embedding of user-item and relationships by applying convolutional processing to the graph data's features and performing data fusion, the new algorithm uncovers potential alignment relationships, and learns embedding of user-item and relationships. The experimental results on the Mean Reciprocal Rank (MRR) and Hits@k demonstrate that the proposed algorithm outperforms state-of-the-art algorithms in terms of the credibility and accuracy of recommendation results.

Study on the Integration of Ideological and Political Education and Students’ Mental Health Education

In the new era, the rapid advancement of Internet technology has promoted the development of social economy and education. Although the current education conditions and education system of colleges and universities have been significantly improved, the attention to students’ mental health education is low. Nowadays, there is various uneven and unhealthy information on the Internet, which will negatively impact the shaping of correct values in students, and play an essential role in improving students’ discrimination ability. Therefore, it is very important to realize the good integration between ideological and political education and students’ mental health education in college education, which can promote the all-round development of students. Based on this, this paper mainly focuses on the integration of ideological and political education and students’ mental health education, so as to provide theoretical reference for the smooth development of relevant research in the future.

Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus.

Foot-and-mouth disease (FMD) is one of the most devastating diseases of livestock which can cause significant economic losses, especially when introduced to FMD-free countries. FMD virus (FMDV) belongs to the family Picornaviridae and is antigenically heterogeneous with seven established serotypes. The prevailing preventive and control strategies are limited to restriction of animal movement and elimination of infected or exposed animals, which can be potentially combined with vaccination. However, FMD vaccination has limitations including delayed protection and lack of cross-protection against different serotypes. Recently, antiviral drug use for FMD outbreaks has increasingly been recognized as a potential tool to augment the existing early response strategies, but limited research has been reported on potential antiviral compounds for FMDV. FMDV 3C protease (3Cpro) cleaves the viral-encoded polyprotein into mature and functional proteins during viral replication. The essential role of viral 3Cpro in viral replication and the high conservation of 3Cpro among different FMDV serotypes make it an excellent target for antiviral drug development. We have previously reported multiple series of inhibitors against picornavirus 3Cpro or 3C-like proteases (3CLpros) encoded by coronaviruses or caliciviruses. In this study, we conducted structure-activity relationship studies for our in-house focused compound library containing 3Cpro or 3CLpro inhibitors against FMDV 3Cpro using enzyme and cell-based assays. Herein, we report the discovery of aldehyde and α-ketoamide inhibitors of FMDV 3Cpro with high potency. These data inform future preclinical studies that are related to the advancement of these compounds further along the drug development pathway.IMPORTANCEFood-and-mouth disease (FMD) virus (FMDV) causes devastating disease in cloven-hoofed animals with a significant economic impact. Emergency response to FMD outbreaks to limit FMD spread is critical, and the use of antivirals may overcome the limitations of existing control measures by providing immediate protection for susceptible animals. FMDV encodes 3C protease (3Cpro), which is essential for virus replication and an attractive target for antiviral drug discovery. Here, we report a structure-activity relationship study on multiple series of protease inhibitors and identified potent inhibitors of FMDV 3Cpro. Our results suggest that these compounds have the potential for further development as FMD antivirals.

The deubiquitinase cofactor UAF1 interacts with USP1 and plays an essential role in spermiogenesis

Spermiogenesis defines the final phase of male germ cell differentiation. While multiple deubiquitinating enzymes have been linked to spermiogenesis, the impacts of deubiquitination on spermiogenesis remain poorly characterized. Here, we investigated the function of UAF1 in mouse spermiogenesis. We selectively deleted Uaf1 in premeiotic germ cells using the Stra8-Cre knock-in mouse strain (Uaf1 sKO), and found that Uaf1 is essential for spermiogenesis and male fertility. Further, UAF1 interacts and colocalizes with USP1 in the testes. Conditional knockout of Uaf1 in testes results in disturbed protein levels and localization of USP1, suggesting that UAF1 regulates spermiogenesis through the function of the deubiquitinating enzyme USP1. Using tandem mass tag-based proteomics, we identified that conditional knockout of Uaf1 in the testes results in reduced levels of proteins that are essential for spermiogenesis. Thus, we conclude that the UAF1/USP1 deubiquitinase complex is essential for normal spermiogenesis by regulating the levels of spermiogenesis-related proteins.

ABSCISIC ACID-INSENSITIVE 5-KIP-RELATED PROTEIN 1-SHOOT MERISTEMLESS modulates reproductive development of Arabidopsis.

Soil (or plant) water deficit accelerates plant reproduction. However, the underpinning molecular mechanisms remain unknown. By modulating cell division/number, ABSCISIC ACID-INSENSITIVE 5 (ABI5), a key bZIP (basic (region) leucine zippers) transcription factor, regulates both seed development and abiotic stress responses. The KRP (KIP-RELATED PROTEIN) cyclin-dependent kinases (CDKs) play an essential role in controlling cell division, and SHOOT MERISTEMLESS (STM) plays a key role in the specification of flower meristem identity. Here, our findings show that abscisic acid (ABA) signaling and/or metabolism in adjust reproductive outputs (such as rosette leaf number and open flower number) under water-deficient conditions in Arabidopsis (Arabidopsis thaliana) plants. Reproductive outputs increased under water-sufficient conditions but decreased under water-deficient conditions in the ABA signaling/metabolism mutants abscisic acid2-1 (aba2-1), aba2-11, abscisic acid insensitive3-1 (abi3-1), abi4-1, abi5-7, and abi5-8. Further, under water-deficient conditions, ABA induced-ABI5 directly bound to the promoter of KRP1, which encodes a CDK that plays an essential role in controlling cell division, and this binding subsequently activated KRP1 expression. In turn, KRP1 physically interacted with SHOOT MERISTEMLESS (STM), which functions in the specification of flower meristem identity, promoting STM degradation. We further demonstrate that reproductive outputs are adjusted by the ABI5-KRP1-STM molecular module under water-deficient conditions. Together, our findings reveal the molecular mechanism by which ABA signaling and/or metabolism regulate reproductive development under water-deficient conditions. These findings provide insights that may help guide crop yield improvement under water deficiency.

The price continuity, return and volatility spillover effects of regular and after-hours trading.

This study employs a bivariate EGARCH model to examine the Taiwan Futures Exchange's regular and after-hours trading, focusing on the critical aspects of spillover and expiration effects, as well as volatility clustering and asymmetry. The objective of this study is to observe the impact on the trading sessions in Taiwan by the influences of the European and American markets, focusing on the essential roles of the price discovery function and risk disclosure effectiveness of the regular hours trading. This research is imperative considering the increasing interconnectedness of global financial markets and the need for comprehensive risk assessment for investment strategies. It also examines the hedging behavior of after-hours traders, thereby aiming to contribute to pre-investment analysis by future investors. This examination is vital for understanding the dynamics of after-hours trading and its influence on market stability. Results indicate price continuity between both trading sessions, with regular trading often determining after-hours price ranges. Consequently, after-hours price changes can inform regular trading decisions. This finding highlights the importance of after-hours trading for shaping market expectations. Significant profit potential exists in after-hours trading open interest, which serves speculative and hedging purposes. While regular trading volatility influences after-hours trading, the reverse is not true. This suggests Taiwan market information poses a higher risk impact than European and American market data, emphasizing the unique position of the Taiwan market in the global financial ecosystem. After-hours trading volatility reflects the absorption of international market information and plays a crucial role in advance revelation of risks. This underscores the importance of after-hours trading in global risk management and strategy formulation.

Structural insights into the recognition of the A/T-rich motif in target gene promoters by the LMX1a homeobox domain.

LIM homeodomain transcription factor 1-alpha (LMX1a) is a neuronal lineage-specific transcription activator that plays an essential role during the development of midbrain dopaminergic (mDA) neurons. LMX1a induces the expression of multiple key genes, which ultimately determine the morphology, physiology, and functional identity of mDA neurons. This function of LMX1a is dependent on its homeobox domain. Here, we determined the structures of the LMX1a homeobox domain in complex with the promoter sequences of the Wnt family member 1 (WNT1) or paired like homeodomain 3 (Pitx3) gene, respectively. The complex structures revealed that the LMX1a homeobox domain employed its α3 helix and an N-terminal loop to achieve specific target recognition. The N-terminal loop (loop1) interacted with the minor groove of the double-stranded DNA (dsDNA), whereas the third α-helix (α3) was tightly packed into the major groove of the dsDNA. Structure-based mutations in the α3 helix of the homeobox domain significantly reduced the binding affinity of LMX1a to dsDNA. Moreover, we identified a nonsyndromic hearing loss (NSHL)-related mutation, R199, which yielded a more flexible loop and disturbed the recognition in the minor groove of dsDNA, consistent with the molecular dynamics (MD) simulations. Furthermore, overexpression of Lmx1a promoted the differentiation of SH-SY5Y cells and upregulated the transcription of WNT1 and PITX3 genes. Hence, our work provides a detailed elucidation of the specific recognition between the LMX1a homeobox domain and its specific dsDNA targets, which represents valuable information for future investigations of the functional pathways that are controlled by LMX1a during mDA neuron development.

COVID-19 Information Platform for Primary Care: Emergence and Development of a Web-based Knowledge Platform in the COVID-19 Pandemic

The SARS-Cov-2 outbreak in the spring of 2020 challenged the health care system, and thus primary care, on an unprecedented scale. Knowledge about the new disease was low, whereas the dynamics of knowledge generation were high and inhomogeneous. A number of new primary care tasks related to the pandemic situation emerged. Guidance in the management of COVID-19 was therefore needed, although robust evidence was not yet available. The information required concerned not only the virus and the new disease COVID-19, but also regulatory requirements and organizational issues. In this situation, a flexible, web-based information tool, easy to update and usable at the point of care, was developed at Karl Landsteiner Private University Krems and put online under the name of "COVID-19: prevention and management in primary care practices" on March 25, 2020. In a retrospective process description, we describe the needs-triggered process of developing and disseminating a practice-based tool to support practicing primary care physicians in a period of high uncertainty with an urgent need for information. Afterwards, we reflect on the learning process from a purely pragmatic to an increasingly structured approach and try to draw conclusions regarding optimization possibilities in terms of creation and dissemination. In situations of high uncertainty combined with an acute need for action and decision-making, there is a significant need for information that is as reliable as possible. Science transfer must be done in such a way that information can be implemented quickly. Dissemination, as always, plays an essential role. Gaps must be accepted. A structured process of quality assurance must be established in parallel. Funds and resources for knowledge transfer should be included in future pandemic plans.

Mechanistic insight into the catalytic CO oxidation and SO2 resistance over Mo-decorated Pt/TiO2 catalyst: The essential role of Mo

The problem of CO oxidation in incomplete combustion from steel industry is that the deactivation of Pt-based catalysts by SO2. Here, we have elaborately designed a series of Mo-decorated 0.1 wt.% Pt/TiO2 catalyst (Pt/Mo/Ti) catalyst. The catalytic test showed that the Pt/3Mo/Ti catalyst achieved 100 % CO conversion above 200 °C and maintained excellent long-term catalytic stability in the presence of SO2. The enhancement in SO2-tolerance ability was due to the suitable Brønsted acidity to weaken the SO2 adsorption and strong charge transfer ability to reduce the oxidation of SO2 to SO3. Aberration-corrected scanning transmission electron microscopy (STEM) suggests that the Pt-O-Mo species are present in atomically dispersed form in the Pt/3Mo/Ti catalyst. The surface O = MoO4 sites with terminal Mo = O bond prevented SO2 from reacting with platinum, thus inhibiting its migration to TiO2 and TiOSO4 formation. We also revealed the strong interaction between platinum and molybdenum and characterized the CO oxidation pathway in the presence of SO2. This research offers new insights into the mechanism of the catalytic CO oxidation and SO2 resistance over Mo-decorated Pt/TiO2 catalyst.

A Novel Fluorogenic Probe Reveals Lipid Droplet Dynamics in ME/CFS Fibroblasts

AbstractLipid droplets (LDs) are dynamic cellular organelles that play an essential role in lipid metabolism and storage. LD dysregulation has been implicated in various diseases. However, investigations into the cellular LD dynamics under disease conditions have been rarely reported, possibly due to the absence of high performing LD imaging agents. Here a novel fluorogenic probe, AM‐QTPA, is reported for specific LD imaging. AM‐QTPA demonstrates viscosity sensitivity and aggregation‐induced emission enhancement characteristics. It is live cell permeable and can specifically light up LDs in cells, with low background noise and superior signals that can be quantified. After validation in cell model with LD accumulation induced by oleic acid treatment, AM‐QTPA is applied in a small proof‐of‐concept number of human fibroblast samples derived from people diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex and debilitating disease with unknown cause. The results indicate the presence of larger but fewer LDs in ME/CFS fibroblasts compared to the healthy counterparts, accompanying with frequent LD‐mitochondria contacts, suggesting potential upregulation of lipolysis in ME/CFS connective tissue like fibroblasts. Overall, AM‐QTPA provides new understanding of the anomalous LD dynamics in disease status, which, potentially, will facilitate in‐depth investigation of the pathogenesis of ME/CFS.

The Urgency of Implementing Meaningful Participation in Forming Laws in Indonesia

This research engages regarding meaningful participation in the formation of laws. There have been several demonstrations over the Bill discussion. The most recent demonstration is a protest opposing the Health Bill discussion. Demonstrations signify that meaningful participation needs to be appropriately implemented. This research is intended to determine the urgency, implementation and challenges of meaningful participation. The research method used is normative juridical research. The finding revealed the essential and strategic role of meaningful participation on the formation of laws. Ideally, the Formation of Law should facilitate genuine public participation and active involvement. The public's right to provide input is an implementation of 1) right to be heard, 2) right to be considered, and 3) right to be explained. Even if the input is not accepted, it is expected that the community will acknowledge the decision with a reasonable explanation (legowo). Given that Meaningful participation is a novel concept, it is anticipated to encounter challenges, primarily concerning the political factor of law, which is inseparably linked to the political configuration of the governing regime.