Dynamic Occupancy Grid Map with Semantic Information Using Deep Learning-Based BEVFusion Method with Camera and LiDAR Fusion.

In the field of robotics and autonomous driving, dynamic occupancy grid maps (DOGMs) are typically used to represent the position and velocity information of objects. Although three-dimensional light detection and ranging (LiDAR) sensor-based DOGMs have been actively researched, they have limitations, as they cannot classify types of objects. Therefore, in this study, a deep learning-based camera-LiDAR sensor fusion technique is employed as input to DOGMs. Consequently, not only the position and velocity information of objects but also their class information can be updated, expanding the application areas of DOGMs. Moreover, unclassified LiDAR point measurements contribute to the formation of a map of the surrounding environment, improving the reliability of perception by registering objects that were not classified by deep learning. To achieve this, we developed update rules on the basis of the Dempster-Shafer evidence theory, incorporating class information and the uncertainty of objects occupying grid cells. Furthermore, we analyzed the accuracy of the velocity estimation using two update models. One assigns the occupancy probability only to the edges of the oriented bounding box, whereas the other assigns the occupancy probability to the entire area of the box. The performance of the developed perception technique is evaluated using the public nuScenes dataset. The developed DOGM with object class information will help autonomous vehicles to navigate in complex urban driving environments by providing them with rich information, such as the class and velocity of nearby obstacles.

Immune Cells Are Differentially Affected by SARS-CoV-2 Viral Loads in K18-hACE2 Mice.

Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019. In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virus-infected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105 PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.

Discontinuation of blood pressure-lowering, glucose-lowering, and lipid-lowering medications after bariatric surgery in patients with morbid obesity: a nationwide cohort study in South Korea.

BACKGROUND: Limited evidence exists on the patterns of medication use for hypertension, diabetes mellitus (DM), and dyslipidemia after bariatric surgery among Asian patients. OBJECTIVES: To investigate the patterns in the use of blood pressure-lowering, glucose-lowering, and lipid-lowering medications following BS in Korean patients with morbid obesity. SETTING: This study is a retrospective cohort study using the Health Insurance Review and Assignment claims database of South Korea (from 2019 to 2021). METHODS: We included patients who underwent BS between 2019 and 2020 in South Korea. We evaluated the treatment patterns of blood pressure-lowering, glucose-lowering, and lipid-lowering medications at 3-month intervals for 1-year following BS, including medication use, individual medication classes, and the number of medications prescribed. Furthermore, we estimated remission rates for each disorder based on patient characteristics by defining patients who discontinued their medications for at least 2 consecutive quarters as remission. RESULTS: A total of 3810 patients were included in this study. For 1-year following BS, a marked decrease in the number of patients using blood pressure-lowering, glucose-lowering, and lipid-lowering medications was observed. The most remarkable decrease occurred in glucose-lowering medications, which decreased by approximately -75.1% compared with that at baseline. This tendency was consistently observed when analyzing both the number of medications prescribed and the specific medication classes. Regarding remission rates, patients who were female, younger, and received the biliopancreatic diversion-duodenal switch as their BS showed a relatively higher incidence of remission than other groups. CONCLUSIONS: BS was associated with a decrease in the use of medications for hypertension, diabetes mellitus (DM), and dyslipidemia.

Nonprehensile Manipulation for Rapid Object Spinning via Multisensory Learning from Demonstration.

Dexterous manipulation concerns the control of a robot hand to manipulate an object in a desired manner. While classical dexterous manipulation strategies are based on stable grasping (or force closure), many human-like manipulation tasks do not maintain grasp stability and often utilize the dynamics of the object rather than the closed form of kinematic relation between the object and the robotic hand. Such manipulation strategies are referred as nonprehensile or dynamic dexterous manipulation in the literature. Nonprehensile manipulation often involves fast and agile movements such as throwing and flipping. Due to the complexity of such motions and uncertainties associated with them, it has been challenging to realize nonprehensile manipulation tasks in a reliable way. In this paper, we propose a new control strategy to realize practical nonprehensile manipulation. First, we make explicit use of multiple modalities of sensory data for the design of control law. Specifically, force data are employed for feedforward control, while position data are used for feedback control. Secondly, control signals (both feedback and feedforward) are obtained through multisensory learning from demonstration (LfD) experiments designed and performed for specific nonprehensile manipulation tasks of concern. To prove the concept of the proposed control strategy, experimental tests were conducted for a dynamic spinning task using a sensory-rich, two-finger robotic hand. The control performance (i.e., the speed and accuracy of the spinning task) was also compared with that of classical dexterous manipulation based on force closure and finger gaiting.

Assessing the Labeling Information on Drugs Associated With Suicide Risk: Systematic Review.

BACKGROUND: Drug-induced suicide (DIS) is a severe adverse drug reaction (ADR). Although clinical trials have provided evidence on DIS, limited investigations have been performed on rare ADRs, such as suicide. OBJECTIVE: We aimed to systematically review case reports on DIS to provide evidence-based drug information. METHODS: We searched PubMed to obtain case reports regarding DIS published until July 2021. Cases resulting from drugs that are no longer used or are nonapproved, substance use, and suicidal intentions were excluded. The quality of each case report was assessed using the CASE (Case Reports) checklist. We extracted data regarding demographics, medication history, suicide symptoms, and symptom improvement and evaluated the causality of DIS using the Naranjo score. Furthermore, to identify the potential suicidal risk of the unknown drugs, we compared the results of the causality assessment with those of the approved drug labels. RESULTS: In 83 articles, we identified 152 cases involving 61 drugs. Antidepressants were reported as the most frequent causative drugs of DIS followed by immunostimulants. The causality assessment revealed 61 cases having possible, 89 cases having probable, and 2 cases having definite relationships with DIS. For approximately 85% of suspected drugs, the risk of suicidal ADRs was indicated on the approved label; however, the approved labels for 9 drugs, including lumacaftor/ivacaftor, doxycycline, clozapine, dextromethorphan, adalimumab, infliximab, piroxicam, paclitaxel, and formoterol, did not provide information about these risks. CONCLUSIONS: We found several case reports involving drugs without suicide risk information on the drug label. Our findings might provide valuable insights into drugs that may cause suicidal ADRs.

A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic mice.

BACKGROUND: The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to approximately 500 million cases and 6 million deaths worldwide. Previous investigations into the pathophysiology of SARS-CoV-2 primarily focused on peripheral blood mononuclear cells from patients, lacking detailed mechanistic insights into the virus's impact on inflamed tissue. Existing animal models, such as hamster and ferret, do not faithfully replicate the severe SARS-CoV-2 infection seen in patients, underscoring the need for more relevant animal system-based research. METHODS: In this study, we employed single-cell RNA sequencing (scRNA-seq) with lung tissues from K18-hACE2 transgenic (TG) mice during SARS-CoV-2 infection. This approach allowed for a comprehensive examination of the molecular and cellular responses to the virus in lung tissue. FINDINGS: Upon SARS-CoV-2 infection, K18-hACE2 TG mice exhibited severe lung pathologies, including acute pneumonia, alveolar collapse, and immune cell infiltration. Through scRNA-seq, we identified 36 different types of cells dynamically orchestrating SARS-CoV-2-induced pathologies. Notably, SPP1+ macrophages in the myeloid compartment emerged as key drivers of severe lung inflammation and fibrosis in K18-hACE2 TG mice. Dynamic receptor-ligand interactions, involving various cell types such as immunological and bronchial cells, defined an enhanced TGFß signaling pathway linked to delayed tissue regeneration, severe lung injury, and fibrotic processes. INTERPRETATION: Our study provides a comprehensive understanding of SARS-CoV-2 pathogenesis in lung tissue, surpassing previous limitations in investigating inflamed tissues. The identified SPP1+ macrophages and the dysregulated TGFß signaling pathway offer potential targets for therapeutic intervention. Insights from this research may contribute to the development of innovative diagnostics and therapies for COVID-19. FUNDING: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020M3A9I2109027, 2021R1A2C2004501).

Unsupervised Stereo Matching with Surface Normal Assistance for Indoor Depth Estimation.

To obtain more accurate depth information with stereo cameras, various learning-based stereo-matching algorithms have been developed recently. These algorithms, however, are significantly affected by textureless regions in indoor applications. To address this problem, we propose a new deep-neural-network-based data-driven stereo-matching scheme that utilizes the surface normal. The proposed scheme includes a neural network and a two-stage training strategy. The neural network involves a feature-extraction module, a normal-estimation branch, and a disparity-estimation branch. The training processes of the feature-extraction module and the normal-estimation branch are supervised while the training of the disparity-estimation branch is performed unsupervised. Experimental results indicate that the proposed scheme is capable of estimating the surface normal accurately in textureless regions, leading to improvement in the disparity-estimation accuracy and stereo-matching quality in indoor applications involving such textureless regions.

How Deep Learning in Antiviral Molecular Profiling Identified Anti-SARS-CoV-2 Inhibitors.

The integration of artificial intelligence (AI) into drug discovery has markedly advanced the search for effective therapeutics. In our study, we employed a comprehensive computational-experimental approach to identify potential anti-SARS-CoV-2 compounds. We developed a predictive model to assess the activities of compounds based on their structural features. This model screened a library of approximately 700,000 compounds, culminating in the selection of the top 100 candidates for experimental validation. In vitro assays on human intestinal epithelial cells (Caco-2) revealed that 19 of these compounds exhibited inhibitory activity. Notably, eight compounds demonstrated dose-dependent activity in Vero cell lines, with half-maximal effective concentration (EC50) values ranging from 1 µM to 7 µM. Furthermore, we utilized a clustering approach to pinpoint potential nucleoside analog inhibitors, leading to the discovery of two promising candidates: azathioprine and its metabolite, thioinosinic acid. Both compounds showed in vitro activity against SARS-CoV-2, with thioinosinic acid also significantly reducing viral loads in mouse lungs. These findings underscore the utility of AI in accelerating drug discovery processes.

A bivalent form of a RBD-specific synthetic antibody effectively neutralizes SARS-CoV-2 variants.

Coronavirus Disease 2019 (COVID-19) pandemic is severely impacting the world, and tremendous efforts have been made to deal with it. Despite many advances in vaccines and therapeutics, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants remains an intractable challenge. We present a bivalent Receptor Binding Domain (RBD)-specific synthetic antibody, specific for the RBD of wild-type (lineage A), developed from a non-antibody protein scaffold composed of LRR (Leucine-rich repeat) modules through phage display. We further reinforced the unique feature of the synthetic antibody by constructing a tandem dimeric form. The resulting bivalent form showed a broader neutralizing activity against the variants. The in vivo neutralizing efficacy of the bivalent synthetic antibody was confirmed using a human ACE2-expressing mouse model that significantly alleviated viral titer and lung infection. The present approach can be used to develop a synthetic antibody showing a broader neutralizing activity against a multitude of SARS-CoV-2 variants.

SARS-CoV-2 infection engenders heterogeneous ribonucleoprotein interactions to impede translation elongation in the lungs.

Translational regulation in tissue environments during in vivo viral pathogenesis has rarely been studied due to the lack of translatomes from virus-infected tissues, although a series of translatome studies using in vitro cultured cells with viral infection have been reported. In this study, we exploited tissue-optimized ribosome profiling (Ribo-seq) and severe-COVID-19 model mice to establish the first temporal translation profiles of virus and host genes in the lungs during SARS-CoV-2 pathogenesis. Our datasets revealed not only previously unknown targets of translation regulation in infected tissues but also hitherto unreported molecular signatures that contribute to tissue pathology after SARS-CoV-2 infection. Specifically, we observed gradual increases in pseudoribosomal ribonucleoprotein (RNP) interactions that partially overlapped the trails of ribosomes, being likely involved in impeding translation elongation. Contemporaneously developed ribosome heterogeneity with predominantly dysregulated 5 S rRNP association supported the malfunction of elongating ribosomes. Analyses of canonical Ribo-seq reads (ribosome footprints) highlighted two obstructive characteristics to host gene expression: ribosome stalling on codons within transmembrane domain-coding regions and compromised translation of immunity- and metabolism-related genes with upregulated transcription. Our findings collectively demonstrate that the abrogation of translation integrity may be one of the most critical factors contributing to pathogenesis after SARS-CoV-2 infection of tissues.

Psychiatric Comorbidities and Schizophrenia in Youths With Attention-Deficit/Hyperactivity Disorder.

Importance: The association between attention-deficit/hyperactivity disorder (ADHD) and schizophrenia has received increased attention; however, evidence on the association between psychiatric comorbidities and subsequent schizophrenia in patients with ADHD is limited. Objective: To investigate the risk of being diagnosed with schizophrenia in children and adolescents with ADHD considering the presence of psychiatric comorbidity. Design, Setting, and Participants: This was a population-based, retrospective cohort study using the Health Insurance Review and Assessment claims database from January 1, 2007, to December 31, 2019. Participants were children and adolescents aged 5 to 19 years who received an ADHD diagnosis between January 1, 2010, and December 31, 2018, in the nationwide claims data of Korea. Data were analyzed from January 2010 to December 2019. Interventions or Exposures: The presence of psychiatric comorbidity was assessed from diagnosis records within 1 year before ADHD diagnosis. Comorbidities were further categorized according to the number of comorbidities and specific comorbid disorders. Main Outcomes and Measures: Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs, examining the association between psychiatric comorbidities and the risk of being diagnosed with schizophrenia. Furthermore, the occurrence of psychiatric comorbidity during the follow-up period was explored among patients without psychiatric comorbidity at baseline. Results: A total of 211 705 patients with newly diagnosed ADHD were included. A total of 157 272 patients (74.3%) were male, and the age of 5 to 9 years showed the highest distribution (115 081 patients [54.4%]). Patients with psychiatric comorbidity had a significantly higher risk of being diagnosed with schizophrenia than those without (adjusted HR, 2.14; 95% CI, 2.05-2.23). The association between schizophrenia and psychiatric comorbidity became progressively greater with the increasing number of comorbidities. Several individual psychiatric disorders showed an association with development of schizophrenia, with ASD, intellectual disability, tic disorder, depression, and bipolar disorder being the top 5 disorders most associated. Furthermore, 3244 patients (73.8%) without psychiatric comorbidities experienced the emergence of other psychiatric disorders before schizophrenia occurrence. Conclusions and Relevance: In this retrospective cohort study involving children and adolescents with ADHD, the presence of psychiatric comorbidity in patients with ADHD was associated with an increased risk of being diagnosed with schizophrenia, with an increased risk observed in multiple comorbidities and a wide variety of comorbidities. These findings highlight the significance of assessing and managing psychiatric comorbidities in patients with ADHD to decrease subsequent schizophrenia risk and allow for early intervention.

Visual feedback decoding during bimanual circle drawing.

The between-hand interference during bimanual tasks is a consequence of the connection between the neural controllers of movement. Previous studies showed the existence of an asymmetric between-hand interference (caused by neural cross talk) when different kinematics plans were to be executed by each hand or when only one was visually guided and received perturbed visual feedback. Here, in continuous bimanual circle drawing tasks, we investigated if the central nervous system (CNS) can benefit from visual composite feedback, i.e., a weighted sum of hands' positions presented for the visually guided hand, to control the nonvisible hand. Our results demonstrated improvement in the nonvisible nondominant hand (NDH) performance in the presence of the composite feedback. When NDH was visually guided, the dominant hand's (DH) performance during asymmetric drawing deteriorated, whereas its performance during symmetric drawing improved. This indicates that the CNS's ability to leverage composite feedback, which can be the result of decoding the nonvisible hand positional information from the composite feedback, is task-dependent and can be asymmetric. Also, the nonvisible hand's performance degraded when DH or NDH was visually guided with amplified error feedback. The results of the amplified feedback condition do not strongly support the asymmetry of the interference during asymmetric circle drawing. Comparing muscle activations in the asymmetric experiment, we concluded that the observed kinematic differences were not due to alternation in muscle co-contractions.NEW & NOTEWORTHY Many daily activities involve bimanual coordination while simultaneous movement of the hands may result in interference with their movements. Here, we studied whether the central nervous system could use the relevant information in composite feedback, i.e., a weighted sum of positional information of nonvisible and visible hands, to improve the movement of the nonvisible hand. Our results suggest the ability to decode and associate task-relevant information from the composite feedback.

A Moonlighting Protein Secreted by a Nasal Microbiome Fortifies the Innate Host Defense Against Bacterial and Viral Infections.

Evidence suggests that the human respiratory tract, as with the gastrointestinal tract, has evolved to its current state in association with commensal microbes. However, little is known about how the airway microbiome affects the development of airway immune system. Here, we uncover a previously unidentified mode of interaction between host airway immunity and a unique strain (AIT01) of Staphylococcus epidermidis, a predominant species of the nasal microbiome. Intranasal administration of AIT01 increased the population of neutrophils and monocytes in mouse lungs. The recruitment of these immune cells resulted in the protection of the murine host against infection by Pseudomonas aeruginosa, a pathogenic bacterium. Interestingly, an AIT01-secreted protein identified as GAPDH, a well-known bacterial moonlighting protein, mediated this protective effect. Intranasal delivery of the purified GAPDH conferred significant resistance against other Gram-negative pathogens (Klebsiella pneumoniae and Acinetobacter baumannii) and influenza A virus. Our findings demonstrate the potential of a native nasal microbe and its secretory protein to enhance innate immune defense against airway infections. These results offer a promising preventive measure, particularly relevant in the context of global pandemics.

USP13 deubiquitinates p62/SQSTM1 to induce autophagy and Nrf2 release for activating antioxidant response genes.

SQSTM1/p62 (sequestosome 1) is a multifunctional protein that serves as a receptor for selective autophagy and scaffold. In selective autophagy, p62 functions as a bridge between polyubiquitinated proteins and autophagosomes. Further, p62 acts as a signaling hub for many cellular pathways including mTORC1, NF-κB, and Keap1-Nrf2. Post-translational modifications of p62, such as ubiquitination and phosphorylation, are known to determine its binding partners and regulate their intracellular functions. However, the mechanism of p62 deubiquitination remains unclear. In this study, we found that ubiquitin-specific protease 13 (USP13), a member of the USP family, directly binds p62 and removes ubiquitin at Lys7 (K7) of the PB1 domain. USP13-mediated p62 deubiquitination enhances p62 protein stability and facilitates p62 oligomerization, resulting in increased autophagy and degradation of Keap1, which is a negative regulator of the antioxidant response that promotes Nrf2 activation. Thus, USP13 can be considered a therapeutic target as a deubiquitination enzyme of p62 in autophagy-related diseases.

Ferric citrate and apo-transferrin enable erythroblast maturation with ß-globin from hemogenic endothelium.

Red blood cell (RBC) generation from human pluripotent stem cells (PSCs) offers potential for innovative cell therapy in regenerative medicine as well as developmental studies. Ex vivo erythropoiesis from PSCs is currently limited by the low efficiency of functional RBCs with ß-globin expression in culture systems. During induction of ß-globin expression, the absence of a physiological microenvironment, such as a bone marrow niche, may impair cell maturation and lineage specification. Here, we describe a simple and reproducible culture system that can be used to generate erythroblasts with ß-globin expression. We prepared a two-dimensional defined culture with ferric citrate treatment based on definitive hemogenic endothelium (HE). Floating erythroblasts derived from HE cells were primarily CD45+CD71+CD235a+ cells, and their number increased remarkably upon Fe treatment. Upon maturation, the erythroblasts cultured in the presence of ferric citrate showed high transcriptional levels of ß-globin and enrichment of genes associated with heme synthesis and cell cycle regulation, indicating functionality. The rapid maturation of these erythroblasts into RBCs was observed when injected in vivo, suggesting the development of RBCs that were ready to grow. Hence, induction of ß-globin expression may be explained by the effects of ferric citrate that promote cell maturation by binding with soluble transferrin and entering the cells.Taken together, upon treatment with Fe, erythroblasts showed advanced maturity with a high transcription of ß-globin. These findings can help devise a stable protocol for the generation of clinically applicable RBCs.

The relative importance of friendship to happiness increases with age.

Happiness is predicted by social relationships in general and contact frequency in particular. This study aims to examine if the relative importance of social contacts with the closest family/relative, friend, and neighbor in happiness changes with advancing age. We used data for all participants aged 19 years and older (n = 229,099) in the 2019 Community Health Survey, which measured the frequency of contact with the closest relative/family, neighbor, and friend among a representative sample of Koreans between August 16 and October 31, 2019. The Shapley value decomposition method was used to measure the relative importance of each predictor of happiness. Overall, contact frequency was positively associated with happiness (p<0.001). The relative importance value of contact with the closest family, neighbor, and friend to happiness increased from 4.70%, 3.98%, and 7.35%, respectively, in the 19-29 years group to 8.09%, 4.44%, and 11.00%, respectively, in the 60 years and older group. Frequent interactions with the closest friend could have a greater impact on happiness in old age than those with the closest family and neighbor.

Identification of Pyrido[3,4-d]pyrimidine derivatives as RIPK3-Mediated necroptosis inhibitors.

Necroptosis executed by RIPK3-mediated phosphorylation of MLKL is a programmed necrotic cell death and implicated with various diseases such as sterile inflammation. We designed and synthesized pyrido[3,4-d]pyrimidine derivatives as novel necroptosis inhibitors capable of suppressing the phosphorylation of MLKL. Our SAR studies reveal that 20 possesses comparable inhibitory activity against RIPK3-mediated pMLKL in HT-29 cells relative to GSK872 (2), a representative selective RIPK3 inhibitor. Based on biochemical kinase assay results, 20 is comparable to GSK872 (2) with regard to activity against RIPK3 and less potent against RIPK1 than GSK872, indicating selectivity of 20 towards RIPK3 over RIPK1 is higher than that of GSK872. In HT-29 cells, 20 inhibits necroptosis via MLKL oligomerization impediment. Moreover, 20 suppresses migration and invasion of AsPC-1 cells by necroptosis induced- CXCL5 secretion downregulation. Significantly, 20 could relieve the TNFα-induced systemic inflammatory response syndrome in vivo. Taken together, this study would provide a useful insight into the design of novel necroptosis inhibitors possessing RIPK3-mediated pMLKL inhibitory activity.