Single-cell and spatial transcriptomics analysis of non-small cell lung cancer.

Lung cancer is the second most frequently diagnosed cancer and the leading cause of cancer-related mortality worldwide. Tumour ecosystems feature diverse immune cell types. Myeloid cells, in particular, are prevalent and have a well-established role in promoting the disease. In our study, we profile approximately 900,000 cells from 25 treatment-naive patients with adenocarcinoma and squamous-cell carcinoma by single-cell and spatial transcriptomics. We note an inverse relationship between anti-inflammatory macrophages and NK cells/T cells, and with reduced NK cell cytotoxicity within the tumour. While we observe a similar cell type composition in both adenocarcinoma and squamous-cell carcinoma, we detect significant differences in the co-expression of various immune checkpoint inhibitors. Moreover, we reveal evidence of a transcriptional "reprogramming" of macrophages in tumours, shifting them towards cholesterol export and adopting a foetal-like transcriptional signature which promotes iron efflux. Our multi-omic resource offers a high-resolution molecular map of tumour-associated macrophages, enhancing our understanding of their role within the tumour microenvironment.

Classification of Small Drones Using Low-Uncertainty Micro-Doppler Signature Images and Ultra-Lightweight Convolutional Neural Network.

Many studies have attempted to classify small drones in response to threats posed by the technical progress of small drones. Recently, small drones have been classified utilizing convolutional neural networks (CNNs) with micro-Doppler signature (MDS) images generated from frequency-modulated continuous-wave (FMCW) radars. This study proposes a comprehensive method for classifying small drones in real-time using high-quality MDS images and an ultra-lightweight CNN. The proposed comprehensive method comprises an MDS image generation technique, which can improve the quality of MDS images generated via FMCW radars, and the ultra-lightweight CNN with high accuracy performance despite its remarkable lightness. Experimental results show that the proposed MDS image generation technique increases the accuracy of CNNs by enhancing the MDS image quality. This is further verified using the results of uncertainty quantification. The proposed ultra-lightweight CNN significantly decreases the computational cost while achieving high accuracy. Finally, we demonstrate that the proposed comprehensive method successfully classifies small drones from far distances with high efficiency and accuracy: the maximum and average accuracies for classification are 100% and 99.21%, respectively, and the numbers of parameters, nodes, and floating-point operations of the proposed ultra-lightweight CNN are approximately 4.88 K, 21.51 K, and 31.52 M, respectively.

Critical appraisal of machine learning prognostic models for acute pancreatitis: protocol for a systematic review.

Acute pancreatitis (AP) is an acute inflammatory disorder that is common, costly, and is increasing in incidence worldwide with over 300,000 hospitalizations occurring yearly in the United States alone. As its course and outcomes vary widely, a critical knowledge gap in the field has been a lack of accurate prognostic tools to forecast AP patients' outcomes. Despite several published studies in the last three decades, the predictive performance of published prognostic models has been found to be suboptimal. Recently, non-regression machine learning models (ML) have garnered intense interest in medicine for their potential for better predictive performance. Each year, an increasing number of AP models are being published. However, their methodologic quality relating to transparent reporting and risk of bias in study design has never been systematically appraised. Therefore, through collaboration between a group of clinicians and data scientists with appropriate content expertise, we will perform a systematic review of papers published between January 2021 and December 2023 containing artificial intelligence prognostic models in AP. To systematically assess these studies, the authors will leverage the CHARMS checklist, PROBAST tool for risk of bias assessment, and the most current version of the TRIPOD-AI. (Research Registry ( http://www.reviewregistry1727 .).

Analyzing isolated degeneration of lumbar facet joints: implications for degenerative instability and lumbar biomechanics using finite element analysis.

The facet joint contributes to lumbar spine stability as it supports the weight of body along with the intervertebral discs. However, most studies on the causes of degenerative lumbar diseases focus on the intervertebral discs and often overlook the facet joints. This study aimed to investigate the impact of facet joint degeneration on the degenerative changes and diseases of the lumbar spine. A finite element model of the lumbar spine (L1-S1) was fabricated and validated to study the biomechanical characteristics of the facet joints. To simulate degeneration of the facet joint, the model was divided into four grades based on the number of degenerative segments (L4-L5 or L4-S1) and the contact condition between the facet joint surfaces. Finite element analysis was performed on four spine motions: flexion, extension, lateral bending, and axial torsion, by applying a pure moment to the upper surface of L1. Important parameters that could be used to confirm the effect of facet joint degeneration on the lumbar spine were calculated, including the range of motion (ROM) of the lumbar segments, maximum von Mises stress on the intervertebral discs, and reaction force at the facet joint. Facet joint degeneration affected the biomechanical characteristics of the lumbar spine depending on the movements of the spine. When analyzed by dividing it into degenerative onset and onset-adjacent segments, lumbar ROM and the maximum von Mises stress of the intervertebral discs decreased as the degree of degeneration increased in the degenerative onset segments. The reaction force at the facet joint decreased with flexion and increased with lateral bending and axial torsion. In contrast, lumbar ROM of the onset-adjacent segments remained almost unchanged despite severe degeneration of the facet joint, and the maximum von Mises stress of the intervertebral discs increased with flexion and extension but decreased with lateral bending and axial torsion. Additionally, the facet joint reaction force increased with extension, lateral bending, and axial rotation. This analysis, which combined the ROM of the lumbar segment, maximum von Mises stress on the intervertebral disc, and facet joint reaction force, confirmed the biomechanical changes in the lumbar spine due to the degeneration of isolated facet joints under the load of spinal motion. In the degenerative onset segment, spinal instability decreased, whereas in the onset-adjacent segment, a greater load was applied than in the intact state. When conducting biomechanical studies on the lumbar spine, considering facet joint degeneration is important since it can lead to degenerative spinal diseases, including adjacent segment diseases.

Physical Unclonable Functions Employing Circularly Polarized Light Emission from Nematic Liquid Crystal Ordering Directed by Helical Nanofilaments.

This study proposes the use of physical unclonable functions employing circularly polarized light emission (CPLE) from nematic liquid crystal (NLC) ordering directed by helical nanofilaments in a mixed system composed of a calamitic NLC mixture and a bent-core molecule. To achieve this, an intrinsically nonemissive NLC is blended with a high concentration of a luminescent rod-like dye, which is miscible up to 10 wt % in the calamitic NLC without a significant decrease in the degree of alignment. The luminescence dissymmetry factor of CPLEs in the mixed system strongly depends on the degree of alignment of the dye-doped NLCs. Furthermore, the mixed system prepared in this study exhibits two randomly generated chiral domains with CPLEs of opposite signs. These chiral domains are characterized not only by their CPLE performances but also by their ability to generate random patterns up to several millimeters, making them promising candidates for high-performance secure authentication applications.

Circularly Polarized Light Emission from Nonchiral Perovskites Incorporated into Nanoporous Cholesteric Polymer Templates.

Chiral perovskites have garnered significant attention, owing to their chiroptical properties and emerging applications. Current fabrication methods often involve complex chemical synthesis routes. Herein, an alternative approach for introducing chirality into nonchiral hybrid organic-inorganic perovskites (HOIPs) using nanotemplates composed of cholesteric polymeric networks is proposed. This method eliminates the need for additional molecular design. In this process, HOIP precursors are incorporated into a porous cholesteric polymer film, and two-dimensional (2D) HOIPs grow inside the nanopores. Circularly polarized light emission (CPLE) was observed even though the selective reflection band of the cholesteric polymer films containing a representative HOIP deviated from the emission wavelength of the 2D HOIP. This effect was confirmed by the induced circular dichroism (CD) observed in the absorbance band of the HOIP. The observed CPLE and CD are attributed to the chirality induced by the template in the originally nonchiral 2D HOIP. Additionally, the developed 2D HOIP exhibited a long exciton lifetime and good stability under harsh conditions. These findings provide valuable insights into the development and design of innovative optoelectronic materials.

Neuroprotective Effects of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) against Amyloid-ß-Induced Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD), is a progressive neurodegenerative disorder that involves the deposition of ß-amyloid plaques and the clinical symptoms of confusion, memory loss, and cognitive dysfunction. Despite enormous progress in the field, no curative treatment is available. Therefore, the current study was designed to determine the neuroprotective effects of N-methyl-(2S, 4R)-Trans-4-hydroxy-L-proline (NMP) obtained from Sideroxylon obtusifolium, a Brazilian folk medicine with anti-inflammatory and anti-oxidative properties. Here, for the first time, we explored the neuroprotective role of NMP in the Aß1-42-injected mouse model of AD. After acclimatization, a single intracerebroventricular injection of Aß1-42 (5 µL/5 min/mouse) in C57BL/6N mice induced significant amyloidogenesis, reactive gliosis, oxidative stress, neuroinflammation, and synaptic and memory deficits. However, an intraperitoneal injection of NMP at a dose of (50 mg/kg/day) for three consecutive weeks remarkably decreased beta secretase1 (BACE-1) and Aß, activated the astrocyte and microglia expression level as well as downstream inflammatory mediators such as pNF-ĸB, TNF-α, and IL-1ß. NPM also strongly attenuated oxidative stress, as evaluated by the expression level of NRF2/HO-1, and synaptic failure, by improving the level of both the presynaptic (SNAP-25 and SYN) and postsynaptic (PSD-95 and SNAP-23) regions of the synapses in the cortexes and hippocampi of the Aß1-42-injected mice, contributing to cognitive improvement in AD and improving the behavioral deficits displayed in the Morris water maze and Y-maze. Overall, our data suggest that NMP provides potent multifactorial effects, including the inhibition of amyloid plaques, oxidative stress, neuroinflammation, and cognitive deficits.

Immunization Effects of a Novel α-Synuclein-Based Peptide Epitope Vaccine in Parkinson's Disease-Associated Pathology.

Parkinson's disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, specifically the motor system. It is mainly caused by the loss of dopamine due to the accumulation of α-synuclein (α-syn) protein in the striatum and substantia nigra pars compacta (SNpc). Previous studies have reported that immunization may be a potential preventive strategy for neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Therefore, the aim of the study was to design an α-syn specific epitope vaccine and investigate its effect in PD-related pathophysiology using an α-syn-induced mouse model. We used an in silico model to identify and design a non-toxic α-syn-based peptide epitope vaccine and, to overcome poor immunogenicity, the vaccine was coupled with immunogenic carrier proteins, i.e., ovalbumin (OVA) and keyhole limpet haemocyanin (KLH). Our results showed that vaccinated PD mouse models, especially with vaccines with carrier proteins, improved in motor functions compared with the non-vaccinated PD model. Additionally, the vaccinated groups showed increased immunoglobulin G (IgG) levels in the spleen and plasma as well as decreased interleukin-10 (IL-10) levels in the plasma. Furthermore, vaccinated groups, especially OVA and KLH groups, showed decrease in α-syn levels and increased dopamine-related markers, i.e., tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and dopamine transporter (DAT), and autophagy activities in the striatum and SNpc. Lastly, our data showed decreased neuroinflammation by reducing the activation of microglia and astrocytes and pro-inflammatory cytokines in the immunized groups, especially with OVA and KLH carrier proteins. Overall, these results suggest that vaccination, especially with immunogenic carrier proteins, is effective in reducing the accumulation of α-syn aggregates in the brain and ameliorate PD-related pathophysiology. Hence, further development of this approach might have a potential role in preventing the development of PD.

Neuroprotective effects of osmotin in Parkinson's disease-associated pathology via the AdipoR1/MAPK/AMPK/mTOR signaling pathways.

BACKGROUND: Parkinson's disease (PD) is the second most frequent age-related neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Both environmental and genetic aspects are involved in the pathogenesis of PD. Osmotin is a structural and functional homolog of adiponectin, which regulates the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) via adiponectin receptor 1 (AdipoR1), thus attenuating PD-associated pathology. Therefore, the current study investigated the neuroprotective effects of osmotin using in vitro and in vivo models of PD. METHODS: The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and neuron-specific enolase promoter human alpha-synuclein (NSE-hαSyn) transgenic mouse models and 1-methyl-4-phenylpyridinium (MPP+)- or alpha-synuclein A53T-treated cell models. MPTP was injected at a dose of 30 mg/kg/day for five days, and osmotin was injected twice a week at a dose of 15 mg/kg for five weeks. We performed behavioral tests and analyzed the biochemical and molecular changes in the substantia nigra pars compacta (SNpc) and the striatum. RESULTS: Based on our study, osmotin mitigated MPTP- and α-synuclein-induced motor dysfunction by upregulating the nuclear receptor-related 1 protein (Nurr1) transcription factor and its downstream markers tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2). From a pathological perspective, osmotin ameliorated neuronal cell death and neuroinflammation by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, osmotin alleviated the accumulation of α-synuclein by promoting the AMPK/mammalian target of rapamycin (mTOR) autophagy signaling pathway. Finally, in nonmotor symptoms of PD, such as cognitive deficits, osmotin restored synaptic deficits, thereby improving cognitive impairment in MPTP- and α-synuclein-induced mice. CONCLUSIONS: Therefore, our findings indicated that osmotin significantly rescued MPTP/α-synuclein-mediated PD neuropathology. Altogether, these results suggest that osmotin has potential neuroprotective effects in PD neuropathology and may provide opportunities to develop novel therapeutic interventions for the treatment of PD.

Implementing Point-of-Care Ultrasound for Acute Scrotal Pain in the Pediatric Emergency Department: Screening Testicular Torsion and Patient Flow Analysis.

OBJECTIVES: Testicular torsion (TT) is a pediatric surgical emergency that requires prompt treatment. This study investigated the feasibility of point-of-care ultrasound (POCUS) for diagnosing TT in the pediatric emergency department (ED). METHODS: We retrospectively reviewed the medical records of patients, aged 18 years or younger, who visited a university-affiliated hospital pediatric ED with acute scrotal pain without trauma history and underwent diagnostic ultrasounds between January 2010 and October 2022. RESULTS: This study included 731 patients (median age: 9 years), Of these, 315 (43%) were in the POCUS-performed group: 188 in the POCUS-only group, and 127 in the POCUS-and-RADUS group. The other 416 patients (56.9%) were in the RADUS-only group. In total, 45 patients (6.2%) were diagnosed with TT (19 in the POCUS-performed group and 26 in the RADUS-only group). The sensitivity, specificity, and positive and negative predictive values of POCUS for diagnosing TT were 94.7%, 92.9%, 46.2%, and 99.6%, respectively. The median time to perform POCUS was shorter than RADUS (23 versus 61 minutes, P < .001). The POCUS-performed group had a shorter ED length of stay than the RADUS-only group (93 versus 170 minutes, P < .001). Among the patients diagnosed with TT, performing POCUS first did not significantly delay the ED process, including time to operation (250 versus 205 minutes, P = .142). CONCLUSIONS: For patients with acute scrotal pain, evaluation performed by pediatric emergency physicians using POCUS performs well in screening TT, and can decrease length of stay in the ED.

A Triterpenoid Lupeol as an Antioxidant and Anti-Neuroinflammatory Agent: Impacts on Oxidative Stress in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease illustrated by neuronal dysfunctions, leading to memory weaknesses and personality changes mostly in the aged population worldwide. The exact cause of AD is unclear, but numerous studies have addressed the involvement of oxidative stress (OS), induced by reactive oxygen species (ROS), to be one of the leading causes in developing AD. OS dysregulates the cellular homeostasis, causing abnormal protein and lipid metabolism. Nutrition plays a pivotal role in modulating the antioxidant system and decreases the neuronal ROS level, thus playing an important therapeutic role in neurodegenerative diseases, especially in AD. Hence, medicinal herbs and their extracts have received global attention as a commercial source of antioxidants Lupeol. Lupeol is a pentacyclic triterpenoid and has many biological functions. It is available in fruits, vegetables, and medicinal plants. It has shown effective antioxidant and anti-inflammatory properties, and higher blood-brain barrier permeability. Also, the binding and inhibitory potentials of Lupeol have been investigated and proved to be effective against certain receptor proteins and enzymes in AD studies by computational molecular docking approaches. Therefore, AD-related research has gained interest in investigating the therapeutic effects of Lupeol. However, despite its beneficial effects in AD, there is still a lack of research in Lupeol. Hence, we compiled in this analysis all preclinical research that looked at Lupeol as an antioxidant and anti-inflammatory agent for AD.

Caffeic Acid, a Polyphenolic Micronutrient Rescues Mice Brains against Aß-Induced Neurodegeneration and Memory Impairment.

Oxidative stress plays an important role in cognitive dysfunctions and is seen in neurodegeneration and Alzheimer's disease (AD). It has been reported that the polyphenolic compound caffeic acid possesses strong neuroprotective and antioxidant effects. The current study was conducted to investigate the therapeutic potential of caffeic acid against amyloid beta (Aß1-42)-induced oxidative stress and memory impairments. Aß1-42 (5 µL/5 min/mouse) was administered intracerebroventricularly (ICV) into wild-type adult mice to induce AD-like pathological changes. Caffeic acid was administered orally at 50 mg/kg/day for two weeks to AD mice. Y-maze and Morris water maze (MWM) behavior tests were conducted to assess memory and cognitive abilities. Western blot and immunofluorescence analyses were used for the biochemical analyses. The behavioral results indicated that caffeic acid administration improved spatial learning, memory, and cognitive abilities in AD mice. Reactive oxygen species (ROS) and lipid peroxidation (LPO) assays were performed and showed that the levels of ROS and LPO were markedly reduced in the caffeic acid-treated mice, as compared to Aß-induced AD mice brains. Moreover, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were regulated with the administration of caffeic acid, compared to the Aß-injected mice. Next, we checked the expression of ionized calcium-binding adaptor molecule 1 (Iba-1), glial fibrillary acidic proteins (GFAP), and other inflammatory markers in the experimental mice, which suggested enhanced expression of these markers in AD mice brains, and were reduced with caffeic acid treatment. Furthermore, caffeic acid enhanced synaptic markers in the AD mice model. Additionally, caffeic acid treatment also decreased Aß and BACE-1 expression in the Aß-induced AD mice model.

Safety and efficacy of pediatric sedation protocol for diagnostic examination in a pediatric emergency room: A retrospective study.

Pediatric patients undergoing diagnostic tests in the pediatric emergency room are frequently sedated. Although efforts are made to prevent adverse events, no sedation protocol has specified the optimal regimen, dosage, and interval of medication to prevent adverse events. This study analyzed the safety and efficacy of sequential pediatric sedation protocols for pediatric patients undergoing diagnostic tests in the pediatric emergency room of a single tertiary medical center. The medical records of patients aged < 18 years who visited the pediatric emergency room of Seoul Asan Medical Center between January and December 2019 for diagnostic testing were retrospectively reviewed. Sedation protocols consisted of 50 mg/kg and 25 mg/kg chloral hydrate, 0.1 mg/kg and 0.1 mg/kg midazolam, and 1 mg/kg and 0.5 to 1 mg/kg ketamine, administered sequentially at intervals of 30, 20, 10, 10, and 10 minutes, respectively. Patients were assessed prior to sedation, and adverse events were investigated. Of the 289 included patients, 20 (6.9%) experienced adverse events, none serious, and nine (3.1%) failed to reach the depth of sedation required to complete the test. The regimen (P = .622) and dosage (P = .777) of the sedatives were unrelated to the occurrence of adverse events when sedation was performed according to protocol. The sedation protocol used in these patients, consisting of sequential administration of minimum dosages, achieved a sufficient depth of sedation with relatively few adverse events, indicating that this protocol can be used safely and effectively for painless sedation in pediatric patients undergoing diagnostic testing.

Vitamin E Analog Trolox Attenuates MPTP-Induced Parkinson's Disease in Mice, Mitigating Oxidative Stress, Neuroinflammation, and Motor Impairment.

Trolox is a potent antioxidant and a water-soluble analog of vitamin E. It has been used in scientific studies to examine oxidative stress and its impact on biological systems. Trolox has been shown to have a neuroprotective effect against ischemia and IL-1ß-mediated neurodegeneration. In this study, we investigated the potential protective mechanisms of Trolox against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. Western blotting, immunofluorescence staining, and ROS/LPO assays were performed to investigate the role of trolox against neuroinflammation, the oxidative stress mediated by MPTP in the Parkinson's disease (PD) mouse model (wild-type mice (C57BL/6N), eight weeks old, average body weight 25-30 g). Our study showed that MPTP increased the expression of α-synuclein, decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels in the striatum and substantia nigra pars compacta (SNpc), and impaired motor function. However, Trolox treatment significantly reversed these PD-like pathologies. Furthermore, Trolox treatment reduced oxidative stress by increasing the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Lastly, Trolox treatment inhibited the activated astrocytes (GFAP) and microglia (Iba-1), also reducing phosphorylated nuclear factor-κB, (p-NF-κB) and tumor necrosis factor-alpha (TNF-α) in the PD mouse brain. Overall, our study demonstrated that Trolox may exert neuroprotection on dopaminergic neurons against MPTP-induced oxidative stress, neuroinflammation, motor dysfunction, and neurodegeneration.

Establishing Co-Culture Blood-Brain Barrier Models for Different Neurodegeneration Conditions to Understand Its Effect on BBB Integrity.

The blood-brain barrier (BBB) is a functional interface that provides selective permeability, protection from toxic substances, transport of nutrients, and clearance of brain metabolites. Additionally, BBB disruption has been shown to play a role in many neurodegenerative conditions and diseases. Therefore, the aim of this study was to establish a functional, convenient, and efficient in vitro co-cultured BBB model that can be used for several physiological conditions related to BBB disruption. Mouse brain-derived endothelial (bEnd.3) and astrocyte (C8-D1A) cells were co-cultured on transwell membranes to establish an intact and functional in vitro model. The co-cultured model and its effects on different neurological diseases and stress conditions, including Alzheimer's disease (AD), neuroinflammation, and obesity, have been examined by transendothelial electrical resistance (TEER), fluorescein isothiocyanate (FITC) dextran, and tight junction protein analyses. Scanning electron microscope images showed evidence of astrocyte end-feet processes passing through the membrane of the transwell. Moreover, the co-cultured model showed effective barrier properties in the TEER, FITC, and solvent persistence and leakage tests when compared to the mono-cultured model. Additionally, the immunoblot results showed that the expression of tight junction proteins such as zonula occludens-1 (ZO-1), claudin-5, and occludin-1 was enhanced in the co-culture. Lastly, under disease conditions, the BBB structural and functional integrity was decreased. The present study demonstrated that the co-cultured in vitro model mimicked the BBB's structural and functional integrity and, under disease conditions, the co-cultured model showed similar BBB damages. Therefore, the present in vitro BBB model can be used as a convenient and efficient experimental tool to investigate a wide range of BBB-related pathological and physiological studies.

Comparison of febrile seizures in children with or without coronavirus disease-2019: A single-center observational study.

BACKGROUND: Febrile seizure (FS) is one of the most common neurological manifestations of coronavirus disease-2019 (COVID-19) in children. We compared the clinical characteristics of FS in patients with and without COVID-19 during the pandemic period. METHODS: This retrospective single-center study included patients aged 0-18 years who visited the pediatric emergency department (ED) with FS from January 1, 2022, to April 30, 2022. RESULTS: A total of 186 patients visited the pediatric ED with FS during the study period: 123 (66.1%) were positive for COVID-19 and 63 (33.9%) were negative. Patients with COVID-19 were predominantly male (70.7% vs. 50.8%, p = 0.007) and older (2.4 vs. 1.8 years, p = 0.005) than those without COVID-19. A higher proportion of patients with COVID-19 were of atypical age (age > 5 years or <6 months) than those without COVID-19 (26.8% vs. 9.5%, p = 0.006). This was especially true for those aged >5 years (22% vs. 4.8%, p = 0.003). Patients with COVID-19 had a higher probability of multiple episodes of convulsion within 24 h than those without COVID-19 (10.6% vs. 1.6%, p = 0.037). Among patients with COVID-19, males had a shorter fever-to-seizure duration than females (3 h vs. 6.5 h, p = 0.045). CONCLUSIONS: Patients with FS with COVID-19 tend to be predominantly male and have older age of onset than those without COVID-19. Because of the atypical age of onset and probability of multiple convulsion episodes, vigilance for FS is needed in patients with COVID-19, especially males.

Spatial genomics maps the structure, nature and evolution of cancer clones.

Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1-3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.

O-Cyclic Phytosphingosine-1-Phosphate Protects against Motor Dysfunctions and Glial Cell Mediated Neuroinflammation in the Parkinson's Disease Mouse Models.

O-cyclic phytosphingosine-1-phosphate (cPS1P) is a novel and chemically synthesized sphingosine metabolite derived from phytosphingosine-1-phosphate (S1P). This study was undertaken to unveil the potential neuroprotective effects of cPS1P on two different mouse models of Parkinson's disease (PD). The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and neuron specific enolase promoter human alpha-synuclein (NSE-hαSyn) Korl transgenic mice. MPTP was injected for five consecutive days and cPS1P was injected for alternate days for six weeks intraperitoneally. We performed behavioral tests and analyzed the immunohistochemistry and immunofluorescence staining in the substantia nigra pars compacta (SNpc) and the striatum. The behavior tests showed a significant reduction in the motor functions in the PD models, which was reversed with the administration of cPS1P. In addition, both PD-models showed reduced expression of the sphingosine-1-phosphate receptor 1 (S1PR1), and α-Syn which was restored with cPS1P treatment. In addition, administration of cPS1P restored dopamine-related proteins such as tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT). Lastly, neuroinflammatory related markers such as glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter protein-1 (Iba-1), c-Jun N-terminal kinases (JNK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), tumor necrosis factor-alpha (TNF-α), and interleukin 1 beta (IL-1ß) were all reduced after cPS1P administration. The overall findings supported the notion that cPS1P protects against dopamine depletion, neuroinflammation, and PD-associated symptoms.

Identification of a pleiotropic effect of ADIPOQ on cardiac dysfunction and Alzheimer's disease based on genetic evidence and health care records.

Observations of comorbidity in heart diseases, including cardiac dysfunction (CD) are increasing, including and cognitive impairment, such as Alzheimer's disease and dementia (AD/D). This comorbidity might be due to a pleiotropic effect of genetic variants shared between CD and AD/D. Here, we validated comorbidity of CD and AD/D based on diagnostic records from millions of patients in Korea and the University of California, San Francisco Medical Center (odds ratio 11.5 [8.5-15.5, 95% Confidence Interval (CI)]). By integrating a comprehensive human disease-SNP association database (VARIMED, VARiants Informing MEDicine) and whole-exome sequencing of 50 brains from individuals with and without Alzheimer's disease (AD), we identified missense variants in coding regions including APOB, a known risk factor for CD and AD/D, which potentially have a pleiotropic role in both diseases. Of the identified variants, site-directed mutation of ADIPOQ (268 G > A; Gly90Ser) in neurons produced abnormal aggregation of tau proteins (p = 0.02), suggesting a functional impact for AD/D. The association of CD and ADIPOQ variants was confirmed based on domain deletion in cardiac cells. Using the UK Biobank including data from over 500000 individuals, we examined a pleiotropic effect of the ADIPOQ variant by comparing CD- and AD/D-associated phenotypic evidence, including cardiac hypertrophy and cognitive degeneration. These results indicate that convergence of health care records and genetic evidences may help to dissect the molecular underpinnings of heart disease and associated cognitive impairment, and could potentially serve a prognostic function. Validation of disease-disease associations through health care records and genomic evidence can determine whether health conditions share risk factors based on pleiotropy.