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The phospholipase A(2) (PLA(2)) superfamily hydrolyzes phospholipids to release free fatty acids and lysophospholipids, some of which can mediate inflammation and demyelination, hallmarks of the CNS autoimmune disease multiple sclerosis. The expression of two of the intracellular PLA(2)s (cPLA(2) GIVA and iPLA(2) GVIA) and two of the secreted PLA(2)s (sPLA(2) GIIA and sPLA(2) GV) are increased in different stages of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We show using small molecule inhibitors, that cPLA(2) GIVA plays a role in the onset, and iPLA(2) GVIA in the onset and progression of EAE. We also show a potential role for sPLA(2) in the later remission phase. These studies demonstrate that selective inhibition of iPLA(2) can ameliorate disease progression when treatment is started before or after the onset of symptoms. The effects of these inhibitors on lesion burden, chemokine and cytokine expression as well as on the lipid profile provide insights into their potential modes of action. iPLA(2) is also expressed by macrophages and other immune cells in multiple sclerosis lesions. Our results therefore suggest that iPLA(2) might be an excellent target to block for the treatment of CNS autoimmune diseases, such as multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: Folic acid (FA) supplementation during pregnancy aims to protect foetal development. However, maternal over-supplementation of FA has been demonstrated to cause metabolic dysfunction and increase the risk of autism, retinoblastoma, and respiratory illness in the offspring. Moreover, FA supplementation reduces the risk of congenital heart disease. However, little is known about its possible adverse effects on cardiac health resulting from maternal over-supplementation. In this study, we assessed the detrimental effects of maternal FA over-supplementation on the cardiac health of the offspring., Methods and Results: Eight-week-old C57BL/6J pregnant mice were randomly divided into control and over-supplemented groups. The offspring cardiac function was assessed using echocardiography. Cardiac fibrosis was assessed in the left ventricular myocardium by histological analysis. Proteomic, protein, RNA, and DNA methylation analyses were performed by liquid chromatography-tandem mass spectrometry, western blotting, real-time quantitative PCR, and bisulfite sequencing, respectively. We found that maternal periconceptional FA over-supplementation impaired cardiac function with the decreased left ventricular ejection fraction in the offspring. Biochemical indices and tissue staining further confirmed impaired cardiac function in offspring caused by maternal FA over-supplementation. The combined proteomic, RNA expression, and DNA methylation analyses suggested that key genes involved in cardiac function were inhibited at the transcriptional level possibly due to increased DNA methylation. Among these, superoxide dismutase 1 was downregulated, and reactive oxygen species (ROS) levels increased in the mouse heart. Inhibition of ROS generation using the antioxidant N-acetylcysteine rescued the impaired cardiac function resulting from maternal FA over-supplementation., Conclusions: Our study revealed that over-supplementation with FA during mouse pregnancy is detrimental to cardiac function with the decreased left ventricular ejection fraction in the offspring and provides insights into the mechanisms underlying the association between maternal FA status and health outcomes in the offspring., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The high sensitivity of HBsAg quantitative tests has led to some challenges in the qualitative interpretation of weakly positive specimens. This study aimed to explore the clinical utility of neutralization confirma-tory testing for specimens with low positive hepatitis B surface antigen (HBsAg)., Methods: A retrospective analysis was conducted on outpatient and inpatient cases, from January 2021 to January 2022, at the Zhongshan City People's Hospital, Zhongshan. Confirmatory testing as well as enzyme-linked immunosorbent assay (ELISA) was applied to reanalyze 382 samples with low positive HBsAg detected by chemilumi-nescence microparticle immunoassay (CMIA). A retrospective analysis of hepatitis B serum markers, including e-antigen, e-antibody, and core antibody patterns, was also performed., Results: When the HBsAg value ranged from 0.05 - 0.09 IU/mL, the positivity rate of the confirmatory testing was 34.5%. The HBsAg true positivity levels were all between 0.07 and 0.09. In the range of 0.10 - 0.49, the positivity rate of confirmatory testing was 96.1%. The three methods exhibited a high consistency, when testing samples with relatively high HBsAg values. A receiver operating characteristic (ROC) analysis showed that the optimal sensitivity and specificity were achieved at 0.14 IU/mL. For the HBV e-antigen-positive and negative groups, the positivity rate of confirmatory testing was 100% and 93.8%, with no statistical difference between them., Conclusions: For specimens with weakly positive, low-value HBsAg, particularly when the hepatitis B surface an-tigen level is less than 0.14 IU/mL, neutralization confirmatory testing can serve as a means for further confirmation.

Mitochondria form a dynamic network within skeletal muscle. This network is not only responsible for producing adenosine triphosphate (ATP) through oxidative phosphorylation, but also responds through fission, fusion and mitophagy to various factors, such as increased energy demands, oxidative stress, inflammation, and calcium dysregulation. Mitochondrial dysfunction in skeletal muscle not only occurs in primary mitochondrial myopathies, but also other hereditary and acquired myopathies. As such, this review attempts to highlight the clinical and histopathologic aspects of mitochondrial dysfunction seen in hereditary and acquired myopathies, as well as discuss potential mechanisms leading to mitochondrial dysfunction and therapies to restore mitochondrial function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults and is driven by self-renewing glioblastoma stem cells (GSCs) that persist after therapy and seed treatment refractory recurrent tumors. GBM tumors display a high degree of intra- and inter-tumoral heterogeneity that is a prominent barrier to targeted treatment strategies. This heterogeneity extends to GSCs that exist on a gradient between two transcriptional states or subtypes termed developmental and injury-response. Drug targets for each subtype are needed to effectively target GBM. To identify conserved and subtype-specific genetic dependencies across a large and heterogeneous panel of GSCs, we designed the GBM5K targeted gRNA library and performed fitness screens in a total of 30 patient-derived GSC cultures. The focused CRISPR screens identified the most conserved subtype-specific vulnerabilities in GSCs and elucidated the functional dependency gradient existing between the developmental and injury-response states. Developmental-specific fitness genes were enriched for transcriptional regulators of neurodevelopment, whereas injury-response-specific fitness genes were highlighted by several genes implicated in integrin and focal adhesion signaling. These context-specific vulnerabilities conferred differential sensitivity to inhibitors of β1 integrin, FAK, MEK and OLIG2. Interestingly, the screens revealed that the subtype-specific signaling pathways drive differential cyclin D (CCND1 vs. CCND2) dependencies between subtypes. These data provide biological insight and mechanistic understanding of GBM heterogeneity and point to opportunities for precision targeting of defined GBM and GSC subtypes to tackle heterogeneity.

Selective producing ethanol from CO 2 electroreduction is highly demanded, yet the competing ethylene generation route is commonly more thermodynamically preferred. Herein, we reported an efficient CO 2 -to-ethanol conversion (53.5 % faradaic efficiency at -0.75 V versus reversible hydrogen electrode (vs. RHE)) over an oxide-derived nanocubic catalyst featured with abundant "embossment-like" structured grain-boundaries. The catalyst also attains a 23.2 % energy efficiency to ethanol within a flow cell reactor. In situ spectroscopy and electrochemical analysis identified that these dualphase Cu(I) and Cu(0) sites stabilized by grain-boundaries are very robust over the operating potential window, which maintains a high concentration of co-adsorbed *CO and hydroxyl (*OH) species. Theoretical calculations revealed that the presence of *OH ad not only promote the easier dimerization of *CO to form *OCCO (ΔG~0.20 eV) at low overpotentials but also preferentially favor the key *CHCOH intermediate hydrogenation to *CHCHOH (ethanol pathway) while suppressing its dehydration to *CCH (ethylene pathway), which is believed to determine the remarkable ethanol selectivity. Such imperative intermediates associated with the bifurcation pathway were directly distinguished by isotope labelling in situ infrared spectroscopy. Our work promotes the understanding of bifurcating mechanism of CO 2 ER-to-hydrocarbons more deeply, providing a feasible strategy for the design of efficient ethanol-targeted catalysts., (© 2024 Wiley-VCH GmbH.)

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood-brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50-100% of mice. Our study identifies a promising multi-targetable PTP4A-ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Brain abscesses (BA) are focal parenchymal infections that remain life-threatening conditions. Polymicrobial BAs (PBAs) are complex coinfections of bacteria or bacterial and nonbacterial pathogens such as fungi or parasites, with diagnostic and therapeutic challenges. In this article, we comprehensively review the prevalence, pathogenesis, clinical manifestations, and microbiological, histopathological, and radiological features of PBAs, as well as treatment and prognosis. While PBAs and monomicrobial BAs have some similarities such as nonspecific clinical presentations, PBAs are more complex in their pathogenesis, pathological, and imaging presentations. The diagnostic challenges of PBAs include nonspecific imaging features at early stages and difficulties in identification of some pathogens by routine techniques without the use of molecular analysis. Imaging of late-stage PBAs demonstrates increased heterogeneity within lesions, which corresponds to variable histopathological features depending on the dominant pathogen-induced changes in different areas. This heterogeneity is particularly marked in cases of coinfections with nonbacterial pathogens such as Toxoplasma gondii. Therapeutic challenges in the management of PBAs include initial medical therapy for possibly underrecognized coinfections prior to identification of multiple pathogens and subsequent broad-spectrum antimicrobial therapy to eradicate identified pathogens. PBAs deserve more awareness to facilitate prompt and appropriate treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

Dengue human infection models present an opportunity to explore the potential of a vaccine, anti-viral or immuno-compound for clinical benefit in a controlled setting. Here we report the outcome of a phase 1 open-label assessment of a low-dose dengue virus 3 (DENV-3) challenge model (NCT04298138), in which nine participants received a subcutaneous inoculation with 0.5 ml of a 1.4 × 10 3 plaque-forming unit per ml suspension of the attenuated DENV-3 strain CH53489. The primary and secondary endpoints of the study were to assess the safety of this DENV-3 strain in healthy flavivirus-seronegative individuals. All participants developed RNAaemia within 7 days after inoculation with peak titre ranging from 3.13 × 10 4 to 7.02 × 10 8  genome equivalents per ml. Solicited symptoms such as fever and rash, clinical laboratory abnormalities such as lymphopenia and thrombocytopenia, and self-reported symptoms such as myalgia were consistent with mild-to-moderate dengue in all volunteers. DENV-3-specific seroconversion and memory T cell responses were observed within 14 days after inoculation as assessed by enzyme-linked immunosorbent assay and interferon-gamma-based enzyme-linked immunospot. RNA sequencing and serum cytokine analysis revealed anti-viral responses that overlapped with the period of viraemia. The magnitude and frequency of clinical and immunologic endpoints correlated with an individual's peak viral titre., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Pompe disease is a lysosomal storage disorder that preferentially affects muscles, and it is caused by GAA mutation coding acid alpha-glucosidase in lysosome and glycophagy deficiency. While the initial pathology of Pompe disease is glycogen accumulation in lysosomes, the special role of the lysosomal pathway in glycogen degradation is not fully understood. Hence, we investigated the characteristics of accumulated glycogen and the mechanism underlying glycophagy disturbance in Pompe disease. Skeletal muscle specimens were obtained from the affected sites of patients and mouse models with Pompe disease. Histological analysis, immunoblot analysis, immunofluorescence assay, and lysosome isolation were utilized to analyze the characteristics of accumulated glycogen. Cell culture, lentiviral infection, and the CRISPR/Cas9 approach were utilized to investigate the regulation of glycophagy accumulation. We demonstrated residual glycogen, which was distinguishable from mature glycogen by exposed glycogenin and more α-amylase resistance, accumulated in the skeletal muscle of Pompe disease. Lysosome isolation revealed glycogen-free glycogenin in wild type mouse lysosomes and variously sized glycogenin in Gaa -/- mouse lysosomes. Our study identified that a defect in the degradation of glycogenin-exposed residual glycogen in lysosomes was the fundamental pathological mechanism of Pompe disease. Meanwhile, glycogenin-exposed residual glycogen was absent in other glycogen storage diseases caused by cytoplasmic glycogenolysis deficiencies. In vitro, the generation of residual glycogen resulted from cytoplasmic glycogenolysis. Notably, the inhibition of glycogen phosphorylase led to a reduction in glycogenin-exposed residual glycogen and glycophagy accumulations in cellular models of Pompe disease. Therefore, the lysosomal hydrolysis pathway played a crucial role in the degradation of residual glycogen into glycogenin, which took place in tandem with cytoplasmic glycogenolysis. These findings may offer a novel substrate reduction therapeutic strategy for Pompe disease. © 2024 The Pathological Society of Great Britain and Ireland., (© 2024 The Pathological Society of Great Britain and Ireland.)

Hyperglycemia in pregnancy can increase the risk of congenital disorders, but little is known about craniofacial skeleton malformation and its corresponding medication. Our study first used meta-analysis to review the previous findings. Second, baicalin, an antioxidant, was chosen to counteract high glucose-induced craniofacial skeleton malformation. Its effectiveness was then tested by exposing chicken embryos to a combination of high glucose (HG, 50 mM) and 6 μM baicalin. Third, whole-mount immunofluorescence staining and in situ hybridization revealed that baicalin administration could reverse HG-inhibited neural crest cells (NCC) delamination and migration through upregulating the expression of Pax7 and Foxd3, and mitigate the disordered epithelial-mesenchymal transition (EMT) process by regulating corresponding adhesion molecules and transcription factors (i.e., E-cadherin, N-cadherin, Cadherin 6B, Slug and Msx1). Finally, through bioinformatic analysis and cellular thermal shift assay, we identified the AKR1B1 gene as a potential target. In summary, these findings suggest that baicalin could be used as a therapeutic agent for high glucose-induced craniofacial skeleton malformation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer XL is currently organizing a Research Topic with the author GW. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lu, Luo, Sun, Wang, Sun, Huang, Yang, Ding and Wang.)

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumor-like fibro-osseous lesion that can develop anywhere in the neuraxis. Approximately a half of reported CAPNONs developed in the spinal region, mostly close to the facet joint (FJ). The diagnosis of spinal CAPNONs is challenging given the existence of mimics and associated pathologies including calcific degeneration of the FJ ligaments (DFJL) and synovial cysts (SCs). The pathogenesis of CAPNON remains elusive, although there have been a few hypotheses including degenerative, reactive, proliferative and immune-mediated processes. Our present study examined clinical, radiological and pathological features of 12 spinal CAPNONs in comparison to 9 DFJL foci, and diagnostic and pathogenic relationship between CAPNONs and FJ pathologies. On imaging, CAPNONs were all tumor-like and typically bigger than DFJL foci. All CAPNONs showed pathologically diagnostic features including characteristic cores, consistently identifiable core-surrounding/peripheral palisading of macrophages and other cells including multinucleated giant cells, variable infiltration of CD8 + T-cells, and multifocal immunopositivity of neurofilament light chain (NF-L). These features were absent or limited in the DFJL foci with statistically significant differences from CAPNONs, except calcifications. Spinal CAPNONs co-existed with DFJL foci in all cases; some had transitional foci with overlapping focal CAPNON and DFJL-like features. These findings, along with our previously reported relationship between CAPNONs and SCs, suggest that spinal CAPNONs may occur in association with or in transition from calcifying/calcified degenerative lesions of FJ ligaments and/or SCs when a reactive proliferative process is complemented by other pathogenic changes such as immune-mediated pathology and NF-L deposition/expression., Competing Interests: Declaration of competing interest Dr. Faiha Fareez has received the Resident Research Grant from Department of Pathology and Molecular Medicine, McMaster University. The other authors receive no funding specified for this work and report no conflicts of interest. Parts of this study have been presented at the 20th International Congress of Neuropathology. Berlin, Germany (September 13–16, 2023), and as an abstract, published in Brain Pathology 2023; 33(S1):189., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Gorals Naemorhedus resemble both goats and antelopes, which prompts much debate about the intragenus species delimitation and phylogenetic status of the genus Naemorhedus within the subfamily Caprinae. Their evolution is believed to be linked to the uplift of the Qinghai-Tibet Plateau (QTP). To better understand its phylogenetics, the genetic information is worth being resolved., Results: Based on a sample from the eastern margin of QTP, we constructed the first reference genome for Himalayan goral Naemorhedus goral, using PacBio long-read sequencing and Hi-C technology. The 2.59 Gb assembled genome had a contig N50 of 3.70 Mb and scaffold N50 of 106.66 Mb, which anchored onto 28 pseudo chromosomes. A total of 20,145 protein-coding genes were predicted in the assembled genome, of which 99.93% were functionally annotated. Phylogenetically, the goral was closely related to muskox on the mitochondrial genome level and nested into the takin-muskox clade on the genome tree, rather than other so-called goat-antelopes. The cladogenetic event among muskox, takin and goral occurred sequentially during the late Miocene (~ 11 - 5 Mya), when the QTP experienced a third dramatic uplift with consequent profound changes in climate and environment. Several chromosome fusions and translocations were observed between goral and takin/muskox. The expanded gene families in the goral genome were mainly related to the metabolism of drugs and diseases, so as the positive selected genes. The Ne of goral continued to decrease since ~ 1 Mya during the Pleistocene with active glaciations., Conclusion: The high-quality goral genome provides insights into the evolution and valuable information for the conservation of this threatened group., (© 2024. The Author(s).)

Nocardia brain abscesses are rare bacterial infections associated with a high mortality rate, and their preoperative diagnosis can be difficult for various reasons including a nonspecific clinical presentation. While late-stage nocardial brain abscesses may be radiologically characteristic, early-stage lesions are nonspecific and indistinguishable from another inflammatory/infectious process and other mimics. Despite the paucity of previous histopathological descriptions, histopathological examination is critical for the identification of the pathogen, lesion stage(s), and possible coexisting pathology. In this study, we examined the clinical, radiological and histopathological features of 10 patients with brain nocardiosis. Microscopic findings were analysed in correlation with clinical and radiological features in 9 patients, which revealed that brain nocardiosis was characterized by numerous necrotic and non-necrotic foci of various stages (I-IV) along with Nocardia identification, as well as the leptomeningeal involvement in most cases, and co-infection of brain nocardiosis with toxoplasmosis in 2 patients. The imaging features were characteristic with a multilobulated/bilobed ring-enhancing appearance in 8 patients including 2 patients with multiple lobulated and non-lobulated lesions and 1 patient showing the progression from a non-lobulated to lobulated lesion. These findings suggest that nocardial brain abscesses particularly at late-stages share common characteristics. Nevertheless, given the complex pathologic features, including possible co-infection by other pathogens, nocardial brain abscesses remain a therapeutic challenge., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Significance: Multiparameter spectrophotometry (MPS) provides a powerful tool for accurate characterization of turbid materials in applications such as analysis of material compositions, assay of biological tissues for clinical diagnosis and food safety monitoring., Aim: This work is aimed at development and validation of a rapid inverse solver based on a particle swarm optimization (PSO) algorithm to retrieve the radiative transfer (RT) parameters of absorption coefficient, scattering coefficient and anisotropy factor of a turbid sample., Approach: Monte Carlo (MC) simulations were performed to obtain calculated signals for comparison to the measured ones of diffuse reflectance, diffuse transmittance and forward transmittance. An objective function has been derived and combined with the PSO algorithm to iterate MC simulations for MPS., Results: We have shown that the objective function can significantly reduce the variance in calculated signals by local averaging of an inverse squared error sum function between measured and calculated signals in RT parameter space. For validation of the new objective function for PSO based inverse solver, the RT parameters of 20% Intralipid solutions have been determined from 520 to 1000 nm which took about 2.7 minutes on average to complete signal measurement and inverse calculation per wavelength., Conclusion: The rapid solver enables MPS to be translated into easy-to-use and cost-effective instruments without integrating sphere for material characterization by separating and revealing compositional profiles at the molecular and particulate scales., (© 2024 The Authors.)

The rice leaf folder, Cnaphalocrocis medinalis (Lepidoptera: Pyralidae), is a notorious pest of rice in Asia. The larvae and adults of C. medinalis utilize specialized chemosensory systems to adapt to different environmental odors and physiological behaviors. However, the differences in chemosensory genes between the olfactory organs of these two different developmental stages remain unclear. Here, we conducted a transcriptome analysis of larvae heads, male antennae, and female antennae in C. medinalis and identified 131 putative chemosensory genes, including 32 OBP s (8 novel OBP s), 23 CSP s (2 novel CSP s), 55 OR s (17 novel OR s), 19 IR s (5 novel IR s) and 2 SNMP s. Comparisons between larvae and adults of C. medinalis by transcriptome and RT-qPCR analysis revealed that the number and expression of chemosensory genes in larval heads were less than that of adult antennae. Only 17 chemosensory genes (7 OBP s and 10 CSP s) were specifically or preferentially expressed in the larval heads, while a total of 101 chemosensory genes (21 OBP s, 9 CSP s, 51 OR s, 18 IR s, and 2 SNMP s) were specifically or preferentially expressed in adult antennae. Our study found differences in chemosensory gene expression between larvae and adults, suggesting their specialized functions at different developmental stages of C. medinalis . These results provide a theoretical basis for screening chemosensory genes as potential molecular targets and developing novel management strategies to control C. medinalis .

Brain metastases are a frequent occurrence in neuropathology practices. The literature on their neuroanatomical location is frequently derived from radiological analyses. This work examines brain metastases through the lens of pathology specimens. All brain surgical pathology reports for cases accessioned 2011-2020 were retrieved from a laboratory. Specimens were classified by neuroanatomical location, diagnosis and diagnostic category with a hierarchical free text string-matching algorithm (HFTSMA) and also subsequently audited. All reports classified as probable metastasis were reviewed by a pathologist. The provided history was compared to the final categorization by a pathologist. The cohort had 4,625 cases. The HFTSMA identified 854 cases (including metastases from a definite primary, metastases from primary not known and improperly classified cases). 514/854 cases had one definite primary site per algorithm and on report review 538/854 cases were confirmed as such. The 538 cases originated from 511 patients. Primaries from breast, gynecologic tract, and gastrointestinal tract not otherwise specified were most frequently found in the cerebellum. Kidney metastases were most frequently found in the occipital lobe. Lung, metastatic melanoma and colorectal primaries were most commonly found in the frontal lobe. The provided clinical history predicted the primary in 206 cases (40.3%), was discordant in 17 cases (3.3%) and non-contributory in 280 cases (54.8%). The observed distribution of the metastatic tumours in the brain is dependent on the primary site. In the majority (54.8%) of cases, the provided clinical history was non-contributory; this suggests surgeon-pathologist communication may have the potential for optimization., Competing Interests: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.The corresponding author (MB) retains the copyright on the computer code that was written outside of his employment relationship with McMaster University/St. Joseph’s Healthcare Hamilton/Hamilton Regional Laboratory Medicine Program. The above does not in any way limit adherence to the PLOS ONE data availability policy, as found here: https://journals.plos.org/plosone/s/data-availability. There is no financial conflict of interest. There are no conflicts for the other authors., (Copyright: © 2023 Bonert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Central nervous system (CNS) lymphomas frequently pose a diagnostic challenge to physicians. CNS anaplastic large cell lymphoma (ALCL) is a rare condition. A majority (80%) of ALCLs harbour anaplastic lymphoma kinase 1 (ALK-1) mutation with only a minority testing negative for this mutation., Methods: Here we report a rare case of ALK-negative CNS ALCL with dural involvement. We conducted a literature search using PubMed for published studies in English on cases of patients with ALCL of the brain. The keywords used were 'anaplastic large cell lymphoma', 'ALK' and 'primary central nervous system lymphoma'., Results: A 63-year-old man presents with waxing and waning cranial nerve and spinal cord symptoms. MRI revealed multiple intracranial and intra-spinal lesions that were highly steroid responsive. A wide range of serum and CSF tests were non-diagnostic during three months of workup before a lesion appeared in the cervical spine that required decompression and allowed us to obtain a tissue sample. Final pathology revealed ALK-negative ALCL. There are only 24 reported adult cases to date of CNS ALCL in the English literature. To our knowledge, this is the first case of ALK-negative ALCL with primarily CNS and meningeal involvement., Conclusions: ALK-negative ALCL with CNS involvement is extremely rare, which frequently results in delayed diagnosis (average 40.5 days). The diagnostic challenge posed by this case highlights the importance of a team approach to workup and diligent patient follow-up for such a rare disease.

Introduction: Blood urea nitrogen (BUN) is a metabolic product validated to be an independent risk factor in the prognosis of several diseases. However, the prognostic value of BUN in patients with infective endocarditis (IE) remains unevaluated., Methods: A total of 1371 patients with a diagnosis of IE were included and divided into four groups according to BUN (mmol/L) at admission: < 3.5 (n = 343), 3.5-4.8 (n = 343), 4.8-6.8 (n = 341), and ≥ 6.8 (n = 344). Restricted cubic spline was used to assess the association of BUN with in-hospital mortality. Multivariate analysis was performed to identify the independent risk factors for adverse outcomes., Results: The in-hospital mortality reached 7.4%, while the 6-month mortality was 9.8%. The restricted cubic spline plot exhibited an approximately linear relationship between BUN and in-hospital mortality. Receiver operating characteristics curve analysis showed that the optimal cut-off of BUN for predicting in-hospital death was 6.8 mmol/L. Kaplan-Meier analysis showed that patients with BUN > 6.8 mmol/L had a higher 6-month mortality than other groups (log rank = 97.9, P < 0.001). Multivariate analysis indicated that BUN > 6.8 mmol/L was an independent predictor indicator for both in-hospital [adjusted odds ratio (aOR) = 2.365, 95% confidence interval (CI) 1.292-4.328, P = 0.005] and 6-month mortality [adjusted hazard ratio (aHR) = 2.171, 95% CI 1.355-3.479, P = 0.001]., Conclusions: BUN is suitable for independently predicting short-term mortality in patients with IE., (© 2023. The Author(s).)

Antibiotic resistance caused by biofilm formation is a clinical challenge. Nitric oxide (NO) can effectively disperse a mature biofilm and can also synergistically influence the level of cyclic diguanylate (c-di-GMP), a universal secondary messenger that plays an important role in biofilm formation in bacteria. Based on our previous finding that c-di-GMP G-quadruplex inducers are effective biofilm formation inhibitors, we designed and synthesized a c-di-GMP G-quadruplex inducer-NO donor conjugate ( A11@NO ) as a bifunctional antibiofilm agent after obtaining the c-di-GMP G-quadruplex inducer ( A11 ), which has an amino group capable of binding to a nitroso group (NO donor). The conjugate A11@NO showed better biofilm inhibition efficiency than A11 , and it can also eradicate mature biofilm. Additionally, it exhibited good antimicrobial synergism against Pseudomonas aeruginosa and helped elevate the bactericidal efficiency of tobramycin against biofilm-formed bacteria. In combination with tobramycin, A11@NO also improved the survival rate of Caenorhabditis elegans in a hyperbiofilm environment.

Dengue represents a growing public health burden worldwide, accounting for approximately 100 million symptomatic cases and tens of thousands of fatalities yearly. Prior infection with one serotype of dengue virus (DENV) is the greatest known risk factor for severe disease upon secondary infection with a heterologous serotype, a risk which increases as serotypes co-circulate in endemic regions. This disease risk is thought to be mediated by IgG-isotype antibodies raised during a primary infection, which poorly neutralize heterologous DENV serotypes and instead opsonize virions for uptake by FcγR-bearing cells. This antibody-dependent enhancement (ADE) of infection leads to a larger proportion of susceptible cells infected, higher viremia and greater immunopathology. We have previously characterized the induction of a serum IgA response, along with the typical IgM and IgG responses, during dengue infection, and have shown that DENV-reactive IgA can neutralize DENV and competitively antagonize IgG-mediated ADE. Here, we evaluate the potential for IgA itself to cause ADE. We show that IgG, but not IgA, mediated ADE of infection in cells expressing both FcαR and FcγRs. IgG-mediated ADE stimulated significantly higher pro-inflammatory cytokine production by primary human macrophages, while IgA did not affect, or slightly suppressed, this production. Mechanistically, we show that DENV/IgG immune complexes bind susceptible cells significantly more efficiently than DENV/IgA complexes or virus alone. Finally, we show that over the course of primary dengue infection, the expression of FcγRI (CD64) increases during the period of acute viremia, while FcγRIIa (CD32) and FcαR (CD89) expression decreases, thereby further limiting the ability of IgA to facilitate ADE in the presence of DENV. Overall, these data illustrate the distinct protective role of IgA during ADE of dengue infection and highlight the potential therapeutic and prognostic value of DENV-specific IgA., Competing Interests: ADW and ATW are co-inventors on the provisional patent “IgA monoclonal antibodies as a prophylactic and therapeutic treatment for acute flavivirus infection.” ATW and SJT are co-founders of Azimuth Biologics, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright: © 2023 Wegman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Electrochemical CO 2 reduction reaction (CO 2 RR) provides a promising approach for sustainable chemical fuel production of carbon neutrality. Neutral and alkaline electrolytes are predominantly employed in the current electrolysis system, but with striking drawbacks of (bi)carbonate (CO 3 2- /HCO 3 - ) formation and crossover due to the rapid and thermodynamically favourable reaction between hydroxide (OH - ) with CO 2 , resulting in low carbon utilization efficiency and short-lived catalysis. Very recently, CO 2 RR in acidic media can effectively address the (bi)carbonate issue; however, the competing hydrogen evolution reaction (HER) is more kinetically favourable in acidic electrolytes, which dramatically reduces CO 2 conversion efficiency. Thus, it is a big challenge to effectively suppress HER and accelerate acidic CO 2 RR. In this review, we begin by summarizing the recent progress of acidic CO 2 electrolysis, discussing the key factors limiting the application of acidic electrolytes. We then systematically discuss addressing strategies for acidic CO 2 electrolysis, including electrolyte microenvironment modulation, alkali cations adjusting, surface/interface functionalization, nanoconfinement structural design, and novel electrolyzer exploitation. Finally, the new challenges and perspectives of acidic CO 2 electrolysis are suggested. We believe this timely review can arouse researchers' attention to CO 2 crossover, inspire new insights to solve the "alkalinity problem" and enable CO 2 RR as a more sustainable technology., (© 2023 Wiley-VCH Verlag GmbH.)

Cylindrical spirals (CSs) are ultrastructurally distinct, intracytoplasmic inclusions characterized by concentrically wrapped lamellae, which are rarely found in skeletal muscle biopsies on electron microscopy (EM). CSs are often confused with other EM concentric structures including concentric laminated bodies and mitochondrial concentric cristae (MCC), due to similarities in these ultrastructures. In this study, we found CSs in 9 muscle biopsies from 9 patients, accounting for 0.5% of the biopsies examined routinely by EM. The frequency of CSs in these muscles varied from sparse and segregated to focally frequent and aggregated. CS-associated features included muscle fiber denervation atrophy in all 9 cases, fiber type grouping in 7/8 cases, tubular aggregates in 3/9 cases, and MCC in 2/9 cases. We also compared the concentric structures and highlighted their differences to distinguish CSs from other similar structures. Clinically, 8 out of 9 patients were adults aged 41-74 years and only one patient was 17 month-old. CSs were associated with several neurological diseases including Huntington's disease, amyotrophic lateral sclerosis, Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes, and other complex neurological disorders with neuropathy/encephalopathy, as well as anti-MDA5+ dermatomyositis. Eight of nine patients had genetic findings such as trinucleotide repeat expansion of huntingtin gene, ALS2 variant, MT-TL1 m.3243A > G mutation, and PMP 22 gene deletion. These results suggest that CSs may be highly variable in frequency and likely are under-reported/under-detected; they may be associated with neurogenic myopathy or central/peripheral nervous system disorders including some genetic neurological/neuromuscular diseases. Our findings of more CS-associated neurological diseases and an association of CSs with muscle neurogenic features may contribute to a better understanding of the clinico-pathological significance of CSs., Competing Interests: Declaration of Competing Interest Dr. Mark A. Tarnopolsky is the CEO of Exerkine Corporation and the company is working on therapies that target mitochondrial dysfunction. The remaining authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is thought to be a rare tumefactive lesion with unknown pathogenesis. Its prevalence is questionable with few previously reported cases of incidental CAPNON, and likely underdiagnosis. We report a unique case of incidental multifocal CAPNON. A 64-year-old female was admitted with loss of consciousness due to a ruptured right middle cerebral artery aneurysm with subarachnoid and intraventricular hemorrhage. She has a craniotomy and clipping. At time of operation, numerous small dural-based nodules were found, and one was excised for biopsy and was diagnosed as CAPNON. Retrospective review of her CT images identified nodules that were all ipsilateral to the ruptured aneurysm. A literature review revealed that incidental and/or multifocal CAPNONs are rare but likely underreported. Our case suggests a reactive process in the pathogenesis of CAPNON.

Uterus transplantation has become an option for women suffering from some form of infertility. Current review discusses key physiological functions of the endometrium requiring the transition of tissue cells between the mesenchyme and epithelial cell phenotype, a process known as epithelial-mesenchymal transition (EMT). Estrogen and EMT play a key role in the pathogenesis and treatment of intrauterine adhesion and endometriosis. There is also a close regulatory relationship between estrogen and EMT, and investigation of this relationship is of great significance for the treatment of endometrial disorders. The present review discusses the effects of estrogen on endometrial dysfunction, with a focus on the relationship between estrogen and EMT in endometrial disorders, taking into consideration the mechanisms by which receptors that regulate their functions and proteins that regulate their local biological functions interact with the factors involved in EMT. In addition, the review summarizes emerging drugs targeting receptors or proteins and provides information on the direction of new therapies for endometrial disorders., (Copyright © 2022. Published by Elsevier B.V.)

Rheumatoid nodules (RNs) are the most common extra-articular manifestation of rheumatoid arthritis and are also seen in patients with other autoimmune and inflammatory diseases. The development of RNs includes histopathological stages of acute unspecified inflammation, granulomatous inflammation with no or minimal necrosis, necrobiotic granulomas typically with central fibrinoid necrosis surrounded by palisading epithelioid macrophages and other cells, and likely an advanced stage of "ghost" lesions containing cystic or calcifying/calcified areas. In this article, we review RN pathogenesis, histopathological features in different stages, diagnostically related clinical manifestations, as well as diagnosis and differential diagnosis of RNs with an in-depth discussion about challenges in distinguishing RNs from their mimics. While the pathogenesis of RN formation remains elusive, it is hypothesized that some RNs with dystrophic calcification may be in transition and may be in coexistence or collision with another lesion in patients with RA or other soft tissue diseases and comorbidities. The diagnosis of typical or mature RNs in usual locations can be readily made by clinical findings often with classic RN histopathology, but in many cases, particularly with atypical or immature RNs and/or unusual locations, the clinical and histopathological diagnosis can be challenging requiring extensive examination of the lesional tissue with histological and immunohistochemical markers to identify unusual RNs in the clinical context or other lesions that may be coexisting with classic RNs. Proper diagnosis of RNs is critical for appropriate treatment of patients with RA or other autoimmune and inflammatory diseases., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

This study aimed to investigate the development status of traditional Chinese medicine(TCM) intervention in psoriasis in recent ten years, analyze the research hotspots, and summarize the development trends to provide reference materials for scholars in this field. Taking the available literature related to the field of TCM intervention in psoriasis as the research object, the trends, contents, and source publications were statistically analyzed based on bibliometrics. The research cooperation and co-occurrence of keywords in this field were studied by the knowledge map analysis method based on CiteSpace. The total number of Chinese papers was 2 993 and English papers 285. In terms of publication trend, the annual publication of English papers was low but showed an obvious upward trend, while the increase in Chinese papers fluctuated and tended to be flat. In terms of the content of Chinese papers published, TCM ranked first according to the discipline(2 415). In English papers, the number of publications in pharmacology and pharmaceutical science was the highest(87). Literature source analysis showed that the Chinese and English journals with the most publications were China Journal of Traditional Chinese Medicine and Pharmacy and Evidence Based Complementary and Alternative Medicine, respectively. Beijing University of Chinese Medicine published the most dissertations in China(99). The authors with the most publications in Chinese and English were LI Bin(Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine) and LU Chuan-jian(Guangdong Hospital of Traditional Chinese Medicine). As revealed by the CiteSpace analysis of the research cooperation network, there were four mature and stable core teams in this field, but the cooperation intensity between different teams was weak. According to the keywords co-occurrence knowledge graph constructed by CiteSpace, the current hot keywords in this field are as follows: psoriasis, blood-heat syndrome, blood-stasis syndrome, fire needle, blood-dryness type, imiquimod, TCM bath, etiology and pathogenesis, cytokines, cupping therapy, etc. In summary, Chinese scholars have conducted active exploration and research in the field of TCM intervention in psoriasis in recent ten years. The overall development trend is good, and the breadth and depth of the research are constantly extending. It is suggested that relevant research should be free from discipline restrictions and strive for interdisciplinary integration.

Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem syndrome caused by mutations in the neurofibromin 1 (NF1) gene that encodes for the protein neurofibromin acting as a tumour suppressor. Neurofibromin functions primarily as a GTPase-activating protein for the Ras family of oncogenes, which activates many signalling pathways for cell proliferation and differentiation; without neurofibromin, Ras is constitutively activated, thereby turning on many downstream signalling pathways related to oncogenesis. Patients with NF1 have a well known predisposition for certain types of malignancies including malignant peripheral nerve sheath tumours, gliomas, and breast cancers, as well as a potential association of NF1 with lymphoproliferative disorders such as lymphomas. In this article, we review the pathophysiology and tumourigenesis of NF1, previously reported cases of cutaneous lymphomas in NF1 patients along with our case demonstration of a NF1-associated scalp B-cell lymphoma, and NF1-associated extra cutaneous lymphomas. The diagnosis of lymphomas particularly cutaneous lymphomas may be difficult in NF1 patients as they often have skin lesions and/or cutaneous/subcutaneous nodules or tumours like neurofibromas, which raises the possibility of underdiagnosed cutaneous lymphomas in NF1 patients. We also comprehensively discuss the association between NF1 and lymphomas. In summary, most studies support a potential association between NF1 and lymphomas. Further investigation is needed to clarify the association between NF1 and lymphomas in order to bring clinical awareness of possibly underdiagnosed NF1-associated lymphomas and individualised management of NF1 patients to practice., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

There is significant enterohepatic circulation (EHC) during the disposition of mycophenolic acid (MPA). The aim of this study was to elucidate factors influencing the EHC of MPA in Chinese adult renal allograft recipients. After 2 weeks of therapy with mycophenolate mofetil or enteric-coated mycophenolate sodium, blood samples were collected from 125 patients at 0 to 12 hours post-administration and MPA concentrations were determined. The influence of calcineurin inhibitors (CNIs) and genetic polymorphisms on MPA exposure and EHC was studied. The Shapley additive explanations method was used to estimate the impact of various factors on the area under the plasma drug concentration-time curve (AUC 0-12h ) for MPA. An extreme gradient boosting (XGboost) machine learning-based model was established to predict AUC 0-12h . Results showed that the dose-normalized AUC 6-12h (dn-AUC 6-12h ) of MPA was significantly lower in patients co-administered with cyclosporine (CsA) than in patients co-administered with tacrolimus (TAC) (P < .05). For patients co-administered with TAC, patients with ABCC2 C-24T CC or SLCO1B1 T521C TT genotypes had significantly higher values of dn-AUC 6-12h (P < .05). Patients with SLCO1B3 334T/699G alleles had significantly lower dn-AUC 6-12h values than homozygotes (P < .05). By introducing body weight, age, and EHC-related factors, including co-administered CNIs and genetic polymorphism of drug transporters, as covariates in the XGboost machine learning model, the prediction performance of AUC 0-12h for MPA in Chinese adult renal allograft recipients can be improved., (© 2022, The American College of Clinical Pharmacology.)

Background: Capsular contracture may occur after rhinoplasty due to rejection of silicone implants by the immune system. Our previous high-throughput sequencing of RNA in nasal capsular contracture tissue revealed that FPR3 was significantly increased in grade IV capsular contracture tissue, compared with grade II., Objective: This study aimed to elucidate the effect and specific mechanism of FPR3 on capsular formation and contracture following rhinoplasty., Methods: Using the GeneMANIA Database, the genes involved with FPR3 expression were searched, and the Gene Ontology analysis was performed to annotate the biological functions of the aforementioned genes. The mRNA and protein expressions of related genes in fibroblasts and capsular contracture tissues were analyzed using quantitative real-time PCR, western blot, and immunohistochemical staining. CCK-8 was used to determine the viability of cells. The migration capacity of fibroblasts was assessed using a wound healing assay. ELISA was used to detect levels of IL-1β, TNF-α, and IL-6., Results: After rhinoplasty, the expression of FPR3 in the capsular tissue increased in proportion to the degree of contracture. By activating the PKA/Rap1/ERK1/2 axis, overexpression of FPR3 can significantly increase the cell viability of fibroblasts and promote their transformation into myofibroblasts. Moreover, FPR3 phosphorylates IκB to decrease NF-κB inhibition, thereby promoting the synthesis and release of the inflammatory cytokines IL-1β, TNF-α, and IL-6., Conclusion: FPR3 is a crucial molecule that causes capsular development and contracture following rhinoplasty. In the future, local suppression of FPR3 may be an effective treatment for relieving capsular contracture., (Copyright © 2022. Published by Elsevier Ltd.)

Copper compounds have been extensively investigated for diverse applications. However, studies of cuprous hydroxide (CuOH) have been scarce due to structural metastability. Herein, a facile, wet-chemistry procedure is reported for the preparation of stable CuOH nanostructures via deliberate functionalization with select organic ligands, such as acetylene and mercapto derivatives. The resulting nanostructures are found to exhibit a nanoribbon morphology consisting of small nanocrystals embedded within a largely amorphous nanosheet-like scaffold. The acetylene derivatives are found to anchor onto the CuOH forming CuC linkages, whereas CuS interfacial bonds are formed with the mercapto ligands. Effective electronic coupling occurs at the ligand-core interface in the former, in contrast to mostly non-conjugated interfacial bonds in the latter, as manifested in spectroscopic measurements and confirmed in theoretical studies based on first principles calculations. Notably, the acetylene-capped CuOH nanostructures exhibit markedly enhanced photodynamic activity in the inhibition of bacteria growth, as compared to the mercapto-capped counterparts due to a reduced material bandgap and effective photocatalytic generation of reactive oxygen species. Results from this study demonstrate that deliberate structural engineering with select organic ligands is an effective strategy in the stabilization and functionalization of CuOH nanostructures, a critical first step in exploring their diverse applications., (© 2022 Wiley-VCH GmbH.)

Background: Intracranial rhabdomyosarcomas represent a rare condition, posing a diagnostic challenge to physicians. Brain intraparenchymal rhabdomyosarcomas are exceptionally rare with poorly understood pathogenesis., Methods: Here we report the first adult case of intraparenchymal rhabdomyosarcoma (RMS) with brainstem and cranial nerve involvement. We conducted a literature search using Embase, MEDLINE, and PubMed for published cases of patients with rhabdomyosarcoma of the brain. The keywords used were 'rhabdomyosarcoma' combined with 'intraparenchymal', 'parenchymal', 'cerebral' or 'brain' for title/abstract. Included cases were adult patients (>18 years of age)., Results: A 59-year-old man presents with multiple cranial nerve palsies. MRI revealed a solitary pontine lesion that was not responsive to steroids. No systemic lesions were identified with an extensive imaging workup. A wide range of serum and cerebrospinal fluid tests were non-diagnostic during a ten-month workup until, ultimately, the patient died as a result of aspiration pneumonia. At autopsy, pathological examination on whole-brain autopsy revealed RMS, centred in the left side of pons with extension to the left side of the midbrain and the right side of pons with multiple cranial nerve involvement. There are only 20 adult cases of primary intraparenchymal RMS reported in the literature. Our present case is the first reported adult RMS in this location, with novel molecular information, providing some insight into the pathogenesis of this rare diagnosis., Conclusions: Intraparenchymal rhabdomyosarcoma without evidence of systemic primary disease is extremely rare, resulting in delayed diagnosis in some cases, particularly those not amenable to biopsy. The diagnostic challenge posed by this complementary case highlights the importance of maintaining a differential of neoplasm in the face of non-diagnostic investigations to the contrary.

Design and engineering of effective electrode catalysts represents a critical first step for hydrogen production by electrochemical water splitting. Nanocomposites based on ruthenium atomically dispersed within a carbon scaffold have emerged as viable candidates. In the present study, ruthenium metal centers are atomically embedded within graphitic carbon nitride/reduced graphene oxide nanosheets by thermal refluxing. Subsequent chemical reduction/oxidation leads to ready manipulation of the ruthenium valence state, as evidenced in microscopic and spectroscopic measurements, and hence enhancement/diminishment of the electrocatalytic activity towards hydrogen evolution reaction in both acidic and alkaline media. This is largely ascribed to the increased/reduced contribution of the Ru valence electrons to the density of state near the Fermi level which dictates the binding and reduction of hydrogen. Results from this study highlight the significance of the valence state of metal centers in the manipulation and optimization of the catalytic performance of single atom catalysts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Significance: As a noncontact method, imaging photoplethysmography (iPPG) may provide a powerful tool to measure pulsatile pressure wave (PPW) in superficial arteries and extract biomarkers for monitoring of artery wall stiffness., Aim: We intend to develop a approach for extraction of the very weak cardiac component from iPPG data by identifying locations of strong PPW signals with optimized illumination wavelength and determining pulse wave velocity (PWV)., Approach: Monochromatic in vivo iPPG datasets have been acquired from left hands to investigate various algorithms for retrieval of PPW signals, distribution maps and waveforms, and their dependence on arterial location and wavelength., Results: A robust algorithm of pixelated independent component analysis (pICA) has been developed and combined with spatiotemporal filtering to retrieve PPW signals. Spatial distributions of PPW signals have been mapped in 10 wavelength bands from 445 to 940 nm and waveforms were analyzed at multiple locations near the palmar artery tree. At the wavelength of 850 nm selected for timing analysis, we determined PWV values from 12 healthy volunteers in a range of 0.5 to 5.8 m/s across the hand region from wrist to midpalm and fingertip., Conclusions: These results demonstrate the potentials of the iPPG method based on pICA algorithm for translation into a monitoring tool to characterize wall stiffness of superficial artery by rapid and noncontact measurement of PWV and other biomarkers within 10 s.

Dengue virus (DENV) infections are major causes of morbidity and mortality throughout the tropics and subtropics. More than 400 million infections are estimated to occur every year, resulting in nearly 100 million symptomatic infections and more than 20,000 deaths. Early immune response kinetics to infection remain unclear, in large part due to the variable incubation period exhibited by the DENVs after introduction into a susceptible host. To fill this knowledge gap, we performed a comprehensive virologic and immunologic analysis of individuals experimentally infected with the underattenuated DENV-1 strain 45AZ5. This analysis captured both the kinetics and composition of the innate, humoral, and cellular immune responses elicited by experimental DENV-1 infection, as well as virologic and clinical features. We observed a robust DENV-specific immunoglobulin A (IgA) antibody response that manifested between the appearance of DENV-specific IgM and IgG in all challenged individuals, as well as the presence of a non-neutralizing/NS1-specific antibody response that was delayed relative to the appearance of DENV virion-specific humoral immunity. RNA sequencing analysis revealed discrete and temporally restricted gene modules that correlated with acute viremia and the induction of adaptive immunity. Our analysis provides a detailed description, in time and space, of the evolving matrix of DENV-elicited human inflammation and immunity and reveals several previously unappreciated immunological aspects of primary DENV-1 infection that can inform countermeasure development and evaluation.