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Direct non-oxidative methane conversion (DNMC) converts methane (CH4) in one step to olefin and aromatic hydrocarbons and hydrogen (H2) co-product. Membrane reactors comprising methane activation catalysts and H2-permeable membranes can enhance methane conversion by in situ H2 removal via Le Chatelier's principle. Rigorous description of H2 kinetic effects on both membrane and catalyst materials in the membrane reactor, however, has been rarely studied. In this work, we report the impact of hydrogen activation by hydrogen-permeable SrCe0.8Zr0.2O3−δ (SCZO) perovskite oxide material on DNMC over an iron/silica catalyst. The SCZO oxide has mixed ionic and electronic conductivity and is capable of H2 activation into protons and electrons for H2 permeation. In the fixed-bed reactor packed with a mixture of SCZO oxide and iron/silica catalyst, stable and high methane conversion and low coke selectivity in DNMC was achieved by co-feeding of H2 in methane stream. The characterizations show that SCZO activates H2 to favor “soft coke” formation on the catalyst. The SCZO could absorb H2in situ to lower its local concentration to mitigate the reverse reaction of DNMC in the tested conditions. The co-existence of H2 co-feed, SCZO oxide, and DNMC catalyst in the present study mimics the conditions of DNMC in the H2-permeable SCZO membrane reactor. The findings in this work offer the mechanistic understanding of and guidance for the design of H2-permeable membrane reactors for DNMC and other alkane dehydrogenation reactions.

High-quality (Q)-factor optical resonators with extreme temporal coherence are of both technological and fundamental importance in optical metrology, continuous-wave lasing, and semiconductor quantum optics. Despite extensive efforts in designing high-Q resonators across different spectral regimes, the experimental realization of very large Q-factors at visible wavelengths remains challenging due to the small feature size that is sensitive to fabrication imperfections, and thus is typically implemented in integrated photonics. In the pursuit of free-space optics with the benefits of large space-bandwidth product and massive parallel operations, here we design and fabricate a near-visible-wavelength etch-free metasurface with minimized fabrication defects and experimentally demonstrate a million-scale ultrahigh-Q resonance. A new laser-scanning momentum-space-resolved spectroscopy technique with extremely high spectral and angular resolution is developed to characterize the record-high Q-factor as well as the dispersion of the million-Q resonance in free space. By integrating monolayer WSe 2 into our ultrahigh-Q meta-resonator, we further demonstrate laser-like highly unidirectional and narrow-linewidth exciton emission, albeit without any operating power density threshold. Under continuous-wave laser pumping, we observe pump-power-dependent linewidth narrowing at room temperature, indicating the potential of our meta-optics platform in controlling coherent quantum light-sources. Our result also holds great promise for applications like optical sensing, spectral filtering, and few-photon nonlinear optics., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Aims: Autoimmune hepatitis (AIH) is a severe disease characterized by elevated immunoglobin levels. However, the role of autoantibodies in the pathophysiology of AIH remains uncertain., Methods: Phage Immunoprecipitation-Sequencing (PhIP-seq) was employed to identify autoantibodies in the serum of patients with AIH ( n = 115), compared to patients with other liver diseases (metabolic associated steatotic liver disease (MASH) n = 178, primary biliary cholangitis (PBC), n = 26, or healthy controls, n = 94)., Results: Logistic regression using PhIP-seq enriched peptides as inputs yielded a classification AUC of 0.81, indicating the presence of a predictive humoral immune signature for AIH. Embedded within this signature were disease relevant targets, including SLA/LP, the target of a well-recognized autoantibody in AIH, disco interacting protein 2 homolog A (DIP2A), and the relaxin family peptide receptor 1 (RXFP1). The autoreactive fragment of DIP2A was a 9-amino acid stretch nearly identical to the U27 protein of human herpes virus 6 (HHV-6). Fine mapping of this epitope suggests the HHV-6 U27 sequence is preferentially enriched relative to the corresponding DIP2A sequence. Antibodies against RXFP1, a receptor involved in anti-fibrotic signaling, were also highly specific to AIH. The enriched peptides are within a motif adjacent to the receptor binding domain, required for signaling and serum from AIH patients positive for anti-RFXP1 antibody was able to significantly inhibit relaxin-2 singling. Depletion of IgG from anti-RXFP1 positive serum abrogated this effect., Conclusions: These data provide evidence for a novel serological profile in AIH, including a possible functional role for anti-RXFP1, and antibodies that cross react with HHV6 U27 protein., Competing Interests: Declaration of interests statement Dr. DeRisi reports being a consultant for Delve Bio., Inc., Public Health Company Inc., and Allen & Co. Dr Khalili reports receipt of grant funding to her institution from Gilead Sciences Inc and Intercept pharmaceuticals and she serves as a consultant to Gilead Sciences Inc and GlaxoSmithKline Pharmaceuticals.

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Diffractive nonlocal metasurfaces have recently opened a broad range of exciting developments in nanophotonics research and applications, leveraging spatially extended-yet locally patterned-resonant modes to control light with new degrees of freedom. While conventional grating responses are elegantly captured by temporal coupled mode theory, current approaches are not well equipped to capture the arbitrary spatial response observed in the nascent field of nonlocal metasurfaces. Here, we introduce spatio-temporal coupled mode theory (STCMT), capable of elegantly capturing the key features of the resonant response of wavefront-shaping nonlocal metasurfaces. This framework can quantitatively guide nonlocal metasurface design while maintaining compatibility with local metasurface frameworks, making it a powerful tool to rationally design and optimize a broad class of ultrathin optical components. We validate this STCMT framework against full-wave simulations of various nonlocal metasurfaces, demonstrating that this tool offers a powerful semi-analytical framework to understand and model the physics and functionality of these devices, without the need for computationally intense full-wave simulations. We also discuss how this model may shed physical insights into nonlocal phenomena in photonics and the functionality of the resulting devices. As a relevant example, we showcase STCMT's flexibility by applying it to study and rapidly prototype nonlocal metasurfaces that spatially shape thermal emission., (© 2024. The Author(s).)

Objective: Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known., Methods: We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive., Results: Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases., Interpretation: TRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies., Competing Interests: SV, SM, AB, AK, ZQ, EF, NL, DE, PB, SZ, JL, AM, IP, DY, CM, CW, BM, GS, KZ, AC, VT, CS, AT, KL, MW, OK, KD, OD, RB, LN, JB, JC, ML, TT, MA, JD No competing interests declared

While SARS-CoV-2 vaccines prevent severe disease effectively, postvaccination "breakthrough" COVID-19 infections and transmission among vaccinated individuals remain ongoing concerns. We present an in-depth characterization of transmission and immunity among vaccinated individuals in a household, revealing complex dynamics and unappreciated comorbidities, including autoimmunity to type 1 interferon in the presumptive index case., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objective: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co-occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD., Methods: Immunoglobulin G (IgG) from pediatric ROHHAD patients (n = 9), non-inflammatory individuals (n = 100) and relevant pediatric controls (n = 25) was screened using a programmable phage display of the human peptidome (PhIP-Seq). Putative ROHHAD-specific autoantibodies were orthogonally validated using radioactive ligand binding and cell-based assays. Expression of autoantibody targets in ROHHAD tumor and healthy brain tissue was assessed with immunohistochemistry and mass spectrometry, respectively., Results: Autoantibodies to ZSCAN1 were detected in ROHHAD patients by PhIP-Seq and orthogonally validated in 7/9 ROHHAD patients and 0/125 controls using radioactive ligand binding and cell-based assays. Expression of ZSCAN1 in ROHHAD tumor and healthy human brain tissue was confirmed., Interpretation: Our results support the notion that tumor-associated ROHHAD syndrome is a pediatric PNS, potentially initiated by an immune response to peripheral neuroblastic tumor. ZSCAN1 autoantibodies may aid in earlier, accurate diagnosis of ROHHAD syndrome, thus providing a means toward early detection and treatment. This work warrants follow-up studies to test sensitivity and specificity of a novel diagnostic test. Last, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches for detecting novel PNS subtypes. ANN NEUROL 2022;92:279-291., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The wide spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with phenotypes impacting transmission and antibody sensitivity necessitates investigation of immune responses to different spike protein versions. Here, we compare neutralization of variants of concern, including B.1.617.2 (delta) and B.1.1.529 (omicron), in sera from individuals exposed to variant infection, vaccination, or both. We demonstrate that neutralizing antibody responses are strongest against variants sharing certain spike mutations with the immunizing exposure, and exposure to multiple spike variants increases breadth of variant cross-neutralization. These findings contribute to understanding relationships between exposures and antibody responses and may inform booster vaccination strategies., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Sequencing of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral genome from patient samples is an important epidemiological tool for monitoring and responding to the pandemic, including the emergence of new mutations in specific communities., Methods: SARS-CoV-2 genomic sequences were generated from positive samples collected, along with epidemiological metadata, at a walk-up, rapid testing site in the Mission District of San Francisco, California during 22 November to 1 December, 2020, and 10-29 January 2021. Secondary household attack rates and mean sample viral load were estimated and compared across observed variants., Results: A total of 12 124 tests were performed yielding 1099 positives. From these, 928 high-quality genomes were generated. Certain viral lineages bearing spike mutations, defined in part by L452R, S13I, and W152C, comprised 54.4% of the total sequences from January, compared to 15.7% in November. Household contacts exposed to the "California" or "West Coast" variants (B.1.427 and B.1.429) were at higher risk of infection compared to household contacts exposed to lineages lacking these variants (0.36 vs 0.29, risk ratio [RR] = 1.28; 95% confidence interval [CI]: 1.00-1.64). The reproductive number was estimated to be modestly higher than other lineages spreading in California during the second half of 2020. Viral loads were similar among persons infected with West Coast versus non-West Coast strains, as was the proportion of individuals with symptoms (60.9% vs 64.3%)., Conclusions: The increase in prevalence, relative household attack rates, and reproductive number are consistent with a modest transmissibility increase of the West Coast variants. Summary: We observed a growing prevalence and modestly elevated attack rate for "West Coast" severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in a community testing setting in San Francisco during January 2021, suggesting its modestly higher transmissibility., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Chloroquine and hydroxychloroquine have been proposed recently as therapy for SARS-CoV-2-infected patients, but during 3 months of extensive use concerns were raised related to their clinical effectiveness and arrhythmogenic risk. Therefore, we estimated for these compounds several proarrhythmogenic risk predictors according to the Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm. Experiments were performed with either CytoPatch™2 automated or manual patch-clamp setups on HEK293T cells stably or transiently transfected with hERG1, hNav1.5, hKir2.1, hKv7.1+hMinK, and on Pluricyte® cardiomyocytes (Ncardia), using physiological solutions. Dose-response plots of hERG1 inhibition fitted with Hill functions yielded IC50 values in the low micromolar range for both compounds. We found hyperpolarizing shifts of tens of mV, larger for chloroquine, in the voltage-dependent activation but not inactivation, as well as a voltage-dependent block of hERG current, larger at positive potentials. We also found inhibitory effects on peak and late I Na and on I K1 , with IC50 of tens of μM and larger for chloroquine. The two compounds, tested on Pluricyte® cardiomyocytes using the β-escin-perforated method, inhibited I Kr , I CaL , I Na peak , but had no effect on I f . In current-clamp they caused action potential prolongation. Our data and those from literature for I to were used to compute proarrhythmogenic risk predictors B net (Mistry HB, 2018) and Q net (Dutta S et al., 2017), with hERG1 blocking/unblocking rates estimated from time constants of fractional block. Although the two antimalarials are successfully used in autoimmune diseases, and chloroquine may be effective in atrial fibrillation, assays place these drugs in the intermediate proarrhythmogenic risk group., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN–specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non–COVID-19 controls revealed a lack of type I IFN–stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN–specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN–specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.

Topological photonic insulators have attracted significant attention for their robust transport of light, impervious to scattering and disorder. This feature is ideally suited for slow light applications, which are typically limited by disorder-induced attenuation. However, no practical approach to broadband topologically protected slow light has been demonstrated yet. In this work, we achieve slow light in topologically unidirectional waveguides based on periodically loading an edge termination with suitably tailored resonances. The resulting edge state dispersion can wind around the Brillouin zone multiple times sustaining broadband, topologically robust slow light, opening exciting opportunities in various photonic scenarios.

While many landmark solid tumor immunotherapy studies show clinical benefits for solid tumors with high microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR), the methodologies focus only on confirmatory polymerase chain reaction (PCR) testing for MSI-H. Because some tumors are either dMMR or MSI-H but not the other, clinicians must choose between two testing methods for a broad patient population. We investigated the level of correlation between MMR protein immunohistochemistry (IHC) and microsatellite PCR testing results in 62 cancer patients. Thirty-five of the 62 cases (56.5%) were MSI-H by PCR, whereas 35 (56.5%) were dMMR by IHC. MMR IHC results correlated well with MSI PCR in 32 co-positive cases (91.4%) and 24 co-negative cases (88.9%). Six discrepant cases (9.7%) were identified, among which three were MSI-H and MMR intact, and three were dMMR and microsatellite stable. The results of this study highlight the implications of dMMR/MSI testing strategies on precision oncology. Co-testing with both MMR IHC and MSI PCR may be an effective screening strategy for evaluating immunotherapy eligibility status for solid tumors., (Copyright © 2021. Published by Elsevier Inc.)

Advanced computational techniques and mathematical modeling have become more and more important to the study of cardiac electrophysiology. In this review, we provide a brief history of the evolution of cardiomyocyte electrophysiology models and highlight some of the most important ones that had a major impact on our understanding of the electrical activity of the myocardium and associated transmembrane ion fluxes in normal and pathological states. We also present the use of these models in the study of various arrhythmogenesis mechanisms, particularly the integration of experimental pharmacology data into advanced humanized models for in silico proarrhythmogenic risk prediction as an essential component of the Comprehensive in vitro Proarrhythmia Assay (CiPA) drug safety paradigm., 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 © 2021 Elsevier Inc. All rights reserved.)

Testicular germ cell tumors are among the most common malignancies seen in children and young adults. Genomic studies have identified characteristic molecular profiles in testicular cancer, which are associated with histologic subtypes and may predict clinical behavior including treatment responses. Emerging molecular technologies analyzing tumor genomics, transcriptomics, and proteomics may now guide precision management of testicular tumors. Laser-assisted microdissection methods such as laser capture microdissection efficiently isolate selected tumor cells from routine pathology specimens, avoiding contamination from nontarget cell populations. Laser capture microdissection in combination with next generation sequencing makes precise high throughput genetic evaluation effective and efficient. The use of laser capture microdissection (LCM) for molecular testing may translate into great benefits for the clinical management of patients with testicular cancers. This review discusses application protocols for laser-assisted microdissection to investigate testicular germ cell tumors.

SARS-CoV-2 infection is characterized by peak viral load in the upper airway prior to or at the time of symptom onset, an unusual feature that has enabled widespread transmission of the virus and precipitated a global pandemic. How SARS-CoV-2 is able to achieve high titer in the absence of symptoms remains unclear. Here, we examine the upper airway host transcriptional response in patients with COVID-19 (n = 93), other viral (n = 41) or non-viral (n = 100) acute respiratory illnesses (ARIs). Compared with other viral ARIs, COVID-19 is characterized by a pronounced interferon response but attenuated activation of other innate immune pathways, including toll-like receptor, interleukin and chemokine signaling. The IL-1 and NLRP3 inflammasome pathways are markedly less responsive to SARS-CoV-2, commensurate with a signature of diminished neutrophil and macrophage recruitment. This pattern resembles previously described distinctions between symptomatic and asymptomatic viral infections and may partly explain the propensity for pre-symptomatic transmission in COVID-19. We further use machine learning to build 27-, 10- and 3-gene classifiers that differentiate COVID-19 from other ARIs with AUROCs of 0.981, 0.954 and 0.885, respectively. Classifier performance is stable across a wide range of viral load, suggesting utility in mitigating false positive or false negative results of direct SARS-CoV-2 tests.

Gonadoblastoma occurring in a normal girl or woman has been confused with ovarian mixed germ cell-sex cord stromal tumor (MGC-SCST) due to a lack of knowledge that the former occurs occasionally in a normal woman or girl. In this article, we develop histological criteria that facilitate the distinction of gonadoblastoma in an individual with a normal karyotype and no evidence of a disorder of sex development from ovarian MGC-SCST. We reviewed the histological findings of gonadoblastoma occurring in normal individuals and compared them to cases of ovarian MGC-SCST in our files. The histological findings of gonadoblastoma differ substantially from those of ovarian MGC-SCST. Importantly, gonadoblastoma contains two types of transformed germ cells, some histologically benign and others premalignant, whereas MGC-SCST contains only a single type, typically premalignant in the ovary and benign in the testis. Furthermore, degenerative changes of hyalinization and calcification are common in gonadoblastoma, whereas they are extremely rare in MGC-SCST. Although the great majority of cases of gonadoblastoma occur in an individual with a disorder of sex development and an abnormal karyotype, a substantial number arise in a normal woman or girl with no evidence of a disorder of sex development. In the latter circumstance, it is important to distinguish gonadoblastoma from ovarian MGC-SCST. It is very likely that those gonadoblastomas arising in a normal individual develop through a different molecular pathway than the ones that occur in the dysgenetic gonads of an individual with a disorder of sex development., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

TFE3-fusion associated renal cell carcinoma (TFE3-RCC) accounts for up to 5% adults and 40% of childhood RCC. Their comprehensive immunohistochemical (IHC) profile in correlation to fluorescence in situ hybridization (FISH) testing and their role in the diagnostic approach are not well documented because of lacking published data. FISH confirmed TFE3-RCC between years 2010 and 2020 were identified from institutional electronic database and retrospectively reviewed. Eighty-five TFE3-RCC were identified. Seventy-six of 85 (89.4%) TFE3-RCC cases had positive TFE3 expression, with diffuse and strong/moderate TFE3 expression in 45 (54.2%). Three (3.5%) TFE3-RCC had negative TFE3 expression whereas 6 (7%) cases had equivocal TFE3 expression. On the other hand, positive TFE3-IHC expression was observed in 17/29 (58.6%) TFE3-FISH negative RCC cases, although only 8 (27.5%) had diffuse and moderate/strong TFE3 expression. Diffuse and strong TFE3-IHC expression was statistically significant in predicting TFE3-FISH positivity (P<0.0001) regardless of morphologic features. After univariate and multivariate analyses, TFE3-IHC was the only parameter with significant predictive value for detecting positive TFE3-FISH (P<0.0001). On univariate analysis, sex, classic morphology, age, negative AE1/AE3 or cytokeratin 7 were not predictive of TFE3-FISH positivity. Diffuse and strong nuclear TFE3-IHC expression is significantly associated with TFE3-FISH positivity and can be used as a surrogate marker to confirm translocation associated cases. TFE3-rearranged RCCs show variable histomorphologic features and TFE3-FISH should be performed in cases presenting at a younger age or, regardless of the age, tumors with unusual morphology. Despite previous reports, negative pancytokeratin and positive cathepsin K expression may not be reliable markers for TFE3-RCC.

Comprehensive understanding of the serological response to SARS-CoV-2 infection is important for both pathophysiologic insight and diagnostic development. Here, we generate a pan-human coronavirus programmable phage display assay to perform proteome-wide profiling of coronavirus antigens enriched by 98 COVID-19 patient sera. Next, we use ReScan, a method to efficiently sequester phage expressing the most immunogenic peptides and print them onto paper-based microarrays using acoustic liquid handling, which isolates and identifies nine candidate antigens, eight of which are derived from the two proteins used for SARS-CoV-2 serologic assays: spike and nucleocapsid proteins. After deployment in a high-throughput assay amenable to clinical lab settings, these antigens show improved specificity over a whole protein panel. This proof-of-concept study demonstrates that ReScan will have broad applicability for other emerging infectious diseases or autoimmune diseases that lack a valid biomarker, enabling a seamless pipeline from antigen discovery to diagnostic using one recombinant protein source., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)

Background: Most data on the clinical presentation, diagnostics, and outcomes of patients with COVID-19 have been presented as case series without comparison to patients with other acute respiratory illnesses., Methods: We examined emergency department patients between February 3 and March 31, 2020 with an acute respiratory illness who were tested for SARS-CoV-2. We determined COVID-19 status by PCR and metagenomic next generation sequencing (mNGS). We compared clinical presentation, diagnostics, treatment, and outcomes., Findings: Among 316 patients, 33 tested positive for SARS-CoV-2; 31 without COVID-19 tested positive for another respiratory virus. Among patients with additional viral testing (27/33), no SARS-CoV-2 co-infections were identified. Compared to those who tested negative, patients with COVID-19 reported longer symptoms duration (median 7d vs. 3d, p  < 0.001). Patients with COVID-19 were more often hospitalized (79% vs. 56%, p  = 0.014). When hospitalized, patients with COVID-19 had longer hospitalizations (median 10.7d vs. 4.7d, p  < 0.001) and more often developed ARDS (23% vs. 3%, p  < 0.001). Most comorbidities, medications, symptoms, vital signs, laboratories, treatments, and outcomes did not differ by COVID-19 status., Interpretation: While we found differences in clinical features of COVID-19 compared to other acute respiratory illnesses, there was significant overlap in presentation and comorbidities. Patients with COVID-19 were more likely to be admitted to the hospital, have longer hospitalizations and develop ARDS, and were unlikely to have co-existent viral infections., Funding: National Center for Advancing Translational Sciences, National Heart Lung Blood Institute, National Institute of Allergy and Infectious Diseases, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative., Competing Interests: Dr. Prasad reports personal fees from EpiExcellence, LLC, outside the submitted work. Dr. Chiu reports grants from National Institutes of Health/NHLBI, grants from National Institutes of Health/NIAID, during the conduct of the study. Dr. Peluso reports grants from Gilead Sciences, outside the submitted work. Dr. Deng has a patent 62/667,344 pending. All other authors have nothing to disclose., (© 2020 The Author(s).)

Methylation of arginine residues occurs on a number of protein substrates, most notably the N-terminal tails of histones, and is catalyzed by a family of enzymes called the protein arginine methyltransferases (PRMTs). This modification can lead to transcriptional activation or repression of cancer-related genes. To date, a number of inhibitors, based on natural peptide substrates, have been developed for the PRMT family of enzymes. However, because peptides are easily degraded in vivo, the utility of these inhibitors as potential therapeutics is limited. The use of peptoids, which are peptide mimetics where the amino acid side chain is attached to the nitrogen in the amide backbone instead of the α-carbon, may circumvent the problems associated with peptide degradation. Given the structural similarities, peptoid scaffolds may provide enhanced stability, while preserving the mechanism of action. Herein, we have identified that peptoids based on natural peptide substrates are not catalyzed to the product by PRMT1, but instead are inhibitors of this enzyme. Reducing the length of the peptoid reduces inhibition and suggest the residues distal from the site of modification are important for binding. Furthermore, a positive charge on the N-terminus helps promote binding and improves inhibition. Selectivity among family members is likely possible based on inhibition being moderately selective for PRMT1 over PRMT5 and provides a scaffold that can be used to develop pharmaceuticals against this class of enzymes., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative proposes a three-step approach to evaluate proarrhythmogenic liability of drug candidates: effects on individual ion channels in heterologous expression systems, integrating these data into in-silico models of the electrical activity of human cardiomyocytes, and comparison with experiments on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Here we introduce patch-clamp electrophysiology techniques on hiPSC-CM to combine two of the CiPA steps in one assay., Methods: We performed automated patch-clamp experiments on hiPSC-CM (Cor.4U ® , Ncardia) using the CytoPatch™2 platform in ruptured whole-cell and β-escin-perforated-patch configurations. A combination of three voltage-clamp protocols allowed recording of five distinct ion current components (voltage-gated Na + current, L-type Ca 2+ current, transient outward K + current, delayed rectifier K + current, and "funny" hyperpolarization-activated current) from the same cell. We proved their molecular identity by either Na + replacement with choline or by applying specific blockers: nifedipine, cisapride, chromanol 293B, phrixotoxin-1, ZD7288. We developed a C++ script for automated analysis of voltage-clamp recordings and computation of ion current/conductance surface density for these five cardiac ion currents., Results: The distributions from n = 54 hiPSC-CM in "ruptured" patch-clamp vs. n = 35 hiPSC-CM in β-escin-perforated patch-clamp were similar for membrane capacitance, access resistance, and ion current/conductance surface densities. The β-escin-perforated configuration resulted in improved stability of action potential (AP) shape and duration over a 10-min interval, with APD90 decay rate 0.7 ± 1.6%/min (mean ± SD, n = 4) vs. 4.6 ± 1.1%/min. (n = 3) for "ruptured" approach (p = 0.0286, one-tailed Mann-Whitney test)., Discussion: The improved stability obtained here will allow development of CiPA-compliant automated patch-clamp assays on hiPSC-CM. Future applications include the study of multi ion-channel blocking properties of drugs using dynamic-clamp protocols, adding a valuable new tool to the arsenal of safety-pharmacology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Quantum emitters such as the diamond nitrogen-vacancy (NV) center are the basis for a wide range of quantum technologies. However, refraction and reflections at material interfaces impede photon collection, and the emitters' atomic scale necessitates the use of free space optical measurement setups that prevent packaging of quantum devices. To overcome these limitations, we design and fabricate a metasurface composed of nanoscale diamond pillars that acts as an immersion lens to collect and collimate the emission of an individual NV center. The metalens exhibits a numerical aperture greater than 1.0, enabling efficient fiber-coupling of quantum emitters. This flexible design will lead to the miniaturization of quantum devices in a wide range of host materials and the development of metasurfaces that shape single-photon emission for coupling to optical cavities or route photons based on their quantum state.

Protein arginine methyltransferases (PRMTs) are a family of mammalian enzymes catalyzing the symmetric dimethylation (Type I), asymmetric dimethylation (Type II), or monomethylation (Type III) of arginine residues within proteins. This family is composed of 11 isozymes, however the vast majority of asymmetric and symmetric dimethylation in mammals is completed by either PRMT1 or PRMT5, respectively. In recent years, a number of chemical probes targeting this family of enzymes have been developed, but the majority of these probes lack isozyme specificity. Herein, we report the development of a chemical probe, based on a non-natural peptide sequence, which specifically labels PRMT1 over PRMT5 with high selectivity and sensitivity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Controlling the directivity of emission and absorption at the nanoscale holds great promise for improving the performance of optoelectronic devices. Previously, directive structures have largely been centered in two categories-nanoscale antennas, and classical lenses. Herein, we utilize an evolutionary algorithm to design 3D dielectric nanophotonic lens structures leveraging both the interference-based control of antennas and the broadband operation of lenses. By sculpting the dielectric environment around an emitter, these nanolenses achieve directivities of 101 for point-sources, and 67 for finite-source nanowire emitters; 3× greater than that of a traditional spherical lens with nearly constant performance over a 200 nm wavelength range. The nanolenses are experimentally fabricated on GaAs nanowires, and characterized via photoluminescence Fourier microscopy, with an observed beaming half-angle of 3.5° and a measured directivity of 22. Simulations attribute the main limitation in the obtained directivity to imperfect alignment of the nanolens to the nanowire beneath.

Paired Box 5 (PAX5), a well-established B-cell marker, is preferentially expressed in small cell lung carcinoma and regulates the transcription of c-Met, offering a potential for therapeutic target. Its expression in poorly differentiated neuroendocrine carcinoma (PDNEC) of the digestive system has not been systemically evaluated. Archived pathology materials from 38 PDNEC in the gastrointestinal (GI) and pancreatobiliary (PB) tract were reviewed. Representative tumor sections were subject to immunohistochemical stain for PAX5, c-Met, and CD20. The extent of the staining [focal (<10%), patchy (10% to 50%), and diffuse (>50%)] and intensity (1+ to 3+) was evaluated. In total, 38 cases of well-differentiated neuroendocrine tumors from GI/PB tract served as controls. Nuclear PAX5 staining was observed in 16 (42%) cases in total, in 46% (11/24) of large cell neuroendocrine carcinoma, 67% (4/6) of small cell neuroendocrine carcinoma, and 13% (1/8) of mixed adenoneuroendocrine carcinoma, with diffuse (8), patchy (4), or focal (4) staining. The intensity was 3+ (2), 2+ (6), and 1+ (8). PAX5 expression was common in ampullary (4/5) and gastroesophageal junctional/esophageal (5/9) PDNEC. Two (5%) of 38 well-differentiated neuroendocrine tumors were positive for PAX5. Three PAX5 positive PDNEC showed weak cytoplasmic c-Met immunolabeling. CD20 was negative in all tumors. Our data show that PAX5 is commonly expressed in PDNEC of the GI/PB tract including small cell neuroendocrine carcinoma. This observation warrants a cautious approach when interpreting small biopsy of poorly differentiated neoplasms, especially when lymphoma is considered in the differentials. Further study of PAX5/c-Met signaling pathway and its potential therapeutic value in GI/PB PDNEC is warranted.

Testicular plasmacytomas are rare, accounting for only 1.3% of all extramedullary plasmacytomas. The infrequency in which it is encountered, coupled with its non-specific clinical and sonographic presentation, makes its diagnosis a challenge. We present a case of a 70-year-old man with multiple myeloma, which was systemically responding to chemotherapy, who developed testicular swelling, erythema and pain. Ultrasound findings were concerning for infection, although urine and serum testing were unremarkable. The patient did not improve after several rounds of antibiotics prompting further evaluation. The patient underwent radical orchiectomy which revealed testicular plasmacytoma. Fluorescent in situ hybridisation (FISH) of the testicular tissue noted mutations which had not been present in the FISH analysis of bone marrow. Positron emission tomography scan later revealed new retroperitoneal plasmacytomas involving the new clone and his chemotherapy regimen needed to be adjusted for treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Daily laboratory testing (DLT) is an important cause of iatrogenic anemia. Therapeutic plasma exchanges (TPE) represent another source of blood loss. This study investigated the contributions of DLT and TPE to changes in hemoglobin of inpatients with myasthenia gravis (MG) exacerbation., Study Design and Methods: All admissions for MG that included TPE between 2008 and 2012 were identified. The DLT- and TPE-related blood losses per patient were estimated based on the number of laboratory tests and TPE procedures. The primary endpoint was the difference between the discharge hemoglobin (Hgb) and the admission Hgb (ΔHgb). Univariate and multivariable analyses were used to identify clinical predictors of ΔHgb., Results: A total of 46 patients (52% male, average age of 58 years) had 90 hospitalizations and underwent 424 TPEs during the study-period. Their average length of stay (LOS) was 10.4 days, and total DLT and TPE-related blood losses were 107 and 94 mL, respectively. While 41% of patients were anemic on admission, 90% were anemic at discharge. The average ΔHgb was -2.2 g/dL. The patient's blood volume, renal function, admission number, LOS, and combined blood losses correlated with ΔHgb by linear regression, but only DLT was an independent predictor of ΔHgb in the multivariable analysis., Conclusion: Approximately 50% of MG patients admitted for TPE developed hospital-acquired anemia, which was directly correlated with the volume of blood collected for laboratory tests. A variety of strategies to reduce DLT could circumvent this iatrogenic complication., (© 2017 Wiley Periodicals, Inc.)

The defect tolerance of halide perovskite materials has led to efficient optoelectronic devices based on thin-film geometries with unprecedented speed. Moreover, it has motivated research on perovskite nanowires because surface recombination continues to be a major obstacle in realizing efficient nanowire devices. Recently, ordered vertical arrays of perovskite nanowires have been realized, which can benefit from nanophotonic design strategies allowing precise control over light propagation, absorption, and emission. An anodized aluminum oxide template is used to confine the crystallization process, either in the solution or in the vapor phase. This approach, however, results in an unavoidable drawback: only nanowires embedded inside the AAO are obtainable, since the AAO cannot be etched selectively. The requirement for a support matrix originates from the intrinsic difficulty of controlling precise placement, sizes, and shapes of free-standing nanostructures during crystallization, especially in solution. Here we introduce a method to fabricate free-standing solution-based vertical nanowires with arbitrary dimensions. Our scheme also utilizes AAO; however, in contrast to embedding the perovskite inside the matrix, we apply a pressure gradient to extrude the solution from the free-standing templates. The exit profile of the template is subsequently translated into the final semiconductor geometry. The free-standing nanowires are single crystalline and show a PLQY up to ∼29%. In principle, this rapid method is not limited to nanowires but can be extended to uniform and ordered high PLQY single crystalline perovskite nanostructures of different shapes and sizes by fabricating additional masking layers or using specifically shaped nanopore endings.

Background: Immune checkpoint inhibitors have revolutionized the treatment of many malignancies with over a dozen new United States Food and Drug Administration (FDA) approvals in the past six years. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors, gathering prognostic and predictive information about FDA-indicated tumors is prudent., Method: PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including Renal Cell Carcinoma (RCC) and urothelial carcinoma. Each FDAapproved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. The majority of PD-1/PDL1 inhibitor clinical trials use proprietary IHC antibodies with undefined validation data. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers. There is a wealth of recent publications using antibody clones to characterize tumor PD-1/PD-L1 expression profiles., Results: PD-1 is expressed on lymphocytes. PD-L1 is expressed on both tumor cells and immune cells. IHC staining appears in membranous fashion. A cutoff of at least 5% tumor cell PD-L1 staining for positivity has worked for most studies. Caution should be observed when employing tissue microarray techniques., Conclusion: RCC has been the most studied of the genitourinary malignancies for PD-L1 expression. The atezolizumab- approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in urothelial carcinoma. With familiarity of the current FDA guidelines, published medical literature, and general immunohistochemical considerations, the use of immune checkpoint biomarkers can continue to flourish., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Von Meyenburg complex (VMC) is generally thought to be benign, although its preneoplastic potential for intrahepatic cholangiocarcinoma (iCC) has been a subject of contention. We retrospectively reviewed 86 hepatectomy specimens with a diagnosis of iCC. Morphologically, an association between iCC and VMC was appreciated in 35% of cases that illustrated a gradual neoplastic progression from benign VMC to dysplasia and then to iCC. Among them, 24 cases had VMC lined by epithelial cells with low-grade biliary dysplasia and 13 with high-grade biliary dysplasia. VMC-associated iCCs were smaller in size and well to moderately differentiated, with features of anastomosing glandular architecture, ductal carcinoma in situ-like growth pattern, peritumoral lymphocytic infiltrate, central fibrous scar, and complete pushing border. They often presented as T1 tumors. In contrast, non-VMC-associated iCCs were moderately to poorly differentiated with solid, cribriform or papillary growth patterns. They likely exhibited necrosis, perineural invasion, positive surgical margin, lymphovascular invasion, and high T stage. Additionally, Ki67 and p53 immunostains support the continuing neoplastic evolution from benign VMC to dysplasia and then to iCC. VMC could become neoplastic, serving as an in situ carcinoma lesion to transform to iCC. The underlying molecular alteration and clinical implication of this neoplastic transformation deserves further investigation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Covering: 1996-December 2016The human Ether-à-go-go Related Gene (hERG) channel is a voltage-gated potassium channel playing an essential role in the normal electrical activity in the heart. It is involved in the repolarization and termination of action potentials in excitable cardiac cells. Mutations in the hERG gene and hERG channel blockage by small molecules are associated with increased risk of fatal arrhythmias. Several drugs have been withdrawn from the market due to hERG channel-related cardiotoxicity. Moreover, as a result of its notorious ligand promiscuity, this ion channel has emerged as an important antitarget in early drug discovery and development. Surprisingly, the hERG channel blocking profile of natural compounds present in frequently consumed botanicals (i.e. dietary supplements, spices, and herbal medicinal products) is not routinely assessed. This comprehensive review will address these issues and provide a critical compilation of hERG channel data for isolated natural products and extracts over the past two decades (1996-2016). In addition, the review will provide (i) a solid basis for the molecular understanding of the physiological functions of the hERG channel, (ii) the translational potential of in vitro/in vivo results to cardiotoxicity in humans, (iii) approaches for the identification of hERG channel blockers from natural sources, (iv) future perspectives for cardiac safety guidelines and their applications within phytopharmaceuticals and dietary supplements, and (v) novel applications of hERG channel modulation (e.g. as a drug target).

We propose two-focus fluorescence correlation spectroscopy (2fFCS) on basis of plasmonic nanoantennas that provide distinct hot spots that are individually addressable through polarization, yet lie within a single diffraction limited microscope focus. The importance of two-focus FCS is that a calibrated distance between foci provides an intrinsic calibration to derive diffusion constants from measured correlation times. Through electromagnetic modelling we analyze a geometry of perpendicular nanorods, and their inverse, i.e., nanoslits. While we find that nanorods are not suited for nano-antenna enhanced 2fFCS due to substantial background signal, a nanoslit geometry is expected to provide a di tinct cross-correlation between orthogonally polarized detection channels. Furthermore, by utilizing a periodic array of nanoslits instead of a single pair, the amplitude of the cross-correlation can be enhanced. To demonstrate this technique, we present a proof of principle experiment on the basis of a periodic array of nanoslits, applied to lipid diffusion in a supported lipid bilayer.

Aim: To evaluate if any association existed between the extent of hepatic necrosis in initial liver biopsies and patient survival., Methods: Thirty-seven patients with fulminant liver failure, whose liver biopsy exhibited substantial necrosis, were identified and included in the study. The histological and clinical data was then analyzed in order to assess the relationship between the extent of necrosis and patient survival, with and without liver transplantation. The patients were grouped based on the etiology of hepatic necrosis. Each of the etiology groups were then further stratified according to whether or not they had received a liver transplant post-index biopsy, and whether or not the patient survived., Results: The core tissue length ranged from 5 to 44 mm with an average of 23 mm. Causes of necrosis included 14 autoimmune hepatitis, 10 drug induced liver injury (DILI), 9 hepatitis virus infection, and 4 unknown origin. Among them, 11 showed submassive (26%-75% of the parenchymal volume) and 26 massive (76%-100%) necrosis. Transplant-free survival was worse in patients with a higher extent of necrosis (40%, 71.4% and 100% in groups with necrosis of 76%-100%, 51%-75% and 26%-50%, respectively). Additionally, transplant-free survival rates were 66.7%, 57.1%, and 25.0% in groups of autoimmune hepatitis, DILI, and viral hepatitis, respectively. Even after liver transplantation, the survival rate in patients as a result of viral hepatitis remained the lowest (80%, 100%, and 40% in groups of autoimmune hepatitis, DILI, and viral hepatitis, respectively)., Conclusion: Adequate liver biopsy with more than 75% necrosis is associated with significant transplant-free mortality that is critical in predicting survival., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to disclose.

A tumor composed of large eosinophilic cells in the liver raises concern for hepatocellular carcinoma, which is typically composed of such cells. However, there are other tumors, both primary and metastatic, that may be composed predominantly of large epithelioid cells. Distinction of these tumors from hepatocellular carcinoma and from each other is of obvious importance for patient management. Similarly, a clear cell tumor anywhere in the body triggers suspicion for renal cell carcinoma. However, other tumors, including hepatocellular carcinoma can rarely be composed entirely of cell cells and the distinction of these from one another, and of primary from metastatic disease is vital. As with the latter, accurate diagnosis is essential for patient management. Using illustrative examples, this article discusses differential diagnosis of liver tumors comprised predominantly of epithelioid cells or clear cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Nanoscale materials are promising for optoelectronic devices because their physical dimensions are on the order of the wavelength of light. This leads to a variety of complex optical phenomena that, for instance, enhance absorption and emission. However, quantifying the performance of these nanoscale devices frequently requires measuring absolute absorption at the nanoscale, and remarkably, there is no general method capable of doing so directly. Here, we present such a method based on an integrating sphere but modified to achieve submicron spatial resolution. We explore the limits of this technique by using it to measure spatial and spectral absorptance profiles on a wide variety of nanoscale systems, including different combinations of weakly and strongly absorbing and scattering nanomaterials (Si and GaAs nanowires, Au nanoparticles). This measurement technique provides quantitative information about local optical properties that are crucial for improving any optoelectronic device with nanoscale dimensions or nanoscale surface texturing.