OCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca2+ release, exocytosis, and pancreatic tissue damage.

Regulated exocytosis is initiated by increased Ca2+ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at rest. Here we showed that exocytosis of zymogen granules in acinar cells was driven by Ca2+ directly released from acidic Ca2+ stores including secretory granules through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded by Tmem63a) as an organellar Ca2+ regulator protein integral to the membrane of secretory granules that controlled Ca2+ release via inhibition of TPC1 and TPC2 currents. Deletion of OCaR1 led to extensive Ca2+ release from NAADP-responsive granules under basal conditions as well as upon stimulation of GPCR receptors. Moreover, OCaR1 deletion exacerbated the disease phenotype in murine models of severe and chronic pancreatitis. Our findings showed OCaR1 as a gatekeeper of Ca2+ release that endows NAADP-sensitive secretory granules with an autoregulatory mechanism preventing uncontrolled exocytosis and pancreatic tissue damage.

Intraosseous myolipoma of the calcaneus.

A man in his 40s presented with an incidental finding of an osteolytic bone lesion. He sustained an ankle injury while inline skating, fracturing his lateral malleolus. Besides the fracture, radiographic imaging on the day of the injury incidentally revealed a well-defined solitary osteolytic lesion with a sclerotic rim within the right calcaneus. MRI showed an intraosseous, fat-containing lesion with focal contrast enhancement, assessed as an intraosseous lipoma with central necrosis. In the pathological analysis of a sample of the lesion an intraosseous myolipoma of the calcaneus was found-an unexpected and extraordinary finding. To prevent pathological fracturing, curettage and bone grafting were performed using autologous iliac crest bone in combination with allogenous bone chips.

Gallium arsenide whispering gallery mode resonators for terahertz photonics.

As the field of terahertz (THz) photonics advances, we present a monolithic gallium arsenide (GaAs) disk-shaped whispering gallery mode resonator that has potential as a component in THz nonlinear optics. GaAs is a material with significant optical nonlinearity which can be enhanced when the crystal is shaped into a microdisk resonator. A 4-mm-disk-resonator was fabricated using single-point diamond turning and was characterized to obtain a quality (Q) factor of 2.21k at ∼150 GHz and 1.41k at ∼300 GHz. We also demonstrated the blue-shifting of up to ∼0.3 GHz of the THz modes using a block of metal. This post-fabrication degree of freedom could be useful for phase-matching requirements for nonlinear optical processes, such as detection based on optical up-conversion of THz radiation. This proof-of-concept demonstration can pave the way for the implementation of a compact, tunable and efficient device which could be integrated into nonlinear photonic platforms for THz generation, manipulation and detection.

Association of Host Factors With Antibody Response to Seasonal Influenza Vaccination in Allogeneic Hematopoietic Stem Cell Transplant Patients.

BACKGROUND: Influenza vaccination efficacy is reduced after hematopoietic stem cell transplantation (HSCT) and patient factors determining vaccination outcomes are still poorly understood. METHODS: We investigated the antibody response to seasonal influenza vaccination in 135 HSCT patients and 69 healthy volunteers (HVs) in a prospective observational multicenter cohort study. We identified patient factors associated with hemagglutination inhibition titers against A/California/2009/H1N1, A/Texas/2012/H3N2, and B/Massachusetts/2012 by multivariable regression on the observed titer levels and on seroconversion/seroprotection categories for comparison. RESULTS: Both regression approaches yielded consistent results but regression on titers estimated associations with higher precision. HSCT patients required 2 vaccine doses to achieve average responses comparable to a single dose in HVs. Prevaccination titers were positively associated with time after transplantation, confirming that HSCT patients can elicit potent antibody responses. However, an unrelated donor, absolute lymphocyte counts below the normal range, and treatment with calcineurin inhibitors lowered the odds of responding. CONCLUSIONS: HSCT patients show a highly heterogeneous vaccine response but, overall, patients benefited from the booster shot and can acquire seroprotective antibodies over the years after transplantation. Several common patient factors lower the odds of responding, urging identification of additional preventive strategies in the poorly responding groups. CLINICAL TRIALS REGISTRATION: NCT03467074.

Terahertz Gas-Phase Spectroscopy Using a Sub-Wavelength Thick Ultrahigh-Q Microresonator.

The terahertz spectrum provides tremendous opportunities for broadband gas-phase spectroscopy, as numerous molecules exhibit strong fundamental resonances in the THz frequency range. However, cutting-edge THz gas-phase spectrometer require cumbersome multi-pass gas cells to reach sufficient sensitivity for trace level gas detection. Here, we report on the first demonstration of a THz gas-phase spectrometer using a sub-wavelength thick ultrahigh-Q THz disc microresonator. Leveraging the microresonator's ultrahigh quality factor in excess of 120,000 as well as the intrinsically large evanescent field, allows for the implementation of a very compact spectrometer without the need for complex multi-pass gas cells. Water vapour concentrations as low as 4 parts per million at atmospheric conditions have been readily detected in proof-of-concept experiments.

Identification of influenza urban transmission patterns by geographical, epidemiological and whole genome sequencing data: protocol for an observational study.

INTRODUCTION: Urban transmission patterns of influenza viruses are complex and poorly understood, and multiple factors may play a critical role in modifying transmission. Whole genome sequencing (WGS) allows the description of patient-to-patient transmissions at highest resolution. The aim of this study is to explore urban transmission patterns of influenza viruses in high detail by combining geographical, epidemiological and immunological data with WGS data. METHODS AND ANALYSIS: The study is performed at the University Hospital Basel, University Children's Hospital Basel and a network of paediatricians and family doctors in the Canton of Basel-City, Switzerland. The retrospective study part includes an analysis of PCR-confirmed influenza cases from 2013 to 2018. The prospective study parts include (1) a household survey regarding influenza-like illness (ILI) and vaccination against influenza during the 2015/2016 season; (2) an analysis of influenza viruses collected during the 2016/2017 season using WGS-viral genomic sequences are compared with determine genetic relatedness and transmissions; and (3) measurement of influenza-specific antibody titres against all vaccinated and circulated strains during the 2016/2017 season from healthy individuals, allowing to monitor herd immunity across urban quarters. Survey data and PCR-confirmed cases are linked to data from the Statistics Office of the Canton Basel-City and visualised using geo-information system mapping. WGS data will be analysed in the context of patient epidemiological data using phylodynamic analyses, and the obtained herd immunity for each quarter. Profound knowledge on the key geographical, epidemiological and immunological factors influencing urban influenza transmission will help to develop effective counter measurements. ETHICS AND DISSEMINATION: The study is registered and approved by the regional ethics committee as an observational study (EKNZ project ID 2015-363 and 2016-01735). It is planned to present the results at conferences and publish the data in scientific journals. TRIAL REGISTRATION NUMBER: NCT03010007.

Free-space coupling to symmetric high-Q terahertz whispering-gallery mode resonators.

We report on the coupling of a free-space Gaussian beam to symmetric high-quality (Q) whispering-gallery mode resonators (WGMRs) for terahertz (THz) radiation. We achieve very high excitation efficiencies up to 50% to THz WGMs with a Q-factor of 1.5×104 at 0.7 THz. The high coupling efficiencies have been realized by leveraging a Gaussian beam with a nearly diffraction-limited focal spot, as well as readily available low-loss, high-index silicon spheres with diameters comparable to the wavelength. The results convincingly underline the viability of free-space coupling in the THz frequency range.

Anomalous blue-shift of terahertz whispering-gallery modes via dielectric and metallic tuning.

The vast majority of resonant systems show a red-shift for the resonance frequency when a perturbation, e.g., losses, is introduced to the system. In contrast, here we report for the first time, to the best of our knowledge, the experimental demonstration of both red- and anomalous blue-shifting of whispering-gallery modes (WGMs) using dielectric and metallic substrates. The maximum blue-shift is more than three times as large as the expected red-shift, proving that the anomalous blue-shift is more than a peculiar curiosity. The experiments are performed in the terahertz frequency range with coherent continuous-wave spectroscopy. The results establish dielectric and metallic tuning as a novel and viable approach to tune high-quality WGMs and provide valuable insights into the anomalous blue-shift of WGM cavity systems. The tuning capabilities for these compact monolithic resonators are of significant interest for fundamental science and technological applications alike.

Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events.

BACKGROUND: Immune checkpoint inhibiting antibodies were introduced into routine clinical practice for cancer patients. Checkpoint blockade has led to durable remissions in some patients, but may also induce immune-related adverse events (irAEs). Lung cancer patients show an increased risk for complications, when infected with influenza viruses. Therefore, vaccination is recommended. However, the efficacy and safety of influenza vaccination during checkpoint blockade and its influence on irAEs is unclear. Similarly, the influence of vaccinations on T cell-mediated immune reactions in patients during PD-1 blockade remains poorly defined. METHODS: We vaccinated 23 lung cancer patients and 11 age-matched healthy controls using a trivalent inactivated influenza vaccine to investigate vaccine-induced immunity and safety during checkpoint blockade. RESULTS: We did not observe significant differences between patients and healthy controls in vaccine-induced antibody titers against all three viral antigens. Influenza vaccination resulted in protective titers in more than 60% of patients/participants. In cancer patients, the post-vaccine frequency of irAEs was 52.2% with a median time to occurrence of 3.2 months after vaccination. Six of 23 patients (26.1%) showed severe grade 3/4 irAEs. This frequency of irAEs might be higher than the rate previously published in the literature and the rate observed in a non-study population at our institution (all grades 25.5%, grade 3/4 9.8%). CONCLUSIONS: Although this is a non-randomized trial with a limited number of patients, the increased rate of immunological toxicity is concerning. This finding should be studied in a larger patient population.

Prism coupling of high-Q terahertz whispering-gallery-modes over two octaves from 0.2 THz to 1.1 THz.

We report on prism coupling of high-quality (high-Q) terahertz (THz) whispering-gallery modes (WGMs) in spherical high resistivity float zone grown silicon (HRFZ-Si) resonators over two octaves from 0.2 THz to 1.1 THz. The WGMs are excited using a HRFZ-Si prism and show unprecedented quality factors of up to 2.2 × 104. A detailed discussion of the phase-and mode-matching criteria of the prism coupling scheme implemented in the continuous wave THz spectroscopy system is presented. The results provide numerous opportunities for passive ultra-broadband high-Q devices operating in the THz frequency range.

An Optimized Hemagglutination Inhibition (HI) Assay to Quantify Influenza-specific Antibody Titers.

Antibody titers are commonly used as surrogate markers for serological protection against influenza and other pathogens. Detailed knowledge of antibody production pre- and post-vaccination is required to understand vaccine-induced immunity. This article describes a reliable point-by-point protocol to determine influenza-specific antibody titers. The first protocol describes a method to specify the antigen amounts required for hemagglutination, which standardizes the concentrations for subsequent usage in the second protocol (hemagglutination assay, HA assay). The second protocol describes the quantification of influenza-specific antibody titers against different viral strains by using a serial dilution of human serum or cell culture supernatants (hemagglutination inhibition assay, HI assay). As an applied example, we show the antibody response of a healthy cohort, which received a trivalent inactivated influenza vaccine. Additionally, the cross-reactivity between the different influenza viruses is shown and methods to minimize cross-reactivity by using different types of animal red blood cells (RBCs) are explained. The discussion highlights advantages and disadvantages of the presented assays and how the determination of influenza-specific antibody titers can improve the understanding of vaccine-related immunity.

Fano resonances in a high-Q terahertz whispering-gallery mode resonator coupled to a multi-mode waveguide.

We report on Fano resonances in a high-quality (Q) whispering-gallery mode (WGM) spherical resonator coupled to a multi-mode waveguide in the terahertz (THz) frequency range. The asymmetric line shape and phase of the Fano resonances detected with coherent continuous-wave (CW) THz spectroscopy measurements are in excellent agreement with the analytical model. A very high Q factor of 1600, and a finesse of 22 at critical coupling is observed around 0.35 THz. To the best of our knowledge this is the highest Q factor ever reported for a THz WGM resonator.

High resolution terahertz spectroscopy of a whispering gallery mode bubble resonator using Hilbert analysis.

We report on data processing for continuous wave (CW) terahertz (THz) spectroscopy measurements based on a Hilbert spectral analysis to achieve MHz resolution. As an example we investigate the spectral properties of a whispering gallery mode (WGM) THz bubble resonator at critical coupling. The experimental verification clearly demonstrates the significant advantages in relative frequency resolution and required acquisition time of the proposed method over the traditional data analysis. An effective frequency resolution, only limited by the precision and stability of the laser beat signal, can be achieved without complex extensions to a standard commercially available CW THz spectrometer.

Pathological fracture of the femoral neck following septic coxitis and chronic osteomyelitis: a potential complication of Lemierre's syndrome.

We portray the case of a 16-year-old girl who was initially admitted to the paediatric emergency department with non-specific symptoms of a severe cold and was first treated symptomatically on an ambulatory basis. Within 6 days she developed the full clinical picture of Lemierre's syndrome with the extraordinary manifestation of involvement of her right hip. Despite an interdisciplinary coordinated treatment as well as surgical therapy, a full-blown sepsis evolved within a short time period and resulted in almost 2 months of intensive care. While the primary focus could be successfully controlled, a progressive avascular necrosis of the right proximal femur developed on the basis of a chronic osteomyelitis. This finally led to a pathological fracture of the femoral neck. After excluding the possibility of an enduring bacterial infection, the fracture was treated with a total hip replacement.

Therapeutic Strategies and Pharmacological Tools Influencing S1P Signaling and Metabolism.

During the last two decades the study of the sphingolipid anabolic, catabolic, and signaling pathways has attracted enormous interest. Especially the introduction of fingolimod into market as first p.o. therapeutic for the treatment of multiple sclerosis has boosted this effect. Although the complex regulation of sphingosine-1-phosphate (S1P) and other catabolic and anabolic sphingosine-related compounds is not fully understood, the influence on different (patho)physiological states from inflammation to cytotoxicity as well as the availability of versatile pharmacological tools that represent new approaches to study these states are described. Here, we have summarized various aspects concerning the many faces of sphingolipid function modulation by different pharmacological tools up to clinical candidates. Due to the immense heterogeneity of physiological or pharmacological actions and complex cross regulations, it is difficult to predict their role in upcoming therapeutic approaches. Currently, inflammatory, immunological, and/or antitumor aspects are discussed.

Characterization of the molecular mechanism of 5-lipoxygenase inhibition by 2-aminothiazoles.

5-Lipoxygenase (5-LO, EC1.13.11.34) has been implicated in the pathogenesis of inflammatory and immune diseases. Recently, aminothiazole comprising inhibitors have been discovered for this valuable target. Yet, the molecular mode of action of this class of substances is only poorly understood. Here, we present the detailed molecular mechanism of action of the compound class and the in vitro pharmacological profile of two lead compounds ST-1853 and ST-1906. Mechanistic studies with recombinant proteins as well as intact cell assays enabled us to define this class as a novel type of 5-LO inhibitors with unique characteristics. The parent compounds herein presented a certain reactivity concerning oxidation and thiol binding: Unsubstituted aminophenols bound covalently to C159 and C418 of human 5-LO. Yet, dimethyl substitution of the aminophenol prevented this reactivity and slowed down phase II metabolism. Both ST-1853 and ST-1906 confirmed their lead likeness by retaining their high potency in physiologically relevant 5-LO activity assays, high metabolic stability, high specificity and non-cytotoxicity.

Maternal programming of offspring in relation to food availability in an insect (Forficula auricularia).

Maternal effects can induce adjustments in offspring phenotype to the environment experienced by the mother. Of particular interest is if mothers can programme their offspring to cope best under matching environmental conditions, but the evidence for such anticipatory maternal effects (AME) is limited. In this study, we manipulated experimentally the food availability experienced by mothers and their offspring in the European earwig (Forficula auricularia). Offspring produced by females that had access to high or low food quantities were cross-fostered to foster mothers experiencing matched or mismatched environments. Offspring experiencing food availability matching the one of their mothers had an increased survival to adulthood compared with offspring experiencing mismatched conditions. Females experiencing high food laid larger clutches. This clutch-size adjustment statistically explained the matching effect when offspring experienced high food, but not when experiencing low food conditions. There were no effects of matching on offspring growth and developmental rate. Overall, our study demonstrates that AME occurs in relation to food availability enhancing offspring survival to adulthood under matching food conditions.

Development of novel aminothiazole-comprising 5-LO inhibitors.

BACKGROUND: Leukotrienes are pivotal lipid mediators in various immune and inflammatory reactions. Herein, 5-LO is a validated target. 2-Aminothiazoles, as a privileged structure, implicate known 5-LO inhibitors like ST-1083 (IC50 [polymorphonuclear leukocytes (PMNL)] = 0.68 µM), yet deep structure-activity relationships (SAR) have not been established. MATERIALS & METHODS: Compounds were synthesized via Hantzsch thiazole synthesis. Inhibitory activities were evaluated using intact PMNL and purified 5-LO together with cytotoxicity measurements in U937 cells. RESULTS: We introduced novel functionalities at 2-, 3-, 4- and 5-position of the 2-aminothiazole scaffold and conducted bioisosteric replacement to optimize the parent scaffold. SARs of the 2-aminothiazole scaffold were deduced and extended primarily for inhibition of the 5-LO enzyme. CONCLUSION: SAR studies provided at least two optimized leads (ST-1853, ST-1906) with high potency (IC50 [polymorphonuclear leukocytes] = 0.05 µM), specificity and noncytotoxic behavior.

Metallic and 3D-printed dielectric helical terahertz waveguides.

We investigate guidance of Terahertz (THz) radiation in metallic and 3D-printed dielectric helical waveguides in the frequency range from 0.2 to 1 THz. Our experimental results obtained from THz time-domain spectroscopy (THz-TDS) measurements are in very good agreement with finite-difference time-domain (FDTD) simulations. We observe single-mode, low loss and low dispersive propagation of THz radiation in metallic helical waveguides over a broad bandwidth. The 3D-printed dielectric helical waveguides have substantially extended the bandwidth of a low loss dielectric tube waveguide as observed from the experimental and simulation results. The high flexibility of the helical design allows an easy incorporation into bench top THz devices.

Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors.

Sphingosine kinases (SphK1, SphK2) are main regulators of sphingosine-1-phosphate (S1P), which is a pleiotropic lipid mediator involved in numerous physiological and pathophysiological functions. SphKs are targets for novel anti-cancer and anti-inflammatory agents that can promote cell apoptosis and modulate autoimmune diseases. Herein, we describe the design, synthesis and evaluation of an aminothiazole class of SphK inhibitors. Potent inhibitors have been discovered through a series of modifications using the known SKI-II scaffold to define structure-activity relationships. We identified N-(4-methylthiazol-2-yl)-(2,4'-bithiazol)-2'-amine (24, ST-1803; IC50 values: 7.3 µM (SphK1), 6.5 µM (SphK2)) as a promising candidate for further in vivo investigations and structural development.