Spontaneous Events Research Articles

Recombinant von Willebrand factor prophylaxis in patients with severe von Willebrand disease: phase 3 study results

AbstractInternational guidelines conditionally recommend long-term prophylaxis in patients with von Willebrand disease (VWD) and severe and frequent bleeding. As recombinant von Willebrand factor (rVWF; vonicog alfa) may reduce the frequency of treated spontaneous bleeding events (BEs), we investigated the efficacy and safety of rVWF prophylaxis in adults with severe VWD. Patients with BEs requiring VWF therapy in the past year (on-demand VWF therapy [prior on-demand group] or plasma-derived VWF prophylaxis [pdVWF; switch group]) were enrolled in a prospective, open-label, nonrandomized, phase 3 study. The planned duration of rVWF prophylaxis was 12 months; starting rVWF dose was 50 ± 10 VWF: ristocetin cofactor (VWF:RCo) IU/kg twice weekly (prior on-demand group) or based on prior pdVWF weekly dose/dosing frequency (switch group). The primary endpoint was annualized bleeding rate (ABR) of treated spontaneous BEs (sABR) during rVWF prophylaxis. Over the 12-month study period, treated sABR decreased by 91.5% on-study vs historical sABR in 13 patients in the prior on-demand group, and by 45.0% in 10 patients in the switch group (model-based analysis ratio, 0.085; 95% confidence interval [CI], 0.021-0.346 and 0.550; 95% CI, 0.086-3.523, respectively). No treated spontaneous BEs were recorded in 84.6% (11/13) and 70.0% (7/10) of patients, respectively. The safety profile of rVWF was consistent with the previously established profile, with no new adverse drug reactions identified. Findings suggest that rVWF prophylaxis can reduce treated spontaneous BEs in patients previously receiving on-demand VWF therapy and maintains at least the same level of hemostatic control in patients who switch from prophylaxis with pdVWF to rVWF, with a favorable safety profile. This trial was registered at www.clinicaltrials.gov (#NCT02973087) and www.clinicaltrialsregister.eu (#EudraCT 2016-001478-14).

Proteins Do Not Replicate, They Precipitate: Phase Transition and Loss of Function Toxicity in Amyloid Pathologies.

Simple SummaryAmyloid aggregation of proteins in disease has been known for over a hundred years; however, effective therapeutics for amyloid pathologies such as Alzheimer’s disease and Parkinson’s disease are still lacking. This review divides the amyloid phenomenon into four major questions: What are amyloids? How do amyloids form? Can proteins replicate? How do amyloids cause toxicity? The aim is to answer these questions within a unified physicochemical framework that links the structural biology of amyloids to the thermodynamics of amyloid formation and the pathophysiology of amyloid aggregates in different diseases. We illustrate that the thermodynamics of protein aggregation does not support the prion protein-only replication hypothesis, and how the structural biology of amyloids makes them largely domainless, generic, and inert. The implications of this understanding for the etiology, pathogenesis and potential therapeutics of amyloid diseases are briefly discussed.Protein aggregation into amyloid fibrils affects many proteins in a variety of diseases, including neurodegenerative disorders, diabetes, and cancer. Physicochemically, amyloid formation is a phase transition process, where soluble proteins are transformed into solid fibrils with the characteristic cross-β conformation responsible for their fibrillar morphology. This phase transition proceeds via an initial, rate-limiting nucleation step followed by rapid growth. Several well-defined nucleation pathways exist, including homogenous nucleation (HON), which proceeds spontaneously; heterogeneous nucleation (HEN), which is catalyzed by surfaces; and seeding via preformed nuclei. It has been hypothesized that amyloid aggregation represents a protein-only (nucleic-acid free) replication mechanism that involves transmission of structural information via conformational templating (the prion hypothesis). While the prion hypothesis still lacks mechanistic support, it is also incompatible with the fact that proteins can be induced to form amyloids in the absence of a proteinaceous species acting as a conformational template as in the case of HEN, which can be induced by lipid membranes (including viral envelopes) or polysaccharides. Additionally, while amyloids can be formed from any protein sequence and via different nucleation pathways, they invariably adopt the universal cross-β conformation; suggesting that such conformational change is a spontaneous folding event that is thermodynamically favorable under the conditions of supersaturation and phase transition and not a templated replication process. Finally, as the high stability of amyloids renders them relatively inert, toxicity in some amyloid pathologies might be more dependent on the loss of function from protein sequestration in the amyloid state rather than direct toxicity from the amyloid plaques themselves.

Doxycycline sclerotherapy of cervical spine aneurysmal bone cysts: single-institution 13-year experience

BackgroundAneurysmal bone cysts (ABCs) are benign, locally aggressive neoplasms that typically affect patients during their first two decades of life. Curettage with or without bone grafting or adjuvants is the current standard treatment; however, other surgical and medical treatments, such as sclerotherapy, have been reported. Treatment options for cervical spine ABCs are more limited because the proximity of ABCs to critical structures leads to greater risk of spontaneous or treatment-related adverse events, including death.ObjectiveTo retrospectively review all children and young adults with cervical spine ABCs treated with doxycycline sclerotherapy at one referral center to assess its viability as a standalone treatment.Materials and methodsWe retrospectively reviewed the clinical notes and imaging of 16 patients treated with doxycycline sclerotherapy for pathologically proven cervical spine ABCs at our institution between May 2008 and March 2021. All patients underwent image-guided percutaneous doxycycline sclerotherapy to ablate the ABC and stimulate bone formation. We assessed clinical outcomes through chart review and described post-treatment imaging outcomes using modified Neer scoring.ResultsOf the 16 total children and young adults treated, 2 were lost to follow-up, leaving 14 patients with a median age of 14.5 years. Twelve of these 14 patients were successfully treated with doxycycline sclerotherapy for a success rate of 86%. One patient experienced one treatment-related complication (Society of Interventional Radiology [SIR] adverse event classification D), before ultimately being successfully treated. Doxycycline treatment failed in two patients, who then underwent surgical management. Post-treatment imaging of successfully treated cases had a mean modified Neer score of 1.3, whereas post-treatment imaging in failed cases had a mean score of 3.5.ConclusionDoxycycline sclerotherapy is a viable standalone treatment for cervical spine ABCs because it is safe and effective while avoiding the morbidity associated with open surgical treatments.

Line identification of extreme ultraviolet (EUV) spectra from iron, copper and molybdenum ions in EAST tokamak

Extreme ultraviolet (EUV) spectra emitted from iron and copper ions in a range of 8–500 Å and molybdenum ions in a range of 8–400 Å were measured in Experimental Advanced Superconducting Tokamak (EAST) discharges accompanied with spontaneous sputtering events, by which metallic impurity influxes are suddenly increased in the discharge. Several spectral lines from L-, M-, and N-shell partially ionized ions have been successfully observed with two EUV spectrometers named EUV_Short and EUV_Long working in wavelength ranges of 8–130 Å and 20–500 Å, respectively. The wavelength position is accurately calibrated in-situ based on several well-known spectra of low-Z impurity ions. The line identification is carefully performed based on the National Institute of Standards Technology (NIST) database and previously published experimental data. As a result, it is found that B-, Be-, and Li-like iron and copper spectra Al-, Mg-, and Na-like molybdenum spectra appear in discharges with high central electron temperature (>1.8 keV). The highest ionization stages identified here are Li-like iron and copper and Na-like molybdenum, e.g. Fe XXIV at 192.028 Å (1s22p 2P3/2 → 1s22s 2S1/2), Cu XXVII at 153.513 Å (1s22p 2P3/2 → 1s22s 2S1/2) and Mo XXXII at 127.868 Å (2p63p 2P3/2 → 2p63s 2S1/2). Two unresolved transition arrays of molybdenum ions (Mo-UTAs) appear at wavelength ranges of 15–30 Å and 65–95 Å, and are preliminarily identified as Mo XX-Mo XXXII and Mo XVII-Mo XXXII, respectively. In addition, six spectral lines are newly found by comparing a time evolution of the line intensity from impurity ions in different ionization stages, i.e. Fe XVIII at 17.60 ± 0.02 Å, Cu XXI at 13.15 ± 0.02 Å, Cu XVIII at 260.32 ± 0.07 Å, Cu XVIII at 261.00 ± 0.06 Å, Mo XXVIII at 85.30 ± 0.03 Å and Mo XXIX at 89.59 ± 0.03 Å. The wavelengths of EUV spectra identified in this work are summarized in tables with transitions for each impurity species.

Identification of prophylactic drugs for oxaliplatin-induced peripheral neuropathy using big data

BackgroundDrug repositioning is a cost-effective method to identify novel disease indications for approved drugs; it requires a shorter developmental period than conventional drug discovery methods. We aimed to identify prophylactic drugs for oxaliplatin-induced peripheral neuropathy by drug repositioning using data from large-scale medical information and life science information databases. MethodsHerein, we analyzed the reported data between 2007 and 2017 retrieved from the FDA’s database of spontaneous adverse event reports (FAERS) and the LINCS database provided by the National Institute of Health. The efficacy of the drug candidates for oxaliplatin-induced peripheral neuropathy obtained from the database analysis was examined using a rat model of peripheral neuropathy. Additionally, we compared the incidence of peripheral neuropathy in patients who received oxaliplatin at the Tokushima University Hospital, Japan. The effects of statins on the animal model were examined in six-week-old male Sprague–Dawley rats and seven or eight-week-old male BALB/C mice. Retrospective medical chart review included clinical data from Tokushima University Hospital from April 2009 to March 2018. ResultsSimvastatin, indicated for dyslipidemia, significantly reduced the severity of peripheral neuropathy and oxaliplatin-induced hyperalgesia. In the nerve tissue of model rats, the mRNA expression of Gstm1 increased with statin administration. A retrospective medical chart review using clinical data revealed that the incidence of peripheral neuropathy decreased with statin use. Conclusion and relevanceThus, drug repositioning using data from large-scale basic and clinical databases enables the discovery of new indications for approved drugs with a high probability of success.

Structure-Activity Relationship (SAR) Model for Predicting Teratogenic Risk of Antiseizure Medications in Pregnancy by Using Support Vector Machine.

Teratogenicity is one of the main concerns in clinical medications of pregnant women. Prescription of antiseizure medications (ASMs) in women with epilepsy during pregnancy may cause teratogenic effects on the fetus. Although large scale epilepsy pregnancy registries played an important role in evaluating the teratogenic risk of ASMs, for most ASMs, especially the newly approved ones, the potential teratogenic risk cannot be effectively assessed due to the lack of evidence. In this study, the analyses are performed on any medication, with a focus on ASMs. We curated a list containing the drugs with potential teratogenicity based on the US Food and Drug Administration (FDA)-approved drug labeling, and established a support vector machine (SVM) model for detecting drugs with high teratogenic risk. The model was validated by using the post-marketing surveillance data from US FDA Spontaneous Adverse Events Reporting System (FAERS) and applied to the prediction of potential teratogenic risk of ASMs. Our results showed that our proposed model outperformed the state-of-art approaches, including logistic regression (LR), random forest (RF) and extreme gradient boosting (XGBoost), when detecting the high teratogenic risk of drugs (MCC and recall rate were 0.312 and 0.851, respectively). Among 196 drugs with teratogenic potential reported by FAERS, 136 (69.4%) drugs were correctly predicted. For the eight commonly used ASMs, 4 of them were predicted as high teratogenic risk drugs, including topiramate, phenobarbital, valproate and phenytoin (predicted probabilities of teratogenic risk were 0.69, 0.60 0.59, and 0.56, respectively), which were consistent with the statement in FDA-approved drug labeling and the high reported prevalence of teratogenicity in epilepsy pregnancy registries. In addition, the structural alerts in ASMs that related to the genotoxic carcinogenicity and mutagenicity, idiosyncratic adverse reaction, potential electrophilic agents and endocrine disruption were identified and discussed. Our findings can be a good complementary for the teratogenic risk assessment in drug development and facilitate the determination of pharmacological therapies during pregnancy.

A Standardized Dataset of a Spontaneous Adverse Event Reporting System.

One of the largest spontaneous adverse events reporting databases in the world is the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Unfortunately, researchers face many obstacles in analyzing data from the FAERS database. One of the major obstacles is the unstructured entry of drug names into the FAERS, as reporters might use generic names or trade names with different naming structures from all over the world and, in some cases, with typographical errors. Moreover, report duplication is a known problem in spontaneous adverse event-reporting systems, including the FAERS database. Hence, thorough text processing for database entries, especially drug name entries, coupled with a practical case-deduplication logic, is a prerequisite to analyze the database, which is a time- and resource-consuming procedure. In this study, we provide a clean, deduplicated, and ready-to-import dataset into any relational database management software of the FAERS database up to September 2021. Drug names are standardized to the RxNorm vocabulary and normalized to the single active ingredient level. Moreover, a pre-calculated disproportionate analysis is provided, which includes the reporting odds ratio (ROR), proportional reporting ratio (PRR), Chi-squared analysis with Yates correction (), and information component (IC) for each drug-adverse event pair in the database.

Dual-Channel Electrochemical Measurements Reveal Rapid Adenosine is Localized in Brain Slices.

Rapid adenosine signaling has been detected spontaneously or after mechanical stimulation in the brain, providing rapid neuromodulation in a local area. To measure rapid adenosine signaling, a single carbon-fiber microelectrode has traditionally been used, which limits spatial resolution and an understanding of regional coordination. In this study, we utilized dual-channel fast-scan cyclic voltammetry to measure the spontaneous or mechanically stimulated adenosine release at two electrodes placed at different spacings in hippocampal CA1 mouse brain slices. For mechanically stimulated adenosine release, adenosine can be detected up to 150 μm away from where it was stimulated, although the signal is smaller and delayed. While spontaneous adenosine transients were detected at both electrodes, only 10 percent of the events were detected concurrently, and that number was similar at 50 and 200 μm electrode spacings. Thus, most adenosine transients were not caused by the widespread coordination of release. There was no evidence of diffusion of spontaneous transients to a second electrode 50-200 μm away. This study shows that spontaneous adenosine events are very localized and thus provide only local neuromodulation. Injury, such as mechanical stimulation, allows adenosine to diffuse farther, but the neuroprotective effects are still regional. These results provide a better understanding of the spatial and temporal profiles of adenosine available to act at receptors, which is crucial for future studies that design neuroprotective treatments based on rapid adenosine signaling.

Presynaptic mechanisms underlying GABAB-receptor-mediated inhibition of spontaneous neurotransmitter release.

SUMMARYInhibition of neurotransmitter release by neurotransmitter substances constitutes a fundamental means of neuromodulation. In contrast to well-delineated mechanisms that underlie inhibition of evoked release via suppression of voltage-gated Ca2+ channels, processes that underlie neuromodulatory inhibition of spontaneous release remain unclear. Here, we interrogated inhibition of spontaneous glutamate and GABA release by presynaptic metabotropic GABAB receptors. Our findings show that this inhibition relies on Gβγ subunit action at the membrane, and it is largely independent of presynaptic Ca2+ signaling for both forms of release. In the case of spontaneous glutamate release, inhibition requires Gβγ interaction with the C terminus of the key fusion machinery component SNAP25, and it is modulated by synaptotagmin-1. Inhibition of spontaneous GABA release, on the other hand, is independent of these pathways and likely requires alternative Gβγ targets at the presynaptic terminal.

Current and future perspectives on CAR-T cell therapy for renal cell carcinoma: A comprehensive review.

In the clinical setting of renal cell carcinoma (RCC), immune reactions such as tumor-specific T cell responses can be spontaneous events or can be elicited by checkpoint inhibitors, cytokines, and other immunotherapy modalities. The results from immunotherapy have led to significant advances in treatment methods and patient outcomes. The approval of nivolumab primarily as a second-line monotherapy and the latest approval of novel combination therapies as first-line treatment have established the significance of immunotherapy in the treatment of RCC. In this perspective, chimeric antigen receptor (CAR)-T cell therapy represents a major advance in the developing field of immunotherapy. This treatment modality facilitates T cells to express specific CARs on the cell surface which are reinfused to the patient to treat the analogous tumor cells. After showing treatment potential in hematological malignancies, this new therapeutic approach has become a strong candidate as a therapeutic modality for solid neoplasms. Although CAR-T cell therapy has shown promise and clinical benefit compared to previous T-cell modulated immunotherapies, further studies are warranted to overcome unfavorable physiological settings and hindrances such as the lack of specific molecular targets, depletion of CAR-T cells, a hostile tumor microenvironment, and on/off-tumor toxicities. Several approaches are being considered and research is ongoing to overcome these problems. In this comprehensive review, we provide the rationale and preliminary results of CAR-T cell therapy in RCC and discuss emerging novel strategies and future directions.

Resumption of anticoagulation therapy after spontaneous intracerebral hemorrhage with patients mechanical heart valves.

BackgroundPatients with mechanical heart valves are usually maintained on anticoagulation therapy. However, after a spontaneous intracerebral hemorrhage event, administration of anticoagulants is temporarily ceased, and it remains unclear when to restart anticoagulation therapy.MethodsA cohort study was conducted to investigate the optimal time for restarting anticoagulation in patients with mechanical heart valves after spontaneous intracerebral hemorrhage. All patients with mechanical valves who experienced spontaneous cerebral hemorrhage and were admitted to the Second Affiliated Hospital of the Zhejiang University Medical School between 2013 and 2018 were retrospectively enrolled in this study. The patient electronic medical records were reviewed and the correlation between the time of restarting anticoagulation (within 3 days or more than 3 days after hemorrhage) and patient prognosis was assessed.ResultsA total of 40 patients with mechanical heart valves who experienced spontaneous cerebral hemorrhage were enrolled in this study. All patients were given oral warfarin anticoagulant therapy prior to admission (1.5–3.25 mg). After admission, patients were administered fresh frozen plasma and/or vitamin K1 to reverse anticoagulation. Out of the 16 patients (40%) who underwent surgical intervention, 4 died from cerebral hemorrhage deterioration during the hospital stay and did not restart anticoagulant therapy. Anticoagulant therapy was resumed within 3 days for 18 patients and more than three days after hemorrhage for the other 18 patients. After discharge, patients were followed up for 12 months or more. Unfortunately, during this period, 17% of patients (6/36) died.ConclusionsDefinitive hemostatic measures can be as an important factor in the clinical resumption of anticoagulation. Halting anticoagulant therapy for 3 to 7 days may be safe. It is recommended that low molecular heparin be administered within 3 days as a bridge treatment, combine with warfarin anticoagulant therapy within 1 week after hemorrhage.

Line identification of extreme ultraviolet spectra of Mo V to Mo XVIII in EAST tokamak

The presence of high-<i>Z</i> impurities in magnetically confined fusion devices has different influences on the confinement property of the plasma due to the high cooling rate of high-<i>Z</i> impurities. The first wall of EAST is equipped with molybdenum tiles, molybdenum particles sputtered from inevitable plasma-wall interaction enter into the plasma and become high-<i>Z</i> impurity. In this paper, four fast-time-response extreme ultraviolet (EUV) spectrometers, a system which is upgraded in the EAST 2021 campaign, are used to monitor the line emission from impurity ions in the 5–500 Å wavelength range simultaneously. The in-situ wavelength calibration is carried out accurately using several well-known emission lines of low- and medium-Z impurity ions. The observed spectral lines are carefully identified based on the National Institute of Standards Technology (NIST) database, previously published experimental data and the time evolution of the normalized line intensity of emission lines from impurity ions. At the lower electron temperature (<i>T</i><sub>e0</sub> = 1.5 keV), the EUV spectra emitted from molybdenum ions in the range of 5–485 Å are systematically identified in EAST discharges accompanied with spontaneous sputtering events. As a result, two unresolved transition arrays of molybdenum spectra composed of Mo<sup>19+</sup>-Mo<sup>24+</sup> (Mo XX-Mo XXV) and Mo<sup>16+</sup>-Mo<sup>29+</sup> (Mo XVII-Mo XXX) are observed in the ranges of 15–30 Å and 65–95 Å. In addition, several spectral lines of lower molybdenum ions of Mo<sup>4+</sup>-Mo<sup>17+</sup> (Mo V-Mo XVIII) in the ranges of 27–60 Å and 120–485 Å are observed and identified on EAST for the first time, including a few strong and isolated forbidden and resonant lines, e.g. Mo XII at 329.414 Å, 336.639 Å and 381.125 Å, Mo XIII at 340.909 Å and 352.994 Å, Mo XIV at 373.647 Å and 423.576 Å, Mo XV at 50.448 Å, 57.927 Å and 58.832 Å. Six spectral lines are newly observed in the range of 27–32 Å, i.e. (27.21 ± 0.01) Å, (27.37 ± 0.01) Å, (28.99 ± 0.01) Å, (30.81 ± 0.01) Å, (31.54 ± 0.01) Å and (31.83 ± 0.01) Å, which may be Mo XV-Mo XVIII spectral lines. As a result, twelve strong and isolated spectral lines are chosen in routine observation for impurity transport physical study. The identification of these spectral lines not only enriches the molybdenum atom database, but also provides a solid experimental data base for magnetically confined devices to study the behavior and transport in core and edge plasmas of high-Z impurity.

Voltage-gated calcium channels contribute to spontaneous glutamate release directly via nanodomain coupling or indirectly via calmodulin.

Neurotransmitter release occurs either synchronously with action potentials (evoked release) or spontaneously (spontaneous release). Whether the molecular mechanisms underlying evoked and spontaneous release are identical, especially whether voltage-gated calcium channels (VGCCs) can trigger spontaneous events, is still a matter of debate in glutamatergic synapses. To elucidate this issue, we characterized the VGCC dependence of miniature excitatory postsynaptic currents (mEPSCs) in various synapses with different coupling distances between VGCCs and synaptic vesicles, known as a critical factor in evoked release. We found that most of the extracellular calcium-dependent mEPSCs were attributable to VGCCs in cultured autaptic hippocampal neurons and the mature calyx of Held where VGCCs and vesicles were tightly coupled. Among loosely coupled synapses, mEPSCs were not VGCC-dependent at immature calyx of Held and CA1 pyramidal neuron synapses, whereas VGCCs contribution was significant at CA3 pyramidal neuron synapses. Interestingly, the contribution of VGCCs to spontaneous glutamate release in CA3 pyramidal neurons was abolished by a calmodulin antagonist, calmidazolium. These data suggest that coupling distance between VGCCs and vesicles determines VGCC dependence of spontaneous release at tightly coupled synapses, yet VGCC contribution can be achieved indirectly at loosely coupled synapses.

Community vibrancy and its relationship with safety in Philadelphia.

To what extent can the strength of a local urban community impact neighborhood safety? We construct measures of community vibrancy based on a unique dataset of block party permit approvals from the City of Philadelphia. Our first measure captures the overall volume of block party events in a neighborhood whereas our second measure captures differences in the type (regular versus spontaneous) of block party activities. We use both regression modeling and propensity score matching to control for the economic, demographic and land use characteristics of the surrounding neighborhood when examining the relationship between crime and our two measures of community vibrancy. We conduct our analysis on aggregate levels of crime and community vibrancy from 2006 to 2015 as well as the trends in community vibrancy and crime over this time period. We find that neighborhoods with a higher number of block parties have a significantly higher crime rate, while those holding a greater proportion of spontaneous block party events have a significantly lower crime rate. We also find that neighborhoods which have an increase in the proportion of spontaneous block parties over time are significantly more likely to have a decreasing trend in total crime incidence over that same time period.

Stochastic Properties of Spontaneous Synaptic Transmission at Individual Active Zones

Using postsynaptically tethered calcium sensor GCaMP, we investigated spontaneous synaptic transmission at individual active zones (AZs) at the Drosophila (both sexes) neuromuscular junction. Optical monitoring of GCaMP events coupled with focal electrical recordings of synaptic currents revealed "hot spots" of spontaneous transmission, which corresponded to transient states of elevated activity at selected AZs. The elevated spontaneous activity had two temporal components, one at a timescale of minutes and the other at a subsecond timescale. We developed a three-state model of AZ preparedness for spontaneous transmission and performed Monte Carlo simulations of the release process, which produced an accurate quantitative description of the variability and time course of spontaneous transmission at individual AZs. To investigate the mechanisms of elevated activity, we first focused on the protein complexin, which binds the SNARE protein complex and serves to clamp spontaneous fusion. Overexpression of Drosophila complexin largely abolished the high-activity states of AZs, while complexin deletion drastically promoted it. A mutation in the SNARE protein Syntaxin-1A had an effect similar to complexin deficiency, promoting the high-activity state. We next tested how presynaptic Ca2+ transients affect the states of elevated activity at individual AZs. We either blocked or promoted Ca2+ influx pharmacologically, and also promoted Ca2+ release from internal stores. These experiments coupled with computations revealed that Ca2+ transients can trigger bursts of spontaneous events from individual AZs or AZ clusters at a subsecond timescale. Together, our results demonstrated that spontaneous transmission is highly heterogeneous, with transient hot spots being regulated by the SNARE machinery and Ca2+ SIGNIFICANCE STATEMENT Spontaneous synaptic transmission is a vital component of neuronal communication, since it regulates the neuronal development and plasticity. Our study demonstrated that spontaneous transmission is highly heterogeneous and that nerve terminals create transient "hot spots" of spontaneous release of neuronal transmitters. We show that these hot spots are regulated by the protein machinery mediating the release process and by calcium ions. These results contribute to our understanding of spontaneous synaptic transmission as a dynamic, plastic, and tightly regulated signaling mechanism and unravel fundamental biophysical properties of neuronal communication.

A Framework for Crowd Management during COVID-19 with Artificial Intelligence

COVID-19 requires crowded events to enforce restrictions, aimed to contain the spread of the virus. However, we have seen numerous events not observing these restrictions, thus becoming super spreader events. In order to contain the spread of a human to human communicable disease, a number of restrictions, including wearing face masks, maintaining social distancing, and adhering to regular cleaning and sanitization, are critical. These restrictions are absolutely essential for crowded events. Some crowded events can take place spontaneously, such as a political rally or a protest march or a funeral procession. Controlling spontaneous crowded events, like a protest march, political rally, celebration after a sporting event, or concert, can be quite difficult, especially during a crisis like the COVID-19 pandemic. In this article, we review some well-known crowded events that have taken place during the ongoing pandemic. Guided by our review, we provide a framework using machine learning to effectively organize crowded events during the ongoing and for future crises. We also provide details of metrics for the validation of some components in the proposed framework, and an extensive algorithm. Finally, we offer explanations of its various functions of the algorithm. The proposed framework can also be adapted in other crises.

Chevalier barley: The influence of a world‐leading malting variety

AbstractDuring the 19th century, ‘Chevalier’, said to have been developed from a single plant found in 1820, was the world‐leading malting barley (Hordeum vulgare). The superior malting quality of Chevalier lead to its world‐wide spread at the time of the development of the malting industry. In this study, we investigate how this cultivar was spread and adopted to Nordic seed systems of the time. Single nucleotide polymorphism genotyping of up to 155‐yr‐old museum specimens of historical grains labelled “Chevalier” and of Chevalier accessions preserved in genebanks, in total 282 individuals representing 47 accessions, allowed us to divide the accessions into four categories: True Chevalier, seed mixtures, crosses, and non‐Chevaliers. Comparisons with previously genotyped Nordic landraces showed how, in the 19th century, Chevalier seed was mixed with locally produced landrace seed and cultivated together. We suggest that spontaneous outbreeding events gave rise to hybrids which were subsequently selected and propagated when resulting in superior genetic combinations. Such farmer‐driven breeding activities would have preceded modern plant breeding but resembled the breeding principles that were later used, even though the scientific understanding of inheritance was not yet known.

Calcium Signaling in the Cerebellar Radial Glia and Its Association with Morphological Changes during Zebrafish Development.

Radial glial cells are a distinct non-neuronal cell type that, during development, span the entire width of the brain walls of the ventricular system. They play a central role in the origin and placement of neurons, since their processes form structural scaffolds that guide and facilitate neuronal migration. Furthermore, glutamatergic signaling in the radial glia of the adult cerebellum (i.e., Bergmann glia), is crucial for precise motor coordination. Radial glial cells exhibit spontaneous calcium activity and functional coupling spread calcium waves. However, the origin of calcium activity in relation to the ontogeny of cerebellar radial glia has not been widely explored, and many questions remain unanswered regarding the role of radial glia in brain development in health and disease. In this study we used a combination of whole mount immunofluorescence and calcium imaging in transgenic (gfap-GCaMP6s) zebrafish to determine how development of calcium activity is related to morphological changes of the cerebellum. We found that the morphological changes in cerebellar radial glia are quite dynamic; the cells are remarkably larger and more elaborate in their soma size, process length and numbers after 7 days post fertilization. Spontaneous calcium events were scarce during the first 3 days of development and calcium waves appeared on day 5, which is associated with the onset of more complex morphologies of radial glia. Blockage of gap junction coupling inhibited the propagation of calcium waves, but not basal local calcium activity. This work establishes crucial clues in radial glia organization, morphology and calcium signaling during development and provides insight into its role in complex behavioral paradigms.

Enhanced burning rates in hydrogen-enriched turbulent premixed flames by diffusion of molecular and atomic hydrogen

Direct numerical simulations (DNS) of fuel-lean turbulent premixed hydrogen-enriched flames are analyzed to improve understanding of local effects of molecular diffusion of fast-diffusing, low-Lewis-number hydrogen species (H2 and H) on the overall burning rates of reactant mixtures. Although it is often assumed that the importance of molecular diffusion decreases with increasing turbulence intensity, our analysis reveals that, on the contrary, diffusion of molecular and atomic hydrogen can remain the rate-controlling processes even at high Karlovitz numbers (Ka≫1). Three-dimensional DNS with detailed chemical kinetics and species transport of turbulent premixed hydrogen-air and hydrogen/ammonia-air flames in the regimes of thin and distributed reaction zones are performed and analyzed at different reactant temperatures and pressure levels. The DNS data reveal a significant impact of H2 and H diffusion in all flames analyzed. In particular, the magnitude of H2 diffusion, occurring from low progress variable near the flame elements of the turbulent reaction front that exhibit convex (positive) curvature towards the fresh mixture, is greatly enhanced at high pressure through increased spatial gradients, resulting in localized equivalence-ratio enrichment and super-adiabatic conditions that accelerate and strengthen the flame front. Moreover, for higher reactant temperatures, back diffusion of atomic hydrogen, transported from the reaction zone into unburnt regions from negatively curved reaction layers surrounding them, facilitates the occurrence of localized spontaneous ignition events at the trailing edges of reaction fronts. For certain conditions these events, induced by differential diffusion, can become the dominant process controlling the overall rate of reactants consumption.

14. Postmarketing Safety Experience With MenACWY-TT

BackgroundMenACWY-TT (Nimenrix®), a quadrivalent meningococcal tetanus toxoid conjugate vaccine, was first licensed in 2012 and is available in 82 countries but not in the United States. MenACWY-TT is administered in infants as a 2 + 1 (6 weeks to < 6 months of age) or 1 + 1 (6 to < 12 months of age) schedule with the booster dose at 12 months of age, and from 12 months of age as a single dose. In addition to its widespread use to protect against meningococcal serogroups A, C, W, and Y, MenACWY-TT is a constituent of an investigational pentavalent meningococcal (MenABCWY) vaccine currently undergoing clinical development. MethodsUsing the MenACWY-TT Periodic Safety Update Report (PSUR) with format and content in accordance with Good Pharmacovigilance Practice Module VII and International Council for Harmonisation Guideline E2C, for data up to April 19, 2020, postmarketing safety experience with MenACWY-TT is considered. The PSUR data included herein are spontaneous adverse events (AEs) from the Pfizer safety database. AEs were coded by system organ class (SOC) and preferred term (PT) using MedDRA v.22.1J. ResultsThe cumulative estimated exposure of MenACWY-TT was nearly 26 million doses, with the majority administered in 0- to 16-year-olds and in the Western European Union (Figure 1). Over the reporting period, 13,301 cumulative AEs occurred. The most common SOCs in the reporting period were general disorders and administration site conditions (n=5169; 39%); nervous system disorders (n=1986; 15%); injury, poisoning and procedural complications (n=1266; 10%); and gastrointestinal disorders (n=1031; 8%) (Figure 2). By PT, the most common AEs were pyrexia (n=1613; 12%), headache (n=738; 6%), and vaccination site pain (n=394; 3%) (Figure 3). Of the 3299 serious AEs reported, the most common were pyrexia (n=317; 10%) and headache (n=209; 6%). ConclusionBased on cumulative safety data in conjunction with existing efficacy and effectiveness data, the benefit-risk profile of MenACWY-TT remains favorable and is consistent with the safety profile of MenACWY-TT established in clinical studies. Disclosures Lidia Serra, MS, Pfizer Inc (Employee, Shareholder) Susan Mather, MD, Pfizer Inc (Employee, Shareholder) Cindy Burman, PharmD, Pfizer Inc (Employee, Shareholder) Chris Webber, MD, Pfizer (Employee, Shareholder)