The mechanism of memory remains one of the great unsolved problems of biology. Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of ...the engram, lasting connections in the brain that result from simultaneous "excitations", whose precise physical nature and consequences were out of reach of the biology of his day. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today.
Polymer thin films that emit and absorb circularly polarised light have been demonstrated with the promise of achieving important technological advances; from efficient, high-performance displays, to ...3D imaging and all-organic spintronic devices. However, the origin of the large chiroptical effects in such films has, until now, remained elusive. We investigate the emergence of such phenomena in achiral polymers blended with a chiral small-molecule additive (1-aza6helicene) and intrinsically chiral-sidechain polymers using a combination of spectroscopic methods and structural probes. We show that - under conditions relevant for device fabrication - the large chiroptical effects are caused by magneto-electric coupling (natural optical activity), not structural chirality as previously assumed, and may occur because of local order in a cylinder blue phase-type organisation. This disruptive mechanistic insight into chiral polymer thin films will offer new approaches towards chiroptical materials development after almost three decades of research in this area.
Conspectus Density functional theory (DFT) calculations are used in over 40,000 scientific papers each year, in chemistry, materials science, and far beyond. DFT is extremely useful because it is ...computationally much less expensive than ab initio electronic structure methods and allows systems of considerably larger size to be treated. However, the accuracy of any Kohn–Sham DFT calculation is limited by the approximation chosen for the exchange-correlation (XC) energy. For more than half a century, humans have developed the art of such approximations, using general principles, empirical data, or a combination of both, typically yielding useful results, but with errors well above the chemical accuracy limit (1 kcal/mol). Over the last 15 years, machine learning (ML) has made major breakthroughs in many applications and is now being applied to electronic structure calculations. This recent rise of ML begs the question: Can ML propose or improve density functional approximations? Success could greatly enhance the accuracy and usefulness of DFT calculations without increasing the cost. In this work, we detail efforts in this direction, beginning with an elementary proof of principle from 2012, namely, finding the kinetic energy of several Fermions in a box using kernel ridge regression. This is an example of orbital-free DFT, for which a successful general-purpose scheme could make even DFT calculations run much faster. We trace the development of that work to state-of-the-art molecular dynamics simulations of resorcinol with chemical accuracy. By training on ab initio examples, one bypasses the need to find the XC functional explicitly. We also discuss how the exchange-correlation energy itself can be modeled with such methods, especially for strongly correlated materials. Finally, we show how deep neural networks with differentiable programming can be used to construct accurate density functionals from very few data points by using the Kohn–Sham equations themselves as a regularizer. All these cases show that ML can create approximations of greater accuracy than humans, and is capable of finding approximations that can deal with difficult cases such as strong correlation. However, such ML-designed functionals have not been implemented in standard codes because of one last great challenge: generalization. We discuss how effortlessly human-designed functionals can be applied to a wide range of situations, and how difficult that is for ML.
This is the second paper of a series in which we present new measurements of the observed rates of supernovae (SNe) in the local Universe, determined from the Lick Observatory Supernova Search ...(LOSS). In this paper, a complete SN sample is constructed, and the observed (uncorrected for host-galaxy extinction) luminosity functions (LFs) of SNe are derived. These LFs solve two issues that have plagued previous rate calculations for nearby SNe: the luminosity distribution of SNe and the host-galaxy extinction. We select a volume-limited sample of 175 SNe, collect photometry for every object and fit a family of light curves to constrain the peak magnitudes and light-curve shapes. The volume-limited LFs show that they are not well represented by a Gaussian distribution. There are notable differences in the LFs for galaxies of different Hubble types (especially for SNe Ia). We derive the observed fractions for the different subclasses in a complete SN sample, and find significant fractions of SNe II-L (10 per cent), IIb (12 per cent) and IIn (9 per cent) in the SN II sample. Furthermore, we derive the LFs and the observed fractions of different SN subclasses in a magnitude-limited survey with different observation intervals, and find that the LFs are enhanced at the high-luminosity end and appear more 'standard' with smaller scatter, and that the LFs and fractions of SNe do not change significantly when the observation interval is shorter than 10 d. We also discuss the LFs in different galaxy sizes and inclinations, and for different SN subclasses. Some notable results are that there is not a strong correlation between the SN LFs and the host-galaxy size, but there might be a preference for SNe IIn to occur in small, late-type spiral galaxies. The LFs in different inclination bins do not provide strong evidence for extreme extinction in highly inclined galaxies, though the sample is still small. The LFs of different SN subclasses show significant differences. We also find that SNe Ibc and IIb come from more luminous galaxies than SNe II-P, while SNe IIn come from less luminous galaxies, suggesting a possible metallicity effect. The limitations and applications of our LFs are also discussed.
The Berkeley sample of stripped-envelope supernovae Shivvers, Isaac; Filippenko, Alexei V; Silverman, Jeffrey M ...
Monthly notices of the Royal Astronomical Society,
01/2019, Letnik:
482, Številka:
2
Journal Article
Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision ...to vaccinate youth.
We retrospectively collected data on patients <21 years old presenting before July 4, 2021, with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions.
We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1-20.3; interquartile range IQR, 14.5-17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0-22; IQR, 1-3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0-10; IQR, 2-3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50-15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25-1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction <55% on echocardiogram. Of 97 patients who underwent cardiac MRI at a median 5 days (range, 0-88; IQR, 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25).
Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.
MicroRNAs (miRNAs) perform critical functions in normal physiology and disease by associating with Argonaute proteins and downregulating partially complementary messenger RNAs (mRNAs). Here we use ...clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) genome-wide loss-of-function screening coupled with a fluorescent reporter of miRNA activity in human cells to identify new regulators of the miRNA pathway. By using iterative rounds of screening, we reveal a novel mechanism whereby target engagement by Argonaute 2 (AGO2) triggers its hierarchical, multi-site phosphorylation by CSNK1A1 on a set of highly conserved residues (S824-S834), followed by rapid dephosphorylation by the ANKRD52-PPP6C phosphatase complex. Although genetic and biochemical studies demonstrate that AGO2 phosphorylation on these residues inhibits target mRNA binding, inactivation of this phosphorylation cycle globally impairs miRNA-mediated silencing. Analysis of the transcriptome-wide binding profile of non-phosphorylatable AGO2 reveals a pronounced expansion of the target repertoire bound at steady-state, effectively reducing the active pool of AGO2 on a per-target basis. These findings support a model in which an AGO2 phosphorylation cycle stimulated by target engagement regulates miRNA:target interactions to maintain the global efficiency of miRNA-mediated silencing.
To identify therapeutic targets for glioblastoma (GBM), we performed genome-wide CRISPR-Cas9 knockout (KO) screens in patient-derived GBM stem-like cells (GSCs) and human neural stem/progenitors ...(NSCs), non-neoplastic stem cell controls, for genes required for their in vitro growth. Surprisingly, the vast majority GSC-lethal hits were found outside of molecular networks commonly altered in GBM and GSCs (e.g., oncogenic drivers). In vitro and in vivo validation of GSC-specific targets revealed several strong hits, including the wee1-like kinase, PKMYT1/Myt1. Mechanistic studies demonstrated that PKMYT1 acts redundantly with WEE1 to inhibit cyclin B-CDK1 activity via CDK1-Y15 phosphorylation and to promote timely completion of mitosis in NSCs. However, in GSCs, this redundancy is lost, most likely as a result of oncogenic signaling, causing GBM-specific lethality.
Display omitted
•CRISPR-Cas9 lethality screens performed in patient brain-tumor stem-like cells•PKMYT1 is identified in GSCs, but not NSCs, as essential for facilitating mitosis•PKMYT1 and WEE1 act redundantly in NSCs, where their inhibition is synthetic lethal•PKMYT1 and WEE1 redundancy can be broken by over-activation of EGFR and AKT
Patient-derived glioblastoma stem-like cells (GSCs) can be grown in conditions that preserve patient tumor signatures and their tumor initiating capacity. Toledo et al. use these conditions to perform genome-wide CRISPR-Cas9 lethality screens in both GSCs and non-transformed NSCs, revealing PKMYT1 as a candidate GSC-lethal gene.
Purpose
Symptomatic adverse events (AEs) are monitored by clinicians as part of all US-based clinical trials in cancer via the U.S. National Cancer Institute’s Common Terminology Criteria for Adverse ...Events (CTCAE) for the purposes of ensuring patient safety. Recently, there has been a charge toward capturing the patient perspective for those AEs amenable to patient self-reporting via patient-reported outcomes (PRO). The aim of this review was to summarize the empirically reported association between analogous CTCAE and PRO ratings.
Methods
A systematic literature search was conducted using PubMed, EMBASE, Web of Science, and Cochrane databases through July 2015. From a total of 5658 articles retrieved, 28 studies met the inclusion criteria.
Results
Across studies, patients were of mixed cancer types, including anal, breast, cervical, chronic myeloid leukemia, endometrial, hematological, lung, ovarian, pelvic, pharyngeal, prostate, and rectal. Given this mixture, the AEs captured were variable, with many common across studies (e.g., dyspnea, fatigue, nausea, neuropathy, pain, vomiting), as well as several that were disease-specific (e.g., erectile dysfunction, hemoptysis). Overall, the quantified association between CTCAE and PRO ratings fell in the fair to moderate range and had a large variation across the majority of studies (
n
= 21).
Conclusions
The range of measures used and symptoms captured varied greatly across the reviewed studies. Regardless of concordance metric employed, reported agreement between CTCAE and PRO ratings was moderate at best. To assist with reconciliation and interpretation of these differences toward ultimately improving patient care, an important next step is to explore approaches to integrate PROs with clinician reporting of AEs.
Metal-organic frameworks have received much attention in recent years especially as newly developed porous materials. As such, they possess a wide array of potential applications including materials ...for gas storage, gas/vapor separation, catalysis, luminescence, and drug delivery. In the review, these potential applications of metal-organic frameworks are examined and an outlook will be proposed.
PDF
