A fast radio burst localized at detection to a galactic disk using very long baseline interferometry

Fast radio bursts (FRBs) are millisecond-duration, luminous radio transients of extragalactic origin. These events have been used to trace the baryonic structure of the Universe using their dispersion measure (DM) assuming that the contribution from host galaxies can be reliably estimated. However, contributions from the immediate environment of an FRB may dominate the observed DM, thus making redshift estimates challenging without a robust host galaxy association. Furthermore, while at least one Galactic burst has been associated with a magnetar, other localized FRBs argue against magnetars as the sole progenitor model. Precise localization within the host galaxy can discriminate between progenitor models, a major goal of the field. Until now, localizations on this spatial scale have only been carried out in follow-up observations of repeating sources. Here we demonstrate the localization of FRB 20210603A with very long baseline interferometry (VLBI) on two baselines, using data collected only at the time of detection. We localize the burst to SDSS J004105.82+211331.9, an edge-on galaxy at $z\approx 0.177$, and detect recent star formation in the kiloparsec-scale vicinity of the burst. The edge-on inclination of the host galaxy allows for a unique comparison between the line of sight towards the FRB and lines of sight towards known Galactic pulsars. The DM, Faraday rotation measure (RM), and scattering suggest a progenitor coincident with the host galactic plane, strengthening the link between the environment of FRB 20210603A and the disk of its host galaxy. Single-pulse VLBI localizations of FRBs to within their host galaxies, following the one presented here, will further constrain the origins and host environments of one-off FRBs.Comment: 40 pages, 13 figures, submitted. Fixed typo in abstrac

CHIME/FRB Discovery of 25 Repeating Fast Radio Burst Sources

We present the discovery of 25 new repeating fast radio burst (FRB) sources found among CHIME/FRB events detected between 2019 September 30 and 2021 May 1. The sources were found using a new clustering algorithm that looks for multiple events co-located on the sky having similar dispersion measures (DMs). The new repeaters have DMs ranging from $\sim$220 pc cm$^{-3}$ to $\sim$1700 pc cm$^{-3}$, and include sources having exhibited as few as two bursts to as many as twelve. We report a statistically significant difference in both the DM and extragalactic DM (eDM) distributions between repeating and apparently nonrepeating sources, with repeaters having lower mean DM and eDM, and we discuss the implications. We find no clear bimodality between the repetition rates of repeaters and upper limits on repetition from apparently nonrepeating sources after correcting for sensitivity and exposure effects, although some active repeating sources stand out as anomalous. We measure the repeater fraction and find that it tends to an equilibrium of $2.6_{-2.6}^{+2.9}$% over our exposure thus far. We also report on 14 more sources which are promising repeating FRB candidates and which merit follow-up observations for confirmation.Comment: Submitted to ApJ. Comments are welcome and follow-up observations are encouraged

Sub-second periodicity in a fast radio burst

Fast radio bursts (FRBs) are millisecond-duration flashes of radio waves that are visible at distances of billions of light-years. The nature of their progenitors and their emission mechanism remain open astrophysical questions. Here we report the detection of the multi-component FRB 20191221A and the identification of a periodic separation of 216.8(1) ms between its components with a significance of 6.5 sigmas. The long (~3 s) duration and nine or more components forming the pulse profile make this source an outlier in the FRB population. Such short periodicity provides strong evidence for a neutron-star origin of the event. Moreover, our detection favours emission arising from the neutron-star magnetosphere, as opposed to emission regions located further away from the star, as predicted by some models.Comment: Updated to conform to the accepted versio

Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy

Purpose: Evaluate response of mismatch repair deficient (dMMR) rectal cancer to neoadjuvant chemotherapy. Experimental Design: dMMR rectal tumors at Memorial Sloan Kettering were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty dMMR rectal cancer patients were identified by immunohistochemistry and/or microsatellite instability analysis, with initial treatment response compared to a matched pMMR rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity. Results: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), 6 (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable to 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome (LS) with enrichment of germline MSH2 and MSH6 mutations when compared to 193 LS-associated colon cancer patients (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P < .003). Conclusions: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for LS in dMMR rectal cancer patients

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

A DISCOURSE ANALYSIS OF POWER AND AGENCY: SINGAPORE’S CHANGING GOVERNMENT-CITIZEN DYNAMIC

Bachelor'sBachelor of Arts (Honours

Impact of Latent State Cues on Behavior in Repeated Games

In social interactions, inferring the interaction partner’s hidden mental state is crucial for predicting their actions and optimiz- ing our responses. Effective models for this inference must account for how these mental states evolve due to the interac- tion history and environmental changes. For example, recog- nizing someone’s emotional state can help forecast their be- havior. Our study investigates how making these latent states visible influences decision-making in social interactions. Us- ing the repeated trust game paradigm, we show how to use hid- den Markov models (HMM) to formally represent latent state dependent strategies of the players. HMMs fitted to human dyadic play in the trust game are then used to specify adap- tive AI agents that simulate changes in mental dispositions of human players, such as the level of trust in the opponent, dur- ing a repeated interaction. Making these artificial HMM based agents take the role of the investor and interact with real hu- man trustees, we then explore how displaying “emotion” cues to the opponent’s latent state affects people’s actions. We find that the presence of cues was associated with more cooperative behavior from the human trustees, and that patterns of behav- ior that promote the maintenance of cooperation emerged in the presence of latent state cues and were transferred to set- tings where the cues were subsequently hidden

The Phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome

Mohr-Tranebjaerg syndrome (MTS) is an X-linked recessive disorder characterized by deafness and dystonia. However the phenotypic expression of dystonia has not been systematically defined. We report clinical, neurophysiological, and ophthalmological data on 6 subjects from 3 Australian kindreds, including 2 with novel mutations, together with a systematic review of the literature, in order to define the phenotypic expression of dystonia. Profound hearing impairment in affected males develops by infancy and precedes the development of dystonia, which varies in time of onset from the first to the sixth decades, with a peak in the second and third decades. Dystonia in MTS tends to be focal, segmental, or multifocal in distribution at onset, with a predilection for the upper body, variably involving the head, neck, and upper limbs. The majority of patients have progression or generalization of their dystonia regardless of age of onset. Within our 3 kindreds, we observed relative intrafamilial homogeneity but interfamilial variation. The median time to the development of moderate-severely disabling dystonia in these subjects was 11 years. Associated features included progressive cognitive decline, pyramidal signs, and in 1 patient, gait freezing and postural instability. Optic atrophy and cortical visual impairment were both observed. We report for the first time a female patient who developed multiple disabling neurological complications of MTS. Our findings more clearly define and expand the phenotype of both the dystonia and other neurological features of MTS and have implications for the diagnosis and management of this condition.7 page(s

Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons

Summary: Parkinson’s disease (PD) is characterized by a progressive deterioration of motor and cognitive functions. Although death of dopamine neurons is the hallmark pathology of PD, this is a late-stage disease process preceded by neuronal dysfunction. Here we describe early physiological perturbations in patient-derived induced pluripotent stem cell (iPSC)-dopamine neurons carrying the GBA-N370S mutation, a strong genetic risk factor for PD. GBA-N370S iPSC-dopamine neurons show an early and persistent calcium dysregulation notably at the mitochondria, followed by reduced mitochondrial membrane potential and oxygen consumption rate, indicating mitochondrial failure. With increased neuronal maturity, we observed decreased synaptic function in PD iPSC-dopamine neurons, consistent with the requirement for ATP and calcium to support the increase in electrophysiological activity over time. Our work demonstrates that calcium dyshomeostasis and mitochondrial failure impair the higher electrophysiological activity of mature neurons and may underlie the vulnerability of dopamine neurons in PD