Clean, High-yield Preparation Of S,S- and R,S- Amino Acid Isosteres

The present invention provides compounds and methods that can be used to convert the intermediate halomethyl ketones (HMKs), e.g., chloromethyl ketones, to the corresponding S,S- and R,S-diastereomers. More particularly, the present invention provides: (1) reduction methods; (2) inversion methods; and (3) methods involving the epoxidation of alkenes. Using the various methods of the present invention, the R,S-epoxide and the intermediary compounds can be prepared reliably, in high yields and in high purity

Preparation of 2S,3S-N-Isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide hydrochloride and other derivatives of 2-hydroxy-1,3-diamines

The present invention provides a new process for the preparation of 2S,3S-N-isobutyl-N-(2-hydroxy-3-amino-4phenylbutyl)- p-nitrobenzenesulfonylamide hydrochloride, wherein this compound is prepared directly from the chloromethylalcohol. Importantly, the process of the present invention results in higher yields of 2S,3S-N-isobutyl-N-(2hydroxy -3 -amino -4-phenylbutyl) -pnitrobenzenesulfonylamide hydrochloride without sacrificing its purity. The processes of the present invention can be used to prepare not only the 2S,3S-derivative, but also the 2R,3S-, 2S,2R- and the 2R,3R-derivatives

Preparation of 2S,3S-N-Isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide hydrochloride and other derivatives of 2-hydroxy-1,3-diamines

The present invention provides a new process for the preparation of 2S,3S-N-isobutyl-N-(2-hydroxy-3-amino-4phenylbutyl)- p-nitrobenzenesulfonylamide hydrochloride, wherein this compound is prepared directly from the chloromethylalcohol. Importantly, the process of the present invention results in higher yields of 2S,3S-N-isobutyl-N-(2hydroxy -3 -amino -4-phenylbutyl) -pnitrobenzenesulfonylamide hydrochloride without sacrificing its purity. The processes of the present inventin can be used to prepare not only the 2S,3S-derivative, but also the 2R,3S-, 2S,2R- and the 2R,3R-derivatives

Constraints on dark matter-nucleon effective couplings in the presence of kinematically distinct halo substructures using the DEAP-3600 detector

DEAP-3600 is a single-phase liquid argon detector aiming to directly detect Weakly Interacting Massive Particles (WIMPs), located at SNOLAB (Sudbury, Canada). After analyzing data taken during the first year of operation, a null result was used to place an upper bound on the WIMP-nucleon spin-independent, isoscalar cross section. This study reinterprets this result within a Non-Relativistic Effective Field Theory framework, and further examines how various possible substructures in the local dark matter halo may affect these constraints. Such substructures are hinted at by kinematic structures in the local stellar distribution observed by the Gaia satellite and other recent astronomical surveys. These include the Gaia Sausage (or Enceladus), as well as a number of distinct streams identified in recent studies. Limits are presented for the coupling strength of the effective contact interaction operators $\mathcal{O}_1$, $\mathcal{O}_3$, $\mathcal{O}_5$, $\mathcal{O}_8$, and $\mathcal{O}_{11}$, considering isoscalar, isovector, and xenonphobic scenarios, as well as the specific operators corresponding to millicharge, magnetic dipole, electric dipole, and anapole interactions. The effects of halo substructures on each of these operators are explored as well, showing that the $\mathcal{O}_5$ and $\mathcal{O}_8$ operators are particularly sensitive to the velocity distribution, even at dark matter masses above 100 GeV/$c^2$

The liquid-argon scintillation pulseshape in DEAP-3600

DEAP-3600 is a liquid-argon scintillation detector looking for dark matter. Scintillation events in the liquid argon (LAr) are registered by 255 photomultiplier tubes (PMTs), and pulseshape discrimination (PSD) is used to suppress electromagnetic background events. The excellent PSD performance of LAr makes it a viable target for dark matter searches, and the LAr scintillation pulseshape discussed here is the basis of PSD. The observed pulseshape is a combination of LAr scintillation physics with detector effects. We present a model for the pulseshape of electromagnetic background events in the energy region of interest for dark matter searches. The model is composed of (a) LAr scintillation physics, including the so-called intermediate component, (b) the time response of the TPB wavelength shifter, including delayed TPB emission at O(ms) time-scales, and c) PMT response. TPB is the wavelength shifter of choice in most LAr detectors. We find that approximately 10% of the intensity of the wavelength-shifted light is in a long-lived state of TPB. This causes light from an event to spill into subsequent events to an extent not usually accounted for in the design and data analysis of LAr-based detectors

First direct detection constraints on Planck-scale mass dark matter with multiple-scatter signatures using the DEAP-3600 detector

Dark matter with Planck-scale mass (similar or equal to 10(19) GeV/c(2)) arises in well-motivated theories and could be produced by several cosmological mechanisms. A search for multiscatter signals from supermassive dark matter was performed with a blind analysis of data collected over a 813 d live time with DEAP-3600, a 3.3 t single-phase liquid argon-based detector at SNOLAB. No candidate signals were observed, leading to the first direct detection constraints on Planck-scale mass dark matter. Leading limits constrain dark matter masses between 8.3 x 10(6) and 1.2 x 10(19) GeV/c(2), and Ar-10-scattering cross sections between 1.0 x 10(-23) and 2.4 x 10(-18) cm(2). These results are interpreted as constraints on composite dark matter models with two different nucleon-to-nuclear cross section scalings

Constraints on dark matter-nucleon effective couplings in the presence of kinematically distinct halo substructures using the DEAP-3600 detector

DEAP-3600 is a single-phase liquid argon detector aiming to directly detect weakly interacting massive particles (WIMPs), located at SNOLAB (Sudbury, Canada). After analyzing data taken during the first year of operation, a null result was used to place an upper bound on the WIMP-nucleon, spin-independent, isoscalar cross section. This study reinterprets this result within a nonrelativistic effective field theory framework and further examines how various possible substructures in the local dark matter halo may affect these constraints. Such substructures are hinted at by kinematic structures in the local stellar distribution observed by the Gaia satellite and other recent astronomical surveys. These include the Gaia Sausage (or Enceladus), as well as a number of distinct streams identified in recent studies. Limits are presented for the coupling strength of the effective contact interaction operators O1, O3, O5, O8, and O11, considering isoscalar, isovector, and xenonphobic scenarios, as well as the specific operators corresponding to millicharge, magnetic dipole, electric dipole, and anapole interactions. The effects of halo substructures on each of these operators are explored as well, showing that the O5 and O8 operators are particularly sensitive to the velocity distribution, even at dark matter masses above 100 GeV=c

Pulse-shape discrimination against low-energy Ar-39 beta decays in liquid argon with 4.5 tonne-years of DEAP-3600 data

The DEAP-3600 detector searches for the scintillation signal from dark matter particles scattering on a 3.3 tonne liquid argon target. The largest background comes from 39Ar beta decays and is suppressed using pulse-shape discrimination (PSD). We use two types of PSD estimator: the prompt-fraction, which considers the fraction of the scintillation signal in a narrow and a wide time window around the event peak, and the log-likelihood-ratio, which compares the observed photon arrival times to a signal and a background model. We furthermore use two algorithms to determine the number of photons detected at a given time: (1) simply dividing the charge of each PMT pulse by the mean single-photoelectron charge, and (2) a likelihood analysis that considers the probability to detect a certain number of photons at a given time, based on a model for the scintillation pulse shape and for afterpulsing in the light detectors. The prompt-fraction performs approximately as well as the log-likelihood-ratio PSD algorithm if the photon detection times are not biased by detector effects. We explain this result using a model for the information carried by scintillation photons as a function of the time when they are detected

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification