Chemical ionization tandem mass spectrometer for the in situ measurement of methyl hydrogen peroxide

A new approach for measuring gas-phase methyl hydrogen peroxide [(MHP) CH_3OOH] utilizing chemical ionization mass spectrometry is presented. Tandem mass spectrometry is used to avoid mass interferences that hindered previous attempts to measure atmospheric CH_3OOH with CF_3O− clustering chemistry. CH_3OOH has been successfully measured in situ using this technique during both airborne and ground-based campaigns. The accuracy and precision for the MHP measurement are a function of water vapor mixing ratio. Typical precision at 500 pptv MHP and 100 ppmv H_2O is ±80 pptv (2 sigma) for a 1 s integration period. The accuracy at 100 ppmv H_2O is estimated to be better than ±40%. Chemical ionization tandem mass spectrometry shows considerable promise for the determination of in situ atmospheric trace gas mixing ratios where isobaric compounds or mass interferences impede accurate measurements

A Cambrian fossil from the Chengjiang fauna sharing characteristics with gilled lobopodians, opabiniids and radiodonts

Parvibellus atavus gen. et sp. nov. from the Early Cambrian Chengjiang fauna of China is a small fossil having a distinct cephalic region bearing a pair of lateral projections and a circular, ventral mouth. The trunk bears eleven pairs of probably flap-like appendages and a short pair of terminal projections. This character combination is unique for the Chengjiang biota. A circular ventral mouth is seen in Radiodonta and in some of the gilled lobopodians which are thought to be among the radiodont’s closest relatives. P. atavus, gilled lobopodians, opabiniids, and radiodonts also share the putative character of flap-like appendages along the trunk. However, the new fossil differs from radiodonts and gilled lobopodians by the absence of enlarged and/or raptorial frontal appendages. It also differs from gilled lobopodians by lacking in ventral lobopod limbs and from radiodonts by lacking in stalked eyes. It provisionally resolves as a sister-group to a clade containing the gilled lobopodians, opabiniids, and radiodonts, and could potentially be part of an early radiation of the nektonic lower stem—Euarthropoda

Inhomogeneous accretion discs and the soft states of black hole X-ray binaries

Observations of black hole binaries (BHBs) have established a rich phenomenology of X-ray states. The soft states range from the low variability, accretion disc dominated thermal state (TD) to the higher variability, non-thermal steep power law state (SPL). The disc component in all states is typically modeled with standard thin disc accretion theory. However, this theory is inconsistent with optical/UV spectral, variability, and gravitational microlensing observations of active galactic nuclei (AGNs), the supermassive analogs of BHBs. An inhomogeneous disc (ID) model with large (~0.4 dex) temperature fluctuations in each radial annulus can qualitatively explain all of these AGN observations. The inhomogeneity may be a consequence of instabilities in radiation dominated discs, and therefore may be present in BHBs as well. We show that ID models can explain many features of the TD and SPL states of BHBs. The observed relationships between spectral hardness, disc fraction, and rms variability amplitude in BHBs are reproduced with temperature fluctuations similar to those inferred in AGNs, suggesting a unified picture of luminous accretion discs across orders of magnitude in black hole mass. This picture can be tested with spectral fitting of ID models, X-ray polarization observations, and radiation MHD simulations. If BHB accretion discs are indeed inhomogeneous, only the most disc dominated states (disc fraction > 0.95) can be used to robustly infer black hole spin using current continuum fitting methods.Comment: 5 pages, 3 figures, submitted to MNRAS Letter

Return to drug use and overdose after release from prison: a qualitative study of risk and protective factors

BACKGROUND: Former inmates are at high risk for death from drug overdose, especially in the immediate post-release period. The purpose of the study is to understand the drug use experiences, perceptions of overdose risk, and experiences with overdose among former prisoners. METHODS: This qualitative study included former prison inmates (N = 29) who were recruited within two months after their release. Interviewers conducted in-person, semi-structured interviews which explored participants' experiences and perceptions. Transcripts were analyzed utilizing a team-based method of inductive analysis. RESULTS: The following themes emerged: 1) Relapse to drugs and alcohol occurred in a context of poor social support, medical co-morbidity and inadequate economic resources; 2) former inmates experienced ubiquitous exposure to drugs in their living environments; 3) intentional overdose was considered "a way out" given situational stressors, and accidental overdose was perceived as related to decreased tolerance; and 4) protective factors included structured drug treatment programs, spirituality/religion, community-based resources (including self-help groups), and family. CONCLUSIONS: Former inmates return to environments that strongly trigger relapse to drug use and put them at risk for overdose. Interventions to prevent overdose after release from prison may benefit from including structured treatment with gradual transition to the community, enhanced protective factors, and reductions of environmental triggers to use drugs

Psychological and Genetic Predictors of Pain Tolerance

Previous studies have shown associations between genetic polymorphisms and pain tolerance, but psychological evaluations are seldom measured. The objective of this study was to determine the independent effects of demographic, psychological, and genetic predictors of cold noxious pain tolerance. Healthy subjects (n = 89) completed the Pain Catastrophizing Scale (PCS) and Fear of Pain Questionnaire (FPQ-III), underwent genotyping for candidate single nucleotide polymorphisms (SNPs), and completed a cold-pressor test in a 1-2 degrees C water bath for a maximum of 3 minutes. The primary outcome measure was pain tolerance, defined as the maximum duration of time subjects left their nondominant hand in the cold-water bath. Cox proportional hazards regression indicated that female sex, Asian race, and increasing PCS and FPQ-III scores were associated with lower pain tolerance. No candidate SNP was significantly associated with pain tolerance. Future genetic studies should include demographic and psychological variables as confounders in experimental pain models.Open access journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Proteomic changes in serum of first onset, antidepressant drug-naïve major depression patients

Major depressive disorder (MDD) is a complex and multi-factorial disorder. Although genetic factors and other molecular aspects of MDD have been widely studied, the underlying pathological mechanisms are still mostly unknown. We sought to investigate the pathophysiology of MDD by identifying and characterising serum molecular differences and their correlation to symptom severity in first onset, antidepressant drug-naïve MDD patients. We performed an exploratory molecular profiling study on serum samples of MDD patients and controls using multiplex immunoassay and label-free liquid chromatography mass spectrometry in data independent mode (LC-MSE). We included two independent cohorts of first onset, antidepressant drug-naïve MDD patients (n = 23 and 15) and matched controls (n = 42 and 21) in our study in order to validate the results. The main outcome included the following list of circulatory molecules changing and/or correlating to symptom severity: angiotensin-converting enzyme, acute phase proteins (e.g. ferritin and serotransferrin), brain-derived neurotrophic factor, complement component C4-B, cortisol, cytokines (e.g. macrophage migration inhibitory factor and interleukin-16), extracellular newly identified receptor for advanced glycosylation end products-binding protein, growth hormone and superoxide dismutase-1. This study provides evidence of an increased pro-inflammatory and oxidative stress response, followed by a hyperactivation of the HPA-axis in the acute stages of first onset MDD, as well as a dysregulation in growth factor pathways. These findings help to elucidate MDD related pathways in more detail and further studies may lead to identification of novel drug targets, inc

Highly fluorinated naphthalenes and bifurcated C–H⋯F–C hydrogen bonding

The synthesis and crystal structures of 1,2,4,5,6,8-hexafluoronaphthalene and 1,2,4,6,8-pentafluoronaphthalene are reported. Intermolecular interactions are dominated by offset stacking and by C–H⋯F–C hydrogen bonds. For hexafluoronaphthalene, molecules are linked in layers with (4,4) network topology via R12(6) C–H⋯(F–C)2 supramolecular synthons that are rationalised by consideration of the calculated electrostatic potential of the molecule. Such an arrangement is prevented by the additional hydrogen atom in pentafluoronaphthalene and molecules instead form tapes via an R12(8) (C–H⋯F)2 synthon. The geometric characteristics of C–H⋯(F–C)2 bifurcated hydrogen bonds have been analysed for crystal structures in the Cambridge Structural Database (6416 crystal structures; 9534 C–H⋯(F–C)2 bifurcated hydrogen bonds). A geometric analysis of these hydrogen bonds has enabled the extent of asymmetry of these hydrogen bonds to be assessed and indicates a preference for symmetrically bifurcated interactions

Safety and Activity of Lenalidomide in Combination With Obinutuzumab in Patients With Relapsed Indolent Non-Hodgkin Lymphoma: A Single Group, Open-Label, Phase 1/2 Trial

BACKGROUND: Rituximab and lenalidomide is a preferred option for relapsed indolent B cell non-Hodgkin lymphoma. Obinutuzumab may be a superior combination partner with lenalidomide given enhanced antibody dependent cellular cytotoxicity and phagocytosis compared to rituximab. Our aim was to determine the recommended phase 2 dose, safety, and activity of lenalidomide in combination with fixed dose of obinutuzumab in relapsed and refractory indolent B cell non-Hodgkin lymphoma. METHODS: In this single-arm, open-label, phase 1/2 trial, we enrolled patients with relapsed or refractory WHO Grade 1-3A follicular lymphoma, marginal zone lymphoma and small lymphocytic lymphoma and adequate performance status (ECOG 0-2) at the MD Anderson Cancer Center. We excluded patients with evidence of ongoing transformation to aggressive lymphoma. During phase 1, 1000 mg intravenous obinutuzumab was administered with three predefined levels of oral lenalidomide in a 3 + 3 dose escalation design to establish lenalidomide 20 mg as the recommended phase 2 dose. During phase 2, patients received induction therapy with six 28-day cycles of lenalidomide 20 mg with intravenous obinutuzumab 1000 mg. In accordance with our prior experience with lenalidomide plus rituximab, patients who were responding to the combination could receive up to 6 additional cycles (up to 12 cycles in total) of combination therapy. Dosing of obinutuzumab was continued in all responding patients after cycle 6 every 2 months for a total of 30 months from the start of therapy. The decision of number of cycles of combination therapy beyond 6 was at discretion of the investigator and was included to allow individualisation of therapy to maximise response while minimising exposure. The co-primary objectives were to evaluate the safety and overall response, defined as the proportion of patients who achieved a complete or partial response in relapsed and refractory indolent non-Hodgkin lymphoma at the end of induction therapy, according to Cheson and colleagues (2007 criteria). The secondary endpoints were complete response after induction therapy and time to event endpoints including time to progression, progression free survival, and overall survival. Analyses were intent to treat in the efficacy cohort and per-treated in the safety population in all patients who received at least one dose of either investigational agent. This trial is registered with ClinicalTrials.gov, NCT01995669. FINDINGS: Between June 03, 2014, and 07 March 2019, we completed planned enrolment, and 66 patients started therapy including 9 patients in phase 1 and 57 patients in phase 2. All patients were evaluated for safety and the 60 patients treated at the recommended phase 2 dose of lenalidomide 20 mg were evaluable for activity. Grade 3-4 haematological toxicities included neutropenia 21% (14/66) and thrombocytopenia 11% (7/66) with no cases of febrile neutropenia. Grade 3-4 non-haematological toxicities included lung infection 8% (5/66), fatigue 8% (5/66) and rash 6% (4/66). By Cheson 2007 criteria, 90% (54/60, 95% CI: 79-96) achieved an overall response at the end of induction meeting the prespecified activity endpoint. Complete responses were seen in 33% (20/60, 95% CI: 22-47) at the end of induction. Median progression free survival, time to progression and overall survival have not been reached after median follow-up of 41.7 months. Estimated 4-year progression free survival rates were 55% (95% CI: 42-73), time to progression of 56% (95% CI: 43-74) and overall survival of 84% (95% CI: 74-95). INTERPRETATION: Our findings suggest that oral lenalidomide with obinutuzumab is safe and highly active in patients with relapsed and refractory indolent B cell non-Hodgkin lymphoma and is associated with prolonged remission duration. The study is limited by the lack of a control arm leading to cross-trial comparisons to evaluate activity. Future randomised trials comparing this regime to rituximab and lenalidomide are warranted. FUNDING: Genentech and an MD Anderson Core grant

Spin-locking in low-frequency reaction yield detected magnetic resonance

The purported effects of weak magnetic fields on various biological systems from animal magnetoreception to human health have generated widespread interest and sparked much controversy in the past decade. To date the only well established mechanism by which the rates and yields of chemical reactions are known to be influenced by magnetic fields is the radical pair mechanism, based on the spin-dependent reactivity of radical pairs. A diagnostic test for the operation of the radical pair mechanism was proposed by Henbest et al. [J. Am. Chem. Soc., 2004, 126, 8102] based on the combined effects of weak static magnetic fields and radiofrequency oscillating fields in a reaction yield detected magnetic resonance experiment. Here we investigate the effects on radical pair reactions of applying relatively strong oscillating fields, both parallel and perpendicular to the static field. We demonstrate the importance of understanding the effect of the strength of the radiofrequency oscillating field; our experiments demonstrate that there is an optimal oscillating field strength above which the observed signal decreases in intensity and eventually inverts. We establish the correlation between the onset of this effect and the hyperfine structure of the radicals involved, and identify the existence of ‘overtone’ type features appearing at multiples of the expected resonance field positio

Effect of Delayed Cell Infusion in Patients With Large B-Cell Lymphoma Treated With Chimeric Antigen Receptor T-Cell Therapy

Complications occurring after lymphodepleting chemotherapy (LDC) may delay chimeric antigen receptor (CAR) T-cell infusion. The effect of these delays on clinical outcomes is unclear. We performed a retrospective analysis of 240 patients with relapsed/refractory large B-cell lymphoma treated with standard-of-care axicabtagene ciloleucel (axi-cel) and identified 40 patients (16.7%) who had delay in axi-cel infusion. Of these, 85% had delay due to infection. At time of LDC initiation, patients with delayed infusion had lower absolute neutrophil count (P=0.006), lower platelets (P=0.004), lower hemoglobin (P5 days (4.6 vs. 8.2 months; P=0.036), but not 1 day (5.7 vs. 8.2 months; P=0.238). Following propensity score matching, patients with delayed infusion continued to have shorter median PFS (3.5 vs. 6.0 months; P=0.015). Levels of pro-inflammatory cytokines on day of infusion were significantly higher in patients with delayed infusion. Together, these findings suggest that delays in CAR T-cell administration after initiation of LDC are associated with inferior outcomes. Further studies are needed to guide strategies to improve efficacy in such patients