Major depressive disorder continues to challenge medical and psychological resources worldwide. A marked surge has occurred recently in China in neuroimaging studies of major depressive disorder. ...Those studies represent an emerging trend in neuropsychiatry in that such research has previously been extremely rare in China. The present article provides a systematic review of reports published in English by research institutes in China on resting-state functional connectivity studied by MRI in depressed subjects and healthy control subjects. Particular attention is given to whether the information may advance effective diagnosis and treatment options for patients with major depressive disorder.
Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis ...of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin-insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal α-chain (αCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The αCT segment displaces the B-chain C-terminal β-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone-insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.
Abstract
Background
Research consistently finds that, on average, firefighters gain weight over time and some data indicate that younger firefighters are more likely to gain weight than older ...firefighters. The purpose of this study was to estimate the 5-year weight change among younger and older US firefighters.
Methods
Data from two occupational medical exams separated by 5 years (2009–2016) were examined from a cohort of US career firefighters in Virginia (males,
n
= 589; females,
n
= 67). The cohort was grouped into two age categories (< 45 years and ≥ 45 years). Weight change subgroups were Loss (decrease of > 3% body weight), Stable (within ±3% body weight) and Gain (increase of > 3% body weight). Multinomial logistic regression models and linear regression models were conducted to examine differences in the probability of being in a particular weight change category, weight change overall and by weight change category between younger and older firefighters.
Results
At baseline, 25 and 35% of younger (< 45 years) and older (≥ 45 years) were obese, respectively. Younger firefighters gained significantly (
P
< 0.05) more weight (3.0 ± 0.2 kg) than older firefighters (0.8 ± 0.5 kg). Younger firefighters were more likely to gain weight (53% versus 39%) and less likely (10% versus 20%) to lose weight as compared to older firefighters. Smaller weight gains were associated with age and BMI with the smallest increases observed in overweight and obese firefighters ≥45 years of age.
Conclusions
Health care providers should be attentive to weight gain, even among young non-obese firefighters, and counsel firefighters to avoid the additive risks of being older and heavier. In addition, weight loss/management programs should be promoted in the fire service to encourage healthy body weight and to prevent unhealthy weight gain among both young and old firefighters alike.
A recently developed extrography separation method fractionates petroleum asphaltenes based on their ionization efficiency, which correlates with polarity, aggregation tendency, and asphaltene ...structure (single-core or island versus multicore or archipelago). Archipelago asphaltenes were recently demonstrated to coexist with island structures in a variety of petroleum samples; however, archipelago compounds ionize much less efficiently than island compounds, making the former difficult to observe by mass spectrometry without prior separation. Highly processed coal-derived asphaltenes have been studied previously to reveal only small, single-core structure asphaltenes; however, the structure(s) of asphaltenes from unaltered coal extracts has not been extensively studied. Thus, this work focuses on the application of the extrography separation to an unaltered Illinois coal No. 6 asphaltene extract to reveal the coexistence of island and archipelago structural motifs by positive-ion (+) atmospheric pressure photoionization (APPI) Fourier transform ion cyclotron resonance mass spectrometry. Asphaltenes from a Wyoming crude oil sample are also characterized for comparison with coal asphaltenes. The results reveal that Wyoming crude oil asphaltenes contain mainly island species, whereas coal asphaltenes contain archipelago and island compounds with high oxygen content. The structural analysis is enabled by a new “multinotch” stored-waveform inverse Fourier transform isolation, which selectively isolates high-aromaticity precursor ions at each of several nominal mass ranges prior to fragmentation by infrared multiphoton dissociation, and enables unambiguous determination of island versus archipelago species in samples that contain compounds with high and low aromaticity. The more polarizable fractions from each asphaltene sample reveal low-aromaticity polyfunctional oxygenated species, with a solubility behavior consistent with asphaltenes but a compositional range typical of maltenes. These atypical asphaltene species, which ionize poorly, are hypothesized to participate in multiple hydrogen bonding interactions and thus exhibit strong adsorption on polar stationary phases such as SiO2. Furthermore, these polarizable polyfunctional species ionize preferentially as protonated cations by (+) APPI, accounting for their capability to hydrogen-bond in solution. Collectively, the results demonstrate the existence of archipelago structures in both coal and petroleum asphaltenes, along with polyoxygenated species with low aromaticity that behave like asphaltenes in terms of solubility, because they can establish stronger intermolecular forces such as hydrogen bonding.
Relationships between dissolved organic matter (DOM) reactivity and chemical composition in a groundwater plume containing petroleum-derived DOM (DOMHC) were examined by quantitative and qualitative ...measurements to determine the source and chemical composition of the compounds that persist downgradient. Samples were collected from a transect down the core of the plume in the direction of groundwater flow. An exponential decrease in dissolved organic carbon concentration resulting from biodegradation along the transect correlated with a continuous shift in fluorescent DOMHC from shorter to longer wavelengths. Moreover, ultrahigh resolution mass spectrometry showed a shift from low molecular weight (MW) aliphatic, reduced compounds to high MW, unsaturated (alicyclic/aromatic), high oxygen compounds that are consistent with carboxyl-rich alicyclic molecules. The degree of condensed aromaticity increased downgradient, indicating that compounds with larger, conjugated aromatic core structures were less susceptible to biodegradation. Nuclear magnetic resonance spectroscopy showed a decrease in alkyl (particularly methyl) and an increase in aromatic/olefinic structural motifs. Collectively, data obtained from the combination of these complementary analytical techniques indicated that changes in the DOMHC composition of a groundwater plume are gradual, as relatively low molecular weight (MW), reduced, aliphatic compounds from the oil source were selectively degraded and high MW, alicyclic/aromatic, oxidized compounds persisted.
Display omitted
•DOM in a petroleum contaminated plume is compositionally similar to that of the parent crude oil.•Degradation rates can be described as a “hockey stick” with both linear and non-linear segments.•Biodegradation follows a continuum model where the most labile compounds degrade first.•Benzene carboxylic acids (BPCA) are quantitative conservative tracers of the DOMHC plume.•High molecular weight, CRAM persist downgradient from the petroleum source.
Thiazolidine carboxylates such as thiazolidine-4-carboxylate (T4C) and thiazolidine-2-carboxylate (T2C) are naturally occurring sulfur analogues of proline. These compounds have been observed to have ...both beneficial and toxic effects in cells. Given that proline dehydrogenase has been proposed to be a key enzyme in the oxidative metabolism of thioprolines, we characterized T4C and T2C as substrates of proline catabolic enzymes using proline utilization A (PutA), which is a bifunctional enzyme with proline dehydrogenase (PRODH) and l-glutamate-γ-semialdehyde dehydrogenase (GSALDH) activities. PutA is shown here to catalyze the FAD-dependent PRODH oxidation of both T4C and T2C with catalytic efficiencies significantly higher than with proline. Stopped-flow experiments also demonstrate that l-T4C and l-T2C reduce PutA-bound FAD at rates faster than proline. Unlike proline, however, oxidation of T4C and T2C does not generate a substrate for NAD+-dependent GSALDH. Instead, PutA/PRODH oxidation of T4C leads to cysteine formation, whereas oxidation of T2C generates an apparently stable Δ4-thiazoline-2-carboxylate species. Our results provide new insights into the metabolism of T2C and T4C.
PURPOSEThis study aimed to assess changes in cardiovascular disease (CVD) risk factors in firefighters who lost, maintained, or gained weight over 5 yr.
METHODSAnthropometrics and biomarkers of CVD ...were measured during two occupational medical exams 4.8 yr apart in 656 career firefighters. Weight change subgroups were loss (decrease of >3% body weight), stable (within ±3% body weight), and gain (increase of >3% body weight). Changes in CVD risk factors in the total sample and within weight change subgroups were tested for statistical significance using paired t-tests.
RESULTSAfter 5 yr, 12% of the sample lost weight, 38% maintained weight, and 50% gained weight. Firefighters on average had significant increases (P < 0.001) in body weight (2.5 ± 0.2 kg), body mass index (0.8 ± 0.1 kg·m), total cholesterol (5.5 ± 1.4 mg·dL), LDL cholesterol (5.2 ± 1.2 mg·dL), and blood glucose (2.1 ± 0.5 mg·dL). Firefighters who gained weight (6.6 ± 0.2 kg) had significant increases (P < 0.001) in total cholesterol (12.9 ± 1.8 mg·dL), LDL cholesterol (11.1 ± 1.6 mg·dL), and blood glucose (2.9 ± 0.7 mg·dL) with a significant decrease (P ≤ 0.01) in HDL cholesterol (−1.3 ± 0.4 mg·dL). Firefighters who lost weight (−7.2 ± 0.5 kg) had significant decreases (P < 0.05) in total cholesterol (−8.5 ± 3.9 mg·dL), LDL cholesterol (−6.7 ± 3.3 mg·dL), and blood pressure (systolic−5.3 ± 1.3 mm Hg; diastolic −4.2 ± 1.0 mm Hg) with a significant increase (P < 0.05) in HDL cholesterol (2.3 ± 1.0 mg·dL).
CONCLUSIONSAlthough improvements in cardiovascular health among firefighters who lost weight were found, 50% of the sample gained weight with adverse changes in measures of cardiovascular health. Given that sudden cardiac death is the most common cause of duty-related death among firefighters, with increased risk among obese firefighters, the amount of weight gain and the adverse changes in cardiovascular health suggest the need for improvements in health promotion programs for firefighters in the United States.
Objective
This study examined cardiovascular disease risk factors by BMI category in firefighters, the association of BMI and age with risk factor prevalence, and the prevalence of risk factors by ...BMI category within age groups.
Methods
Cardiovascular measures from the medical evaluations of 4,453 firefighters, performed between 2015 and 2018 at four occupational health clinics in the United States (South‐West Cohort, Mid‐Atlantic Cohort, South‐East Cohort, and Mid‐West Cohort), were analyzed cross‐sectionally by BMI and age categories.
Results
Among female firefighters with normal weight, 25% had high blood pressure, 8% had low high‐density lipoprotein cholesterol, and 0% had high glucose, whereas the prevalence in female firefighters with obesity was 57%, 45%, and 11%, respectively. Among male firefighters, there were independent and significant associations of BMI and age for the prevalence of high blood pressure, high cholesterol, high triglycerides, and high glucose. Higher BMI category was associated with a higher prevalence of high blood pressure, high triglycerides, and low high‐density lipoprotein cholesterol within all age groups and with a higher prevalence of high glucose and high cholesterol within ages 40 to 49 and 50 to 59 years.
Conclusions
An increasing prevalence of risk factors with older age and higher BMI suggests that preventive strategies should be initiated in younger firefighters and aggressively promoted or mandated throughout firefighters’ careers.
Stored waveform inverse Fourier transform (SWIFT) is a versatile method to generate complex isolation/ejection waveforms for precursor isolation prior to tandem mass spectrometry experiments. Here, ...we report ultrahigh resolving power ion isolation by SWIFT on a 21 T Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. Individual histone proteoforms are isolated (0.6 m/z isolation window) with near 100% efficiency using a 52 ms SWIFT isolation, followed by in-cell fragmentation by ultraviolet photodissociation (UVPD). Ion isolation resolving power of 175 000 (m/Δm) is demonstrated by isolation of individual peaks at a spacing of 0.0034 Da at m/z 597 from a complex mixture of Canadian bitumen. An individual m/z ion, which corresponds to a single elemental composition, from a complex mixture is isolated and fragmented by infrared multiphoton dissociation (IRMPD). Theoretical and experimental considerations that limit achievable ion isolation resolving power are discussed.
Radical S-adenosyl-l-methionine (SAM) enzymes employ a 4Fe–4S cluster and SAM to initiate diverse radical reactions via either H-atom abstraction or substrate adenosylation. Here we use freeze-quench ...techniques together with electron paramagnetic resonance (EPR) spectroscopy to provide snapshots of the reaction pathway in an adenosylation reaction catalyzed by the radical SAM enzyme pyruvate formate-lyase activating enzyme on a peptide substrate containing a dehydroalanine residue in place of the target glycine. The reaction proceeds via the initial formation of the organometallic intermediate Ω, as evidenced by the characteristic EPR signal with g ∥ = 2.035 and g ⊥ = 2.004 observed when the reaction is freeze-quenched at 500 ms. Thermal annealing of frozen Ω converts it into a second paramagnetic species centered at g iso = 2.004; this second species was generated directly using freeze-quench at intermediate times (∼8 s) and unequivocally identified via isotopic labeling and EPR spectroscopy as the tertiary peptide radical resulting from adenosylation of the peptide substrate. An additional paramagnetic species observed in samples quenched at intermediate times was revealed through thermal annealing while frozen and spectral subtraction as the SAM-derived 5′-deoxyadenosyl radical (5′-dAdo•). The time course of the 5′-dAdo• and tertiary peptide radical EPR signals reveals that the former generates the latter. These results thus support a mechanism in which Ω liberates 5′-dAdo• by Fe–C5′ bond homolysis, and the 5′-dAdo• attacks the dehydroalanine residue of the peptide substrate to form the adenosylated peptide radical species. The results thus provide a picture of a catalytically competent 5′-dAdo• intermediate trapped just prior to reaction with the substrate.
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