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Abstract Human interleukin-1β (hIL-1β) is a pro-inflammatory cytokine involved in many diseases. While hIL-1β directed antibodies have shown clinical benefit, an orally available low-molecular weight antagonist is still elusive, limiting the applications of hIL-1β-directed therapies. Here we describe the discovery of a low-molecular weight hIL-1β antagonist that blocks the interaction with the IL-1R1 receptor. Starting from a low affinity fragment-based screening hit 1, structure-based optimization resulted in a compound (S)-2 that binds and antagonizes hIL-1β with single-digit micromolar activity in biophysical, biochemical, and cellular assays. X-ray analysis reveals an allosteric mode of action that involves a hitherto unknown binding site in hIL-1β encompassing two loops involved in hIL-1R1/hIL-1β interactions. We show that residues of this binding site are part of a conformationally excited state of the mature cytokine. The compound antagonizes hIL-1β function in cells, including primary human fibroblasts, demonstrating the relevance of this discovery for future development of hIL-1β directed therapeutics.

Abstract DLCO/NO, the combined single‐breath measurement of the diffusing capacity to carbon monoxide (DLCO) and nitric oxide (DLNO) measured either during exercise or in the resting supine position may be a useful physiological measure of alveolar–capillary reserve. In the present study, we investigated the between‐day test–retest reliability of DLCO/NO‐based metrics. Twenty healthy volunteers (10 males, 10 females; mean age 25 (SD 2) years) were randomized to repeated DLCO/NO measurements during upright rest followed by either exercise (n = 11) or resting in the supine position (n = 9). The measurements were repeated within 7 days. The smallest real difference (SRD), defined as the 95% confidence limit of the standard error of measurement (SEM), the coefficient of variance (CV), and intraclass correlation coefficients were used to assess test–retest reliability. SRD for DLNO was higher during upright rest (5.4 (95% CI: 4.1, 7.5) mmol/(min kPa)) than during exercise (2.7 (95% CI: 2.0, 3.9) mmol/(min kPa)) and in the supine position (3.0 (95% CI: 2.1, 4.8) mmol/(min kPa)). SRD for DLCOc was similar between conditions. CV values for DLNO were slightly lower than for DLCOc both during exercise (1.5 (95% CI: 1.2, 1.7) vs. 3.8 (95% CI: 3.2, 4.3)%) and in the supine position (2.2 (95% CI: 1.8, 2.5) vs. 4.8 (95% CI: 3.8, 5.4)%). DLNO increased by 12.3 (95% CI: 11.1, 13.4) and DLCOc by 3.3 (95% CI: 2.9, 3.7) mmol/(min kPa) from upright rest to exercise. The DLCO/NO technique provides reliable indices of alveolar–capillary reserve, both during exercise and in the supine position.

Background: Desmoid tumors can cause morbidity due to local invasion, potentially being fatal when fast growth compromises vital structures. In this context, a timely treatment response is required. This study aims to compare the activity of sorafenib and anthracycline‐containing regimens during the first year of treatment. Methods: The authors conducted a multi‐institutional retrospective analysis of desmoid tumor patients treated with either sorafenib or an anthracycline‐containing regimen over 1 year. The primary end point was the overall response rate (ORR). The secondary end points were time to response (TTR), progression‐free survival (PFS), and adverse events. Results: From 2005 to 2022, 80 patients received sorafenib and 51 received an anthracycline‐containing regimen with similar baseline characteristics. The 1‐year ORR was 37% for anthracycline and 13% for sorafenib (p =.016). Median best response was –9% (range, –73 to 51) for anthracycline and –4% (range, –69 to 126) for sorafenib. Median TTR was 5.6 months (95% confidence interval [CI], 3.4–7.8) for anthracycline and 8.7 months (95% CI, 6.3–11.1) for sorafenib (p =.2). One‐year PFS was 73% (95% CI, 60–86) for anthracycline and 59% (95% CI, 47–71) for sorafenib (p =.3). Common grade 1–2 adverse events for sorafenib were hand‐foot syndrome (40%), diarrhea (25%), and fatigue (22%); for anthracycline, they were nausea (31%), fatigue (16%), and rash (14%). Grade 3 events were higher in the anthracycline group, 27% versus 14% (p <.05). Conclusion: Anthracycline‐based therapy provided a greater 1‐year response rate than sorafenib but was associated with a higher rate of serious adverse events. Higher‐risk desmoid tumors, which need a more timely response, might benefit from anthracycline‐based therapies, whereas average‐risk tumors could benefit from sorafenib. This article reports a multi‐institutional retrospective comparison of the activity between sorafenib and anthracycline‐based chemotherapies for desmoid tumors. It shows that anthracycline‐based chemotherapies can produce a greater proportion of responses in the first year of treatment at the expense of greater toxicity. [ABSTRACT FROM AUTHOR]

Reducing food loss and waste is crucial for a sustainable global food system and an efficient use of natural resources. Fast-growing tuna provides a key contribution to global nutrition targets; however, reports suggest that an appreciable proportion of the catch is lost from its value chain due to flesh quality issues, one of which is Mushy Tuna Syndrome (MTS). MTS-affected tuna flesh becomes soft and pasty, unfit for canning or human consumption, resulting in high wastage of partially processed material. We investigated the prevalence of MTS globally by surveying the tuna industry using a questionnaire. Of the responses from 32 companies across 14 nations, 97% acknowledged MTS as an issue that predominantly affects skipjack (Katsuwonus pelamis) tuna. The cost of rejects reported by participants from 2017 to 2019 varied greatly, from less than 1000 USD per year to over 1 million USD. The median cost was over 60,000 USD and the average rejection rate was 1.8%. The occurrence of MTS was noted to be seasonal, mainly in the summer months. More than half of the respondents who experience MTS reported an increasing trend of occurrence. Industry perceptions suggest MTS causes are associated with environmental, physiological, and biological factors. The survey results highlight that MTS is prevalent in the industry and demonstrate the need to identify amelioration strategies for the fishers and processors to minimise loss and maximise resource efficiency.

Aim: Skeletal muscle convective and diffusive oxygen (O2) transport are peripheral determinants of exercise capacity in both patients with chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). We hypothesised that differences in these peripheral determinants of performance between COPD and CHF patients are revealed during small muscle mass exercise, where the cardiorespiratory limitations to exercise are diminished.Methods: Eight patients with moderate to severe COPD, eight patients with CHF (NYHA II), and eight age- and sex-matched controls were studied. We measured leg blood flow (Q̇leg) by Doppler ultrasound during submaximal one-legged knee-extensor exercise (KEE), while sampling arterio-venous variables across the leg. The capillary oxyhaemoglobin dissociation curve was reconstructed from paired femoral arterial-venous oxygen tensions and saturations, which enabled the estimation of O2 parameters at the microvascular level within skeletal muscle, so that skeletal muscle oxygen conductance (DSMO2) could be calculated and adjusted for flow (DSMO2/Q̇leg) to distinguish convective from diffusive oxygen transport.Results: During KEE, Q̇leg increased to a similar extent in CHF (2.0 (0.4) L/min) and controls (2.3 (0.3) L/min), but less in COPD patients (1.8 (0.3) L/min) (p

Minichromosome maintenance protein 10 (MCM10) is critical for eukaryotic DNA replication. Here, by modelling MCM10 variants in human cell lines, the authors reveal a mechanism of MCM10-associated disease, finding that loss of MCM10 function constrains telomerase activity.

Abstract Background RNA interference (RNAi) regulates gene expression in most multicellular organisms through binding of small RNA effectors to target transcripts. Exploiting this process is a popular strategy for genetic manipulation and has applications that includes arthropod pest control. RNAi technologies are dependent on delivery method with the most convenient likely being feeding, which is effective in some animals while others are insensitive. The two-spotted spider mite, Tetranychus urticae, is prime candidate for developing RNAi approaches due to frequent occurrence of conventional pesticide resistance. Using a sequencing-based approach, the fate of ingested RNAs was explored to identify features and conditions that affect small RNA biogenesis from external sources to better inform RNAi design. Results Biochemical and sequencing approaches in conjunction with extensive computational assessment were used to evaluate metabolism of ingested RNAs in T. urticae. This chelicerae arthropod shows only modest response to oral RNAi and has biogenesis pathways distinct from model organisms. Processing of synthetic and plant host RNAs ingested during feeding were evaluated to identify active substrates for spider mite RNAi pathways. Through cataloging characteristics of biochemically purified RNA from these sources, trans-acting small RNAs could be distinguished from degradation fragments and their origins documented. Conclusions Using a strategy that delineates small RNA processing, we found many transcripts have the potential to enter spider mite RNAi pathways, however, trans-acting RNAs appear very unstable and rare. This suggests potential RNAi pathway substrates from ingested materials are mostly degraded and infrequently converted into regulators of gene expression. Spider mites infest a variety of plants, and it would be maladaptive to generate diverse gene regulators from dietary RNAs. This study provides a framework for assessing RNAi technology in organisms where genetic and biochemical tools are absent and benefit rationale design of RNAi triggers for T.urticae.

In patients with chronic obstructive pulmonary disease (COPD), pulmonary vascular dysfunction and destruction are observable before the onset of detectable emphysema, but it is unknown whether this is associated with central hypovolemia. We investigated if patients with COPD have reduced pulmonary blood volume (PBV) evaluated by 82Rb-positron emission tomography (PET) at rest and during adenosine-induced hyperemia. This single-center retrospective cohort study assessed 6,301 82Rb-PET myocardial perfusion imaging (MPI) examinations performed over a 6-yr period. We compared 77 patients with COPD with 44 healthy kidney donors (controls). Cardiac output ( Q ˙ ) and mean 82Rb bolus transit time (MBTT) were used to calculate PBV. Q ˙ was similar at rest (COPD: 3,649 ± 120 mL vs. control: 3,891 ± 160 mL, P = 0.368) but lower in patients with COPD compared with controls during adenosine infusion (COPD: 5,432 ± 124 mL vs. control: 6,185 ± 161 mL, P < 0.050). MBTT was shorter in patients with COPD compared with controls at rest (COPD: 8.7 ± 0.28 s vs. control: 11.4 ± 0.37 s, P < 0.001) and during adenosine infusion (COPD: 9.2 ± 0.28 s vs. control: 10.2 ± 0.37 s, P < 0.014). PBV was lower in patients with COPD, even after adjustment for body surface area, sex, and age at rest [COPD: 530 (29) mL vs. 708 (38) mL, P < 0.001] and during adenosine infusion [COPD: 826 (29) mL vs. 1,044 (38) mL, P < 0.001]. In conclusion, patients with COPD show evidence of central hypovolemia, but it remains to be determined whether this has any diagnostic or prognostic impact. NEW & NOTEWORTHY: The present study demonstrated that patients with chronic obstructive pulmonary disease (COPD) exhibit central hypovolemia compared with healthy controls. Pulmonary blood volume may thus be a relevant physiological and/or clinical outcome measure in future COPD studies. [ABSTRACT FROM AUTHOR]

Lung cancer mortality after exposure to radon decay products (RDP) among 16,236 male Eldorado uranium workers was analyzed. Male workers from the Beaverlodge and Port Radium uranium mines and the Port Hope radium and uranium refinery and processing facility who were first employed between 1932 and 1980 were followed up from 1950 to 1999. A total of 618 lung cancer deaths were observed. The analysis compared the results of the biologically-based two-stage clonal expansion (TSCE) model to the empirical excess risk model. The spontaneous clonal expansion rate of pre-malignant cells was reduced at older ages under the assumptions of the TSCE model. Exposure to RDP was associated with increase in the clonal expansion rate during exposure but not afterwards. The increase was stronger for lower exposure rates. A radiation-induced bystander effect could be a possible explanation for such an exposure response. Results on excess risks were compared to a linear dose-response parametric excess risk model with attained age, time since exposure and dose rate as effect modifiers. In all models the excess relative risk decreased with increasing attained age, increasing time since exposure and increasing exposure rate. Large model uncertainties were found in particular for small exposure rates.

The Bible is a sacred book widely accepted in the Christendom, the true word of God. Past and present perceptions have revealed a great deal of importance and significance in the history of mankind. In view of this, several people refer to the Bible as the Holy book, sacred book, Scripture, while some think it is a magical spell book or just one of the mythological books of tales from ancient history and tradition. On the contrary, it is often referred to as the book of the Christian for instruction and worship. In 1 Thessalonians 2:13 we read “For this cause also thank we God without ceasing, because, when ye received the word of God which ye heard of us, ye received it not as the word of men, but as it is in truth, the word of God, which effectually worketh also in you that believe”. As a result, this research explores a rethink on the examination of the Bible as the word of God.