Key points
Leptin is a potent respiratory stimulant.
A long functional isoform of leptin receptor, LepRb, was detected in the carotid body (CB), a key peripheral hypoxia sensor. However, the effect ...of leptin on minute ventilation (VE) and the hypoxic ventilatory response (HVR) has not been sufficiently studied.
We report that LepRb is present in approximately 74% of the CB glomus cells.
Leptin increased carotid sinus nerve activity at baseline and in response to hypoxia in vivo.
Subcutaneous infusion of leptin increased VE and HVR in C57BL/6J mice and this effect was abolished by CB denervation.
Expression of LepRb in the carotid bodies of LepRb deficient obese db/db mice increased VE during wakefulness and sleep and augmented the HVR.
We conclude that leptin acts on LepRb in the CBs to stimulate breathing and HVR, which may protect against sleep disordered breathing in obesity.
Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb, but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE) and the hypoxic ventilatory response to 10% O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb‐deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and on HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10% O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 mL/min/g during normoxia (P < 0.01) and from 3.6 to 4.7 mL/min/g during hypoxia (P < 0.001), augmenting HVR from 0.23 to 0.31 mL/min/g/ΔFIO2 (P < 0.001). The effects of leptin on VE and HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 mL/min/g during normoxia (P < 0.05) and from 2.8 to 3.2 mL/min/g during hypoxia (P < 0.02), increasing HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout non‐rapid eye movement (20.1 vs. −27.7 mL/min respectively, P < 0.05) and rapid eye movement sleep (16.5 vs 23.4 mL/min, P < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity.
Key points
Leptin is a potent respiratory stimulant.
A long functional isoform of leptin receptor, LepRb, was detected in the carotid body (CB), a key peripheral hypoxia sensor. However, the effect of leptin on minute ventilation (VE) and the hypoxic ventilatory response (HVR) has not been sufficiently studied.
We report that LepRb is present in approximately 74% of the CB glomus cells.
Leptin increased carotid sinus nerve activity at baseline and in response to hypoxia in vivo.
Subcutaneous infusion of leptin increased VE and HVR in C57BL/6J mice and this effect was abolished by CB denervation.
Expression of LepRb in the carotid bodies of LepRb deficient obese db/db mice increased VE during wakefulness and sleep and augmented the HVR.
We conclude that leptin acts on LepRb in the CBs to stimulate breathing and HVR, which may protect against sleep disordered breathing in obesity.
Crystal structure determines the distinct deformation mode of crystalline materials and thus plays a critical role in micro-scale deformation. The micro-deformation mechanism at grain level, however, ...is still not well understood and the knowledge of how crystal structure affects size effect and its affected deformation behaviors in micro-scale deformation is not yet systematic and extensive enough to support micro-manufacturing and microproduct development. To explore the influence of crystal structure on size dependent deformation, strain heterogeneity and fracture in micro-scale deformation, a series of micro-scale tensile tests using polycrystalline pure copper (FCC), pure iron (BCC) and pure α-titanium (HCP) sheets with various thicknesses and microstructural grain sizes were conducted. A mechanism-based crystal plasticity (CP) model incorporating size-dependent slip and twinning was proposed. The CP model successfully predicted the influence of grain size and thickness on the flow stress as well as the dependence of twinning volume fraction on the grain size of Ti samples. Full-field simulation was carried out to thoroughly explore the influence of crystal structure on grain-scale strain heterogeneity and fracture behavior via examining strain localization, lattice rotation, slip and twinning activity. Results showed that when only few grains exist in the thickness direction, slip activation is particularly limited in HCP Ti sample, leading to strain concentration and generation of wide and long shear bands thus sharply reduce the fracture toughness. Lattice rotation of Cu samples is most uniform. The large strain in samples of BCC Fe is distributed more dispersedly and more shear bands are formed. This work presents a comprehensive understanding of the effect of crystal structure on the size effect affected micro-scale deformation of metallic materials at grain level and a basis to support the applications of micro-scale deformation for making different crystal structured micro-parts.
•A mechanism-based crystal plasticity model incorporating size-dependent slip and twinning was proposed.•Influence of crystal structure on size dependent deformation behavior in micro-scale deformation was first explored.•Many short shear bands are evenly distributed in the samples with a large ratio of thickness to grain size.•Slip activity is especially limited in HCP Ti sample and long shear bands are formed when only few grains bear the strain.•Large strain is most dispersedly distributed in the samples of BCC Fe and more shear bands are formed in BCC Fe samples.
A software package for the calibration and processing of powder X‐ray diffraction and small‐angle X‐ray scattering data is presented. It provides a multitude of data processing and visualization ...tools as well as a command‐line scripting interface for on‐the‐fly processing and the incorporation of complex data treatment tasks. Customizable processing chains permit the execution of many data processing steps to convert a single image or a batch of raw two‐dimensional data into meaningful data and one‐dimensional diffractograms. The processed data files contain the full data provenance of each process applied to the data. The calibration routines can run automatically even for high energies and also for large detector tilt angles. Some of the functionalities are highlighted by specific use cases.
The Powder Calibration and Processing packages implemented in DAWN 2 provide an automated diffraction‐geometry calibration and data processing environment for two‐dimensional diffraction experiments. The customizable processing chains permit the execution of data processing steps to convert raw two‐dimensional data into meaningful data and diffractograms. The provenance of the processed data is maintained, which guarantees reproducibility and transparency of the data treatment.
Background
Asian infants appear to be over‐represented among patients with clinical food allergy in Australia, but this has not been formally examined at the population level. Any difference in ...prevalence according to parental country of birth may be secondary to modifiable lifestyle factors. We aimed to quantify (i) differences in the prevalence of peanut allergy by parental country of birth and (ii) contribution of measured environmental exposures to these differences.
Methods
The population‐based HealthNuts study in Melbourne, Australia, screened 5276 infants (74% participation) with skin prick tests and sensitized infants underwent food challenge. Of these, 535 had a parent born in East Asia and 574 in UK/Europe. Associations between parents' country of birth and offspring peanut allergy were examined using multiple logistic regression.
Results
Compared to infants with two Australian‐born parents, peanut allergy was more common among infants with parent/s born in East Asia (OR 3.4, 95% CI 2.2–5.1) but not those with parent/s born in the UK/Europe (OR 0.8, 95% CI 0.4–1.5). Paradoxically rates of allergic disease were lower among Asian parents. A higher prevalence of eczema among infants of Asian parents explained around 30% of the increase in peanut allergy, while differences in dog ownership explained around 18%.
Conclusions
The high peanut allergy prevalence among infants of Asian‐born parents appears to have occurred in a single generation and was not present among infants with parents migrating from other countries, suggesting gene–environment interactions are important. The role of eczema and microbial exposure in food allergy prevention warrants exploration.
In this trial, patients receiving oral anticoagulation therapy who required pacemaker or defibrillator surgery were assigned to heparin bridging or continuation of warfarin. Patients receiving ...warfarin had a markedly lower risk of clinically significant device-pocket hematoma.
Each year, an estimated 1.25 million pacemakers and 410,000 implantable cardioverter–defibrillators (ICDs) are implanted worldwide.
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Between 14 and 35% of patients receiving these devices require long-term oral anticoagulation therapy,
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and their periprocedural treatment presents a dilemma to physicians. This is particularly true for the subset of patients at moderate-to-high risk (≥5% per year) for thromboembolic events.
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Current guidelines recommend interruption of oral anticoagulation therapy and the use of bridging therapy with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin around the time of surgery.
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However, there are a number of potential drawbacks to bridging with heparin in the perioperative period. . . .
We report constraints on the dark photon effective kinetic mixing parameter (κ) with data taken from two p-type point-contact germanium detectors of the CDEX-10 experiment at the China Jinping ...Underground Laboratory. The 90% confidence level upper limits on κ of solar dark photon from 205.4 kg-day exposure are derived, probing new parameter space with masses (m_{V}) from 10 to 300 eV/c^{2} in direct detection experiments. Considering dark photon as the cosmological dark matter, limits at 90% confidence level with m_{V} from 0.1 to 4.0 keV/c^{2} are set from 449.6 kg-day data, with a minimum of κ=1.3×10^{-15} at m_{V}=200 eV/c^{2}.
Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often ...transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.
•Ibrutinib/methotrexate/rituximab combination treatment is safe and shows promising clinical activity in CNSL.•Analysis of ctDNA in CSF may be useful to monitor disease burden in patients with CNSL.
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Triple-negative breast cancer (TNBC) has significantly worse prognosis. Acquired chemoresistance remains the major cause of therapeutic failure of TNBC. In clinic, the relapsed TNBC is commonly ...pan-resistant to various drugs with completely different resistant mechanisms. Investigation of the mechanisms and development of new drugs to target pan-chemoresistance will potentially improve the therapeutic outcomes of TNBC patients.
In this study, 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI)-isobologram, western blot, ALDEFLUOR analysis, clonogenic assay and immunocytochemistry were used.
The chemoresistant MDA-MB-231PAC10 cells are highly cross-resistant to paclitaxel (PAC), cisplatin (CDDP), docetaxel and doxorubicin. The MDA-MB-231PAC10 cells are quiescent with significantly longer doubling time (64.9 vs 31.7 h). This may be caused by high expression of p21(Waf1). The MDA-MB-231PAC10 cells express high aldehyde dehydrogenase (ALDH) activity and a panel of embryonic stem cell-related proteins, for example, Oct4, Sox2, Nanog and nuclealisation of HIF2α and NF-κBp65. We have previously reported that disulfiram (DS), an antialcoholism drug, targets cancer stem cells (CSCs) and enhances cytotoxicity of anticancer drugs. Disulfiram abolished CSC characters and completely reversed PAC and CDDP resistance in MDA-MB-231PAC10 cells.
Cancer stem cells may be responsible for acquired pan-chemoresistance. As a drug used in clinic, DS may be repurposed as a CSC inhibitor to reverse the acquired pan-chemoresistance.
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