A Unique Cellular Organization of Human Distal Airways and Its Disarray in Chronic Obstructive Pulmonary Disease

Rationale: Remodeling and loss of distal conducting airways, including preterminal and terminal bronchioles (pre-TBs/TBs), underlie progressive airflow limitation in chronic obstructive pulmonary disease (COPD). The cellular basis of these structural changes remains unknown. Objectives: To identify biological changes in pre-TBs/TBs in COPD at single-cell resolution and determine their cellular origin. Methods: We established a novel method of distal airway dissection and performed single-cell transcriptomic profiling of 111,412 cells isolated from different airway regions of 12 healthy lung donors and pre-TBs of 5 patients with COPD. Imaging CyTOF and immunofluorescence analysis of pre-TBs/TBs from 24 healthy lung donors and 11 subjects with COPD were performed to characterize cellular phenotypes at a tissue level. Region-specific differentiation of basal cells isolated from proximal and distal airways was studied using an air-liquid interface model. Measurements and Main Results: The atlas of cellular heterogeneity along the proximal-distal axis of the human lung was assembled and identified region-specific cellular states, including SCGB3A2+ SFTPB+ terminal airway-enriched secretory cells (TASCs) unique to distal airways. TASCs were lost in COPD pre-TBs/TBs, paralleled by loss of region-specific endothelial capillary cells, increased frequency of CD8+ T cells normally enriched in proximal airways, and augmented IFN-γ signaling. Basal cells residing in pre-TBs/TBs were identified as a cellular origin of TASCs. Regeneration of TASCs by these progenitors was suppressed by IFN-γ. Conclusions: Altered maintenance of the unique cellular organization of pre-TBs/TBs, including loss of the region-specific epithelial differentiation in these bronchioles, represents the cellular manifestation and likely the cellular basis of distal airway remodeling in COPD

Development of a Peripherally Restricted 5-HT2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension

Ligands for the serotonin 2B receptor (5-HT2B) have shown potential to treat pulmonary arterial hypertension in preclinical models but cannot be used in humans because of predicted off-target neurological effects. The aim of this study was to develop novel systemically restricted compounds targeting 5-HT2B. Here, we show that mice treated with VU6047534 had decreased RVSP compared with control treatment in both the prevention and intervention studies using Sugen-hypoxia. VU6047534 is a novel 5-HT2B partial agonist that is peripherally restricted and able to both prevent and treat Sugen-hypoxia–induced pulmonary arterial hypertension. We have synthesized and characterized a structurally novel series of 5-HT2B ligands with high potency and selectivity for the 5-HT2B receptor subtype. Next-generation 5-HT2B ligands with similar characteristics, and predicted to be systemically restricted in humans, are currently advancing to investigational new drug–enabling studies

Cerebellar Nuclear Neurons Use Time and Rate Coding to Transmit Purkinje Neuron Pauses

Copyright: © 2015 Sudhakar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedNeurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it.Peer reviewedFinal Published versio

Towards a new image processing system at Wendelstein 7-X: From spatial calibration to characterization of thermal events

Wendelstein 7-X (W7-X) is the most advanced fusion experiment in the stellarator line and is aimed at proving that the stellarator concept is suitable for a fusion reactor. One of the most important issues for fusion reactors is the monitoring of plasma facing components when exposed to very high heat loads, through the use of visible and infrared (IR) cameras. In this paper, a new image processing system for the analysis of the strike lines on the inboard limiters from the first W7-X experimental campaign is presented. This system builds a model of the IR cameras through the use of spatial calibration techniques, helping to characterize the strike lines by using the information given by real spatial coordinates of each pixel. The characterization of the strike lines is made in terms of position, size, and shape, after projecting the camera image in a 2D grid which tries to preserve the curvilinear surface distances between points. The description of the strike-line shape is made by means of the Fourier Descriptors

Forward modeling of collective Thomson scattering for Wendelstein 7-X plasmas: Electrostatic approximation

In this paper, we present a method for numerical computation of collective Thomson scattering (CTS). We developed a forward model, eCTS, in the electrostatic approximation and benchmarked it against a full electromagnetic model. Differences between the electrostatic and the electromagnetic models are discussed. The sensitivity of the results to the ion temperature and the plasma composition is demonstrated. We integrated the model into the Bayesian data analysis framework Minerva and used it for the analysis of noisy synthetic data sets produced by a full electromagnetic model. It is shown that eCTS can be used for the inference of the bulk ion temperature. The model has been used to infer the bulk ion temperature from the first CTS measurements on Wendelstein 7-X

Main results of the first experimental campaign in the stellarator W7-X

A summary of the first operational phase (OP1.1) at the stellarator W7-X is given. The operational setup of heating and diagnostics as well the results of experiments are briefly described. Plasma parameters and confinement are better than expected: T(b)> 8 keV and T(i)> 2 keV at n(b)≈ 3×10¹⁹ m⁻³ yielding β0 ≈ 2.5 %. The results for ECR heating with X2-mode as well the ECCD are in good agreement with the theory predictions. The heating scenario with the O2-mode alone was successfully first time performed. Stellarator specific regime of core “electron root” confinement was obtained.Представлены итоги первой экспериментальной кампании (ОР1.1) на стеллараторе W7-X. Вкратце описана специфика эксперимента, методов нагрева и основных диагностик. Параметры плазмы и удержание, полученные в экспериментах, превысили ожидаемые: T(b)> 8 кэВ и T(i)> 2 кэВ при ≈ n(b)≈ 3×10¹⁹ m⁻³, что соответствует β0 ≈ 2.5 %. Результаты по ЭЦР-нагреву на Х2-моде, а также по токам увлечения согласуются с теорией. Впервые был успешно реализован сценарий нагрева на О2-моде. Был также получен специфический для стеллараторов режим "электронного корня" удержания.Представлені підсумки першої експериментальної кампанії (ОР1.1) на стелараторі W7-X. Коротко описана специфіка експерименту, методів нагріву та діагностики. Параметри плазми та удержання, отримані в експериментах, перевищили очікувані: T(b)> 8 кеВ та T(i)> 2 > 2 кеВ при ≈ n(b)≈ 3×10¹⁹ m⁻³, що відповідає β0 ≈ 2.5 %. Результати по ЕЦР-нагріву на Х2-моді, а також по струмам захоплення відповідають теорії. Вперше був успішно реалізований сценарій нагріву на О2-моді. Був також успішно реалізований специфічний для стелараторів режим "електронного кореня" утримання

Using a meta-analysis approach to understand complexity in soil biodiversity and phosphorus acquisition in plants

Current soil phosphorus (P) management is neither environmentally nor economically sustainable. Soil biodiversity has been offered as a solution to unsustainable land management and to promote ecosystem service provision. We know soil biology is instrumental in plant access to soil P, but specific effects of biological complexity, (used here to describe the number of links between different organisms), under different P levels on plant productivity are not well understood. We conducted a meta-analysis on relevant literature, which reported the response of terrestrial plants of economic and anthropogenic importance to P conditions, and controlled for biological treatments across different land-uses (arable, grassland and woodland). We hypothesised that: 1) in arable systems increased biological complexity will enhance plant productivity; 2) in perennial systems such as grassland and woodlands, increasing biological complexity will have no effect; 3) increasing the fertility of the system by addition of P fertiliser will reduce any benefits of biological complexity. We found that soil organisms are not always beneficial to plant shoot biomass, but that the effects of - and interaction among - bacteria, protozoa, nematodes, mycorrhizae, collembola and earthworms differ in their impact on plant biomass (positive or negative) dependent on the presence of other community members, P-level status and time. These findings bring into question existing frameworks that link below-ground biodiversity with above-ground plant productivity. We recommend further experimental work be conducted, which controls for land-use, P status, and soil biological composition and complexity. Such work should be followed by future systematic reviews, which could pragmatically inform more tailored biological management for plant P requirements, land-use and ecosystem service provision. To enable further meta-analyses of this type we recommend habitual inclusion of sufficient experimental detail and data, as a prerequisite for publication and a useful way to utilise increased online publication space