Interactions between fibroblastic reticular cells and B cells promote mesenteric lymph node lymphangiogenesis.

Lymphatic growth (lymphangiogenesis) within lymph nodes functions to promote dendritic cell entry and effector lymphocyte egress in response to infection or inflammation. Here we demonstrate a crucial role for lymphotoxin-beta receptor (LTβR) signaling to fibroblastic reticular cells (FRCs) by lymphotoxin-expressing B cells in driving mesenteric lymph node lymphangiogenesis following helminth infection. LTβR ligation on fibroblastic reticular cells leads to the production of B-cell-activating factor (BAFF), which synergized with interleukin-4 (IL-4) to promote the production of the lymphangiogenic factors, vascular endothelial growth factors (VEGF)-A and VEGF-C, by B cells. In addition, the BAFF-IL-4 synergy augments expression of lymphotoxin by antigen-activated B cells, promoting further B cell-fibroblastic reticular cell interactions. These results underlie the importance of lymphotoxin-dependent B cell-FRC cross talk in driving the expansion of lymphatic networks that function to promote and maintain immune responsiveness.The growth of lymph nodes in response to infection requires lymphangiogenesis. Dubey et al. show that the mesenteric lymph node lymphangiogenesis upon helminth infection depends on the signaling loop between the B and fibroblastic reticular cells (FRCs), whereby the FRCs respond to lymphotoxin secreted by B cells by releasing B cell activating factor

IL-4Rα-Expressing B Cells Are Required for CXCL13 Production by Fibroblastic Reticular Cells.

Adaptive type 2 immune responses against the intestinal helminth Heligmosomoides polygyrus (Hp) require the interaction of follicle-associated CXCR5 <sup>+</sup> dendritic cells with naive T cells in the draining mesenteric lymph nodes (mLNs). However, the source of CXCL13 responsible for attracting CXCR5 <sup>+</sup> dendritic cells has remained unclear. Using multiplex imaging combined with deep tissue analysis, we observed new CXCL13 <sup>+</sup> fibroblastic reticular cells surrounding paracortical and cortical B cell follicles in the mLNs of infected mice. CXCL13 <sup>+</sup> fibroblasts expressed markers of marginal reticular cells (MRCs), and their expansion required lymphotoxin (LT)-dependent interactions between IL-4Rα-expressing B cells and CCL19 <sup>+</sup> fibroblasts. Infection-induced follicles did not necessarily contain follicular dendritic cells (FDCs), indicating that CXCL13 <sup>+</sup> fibroblasts may instead drive their formation. These data reveal a role for lymphotoxin signaling to CCL19 <sup>+</sup> fibroblasts in the development of CXCL13 <sup>+</sup> MRC-like cells and adaptive type 2 immunity in response to helminth infection

On the origin of carbon dioxide released from rewetted soils

When dry soils are rewetted a pulse of CO2 is invariably released, and whilst this phenomenon has been studied for decades, the precise origins of this CO2 remain obscure. We postulate that it could be of chemical (i.e. via abiotic pathways), biochemical (via free enzymes) or biological (via intact cells) origin. To elucidate the relative contributions of the pathways, dry soils were either sterilised (double autoclaving) or treated with solutions of inhibitors (15% trichloroacetic acid or 1% silver nitrate) targeting the different modes. The rapidity of CO2 release from the soils after the drying:rewetting (DRW) cycle was remarkable, with maximal rates of evolution within 6 min, and 41% of the total efflux over 96 h released within the first 24 h. The complete cessation of CO2 eflux following sterilisation showed there was no abiotic (dissolution of carbonates) contribution to the CO2 release on rewetting, and clear evidence for an organismal or biochemical basis to the flush. Rehydration in the presence of inhibitors indicated that there were approximately equal contributions from biochemical (outside membranes) and organismal (inside membranes) sources within the first 24 h after rewetting. This suggests that some of the flux was derived from microbial respiration, whilst the remainder was a consequence of enzyme activity, possibly through remnant respiratory pathways in the debris of dead cells

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

BACKGROUND: Src is involved in cancer invasion and metastasis. AZD0424, an oral inhibitor of Src and ABL1, has shown evidence of anti-tumour activity in pre-clinical studies. METHODS: A phase Ia, dose escalation study was performed to assess the safety of continuous oral dosing with AZD0424 in advanced solid tumours. Secondary objectives included investigation of AZD0424 pharmacokinetics, effect on Src activity using markers of bone turnover, and anti-tumour activity. RESULTS: 41 patients were treated; 34 received AZD0424 once-daily at doses ranging from 5 mg to 150 mg, and 7 received 40 mg bi-daily 41.5% of patients experienced at least one AZD0424-related adverse event that was Grade 3-5 in severity, with patients treated at doses above 60 mg per day experiencing multiple treatment-related toxicities. The most commonly observed AZD0424-related adverse events were nausea, fatigue, anorexia and alopecia. Cmaxand AUC increased linearly with dose and the mean±standard deviation t1/2was 8.4±2.8 h. Clear evidence of Src target inhibition was seen at doses ⩾20 mg per day. No responses were observed and 7 patients (17.1%) achieved stable disease lasting 6 weeks or more. CONCLUSIONS: AZD0424 displayed no evidence of efficacy as monotherapy despite a clear pharmacodynamic effect. Further evaluation of AZD0424 monotherapy in patients with solid tumours is not recommended

Spin interactions and switching in vertically tunnel-coupled quantum dots

We determine the spin exchange coupling J between two electrons located in two vertically tunnel-coupled quantum dots, and its variation when magnetic (B) and electric (E) fields (both in-plane and perpendicular) are applied. We predict a strong decrease of J as the in-plane B field is increased, mainly due to orbital compression. Combined with the Zeeman splitting, this leads to a singlet-triplet crossing, which can be observed as a pronounced jump in the magnetization at in-plane fields of a few Tesla, and perpendicular fields of the order of 10 Tesla for typical self-assembled dots. We use harmonic potentials to model the confining of electrons, and calculate the exchange J using the Heitler-London and Hund-Mulliken technique, including the long-range Coulomb interaction. With our results we provide experimental criteria for the distinction of singlet and triplet states and therefore for microscopic spin measurements. In the case where dots of different sizes are coupled, we present a simple method to switch on and off the spin coupling with exponential sensitivity using an in-plane electric field. Switching the spin coupling is essential for quantum computation using electronic spins as qubits.Comment: 13 pages, 9 figure

A multi-component, community-engaged intervention to reduce cardiovascular disease risk in perimenopausal Latinas: pilot study protocol

Background: Cardiovascular disease (CVD) risk increases substantially during perimenopause. Latinas have a significantly worse CVD risk factor profile than non-Hispanic White women, potentially due to multiple sociocultural and environmental factors. To date, interdisciplinary interventions have not focused on improving nutrition, physical activity, stress management, and biologic CVD risk in perimenopausal Latinas. The purpose of this study is to examine the feasibility and initial efficacy of a multi-component intervention to reduce CVD risk in perimenopausal Latinas. Methods: This is a two-group, repeated measures experimental study. Eighty perimenopausal Latinas (age 40–55 years) from two community groups will be randomized: one group will complete the intervention; the other will be a wait-list control. The intervention consists of 12-weekly sessions (education, physical activity, stress management, coping skills training), followed by 3 months of continued support, and 6 months of skill maintenance on their own. The primary outcomes include arterial stiffness, blood pressure, lipids, and blood glucose. Secondary outcomes are health behaviors (nutrition, physical activity, sleep, coping strategies), self-efficacy, and other biological factors related to CVD risk (adiposity, C-reactive protein, hair cortisol, vasomotor symptoms). We will assess changes in outcomes from Time 1 (baseline) to Time 2 (6 months) and Time 3 (12 months) using general linear mixed models to test the hypotheses. We will also evaluate the feasibility of the intervention by assessing enrollment and retention rates, barriers, and facilitators to enrollment, intervention fidelity, the suitability of study procedures, and participant satisfaction with the intervention and study protocol. We hypothesize the intervention group will decrease biologic CVD risk and improve health behaviors and self-efficacy significantly more than the wait-list control. Discussion: Results from this study will contribute to knowledge on the feasibility of behavioral interventions, including stress management and coping skills training, which could reduce CVD burden among perimenopausal Latinas. Because Hispanic/Latinos are the largest ethnic minority in the United States (US), progress regarding CVD risk among perimenopausal Latinas may lead to significant improvement in the overall CVD burden in the US. Trial registration: Prospectively registered, NCT04313751 (03/19/2020), Protocol version 1.

Generation of atom-photon entangled states in atomic Bose-Einstein condensate via electromagnetically induced transparency

In this paper, we present a method to generate continuous-variable-type entangled states between photons and atoms in atomic Bose-Einstein condensate (BEC). The proposed method involves an atomic BEC with three internal states, a weak quantized probe laser and a strong classical coupling laser, which form a three-level Lambda-shaped BEC system. We consider a situation where the BEC is in electromagnetically induced transparency (EIT) with the coupling laser being much stronger than the probe laser. In this case, the upper and intermediate levels are unpopulated, so that their adiabatic elimination enables an effective two-mode model involving only the atomic field at the lowest internal level and the quantized probe laser field. Atom-photon quantum entanglement is created through laser-atom and inter-atomic interactions, and two-photon detuning. We show how to generate atom-photon entangled coherent states and entangled states between photon (atom) coherent states and atom-(photon-) macroscopic quantum superposition (MQS) states, and between photon-MQS and atom-MQS states.Comment: 9 pages, 1 figur

New insights into bacterial chemoreceptor array structure and assembly from electron cryotomography

FWN – Publicaties zonder aanstelling Universiteit Leide

Choosing how to choose : Institutional pressures affecting the adoption of personnel selection procedures

The gap between science and practice in personnel selection is an ongoing concern of human resource management. This paper takes Oliver´s framework of organizations´ strategic responses to institutional pressures as a basis for outlining the diverse economic and social demands that facilitate or inhibit the application of scientifically recommended selection procedures. Faced with a complex network of multiple requirements, practitioners make more diverse choices in response to any of these pressures than has previously been acknowledged in the scientific literature. Implications for the science-practitioner gap are discussed