Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes

CD38 controls the chemotaxis of leukocytes to some, but not all, chemokines, suggesting that chemokine receptor signaling in leukocytes is more diverse than previously appreciated. To determine the basis for this signaling heterogeneity, we examined the chemokine receptors that signal in a CD38-dependent manner and identified a novel "alternative" chemokine receptor signaling pathway. Similar to the "classical" signaling pathway, the alternative chemokine receptor pathway is activated by G{alpha}i2-containing Gi proteins. However, unlike the classical pathway, the alternative pathway is also dependent on the Gq class of G proteins. We show that G{alpha}q-deficient neutrophils and dendritic cells (DCs) make defective calcium and chemotactic responses upon stimulation with N-formyl methionyl leucyl phenylalanine and CC chemokine ligand (CCL) 3 (neutrophils), or upon stimulation with CCL2, CCL19, CCL21, and CXC chemokine ligand (CXCL) 12 (DCs). In contrast, G{alpha}q-deficient T cell responses to CXCL12 and CCL19 remain intact. Thus, the alternative chemokine receptor pathway controls the migration of only a subset of cells. Regardless, the novel alternative chemokine receptor signaling pathway appears to be critically important for the initiation of inflammatory responses, as G{alpha}q is required for the migration of DCs from the skin to draining lymph nodes after fluorescein isothiocyanate sensitization and the emigration of monocytes from the bone marrow into inflamed skin after contact sensitization

Analyses of intra-annual density fluctuation signals in Himalayan cedar trees from Himachal Pradesh, western Himalaya, India, and its relationship with apple production

Intra-annual density fluctuation (IADF) refers to anatomical changes in the tree ring caused by a sudden change in wood density triggered by a combination of climate variations and various biotic and abiotic influences. To reveal the occurrence of IADFs, we analyze the growth rings of Himalayan cedar (Cedrus deodara) growing over the Kullu region, Himachal Pradesh, western Himalaya. Using 30 increment cores, we precisely dated and developed a 214-year-long tree-ring chronology extending back to AD 1808. The tree–growth–climate relationship using ring-width chronology and observed climate data revealed that cool and moist condition provides favorable condition for Himalayan cedar tree growth. Delving deeper into wood anatomy of growth rings, we revealed the frequent occurrences of IADFs in both earlywood (IADFe) and latewood (IADFl). The formation of IADFs in earlywood (IADFe) is related to the reduced precipitation from April to July, causing moisture stress in the soil and surrounding climate. However, wetter conditions in the late growing season, mainly August–October, activated the formation of IADFs in latewood (IADFl). The study revealed several IADF years in earlywood and latewood, such as 1901, 1902, 1903, 1914, 1915, 1919, 1920, 1923, 1925, 1943, 1958, 1959 and 1937, 1955, 1956, 1988, respectively. These IADF years corresponded with unusual climatic fluctuations that severely affected apple production, the major cash crop in the region. The analyses demonstrated that the IADF chronology of Himalayan cedar would be a valuable proxy to understand abrupt and unusual climatic fluctuations from a long-term perspective for the data-scarce western Himalayan region

Subconjunctivally implantable hydrogels with degradable and thermoresponsive properties for sustained release of insulin to the retina.

The objective of this work is to develop subconjunctivally implantable, biodegradable hydrogels for sustained release of intact insulin to the retina to prevent and treat retinal neurovascular degeneration such as diabetic retinopathy. The hydrogels are synthesized by UV photopolymerization of N-isopropylacrylamide (NIPAAm) monomer and a dextran macromer containing multiple hydrolytically degradable oligolactate-(2-hydroxyetheyl methacrylate) units (Dex-lactateHEMA) in 25:75 (v:v) ethanol:water mixture solvent. Insulin is loaded into the hydrogels during the synthesis process with loading efficiency up to 98%. The hydrogels can release biologically active insulin in vitro for at least one week and the release kinetics can be modulated by varying the ratio between NIPAAm and Dex-lactateHEMA and altering the physical size of the hydrogels. The hydrogels are not toxic to R28 retinal neuron cells in culture medium with 100% cell viability. The hydrogels can be implanted under the conjunctiva without causing adverse effects to the retina based on hematoxylin and eosin stain, immunostaining for microglial cell activation, and electroretinography. These subconjunctivally implantable hydrogels have potential for long-term periocular delivery of insulin or other drugs to treat diabetic retinopathy and other retinal diseases

Demarcating circulation regimes of synchronously rotating terrestrial planets within the habitable zone

We investigate the atmospheric dynamics of terrestrial planets in synchronous rotation within the habitable zone of low-mass stars using the Community Atmosphere Model (CAM). The surface temperature contrast between day and night hemispheres decreases with an increase in incident stellar flux, which is opposite the trend seen on gas giants. We define three dynamical regimes in terms of the equatorial Rossby deformation radius and the Rhines length. The slow rotation regime has a mean zonal circulation that spans from day to night side, with both the Rossby deformation radius and the Rhines length exceeding planetary radius, which occurs for planets around stars with effective temperatures of 3300 K to 4500 K (rotation period > 20 days). Rapid rotators have a mean zonal circulation that partially spans a hemisphere and with banded cloud formation beneath the substellar point, with the Rossby deformation radius is less than planetary radius, which occurs for planets orbiting stars with effective temperatures of less than 3000 K (rotation period < 5 days). In between is the Rhines rotation regime, which retains a thermally-direct circulation from day to night side but also features midlatitude turbulence-driven zonal jets. Rhines rotators occur for planets around stars in the range of 3000 K to 3300 K (rotation period ∼ 5 to 20 days), where the Rhines length is greater than planetary radius but the Rossby deformation radius is less than planetary radius. The dynamical state can be observationally inferred from comparing the morphology of the thermal emission phase curves of synchronously rotating planets

Regulation of inflammation in Japanese encephalitis

Uncontrolled inflammatory response of the central nervous system is a hallmark of severe Japanese encephalitis (JE). Although inflammation is necessary to mount an efficient immune response against virus infections, exacerbated inflammatory response is often detrimental. In this context, cells of the monocytic lineage appear to be important forces driving JE pathogenesis

Gαq-containing G proteins regulate B cell selection and survival and are required to prevent B cell–dependent autoimmunity

Survival of mature B cells is regulated by B cell receptor and BAFFR-dependent signals. We show that B cells from mice lacking the Gαq subunit of trimeric G proteins (Gnaq−/− mice) have an intrinsic survival advantage over normal B cells, even in the absence of BAFF. Gnaq−/− B cells develop normally in the bone marrow but inappropriately survive peripheral tolerance checkpoints, leading to the accumulation of transitional, marginal zone, and follicular B cells, many of which are autoreactive. Gnaq−/− chimeric mice rapidly develop arthritis as well as other manifestations of systemic autoimmune disease. Importantly, we demonstrate that the development of the autoreactive B cell compartment is the result of an intrinsic defect in Gnaq−/− B cells, resulting in the aberrant activation of the prosurvival factor Akt. Together, these data show for the first time that signaling through trimeric G proteins is critically important for maintaining control of peripheral B cell tolerance induction and repressing autoimmunity

TOI-1338 : TESS' first transiting circumbinary planet

Funding: Funding for the DPAC has been provided by national institutions, in particular, the institutions participating in the Gaia Multilateral Agreement. W.F.W. and J.A.O.thank John Hood Jr. for his generous support of exoplanet research at SDSU. Support was also provided and acknowledged through NASA Habitable Worlds grant 80NSSC17K0741 and NASA XRP grant 80NSSC18K0519. This work is partly supported by NASA Habitable Worlds grant 80NSSC17K0741. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under grant No.(DGE-1746045). A.H.M.J.T. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 803193/BEBOP) and from a Leverhulme Trust Research Project grant No. RPG-2018-418. A.C. acknowledges support by CFisUC strategic project (UID/FIS/04564/2019).We report the detection of the first circumbinary planet (CBP) found by Transiting Exoplanet Survey Satellite (TESS). The target, a known eclipsing binary, was observed in sectors 1 through 12 at 30 minute cadence and in sectors 4 through 12 at 2 minute cadence. It consists of two stars with masses of 1.1 M⊙ and 0.3 M⊙ on a slightly eccentric (0.16), 14.6 day orbit, producing prominent primary eclipses and shallow secondary eclipses. The planet has a radius of ∼6.9 R⊕ and was observed to make three transits across the primary star of roughly equal depths (∼0.2%) but different durations—a common signature of transiting CBPs. Its orbit is nearly circular (e ≍ 0.09) with an orbital period of 95.2 days. The orbital planes of the binary and the planet are aligned to within ∼1°. To obtain a complete solution for the system, we combined the TESS photometry with existing ground-based radial-velocity observations in a numerical photometric-dynamical model. The system demonstrates the discovery potential of TESS for CBPs and provides further understanding of the formation and evolution of planets orbiting close binary stars.Publisher PDFPeer reviewe

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Martensite-to-austenite reversion and recrystallization in cryogenically-rolled type 321 metastable austenitic steel

The annealing behavior of cryogenically-rolled type 321 metastable austenitic steel was established. Cryogenic deformation gave rise to martensitic transformation which developed preferentially within deformation bands. Subsequent annealing in the range of 600 C to 700 C resulted in reversion of the strain-induced martensite to austenite. At 800 C, the reversion was followed by static recrystallization. At relatively-low temperatures, the reversion was characterized by a very strong variant selection, which led to the restoration of the crystallographic orientation of the coarse parent austenite grains. An increase in the annealing temperature relaxed the variant-selection tendency and provided subsequent recrystallization thus leading to significant grain refinement. Nevertheless, a significant portion of the original coarse grains was found to be untransformed and therefore the fine-grain structure was fairly heterogeneous