The functional units of immune response are lymphocyte clones. Analysis of lymphocyte life span in vivo shows that the overall turnover of CD4 and CD8 lymphocytes does not differ greatly. Recently, ...molecular methods have been developed which allow a global analysis of T-cell clones responding to an antigen in vivo. We have used a sensitive, modified heteroduplex analysis to follow T-cell clones responding to Epstein-Barr virus in acute infectious mononucleosis (AIM). Strikingly, all the many large clones detected in freshly isolated AIM blood were found within the CD8 fraction. CD4 clonal populations responding to the soluble recall antigen tetanus toxoid could only be detected after in vitro re-stimulation. These data imply that CD4 responses may be more polyclonal than those of CD8 cells and that the size of CD4 clones is more tightly regulated. Several molecular mechanisms may contribute to this. Up-regulation of telomerase allows very large expansions of CD8 cells to occur without exhaustion of proliferative capacity.
MONSOON MISSION Rao, Suryachandra A.; Goswami, B. N.; Sahai, A. K. ...
Bulletin of the American Meteorological Society,
12/2019, Letnik:
100, Številka:
12
Journal Article
Recenzirano
Odprti dostop
In spite of the summer monsoon’s importance in determining the life and economy of an agriculture-dependent country like India, committed efforts toward improving its prediction and simulation have ...been limited. Hence, a focused mission mode program Monsoon Mission (MM) was founded in 2012 to spur progress in this direction. This article explains the efforts made by the Earth System Science Organization (ESSO), Ministry of Earth Sciences (MoES), Government of India, in implementing MM to develop a dynamical prediction framework to improve monsoon prediction. Climate Forecast System, version 2 (CFSv2), and the Met Office Unified Model (UM) were chosen as the base models. The efforts in this program have resulted in 1) unparalleled skill of 0.63 for seasonal prediction of the Indian monsoon (for the period 1981–2010) in a high-resolution (~38 km) seasonal prediction system, relative to present-generation seasonal prediction models; 2) extended-range predictions by a CFS-based grand multimodel ensemble (MME) prediction system; and 3) a gain of 2-day lead time from very high-resolution (12.5 km) Global Forecast System (GFS)-based short-range predictions up to 10 days. These prediction skills are on par with other global leading weather and climate centers, and are better in some areas. Several developmental activities like coupled data assimilation, changes in convective parameterization, cloud microphysics schemes, and parameterization of land surface processes (including snow and sea ice) led to the improvements such as reducing the strong model biases in the Indian summer monsoon simulation and elsewhere in the tropics.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
To investigate sensitive ultrasonographic imaging methods for detection of synovial thickness and vascularity to discriminate between patients with early rheumatoid arthritis (RA) receiving ...infliximab + methotrexate (MTX) versus placebo + MTX over 18 weeks, and to compare the relationship between synovial thickening and vascularity at baseline and radiologic damage to joints of the hands and feet at 54 weeks.
Methods
Patients with early RA (duration <3 years) receiving stable dosages of MTX were randomly assigned to receive blinded infusions of 5 mg/kg infliximab (n = 12) or placebo (n = 12) at weeks 0, 2, 6, and then every 8 weeks until week 46. At baseline and week 18, clinical assessments were performed, and metacarpophalangeal joints were assessed by high‐frequency ultrasonography and power Doppler ultrasonography measurements. Radiographs of the hands and feet taken at baseline and at 54 weeks were evaluated using the van der Heijde modification of the Sharp method (vdH‐Sharp score).
Results
Using changes in the total vdH‐Sharp score over 54 weeks and changes in synovial thickening and joint vascularity at 18 weeks, we were able to distinguish those patients receiving infusions of infliximab + MTX from those receiving placebo + MTX. Sonographic measurements of synovial thickening and vascularity at baseline in the placebo + MTX group demonstrated clear relationships with the magnitude of radiologic joint damage at week 54. Infliximab + MTX treatment abolished these relationships.
Conclusion
The delay or reversal of inflammatory and joint‐destructive mechanisms in patients with early RA was already apparent following 18 weeks of treatment with infliximab + MTX and was reflected in radiologic changes at 54 weeks.
Neural crest (NC) cell migration is crucial to the formation of peripheral tissues during vertebrate development. However, how NC cells respond to different microenvironments to maintain persistence ...of direction and cohesion in multicellular streams remains unclear. To address this, we profiled eight subregions of a typical cranial NC cell migratory stream. Hierarchical clustering showed significant differences in the expression profiles of the lead three subregions compared with newly emerged cells. Multiplexed imaging of mRNA expression using fluorescent hybridization chain reaction (HCR) quantitatively confirmed the expression profiles of lead cells. Computational modeling predicted that a small fraction of lead cells that detect directional information is optimal for successful stream migration. Single-cell profiling then revealed a unique molecular signature that is consistent and stable over time in a subset of lead cells within the most advanced portion of the migratory front, which we term trailblazers. Model simulations that forced a lead cell behavior in the trailing subpopulation predicted cell bunching near the migratory domain entrance. Misexpression of the trailblazer molecular signature by perturbation of two upstream transcription factors agreed with the in silico prediction and showed alterations to NC cell migration distance and stream shape. These data are the first to characterize the molecular diversity within an NC cell migratory stream and offer insights into how molecular patterns are transduced into cell behaviors.
Embryonic neural crest cells travel in discrete streams to precise locations throughout the head and body. We previously showed that cranial neural crest cells respond chemotactically to vascular ...endothelial growth factor (VEGF) and that cells within the migratory front have distinct behaviors and gene expression. We proposed a cell-induced gradient model in which lead neural crest cells read out directional information from a chemoattractant profile and instruct trailers to follow. In this study, we show that migrating chick neural crest cells do not display distinct lead and trailer gene expression profiles in culture. However, exposure to VEGF in vitro results in the upregulation of a small subset of genes associated with an in vivo lead cell signature. Timed addition and removal of VEGF in culture reveals the changes in neural crest cell gene expression are rapid. A computational model incorporating an integrate-and-switch mechanism between cellular phenotypes predicts migration efficiency is influenced by the timescale of cell behavior switching. To test the model hypothesis that neural crest cellular phenotypes respond to changes in the VEGF chemoattractant profile, we presented ectopic sources of VEGF to the trailer neural crest cell subpopulation and show diverted cell trajectories and stream alterations consistent with model predictions. Gene profiling of trailer cells that diverted and encountered VEGF revealed upregulation of a subset of ‘lead’ genes. Injection of neuropilin1 (Np1)-Fc into the trailer subpopulation or electroporation of VEGF morpholino to reduce VEGF signaling failed to alter trailer neural crest cell trajectories, suggesting trailers do not require VEGF to maintain coordinated migration. These results indicate that VEGF is one of the signals that establishes lead cell identity and its chemoattractant profile is critical to neural crest cell migration.
•Neural crest cells do not display distinct gene expression profiles in culture.•Timed exposure to VEGF in culture reveals rapid changes in neural crest genes.•Ectopic VEGF presented to trailer neural crest show migratory stream alterations.•Gene profiling of trailer cells that divert to VEGF upregulate lead genes.•Reduction of VEGF signaling within trailer cells does not affect their migration.
This study evaluated changes in lymphocyte subsets in patients with thyroid carcinoma who received iodine-131 for diagnostic and therapeutic purposes. Twenty thyroid cancer patients were entered in ...the study after total thyroidectomy: ten patients (group A) underwent whole-body scintigraphy with 185 MBq of (131)I and the other ten (group B) received 3700 MBq of (131)I therapy. All patients were in a hypothyroid state at the time of administration of (131)I and started L-thyroxine 150 microg/day 3 days after (131)I administration. Free and bound triiodothyronine and thyroxine, thyroid-stimulating hormone, thyroglobulin, thyroglobulin antibodies, thyroid peroxidase/microsomal antibodies, white blood cell, lymphocyte counts and lymphocyte subsets were serially determined at baseline and at days 2, 7, 15, 30 and 60 after (131)I administration. Twenty healthy age- and sex-matched individuals were used as a reference population for lymphocyte subset values. In group A only a reduction in NK cells at days 7 (P=0.043) and 15 (P=0.037) was observed. In group B, patients showed a delayed reduction in the total lymphocyte count at days 15, 30 and 60 (P=0.008, 0.004 and 0. 018, respectively), and a decrease in B cells throughout the study (at days 7, 15, 30 and 60: P=0.006, 0.0017, 0.0017 and 0.0017 respectively). A transient decrease in NK cells was observed at days 15 (P=0.025) and 30 (P=0.008). Among T cells, the helper phenotype (CD4+) was mainly affected, resulting in a reduction in the CD4+/CD8+ ratio at day 60 (P=0.046). Comparing the two groups, the numbers of B lymphocytes at day 30 (P=0.023) and NK cells at days 2 (P=0.037) and 30 (P=0.023) were significantly lower in group B. Neither group showed any clinical sign of immunosuppression during the follow-up period. In patients with thyroid cancer the sensitivity of lymphocytes to the effects of (131)I administered for diagnostic or therapeutic purposes depends upon lymphocyte phenotype and (131)I activity. NK cells are the most radiosensitive cells, being reduced even by low (131)I activity. At higher activity all subtypes show a reduction, which is more marked and prolonged for B lymphocytes and, to a lesser extent, for T-helper lymphocytes. These changes do not result in clinically relevant immunosuppression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of this
critical review
is to provide a broad but digestible overview of mechanochemical synthesis,
i.e.
reactions conducted by grinding solid reactants together with no or minimal solvent. ...Although mechanochemistry has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concentrating on recent advances, this article covers industrial aspects, inorganic materials, organic synthesis, cocrystallisation, pharmaceutical aspects, metal complexes (including metal-organic frameworks), supramolecular aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed (314 references).
The wide applications of mechanochemical synthesis: from inorganic materials to organic reactions, academic research to industrial applications and discussion of opportunities and limitations.
Abstract
Background: The accuracy of the OSNA assay for metastases detection in sentinel lymph nodes (SLNs) has recently been validated in our Institute and adopted as an intra-operative test for ...breast cancer (BC) patient management. The aims of this study in a series of early BC patients, were: 1) to correlate the copy numbers of cytokeratin 19 (CK19) mRNA with the size of nodal metastases and with the risk of additional disease in non-sentinel lymph nodes (NSLNs); 2) to investigate the relationship between SLN status with OSNA method, and conventional bio-pathological factors taking into account the molecular BC classification: luminal A, luminal B, HER2 subtype, and triple-negative; 3) to identify a subgroup of patients with positive SLN with higher risk of NSLNs metastatic involvement. Material and Methods: 750 SLNs from 580 patients were clinically processed using both OSNA assay and post-operative histology. The results of these two methods were then compared. The correlation between the size of metastases and the copy numbers of CK19 mRNA was calculated using the Spearman correlation coefficient. Complementary axillary lymph node dissection (ALND) was performed concurrently in case of OSNA assay positivity and the probability of having a positive lymph node axillary dissection was calculated by the unconditional logistic regression model. This series of BC patients were divided into four main subtypes taking in account the BC classification based on the immunohistochemistry phenotypic patterns.
Results: OSNA positivity was reported in 24.6% of the patients for a sensitivity of 94.2%. Considering the 145 patients with SLN positivity the size of metastatic foci was significantly correlated to the copy numbers of CK19 mRNA. The complex relationships among the bio-pathological variables analyzed by multiple correspondence analysis (MCA) showed that the metastatic involvement of NSLNs is associated with SLNs with a high copy numbers of CK19 mRNA and HER2 subtype tumors. OSNA specificity (95%) and negative predictive value (98.4%) clearly demonstrated its reliability to guide ALND decision. Conclusions: Our results showed that OSNA is an excellent method for the detection of metastases in SLN and its adoption in our clinical practice has determined a significant improvement in the diagnosis of metastatic BC.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-09.
Chiari type I malformation is one of the posterior fossa maldevelopments with which different clinical manifestations have been associated. Seizures have only recently been associated with Chiari ...type I malformation. This study reports on 4 children with epilepsy (2M, 2F; age range 8–15 y) diagnosed with Chiari type I malformation by brain magnetic resonance imaging (MRI), in whom no cortical structural involvement was observed. In these patients an interictal ethylcysteinate‐dimer‐single‐photon emission computed tomographic (ECD‐SPECT) study was performed to define more precisely the relationship between Chiari type I malformation and seizures. In these patients the hypoperfusion area correlated with electroencephalographic (EEG) focal abnormalities. These hypoperfusion s may represent the functional aspect of a cerebral microdysgenesis; seizures and EEG epileptic anomalies may also be linked to the complex network connection between cortices and cerebellar hemispheres. A cerebellar hypoperfusion was also detected in two of the four examined patients, indicating a functional or structural involvement.
Conclusion: Interictal SPECT scans are helpful for the clarification of seizures in patients with Chiari type I malformation.
The purpose of this perspective is to highlight the merit of the reptile integument as an experimental model. Reptiles represent the first amniotes. From stem reptiles, extant reptiles, birds and ...mammals have evolved. Mammal hairs and feathers evolved from Therapsid and Sauropsid reptiles, respectively. The early reptilian integument had to adapt to the challenges of terrestrial life, developing a multi-layered stratum corneum capable of barrier function and ultraviolet protection. For better mechanical protection, diverse reptilian scale types have evolved. The evolution of endothermy has driven the convergent evolution of hair and feather follicles: both form multiple localized growth units with stem cells and transient amplifying cells protected in the proximal follicle. This topological arrangement allows them to elongate, molt and regenerate without structural constraints. Another unique feature of reptile skin is the exquisite arrangement of scales and pigment patterns, making them testable models for mechanisms of pattern formation. Since they face the constant threat of damage on land, different strategies were developed to accommodate skin homeostasis and regeneration. Temporally, they can be under continuous renewal or sloughing cycles. Spatially, they can be diffuse or form discrete localized growth units (follicles). To understand how gene regulatory networks evolved to produce increasingly complex ectodermal organs, we have to study how prototypic scale-forming pathways in reptiles are modulated to produce appendage novelties. Despite the fact that there are numerous studies of reptile scales, molecular analyses have lagged behind. Here, we underscore how further development of this novel experimental model will be valuable in filling the gaps of our understanding of the Evo-Devo of amniote integuments.
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