The ability to develop a chemical into a drug depends on multiple factors. Beyond potency and selectivity, ADME/PK and the toxicological profile of the compound play a significant role in its ...evaluation as a candidate for development. Those factors are being brought into bear earlier in the discovery process and even into the design of libraries for screening. The purpose of our study is the comparative analysis of simple physical characteristics of compounds that have been reported to be mutagens and nonmutagenic ones. The analysis of differences can lead to the development of knowledge-based biases in the libraries designed for massive screening. For each of four Salmonella strains, TA-98, TA-100, TA-1535, and TA-1537, an analysis of the statistical significance of the deviance of the averages for a number of global properties was carried out. The properties studied included parameters, such as topological indices, and bit strings representing the presence or absence of certain chemical moieties. The results suggest that mutagens display a larger number of hydrogen bond acceptor centers for most strains. Moreover, the use of bit strings points to the importance of certain molecular fragments, such a nitro groups, for the outcome of a mutagenicity study. Development of multivariate models based on global molecular properties or bit strings point to a small advantage of the latter for the prediction of mutagenicity. The benefits of the bit strings are in accord with the use of fragment-based approaches for the prediction of carcinogenicity and mutagenicity in methods described in the literature.
In order to ameliorate the dearth of existing scientific knowledge concerning the hydrography of the Pontevedra Ria, a systematic investigation was carried out between October 1997–98. Salinity ...variations were closely related to river discharge whereas bottom waters presented oceanic characteristics over the whole year. Current was controlled by tide, river discharge, and wind in the internal ria where the highest velocities were directed along the ria channel with a low transverse component. Favorable atmospheric conditions in spring induced coastal upwelling up the continental shelf. In May the upwelling was sufficiently strong to be detected in the inner ria and intensified in July and August, cooling the ria water to 12°–14°C. Upwelling ceased in September, and from November to March seawater transported by the poleward current (35.9; 15°C) was detected on the shelf. From January until March, unanticipated favorable upwelling conditions provoked an influx of poleward inside the ria. Ria intrusion of poleward water and association with occasional winter upwelling conditions has not been observed previously. Isopycnic three‐dimensional (3‐D) surface and 2‐D isopycnal maps show that with high river runoff or intense upwelling, lower‐salinity water leaves the ria near the northern margin in the surface layer. Under negative upwelling conditions, the water is partially dammed inside the ria and exits the ria when the wind speed falls. During upwelling events, ENACW penetrated the ria, especially near the southern shore. Arrival of ENACW at the northern entrance impedes the outward water flow through this mouth.
Regional information regarding the characteristics of patients with coronavirus disease (COVID)-19 is needed for a better understanding of the pandemic.
The objective of the study to describe the ...clinical features of COVID-19 patients diagnosed in a tertiary-care center in Mexico City and to assess differences according to the treatment setting (ambulatory vs. hospital) and to the need of intensive care (IC).
We conducted a prospective cohort, including consecutive patients with COVID-19 from February 26, 2020 to April 11, 2020.
We identified 309 patients (140 inpatients and 169 outpatients). The median age was 43 years (interquartile range, 33-54), 59.2% men, and 18.6% healthcare workers (12.3% from our center). The median body mass index (BMI) was 29.00 kg/m
and 39.6% had obesity. Compared to outpatients, inpatients were older, had comorbidities, cough, and dyspnea more frequently. Twenty-nine (20.7%) inpatients required treatment in the IC unit (ICU). History of diabetes (type 1 or 2) and abdominal pain were more common in ICU patients compared to non-ICU patients. ICU patients had higher BMIs, higher respiratory rates, and lower room-air capillary oxygen saturations. ICU patients showed a more severe inflammatory response as assessed by white blood cell count, neutrophil and platelet count, C-reactive protein, ferritin, procalcitonin, and albumin levels. By the end of the study period, 65 inpatients had been discharged because of improvement, 70 continued hospitalized, and five had died.
Patients with comorbidities, either middle-age obese or elderly complaining of fever, cough, or dyspnea, were more likely to be admitted. At admission, patients with diabetes, high BMI, and clinical or laboratory findings consistent with a severe inflammatory state were more likely to require IC.
The Tec family non-receptor tyrosine kinase Itk is expressed in T cells, natural killer (NK) cells and mast cells. The role of this multidomain kinase in T cells has been linked to T-cell ...receptor–CD3 (TCR–CD3) signaling and Itk regulates and amplifies signals through the costimulatory receptors CD28 and CD2. Itk binds a specific subset of membrane inositol phospholipids through its pleckstrin homology (PH) domain; it forms functional molecular complexes with a variety of signaling proteins through its Tec homology (TH), Src homology 3 (SH3) and SH2 domains; and it phosphorylates several protein substrates on tyrosine residues in cells. Among >500 protein kinases expressed in the human proteome, we propose that Itk is a validated T-cell target suitable for pharmaceutical intervention. Targeted disruption of protein–protein interactions between Itk and some of its binding partners, and inhibition of the intrinsic kinase activity of Itk, could provide platforms through which to alter T-cell activation in immunological and inflammatory disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background
The diagnosis of patients with mutations in the
VCP
gene can be complicated due to their broad phenotypic spectrum including myopathy, motor neuron disease and peripheral neuropathy. ...Muscle MRI guides the diagnosis in neuromuscular diseases (NMDs); however, comprehensive muscle MRI features for
VCP
patients have not been reported so far.
Methods
We collected muscle MRIs of 80 of the 255 patients who participated in the “VCP International Study” and reviewed the T1-weighted (T1w) and short tau inversion recovery (STIR) sequences. We identified a series of potential diagnostic MRI based characteristics useful for the diagnosis of
VCP
disease and validated them in 1089 MRIs from patients with other genetically confirmed NMDs.
Results
Fat replacement of at least one muscle was identified in all symptomatic patients. The most common finding was the existence of patchy areas of fat replacement. Although there was a wide variability of muscles affected, we observed a common pattern characterized by the involvement of periscapular, paraspinal, gluteal and quadriceps muscles. STIR signal was enhanced in 67% of the patients, either in the muscle itself or in the surrounding fascia. We identified 10 diagnostic characteristics based on the pattern identified that allowed us to distinguish
VCP
disease from other neuromuscular diseases with high accuracy.
Conclusions
Patients with mutations in the
VCP
gene had common features on muscle MRI that are helpful for diagnosis purposes, including the presence of patchy fat replacement and a prominent involvement of the periscapular, paraspinal, abdominal and thigh muscles.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
There is no data on mortality of acromegaly diagnosed in the elderly.
To compare clinical characteristics, GH-related comorbidities, therapeutic approaches and mortality of patients diagnosed before ...or after 2010 and to assess overall mortality compared with the general Spanish population.
Spanish tertiary care centers.
Retrospective evaluation of 118 patients diagnosed with acromegaly at or above the age of 65. Kaplan-Meier curves were constructed to trace survival, and Cox proportional hazard models were used to assess the risk factors associated with mortality. We also compared mortality with that of the Spanish population by using age- and gender-adjusted standardized mortality ratios (SMR).
No differences were found in first-line treatment or biochemical control, between both periods except for faster biochemical control after 2010. Twenty-nine (24.6%) patients died, without differences between groups, median of follow-up 8.6 years 103, (72.3) months. Overall SMR was 1.02 (95% CI: 0.57-1.54), 0.60 (95% CI: 0.35-1.06) for men and 1.80 (95% CI: 1.07-2.94) for women. The most common cause of death was cardiovascular disease (CVD).
The mortality in patients with acromegaly diagnosed in the elderly was no different between both periods and there was no overall SMR difference from the general Spanish population. However, the SMR was higher in women. As CVD is the leading cause of mortality, it seems advisable to initiate an intense CVD protective treatment as soon as acromegaly is diagnosed, particularly in women, in addition to tight acromegaly control in order to prevent excess mortality.
Human NK cells bear surface receptors that inhibit their cytolytic activity upon specific recognition of MHC class Ia Ags; little is known about the capacity of class Ib molecules to regulate NK cell ...function. We have studied the roles of different NK inhibitory receptors in recognition of the class Ib HLA-G. To this end, we analyzed the ability of an HLA-defective tumor cell line (721.221) transfected with the membrane form of HLA-G1, which contains the three external domains, to inhibit the cytolytic activity mediated by a panel of NK clones from several donors. A substantial proportion of peripheral blood NK clones appeared to be significantly inhibited by the HLA-G1-transfected cell line (referred to as .221-G1); nevertheless, no relation was observed between the expression and the function of serologically identifiable Ig-SF receptors (p58/p70) and specific recognition of .221-G1 cells. Moreover, p58 killer cell inhibitory receptor-IgG soluble fusion proteins specifically bound to 721.221 transfectants bearing their corresponding HLA-C ligands, but only a weak reactivity with .221-G1 cells was detectable. By contrast, most NK clones blocked by HLA-G1 expressed the CD94/NKG2-A inhibitory receptor, and moreover, CD94-specific mAbs reconstituted their cytolytic activity comparably to anti-HLA class I mAbs. These data support the idea that the CD94/NKG2 receptor complex is involved in the recognition of cells expressing HLA-G1.
COVID‐19 in elderly kidney transplant recipients Crespo, Marta; Pérez‐Sáez, María J.; Redondo‐Pachón, Dolores ...
American journal of transplantation,
October 2020, Volume:
20, Issue:
10
Journal Article
Peer reviewed
Open access
The SARS‐Cov‐2 infection disease (COVID‐19) pandemic has posed at risk the kidney transplant (KT) population, particularly the elderly recipients. From March 12 until April 4, 2020, we diagnosed ...COVID‐19 in 16 of our 324 KT patients aged ≥65 years old (4.9%). Many of them had had contact with healthcare facilities in the month prior to infection. Median time of symptom onset to admission was 7 days. All presented with fever and all but one with pneumonia. Up to 33% showed renal graft dysfunction. At infection diagnosis, mTOR inhibitors or mycophenolate were withdrawn. Tacrolimus was withdrawn in 70%. The main treatment combination was hydroxychloroquine and azithromycin. A subset of patients was treated with anti‐retroviral and tocilizumab. Short‐term fatality rate was 50% at a median time since admission of 3 days. Those who died were more frequently obese, frail, and had underlying heart disease. Although a higher respiratory rate was observed at admission in nonsurvivors, symptoms at presentation were similar between both groups. Patients who died were more anemic, lymphopenic, and showed higher D‐dimer, C‐reactive protein, and IL‐6 at their first tests. COVID‐19 is frequent among the elderly KT population and associates a very early and high mortality rate.
The authors report early and high mortality rates for elderly kidney transplant recipients.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
The Emt/Itk/Tsk tyrosine kinase is involved in intracellular signaling events induced by several lymphocyte surface receptors. Modulation of TCR/CD3-induced phospholipase-Cγ1 (PLCγ1) ...activity by the tyrosine kinase Emt/Itk/Tsk has been demonstrated based on studies of Itk-deficient murine T lymphocytes. Here we report a TCR/CD3-regulated association between Emt and PLCγ1 in both normal and leukemic T cells. In addition, this association was enhanced following independent ligation of the CD2, CD4, or CD28 costimulatory molecules, but not of CD5 or CD6 surface receptors, correlating to the induced tyrosine phosphorylation of Emt. Before Ab-induced T cell activation, we found that the Emt-SH3 domain was crucial for the constitutive Emt/PLCγ1 association; however, upon TCR/CD3 engagement, the Emt-SH2 domain was more efficient in mediating the enhanced Emt/PLCγ1 interaction. Furthermore, the PLCγ1-SH3 domain, but not the two PLCγ1-SH2 domains, contributed to formation of the protein complex. Thus, we describe a regulated interaction between Emt and PLCγ1, and based on our studies with individual Emt and PLCγ1 SH2/SH3 domains, we propose a mechanism for this association.
Paracrine and endocrine roles have increasingly been ascribed to extracellular vesicles (EVs) generated by multicellular organisms. Central to the biogenesis, content, and function of EVs are their ...delimiting lipid bilayer membranes. To evaluate research progress on membranes and EVs, the International Society for Extracellular Vesicles (ISEV) conducted a workshop in March 2018 in Baltimore, Maryland, USA, bringing together key opinion leaders and hands-on researchers who were selected on the basis of submitted applications. The workshop was accompanied by two scientific surveys and covered four broad topics: EV biogenesis and release; EV uptake and fusion; technologies and strategies used to study EV membranes; and EV transfer and functional assays. In this ISEV position paper, we synthesize the results of the workshop and the related surveys to outline important outstanding questions about EV membranes and describe areas of consensus. The workshop discussions and survey responses reveal that while much progress has been made in the field, there are still several concepts that divide opinion. Good consensus exists in some areas, including particular aspects of EV biogenesis, uptake and downstream signalling. Areas with little to no consensus include EV storage and stability, as well as whether and how EVs fuse with target cells. Further research is needed in these key areas, as a better understanding of membrane biology will contribute substantially towards advancing the field of extracellular vesicles.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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