662 Dissecting the CD226 immune axis in the tumor microenvironment using CyTOF-based high-dimensional immunophenotyping

BackgroundIn recent years, a regulatory network involving nectin/nectin-like immune receptors has emerged as a potential point of manipulation for cancer immunotherapy. Central to this axis, CD226 (DNAM-1) is a T and NK cell co-stimulatory receptor that competes for ligand (CD155 and CD112) binding with multiple inhibitory receptors (TIGIT, CD96, and PVRIG [CD112R]). Despite a large body of literature for TIGIT, detailed cellular characterization of the entire axis is still lacking. Therefore, we used mass cytometry (CyTOF) to systematically evaluate expression of the CD226 axis in tumors from a range of indications.MethodsTo thoroughly characterize the CD226 axis in the tumor microenvironment, we immunophenotyped approximately 100 tumor samples derived from a variety of cancer types using a bespoke 46-parameter CyTOF panel. Human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents under an IRB/EC approved protocol. Using a suite of high-dimensional analytical tools, including FlowSOM, UMAP, and tSNE, we revealed distinct expression profiles for each receptor; a finding that was previously obscured due to a lack of sufficient resolution.ResultsWe observed a notable divergence in expression profiles between the CD226 axis members across tumor indications. For example, TIGIT expression was found to be highest on activated CD4+ regulatory T (Treg) cells, where its expression correlated strongly with ICOS, FoxP3, CD25, and CCR8. By contrast, CD96 and PVRIG exhibited broad expression across intratumoral T and NK cell populations. Other receptors (e.g., CD226) demonstrated variegated expression profiles across T and NK cell subsets. Finally, despite relatively consistent expression profiles of certain CD226 axis (i.e., TIGIT on Treg cells) across tumors, we also found several cell subsets/clusters unique to specific indications.ConclusionsUsing high-parameter CyTOF analysis, we were able to thoroughly characterize the CD226 axis (CD226, TIGIT, CD96, PVRIG) and related immune receptors across a range of tumor indications. These analyses revealed divergent expression profiles for each CD226 axis member, suggesting distinct/contextual biological role(s) for each receptor. However, future studies will need to dissect the importance of the distinct cellular representation for each CD226 axis member.Ethics ApprovalAll samples were purchased from Discovery Life Sciences (DLS). DLS represents and warrants that it has ownership of all Products available for sale and has properly obtained, where required under HHS/OHRP 45 CFR 46.102 (d) (f), IRB approval (or appropriate research approval for institutions outside the U.S.) for study protocols and informed consent documents for all human subject derived biological materials.

Suscetibilidade à erosão hídrica do solo: bacia hidrográfica do rio Capim (MA-PA)

The objective of this study was to analyze the sustainability to water erosion in the Capim river/PA-MA. Acquired precipitation (GPCC), slope (TOPODATA project), land use and land cover data (MapBiomas) and pedology (Brazilian Soil Classification System) were obtained. Based on these variables, in a Geographic Information System environment, the product representing the sustainability to soil water erosion was generated. A sustainability gradient for soil water erosion was observed in the SE-NW direction, where it was higher near the mouth of the Capim River. The other variables were: clinical component presenting predominance of stability and high sustainability in the south of the basin; land use influences the entire axis of the basin, indicating instability in the medium-low Capim and in the extreme southeast. It was observed that the sustainability to erosion in the Capim watershed is motivated by intensified land use near the mouth. The zoning carried out in the basin is a warning sign for the municipalities of São Domingos do Capim, Rondon do Pará and Goianésia do Pará.

Natural agents modulating ACE-2: A review of compounds with potential against SARS-CoV-2 infections

: One of the biggest challenges of public health worldwide is reducing the number of events and deaths related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase that degrades angiotensin II into angiotensin 1-7, has been identified as a potent receptor for SARSCoV-2. In the last decades, ACE inhibition has assumed a central role in reducing cardiovascular and renal events. However, with the advent of COVID-19, attention has been turned to ACE-2 as a possible target to reduce virus binding to different human cells. This review aims to discuss recent developments related to medicinal properties of natural compounds as ACE/ACE-2 inhibitors, which should be highlighted in the future development of studies looking for modulators in SARSCoV-2 infection. Data show that bioactive compounds isolated from several natural products act by inhibiting ACE/ACE2, which changes the entire axis of this system. Of the compounds addressed in this review, 7 phenolic compounds, including quercetin, curcumin, naringenin, luteolin, hesperidin, mangiferin, and gallic acid showed binding affinity with molecular ACE-2 target in silico, and 1, esculetin, decreased ACE-2 expression in vivo. Regarding terpenoids and alkaloids, nimbin, withaferin A, andrographolide, zingiberene and, berberine, piperine and thebaine, respectively, showed binding affinity with molecular ACE-2 target in silico. These findings reinforce the need for future preclinical and clinical studies on these compounds and specific inhibitory effects on ACE-2 of all the other compounds described herein only as nonspecific ACE inhibitors. It is important to mention that some natural compounds such as magnolol, resveratrol, rosmarinic acid, tanshinone IIA, and nicotine have also demonstrated the potential to increase the activity or expression of ACE-2, and could therefore aggravate SARS-CoV-2 infection.

MAKNA TEOLOGI DALAM NOVEL TUHAN MAHA ASYIK SUDJIWO TEDJO DAN DR. MN. KAMBA

God, with its various mysteries, has given man the element that the search for Him for a search which - apart from being a continuous and unending activity - also gives pleasure. That is why God is most fun: either as an object of study, or as the goal of the entire axis of human activity. The author's understanding of God is very interesting to know, because this book of God is Most Fun is very different from other Theology books. The thinking method used is hermeneutics. The results of research on the novel Tuhan Maha Asik written by Sudjiwo Tedjo and DR. M N. Kamba, shows a direction in unique stories, starting from the discussion of wayang, marhain, worms, self and so on, which is presented with analogies in the style of children. The theological meaning contained in this book is theology of authentic self. Where we can know God through each human being, the self that is meant here is a natural self, not a self that has been entered by concepts formed from society or from outside.

Holocene Evolution of the Burano Paleo-Lagoon (Southern Tuscany, Italy)

The study of Burano paleo-lagoon—Wetland of International Value, has allowed us to better define and extend the reconstruction of the Holocene paleoenvironmental evolution of the paleo-lagoons previously studied, located on the Tyrrhenian coast in central Italy. The investigated area is located in Southern Tuscany near the Burano Lake. The area was investigated by means of field surveys, historical maps, 16 coring, sedimentological, palynological and microfaunal analyses (foraminifera and ostracods), combined with robust geochronological control provided by 52 datings (14C and OSL). The study allowed us to reconstruct the environmental and morphological evolution of the Burano paleo-lagoon during the last 8000 years and to hypothesize a Rise Sea Level (RSL) curve. In this context, 5 main evolutionary phases have been recognized. (1) before 7.5 ka BP in the southern-eastern part, an open lagoon developed; (2) ~6 ka BP a barrier-lagoon system develops throughout the entire area and the lagoon progressively changed from open to closed one; (3) ~5 ka BP the width of the lagoon increases and a lacustrine facies appears along the entire axis of the coastal basin; (4) ~4 ka BP the lacustrine facies shows a discontinuous distribution respect to the previous phase; (5) during the last 4 ka the lacustrine facies disappear and the lagoon turns into a wetland area.

COERCIVE SOLVABILITY CONDITIONS OF THE THREE-ORDER DEGENERATE DIFFERENTIAL EQUATIONS

In this paper, we consider one class of the singular nonlinear third-order differential equations given on the entire axis. We show sufficient conditions for the existence of a solution to this equation and the satisfiability of the coercive estimate for solution. The considered equation has the following features. Its intermediate coefficient is not bounded and does not obey to a lower coefficient. In the literature, such equations are called the degenerate differential equations. Further, the corresponding differential operator is not semi-bounded: its energy space may not belong to the Sobolev classes. Previously, the solvability questions of the third-order singular differential equations was studied only in the case that their intermediate coefficients are equal to zero. The main result of this work is proved on the basis of one separability theorem for the linear third-order degenerate differential operators, Schauder's fixed point theorem and some Hardy type weighted integral inequalities.

Paracellular transport of phosphate along the intestine

Inorganic phosphate (Pi) is crucial for many biological functions, such as energy metabolism, signal transduction, and pH buffering. Efficient systems must exist to ensure sufficient supply for the body of Pi from diet. Previous experiments in humans and rodents suggest that two pathways for the absorption of Pi exist, an active transcellular Pi transport and a second paracellular pathway. Whereas the identity, role, and regulation of active Pi transport have been extensively studied, much less is known about the properties of the paracellular pathway. In Ussing chamber experiments, we characterized paracellular intestinal Pi permeabilities and fluxes. Dilution potential measurements in intestinal cell culture models demonstrated that the tight junction is permeable to Pi, with monovalent Pi having a higher permeability than divalent Pi. These findings were confirmed in rat and mouse intestinal segments by use of Ussing chambers and a combination of dilution potential measurements and fluxes of radiolabeled 32Pi. Both techniques yielded very similar results, showing that paracellular Pi fluxes were bidirectional and that Pi permeability was ~50% of the permeability for Na+ or Cl−. Pi fluxes were a function of the concentration gradient and Pi species (mono- vs. divalent Pi). In mice lacking the active transcellular Pi transport component sodium-dependent Pi transporter NaPi-IIb, the paracellular pathway was not upregulated. In summary, the small and large intestines have a very high paracellular Pi permeability, which may favor monovalent Pi fluxes and allow efficient uptake of Pi even in the absence of active transcellular Pi uptake. NEW & NOTEWORTHY The paracellular permeability for phosphate is high along the entire axis of the small and large intestine. There is a slight preference for monovalent phosphate. Paracellular phosphate fluxes do not increase when transcellular phosphate transport is genetically abolished. Paracellular phosphate transport may be an important target for therapies aiming to reduce intestinal phosphate absorption.

On the Complexity of Logistic Regression Models

We investigate the complexity of logistic regression models, which is defined by counting the number of indistinguishable distributions that the model can represent (Balasubramanian, 1997 ). We find that the complexity of logistic models with binary inputs depends not only on the number of parameters but also on the distribution of inputs in a nontrivial way that standard treatments of complexity do not address. In particular, we observe that correlations among inputs induce effective dependencies among parameters, thus constraining the model and, consequently, reducing its complexity. We derive simple relations for the upper and lower bounds of the complexity. Furthermore, we show analytically that defining the model parameters on a finite support rather than the entire axis decreases the complexity in a manner that critically depends on the size of the domain. Based on our findings, we propose a novel model selection criterion that takes into account the entropy of the input distribution. We test our proposal on the problem of selecting the input variables of a logistic regression model in a Bayesian model selection framework. In our numerical tests, we find that while the reconstruction errors of standard model selection approaches (AIC, BIC, [Formula: see text] regularization) strongly depend on the sparsity of the ground truth, the reconstruction error of our method is always close to the minimum in all conditions of sparsity, data size, and strength of input correlations. Finally, we observe that when considering categorical instead of binary inputs, in a simple and mathematically tractable case, the contribution of the alphabet size to the complexity is very small compared to that of parameter space dimension. We further explore the issue by analyzing the data set of the “13 keys to the White House,” a method for forecasting the outcomes of US presidential elections.

FORMULA OF INVERSION FOR RATIONAL CHARACTERISTIC FUNCTIONS OF PROBABILITY DISTRIBUTIONS

The paper deals with the problem of clarifying the well-known inversion formulas for distribution functions, usually describing the increment of these functions. The validity of the corresponding inversion formulas for the distribution function π and their densities has been proved for the particular case of distributions with rational characteristic functions. The obtained formulas for distribution functions, which include additionally constant terms equal to 0.5, were not previously known. Functions of positively distributed random variables and quantities distributed over the entire axis have been considered separately. To test the hypothesis of fairness of the obtained treatment formula, including a previously unknown term equal to 0.5, in the general case there have been given examples of calculating distribution functions, whose characteristic functions are not considered as rational functions: for constant and uniform laws. The verification confirmed the objectiveness of the formulated hypothesis about the obtained validity of the inversion form for arbitrary distribution functions. It has also been shown that any distribution function and any density can be represented as a limit of a mixture of gamma distributions (distribution functions and densities), having shifts along the abscissa axis and, possibly, with altered signs of the arguments. The obtained result proves that the set of gamma distributions with shifted arguments is uniformly dense in the set of all distributions.