An intermediate effect size variant in UMOD confers risk for chronic kidney disease

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare, large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD) while common, low-effect variants strongly associate with kidney function and risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in gnomAD with MAF ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ~1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD and is associated with kidney failure in the 100,000 Genomes Project (OR 3.99; 1.84-8.98) and the UK Biobank (OR 4.12; 1.32-12.85). Compared to canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD, intermediate reduction of urinary UMOD levels, in line with an intermediate trafficking defect in vitro. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides novel insights into the mechanisms of ADTKD and the genetic architecture of CKD.

Reduction Effect and Mechanism Analysis of Carbon Trading Policy on Carbon Emissions from Land Use

The reduction of carbon emissions from land use (CELU) is critical for China to achieve carbon neutrality, which may be greatly facilitated by carbon trading policies. Previous studies of the emission reduction effects of carbon trading policies focused mostly on the reduction of carbon source emissions, and there is a lack of research from the comprehensive perspective of carbon sources and carbon sinks. Understanding the effect of carbon trading policies on emission reduction from the perspective of CELU may help to improve the evaluation system of carbon trading policies, as well as provide important implications for the construction of China’s carbon trading market in the context of global carbon neutrality. Here, based on China’s current carbon-trading pilot areas, quasi-natural experiments were conducted by using the CELU data from 2005 to 2017, the synthetic control method (SCM) and the mediation effect model, aiming to empirically study the reduction effect and mechanism of carbon trading policies on CELU. The following main findings were obtained. (1) Carbon trading policies have had a significant reduction effect on the average CELU of the pilot areas by at least four million tons per year during the study period. (2) The carbon emission reduction effect of carbon trading policies has certain regional heterogeneity. (3) Carbon trading policies reduce CELU through the intermediate effect of energy structure, whose contribution rate reaches 30.433%. (4) Carbon trading policies did not achieve the Porter effect of technological progress during the study period, and technological progress has no significant intermediate effect on the reduction of CELU by carbon trading policy. Based on the above findings, the following policy implications can be proposed. Carbon trading and carbon offset should be studied from a comprehensive perspective of land use; regional heterogeneity should be considered when promoting the carbon emission trading system nationwide; and the energy structure should be optimized continuously.

Research on the Influence of Major Shareholders’ Reduction of Tobacco Related Listed Companies on Enterprise Value: Based on the Intermediate Effect of Financing Constraints

Objectives: Compared with ordinary consumer goods, tobacco and tobacco products have their particularity, which not only plays an important role in the economic development of all countries in the world, but also plays a different role in people’s daily life. In China, the production and sales of tobacco leaves, cigarettes and other tobacco products as well as related tobacco machinery and raw and auxiliary materials have an important impact on fiscal revenue. As the Chinese stock market has basically completed the share-trading reform, stocks that were originally restricted from circulation have begun to circulate. With the continuous increase in the number of lifted bans, the phenomenon of major shareholders reducing their shareholding is also happening constantly. Methods: the paper provides empirical evidence to avoid the adverse effects of major shareholders’ reductions on the promotion of corporate value of listed tobacco Enterprises. From the perspective of the flow of shares after the major shareholders reduce their holdings, with the help of the theory of financing constraints, the article uses an empirical analysis method to explore the effect of the major shareholders of listed tobacco Enterprises on the value of the reduced listed private companies after they reduce their holdings. Results: the results show that when the equity of listed tobacco Enterprises is acquired by state-owned enterprises after the reduction of major shareholders, that is, when state-owned enterprises participate in the shares, the reduction of major shareholders contributes to the increase of the value of tobacco Enterprises. And the larger the reduction proportion of major shareholders, the greater the value of the enterprise. However, when major shareholders reduce their holdings and the equity is acquired by investment institutions and small and medium shareholders, it is not conducive to the improvement of corporate value. Especially when major shareholders maliciously reduce their holdings, it would have an adverse impact on the company’s development and stock price. Conclusion: therefore, from the perspective of enterprise value appreciation, no matter what the purpose is for major shareholders to reduce their holdings, the flow of equity to state-owned enterprises after the reduction is the best choice. The financing constraints of the enterprise could be reduced and it helps enhance the value of the enterprise.

Efficiency of phonolite as a potassium source for Paiaguás palisadegrass

ABSTRACT Potassium chloride (KCl) is the most widely used potassium source to meet crops requirements. However, Brazil’s dependence on imports to meet the national demand demonstrates the need to assess the efficiency of other sources of this nutrient. The present study aimed to assess the agronomic efficiency of phonolite in natura and its mixture with a water-soluble source (KCl), for Paiaguás palisadegrass. The experiment was conducted in a greenhouse, with a sandy clay loam typic Hapludox. A completely randomized block design was used, in a 3 x 5 factorial scheme, consisting of three K sources (KCl, phonolite and a 30 % of KCl + 70 % of phonolite blend) and five doses of the nutrient (0, 50, 100, 150 and 200 mg kg-1), with four replications. The phonolite doses promoted a linear increase in the dry weight production, albeit inferior to KCl for all the cuttings, whereas the KCl (30 %) and phonolite (70 %) blend showed a better fertilization efficiency than phonolite alone, which exhibited an intermediate effect. The agronomic efficiency was 29 % for the phonolite alone and 63 % for the blend, and the critical K levels in the soil and shoots were, respectively, 1.4 mmolc dm-3 and 8.7 g kg-1.

The N-Terminal Region of Yeast Protein Phosphatase Ppz1 Is a Determinant for Its Toxicity

The Ppz enzymes are Ser/Thr protein phosphatases present only in fungi that are characterized by a highly conserved C-terminal catalytic region, related to PP1c phosphatases, and a more divergent N-terminal extension. In Saccharomyces cerevisiae, Ppz phosphatases are encoded by two paralog genes, PPZ1 and PPZ2. Ppz1 is the most toxic protein when overexpressed in budding yeast, halting cell proliferation, and this effect requires its phosphatase activity. We show here that, in spite of their conserved catalytic domain, Ppz2 was not toxic when tested under the same conditions as Ppz1, albeit Ppz2 levels were somewhat lower. Remarkably, a hybrid protein composed of the N-terminal extension of Ppz1 and the catalytic domain of Ppz2 was as toxic as Ppz1, even if its expression level was comparable to that of Ppz2. Similar amounts of yeast PP1c (Glc7) produced an intermediate effect on growth. Mutation of the Ppz1 myristoylable Gly2 to Ala avoided the localization of the phosphatase at the cell periphery but only slightly attenuated its toxicity. Therefore, the N-terminal extension of Ppz1 plays a key role in defining Ppz1 toxicity. This region is predicted to be intrinsically disordered and contains several putative folding-upon-binding regions which are absent in Ppz2 and might be relevant for toxicity.

Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β7 integrin expression

The regulation of integrin expression and function controls interactions of immune cells and targets their trafficking locally and systemically. We show here that the tyrosine phosphatase SHP-1 is required for lymphocyte surface expression of the intestinal immune response-associated integrin β7, but not for β1 or β2 integrins. Viable motheaten mice deficient for SHP-1 have less β7 on T cells and lack β7 on B cells. SHP-1 function is targeted in B cells by the B cell specific lectin CD22 (Siglec-2), suggesting a potential role for CD22 in β7 expression. CD22-deficiency on B cells phenocopies the effects of SHP-1 haplodeficiency. Mechanistically, we show that SHP-1 suppresses β7 endocytosis: internalization of β7 but not β1 integrin is accelerated in SHP-1+/− and CD22−/− B cells. Moreover, mutations in CD22 cytoplasmic SHP1-binding ITIM sequences reduce α4β7 comparably, and loss of CD22 lectin activity has an intermediate effect suggesting a model in which the CD22 ITIM sequences recruit SHP-1 to control β7 expression. Integrin α4β7 selectively contributes to cell interactions in intestinal immunity. Consistent with this, CD22 deficient and SHP-1+/− B cells display reduced β7-dependent homing to gut associated Peyer’s patches (PP); and CD22-deficiency impairs intestinal but not systemic antibody responses and delays clearance of the gut pathogen rotavirus. The results define a novel role for SHP-1 in the differential control of leukocyte integrins and an unexpected integrin β7-specific role for CD22-SHP-1 interplay in mucosal immunity.

EFFECTS OF EXERCISE PROGRAM ON COORDINATION AND EXPLOSIVE POWER IN UNIVERSITY DANCE STUDENTS

The aim of this research is to determine the effects of a ten-week modern and recreational dance exercise program and trunk and leg muscle strengthening exercises on the coordination and explosive power of student-age female dancers. The total number of participants was 54, of which 27 made up the experimental group who participated in an experimental exercise program and 27 the control group. The experimental group performed Hip Hop and Dancehall dances and trunk and leg muscle strengthening exercises 3 times a week for 90 min each. The control group had no additional forms of exercise other than regular daily activities. The coordination of the participants was evaluated on the basis of six tests (Side Steps, 20 Steps forward Twirling a Baton, Skipping the Horizontal Jump Rope, Turning in 6 squares, Hand-Foot Drumming and Agility test with a Baton) and two tests for determining explosive power parameters (the squat jump and countermovement jump). Results showed statistical significance between the groups in 5 variables of coordination at the multivariate and univariate level (p<.05, p<.01), and in both variables of explosive power at the univariate level (p<.05). A large and intermediate effect size of the experimental program was determined for 5 variables of coordination, and intermediate effect size for both variables of explosive power. The results of this study showed that a ten-week exercise program for recreational and modern dance and exercises for strengthening the muscles of the torso and legs have a positive effect on the changes in the parameters of coordination and explosive power in student-age female dancers.

Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents

It is acknowledged that cancer cells are able to undergo senescence in response to clinically used chemotherapeutics. Moreover, recent years have provided evidence that some drugs can selectively remove senescent cells. Therefore, it is essential to properly identify and characterize senescent cells, especially when it comes to cancer. Senescence was induced in various cancer cell lines (A549, SH-SY-5Y, HCT116, MDA-MB-231, and MCF-7) following treatment with doxorubicin, irinotecan, methotrexate, 5-fluorouracil, oxaliplatin, or paclitaxel. Treatment with tested chemotherapeutics resulted in upregulation of p21 and proliferation arrest without cytotoxicity. A comparative analysis with the use of common senescence markers (i.e., morphology, SA-β-galactosidase, granularity, secretory phenotype, and the level of double-stranded DNA damage) revealed a large diversity in response to the chemotherapeutics used. The strongest senescence inducers were doxorubicin, irinotecan, and methotrexate; paclitaxel had an intermediate effect and oxaliplatin and 5-fluorouracil did not induce senescence. In addition, different susceptibility of cancer cells to senescence was observed. A statistical analysis aimed at finding any relationship between the senescence markers applied did not show clear correlations. Moreover, increased SA-β-gal activity coupled with p21 expression proved not to be an unequivocal senescence marker. This points to a need to simultaneously analyze multiple markers, given their individual limitations.