Miracle-dz/UniFAR-FTUs huggingface dataset:
A High Endothelial Venule Secretory Protein, Mac25/Angiomodulin, Interacts with Multiple High Endothelial Venule-Associated Molecules Including Chemokines1

We previously reported that mac25/angiomodulin (AGM), a 30-kDa secretory protein, is abundantly expressed in high endothelial venules (HEVs), which play a crucial role in lymphocyte trafficking to the lymph nodes and Peyer’s patches. We report that mac25/AGM interacts preferentially with certain molecules that are expressed in or around HEVs. In particular, mac25/AGM interacted with not only the extracellular matrix proteins and glycosaminoglycans that are expressed in most blood vessels including HEVs, but also with some chemokines that are implicated in the regulation of lymphocyte trafficking, such as the secondary lymphoid-tissue chemokine (SLC; CCL21), IFN-γ-inducible protein 10 (IP-10; CXCL10), and RANTES (CCL5). The binding of mac25/AGM to SLC and IP-10 was dose-dependent and saturable. The binding to IP-10 could be inhibited by SLC but not by a non-mac25/AGM-binding chemokine, EBI1-ligand chemokine (ELC; CCL19). Interestingly, mac25/AGM failed to interact with 18 other chemokines, suggesting that it binds to certain chemokines preferentially. Immunohistochemical analysis indicated that mac25/AGM colocalizes at least partially with SLC and IP-10 at the basal lamina of HEVs. Upon binding with mac25/AGM, SLC and IP-10 retained all their Ca2+-signaling activity in vitro, suggesting that mac25/AGM can hold and present chemokines in the basal lamina of HEVs. These results imply that mac25/AGM plays a multifunctional role, serving not only as an adhesion protein to interact with glycosaminoglycans and extracellular matrix proteins but also as a molecule to present chemokines so that lymphocytes extravasating through HEVs receive further directional cues subsequent to the luminal encounter with lymphoid chemokines.
Astrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition

Accumulation and deposition of amyloid-β (Aβ) in the brain represent an early and perhaps necessary step in the pathogenesis of Alzheimer's disease (AD). Aβ accumulation leads to the formation of Aβ aggregates, which may directly and indirectly lead to eventual neurodegeneration. While Aβ production is accelerated in many familial forms of early-onset AD, increasing evidence indicates that impaired clearance of Aβ is more evident in late-onset AD. To uncover the mechanisms underlying impaired Aβ clearance in AD, we examined the role of low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. Although LRP1 has been shown to play critical roles in brain Aβ metabolism in neurons and vascular mural cells, its role in astrocytes, the most abundant cell type in the brain responsible for maintaining neuronal homeostasis, remains unclear. Here, we show that astrocytic LRP1 plays a critical role in brain Aβ clearance. LRP1 knockdown in primary astrocytes resulted in decreased cellular Aβ uptake and degradation. In addition, silencing of LRP1 in astrocytes led to downregulation of several major Aβ-degrading enzymes, including matrix metalloproteases MMP2, MMP9, and insulin-degrading enzyme. More important, conditional knock-out of the Lrp1 gene in astrocytes in the background of APP/PS1 mice impaired brain Aβ clearance, exacerbated Aβ accumulation, and accelerated amyloid plaque deposition without affecting its production. Together, our results demonstrate that astrocytic LRP1 plays an important role in Aβ metabolism and that restoring LRP1 expression and function in the brain could be an effective strategy to facilitate Aβ clearance and counter amyloid pathology in AD. SIGNIFICANCE STATEMENT Astrocytes represent a major cell type regulating brain homeostasis; however, their roles in brain clearance of amyloid-β (Aβ) and underlying mechanism are not clear. In this study, we used both cellular models and conditional knock-out mouse models to address the role of a critical Aβ receptor, the low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. We found that LRP1 in astrocytes plays a critical role in brain Aβ clearance by modulating several Aβ-degrading enzymes and cellular degradation pathways. Our results establish a critical role of astrocytic LRP1 in brain Aβ clearance and shed light on specific Aβ clearance pathways that may help to establish new targets for AD prevention and therapy.
Usefulness of Exercise Test and Myocardial Perfusion–Gated Single Photon Emission Computed Tomography to Improve the Prediction of Major Events

Background—The incremental prognostic value of myocardial perfusion–gated single photon emission computed tomography (MPGS) compared with exercise test has not yet been properly evaluated. Methods and Results—Five thousand six hundred seventy-two consecutive patients with known or suspected coronary disease undergoing exercise MPGS between 1997 and 2007 were included. Three-year predictive models for total death and death from cardiovascular causes or acute myocardial infarction (ie, major cardiovascular events [MCE]) were built using Cox-regression modeling, including only the clinical information. Then the exercise and MPGS information was sequentially added. The added discriminative ability of exercise test information and MPGS was assessed by net reclassification improvement and integrated discrimination improvement. The increase in predictive ability of exercise information for death and MCE was high as assessed by net reclassification improvement (0.199 and 0.263) and integrated discrimination improvement (0.042 and 0.021). The only variable of MPGS associated with total death was ejection fraction (hazard ratio, 0.84; 95% confidence interval, 0.79–0.89; P<0.001). Global stress ischemic score emerged as an additional variable associated with MCE (hazard ratio, 1.07; 95% confidence interval, 1.02–1.12; P=0.007). Adding MPGS information barely improved the prognostic value for total death (net reclassification improvement, 0.017; integrated discrimination improvement, 0.013), but it increased for MCE (net reclassification improvement, 0.122; integrated discrimination improvement, 0.033). Conclusions—Adding MPGS information to exercise information does not improve prediction of total death, although it allows a more accurate prediction of MCE.
AGRICULTURAL TOTAL FACTOR PRODUCTIVITY CHANGE AND ITS DETERMINANTS IN EUROPEAN UNION COUNTRIES

DomansKa, K. , T. KijeK and a. nowaK, 2014. agricultural total factor productivity change and its determinants in european Union countries. Bulg. J. Agric. Sci., 20: 1273-1280 The present study concerns the measurement of changes in agricultural total factor productivity in 27 european Union (eU) countries. The analysis included the years 2007--2011. The study was conducted based on malmquist productivity index completed with decomposition on technological changes and technical efficiency changes. In addition, the determinants of total productivity were identified in the study, and econometric modeling of their effect on total factor productivity (TFP) was conducted using Tobit model. The study demonstrated a small increase in agricultural TFP for the whole sample of 27 EU countries over the examined period. The reason of this increase was mainly the changes in technical efficiency. An effect of technological changes was in turn relatively low and of negative character. The analysis of the factors determining TFP changes demonstrated that factors like: percentage of farm managers with complete agricultural education, average farm area and economy openness measured as a ratio of total export to total import are the stimulants. in turn, the variable like the share of farm managers aged above 55 years appeared to be dissimulated. it is worth to emphasize that soil quality, additional payment to investments and number of students’ in agricultural and related fields of study was insignificant from the total productivity changes point of view.
Picosecond kinetics of the initial photochemical electron-transfer reaction in bacterial photosynthetic reaction centers.

The absorption changes that occur in reaction centers of the photosynthetic bacterium Rhodopseudomonas sphaeroides during the initial photochemical electron-transfer reaction have been examined. Measurements were made between 740 and 1300 nm at 295 and 80 K by using a pulse-probe technique with 610-nm, 0.8-ps flashes. An excited singlet state of the bacteriochlorophyll dimer P* was found to give rise to stimulated emission with a spectrum similar to that determined previously for fluorescence from reaction centers. The stimulated emission was used to follow the decay of P*; its lifetime was 4.1 +/- 0.2 ps at 295 K and 2.2 +/- 0.1 ps at 80 K. Within the experimental uncertainty, the absorption changes associated with the formation of a bacteriopheophytin anion, Bph-, develop in concert with the decay of P* at both temperatures, as does the absorption increase near 1250 nm due to the formation of the cation of P, P+. No evidence was found for the formation of a bacteriochlorophyll anion, Bchl-, prior to the formation of Bph-. This is surprising, because in the crystal structure of the Rhodopseudomonas viridis reaction center [Deisenhofer, J., Epp, O. , Miki, K. , Huber, R. , & Michel, H. (1984) J. Mol. Biol. 180, 385-398] a Bchl is located approximately in between P and the Bph. It is possible that Bchl- (or Bchl+) is formed but, due to kinetic or thermodynamic constraints, is never present at a sufficient concentration for us to observe. Alternatively, a virtual charge-transfer state, such as P+Bchl-Bph or PBchl+Bph-, could serve to lower the energy barrier for direct electron transfer between P* and the Bph.
A phylogenetic analysis of morphological and molecular characters of Boraginaceae: evolutionary relationships, taxonomy, and patterns of character evolution

The angiosperm family Boraginaceae includes ca. 1600 species distributed among ca. 110 genera. Some floral features are constant within the family, but many vegetative, floral, pollen, and nutlet traits vary. Utilizing 224 species of Boraginaceae and related taxa, five matrices were constructed with various combinations of morphological characters, three chloroplast DNA regions, and one nuclear ribosomal DNA region. Phylogenetic analyses were conducted for these matrices, and patterns of character evolution were examined. Boraginaceae is resolved as monophyletic, with Wellstedia as its sister. Codon is sister to Boraginaceae + Wellstedia. Although most of the investigated morphological characters have a low consistency index, particular character states are synapomorphies for large clades in each of the tribes of the family. In Boraginaceae, the breeding system heterostyly evolved at least 12 times, which is the largest number of origins resolved in any family; therefore Boraginaceae can serve as a model for the evolution and development of heterostyly. Nutlet ornamentation is most diverse in Cynoglosseae and Trichodesmeae, while pollen and floral features are most variable in Boragineae and Lithospermeae. Phylogenetic relationships and patterns of character evolution identified in the present study set the stage for future work creating an updated taxonomic system of Boraginaceae.
Cleavage of poly(ADP-ribose) polymerase: a sensitive parameter to study cell death.

Proteases play a crucial role in apoptosis or programmed cell death. The aim of this review is to highlight the purpose for which these proteases are activated, i.e., to specifically cleave a select subset of cellular proteins at an appropriate time during cell death. Poly(ADP-ribose) polymerase (PARP), a nuclear protein implicated in DNA repair, is one of the earliest proteins targeted for a specific cleavage to the signature 89-kDa fragment during apoptosis. Characterization of the apoptotic cleavage of PARP and other target proteins helped in understanding the role of cysteine aspartic acid specific proteases (caspases) in the apoptotic process. We have recently identified that in some models of cell death, the cleavage pattern for PARP is different from production of the signature 89-kDa fragment. Necrotic death of HL-60 cells and apoptotic death of Jurkat cells mediated by granzyme B and perforin were accompanied by distinct additional fragments, suggesting cleavage of PARP at other sites by caspases or other death proteases. This review summarizes how detection and characterization of PARP cleavage could serve as a sensitive parameter for identification of different types of cell death and as a marker for activation of different death proteases. The putative biological functions for early cleavage of PARP in apoptosis are also discussed.
The Effects of BMP-2, miR-31, miR-106a, and miR-148a on Osteogenic Differentiation of MSCs Derived from Amnion in Comparison with MSCs Derived from the Bone Marrow

Mesenchymal stromal cells (MSCs) offering valuable anticipations for the treatment of degenerative diseases. They can be found in many tissues including amnion. MSCs from amnion (AM-MSCs) can differentiate into osteoblast similar to that of bone marrow-derived MSCs (BM-MSCs). However, the ability is not much efficient compared to BM-MSCs. This study aimed to examine the effects of BMP-2 and miRNAs on osteogenic differentiation of AM-MSCs compared to those of BM-MSCs. The osteogenic differentiation capacity after miRNA treatment was assessed by ALP expression, ALP activity, and osteogenic marker gene expression. The results showed that the osteogenic differentiation capacity increased after BMP-2 treatment both in AM-MSCs and BM-MSCs. MiR-31, miR-106a, and miR-148a were downregulated during the osteogenic differentiation. After transfection with anti-miRNAs, ALP activity and osteogenic genes were increased over the time of differentiation. The data lead to the potential for using AM-MSCs as an alternative source for bone regeneration. Moreover, the information of miRNA expression and function during osteogenic differentiation may be useful for the development of new therapeutics or enhanced an in vitro culture technique required for stem cell-based therapies in the bone regeneration.
Longitudinal effects of dietary sodium and potassium on blood pressure in adolescent girls.

IMPORTANCE Identification of risk factors early in life for the development of high blood pressure is critical to the prevention of cardiovascular disease. OBJECTIVE To study prospectively the effect of dietary sodium, potassium, and the potassium to sodium ratio on adolescent blood pressure. DESIGN, SETTING, AND PARTICIPANTS The National Heart, Lung, and Blood Institute's Growth and Health Study is a prospective cohort study with sites in Richmond, California; Cincinnati, Ohio; and Washington, DC. Participants included 2185 black and white girls initially aged 9 to 10 years with complete data for early-adolescent to midadolescent diet and blood pressure who were followed up for 10 years. The first examination visits were from March 1987 through February 1988 and follow-up continued until February 1999. Longitudinal mixed models and analysis of covariance models were used to assess the effect of dietary sodium, potassium, and the potassium to sodium ratio on systolic and diastolic blood pressures throughout adolescence and after 10 years of follow-up, adjusting for race, height, activity, television/video time, energy intake, and other dietary factors. EXPOSURES Mean dietary sodium and potassium intakes and the mean potassium to sodium ratio in individuals aged 9 to 17 years. To eliminate potential confounding by energy intake, energy-adjusted sodium and potassium residuals were estimated. MAIN OUTCOMES AND MEASURES Mean systolic and diastolic blood pressures throughout adolescence and at the end of follow-up (individuals aged 17-21 years). RESULTS Sodium intakes were classified as less than 2500 mg/d (19.4% of participants), 2500 mg/d to less than 3000 mg/d (29.5%), 3000 mg/d to less than 4000 mg/d (41.4%), and 4000 mg/d or more (9.7%). Potassium intakes ranged from less than 1800 mg/d (36.0% of participants) to 1800 mg/d to less than 2100 mg/d (26.2%), 2100 mg/d to less than 2400 mg/d (18.8%), and 2400 mg/d or more (19.0%). There was no evidence that higher sodium intakes (3000 to <4000 mg/d and ≥4000 mg/d vs <2500 mg/d) had an adverse effect on adolescent blood pressure and longitudinal mixed models showed that those consuming 3500 mg/d or more had generally lower diastolic blood pressures compared with individuals consuming less than 2500 mg/d (P = .18). However, higher potassium intakes were inversely associated with blood pressure change throughout adolescence (P < .001 for systolic and diastolic) and at the end of follow-up (P = .02 and P = .05 for systolic and diastolic, respectively). While the potassium to sodium ratio was also inversely associated with systolic blood pressure (P = .04), these effects were generally weaker compared with effects for potassium alone. CONCLUSIONS AND RELEVANCE In this study of adolescent girls, consumption of 3500 mg/d of sodium or more had no adverse effect on blood pressure. The beneficial effects of dietary potassium on both systolic and diastolic blood pressures suggest that consuming more potassium-rich foods during childhood may help suppress the adolescent increase in blood pressure.
Further evidence for involvement of the dorsal hippocampus serotonergic and γ-aminobutyric acid (GABA)ergic pathways in the expression of contextual fear conditioning in rats

Intra-dorsal hippocampus (DH) injections of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a serotonin-1A (5-hydroxytryptamine (5-HT)-1A) receptor agonist, were previously shown to inhibit the expression of contextual fear when administered six hours after conditioning. However, further understanding of the consolidation and expression of aversive memories requires investigations of these and other mechanisms at distinct time points and the regions of the brain to which they are transferred. Thus, the purpose of the present study was to investigate the role of DH serotonergic and γ-aminobutyric acid (GABA)ergic mechanisms in the expression of contextual fear 24 h after conditioning, reflected by fear-potentiated startle (FPS) and freezing behavior. The recruitment of the amygdala and medial prefrontal cortex (mPFC) in these processes was also evaluated by measuring Fos protein immunoreactivity. Although intra-DH injections of 8-OH-DPAT did not produce behavioral changes, muscimol reduced both FPS and the freezing response. Fos protein immunoreactivity revealed that contextual fear promoted wide activation of the mPFC, which was significantly reduced after intra-DH infusions of muscimol. The present findings, together with previous data, indicate that in contrast to 5-HT, which appears to play a role during the early phases of contextual aversive memory consolidation, longer-lasting GABA-mediated mechanisms are recruited during the expression of contextual fear memories.
A model for amyloid fibril formation in immunoglobulin light chains based on comparison of amyloidogenic and benign proteins and specific antibody binding

In an attempt to understand the mechanism of amyloid fibril formation in light chain amyloidosis, the properties of amyloidogenic (SMA) and benign (LEN) immunoglobulin light chain variable domains (VL) were compared. The conformations of LEN and SMA were measured using secondary and tertiary structural probes over the pH range from 2 and 8. At all pH values, LEN was more stable than SMA. The CD spectra of LEN at pH 2 were comparable to those of SMA atpH 7.5, indicating that the low pH conformation of LEN closely resembles that of SMA at physiological pH. At low pH, a relatively unfolded intermediate conformation is populated for SMA and rapidly leads to amyloid fibrils. The luck of such an intermediate with LEN, is attributed to sequence differences and accounts for the lack of LEN fibrils in the absence of agitation. A κIV-specific monoclonal antibody that recognizes the N-terminal of SMA caused unraveling of the fibrils to the protofilaments and was observed to bind to one end of SMA protofilaments by atomic force microscopy. The antibody result indicates that each protofilament is asymmetric with different ends. A model for the formation of fibrils by SMA is proposed.
Genome-wide linkage analyses of systolic blood pressure using highly discordant siblings.

BACKGROUND Elevated blood pressure is a risk factor for cardiovascular, cerebrovascular, and renal diseases. Complex mechanisms of blood pressure regulation pose a challenge to identifying genetic factors that influence interindividual blood pressure variation in the population at large. METHODS AND RESULTS We performed a genome-wide linkage analysis of systolic blood pressure in humans using an efficient, highly discordant, full-sibling design. We identified 4 regions of the human genome that show statistical significant linkage to genes that influence interindividual systolic blood pressure variation (2p22.1 to 2p21, 5q33.3 to 5q34, 6q23.1 to 6q24.1, and 15q25.1 to 15q26.1). These regions contain a number of candidate genes that are involved in physiological mechanisms of blood pressure regulation. CONCLUSIONS These results provide both novel information about genome regions in humans that influence interindividual blood pressure variation and a basis for identifying the contributing genes. Identification of the functional mutations in these genes may uncover novel mechanisms for blood pressure regulation and suggest new therapies and prevention strategies.
The Bidirectional Crosstalk between Human Dendritic Cells and Natural Killer Cells

Dendritic cells (DCs) are professional antigen-presenting cells, which display an extraordinary capacity to induce T-cell responses. Recent findings revealed that DCs also play a crucial role in the activation of natural killer (NK) cells representing important effectors in the innate immune defense against viruses and tumors. Here, we summarize various studies investigating the bidirectional crosstalk between human DCs and NK cells. In this context, it has been reported that DCs efficiently enhance CD69 expression, proliferation, interferon (IFN)-γ secretion and cytotoxic activity of NK cells. Cell membrane-associated molecules as well as soluble factors such as interleukin-12, tumor necrosis factor-α and type I IFNs contributed to DC-mediated NK cell activation. Reciprocally, the ability of human NK cells to enhance the immunostimulatory capacity of DCs was shown. Thus, NK cells promoted the maturation of DCs and markedly augmented their capacity to produce proinflammatory cytokines and to stimulate T-cell responses. The NK cell-mediated effects on DCs were dependent on cell membrane-associated molecules such as NKp30 and soluble factors such as tumor necrosis factor-α and IFN-γ. In conclusion, the reciprocal activating interaction between human DCs and NK cells may play a pivotal role in the immune defense against viruses and tumors.