Miracle-dz/UniFAR-FTUs huggingface dataset:
Presenilin-Dependent Gamma-Secretase Activity Modulates Neurite Outgrowth

Demonstration that cleavage of both APP and Notch are dependent on the product of the early onset Alzheimer's disease gene, presenilin-1 (PS1), has raised the possibility that Notch function may be altered in AD. This finding also suggests that Notch may be affected by APPgamma-secretase inhibitors under development for the treatment of Alzheimer's disease, as these target PS1. Data that address these questions have been lacking, due to inability to specifically modulate PS1 activity in a system directly relevant to the adult human brain. Using novel highly specific inhibitors of PS1/gamma-secretase, we demonstrate that modulation of PS1 activity in human CNS neurons not only affects Abeta generation, but also has unanticipated effects on Notch and its activity. We demonstrate that intracellular trafficking of Notch in human CNS neurons is altered by inhibition of PS1 and is accompanied by dramatic changes in neurite morphology, consistent with inhibition of Notch activity. These data, together with immunohistochemical evidence of elevation of Notch pathway expression in AD brain, suggest that Notch dysregulation may contribute to the neuritic dystrophy characteristically seen in Alzheimer's disease brain. In addition, they raise the possibility that inhibition of gamma-secretase/PS1 may have clinically beneficial effects on the neuritic pathology of AD, in addition to its expected effect to reduce amyloid burden.
Impact of medical treatments for benign prostatic hyperplasia on sexual function

Lower urinary tract symptoms (LUTS) and male sexual dysfunction are highly prevalent in ageing men, and are strongly linked. Various treatment strategies for benign prostatic hyperplasia (BPH)/LUTS may affect sexuality, with differences between drug classes and between drugs within a same class. The 5α‐reductase inhibitors, finasteride and dutasteride, are associated with a greater risk of erectile dysfunction (ED), ejaculatory dysfunction (EjD) and decreased libido than is placebo. α1‐adrenoceptor blockers (alfuzosin, doxazosin, tamsulosin, terazosin) show an incidence of decreased libido and ED closely similar to placebo, but differ in their impact on ejaculation, tamsulosin being associated with a higher incidence of EjD (10%) than other α1‐adrenoceptor blockers (0–1%) and placebo (1%), which is unrelated to retrograde ejaculation or higher efficacy. A randomized, placebo‐controlled, cross‐over study conducted in healthy volunteers showed that tamsulosin 0.8 mg once daily markedly decreased mean ejaculate volume in almost 90% of subjects, with 35% having no ejaculation. By contrast, there was no lack of ejaculation in subjects receiving alfuzosin 10 mg once daily or placebo. Sperm concentrations in urine after ejaculation were similar for the three treatment groups, confirming that the EjD with tamsulosin was unrelated to retrograde ejaculation. It may be related to a peripheral effect on seminal vesicles and/or the vas deferens. A central effect is also plausible, as tamsulosin shows a strong affinity for 5HT1A‐ and D2‐like receptors, both of which are involved in the central command of ejaculation. In conclusion, because treatment options for managing BPH have different effects on sexuality, the sexual dimension should be considered when assessing patients’ expectations and the choice of treatment.
Plants and natural compounds with antidiabetic action.

Diabetes has become the most common metabolic disease worldwide. In particular, type 2 diabetes is the most commonly encountered type of diabetes, which is characterised by the inability of the organism to respond to normal levels of circulating insulin, also called insulin resistance. Current antidiabetic therapy is based on synthetic drugs that very often have side effects. For this reason, there is a continuous need to develop new and better pharmaceuticals as alternatives for the management and treatment of the disease. Natural hypoglycaemic compounds may be attractive alternatives to synthetic drugs or reinforcements to currently used treatments. Their huge advantage is that they can be ingested in everyday diet. Recently, more attention is being paid to the study of natural products as potential antidiabetics. This mini review of the current literature is structured into three main sections focused on: (a) plant extracts, (b) plant biomolecules, and (c) other natural molecules that have been used for their antidiabetic effects. Potential molecular mechanisms of action are also discussed.
Diagnosis of infection in sepsis: An evidence-based review

Objective:In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for the diagnosis of infection in sepsis that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis. Design:The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. Methods:The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade. Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al. on p. S591. Conclusions:Obtaining a precise bacteriological diagnosis before starting antibiotic therapy is, when possible, of paramount importance for the success of therapeutic strategy during sepsis. Two to three blood cultures should be performed, preferably from a peripheral vein, without interval between samples to avoid delaying therapy. A quantitative approach is preferred in most cases when possible, in particular for catheter-related infections and ventilator-associated pneumonia. Diagnosing community-acquired pneumonia is complex, and a diagnostic algorithm is proposed. Appropriate samples are indicated during soft tissue and intraabdominal infections, but cultures obtained through the drains are discouraged.
The Effects of Government Subsidies on Investment : A Dynamic Model of the Ethanol Industry

This paper analyses the effects of government subsidies and the Renewable Fuel Standard (RFS) on the U.S. ethanol industry. Analyses that ignore the dynamic implications of these policies, including their effects on incumbent ethanol firms’ investment, production, and exit decisions and on potential entrants’ entry behavior, may generate incomplete estimates of the impact of the policies and misleading predictions of the future evolution of the ethanol industry. In this paper, we first develop a stylized theory model of subsidies in which we examine which types of subsidies are more costeffective for inducing investment in firm capacity. We then empirically analyze how government subsidies and the Renewable Fuel Standard affect ethanol production, investment, entry, and exit by estimating a structural econometric model of a dynamic game that enables us to recover the entire cost structure of the industry, including the distributions of investment costs, entry costs, and exit scrap values. We use the estimated parameters to evaluate three different types of subsidy: a volumetric production subsidy, an investment subsidy, and an entry subsidy, each with and without the RFS. Results show that investment subsidies and entry subsidies are more cost-effective than production subsidies.
Cell-fate choice in Dictyostelium: intrinsic biases modulate sensitivity to DIF signaling.

Cell fate in Dictyostelium development depends on intrinsic differences between cells, dating from their growth period, and on cell interactions occurring during development. We have sought for a mechanism linking these two influences on cell fate. First, we confirmed earlier work showing that the vegetative differences are biases, not commitments, since cells that are stalky-biased when developed with one partner are sporey with another. Then we tested the idea that these biases operate by modulating the sensitivity of cells to the signals controlling cell fate during development. Cells grown without glucose are stalky-biased when developed with cells grown with glucose. We find, using monolayer culture conditions, that they are more sensitive to each of the stalk-inducing signals, DIFs 1-3. Mixing experiments show that this bias is a cell-intrinsic property. Cells initiating development early in the cell cycle are stalky compared to those initiating development later in the cycle. Likewise, they are more sensitive to DIF-1. Assays of standard markers for prestalk and prespore cell differentiation reveal similar differences in DIF-1 sensitivity between biased cells; DIF-1 dechlorinase (an early prestalk cell marker enzyme) behaves in a consistent manner. We propose that cell-fate biases are manifest as differences in sensitivity to DIF.
Pilot evaluation of venlafaxine for the treatment of hot flashes in men undergoing androgen ablation therapy for prostate cancer.

PURPOSE Hot flashes may be a significant clinical problem in men undergoing androgen deprivation therapy with gonadotropin releasing hormone analogues, oral antiandrogens and/or surgical bilateral orchiectomy. Anecdotal information suggests that a low dose of the relatively new antidepressant venlafaxine may abrogate this clinical problem. We developed the current pilot trial to investigate further whether venlafaxine alleviates hot flashes in such men. MATERIALS AND METHODS The study included men in whom substantial hot flashes were associated with androgen deprivation therapy. Hot flash data were collected by daily diary questionnaires during a 1-week baseline period when no therapy was given for hot flashes, as well as for the next 4 weeks when study participants received 12.5 mg. venlafaxine orally twice daily. Questionnaires completed during the 4 weeks ofvenlafaxine therapy also documented data on potential drug toxicity. RESULTS Of the 16 evaluable patients who completed the study 10 (63%) had a greater than 50% decrease in hot flash score, as determined using the formula, frequency x severity, by week 4 of treatment versus the baseline week. Median weekly hot flash scores decreased 54% from baseline during week 4 of venlafaxine therapy. Average incidence of severe and very severe hot flashes was reduced from 2.3 daily at baseline to 0.6 daily at study end (p = 0.003). Therapy was generally well tolerated. CONCLUSIONS Venlafaxine hydrochloride appears to represent an efficacious new method for alleviating hot flashes in men undergoing androgen ablation therapy. Further evaluation of this compound for alleviating hot flashes is indicated.
Establishment of Monitoring Methods for Autophagy in Rice Reveals Autophagic Recycling of Chloroplasts and Root Plastids during Energy Limitation1[OPEN]

Autophagy is responsible for the degradation of leaf chloroplasts and root plastids in rice plants and functions during energy limitation caused by interruption of photosynthesis. Autophagy is an intracellular process leading to vacuolar or lysosomal degradation of cytoplasmic components in eukaryotes. Establishment of proper methods to monitor autophagy was a key step in uncovering its role in organisms, such as yeast (Saccharomyces cerevisiae), mammals, and Arabidopsis (Arabidopsis thaliana), in which chloroplastic proteins were found to be recycled by autophagy. Chloroplast recycling has been predicted to function in nutrient remobilization for growing organs or grain filling in cereal crops. Here, to develop our understanding of autophagy in cereals, we established monitoring methods for chloroplast autophagy in rice (Oryza sativa). We generated transgenic rice-expressing fluorescent protein (FP) OsAuTophaGy8 (OsATG8) fusions as autophagy markers. FP-ATG8 signals were delivered into the vacuolar lumen in living cells of roots and leaves mainly as vesicles corresponding to autophagic bodies. This phenomenon was not observed upon the addition of wortmannin, an inhibitor of autophagy, or in an ATG7 knockout mutant. Markers for the chloroplast stroma, stromal FP, and FP-labeled Rubisco were delivered by a type of autophagic body called the Rubisco-containing body (RCB) in the same manner. RCB production in excised leaves was suppressed by supply of external sucrose or light. The release of free FP caused by autophagy-dependent breakdown of FP-labeled Rubisco was induced during accelerated senescence in individually darkened leaves. In roots, nongreen plastids underwent both RCB-mediated and entire organelle types of autophagy. Therefore, our newly developed methods to monitor autophagy directly showed autophagic degradation of leaf chloroplasts and root plastids in rice plants and its induction during energy limitation.
Frameless neuronavigation based only on 3D digital subtraction angiography using surface-based facial registration.

OBJECT Cerebrovascular lesions can have complicated abnormal anatomy that is not completely characterized by CT or MR angiography. Although 3D rotational angiography provides superior spatial and temporal resolution, catheter angiograms are not easily registered to the patient, limiting the use of these images as a source for neuronavigation. However, 3D digital subtraction angiography (DSA) contains not only vascular anatomy but also facial surface anatomy data. The authors report a novel technique to register 3D DSA images by using only the surface anatomy contained within the data set without having to fuse the DSA image set to other imaging modalities or use fiducial markers. METHODS A cadaver model was first created to assess the accuracy of neuronavigation based on 3D DSA images registered by facial surface anatomy. A 3D DSA scan was obtained of a formalin-fixed cadaver head, with acquisitions of mask and contrast runs. The right common carotid artery was injected prior to the contrast run with a 45% contrast solution diluted with water-soluble red liquid latex. One week later, the head was registered to a neuronavigation system loaded with the 3D DSA images acquired earlier using facial surface anatomy. A right pterional craniotomy was performed and 10 different vascular landmarks were identified and measured for accuracy using the neuronavigation system. Neuronavigation based only on 3D DSA was then used to guide an open clipping procedure for a patient who presented with a ruptured distal lenticulostriate aneurysm. RESULTS The accuracy of the measurements for the cadaver model was 0.71 ± 0.25 mm (mean ± SE), which is superior to the 1.8-5 mm reported for neuronavigation. The 3D DSA-based navigation-assisted surgery for the distal lenticulostriate aneurysm aided in localization, resulting in a small craniotomy and minimal brain dissection. CONCLUSIONS This is the first example of frameless neuronavigation based on 3D catheter angiography registered by only the surface anatomy data contained within the 3D DSA image set. This is an easily applied technique that is beneficial for accurately locating vascular pathological entities and reducing the dissection burden of vascular lesions.
Canine atopic dermatitis in the Middle East: clinical signs, signalment and common allergens

The aim of the study was to examine for the first time the various aspects of canine atopic dermatitis (CAD) presenting in a Middle Eastern country. Medical records of 164 dogs diagnosed with CAD were evalu- ated. Associations between signalment, lifestyle, clinical signs and allergens were evaluated statistically. Labrador Retriever, German Shepherd dog, Boxer, French Bulldog, Golden Retriever and Shar-Pei breeds were presented more frequently than the regular hospital population (P < 0.0001), and had an earlier disease onset time (P < 0.01). In 22 dogs (13%) signs of CAD were noticed at less than six months of age. Most dogs (75%) lived indoors. Most dogs (83%) had lesions on the ventral part of the body and 68% had foot lesions. After excluding flea allergy dermatitis by implementing strict flea control, 60% of the dogs presented with dorsal distribution of skin lesions. Dogs with ventral lesions were younger when clinical signs first appeared (P < 0.05). Most of the dogs were aller - gic to dust and/or dust mites (75.6%), with weeds and trees as the next most common allergens. CAD is similar worldwide, but geographic differences may be attributable to genetic pools and allergen loading. This study also shows that early onset of clinical signs, especially in breeds predisposed to CAD and with a dorsal distribution of skin lesions, should not rule out the diagnosis of CAD.
Lithostratigraphy of the late Early Permian (Kungurian) Wandrawandian Siltstone, New South Wales: record of glaciation?

The late Early Permian (273 – 271 Ma) Wandrawandian Siltstone in the southern Sydney Basin of New South Wales represents a marine highstand that can be correlated over 2000 km. A mainly fine-grained terrigenous clastic succession, the Wandrawandian Siltstone contains evidence for cold, possibly glacial conditions based on the presence of outsized clasts and glendonites, mineral pseudomorphs after ikaite, a mineral that forms in cold (0 – 7°C) marine sediments. A lithostratigraphic and facies analysis of the unit was conducted, based on extensive coastal outcrops and continuous drillcores. Eight facies associations were identified: (i) siltstone; (ii) siltstone with minor interbedded sandstone; (iii) interbedded tabular sandstone and siltstone; (iv) admixed sandstone and siltstone to medium-grained sandstone; (v) discrete, discontinuous sandstone intervals; (vi) chaotic conglomerate and sandstone in large channel forms; (vii) chaotically bedded and pervasively soft-sediment-deformed intervals; and (viii) tuffaceous siltstone and claystone. Using lithology and ichnology, relative water depths were ascribed to each facies association. Based on these associations, the unit was divided into five informal members that reveal a history of significant relative sea-level fluctuations throughout the formation: member I, interbedded/admixed sandstone and siltstone; member II, siltstone; member III, slumped masses of members I and II; member IV, siltstone and erosionally based lensoid sandstone beds and channel bodies; and member V, interbedded/admixed sandstone and siltstone with abundant tuffs. Member I marks an initial marine transgression from shoreface to offshore depths. Member II records the maximum water depth of the shelf. Member III is interpreted to be a slump sheet; plausible mechanisms for its emplacement include seismicity produced by tectonism or glacio-isostatic rebound, changes in pore-water pressures due to sea-level fluctuations, or an increase in sedimentation rates. Members IV and V record minor fluctuations in depositional environments from offshore to shoreface water depths. Member IV includes regionally extensive, large channel bodies, with composite fills that are interpreted as storm-influenced mass-flow deposits. Member V includes a greater abundance of volcanic ash. Glacial controls (isostasy, eustasy) and tectonic affects may have worked in concert to produce the changes in depositional environments observed in the Wandrawandian Siltstone.
Public Schooling ,

Governments use public education and public ownership of the media to control the information that their citizens receive. More totalitarian governments as well as those with larger wealth transfers make greater investments in publicly controlled information. This finding is borne out from cross-sectional time-series evidence across countries and is confirmed when the recent fall of communism is specifically examined. My results reject the standard publicgood view linking education and democracy, and I find evidence that public educational expenditures vary in similar ways to government ownership of television stations. Country-level data on the organization of families as well as data on South African public schools are also examined.
Plasma Ferritin and Hepcidin Are Lower at 4 Months Postpartum among Women with Elevated C-Reactive Protein or α1-Acid Glycoprotein.

Background: Ferritin and hepcidin are markers of iron status that typically increase during inflammation or infection. The postpartum period is a physiologically unique life stage in which the relations between these proteins and other markers of inflammation have not been extensively studied.Objective: We aimed to determine whether 2 markers of inflammation [high-sensitivity C-reactive protein (CRP) and α1-acid glycoprotein (AGP)] were associated with ferritin or hepcidin in postpartum women in California.Methods: This is a secondary analysis of a randomized controlled iron-intervention trial. Plasma CRP, AGP, ferritin, and hepcidin were analyzed at 2 and 17 wk postpartum in 114 lactating women. We examined Pearson correlation coefficients between all biomarkers at both time points and differences in mean values of ferritin and hepcidin between those with and without elevated CRP and/or AGP.Results: At 2 and 17 wk postpartum, 58% and 26% of women had CRP >5 mg/L and 78% and 29% had AGP >1 g/L, respectively. Neither CRP nor AGP was significantly correlated with ferritin (r = 0.07 and -0.06; n = 114 at 2 wk; -0.14 and -0.14; n = 95 at 17 wk) or hepcidin (r = 0.18 and -0.03 at 2 wk; -0.05 and -0.14 at 17 wk; P > 0.05 for all). At 2 wk, geometric mean plasma ferritin and hepcidin concentrations did not differ between women with and without elevated CRP or AGP (P > 0.5), but at 17 wk women with elevated CRP or AGP had lower mean (95% CI) ferritin and hepcidin than did women without either elevated CRP or AGP [ferritin: 30.3 ng/mL (23.4, 39.1 ng/mL) compared with 40.2 ng/mL (32.9, 49.2 ng/mL); P < 0.01; hepcidin: 44.3 ng/mL (32.3, 60.9 ng/mL) compared with 67.6 ng/mL (56.1, 81.5 ng/mL); P = 0.02]. Conclusion: Lower ferritin and hepcidin among women with elevated CRP or AGP at 17 wk postpartum suggests that these markers of iron status react differently to physiologic immune activation than to pathologic inflammatory states.
RAD21 and KIAA0196 at 8q24 are amplified and overexpressed in prostate cancer

To detect genes that are overexpressed in prostate cancer, a subtracted cDNA library was first constructed from the PC‐3 cell line and subsequently screened by using cDNA microarray hybridization. Sixty‐eight genes were found to be overexpressed (ratio > 3) in PC‐3. Half of these genes were in chromosomal regions, which, using comparative genomic hybridization, we previously showed to be gained in PC‐3. Subsequently, the expression and copy number of selected genes were studied by quantitative RT‐PCR and fluorescence in situ hybridization in prostate cancer cell lines, xenografts, and clinical tumor specimens of benign prostate hyperplasia and untreated as well as hormone‐refractory prostate carcinomas. Two genes from chromosomal region 8q24—RAD21 and KIAA0196—showed increased expression in clinical prostate carcinomas and were also amplified in 30–40% of xenografts and hormone‐refractory tumors. In addition, the expression of KIAA0196 was significantly (P = 0.0051) higher in tumors with the gene amplification than in those without it. The data suggest that KIAA0196 and possibly RAD21 are putative target genes for the common amplification of 8q23‐24 in prostate cancer. © 2003 Wiley‐Liss, Inc.