Miracle-dz/UniFAR-FTUs huggingface dataset:
Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy

ABSTRACT Defective autophagy contributes to Alzheimer disease (AD) pathogenesis although evidence is conflicting on whether multiple stages are impaired. Here, for the first time, we have comprehensively evaluated the entire autophagic process specifically in CA1 pyramidal neurons of hippocampus from early and late-stage AD subjects and nondemented controls. CA1 neurons aspirated by laser capture microdissection were analyzed using a custom-designed microarray comprising 578 neuropathology- and neuroscience-associated genes. Striking upregulation of autophagy-related genes, exceeding that of other gene ontology groups, reflected increases in autophagosome formation and lysosomal biogenesis beginning at early AD stages. Upregulated autophagosome formation was further indicated by elevated gene and protein expression levels for autophagosome components and increased LC3-positive puncta. Increased lysosomal biogenesis was evidenced by activation of MiTF/TFE family transcriptional regulators, particularly TFE3 (transcription factor binding to IGHM enhancer 3) and by elevated expression of their target genes and encoded proteins. Notably, TFEB (transcription factor EB) activation was associated more strongly with glia than neurons. These findings establish that autophagic sequestration is both competent and upregulated in AD. Autophagosome-lysosome fusion is not evidently altered. Despite this early disease response, however, autophagy flux is progressively impeded due to deficient substrate clearance, as reflected by autolysosomal accumulation of LC3-II and SQSTM1/p62 and expansion of autolysosomal size and total area. We propose that sustained induction of autophagy in the face of progressively declining lysosomal clearance of substrates explains the uncommonly robust autophagic pathology and neuritic dystrophy implicated in AD pathogenesis.
Identification In Vivo of Different Rate-Limiting Steps Associated with Transcriptional Activators in the Presence and Absence of a GAGA Element

ABSTRACT We analyzed the impact of a GAGA element on a transgenic promoter in Drosophila melanogaster that was activated by proteins composed of the Teton DNA binding domain and either the heat shock factor (HSF) activation domain or a potent subdomain of VP16. Permanganate footprinting was used to monitor polymerase II (Pol II) on the transgenic promoters in vivo. Activation by Teton-HSF but not by Teton-VP16A2 required the GAGA element; this correlated with the ability of the GAGA element to establish a paused Pol II. Although the GAGA element was not required for activation by Teton-VP16A2, the GAGA element greatly accelerated the rate of activation. The permanganate data also provided evidence that Pol II encountered different rate-limiting steps, following initiation in the presence of Teton-HSF and Teton-VP16A2. The rate-limiting step in the presence of Teton-HSF was release of Pol II paused about 20 to 40 nucleotides downstream from the start site. The rate-limiting step in the presence of Teton-VP16A2 occurred much closer to the transcription start site. Several biochemical studies have provided evidence for a structural transition shortly after Pol II initiates transcription. The behavior of Pol II in the presence of Teton-VP16A2 provides the first evidence that this transition occurs in vivo.
Nicotinic and Muscarinic Reduction of Unitary Excitatory Postsynaptic Potentials in Sensory Cortex; Dual Intracellular Recording in Vitro Slice Preparation and Recording

muscarinic reduction of unitary excitatory postsynaptic potentials in sensory cortex: dual intracellular recording in vitro. We studied the cholinergic modulation of glutamatergic transmission between neighboring layer 5 regular-spiking pyramidal neurons in somatosensory cortical slices from young rats (P10-P26). Brief bath application of 5–10 ␮M carbachol, a nonspecific cholinergic agonist, decreased the amplitude of evoked unitary excitatory postsynaptic potentials (EPSPs). This effect was blocked by 1 ␮M atropine, a muscarinic receptor antagonist. Nicotine (10 ␮M), in contrast to carbachol, reduced EPSPs in nominally magnesium-free solution but not in the presence of 1 mM Mg ϩ2 , indicating the involvement of NMDA receptors. Likewise, when the postsynaptic cell was depolarized under voltage clamp to allow NMDA receptor activation in the presence of 1 mM Mg ϩ2 , synaptic currents were reduced by nicotine. Nicotinic EPSP reduction was prevented by the NMDA receptor antagonist D-AP5 (50 ␮M) and by the nicotinic receptor antagonist mecamylamine (10 ␮M). Both carbachol and nicotine reduced short-term depression of EPSPs evoked by 10 Hz stimulation, indicating that EPSP reduction happens via reduction of presynaptic glutamate release. In the case of nicotine, several possible mechanisms for NMDAR-dependent EPSP reduction are discussed. As a result of NMDA receptor dependence, nicotinic EPSP reduction may serve to reduce the local spread of cortical excitation during heightened sensory activity. Cholinergic input from the basal forebrain influences corti-cal functions such as learning, memory, and attention (Descar-ries et al. 2004) through the activity of nicotinic and muscarinic receptors. Much of the effect of acetylcholine (ACh) may arise from modulation of excitatory (glutamatergic) synaptic trans-consequent 'gating' of sensory information during arousal (Steriade et al. 2001). Past in vitro studies have used whole cell recording in conjunction with extracellular stimulation in slice preparations to examine cholinergic modulation of cortical excitatory pathways. The general consensus among these studies is that ACh enhances glutamate release at thalamo-cortical synapses via nicotinic receptors while reducing glutamate release at cortico-cortical synapses via muscarinic receptors, at least within superficial, presumably thalamo-recipient layers Acetylcholine's selective enhancement of sensory responses relative to cortico-cortical responses has been corroborated in vivo using natural stimuli (Oldford and Castro-Alamancos 2003). In addition to synaptic effects, ACh and cholinergic agonists change the excitability and firing properties of cortical pyra-midal neurons, primarily through the activity of muscarinic receptors (Krnjevic et al. 1971; McCormick 1992). Moreover, ACh acts on inhibitory neurons as well, both through synaptic effects on GABA release (Metherate and …
A 2.4 GHz 4 mW Integer-N Inductorless RF Synthesizer

The high phase noise of ring oscillators has generally discouraged their use in RF synthesis. This paper introduces an integer-N synthesizer that employs a type-I loop to achieve a wide bandwidth, allowing the use of ring oscillators, and a master-slave sampling loop filter along with harmonic traps to suppress spurs. A 2.4 GHz prototype fabricated in 45 nm digital CMOS technology provides a loop bandwidth of 10 MHz and a spur level of -65 dBc. The phase noise is -114 dBc/Hz at 1 MHz offset.
Introduction and Assessment of a Blended-Learning Model to Teach Patient Assessment in a Doctor of Pharmacy Program

Objective. To integrate a blended-learning model into a two-course patient assessment sequence in a doctor of pharmacy (PharmD) program and to assess the academic performance and perceptions of enrolled students. Design. A blended-learning model consisting of a flipped classroom format was integrated into a patient assessment (PA) course sequence. Course grades of students in the blended-learning (intervention) and traditional-classroom (control) groups were compared. A survey was administered to assess student perceptions. Assessment. The mean numeric grades of students in the intervention group were higher than those of students in the traditional group (PA1 course: 92.2±3.1 vs 90.0±4.3; and PA2 course: 90.3±4.9 vs 85.8±4.2). Eighty-six percent of the students in the intervention group agreed that the instructional methodologies used in this course facilitated understanding of the material. Conclusion. The blended-learning model was associated with improved academic performance and was well-received by students.
Cell Surface Rescue of Kidney Anion Exchanger 1 Mutants by Disruption of Chaperone Interactions*

Mutations in the human kidney anion exchanger 1 (kAE1) membrane glycoprotein cause impaired urine acidification resulting in distal renal tubular acidosis (dRTA). Dominant and recessive dRTA kAE1 mutants exhibit distinct trafficking defects with retention in the endoplasmic reticulum (ER), Golgi, or mislocalization to the apical membrane in polarized epithelial cells. We examined the interaction of kAE1 with the quality control system responsible for the folding of membrane glycoproteins and the retention and degradation of misfolded mutants. Using small molecule inhibitors to disrupt chaperone interactions, two functional, dominant kAE1 mutants (R589H and R901stop), retained in the ER and targeted to the proteasome for degradation by ubiquitination, were rescued to the basolateral membrane of Madin-Darby canine kidney cells. In contrast, the Golgi-localized, recessive G701D and the severely misfolded, ER-retained dominant Southeast Asian ovalocytosis (SAO) mutants were not rescued. These results show that functional dRTA mutants are retained in the ER due to their interaction with molecular chaperones, particularly calnexin, and that disruption of these interactions can promote their escape from the ER and cell surface rescue.
Microarray Assessment of Fibronectin, Collagen and Integrin Expression and the Role of Fibronectin–Collagen Coating in the Growth of Normal, SV40 T-antigen-immortalised and Malignant Human Oral Keratinocytes

Extracellular matrix proteins affect the growth and survival of epithelial tissues. Accordingly, surface coating with fibronectin and collagen is a common practice for promoting keratinocyte culture. In this study, the expression of fibronectin and collagen-related factors, including integrins, by normal (NOK), SV40 T-antigen-immortalised (SVpgC2a) and malignant (SqCC/Y1) human oral keratinocytes, under standardised, serum-free conditions, was investigated by using microarray analysis. Cell growth was also studied in the presence and absence of a matrix consisting of human fibronectin and bovine collagen type I (FN–COL). Fibronectin transcripts were abundant in all cells, whereas 16 of 29 collagen chains and 14 of 24 integrin subunits were variably detected. With regard to both the expression level and the number of transcripts, higher collagen and lower integrin expression was observed in SVpgC2a cells than in NOKs and SqCC/Y1 cells. The cell types differed with regard to colony-forming efficiency and the rate and kinetics of growth at high cell density. For all cell types, FN–COL coating consistently stimulated cell migration, without influencing growth in mass culture or clonal density. The results demonstrate the transcription of genes associated with the formation and function of fibronectin and collagen in oral epithelium, and variably altered expression patterns in transformed states, and show that keratinocyte lines can be successfully transferred without the stimulus from extracellular FN–COL.
Selective depletion of fibroblasts preserves morphology and the functional integrity of peritoneum in transgenic mice with peritoneal fibrosing syndrome.

BACKGROUND A peritoneal fibrosing syndrome (PFS) can progressively reduce peritoneal ultrafiltration during chronic peritoneal dialysis in patients with renal failure. The pathogenesis of PFS is unclear and the role of peritoneal fibroblasts has not been evaluated experimentally. METHODS We followed the fate of fibroblasts producing PFS in a mouse model using fibroblast-specific protein 1 (FSP1) as a marker. PFS was induced by daily peritoneal infusions of chlorhexidine gluconate (CHG) saline into transgenic mice expressing the thymidine kinase (Delta tk) gene under the control of the FSP1 promoter (FSP1.Delta tk mice). To demonstrate the role of fibroblasts in PFS, we treated these FSP1.Delta tk mice with a nucleoside analogue to induce DNA chain termination and fibroblast death. RESULTS Mice receiving peritoneal infusions of CHG saline every other day for 2 weeks developed increasing numbers of FSP1+ fibroblasts in the subserosal layers of the visceral peritoneum. Mac-3+ monocytes (macrophages) subsequently accumulated over the next 2 weeks in association with increased deposition of type I collagen and increased endothelial vascularity (CD31+) in these subserosal tissues. Since these peritoneal fibroblasts expressed monocyte chemoattractant protein-1 (MCP-1), heat shock protein 47 (HSP47), and vascular endothelial growth factor (VEGF), we suspect they were partially responsible for macrophage recruitment, matrix production, and the neoangiogenesis in the subserosal tissue. Treatment of PFS in FSP1.Delta tk transgenic mice with a nucleoside analogue selectively reduced the numbers of peritoneal fibroblasts and attenuated the attendant changes in peritoneal histology. Rescuing the peritoneal membrane from chronic thickening and neoangiogenesis by reducing the number of fibroblasts also preserved ultrafiltration. CONCLUSION Peritoneal fibroblasts play a pivotal role in PFS, and their deletion using a fibroblasts-specific transgene was effective in preventing peritoneal fibrogenesis.
New Teachers’ Perceptions of Induction: Insights Into Principled Practices

Successfully inducting new teachers creates professional alliances to sustain learning organizational cultures. This research involved 30 beginning teachers from a large school board in southern Ontario. The theoretical frame of the study consists of a mixed qualitative data analysis methodology of grounded theory and discourse analysis. The findings elaborate on the value of induction programs that are modeled on individual differentiation according to teachers’ unique capacities. The new teachers who benefited most from their induction were those who were part of school cultures that integrated their professional development in meaningful endeavors. New teachers readily shared their self-declared accomplishments in induction experiences wherein they resolved their dilemmas through critical reflection and professional collaboration.
Selective Killing of Cancer Cells by Leaf Extract of Ashwagandha: Identification of a Tumor-Inhibitory Factor and the First Molecular Insights to Its Effect

Purpose: Ashwagandha is regarded as a wonder shrub of India and is commonly used in Ayurvedic medicine and health tonics that claim its variety of health-promoting effects. Surprisingly, these claims are not well supported by adequate studies, and the molecular mechanisms of its action remain largely unexplored to date. We undertook a study to identify and characterize the antitumor activity of the leaf extract of ashwagandha. Experimental Design: Selective tumor-inhibitory activity of the leaf extract (i-Extract) was identified by in vivo tumor formation assays in nude mice and by in vitro growth assays of normal and human transformed cells. To investigate the cellular targets of i-Extract, we adopted a gene silencing approach using a selected small hairpin RNA library and found that p53 is required for the killing activity of i-Extract. Results: By molecular analysis of p53 function in normal and a variety of tumor cells, we found that it is selectively activated in tumor cells, causing either their growth arrest or apoptosis. By fractionation, purification, and structural analysis of the i-Extract constituents, we have identified its p53-activating tumor-inhibiting factor as withanone. Conclusion: We provide the first molecular evidence that the leaf extract of ashwagandha selectively kills tumor cells and, thus, is a natural source for safe anticancer medicine.
Reproducibility of the Surveillance Effect to Decrease Nosocomial Infection Rates

Objective. To investigate whether the reduction effect due to participation in a nosocomial infection surveillance system for laboratory-confirmed central venous catheter (CVC)-associated primary bloodstream infection (BSI), ventilator-associated pneumonia (VAP), and surgical site infection (SSI) is reproducible for different time periods, independent of confounding factors that might occur during a specific time period. Methods. Data from the German national nosocomial infection surveillance system from the period January 1997 through June 2008 were used. CVC-associated BSI data and SSI data were analyzed for 3 starting periods, and VAP data were analyzed for 2 starting periods. Monthly infection rates were calculated for the following 36 months, and relative risks comparing the first and third surveillance years of each period were calculated. Results. A total of 2,399 CVC-associated BSI cases from 267 intensive care units, 3,637 VAP cases from 150 intensive care units, and 829 SSIs following 3 different procedures from 113 departments were analyzed. A significant reduction in VAP was shown for both starting periods investigated (overall relative risk [RR], 0.80 [95% CI, 0.74-0.86]). A significant reduction in CVC-associated BSI was demonstrated for 2 of 3 starting periods (overall RR, 0.83 [95% CI, 0.75-0.91]). A significant reduction in SSI was found for 2 starting periods for knee prosthesis insertion (overall RR, 0.56 [95% CI, 0.38-0.82]), for all of the 3 starting periods for cesarean delivery (overall RR, 0.75 [95% CI, 0.61-0.93]), and for none of the 3 starting periods for endoscopically performed cholecystectomy (overall RR, 0.89 [95% CI, 0.62-1.27]). Conclusions. The surveillance effect, manifest as a significant reduction of nosocomial infection rates between the first and third years of participation in a surveillance system, was observed independently from the calendar year in which the surveillance activities started.
A power modeling and characterization method for the CMOS standard cell library

In this paper, we propose power consumption models for complex gates and transmission gates, which are extended from the model of basic gates proposed in [1]. We also describe an accurate power characterization method for CMOS standard cell libraries which accounts for the effects of input slew rate, output loading, and logic state dependencies. The characterization methodology separates the power consumption of a cell into three components, e.g., capacitive feedthrough power, short-circuit power, and dynamic power. For each component, power equation is derived from SPICE simulation results where the netlist is extracted from cell's layout. Experimental results on a set of ISCAS'85 benchmark circuits show that the power estimation based on our power modeling and characterization provides within 7% error of SPICE simulation on average while the CPU time consumed is more than two orders of magnitude less.
Convergence Rates in Forward-Backward Splitting

Forward--backward splitting methods provide a range of approaches to solving large-scale optimization problems and variational inequalities in which structures conducive to decomposition can be utilized. Apart from special cases where the forward step is absent and a version of the proximal point algorithm comes out, efforts at evaluating the convergence potential of such methods have so far relied on Lipschitz properties and strong monotonicity, or inverse strong monotonicity, of the mapping involved in the forward step, the perspective mainly being that of projection algorithms. Here, convergence is analyzed by a technique that allows properties of the mapping in the backward step to be brought in as well. For the first time in such a general setting, global and local contraction rates are derived; moreover, they are derived in a form which makes it possible to determine the optimal step size relative to certain constants associated with the given problem. Insights are thereby gained into the effects of shifting strong monotonicity between the forward and backward mappings when a splitting is selected.
Effects of epigallocatechin gallate on the cell-wall structure of Mycobacterial smegmatis mc2155

Epigallocatechin gallate (EGCG) is the main component of green tea extracts that inhibits the growth of Mycobacterial smegmatis mc2155, and the mechanism is not clear. This study showed the effects of EGCG on the growth of mc2155. The content and the structure of EGCG in LB medium with mc2155 were identified by HPLC and LC/MS. Transmission electron microscopy was utilised to identify the cell envelope structure. As a result, the optional inhibition concentration was determined to be 20 μg mL− 1. Most of EGCG was transferred into its isomeride in LB medium, but the inhibition effects against mc2155 had yet been maintained. The changes of cell envelope structure were showed after EGCG treatment for 18 h. The cell wall appeared to have a less electron-translucent zone, turn rougher and thicker. The results show that EGCG impacts the integrity of mycobacterial cell wall and is likely be a better prophylactic agent against tuberculosis.
Genetic parameters of milk and fat yield in normal and high yielding dairy cows

In order to estimate the genetic parameters of productive traits (milk yield and milk fat) and the genetic correlation among them in two groups of normal and high yielding Holstein dairy cows of Iran, 67830 and 32787 records of first lactation were used respectively. A bivariate animal model using DF-REML algorithm was applied to estimate the heritability of traits and also the genetic and phenotypic correlations among them. Also a comparison between these two groups was made for productive traits using T-test procedure. Results show that heritability for both traits are lower for high yielding cows. Also the genetic and phenotypic correlations between two productive traits are lower for high producing animals. This shows the importance of environmental factors on high producing animals. Also the lower diversity in uniform high yielding cows for production traits must be considered in constructing the selection indices for improving such traits. The higher phenotypic correlation in comparison to genetic one also indicates the importance of environment and management, especially in higher levels of production. Keywords-dairy cattle; high yielding; production trait; genetic parameter.
Adaptive Transferred-profile Likelihood Learning

The recent success of representation learning is built upon the learning of relevant features, in particular from unlabelled data available in different domains. This raises the question of how to transfer and reuse such knowledge effectively so that the learning of a new task can be made easier or be improved. This poses a difficult challenge for the area of transfer learning where there is no label in the source data, and no source data is ever transferred to the target domain. In previous work, the most capable approach has been self-taught learning which, however, relies heavily upon the compatibility across the domains. In this paper, we propose a novel transfer learning framework called Adaptive Transferred-profile Likelihood Learning (aTPL), which performs adaptation on the representations to be transferred, so that they become more compatible with the target domain. At the same time, it learns supplementary knowledge about the target domain. Experiments on five images datasets and a sentiment dataset demonstrate the effectiveness of the approach in comparison with self-taught learning and other common feature extraction methods. The results also indicate that the new transfer method is less sensitive to negative transfer.