Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress

With increasing life expectancy, Alzheimer's disease (AD) and other types of age-associated dementia are on the rise worldwide. Treatment approaches for dementia are insufficient and novel therapies are not readily available. In this context repurposing of established drugs appears attractive. A well-established class of cardiovascular drugs, which targets the angiotensin II system, is such a candidate, which currently undergoes a paradigm shift with regard to the potential benefit for treatment of neurodegenerative symptoms. In search for additional evidence, we subjected aged rats to chronic unpredictable mild stress, which is known to enhance the development of AD-related neuropathological features. We report here that four weeks of chronic mild stress induced a strong upregulation of the hippocampal angiotensin-converting enzyme (Ace) at gene expression and protein level. Concomitantly, tau protein hyperphosphorylation developed. Signs of neurodegeneration were detected by the significant downregulation of neuronal structure proteins such as microtubule-associated protein 2 (Map2) and synuclein-gamma (Sncg). Ace was involved in neurodegenerative symptoms because treatment with the brain-penetrating ACE inhibitor, captopril, retarded tau hyperphosphorylation and signs of neurodegeneration. Moreover, ACE inhibitor treatment could counteract glutamate neurotoxicity by preventing the downregulation of glutamate decarboxylase 2 (Gad2). Taken together, ACE inhibition targets neurodegeneration triggered by environmental stress.
Mutational Analysis of a Fatty Acyl-Coenzyme A Synthetase Signature Motif Identifies Seven Amino Acid Residues That Modulate Fatty Acid Substrate Specificity*

Fatty acyl-CoA synthetase (fatty acid:CoA ligase, AMP-forming; EC 6.2.1.3) catalyzes the formation of fatty acyl-CoA by a two-step process that proceeds through the hydrolysis of pyrophosphate. In Escherichia coli this enzyme plays a pivotal role in the uptake of long chain fatty acids (C12-C18) and in the regulation of the global transcriptional regulator FadR. The E. coli fatty acyl-CoA synthetase has remarkable amino acid similarities and identities to the family of both prokaryotic and eukaryotic fatty acyl-CoA synthetases, indicating a common ancestry. Most notable in this regard is a 25-amino acid consensus sequence, DGWLHTGDIGXWXPXGXLKIIDRKK, common to all fatty acyl-CoA synthetases for which sequence information is available. Within this consensus are 8 invariant and 13 highly conserved amino acid residues in the 12 fatty acyl-CoA synthetases compared. We propose that this sequence represents the fatty acyl-CoA synthetase signature motif (FACS signature motif). This region of fatty acyl-CoA synthetase from E. coli, 431NGWLHTGDIAVMDEEGFLRIVDRKK455, contains 17 amino acid residues that are either identical or highly conserved to the FACS signature motif. Eighteen site-directed mutations within the fatty acyl-CoA synthetase structural gene (fadD) corresponding to this motif were constructed to evaluate the contribution of this region of the enzyme to catalytic activity. Three distinct classes of mutations were identified on the basis of growth characteristics on fatty acids, enzymatic activities using cell extracts, and studies using purified wild-type and mutant forms of the enzyme: 1) those that resulted in either wild-type or nearly wild-type fatty acyl-CoA synthetase activity profiles; 2) those that had little or no enzyme activity; and 3) those that resulted in lowering and altering fatty acid chain length specificity. Among the 18 mutants characterized, 7 fall in the third class. We propose that the FACS signature motif is essential for catalytic activity and functions in part to promote fatty acid chain length specificity and thus may compose part of the fatty acid binding site within the enzyme.
Adriamycin-induced fetal hydronephrosis.

INTRODUCTION At the end of pregnancy, the amniotic fluid (AF) depends basically on renal function, corresponding to fetal urine. Changes in AF, especially oligohydramnios, are reported in association with fetal hydronephrosis (FH). The experimental model using adriamycin in pregnant female rats has a teratogenic effect and has been classically employed to study esophageal atresia. Nevertheless, adriamycin promotes FH with high frequency as well. In the present study, using this animal model, we tried to identify the incidence and microscopic changes of FH, as well as its correlation with AF weight. MATERIALS AND METHODS Eight Spreague-Dawley pregnant female rats received adriamycin 2.2 mg/kg on the 8th and 9th gestational days (considering term gestation = 22 days). Those fetuses that received adriamycin (Adriamycin Group) were compared with fetuses from 2 female rats (Control Group), which received 0.9% saline solution. On the 21.5 gestational day, the fetuses were collected by cesarean incision, sacrificed, and examined for macro and microscopic changes in kidneys and ureters. Fetuses with bilateral hydronephrosis formed the Hydronephrosis Group. AF weight was determined as well. RESULTS Hydronephrosis occurred in 70 (95%) of the 74 fetuses in the adriamycin group against none of the 21 fetuses from the control group. The amniotic fluid weight was increased in the adriamycin group in relation to the control group (p < 0.001). The histomorphometric study revealed dilation of the renal pelvis and reduction of renal parenchyma in the hydronephrosis group in relation to the control group. Severe cortical atrophy, cortical tubular atrophy and medullar atrophy were observed in the hydronephrosis group. CONCLUSIONS Slight renal lesions were in agreement with changes in AF weight, since they suggest that there was production of urine with the maintenance of AF.
Aggressive elimination of precancerous lesions of the vocal cords to avoid risk of cancer.

INTRODUCTION Several studies show that early histological classification and excision of precancerous lesions of the vocal cords reduces the risk of cancer development. National Danish guidelines have not been established. The purpose of this study was to describe a Danish series of patients with precancerous lesions of the vocal cords and to estimate the risk of malignant transformation. MATERIAL AND METHODS This was a retrospective cohort study, including a total of 101 patients with histologically verified precancerous lesions of the vocal cords who were treated from 1997 to 2007 at Odense University Hospital (OUH). RESULTS Among the 101 patients, 18 (18%) were diagnosed with mild dysplasia, 16 (16%) with moderate dysplasia, 35 (35%) with severe dysplasia and 32 (32%) with carcinoma in situ (CIS) at the initial examination at OUH. Fifteen patients (15%), all males, developed invasive cancer. Among these, one patient was initially diagnosed with mild dysplasia, one with moderate dysplasia, seven with severe dysplasia and six with CIS. In 11 of the 15 patients (73%), cancer occurred within one year from the time of diagnosis of the precancerous lesion, whereas four cancers occurred years later. CONCLUSION The malignant transformation rate is comparable with other recent series. A strategy with elimination of all visible pathology is preferable. FUNDING not relevant. TRIAL REGISTRATION not relevant.
Arrangement of subunits in intact mammalian mitochondrial ATP synthase determined by cryo-EM

Mitochondrial ATP synthase is responsible for the synthesis of ATP, a universal energy currency in cells. Whereas X-ray crystallography has revealed the structure of the soluble region of the complex and the membrane-intrinsic c-subunits, little is known about the structure of the six other proteins (a, b, f, A6L, e, and g) that comprise the membrane-bound region of the complex in animal mitochondria. Here, we present the structure of intact bovine mitochondrial ATP synthase at ∼18 Å resolution by electron cryomicroscopy of single particles in amorphous ice. The map reveals that the a-subunit and c8-ring of the complex interact with a small contact area and that the b-subunit spans the membrane without contacting the c8-ring. The e- and g-subunits extend from the a-subunit density distal to the c8-ring. The map was calculated from images of a preparation of the enzyme solubilized with the detergent dodecyl maltoside, which is visible in electron cryomicroscopy maps. The structure shows that the micelle surrounding the complex is curved. The observed bend in the micelle of the detergent-solubilized complex is consistent with previous electron tomography experiments and suggests that monomers of ATP synthase are sufficient to produce curvature in lipid bilayers.
Neural Correlates of Attentional Capture in Visual Search

Much behavioral research has shown that the presence of a unique singleton distractor during a task of visual search will typically capture attention and thus disrupt target search. Here we examined the neural correlates of such attentional capture using functional magnetic resonance imaging in human subjects during performance of a visual search task. The presence (vs. absence) of a salient yet irrelevant color singleton distractor was associated with activity in the superior parietal cortex and frontal cortex. These findings imply that the singleton distractor induced spatial shifts of attention despite its irrelevance, as predicted from an AC account. Moreover, behavioral interference by singleton distractors was strongly and negatively correlated with frontal activity. These findings provide direct evidence that the frontal cortex is involved in control of interference from irrelevant but attention-capturing distractors.
THE EVOLUTIONARY ECOLOGY OF AN ANTIPREDATOR REACTION NORM: DAPHNIA PULEX AND CHAOBORUS AMERICANUS

Ponds containing the parthenogenetic zooplankter Daphnia pulex with and without chaoborid predators were sampled over the course of a season. A significant (P < 0.05) Spearman rank correlation was found between predator density and the expression of an antipredator defense (neckteeth) by the Daphnia. The reaction norms (percent induction of a single genotype versus predator density) of clones isolated from predator‐free and predator‐rich habitats were determined in a laboratory setting. There was a statistically significant different response among the six clones tested (P < 0.05). Clones isolated from chaoborid ponds showed significantly greater sensitivity to the presence of predator than clones from predator‐free ponds (P < 0.05). In the laboratory, food levels under which prey were cultured affected induction of the antipredator response. Highest induction was found at the lowest food level used.
EFFECTS OF UREA AND SODIUM BICARBONATE NUTRIENT DIGESTION AND RUMINAL CHARACTERISTICS OF DEFAUNATED SHEEP SUPPLEMENTATION OF A HIGH-FIBER DIET ON

Five sheep (average BW 48 kg) with ruminal, duodenal, and ileal cannulas were fed 63% roughage:37% concentrate diets (CP = 14.5%) in a 5 x 5 Latin square design to study effects of urea and sodium bicarbonate supplementation on nutrient digestion and ruminal characteristics of defaunated sheep. Diets were fed twice daily @MI = 1,076 g/d). Defaunation was accomplished with 25-ml doses of alkanate 3SL3hheep daily for 3 d. Control sheep were faunated (Treatment 1) and fed soybean meal as the major N supplement. Remaining sheep were maintained defaunated and fed either the same diet as Treatment 1 (Treatment 2). Treatment 1 with urea replacing 30% of the soybean meal N (Treatment 3), or Treatment 1 with 2% sodium bicarbonate in the diet (Treatment 4). Treatment 5 was a Combination of Treatments 3 and 4. Compared with the faunated control, defaunation decreased (P < .05) total tract DM, OM, NDF, ADF, and CP digestibilities (71.5 vs 69.4, 73.8 vs 71.7, 64.6 vs 61.4, 58.7 vs 55.8, and 74.2 vs 70.6%, respectively) and average (2 to 12 h postfeeding) ruminal fluid ammonia (23.5 vs 13.7 mgl dl) and isobutyrate (.9 vs .7 mM) concentrations. However, defaunation increased (P < .05) linoleic and linolenic acid flows (.58 vs .45 g .17 vs .14 g c18:dd) to and disappearance (SO vs .39 g c18:2/d; .14 vs .ll g c18:3/d) from the small intestine. Urea supplementation increased (P < .05) total tract DM (70.2 vs 68.6%) and OM (72.3 vs 71.0%) digestibilities of defaunated sheep but lowered (P < .05) ruminal fluid isobutyrate concentration (.6 vs .8 mM). Sodium bicarbonate supplementation increased (P < .05) ruminal fluid pH (6.4 vs 6.2), isobutyrate concenaation (.75 vs .60 mM), total tract ADF digestibility (57.6 vs 54.2%), and ruminal NDF (41.6 vs 28.5%), ADF (36.6 vs 22.8%). and CP (-5.5 vs -26.8%) digestibilities in defaunated sheep. Dietary supplementation of urea or sodium bicarbonate increased nutrient digestion by defaunated sheep.
Transcript and protein profiling identifies signaling, growth arrest, apoptosis, and NF-κB survival signatures following GNRH receptor activation

GNRH significantly inhibits proliferation of a proportion of cancer cell lines by activating GNRH receptor (GNRHR)-G protein signaling. Therefore, manipulation of GNRHR signaling may have an under-utilized role in treating certain breast and ovarian cancers. However, the precise signaling pathways necessary for the effect and the features of cellular responses remain poorly defined. We used transcriptomic and proteomic profiling approaches to characterize the effects of GNRHR activation in sensitive cells (HEK293-GNRHR, SCL60) in vitro and in vivo, compared to unresponsive HEK293. Analyses of gene expression demonstrated a dynamic response to the GNRH superagonist Triptorelin. Early and mid-phase changes (0.5–1.0 h) comprised mainly transcription factors. Later changes (8–24 h) included a GNRH target gene, CGA, and up- or downregulation of transcripts encoding signaling and cell division machinery. Pathway analysis identified altered MAPK and cell cycle pathways, consistent with occurrence of G2/M arrest and apoptosis. Nuclear factor kappa B (NF-κB) pathway gene transcripts were differentially expressed between control and Triptorelin-treated SCL60 cultures. Reverse-phase protein and phospho-proteomic array analyses profiled responses in cultured cells and SCL60 xenografts in vivo during Triptorelin anti-proliferation. Increased phosphorylated NF-κB (p65) occurred in SCL60 in vitro, and p-NF-κB and IκBϵ were higher in treated xenografts than controls after 4 days Triptorelin. NF-κB inhibition enhanced the anti-proliferative effect of Triptorelin in SCL60 cultures. This study reveals details of pathways interacting with intense GNRHR signaling, identifies potential anti-proliferative target genes, and implicates the NF-κB survival pathway as a node for enhancing GNRH agonist-induced anti-proliferation.
Profile of sapacitabine: potential for the treatment of newly diagnosed acute myeloid leukemia in elderly patients

Acute myeloid leukemia (AML) is a hematopoietic stem cell disorder that affects approximately 14,000 persons each year in the US. AML occurs at all ages but the incidence increases with age with the median age at diagnosis being 67 years. Advances in the treatment of AML over the past decades have led to improved survival, albeit mostly in younger patients. The prognosis of older patients with this disease over the same time span has not changed much and remains dismal. This review focuses on the epidemiology and characteristics of AML in elderly patients, the rationale for treating elderly AML patients, and the currently available and potential future treatment options such as sapacitabine. Elderly AML patients treated with intensive chemotherapy have a higher mortality rate, and a lower rate of complete remission and overall survival when compared to the younger population. This is due to both the different biology of the disease and the number of patient-specific factors. However, elderly AML patients treated with aggressive chemotherapy can achieve durable remissions, which offer prolonged survival and improved quality of life. Recent data also indicates that elderly AML patients deemed unfit for intensive chemotherapy benefit from leukemia-specific attenuated dose chemotherapy compared to supportive care alone. This has led to renewed interest to look for anti-leukemic therapies designed specifically for older patients. Sapacitabine, a novel oral nucleoside analog, promises good efficacy, favorable toxicity profile, and ease of administration; all of which makes it very appealing. Results from pre-clinical and clinical studies have been very encouraging and sapacitabine is currently being evaluated in a Phase III study, of which the results are eagerly awaited.
Valgrind: a framework for heavyweight dynamic binary instrumentation

Dynamic binary instrumentation (DBI) frameworks make it easy to build dynamic binary analysis (DBA) tools such as checkers and profilers. Much of the focus on DBI frameworks has been on performance; little attention has been paid to their capabilities. As a result, we believe the potential of DBI has not been fully exploited. In this paper we describe Valgrind, a DBI framework designed for building heavyweight DBA tools. We focus on its unique support for shadow values-a powerful but previously little-studied and difficult-to-implement DBA technique, which requires a tool to shadow every register and memory value with another value that describes it. This support accounts for several crucial design features that distinguish Valgrind from other DBI frameworks. Because of these features, lightweight tools built with Valgrind run comparatively slowly, but Valgrind can be used to build more interesting, heavyweight tools that are difficult or impossible to build with other DBI frameworks such as Pin and DynamoRIO.
Exposure to zinc deficiency in fetal and postnatal life determines nitric oxide system activity and arterial blood pressure levels in adult rats

We had previously shown that prenatal exposure to Zn-deficient diets induces an increase in blood pressure and impairs renal function in adult rats. The aim of the present study was to investigate if moderate Zn restriction during early growth periods, fetal life and lactation would induce impairment in the vascular and renal NO system and alterations in plasma lipid profile. We also investigated if these effects persisted into adult life, even when a Zn-replete diet was provided after weaning. Pregnant rats were fed control (30 parts per million (ppm)) or low (8 ppm) Zn diets throughout gestation up to weaning. Afterwards, male offspring from low-Zn mothers were assigned to low- or control-Zn diets during 60 d. Male offspring from control mothers were fed a control diet. Animals exposed to Zn restriction showed low birth weight, increased systolic blood pressure and serum TAG levels, and decreased glomerular filtration rate in adulthood. Zn restriction induced a decrease in vascular and renal NO synthase activity and a reduced expression of the endothelial NO synthase isoform in aorta. A control-Zn diet during post-weaning growth returned TAG levels to normal but was unsuccessful in normalising systolic blood pressure, glomerular filtration rate or NO system activity in Zn-deficient offspring. Zn restriction during fetal life, lactation and/or post-weaning growth induced alterations in the vascular and renal NO system and in lipid metabolism that could contribute to the programming of hypertension and renal dysfunction in adulthood.
Design of an Alkaline Electrolysis Stack

Renewable energy promises a green energy future for the world. Hence, the electrolysis process has been identified as the most important method to produce hydrogen using renewable energy source. Moreover, during the last few years, people have enhanced the interest to expand and use the alkaline water electrolysis technology in different fields. Thus, the design of high performance compact electrolysis stack according to the selected specification is very important. The main purpose of this research work is to design and fabricate a compact high performance electrolysis stack and to observe the electrolysis performance. Under this study, twelve different experiments have been implemented to observe the electrolysis performance. At the beginning, two different single cell alkaline electrolysers were fabricated and their performances monitored to select best cell for the stack. Thereafter, the several experiments were devised to improve the performance of the selected cell. Thus, the best performing cell was selected for the final stack. At last both monopolar and bipolar configuration of alkaline electrolysis stack are designed and implemented to compare the electrolysis performance of both configurations. Throughout the design process, the SolidWorks was adopted as the design software platform. The modeling part of alkaline electrolyser was done using the MATLAB/SIMULINK environment. Under the modeling process the electrochemical equations are used to develop MATLAB/SIMULINK model. Consequently, the theoretical results are obtained by using developed mathematical model. Later, the performance of designed alkaline electrolysis stack is analyzed and compared with the theoretical results.
The Performance of German Firms in the Business-Related Service Sector

We analyze the performance of firms from the German business-related service sector for 1994–2000. Performance is measured by ordinal assessment of changes in total sales. We estimate first-order Markov chain models using extensions of the multinomial logit model: a linear index model with alternative specifications of heterogeneity and a semiparametric model. The preferred specification involves heterogeneity connected to the firm and the type of transition. Our findings include that size has a positive effect on performance, young firms outperform older competitors, a single creditor has a stabilizing effect, diversification has a negative impact, and performance is significantly affected by legal status. Measuring performance through profit rather than sales does not alter the qualitative results.
Effect of teriflunomide on cortex-basal ganglia-thalamus (CxBGTh) circuit glutamatergic dysregulation in the Theiler's Murine Encephalomyelitis Virus mouse model of multiple sclerosis

Background Pathology of gray matter is associated with development of physical and cognitive disability in patients with multiple sclerosis. In particular, glutamatergic dysregulation in the cortex-basal ganglia-thalamus (CxBGTh) circuit could be associated with decline in these behaviors. Objectives To investigate the effect of an immunomodulatory therapy (teriflunomide, Aubagio®) on changes of the CxBGTh loop in the Theiler’s Murine Encephalomyelitis Virus, (TMEV) mouse model of MS. Methods Forty-eight (48) mice were infected with TMEV, treated with teriflunomide (24) or control vehicle (24) and followed for 39 weeks. Mice were examined with MRS and volumetric MRI scans (0, 8, 26, and 39 weeks) in the cortex, basal ganglia and thalamus, using a 9.4T scanner, and with behavioral tests (0, 4, 8, 12, 17, 26, and 39 weeks). Within conditions, MRI measures were compared between two time points by paired samples t-test and across multiple time points by repeated measures ANOVA (rmANOVA), and between conditions by independent samples t-test and rmANOVA, respectively. Data were considered as significant at the p<0.01 level and as a trend at p<0.05 level. Results In the thalamus, the teriflunomide arm exhibited trends toward decreased glutamate levels at 8 and 26 weeks compared to the control arm (p = 0.039 and p = 0.026), while the control arm exhibited a trend toward increased glutamate between 0 to 8 weeks (p = 0.045). In the basal ganglia, the teriflunomide arm exhibited a trend toward decreased glutamate earlier than the control arm, from 0 to 8 weeks (p = 0.011), resulting in decreased glutamate compared to the control arm at 8 weeks (p = 0.016). Conclusions Teriflunomide may reduce possible excitotoxicity in the thalamus and basal ganglia by lowering glutamate levels.