Miracle-dz/UniFAR-FTUs huggingface dataset:
BBR induces apoptosis in HepG2 cell through an Akt‐ASK1‐ROS‐p38MAPKs‐linked cascade

Berberine (BBR) has indicated significant antimicrobial activity against a variety of organisms including bacteria, viruses, and fungi. The mechanism by which BBR initiates apoptosis remains poorly understood. In the present study, we demonstrated that BBR exhibited significant cytotoxicity in human hepatoma HepG2 cells. Herein, we investigated cytotoxicity mechanism of BBR in HepG2 cells. The results showed that the induction of apoptosis in HepG2 cells by BBR was characterized by DNA fragmentation, an increased percentage of annexin V, and the activation of caspase‐3. The expressions of Bcl‐2 protein and pro‐caspase‐3 were reduced by BBR in HepG2 cells. However, Bax protein was increased in the cells. BBR‐induced apoptosis was preceded by increased generation of reactive oxygen species (ROS). NAC treatment, a scavenger of ROS, reversed BBR‐induced apoptosis effects via inhibition of Bax activation and Bcl‐2 inactivation. BBR‐induced, dose‐dependent induction of apoptosis was accompanied by sustained phosphorylation of MAP Kinases (JNK and p38 MAPK), ASK1, Akt, and p53. Furthermore, SB203580, p38 inhibitor, reduced the apoptotic effect of BBR, and blocks the generation of ROS and NO as well as activation of Bax. We found that the treatment of HepG2 cells with BBR triggers generation of ROS through Akt phosphorylation, resulting in dissociation of the ASK1‐mediated activation of JNK and p38 pathways. J. Cell. Biochem. 109: 329–338, 2010. © 2009 Wiley‐Liss, Inc.
The Fidelity of HPV16 E1/E2-mediated DNA Replication*

Human papillomaviruses (HPV) are causative agents in a variety of human diseases; for example over 99% of cervical carcinomas contain HPV DNA sequences. Often in cervical carcinoma the HPV genome is integrated into the host genome resulting in unregulated expression of the viral transforming proteins E6 and E7. Therefore viral integration is a step toward HPV-induced carcinogenesis. Integration of the HPV genome could occur following double-strand DNA breaks that could arise during viral DNA replication. We investigated the fidelity of HPV 16 E1- and E2-mediated DNA replication of non-damaged and UVC-damaged templates in a variety of cell lines with different genetic backgrounds; C33a (derived from an HPV-negative cervical carcinoma), XP30RO (deficient in the by-pass polymerase η (polη)), XP30η (expressing a restored wild-type polη), XP12RO (nucleotide excision repair defective), and MRC5 (derived from a 14-week-old human fetus). The results demonstrate that the fidelity of E1- and E2-mediated DNA replication is reflective of the genetic background in which the assays are carried out. For example, restoring polη to the XP30 cell line results in a 3-fold drop in the number of mutants obtained following replication of a UVC-damaged template. A relatively high percentage of the mutant-replicated molecules arise as a result of genetic rearrangement. This is the first time such studies have been carried out with an HPV replication system, and the results are discussed in the context of the HPV life cycle and what is known about HPV genomes in human cancers.
Teaching and learning in an 80-hour work week

The 80-hour workweek limit for residents provides an opportunity for residency directors to creatively innovate their programs. Our novel day-float rotation augmented both the educational structure within the inpatient team setting and the ability for house staff to complete their work within the mandated limits. Descriptive evaluation of the rotation was performed through an end-of-rotation questionnaire. The average length of the ward residents’ work week was quantified before and after the rotation’s implementation. Educational portfolios and mentored peer-teaching opportunities enriched the rotation. As measured by our evaluation, this new rotation enhanced learning and patient care while reducing work hours for inpatient ward residents.
Attitude determination module for CubeSat

The increasing interest of medium and small companies in CubeSats is due to their inherent characteristics like low cost, reduced requirements and short term startup of such space missions. New navigation instruments and modules are being designed and manufacturing in order to increase the functionality and performance of this kind of picosatellites. Size, cost and power limits are several of the restrictions applied to design criteria of such instruments. This paper introduces a new hardware module to be used in attitude determination, specially designed for CubeSat missions, and composed by a star tracker and a set of sun sensors. While appropriate sun sensors have been selected from space industry, a new star tracker has been designed and manufactured for this purpose.
An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia.

Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials. gov as #NCT01799889.
Methamphetamine exposure during the preweanling period causes prolonged changes in dorsal striatal protein kinase A activity, dopamine D2‐like binding sites, and dopamine content

Exposure to methamphetamine (METH) during the preweanling period produces few, if any, neurotoxic effects (using criteria established in adult rats), yet it has substantial long‐term effects on a variety of behavioral measures (e.g., locomotor activity, acoustic startle response, and spatial learning). The purpose of the present study was to examine the long‐term changes in dopaminergic functioning brought about by early METH exposure. Rats were injected with METH (10 mg/kg) or saline four times daily on postnatal days (PD) 11–20 and housed undisturbed until PD 90, at which time they were killed and their dorsal striata (i.e., caudate–putamen) were removed and frozen for assay. The ability of early METH exposure to alter protein kinase A (PKA) activity and dopamine (DA) D2‐like binding sites, as well as DA and DOPAC content, were assessed. Results showed that METH exposure on PD 11–20 caused long‐term reductions in all of the dopaminergic markers assayed. METH‐induced reductions in DA content and D2‐like receptors were observed. Some sex differences were apparent, as the METH‐induced decreases in PKA activity and DOPAC content were more evident in male rats. In conclusion, preweanling METH exposure caused changes in DA markers that were still detectable at PD 90; however the magnitude of many of these effects (e.g., the reductions in DA and DOPAC levels) was substantially less than typically reported for rats treated with METH in adulthood. The ability of METH to cause long‐term reductions in PKA activity may partially account for some of behavioral deficits exhibited by rats exposed to METH prior to weaning. Synapse 48:131–137, 2003. © 2003 Wiley‐Liss, Inc.
Melatonin exhibits supportive effects on oxidants and anastomotic healing during intestinal ischemia/reperfusion injury.

BACKGROUND The aim of this study was to investigate the effects of melatonin on intestinal anastomosis after intestinal ischemia/ reperfusion injury (IRI). METHODS Thirty Wistar albino rats of both sexes were divided into 3 groups: sham, control, and treatment. IRI was performed by clamping the superior mesenteric artery (SMA) for 30 minutes, followed by reperfusion. The sham rats received only manipulation of the SMA. Melatonin (10 mg/kg) was administered to the treatment group, and the control group was given a vehicle injection. Both the treatment group and the control group further underwent ileal resection of a 1-cm segment and anastomosis. On the postoperative seventh day, the anastomotic burst pressure, hydroxyproline level, histological indices of wound healing, and oxidative parameters of catalase (CAT), superoxide dismutase (SOD), total glutathione (T-GSH), and glutathione peroxidase (GSH-Px) levels were measured. A one-way analysis of variance and chi-square test were used for the categorical data. RESULTS Melatonin treatment led to a significantly higher burst pressure (p=0.027 and p<0.001, respectively). The 2 antioxidant enzymes, CAT and SOD, were at the highest level in the sham and melatonin groups and the lowest level in the control group (p=0.001 and p=0.002, respectively). Melatonin treatment resulted in a significantly higher level of both enzymes compared with the control group (p=0.026 and 0.003, respectively). The GSHpx and total GSH levels were slightly elevated in the treated rats, but the difference was not statistically significant (p=0.205 and 0.216, respectively). Fibroblast infiltration, capillary formation, and epithelialization were significantly better in the melatonin-treated animals. The granulocyte and mononuclear infiltration scores were similar between all groups. CONCLUSION It was concluded that melatonin had marked effects on intestinal anastomotic healing during intestinal IRI.
Targeting of the CREB gene leads to up‐regulation of a novel CREB mRNA isoform.

To define the role of cAMP signaling in gene control, we have generated mice with a mutation in the cAMP response element binding protein (CREB) gene. Mice carrying this mutation are viable but show an impairment in memory consolidation. In further analysis of these mice, we have found an up‐regulation of a CREB isoform that has not been described previously . The new isoform, termed CREB beta, has nearly the same transactivation potential as the other CREB isoforms and is expressed ubiquitously. The up‐regulation appears to be due to an increase in alternative splicing or mRNA stability, but not to an increase in transcriptional rate. Due to the relatively low levels of expression in all tissues, the role of this isoform is likely to be minor in the wild‐type mouse. However, its dramatic up‐regulation in the mutant mouse, together with the specific deficiencies recently observed in these mice, suggest that it has a very specific role in compensating for CREB alpha and delta in some, but not all, areas where CREB function has been implicated. Together with the up‐regulation of the cAMP response element modulator protein (CREM) mRNA and protein levels demonstrated previously in CREB mutant mice, we suggest that the up‐regulation of CREB beta may also contribute to compensation within the CREB/ATF family of transcription factors, when CREB delta and CREB alpha are absent.
Cellular pathology changes in rat skin following intradermal injection of nerve growth factor: neutrophil‐dependent and ‐independent events

Nerve growth factor (NGF) regulates the survival and development of specific populations of neurones and is involved in wound healing. A further area of study relating to the role of neurotrophins in the mature animal has concerned the possibility that NGF may be a pivotal mediator of inflammation and pain. It has previously been shown that injection of intradermal NGF can result in a neutrophil‐dependent hyperalgesia in the rat. The purpose of the present study was to examine the pathological consequence of NGF injected intradermally into mature rat skin and to examine further the role of neutrophils. Standard histopathology techniques (H & E) were employed to determine inflammatory cell counts. Circulating neutrophils were depleted using an anti‐rat neutrophil antiserum and results were compared to treatment with vehicle controls. Saline‐pretreated rats exhibited normal circulating neutrophil numbers and the dorsal skin showed a significant increase of neutrophil and macrophages at 3 and 5 h and lymphocytes at 5 h after NGF treatment. By comparison, skin sites from neutrophil‐depleted rats did not demonstrate a significant increase in neutrophil and macrophage accumulation after NGF administration. All NGF‐treated sites, independent of pretreatment, demonstrated abnormal muscle fibre morphology and proliferation of the muscle sarcolemmal nuclei after NGF injection, indicative of tissue injury. In addition, oedema and some fibroplasia were also noted. Furthermore, fibrin production was increased at 3 and 5 h after NGF administration. It is suggested that NGF has a damaging effect on rat muscle which is independent of accumulating neutrophil and other inflammatory cells. In conclusion, the findings indicate a link between NGF‐induced neutrophil and macrophage accumulation, as the increase in dermal macrophages was not observed in neutrophil‐depleted rats. The results also suggest that NGF can have a profound effect on rat muscle and that this effect may be related to muscle regeneration. Copyright © 2002 John Wiley & Sons, Ltd.
Danger and loss events and the incidence of anxiety and depressive disorders: a prospective-longitudinal community study of adolescents and young adults

Background There are inconclusive findings regarding whether danger and loss events differentially predict the onset of anxiety and depression. Method A community sample of adolescents and young adults (n = 2304, age 14–24 years at baseline) was prospectively followed up in up to four assessments over 10 years. Incident anxiety and depressive disorders were assessed at each wave using the DSM-IV/M-CIDI. Life events (including danger, loss and respectively mixed events) were assessed at baseline using the Munich Event List (MEL). Logistic regressions were used to reveal associations between event types at baseline and incident disorders at follow-up. Results Loss events merely predicted incident ‘pure’ depression [odds ratio (OR) 2.4 per standard deviation, 95% confidence interval (CI) 1.5–3.9, p < 0.001] whereas danger events predicted incident ‘pure’ anxiety (OR 2.3, 95% CI 1.1–4.6, p = 0.023) and ‘pure’ depression (OR 2.5, 95% CI 1.7–3.5, p < 0.001). Mixed events predicted incident ‘pure’ anxiety (OR 2.9, 95% CI 1.5–5.7, p = 0.002), ‘pure’ depression (OR 2.4, 95% CI 1.6–3.4, p < 0.001) and their co-morbidity (OR 3.6, 95% CI 1.8–7.0, p < 0.001). Conclusions Our results provide further evidence for differential effects of danger, loss and respectively mixed events on incident anxiety, depression and their co-morbidity. Since most loss events referred to death/separation from significant others, particularly interpersonal loss appears to be highly specific in predicting depression.
Toll‐like receptors 2 and 4 mediate Aβ(1–42) activation of the innate immune response in a human monocytic cell line

The primary molecules for mediating the innate immune response are the Toll‐like family of receptors (TLRs). Recent work has established that amyloid‐beta (Aβ) fibrils, the primary components of senile plaques in Alzheimer’s disease (AD), can interact with the TLR2/4 accessory protein CD14. Using antibody neutralization assays and tumor necrosis factor alpha release in the human monocytic THP‐1 cell line, we determined that both TLR2 and TLR4 mediated an inflammatory response to aggregated Aβ(1–42). This was in contrast to exclusive TLR ligands lipopolysaccharide (LPS) (TLR4) and tripalmitoyl cysteinyl seryl tetralysine (Pam3CSK4) (TLR2). Atomic force microscopy imaging showed a fibrillar morphology for the proinflammatory Aβ(1–42) species. Pre‐treatment of the cells with 10 μg/mL of a TLR2‐specific antibody blocked ∼50% of the cell response to fibrillar Aβ(1–42), completely blocked the Pam3CSK4 response, and had no effect on the LPS‐induced response. A TLR4‐specific antibody (10 μg/mL) blocked ∼35% of the cell response to fibrillar Aβ(1–42), completely blocked the LPS response, and had no effect on the Pam3CSK4 response. Polymyxin B abolished the LPS response with no effect on Aβ(1–42) ruling out bacterial contamination of the Aβ samples. Combination antibody pre‐treatments indicated that neutralization of TLR2, TLR4, and CD14 together was much more effective at blocking the Aβ(1–42) response than the antibodies used alone. These data demonstrate that fibrillar Aβ(1–42) can trigger the innate immune response and that both TLR2 and TLR4 mediate Aβ‐induced tumor necrosis factor alpha production in a human monocytic cell line.
N‐acetylcysteine augmentation therapy for moderate‐to‐severe obsessive–compulsive disorder: randomized, double‐blind, placebo‐controlled trial

N‐acetylcysteine (NAC) has been proposed as a potential therapy for obsessive–compulsive disorder (OCD) as it may regulate the exchange of glutamate and prevent its pre‐oxidant effects. The aim of the present double‐blind, placebo‐controlled trial was to assess the efficacy and tolerability of NAC augmentation in moderate‐to‐severe (OCD) treatment.
Protein and lipid utilization during long-term fasting in emperor penguins.

The body mass of male emperor penguins is approximately 38 kg at the beginning of the 4-mo winter fast connected with breeding, and it is an estimated approximately 18 kg in leanest birds at time of spontaneous refeeding. For a 38- to 18-kg range, we investigated the changes in the rate of body mass loss, body composition, and plasma concentrations of uric acid and urea. After the first few days (phase I) a steady state (phase II) was reached in the proportions of the energy derived from proteins and lipids with proteins accounting for a constant 4%, and the remaining 96% being from lipids. The same proportions were maintained until body mass had decreased to 24 kg. Below this value the proportion of energy derived from proteins increased progressively (phase III), being 14 times higher at 18 kg than during phase II. Rate of body mass loss and plasma uric acid and urea concentrations closely reflected the changes in protein utilization: being at a low and steady value throughout phase II and increasing during phase III. Emperor penguins also fast during the spring, but for periods of only 2-3 wk. We found a 2.5 times higher value for rate of body mass loss, uric acid, and urea during spring phase II, suggesting lower effectiveness in protein sparing at that time. It may be attributed to the lower initial lipid reserves of spring birds. Would these findings be generalized to the wide variety of birds and mammals that spontaneously fast under natural conditions? (ABSTRACT TRUNCATED AT 250 WORDS)
Funktion des zellspezifischen Transkriptionsfaktors HNF4alpha bei der Zellproliferation und Identifizierung von HNF4-alpha-regulierten Genen in Nierenzellen

Der zellspezifische Transkriptionsfaktor HNF4alpha ist fur die transkriptionelle Kontrolle von Genen wichtig, die in der Leber, der Niere, dem Magen-Darmtrakt und den b-Zellen des Pankreas exprimiert werden. Obwohl HNF4alpha in den proximalen Tubuli der Niere reichlich exprimiert wird, sind die Funktion und die Zielgene von HNF4alpha in diesem Organ noch unbekannt. Da ein Funktionsausfall von HNF4alpha bei Nierenzellkarzinomen beschrieben worden ist, besteht die Moglichkeit, dass HNF4alpha als Tumorsuppressor in Nierenzellen agiert. Die Erforschung der HNF4alpha-Funktion und der HNF4alpha-Zielgene in Nierenzellen ist daher ein wichtiges Ziel, um aufzuklaren, ob HNF4alpha eine Tumorsuppressorfunktion im Nierenzellkarzinom ausubt. Unter Verwendung der Zelllinie Flp-In T-REx 293 wurden zunachst humane embryonale Nierenzellen (HEK293) etabliert, die HNF4alpha wt in einer induzierbaren Form exprimieren. Es zeigte sich, dass die Expression von HNF4alpha wt in HEK293 Zellen zu einer verzogerten Zellproliferation fuhrte. Die Verringerung der Proliferation nach HNF4alpha-Expression war von einer Veranderung der Zellmorphologie begleitet. Um die Gene zu erfassen, deren Aktivitat durch HNF4alpha in den HEK293 Zellen spezifisch verandert wird, wurde eine Mikroarray-Analyse durchgefuhrt. Eine Vielzahl neuer HNF4alpha-regulierter Gene wurde identifiziert. Die verwendeten Filterbedingungen zur Datenanalyse ergaben 65 Gene, die nach 24 Stunden HNF4alpha-Induktion in den HEK293 Zellen reguliert waren. Die differentielle Expression ausgewahlter Kandidatengene wurde mittels Real-time PCR und Western Blot bestatigt. Die Analyse der gewebespezifischen Expression der identifizierten HNF4alpha-Zielgene belegte, dass eine hohe Anzahl der identifizierten Gene in der Niere exprimiert werden. Weiterhin wurden die identifizierten HNF4alpha-Zielgene mit den Genen, die im Nierenzellkarzinom differentiell exprimiert werden, verglichen. Dabei zeigte es sich, dass 13 von den 65 HNF4alpha-Zielgenen im Nierenzellkarzinom genau in der umgekehrten Richtung wie in den HEK293 Zellen reguliert sind. Man kann folglich spekulieren, dass diese 13 Gene (ACY1, WT1, SELENBP1, COBL, EFHD1, AGXT2L1, ALDH5A1, THEM2, ABCB1, FLJ14146, CSPG2, TRIM9 und HEY1) im Nierenzellkarzinom aufgrund der verminderten Expression von HNF4alpha dereguliert sind. Sowohl die antiproliferative Wirkung von HNF4alpha in Nierenzellen als auch die Deregulation vieler HNF4alpha-Zielgene im Nierenzellkarzinom stellen Hinweise auf eine Beteiligung von HNF4alpha an der Entstehung des Nierenzellkarzinoms dar.
Femtosecond Information Processing Using Low Density Gratings

We proposed and demonstrated the novel femtosecond laser processing techniques using two- layered low density gratings, such as splitting, measurement, multipulses generation, and compression. As to our knowledge, we are the first to introduce Dammann grating into femtosecond laser technology, which should be interesting for practical applications.
A Fast and Accurate Fault Tree Analysis Based on Stochastic Logic Implemented on Field-Programmable Gate Arrays

This paper presents a method based on stochastic logic to analyse fault trees. This method supports both static and dynamic gates, and can be applied to any type of fault trees. In this paper, static and dynamic gates would be translated into stochastic logic templates, and a hardware implementation for each gate would be achieved. Based on these hardware templates, it is possible to implement the whole logic on a Field-Programmable Gate Array (FPGA). Utilizing the stochastic logic for implementing a given fault tree on FPGA, the analysis would outperform the following parameters compared to traditional methods: 1) Speed-up, 2) Simplicity, 3) Reliability, and 4) Accuracy. Experimental results illustrate that using stochastic logic for modeling fault trees results in fast convergence of Monte Carlo simulation. Moreover, on average, our FPGA approach takes 50% of the time required by previous emulation approaches. Simplicity is an additional advantage of the proposed approach, achieved because of simplicity behind stochastic logic. Also, the stochastic logic is more reliable compared to traditional logic because any faults like SEUs in stochastic logic have less impact on the whole results compared to traditional arithmetic logic. To evaluate the proposed technique, the analysis is performed on several standard benchmarks composed of static and dynamic gates. The results obtained using this approach agree with those obtained from an analytical approach, which proves that the method is an accurate tool for system reliability modeling.