Miracle-dz/UniFAR-FTUs huggingface dataset:
Oligomerization Is a General Mechanism for the Activation of Apoptosis Initiator and Inflammatory Procaspases*

Proteolytic activation of initiator procaspases is a crucial step in the cellular commitment to apoptosis. Alternative models have been postulated for the activation mechanism, namely the oligomerization or induced proximity model and the allosteric regulation model. While the former holds that procaspases become activated upon proper oligomerization by an adaptor protein, the latter states that the adaptor is an allosteric regulator for procaspases. The allosteric regulation model has been applied for the activation of procaspase-9 by apoptotic protease-activating factor (Apaf-1) in an oligomeric complex known as the apoptosome. Using approaches that allow for controlled oligomerization, we show here that aggregation of multiple procaspase-9 molecules can induce their activation independent of the apoptosome. Oligomerization-induced procaspase-9 activation, both within the apoptosome and in artificial systems, requires stable homophilic association of the protease domains, raising the possibility that the function of Apaf-1 is not only to oligomerize procaspase-9 but also to maintain the interaction of the caspase-9 protease domain after processing. In addition, we provide biochemical evidence that other apoptosis initiator caspases (caspase-2 and -10) as well as a procaspase involved in inflammation (murine caspase-11) are also activated by oligomerization. Thus, oligomerization of precursor molecules appears to be a general mechanism for the activation of both apoptosis initiator and inflammatory procaspases.
Crucial Role of TNF-α in CD8 T Cell-Mediated Elimination of 3LL-A9 Lewis Lung Carcinoma Cells In Vivo1

The role of perforin, IFN-γ, and TNF-α in anti-tumor CD8 T cell immunity was examined in a new tumor model using a CD8 T cell epitope (GP33) derived from lymphocytic choriomeningitis virus as a tumor-associated Ag. In contrast with parental 3LL-A9 (A9) Lewis lung carcinoma cells that progressively grow in C57BL/6 mice, s.c. injection of GP33-transfected A9GP33 tumor cells induced a protective GP33-specific CD8 T cell response that led to complete tumor cell elimination. Tumor regression was dependent on perforin, IFN-γ, or TNF-α, because A9GP33 tumors developed in mice deficient in one of these genes. A9GP33 tumors arising in perforin- and IFN-γ-deficient mice represented GP33 Ag-loss variants, demonstrating that GP33-specific CD8 T cells from these mice were able to exert an Ag selection pressure. In contrast, tumor cells growing in TNF-α knock-out mice still expressed the tumor-associated GP33 peptide despite the presence of activated GP33-specific CD8 T cells. These findings provide evidence for a crucial role of TNF-α in A9 tumor cell elimination by CD8 T cells in vivo.
The Generation of the Oxidized Form of Creatine Kinase Is a Negative Regulation on Muscle Creatine Kinase*

Muscle creatine kinase (CK) is a crucial enzyme in energy metabolism, and it exists in two forms, the reduced form (R-CK) and the oxidized form (O-CK). In contrast with R-CK, O-CK contained an intrachain disulfide bond in each subunit. Here we explored the properties of O-CK and its regulatory role on muscle CK. The intrachain disulfide bond in O-CK was demonstrated to be formed between Cys74 and Cys146 by site-directed mutagenesis. Biophysical analysis indicated that O-CK showed decreased catalytic activity and that it might be structurally unstable. Further assays through guanidine hydrochloride denaturation and proteolysis by trypsin and protease K revealed that the tertiary structure of O-CK was more easily disturbed than that of R-CK. Surprisingly, O-CK, unlike R-CK, cannot interact with the M-line protein myomesin through biosensor assay, indicating that O-CK might have no role in muscle contraction. Through in vitro ubiquitination assay, CK was demonstrated to be a specific substrate of muscle ring finger protein 1 (MURF-1). O-CK can be rapidly ubiquitinated by MURF-1, while R-CK can hardly be ubiquitinated, implying that CK might be degraded by the ATP-ubiquitin-proteasome pathway through the generation of O-CK. The results above were further confirmed by molecular modeling of the structure of O-CK. Therefore, it can be concluded that the generation of O-CK was a negative regulation of R-CK and that O-CK might play essential roles in the molecular turnover of MM-CK.
Aggressive Lipid Management for Cardiovascular Prevention: Evidence from Clinical Trials

Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases the risk of coronary heart disease (CHD). Moreover, large-scale intervention trials demonstrate that treatment with HMG-CoA reductase inhibitors (statins), the most effective drug class for lowering LDL-C, significantly reduces the risk of CHD events. Unfortunately, only a moderate percentage of hypercholesterolemic patients are achieving LDL-C targets specified by the National Cholesterol Education Program (NCEP), in part because clinicians are not effectively titrating medications as needed to achieve LDL-C goals. Recent evidence suggests that more aggressive LDL-C lowering may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. Furthermore, recent studies suggest that statins have cardioprotective effects in many high-risk individuals, including those with baseline LDL-C <100 mg/dl. High-density lipoprotein cholesterol (HDL-C) was recognized by the NCEP-Adult Treatment Panel II (ATP II) as a negative risk factor for CHD. The NCEP-ATP III guidelines have also reaffirmed the importance of HDL-C by increasing the low HDL-C designation from <35 to <40 mg/dl as a major risk factor for CHD. Similarly, triglyceride control will play a larger role in dyslipidemia management. As more clinicians effectively treat adverse lipid and lipoprotein cardiovascular risk factors, patients will likely benefit from reductions in cardiovascular events.
Sprouty4, a suppressor of tumor cell motility, is downregulated by DNA methylation in human prostate cancer

Alterations of fibroblast growth factors (FGFs) and their receptors contribute to prostate cancer progression by enhancing cellular proliferation, survival, and motility. The Sprouty gene family negatively regulates FGF signaling and may limit the ability of FGFs to enhance tumor progression. Sprouty1 is downregulated in human prostate cancers and Sprouty1 expression can markedly inhibit prostate cancer proliferation in vitro. Sprouty4 has been shown to negatively regulate both proliferation and cell migration in other systems. We therefore examined whether Sprouty4 expression was altered in prostate cancer.
Technology shocks and the dynamic response of labor employment

In this paper, we empirically investigate the dynamic effects of neutral & investment-specific technology shocks on labor employment in China. Under the assumption that investment-specific technology shock is the unique source of secular trend in relative price of investment goods, we find that labor employment increases (decreases) in response to a positive investment-specific (neutral) shock in an identified SVAR with long-run restriction. We argue that empirical results obtained in one-neutral-shock model do misrepresent the important short-run dynamics of employment to different technology shocks in the actual economy.
First generation expert systems: a review of knowledge acquisition methodologies

Abstract This paper reviews a wide range of knowledge acquisition techniques in the context of attempts to achieve a systematic methodology. These have been poorly documented by expert system builders, who are often inclined to overvalue textbooks and the ways experts themselves claim they solve problems. No one method has a universal advantage; each has some value. Techniques should be selected to suit the domain, the task, the expert and the knowledge engineer. Knowledge acquisition involves creating a conceptual model of expert knowledge and reasoning, from analysis of data elicited by these techniques. A survey of the literature indicates increasing emphasis on tools for knowledge acquisition, used directly by experts. Several projects currently directed towards providing a proper epistemological foundation for knowledge acquisition are discussed and compared. None has yet produced a complete epistemologically sound methodology; however, recognition of the need to create a conceptual model at the knowledge level (rather than the symbol level) is an important advance. An extensive bibliography is appended.
When Supervisors Perceive Non-Work Support: Test of a Trickle-Down Model

ABSTRACT Using the trickle-down model as the theoretical foundation, we explored whether subordinates’ perceived supervisory non-work support (subordinates’ PSNS) mediates the relationship between supervisors’ perception of higher-level managers’ non-work support (supervisors’ PSNS) and subordinates’ organizational citizenship behaviors. Using dyadic data collected from 132 employees and their immediate supervisors, we found support for the aforementioned mediation process. Furthermore, supervisors’ perceived in-group/out-group membership of subordinates moderated the aforementioned supervisors’ PSNS-subordinates’ PSNS relationship, such that this relationship is stronger for out-group subordinates. Theoretical and practical implications and future research directions are discussed.
Addition of adrenaline to pethidine for epidural analgesia after Caesarean section

We have investigated the addition of adrenaline to epidural pethidine for postoperative analgesia in 40 patients after Caesarean section. In a randomised, double‐blind study, patients received pethidine 25 mg with adrenaline 50 μg (adrenaline group, n = 20) or pethidine 25 mg without adrenaline (plain group, n = 18) epidurally at the first request for postoperative analgesia. The median duration of analgesia was longer in the adrenaline group (196 min; IQR 123–286) compared with the plain group (96 min; IQR 43–113; p = 0.002) and plasma concentrations of pethidine in the first 30 min after injection were lower in the adrenaline group (p = 0.003). Visual analogue scale pain scores in the first 30 min after injection and onset of analgesia, defined by the time for pain scores to decrease by 50%, were similar between groups. Addition of adrenaline to epidural pethidine has advantages for analgesia after Caesarean section.
Fibroblast apoptosis induced by Porphyromonas gingivalis is stimulated by a gingipain and caspase‐independent pathway that involves apoptosis‐inducing factor

Porphyromonas gingivalis is an oral bacterium that causes pathology in a number of dental infections that are associated with increased fibroblast cell death. Studies presented here demonstrated that P. gingivalis stimulates cell death by apoptosis rather than necrosis. Unlike previous studies apoptosis was induced independent of proteolytic activity and was also independent of caspase activity because a pancaspase inhibitor, Z‐VAD‐fmk, had little effect. Moreover, P. gingivalis downregulated caspase‐3 mRNA levels and caspase‐3 activity. The consequence of this downregulation was a significant reduction in tumour necrosis factor‐α‐induced apoptosis, which is caspase‐3‐dependent. Immunofluorescence and immunoblot analysis revealed P. gingivalis‐induced translocation of apoptosis‐inducing factor (AIF) from the cytoplasm to the nucleus. siRNA studies were undertaken and demonstrated that P. gingivalis stimulated cell death was significantly reduced when AIF was silenced (P < 0.05). Treatment of human gingival fibroblasts with H‐89, a protein kinase A inhibitor that blocks AIF activation also reduced P. gingivalis‐induced apoptosis (P < 0.05). These results indicate that P. gingivalis causes fibroblast apoptosis through a pathway that involves protein kinase A and AIF, is not dependent upon bacterial proteolytic activity and is also independent of the classic apoptotic pathways involving caspase‐3.
Spectrographic cry analysis in newborns with profound hearing loss and perinatal high-risk newborns.

BACKGROUND Crying is the first neurophysiological demonstration of the newborn. The acoustic analysis of crying episodes can provide useful information in the early diagnosis of several pathologies. METHODS We carried out a spectrographic cry analysis of 40 infants with several diseases such as neonatal asphyxia, breathing disorders, deafness and neurological disorders. Statistical t-test was used in order to compare means of fundamental frequencies (F0) of cries among pathologies, as well as contingency tables for qualitative variables and melodic form. RESULTS No significant differences of F0 were found by applying the t-test among pathologies. Time of inspiration in breathing disorders is higher compared with other groups. Infants with deafness and neurological disorders present poor melodic forms. Qualitative analysis revealed more often glottal roll and vibrato. CONCLUSIONS Cry analysis is clinically useful for early detection of diseases in newborns as a result of alterations in the central nervous system that are reflected in phonoarticulatory and respiratory functions for sound emission.
In vivo proton range verification: a review

Protons are an interesting modality for radiotherapy because of their well defined range and favourable depth dose characteristics. On the other hand, these same characteristics lead to added uncertainties in their delivery. This is particularly the case at the distal end of proton dose distributions, where the dose gradient can be extremely steep. In practice however, this gradient is rarely used to spare critical normal tissues due to such worries about its exact position in the patient. Reasons for this uncertainty are inaccuracies and non-uniqueness of the calibration from CT Hounsfield units to proton stopping powers, imaging artefacts (e.g. due to metal implants) and anatomical changes of the patient during treatment. In order to improve the precision of proton therapy therefore, it would be extremely desirable to verify proton range in vivo, either prior to, during, or after therapy. In this review, we describe and compare state-of-the art in vivo proton range verification methods currently being proposed, developed or clinically implemented.
Low-Power Near-Threshold Design: Techniques to Improve Energy Efficiency Energy-efficient near-threshold design has been proposed to increase energy efficiency across a wid

Energy-efficient near-threshold design has been proposed to increase energy efficiency across a wide range of applications. This article first provides a background motivating near-threshold and how it differs from super-threshold and subthreshold operation. Next, state-of-the-art near-threshold techniques are summarized that help overcome barriers to near-threshold adoption, namely high variation at low voltage. Last, example industrial and academic wide-voltage scaling systems are discussed.
Evaluation of the Performance of a Novel System for Continuous Glucose Monitoring

Background: The performance of a continuous glucose monitoring (CGM) system in the early stage of development was assessed in an inpatient setting that simulates daily life conditions of people with diabetes. Performance was evaluated at low glycemic, euglycemic, and high glycemic ranges as well as during phases with rapid glucose excursions. Methods: Each of the 30 participants with type 1 diabetes (15 female, age 47 ± 12 years, hemoglobin A1c 7.7% ± 1.3%) wore two sensors of the prototype system in parallel for 7 days. Capillary blood samples were measured at least 16 times per day (at least 15 times per daytime and at least once per night). On two subsequent study days, glucose excursions were induced. For performance evaluation, the mean absolute relative difference (MARD) between CGM readings and paired capillary blood glucose readings and precision absolute relative difference (PARD), i.e., differences between paired CGM readings were calculated. Results: Overall aggregated MARD was 9.2% and overall aggregated PARD was 7.5%. During induced glucose excursions, MARD was 10.9% and PARD was 7.8%. Lowest MARD (8.5%) and lowest PARD (6.4%) were observed in the high glycemic range (euglycemic range, MARD 9.1% and PARD 7.4%; low glycemic range, MARD 12.3% and PARD 12.4%). Conclusions: The performance of this prototype CGM system was, particularly in the hypoglycemic range and during phases with rapid glucose fluctuations, better than performance data reported for other commercially available systems. In addition, performance of this prototype sensor was noticeably constant over the whole study period. This prototype system is not yet approved, and performance of this CGM system needs to be further assessed in clinical studies.
Charge Pump Circuits: An Overview on Design Strategies and Topologies

Due to the continuous power supply reduction, charge pumps circuits are widely used in integrated circuits (ICs) devoted to several kind of applications such as smart power, nonvolatile memories, switched capacitor circuits, operational amplifiers, voltage regulators, SRAMs, LCD drivers, piezoelectric actuators, RF antenna switch controllers, etc. The main focus of this tutorial manuscript is to provide a deep understanding of the charge pumps behavior, to present useful models and key parameters and to organically and in details discuss the optimized design strategies. Finally, an overview of the main different topologies is also included.
Effect of Solanum trilobatum on hepatic drug metabolising enzymes during diethylnitrosamine‐induced hepatocarcinogenesis promoted by Phenobarbital in rat

The present study was aimed to investigate the chemopreventive effects of Solanum trilobatum (ST) extract against diethylnitrosamine (DEN)‐induced hepatocarcinogenesis promoted by Phenobarbital (PB) in Wistar rats. Hepatocarcinogenesis was initiated by a single intraperitoneal injection of DEN (200 mg/kg b.w.) and promoted with PB (0.05%) in basal diet. The experimental study extended for periods of 13 and 26 weeks. Alcoholic extract of ST was orally administered for the entire experimental period after initiation along with commencement of promotion. The chemopreventive effect of ST was assessed from the incidence of nodules, drug metabolizing phase I components such as contents of cytochrome P450, cytochrome b5, activities of NADPH cytochrome c reductase, NADH – cytochrome b5 reductase and phase II components such as levels of glutathione, activities of UDP‐glucuronyl transferase, glutathione S‐transferase and γ‐glutamyl transpeptidase in the liver. Lipid peroxidation at basal and prooxidants‐induced (NADPH + ADP + Fe and Ascorbate + Fe) states was assessed in the microsomes. Animals administered with ST extract evidenced significant inhibition of tumor nodular incidence in DEN + PB + ST animals compared to DEN + PB animals, with favorable alterations in the hepatic drug‐metabolizing phase I and phase II components. Administration of ST inhibited basal and pro‐oxidant‐induced lipid peroxidation. The present result suggests the probable mediation of chemoprevention by ST against DEN‐induced carcinogenesis by the modulation of drug metabolizing components in the liver of treated animals.
DP-CORE: A Design Pattern Detection Tool for Code Reuse

: In order to maintain, extend or reuse software projects one has to primarily understand what a system does and how well it does it. And, while in some cases information on system functionality exists, information covering the non-functional aspects is usually unavailable. Thus, one has to infer such knowledge by extracting design patterns directly from the source code. Several tools have been developed to identify design patterns, however most of them are limited to compilable and in most cases executable code, they rely on complex representations, and do not offer the developer any control over the detected patterns. In this paper we present DP-CORE, a design pattern detection tool that deﬁnes a highly descriptive representation to detect known and deﬁne custom patterns. DP-CORE is ﬂexible, identifying exact and approximate pattern versions even in non-compilable code. Our analysis indicates that DP-CORE provides an efﬁcient alternative to existing design pattern detection tools.
Surrogate markers for survival in patients with AIDS and AIDS related complex treated with zidovudine.

OBJECTIVE--To determine whether early effects of zidovudine treatment on CD4+ lymphocyte count and concentrations of beta 2 microglobulin, neopterin, or HIV p24 antigen or antibody are correlated with survival in patients with AIDS or AIDS related complex. DESIGN--Retrospective study of changes in laboratory markers and survival. SETTING--Multicentre trial at university hospital clinics. SUBJECTS--90 Patients with AIDS or AIDS related complex. INTERVENTION--Patients started zidovudine 200 mg orally every four hours. Fifty six of the patients died a median 17 months after starting zidovudine; the remaining 34 patients were followed up for a median 25.5 months. MAIN OUTCOME MEASURES--Changes in CD4+ lymphocyte count and serum concentrations of p24 antigen and antibody, beta 2 microglobulin, and neopterin; survival of the patient. RESULTS--The pretreatment characteristics that independently predicted poor survival were determined using a multivariate proportional hazards model: a diagnosis of AIDS (v AIDS related complex), age over 45 years, and the logarithm of serum neopterin concentration. When these baseline characteristics were controlled for the logarithm of CD4+ lymphocyte count at weeks 8-12 of treatment (p = 0.007) and an increase in serum beta 2 microglobulin concentration at weeks 8-12 (p = 0.05) also independently correlated with survival. In the 38 patients with a better pretreatment prognosis, 24 month survival estimated by the product-limit method was 88% for those with a good response on both surrogate markers during early treatment compared with only 50% for those with a poor response on either marker. In the 38 with a worse pretreatment prognosis, 24 month survival was estimated to be 49% for those with a good response on both surrogate markers compared with only 18% for those with a poor response on either. CONCLUSION--These data suggest that CD4+ lymphocyte count at 8-12 weeks and, perhaps, change in serum beta 2 microglobulin concentration could be surrogate end points for clinical outcome in trials of antiretroviral drugs for patients with HIV disease.