Miracle-dz/UniFAR-FTUs huggingface dataset:
Biased Agonism of Endogenous Opioid Peptides at the μ-Opioid Receptor

Biased agonism is having a major impact on modern drug discovery, and describes the ability of distinct G protein–coupled receptor (GPCR) ligands to activate different cell signaling pathways, and to result in different physiologic outcomes. To date, most studies of biased agonism have focused on synthetic molecules targeting various GPCRs; however, many of these receptors have multiple endogenous ligands, suggesting that “natural” bias may be an unappreciated feature of these GPCRs. The μ-opioid receptor (MOP) is activated by numerous endogenous opioid peptides, remains an attractive therapeutic target for the treatment of pain, and exhibits biased agonism in response to synthetic opiates. The aim of this study was to rigorously assess the potential for biased agonism in the actions of endogenous opioids at the MOP in a common cellular background, and compare these to the effects of the agonist d-Ala2-N-MePhe4-Gly-ol enkephalin (DAMGO). We investigated activation of G proteins, inhibition of cAMP production, extracellular signal-regulated kinase 1 and 2 phosphorylation, β-arrestin 1/2 recruitment, and MOP trafficking, and applied a novel analytical method to quantify biased agonism. Although many endogenous opioids displayed signaling profiles similar to that of DAMGO, α-neoendorphin, Met-enkephalin-Arg-Phe, and the putatively endogenous peptide endomorphin-1 displayed particularly distinct bias profiles. These may represent examples of natural bias if it can be shown that they have different signaling properties and physiologic effects in vivo compared with other endogenous opioids. Understanding how endogenous opioids control physiologic processes through biased agonism can reveal vital information required to enable the design of biased opioids with improved pharmacological profiles and treat diseases involving dysfunction of the endogenous opioid system.
The effects of sertraline administration from adolescence to adulthood on physiological and emotional development in prenatally stressed rats of both sexes

Sertraline (SERT) is a clinically effective Selective Serotonin Reuptake Inhibitor (SSRI) known to increase and stabilize serotonin levels. This neurotransmitter plays an important role in adolescent brain development in both rodents and humans, and its dysregulation has been correlated with deficits in behavior and emotional regulation. Since prenatal stress may disturb serotoninergic homeostasis, the aim of this study was to examine the long-lasting effects of exposure to SERT throughout adolescence on behavioral and physiological developmental parameters in prenatally stressed Wistar rats. SERT was administered (5 mg/kg/day p.o.) from the age of 1–3 months to half of the progeny, of both sexes, of gestating dams stressed by use of a restraint (PS) or not stressed. Our data reveal that long-term SERT treatment slightly reduced weight gain in both sexes, but reversed the developmental disturbed “catch-up” growth found in PS females. Neither prenatal stress nor SERT treatment induced remarkable alterations in behavior and had no effects on mean startle reflex values. However, a sex-dependent effects of PS was found: in males the PS paradigm slightly increased anxiety-like behavior in the open field, while in females, it impaired startle habituation. In both cases, SERT treatment reversed the phenomena. Additionally, the PS animals exhibited a disturbed leukocyte profile in both sexes, which was reversed by SERT. The present findings are evidence that continuous SERT administration from adolescence through adulthood is safe in rodents and lessens the impact of prenatal stress in rats.
ATPase Domain and Interdomain Linker Play a Key Role in Aggregation of Mitochondrial Hsp70 Chaperone Ssc1*

The co-chaperone Hep1 is required to prevent the aggregation of mitochondrial Hsp70 proteins. We have analyzed the interaction of Hep1 with mitochondrial Hsp70 (Ssc1) and the determinants in Ssc1 that make it prone to aggregation. The ATPase and peptide binding domain (PBD) of Hsp70 proteins are connected by a linker segment that mediates interdomain communication between the domains. We show here that the minimal Hep1 binding entity of Ssc1 consists of the ATPase domain and the interdomain linker. In the absence of Hep1, the ATPase domain with the interdomain linker had the tendency to aggregate, in contrast to the ATPase domain with the mutated linker segment or without linker, and in contrast to the PBD. The closest homolog of Ssc1, bacterial DnaK, and a Ssc1 chimera, in which a segment of the ATPase domain of Ssc1 was replaced by the corresponding segment from DnaK, did not aggregate in Δhep1 mitochondria. The propensity to aggregate appears to be a specific property of the mitochondrial Hsp70 proteins. The ATPase domain in combination with the interdomain linker is crucial for aggregation of Ssc1. In conclusion, our results suggest that interdomain communication makes Ssc1 prone to aggregation. Hep1 counteracts aggregation by binding to this aggregation-prone conformer.
Systemic cytokine levels and subsequent risk of gastric cancer in Chinese Women

Although control of the host cytokine network is known to influence gastric cancer susceptibility, the specific inflammatory responses in gastric carcinogenesis remain unclear. We prospectively examined the relationships between gastric cancer risk and plasma levels of interleukin (IL)‐1β, IL‐6, IL‐8 and tumor necrosis factor (TNF)‐α in a nested case control study within The Shanghai Women’s Health Study. Two controls were matched to each case on the basis of age, menopausal status, and sample collection parameters. The associations between gastric cancer risk and tertiles of cytokine levels were estimated by odds ratios (OR) and 95% confidence intervals (CI) from conditional logistic regression, adjusting for education. During a median follow‐up period of 4 years (range 0.1–8 years), 141 women developed gastric cancer and were matched to 282 cancer‐free study participants. Elevated levels of plasma IL‐6 were associated with an increased risk of gastric cancer (Ptrend = 0.04). Risk increased 70% (OR = 1.7; 95% CI 1.0, 3.0) for women in the highest tertile (>4 pg/mL) of IL‐6 compared with those in the lowest tertile (<1.8 pg/mL). The association between gastric cancer risk and IL‐6 was stronger after 4 years of follow‐up (OR = 2.6 [95% CI 1.0, 6.7] for highest versus lowest tertile) compared with an OR of 1.4 (95% CI 0.7, 2.9) for those diagnosed within 1–4 years of follow‐up. No associations were observed with the other pro‐inflammatory cytokines examined, namely IL‐1β, IL‐8, and TNF‐α. Systemic plasma IL‐6 levels may inform long‐term gastric cancer risk. This novel finding awaits confirmation in future studies with sequential plasma collection. (Cancer Sci 2011; 102: 1911–1915)
The Robot's Rebellion: Finding Meaning in the Age of Darwin

The idea that we might be robots is no longer the stuff of science fiction; decades of research in evolutionary biology and cognitive science have led many esteemed thinkers and scientists to the conclusion that, following the precepts of universal Darwinism, humans are merely the hosts for two replicators (genes and memes) that have no interest in us except as conduits for replication. Accepting and now forcefully responding to this disturbing idea that precludes the possibilities of morality or free will, among other things, Keith Stanovich here provides the tools for the "robot's rebellion," a program of cognitive reform necessary to advance human interests over the limited interest of the replicators. He shows how concepts of rational thinking from cognitive science interact with the logic of evolution to create opportunities for humans to structure their behavior to serve their own ends. These evaluative activities of the brain, he argues, fulfill the need that we have to ascribe significance to human life. Only by recognizing ourselves as robots, argues Stanovich, can we begin to construct a concept of self based on what is truly singular about humans: that they gain control of their lives in a way unique among life forms on Earth - through rational self-determination.
Nitrogen Saturation in Temperate Forest Ecosystems Hypotheses revisited

N itrogen emissions to the atmosphere due to human ace tivity remain elevated in industrialized regions of the world and are accelerating in many developing regions (Galloway 1995). Although the deposition of sulfur has been reduced over much of the United States and Europe by aggressive environmental protection policies, current nitrogen deposition reduction targets in the US are modest. Nitrogen deposition remains relatively constant in the northeastern United States and is increasing in the Southeast and the West (Fenn et al. in press). The US acid deposition effects
Evaluation on parallel downloading method using HTTP over UDP

(Parallel downloading) is one of the most effective technologies which speed up downloading large files on the Internet. As ubiquitous networks will be realized in the near future, downloading large files quickly is also very important on various types of networks. However, if we use the parallel downloading method on dynamic networks, such as ad hoc networks, it will not work well because of high loss rate and delay. To address this issue, we adopt UDP as a transport layer protocol instead of TCP which guarantees perfect in-order delivery unnecessary for file downloading. In our previous paper, a prototype of the parallel downloading method using HTTP over UDP is developed, and it is confirmed that our method outperforms the traditional method which adopts TCP, especially when loss rate is high and delay is large. In this paper, the key feature of the parallel downloading method using HTTP/UDP is evaluated through simple theoretical estimation and some simulation experiments. As a result, it is confirmed that the large division number tends to yield short download time. The proposed method can be an attractive protocol to distribute large files on dynamic networks composed of wireless links.
The CHAOS/DIALIGN WWW server for multiple alignment of genomic sequences

Cross-species sequence comparison is a powerful approach to analyze functional sites in genomic sequences and many discoveries have been made based on genomic alignments. Herein, we present a WWW-based software system for multiple alignment of large genomic sequences. Our server utilizes the previously developed combination of CHAOS and DIALIGN to achieve both speed and alignment accuracy. CHAOS is a fast database search tool that creates a list of local sequence similarities. These are used by DIALIGN as anchor points to speed up the final alignment procedure. The resulting alignment is returned to the user in different formats together with a list of anchor points found by CHAOS. The CHAOS/DIALIGN software is freely available at http://dialign.gobics. de/chaos-dialign-submission.
Risky sexual behaviour among adolescents may be related to ADHD

Dear Editor, We would like to comment on the recent paper by Kastbom et al. on Sexual debut before the age of 14 leads to poorer psychosocial health and risky behaviour in later life (1). The study focused on more than 3000 Swedish 18-year-old adolescents, who had completed a survey about sexuality, health and abuse. It compared those who had reported an early sexual debut before 14 years of age with those who had a later sexual debut. Current socio-economic factors, health behaviour, mental health and previous experience of sexual and/or physical abuse in the two groups were analysed. Many factors were associated with early sexual debut, including risky health behaviour, such as increased use of drugs and alcohol and smoking, and antisocial behaviour, such as being violent, lying, stealing and running away. A relationship was also found between early sexual debut and sexual and physical abuse. The authors concluded that early sexual debut was associated with problematic behaviours during later adolescence and that this vulnerability required attention from parents and healthcare providers. We would like to highlight that attentiondeficit/hyperactivity disorder (ADHD) could be an important underlying risk factor for both an early sexual debut and for the risks that this study related to early sexual debut per se, for example using drugs and alcohol, smoking, conduct and antisocial problems and experience of child abuse. Flory et al. (2) found that young people with ADHD were more likely to engage in a variety of risky sexual behaviours. They stated that preventing risky sexual behaviour and associated outcomes, such as unwanted pregnancy, was imperative and appropriate programmes were needed to prevent such behaviour among individuals with ADHD. Similar findings were reported by a longitudinal study by Barkley et al. (3), which emphasised that hyperactivity, or ADHD, was not a benign developmental disorder by young adulthood, and therefore, clinical interventions targeting these adaptive impairments were needed, for example counselling on contraception and health-related behaviour. These authors also stated that children and adolescents with ADHD faced greater risks of lower education levels, being retained in lower grades and failing to graduate than control groups. ADHD is common, affecting about 5% of children and adolescents, and is related to several risks at school and in life in general. Children and adolescents with ADHD require high levels of support and intervention to mitigate their risks of adverse health outcomes.
Analysis and SNR comparision of various adaptive algorithms to denoise the wind driven ambient noise in shallow water

Underwater signal transmission is a challenging task since the usable frequency range is limited to low frequency and the transmission of electromagnetic waves was impossible due to its high attenuation nature. Hence low frequency acoustic signal is more suited for transmission in underwater. Underwater transmission is highly affected by wind noise which is predominant at low frequency. The real time data collected from Indian Seas at Goa are studied in detail using Welch estimation method and the results shows the effect of wind over 100 to 8 kHz range. Different adaptive filter algorithms are analyzed in detail to eliminate the effect due to wind on the signal transmitted and signal to noise ratio is calculated. The SNR obtained for 24 types of adaptive algorithms are analyzed and tabulated for different wind speed. The results shows that RLS algorithm works better when compared to others. The maximum SNR of about 80 dB is achieved.
OBJETOS MUSICAIS COMO OBJETOS DE REPRESENTAÇÃO SOCIAL: PRODUTOS E PROCESSOS DA CONSTRUÇÃO DO SIGNIFICADO DE MÚSICA

In this essay, I seek to present the central aspects of an approach specific to the field of Social Psychology by relating Social Representations to ontological questions in music. The aim is to demonstrate that musical objects are objects of social representation which can be understood as social products reflecting their own conditions of production. These objects also reflect processes of social and psychological elaboration of the reality in which people live, interact and negotiate the distance separating them from one another.
Mentored Simulation Training Improves Procedural Skills in Cardiac Catheterization: A Randomized, Controlled Pilot Study

Background—Despite valuable supplemental training resources for surgical skill acquisition, utility of virtual reality simulators to improve skills relevant to performing cardiac catheterization has not been evaluated. Methods and Results—Post baseline cardiac catheterization performance assessment, 27 cardiology trainees were randomized to either mentored training on a virtual reality simulator (n=12) or no simulator training (control; n=15). Cardiac catheterization performance was reassessed 1 week post baseline assessment. Performance scores at 1 week were compared with baseline within each group, and change in score from baseline to 1 week was compared between groups. Linear regression modeling was performed to assess the effect of simulator training as a function of baseline performance. Technical performance improved postintervention in the simulator group (24 versus 18; P=0.008) and changed marginally in the control group (20 versus 18; P=0.054). Improvement in technical performance was greater in the simulator group (6 versus 1; P=0.04). Global performance improved postintervention in both groups (simulator, 24 versus 17, P=0.01; control, 20 versus 18, P=0.02), with a trend toward greater improvement in the simulator group (5 versus 2; P=0.11). Lower scores at baseline were associated with larger differences in postintervention scores between the simulator and control groups (technical performance, P=0.0006; global performance, P<0.0001). Conclusions—Skills required to perform cardiac catheterization can be learned via mentored simulation training and are transferable to actual procedures in the catheterization laboratory. Less proficient operators derive greater benefit from simulator training than more proficient operators.
Kognitive Neurologie

Zusammenfassung Kognitive Einbußen sind eine häufige Folge verschiedener Hirnerkrankungen. Ihre Erfassung ist hilfreich, da sie einerseits erhebliche Auswirkungen auf das Alltagsleben des Patienten haben und andererseits dem Untersucher Informationen über die Lokalisation von Krankheitsprozessen im Gehirn geben. Viele neuropsychologische Störungen lassen sich in einem klinischen Screening durch gezielte Anamnese, Verhaltensbeobachtung und kurze Untersuchungen erkennen. Allerdings sind einige Defizite, wie z.B. Störungen von Aufmerksamkeit oder Exekutivfunktionen, bei der klinischen Untersuchung schwer zu erfassen da sie weniger augenfällig als andere neurologische Symptome sind und oft vom Betroffenen selbst nicht bemerkt werden. Deshalb ist eine eingehende neuropsychologische Testung unabdingbar, wenn es darum geht ein detailliertes kognitives Leistungsprofil zu erstellen oder eine kognitive Rehabilitationsbehandlung zu planen.
Sub-Botnet Cordination Using Tokens in a Switched Network

—Botnets have evolved to incorporate peer-to-peer communication for the purpose of better hiding the administrative source of the botnet. Current botnet detection mechanisms identify network trafﬁc patterns at strategic locations within a network such as the gateway. As detection techniques improve, botnet design will continue to evolve to evade detection; thus, it is advantageous to identify potential future botnet models for the purpose of developing defense mechanisms before an actual new attack type is seen in the wild. This paper presents a model for coordinating external communication among bots located within the same switched network. This model prevents a gateway-based monitor from correlating external communication dialogs as the internal source of the communication is not a single bot-host. Future phases of this project include developing efﬁcient techniques for mitigating this potential future botnet model.
Clinical, Cognitive and Anatomical Evolution from Nonfluent Progressive Aphasia to Corticobasal Syndrome: A Case Report

Abstract Recent clinical and pathological studies have suggested that frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS) show clinical and pathological overlap. We present four years of longitudinal clinical, cognitive and anatomical data in the case of a 56-year-old woman, AS, whose clinical picture evolved from FTLD to CBS. For the first three years, AS showed a progressive speech and language disorder compatible with a diagnosis of the nonfluent aphasia variant of FTLD. At year four, 10 years after her first symptom, AS developed the classical clinical signs of CBS, including alien limb phenomenon and dystonia. Voxel-based morphometry (VBM) applied to AS's four annual scans showed progression of atrophy from the inferior posterior frontal gyrus, to the left insula and finally to the medial frontal lobe. This case demonstrates the clinical overlap between FTLD and CBS and shows that the two can appear in the same patient at different stages of the disease in relation to the progression of anatomical damage.
Aspects of Japanese computer-mediated communication : linguistic and socio-cultural perspectives

This study discusses Japanese computer-mediated communication (CMC), specifically focusing on messages sent to open-access bulletin board system (BBS) websites. It first compares quantitatively CMC language with speech and writing and finds that interjections distinguish speech from CMC and writing. CMC is distinguished from writing by uses of particles. Uses of auxiliary verbs separate the two target websites, Channel 2 and Yahoo within CMC. Based on the linguistic characterisation of the CMC language, the thesis further discusses qualitatively politeness and impoliteness behaviours in the two target BBS websites with contrasting linguistic features. This study points out that one theory of politeness proposed by Brown and Levinson (1987) can explain impolite behaviour in Channel 2, but not politeness in Yahoo, and that another theory proposed by Ide (1989) can explain polite behaviour in Yahoo, but not impoliteness in Channel 2. A third theory from a discursive approach proposed by Locher and Watts (2005) is shown to be capable of synthesising the two contrasting situations. In the following chapters, concepts of online community are employed to discuss politeness issues in conjunction with the sense of community. Here differences in discussion topics are found to be relevant to both the sense of community and linguistic choices of polite/impolite language, across the two target websites. Seemingly impolite behaviour in Channel 2, where users have a strong sense of community can be explained by the concept of contextual appropriateness by Watts. Underlying the topics specifically addressed in the thesis, this study also identifies the greater role played by technology in Japanese CMC than in English CMC. It fills a research gap in linguistic study on CMC language in Japanese, politeness and impoliteness research in online context as well as online community studies in Japanese cultural contexts. It is expected to contribute to understanding Japanese CMC linguistically and socio-culturally, as well as politeness and impoliteness and online community research in general.