Miracle-dz/UniFAR-FTUs huggingface dataset:
Allozymic Variation and Phylogeography of Two Genetic Types of Onychodactylus japonicus (Amphibia: Caudata: Hynobiidae) Sympatric in the Kinki District, Japan

On the basis of allozyme and mtDNA sequence variation, we elucidated genetic relationships between two sympatric genetic types of Onychodactylus japonicus in Kinki and adjacent districts, and investigated their phylogeography. Allozymic analysis revealed the presence of two distinct genetic types (the SW-Honshu and Kinki groups) in this area, and their sympatric occurrence in three of 10 sampling sites. Fixed or nearly fixed allele differences in several loci strongly suggested reproductive isolation between the two types, although one hybrid specimen was found in a locality. Analyses of mtDNA using 194 specimens from 22 localities also demonstrated two genetic types. From phylogeographic and population genetic analyses, it was surmised that these two types diverged allopatrically, and secondarily contacted to become sympatric by the Pleistocene uplift of mountains. Our results indicate different specific status for these two types and separation of the Kinki group from O. japonicus, to which the SW-Honshu group belongs.
Bombesin, Vasopressin, Endothelin, Bradykinin, and Platelet-derived Growth Factor Rapidly Activate Protein Kinase D through a Protein Kinase C-dependent Signal Transduction Pathway*

Protein kinase D (PKD) is a serine/threonine protein kinase that is activated by phorbol esters via protein kinase C in intact cells. To assess the physiological significance of this putative pathway, we examined the regulation of PKD in living cells by mitogenic regulatory peptides and by platelet-derived growth factors (PDGF). Our results demonstrate that bombesin rapidly induces PKD activation in Swiss 3T3 cells, as shown by autophosphorylation and syntide-2 phosphorylation assays. Maximum PKD activation (14-fold above base-line levels) was obtained 90 s after bombesin stimulation. Bombesin also induced PKD activation in Rat-1 cells stably transfected with the bombesin/gastrin releasing peptide (GRP) receptor and in COS-7 cells transiently co-transfected with PKD and bombesin/GRP receptor expression constructs. No inducible kinase activity was demonstrated when COS-7 cells were transfected with a kinase-deficient PKD mutant. Bombesin-mediated PKD activation was prevented by treatment of Swiss 3T3 cells with the protein kinase C inhibitors GF 1092030X and Ro 31-8220. In contrast, these compounds did not inhibit PKD activity when added directly in vitro. Vasopressin, endothelin, and bradykinin also activated PKD in Swiss 3T3 cells through a PKC-dependent pathway. Platelet-derived growth factor-stimulated PKD activation in Swiss 3T3 cells and in porcine aortic endothelial cells stably transfected with PDGF-β receptors. Treatment with GF 1092030X or Ro 31-8220 inhibited PKD activation induced by PDGF. Thus, our results indicate that PKD is activated by multiple signaling peptides through a protein kinase C-dependent signal transduction pathway in a variety of cell types.
Spatially clustered neuronal assemblies comprise the microstructure of synchrony in chronically epileptic networks

Epilepsy is characterized by recurrent synchronizations of neuronal activity, which are both a cardinal clinical symptom and a debilitating phenomenon. Although the temporal dynamics of epileptiform synchronizations are well described at the macroscopic level using electrophysiological approaches, less is known about how spatially distributed microcircuits contribute to these events. It is important to understand the relationship between micro and macro network activity because the various mechanisms proposed to underlie the generation of such pathological dynamics are united by the assumption that epileptic activity is recurrent and hypersynchronous across multiple scales. However, quantitative analyses of epileptiform spatial dynamics with cellular resolution have been hampered by the difficulty of simultaneously recording from multiple neurons in lesioned, adult brain tissue. We have overcome this experimental limitation and used two-photon calcium imaging in combination with a functional clustering algorithm to uncover the functional network structure of the chronically epileptic dentate gyrus in the mouse pilocarpine model of temporal lobe epilepsy. We show that, under hyperexcitable conditions, slices from the epileptic dentate gyrus display recurrent interictal-like network events with a high diversity in the activity patterns of individual neurons. Analysis reveals that multiple functional clusters of spatially localized neurons comprise epileptic networks, and that network events are composed of the coactivation of variable subsets of these clusters, which show little repetition between events. Thus, these interictal-like recurrent macroscopic events are not necessarily recurrent when viewed at the microcircuit scale and instead display a patterned but variable structure.
Protein Kinase C-δ Transactivates Platelet-derived Growth Factor Receptor-α in Mechanical Strain-induced Collagenase 3 (Matrix Metalloproteinase-13) Expression by Osteoblast-like Cells*

Matrix metalloproteinase-13 (MMP-13, or collagenase 3) has been shown to degrade intact collagen and to participate in situations where rapid and effective remodeling of collagenous ECM is required. Mechanical strain induction of MMP-13 is an example of how osteoblasts respond to high mechanical forces and participate in the bone-remodeling mechanism. Using MC3T3-E1 osteoblast-like cells, we dissected the signaling molecules involved in MMP-13 induction by mechanical strain. Reverse transcription-PCR and zymogram analysis showed that platelet-derived growth factor receptor (PDGFR) inhibitor, AG1296, inhibited the mechanical strain-induced MMP-13 gene and activity. However, the induction was not affected by anti-PDGF-AA serum. Immunoblot analysis revealed time-dependent phosphorylation of PDGFR-α up to 2.7-fold increases within 3 min under strain. Transfection with shPDGFR-α (at 4 and 8 μg/ml) abolished PDGFR-α and reduced MMP-13 expression. Moreover, time-dependent recruitments of phosphoinositide 3-kinase (PI3K) by PDGFR-α were detected by immunoprecipitation with anti-PDGFR-α serum followed by immunoblot with anti-PI3K serum. AG1296 inhibited PDGFR-α/PI3K aggregation and Akt phosphorylation. Interestingly, protein kinase C-δ (PKC-δ) inhibitor, rottlerin, inhibited not only PDGFR-α/PI3K aggregation but PDGFR-α phosphorylation. The sequential activations were further confirmed by mutants ΔPKC-δ, ΔAkt, and ΔERK1. Consistently, the primary mouse osteoblast cells used the same identified signaling molecules to express MMP-13 under mechanical strain. These results demonstrate that, in osteoblast-like cells, the MMP-13 induction by mechanical strain requires the transactivation of PDGFR-α by PKC-δ and the cross-talk between PDGFR-α/PI3K/Akt and MEK/ERK pathways.
Clinical Electrophysiology of the Upper and Lower Motor Neuron in Amyotrophic Lateral Sclerosis

Electrophysiology is important in amyotrophic lateral sclerosis (ALS). It helps in the assessment of disease severity and rate of progression, and it plays a role in evaluating the efficacy of therapeutic trials. Presently, electrophysiology is the only means of confirming suspected ALS, and this has been incorporated into the El Escorial criteria. Needle electromyography identifies disease in clinically "unaffected muscles" including bulbar musculature, confirms involvement of anterior horn cells, and can detect early involvement of respiratory muscles (intercostals and diaphragm). Conduction studies are imperative to rule out motor neuropathy with multifocal conduction block. Various techniques (cortical threshold, cortical silent period, double stimulation) employing transcranial magnetic stimulation have demonstrated that the motor cortex in ALS is hyperexcitable. Central motor conduction is normal in ALS but uniquely slow in the D9OA SOD1 mutation. Using peristimulus time histograms (PSTHs) it is possible to estimate the size of a unitary excitatory postsynaptic potential (EPSP). In ALS the EPSP is typically desynchronized. With time it becomes reduced in amplitude and a slow conducting component becomes recognizable in the primary peak of the PSTH. This reflects conduction through a slow motor pathway. Abnormalities of the PSTH are not seen in Kennedy's disease, implying that the changes seen in ALS are due to supraspinal mechanisms.
Identification of an Essential Signaling Cascade for Mitogen-activated Protein Kinase Activation by Angiotensin II in Cultured Rat Vascular Smooth Muscle Cells

In cultured rat vascular smooth muscle cells, angiotensin II (Ang II) induced a rapid increase in mitogen-activated protein kinase (MAPK) activity through the Ang II type 1 receptor, which was insensitive to pertussis toxin but was abolished by the phospholipase C inhibitor, U73122. The Ang II-induced MAPK activation was not affected by the protein kinase C inhibitor, GF109203X, and was only partially impaired by pretreatment with a phorbol ester, whereas both treatments completely prevented MAPK activation by the phorbol ester. Intracellular Ca2+ chelation by TMB-8, but not extracellular Ca2+ chelation or inhibition of Ca2+ influx, abolished Ang II-induced MAPK activation. The calmodulin inhibitor, calmidazolium, and the tyrosine kinase inhibitor, genistein, completely blocked MAPK activation by Ang II as well as by the Ca2+ ionophore A23187. Ang II caused a rapid increase in the binding of GTP to p21ras, and this was inhibited by genistein, TMB-8, and calmidazolium but not by pertussis toxin or GF109203X. These data suggest that Ang II-induced MAPK activation through the Ang II type 1 receptor could be mediated by p21ras activation through a currently unidentified tyrosine kinase that lies downstream of Gq-coupled Ca2+/calmodulin signals.
Integrase Mutants Defective for Interaction with LEDGF/p75 Are Impaired in Chromosome Tethering and HIV-1 Replication*

The insertion of a DNA copy of its RNA genome into a chromosome of the host cell is mediated by the viral integrase with the help of mostly uncharacterized cellular cofactors. We have recently described that the transcriptional co-activator LEDGF/p75 strongly interacts with HIV-1 integrase. Here we show that interaction of HIV-1 integrase with LEDGF/p75 is important for viral replication. Using multiple approaches including two-hybrid interaction studies, random and directed mutagenesis, we could demonstrate that HIV-1 virus harboring a single mutation that disrupts integrase-LEDGF/p75 interaction, resulted in defective HIV-1 replication. Furthermore, we found that LEDGF/p75 tethers HIV-1 integrase to chromosomes and that this interaction may be important for the integration process and the replication of HIV-1.
Unsupervised Co-Activity Detection from Multiple Videos Using Absorbing Markov Chain

We propose a simple but effective unsupervised learning algorithm to detect a common activity (co-activity) from a set of videos, which is formulated using absorbing Markov chain in a principled way. In our algorithm, a complete multipartite graph is first constructed, where vertices correspond to subsequences extracted from videos using a temporal sliding window and edges connect between the vertices originated from different videos; the weight of an edge is proportional to the similarity between the features of two end vertices. Then, we extend the graph structure by adding edges between temporally overlapped subsequences in a video to handle variable-length co-activities using temporal locality, and create an absorbing vertex connected from all other nodes. The proposed algorithm identifies a subset of subsequences as co-activity by estimating absorption time in the constructed graph efficiently. The great advantage of our algorithm lies in the properties that it can handle more than two videos naturally and identify multiple instances of a co-activity with variable lengths in a video. Our algorithm is evaluated intensively in a challenging dataset and illustrates outstanding performance quantitatively and qualitatively.
The Soluble Interleukin 6 Receptor: Advanced Therapeutic Options in Inflammation

Interleukin (IL)‐6 binds to IL‐6R and the complex of IL‐6 and IL‐6R associates with the receptor subunit gp130, which initiates signaling. gp130 is expressed on all cells. IL‐6R is cleaved by the ADAM17, generating a soluble IL‐6R (sIL‐6R). The sIL‐6R binds IL‐6 and the complex of IL‐6 and sIL‐6R binds to gp130 even on cells that do not express IL‐6R. This process, which has been called IL‐6 trans‐signaling, increases the spectrum of target cells for IL‐6. We generated a protein, sgp130Fc, which inhibits IL‐6 trans‐signaling without affecting IL‐6 classic signaling. Using the sgp130Fc protein we demonstrated that IL‐6 classic signaling is antiinflammatory and protective, whereas IL‐6 trans‐signaling is proinflammatory. Blocking IL‐6 trans‐signaling does not compromise the defense of the body against bacterial infections. We suggest that sgp130Fc is a superior agent as compared to IL‐6 or IL‐6R antibodies to block IL‐6. The sgp130Fc protein is in phase II clinical trials.
The impact of training in unselected patients on mortality and morbidity in carotid endarterectomy in a vascular training center and the recommendations of the European Board of Surgery Qualification in Vascular Surgery.

PURPOSE To investigate the impact of training of vascular fellows on the results of carotid endarterectomy (CEA) in unselected patients and to evaluate the recommendations of the European Board of Surgery Qualification in Vascular Surgery (EBSQ-VASC) concerning CEA. METHODS Complication rates and selection criteria of all CEAs, performed between 1995 and 2000 (n = 200) were retrospectively analysed and correlated to operating surgeon; supervised, nonsupervised vascular trainees, and consultant vascular surgeons. The number of CEAs were compared with the required minimal procedures according to the EBSQ-VASC. RESULTS Selection criteria for CEA did not differ significantly between operating surgeon groups, except that combined procedures were more performed by nonsupervised trainees and asymptomatic stenosis by consultant surgeons. The overall persistent disabling stroke rate and stroke-related mortality was 3%, with 4.3% in the supervised group, 0% in the unsupervised, and 2.8% in the consultant surgeon group, respectively. The amount of CEAs corresponded to the demands of the EBSQ-VASC. CONCLUSIONS In our institution, no significant differences in neurological morbidity and mortality following CEA could be demonstrated in relation to surgeon training level. The number of CEAs performed by residents fulfill the criteria of the EBSQ-VASC. We conclude that CEA can be safely taught to vascular trainees in unselected patients in a vascular training centre.
Imaging early-stage corticobasal degeneration with [99mTc]TRODAT-1 SPET

AimThe aim of this study was to investigate the nigrostriatal dopaminergic function in patients with corticobasal degeneration (CBD) using [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2. 1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2′,S2,S2′]oxo-[1R-(exo-exo)]-[99mTc]technetium ([99mTc]TRODAT-1) brain single-photon emission tomography (SPET). MethodsFive patients with probable CBD, 10 age- and duration-matched patients with idiopathic Parkinson's disease (IPD) and 10 age-matched healthy volunteers completed the SPET study. The images were obtained 4 h after intravenous injection of 925 MBq of [99mTc]TRODAT-1. Using a magnetic resonance imaging atlas of the striatum, the ratios of specific striatal binding to non-specific occipital binding were calculated. ResultsClinical analysis showed that the CBD patients obtained significantly higher scores on the Unified Parkinson's Disease Rating Scale and a significantly worse score for activities of daily living. In the CBD and IPD groups, striatum−occipital/occipital, caudate nucleus−occipital/occipital and putamen−occipital/occipital ratios decreased significantly relative to those of healthy subjects. No statistical difference could be found between the CBD and IPD groups for these ratios, although relatively even, decreased uptakes in the caudate nucleus and putamen were found in the CBD group. On further analysis of the index of binding reduction, the differences between the caudate nucleus and putamen were significantly lower in the CBD group than in the IPD group. The striatal uptake of [99mTc]TRODAT-1 showed a distinct asymmetry in both the CBD and IPD patients. ConclusionFrom this study, it can be concluded that early-stage CBD patients have a worse performance and more difficulties with daily activities than IPD patients. CBD patients demonstrated essentially similar patterns of [99mTc]TRODAT-1 binding as those with IPD. However, there was relatively more homogeneous involvement of the caudate nucleus and putamen in the CBD patients. This provides information about the differences between these patients in the early stages.
Long‐term monitoring of Epstein–Barr virus DNA load and humoral parameter abnormalities in pediatric liver transplant recipients before development of malignancy

Gregorek H, Jankowska I, Dzierżanowska‐Fangrat K, Teisseyre J, Sawicka A, Kasztelewicz B, Pawłowska J. Long‐term monitoring of Epstein–Barr virus DNA load and humoral parameter abnormalities in pediatric liver transplant recipients before development of malignancy. Pediatr Transplantation 2010: 14:629–635. © 2010 John Wiley & Sons A/S.
HPV DNA testing of self-collected vaginal samples compared with cytologic screening to detect cervical cancer.

CONTEXT More than half of the women diagnosed as having cervical cancer in the United States have not been screened within the last 3 years, despite many having had contact with the health care system. In many other regions of the world, there is only limited access to cervical cancer screening. OBJECTIVE To determine whether testing of self-collected vaginal swabs for human papillomavirus (HPV) DNA can be used to screen for cervical disease in women aged 35 years and older. DESIGN Cross-sectional observational study comparing Papanicolaou smears with HPV DNA testing of self-collected vaginal swabs. SETTING Outpatient clinics in a periurban settlement outside of Cape Town, South Africa, between January 1998 and April 1999. PARTICIPANTS Screening was performed on 1415 previously unscreened black South African women aged 35 to 65 years. INTERVENTION Women self-collected a vaginal swab for HPV testing in the clinic and were then screened using 4 different tests: Papanicolaou smear, direct visual inspection of the cervix after the application of 5% acetic acid, cervicography, and HPV DNA testing of a clinician-obtained cervical sample. Women with abnormal results on any of the screening tests were referred for colposcopy. MAIN OUTCOME MEASURE Biopsy-confirmed high-grade cervical squamous intraepithelial lesions or invasive cancer. RESULTS High-grade squamous intraepithelial lesions were identified in 47 (3.4%) of 1365 women adequately assessed, and there were 9 cases of invasive cancer. Of women with high-grade disease, 66.1% (95% confidence interval [CI], 52.1%-77.8%) had high risk for HPV detected in self-collected vaginal samples, and 67.9% (95% CI, 53.9%-79.4%) had an abnormal Papanicolaou smear (P = .78). The false-positive rates for HPV DNA testing of self-collected vaginal samples and Papanicolaou smears were 17.1% (95% CI, 15.1%-19.3%) and 12.3% (95% CI, 10.5%-14.2%), respectively (P<.001). A high-risk type of HPV DNA was detected in 83.9% (95% CI, 71.2%-91.9%) of women with high-grade disease and 15.5% (95% CI, 13.6%-17.7%) of women with no evidence of cervical disease using a clinician-obtained cervical sample. CONCLUSIONS These results indicate that HPV testing of self-collected vaginal swabs is less specific than but as sensitive as Papanicolaou smears for detecting high-grade cervical disease in women aged 35 years and older, and HPV testing offers an important new way to increase screening in settings where cytology is not readily performed.
Biochemical and Biophysical Investigation of the Brain-derived Neurotrophic Factor Mimetic 7,8-Dihydroxyflavone in the Binding and Activation of the TrkB Receptor*

Background: 7,8-DHF (7,8-dihydroxyflavone) is a TrkB agonist, but its receptor activation mechanism is not well understood. Results: 7,8-DHF and BDNF display differential receptor binding affinity, receptor activation kinetics, receptor phosphorylation pattern, and ligand-induced receptor degradation. Conclusion: 7,8-DHF and BDNF utilize different mechanisms to activate TrkB. Significance: This report provides mechanistic insights into how 7,8-DHF induces TrkB activation. 7,8-dihydroxyflavone (7,8-DHF), a newly identified small molecular TrkB receptor agonist, rapidly activates TrkB in both primary neurons and the rodent brain and mimics the physiological functions of the cognate ligand BDNF. Accumulating evidence supports that 7,8-DHF exerts neurotrophic effects in a TrkB-dependent manner. Nonetheless, the differences between 7,8-DHF and BDNF in activating TrkB remain incompletely understood. Here we show that 7,8-DHF and BDNF exhibit different TrkB activation kinetics in which TrkB maturation may be implicated. Employing two independent biophysical approaches, we confirm that 7,8-DHF interacts robustly with the TrkB extracellular domain, with a Kd of ∼10 nm. Although BDNF transiently activates TrkB, leading to receptor internalization and ubiquitination/degradation, in contrast, 7,8-DHF-triggered TrkB phosphorylation lasts for hours, and the internalized receptors are not degraded. Notably, primary neuronal maturation may be required for 7,8-DHF but not for BDNF to elicit the full spectrum of TrkB signaling cascades. Hence, 7,8-DHF interacts robustly with the TrkB receptor, and its agonistic effect may be mediated by neuronal development and maturation.
The return of the guilds

Notes on contributors Preface: S. R. Epstein (1960-2007) and the guilds Maarten Prak 1. The return of the guilds: towards a global history of the guilds in pre-industrial times Jan Lucassen, Tine De Moor, and Jan Luiten van Zanden 2. Women, gender and guilds in early modern Europe: an overview of recent research Clare Crowston 3. The political economy of European craft guilds: power relations and economic strategies of merchants and master artisans in the medieval and early modern textile industries Hugo Soly 4. Ottoman guilds in the early modern era Onur Yildirim 5. The guild in modern South Asia Tirthankar Roy 6. Brotherhoods and stock societies: guilds in pre-modern Japan Mary Louise Nagata 7. Rural guilds and urban-rural guild relations in early modern Central Europe Josef Ehmer 8. Guilds reappraised: Italy in the early modern period Luca Mocarelli 9. The silent revolution: a new perspective on the emergence of commons, guilds and other forms of corporate collective action in Western Europe Tine De Moor 10. Chinese guilds from the seventeenth to the twentieth centuries: an overview Christine Moll-Murata 11. From guild to rotary: hunters' associations and Mali's search for a civil society Jan Jansen.