Miracle-dz/UniFAR-FTUs huggingface dataset:
Sex‐ and cell‐type‐specific patterns of GABAA receptor and estradiol‐mediated signaling in the immature rat substantia nigra

The substantia nigra pars reticulata (SNR) is involved in movement and seizure control. In male but not female postnatal day 15 (PN15) rats, GABAA receptor agonists depolarize the SNR neurons and increase the expression of the calcium‐regulated gene KCC2 (potassium/chloride cotransporter). Moreover, in PN15 rat SNR, 7β‐estradiol down‐regulates KCC2 expression only in the presence of depolarizing GABAA receptor responses. The hypothesis tested here was that GABAA receptors and estradiol also regulate the expression of the phosphorylated form of the transcription factor cAMP responsive element binding protein (phosphoCREB), in PN15 rat SNR and substantia nigra pars compacta (SNC). Rats were injected with muscimol or 17β‐estradiol or their vehicles, and killed 1 h later. Sections were stained with an antibody specific for phosphoCREB alone or counterstained with either tyrosine hydroxylase (TH)‐ or parvalbumin (PRV)‐specific antibodies. Muscimol increased phosphoCREB‐ir in male but not in female SN neurons. Using gramicidin perforated patch clamp of PN14–15 SNC neuron, it was shown that muscimol bath application depolarized male SNC neurons but did not significantly alter membrane potential in females. In males, 17β‐estradiol decreased phosphoCREB expression in all studied cell types. In females, 17β‐estradiol did not influence phosphoCREB expression in PRV‐ir SNR cells, but increased it in the dopaminergic SN neurons. These data suggest that GABAA receptor activation and estradiol promote the sexual differentiation of the SN in a cell‐type‐specific manner, by influencing calcium‐regulated gene transcription, and therefore promoting the acquisition of sex‐specific roles of the SN in movement and seizure control.
Peer observation of teaching for formative evaluation of faculty members

make them habitual. The participants commented that the programme, particularly the improvisation sessions, helped them to nurture flow in the midst of teaching (e.g. ‘[to] press the reset button’). They learned to be more adaptive and more flexible in the moment. Mindfulness and improvisation techniques can be incorporated in a fun, safe and innovative manner into a faculty development programme on teaching. At the conclusion of the programme, several of the faculty participants remarked on how ‘sad’ they were that the programme was ending and suggested a longer programme for the next cohort of faculty staff. Faculty members can be pushed out of their comfort zones and can engage in activities that require spontaneity and creativity with the aim of facilitating translation into improved teaching encounters. These initial pilot results suggest that similar faculty development programmes might improve mindfulness and T2-in-action skills.
Crystal structure of the cinnabar phase of HgTe.

Angle-dispersive powder-diffraction techniques with an image-plate area detector and synchrotron radiation have been used to perform a structural refinement of mercury telluride in its cinnabar phase. We find that the structure is site-ordered with fractional coordinates of (u=0.641(1),0,1/3) and (v=0.562(1),0,5/6) for Hg and Te, respectively, at 3.6 GPa. The structure is substantially different from that of HgS cinnabar, with coordination much closer to fourfold
Differential Survival of Naive CD4 and CD8 T Cells1

In this paper we compare survival characteristics of transgenic and polyclonal CD4 and CD8 T cells. Transgenic CD4 T cells have an intrinsically lower capacity for survival, reflected in their gradual disappearance in thymectomized hosts, their increased sensitivity to apoptosis in vitro, and fewer divisions during homeostatic proliferation upon transfer into syngeneic lymphopenic hosts compared with CD8 T cells. Homeostatic proliferation, however, does not generally result in phenotypic conversion of activation markers unless cognate or cross-reactive Ag is present. T cells from the A18 TCR transgenic strain normally selected into the CD4 lineage are fragile as CD4 T cells, yet display the typical robust survival pattern of CD8 T cells when diverted into the CD8 lineage in a CD4-deficient host. Polyclonal CD4 and CD8 T cells also show distinctive patterns of survival, emphasizing that survival signals are relayed differently in the two lymphocyte subpopulations. However, expression levels of Bcl-2 in either transgenic or polyclonal naive CD4 and CD8 T cells are similar, excluding a role for this molecule as a key factor in differential survival of CD4 vs CD8 T cells.
Growth rate dependent numbers of SeqA structures organize the multiple replication forks in rapidly growing Escherichia coli

When the bacterium Escherichia coli is grown in rich medium, the replication and segregation periods may span two, three or four generations and cells may contain up to 24 replication forks. The newly synthesized, hemimethylated DNA at each fork is bound by SeqA protein. The SeqA–DNA structures form distinct foci that can be observed by immunofluorescence microscopy. The numbers of foci were lower than the numbers of replication forks indicating fork co‐localization. The extent of co‐localization correlated with the extent of replication cycle overlap in wild‐type cells. No abrupt increase in the numbers of foci occurred at the time of initiation of replication, suggesting that new replication forks bind to existing SeqA structures. Manipulations with replication control mechanisms that led to extension or reduction of the replication period and number of forks, did not lead to changes in the numbers of SeqA foci per cell. The results indicate that the number of SeqA foci is not directly governed by the number of replication forks, and supports the idea that new DNA may be ‘captured’ by existing SeqA structures.
Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5

ABSTRACT A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertrophy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation- and CRM1-dependent nuclear export of these chromatin-modifying enzymes. However, the identities of cardiac HDAC kinases have remained unclear. Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. Inhibition of PKC prevents nucleocytoplasmic shuttling of HDAC5 in response to a subset of hypertrophic agonists. Moreover, a nonphosphorylatable HDAC5 mutant is refractory to PKC signaling and blocks cardiomyocyte hypertrophy mediated by pharmacological activators of PKC. We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. These findings reveal a novel function for the PKC/PKD axis in coupling extracellular cues to chromatin modifications that control cellular growth, and they suggest potential utility for small-molecule inhibitors of this pathway in the treatment of pathological cardiac gene expression.
Subharmonic pitches of a pure tone at low S/N ratio.

2AFC scores were obtained on 50 untrained subjects who had to respond to a 3% increment or decrement of the fundamental frequency of two successive signals. The first signal in each trial was a reference, containing six harmonics of 200 Hz. Main variables were the number of harmonics of the second signal in a trial (either 3, 2, or 1) and the presence or absence of continuous background noise. Low scores were observed in the absence of the noise (typically 65% for the 3‐ and 2‐component signals, and virtually 50% for the 1‐component signals), whereas in the presence of the noise much higher scores were observed (typically 90% and 80%, respectively). The results indicate that background noise has great impact on the perceptibility of a ’’low pitch’’ related to the fundamental frequency, even more so than the number of components presented (within the range of three, two, or one components): at a low S/N ratio, even a single harmonic may give rise to the perception of a subharmonic low pitch. Subsequent exp.
Quantitative analysis of diabetic macular ischemia using optical coherence tomography.

PURPOSE We described the optical coherence tomography (OCT) features of diabetic macular ischemia (DMI), and correlate these findings with visual acuity (VA). METHODS Clinical and imaging data were collected from 100 patients with type 2 diabetes. Qualitative grading of DMI severity was determined according to criteria defined by the Early Treatment Diabetic Retinopathy Study. Quantitative analysis of foveal avascular zone (FAZ), and OCT images were performed using custom software. RESULTS In all eyes, the outer retina was thicker in eyes with DMI (167.4 ± 18.5 vs. 150.4 ± 31.4 μm, P = 0.04). However, subanalysis of eyes "without macular edema" revealed the converse; outer retinal thinning in eyes with DMI (223.1 ± 31.2 vs. 244.9 ± 37.2 μm, P = 0.007). A thinner retinal nerve fiber layer also was observed to correlate with increasing FAZ size (r = -0.231, P = 0.03), which strengthened in eyes "without macular edema" (r = -0.62, P = 0.001). In the choroid, quantification of its sublayers revealed a thicker Haller's large vessel layer in the presence of DMI (144.3 ± 51.0 vs. 103.5 ± 39.4 μm, P = 0.01). In eyes with DMI, a thicker retina was correlated with worsening VA (r = 0.52, P = 0.001). However, when eyes with macular edema were excluded, a thinner retina was associated with poor VA (r = -0.37, P = 0.004). CONCLUSIONS In eyes with DMI, we observed thinning of the retinal nerve fiber layer, outer retina, and thickening of Haller's large vessel layer of the choroid. These parameters showed good correlation with VA and may serve as a useful tool for monitoring DMI in clinical practice or future clinical trials.
Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG.

BACKGROUND This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients. PATIENTS AND METHODS DTIC 850 mg/m2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS). RESULTS At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/HLA-B44- haplotype survive significantly longer than patients with a Karnofsky index <100 (P = 0.007 versus P = 0.057 in the DTIC-arm) or other HLA haplotypes (P = 0.04 versus P = 0.57 in DTIC-treated patients). CONCLUSIONS DC vaccination could not be demonstrated to be more effective than DTIC chemotherapy in stage IV melanoma patients. The observed association of overall performance status and HLA haplotype with overall survival for patients treated by DC vaccination should be tested in future trials employing DC vaccines.
Will the Calcium Channel Agonist BAY K8644 Inhibit Halothane‐Induced Impairment of Calcium Current?

The inhaled anesthetics impair transsarcolemmal calcium entry (ICa) in myocardial cells, although the mechanism of this interaction is not known. This inhibition of calcium entry has been implicated in the myocardial depression of the volatile anesthetics. To further characterize this interaction and to evaluate whether a calcium channel agonist could attenuate or prevent the inhibition of calcium entry, the effect of the calcium channel agonist BAY K8644 on the impairment of ICa by halothane was evaluated in single guinea pig ventricular myocytes. Calcium currents were evoked by means of the whole-cell voltage-clamp technique. Baseline peak Ica was higher in the cells exposed to 5 μM BAY K8644 (311 vs 206 pA/cm2, P <0.04). On exposure to 1% halothane, peak ICa was impaired to an identical degree whether or not cells were exposed to BAY K8644 (78% and 79% of baseline value). This is consistent with the suggestion that the effects of these agents on ICa are nonspecific. However, the increase in ICa suggests that appropriate calcium channel agonists might serve to ameliorate the myocardial depressant effects of halothane.
A case-control study on etiological factors involved in patients with burning mouth syndrome.

OBJECTIVE To evaluate and analyze the risk factors for burning mouth syndrome (BMS). METHODS Eighty-seven consecutive patients with BMS and a randomly selected control group (n = 82) were comprehensively investigated with a self-designed questionnaire, Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS). A complete blood count and serum sex hormone were also examined in patients with BMS and control subjects. All the data obtained were transferred to a data bank and analyzed statistically in SPSS 11.5 for windows. RESULTS No statistical difference between the BMS group and the control group was found in blood analyses including white blood cell count, red blood cell count, hemoglobin and platelet count. Among the menopausal or postmenopausal women with BMS, the follicle stimulating hormone (FSH) level was significantly higher, but the estradiol level was significantly lower. The BMS group reported adverse life events more frequently than the control group. Patients with BMS significantly exhibited symptoms of somatization, and both the scores of anxiety, depression in patients with BMS were higher than those of the control group (P < 0.05). A regression equation which included six variables had been established by using logistic regression analysis, indicating that the habit of tongue thrusting, lip sucking, periodontitis, smoking, outcome of recent medication, depression were the principal risk factors, among which tongue thrusting was the most significant. CONCLUSION Our study indicated that BMS may be of psychological origin, and the measures such as refraining from oral parafunctional activities, removing local irritating factors, stopping smoking, good mental health status could help in the prevention of BMS.
Morbidity Profiles of People Living With HIV/AIDS in Urban and Rural Inpatient and Outpatient Settings in Karnataka, South India

We examined the morbidity profiles associated with people living with HIV infection in an urban HIV inpatient treatment site near the city of Bangalore, in southern Karnataka state, south India, and in a rural outpatient site in northern Karnataka. Data from March 2007 until July 2008 were analyzed. The urban cohort comprised 432 patients, and the most common comorbid conditions were unexplained prolonged fever (50.2%) and oral candidiasis (42.6%). The rural cohort comprised 2374 patients, and the most common comorbid conditions were unexplained prolonged fever (58.8%), minor mucocutaneous infections (58.4%), and recurrent upper respiratory tract infections (52.3%). With less than 1% of patients in rural areas on treatment for tuberculosis (vs over one third in the urban cohort), tuberculosis is likely significantly underdiagnosed in rural areas. In addition, only 2.6% of rural outpatients who were eligible for antiretroviral treatment (ART), per Government of India guidelines, were actually on ART, compared to 31.6% of the urban population.
Platelet-activating Factor Induces NF-κB Activation through a G Protein-coupled Pathway (*)

The capability of platelet-activating factor (PAF) to induce transcription factor activation was examined. In stably transfected Chinese hamster ovary cells expressing the PAF receptor (CHO-PAFR), PAF stimulation resulted in the nuclear expression of a DNA binding activity with specificity to the κB sequence. The p50 and p65 proteins, constituents of the prototypic nuclear factor κB (NF-κB), were identified as components of the DNA·protein complexes by antipeptide antibodies in gel supershift as well as UV cross-linking experiments. PAF induced an initial decrease and subsequent increase of cytoplasmic IκBα levels, accompanied by up-regulation of the IκBα messenger RNA, a feature of NF-κB activation. PAF-induced κB binding activity was detected within 15 min after agonist stimulation, peaked at 30-40 min, and remained detectable by 2.5 h. SR 27417, a PAF receptor antagonist, blocked PAF-induced κB binding activity but not that induced by tumor necrosis factor-α (TNFα). Cholera toxin treatment markedly reduced PAF-induced κB binding activity, whereas pertussis toxin had no significant inhibitory effect. Neither of the two toxins affected the κB binding activity induced by TNFα in the same cells. In addition to the CHO-PAFR cells, PAF stimulated κB binding activity in the murine P388D1 macrophage and the human ASK.0 B cell lines that express endogenous PAF receptors. These results imply a potential role of PAF in the regulation of gene expression through a G protein-coupled transcription factor activation pathway.
Radiation of a Hertzian Dipole in a Conducting Circular Cylinder with Narrow Circumferential Slots

Hertzian dipole radiation from narrow circumferential slots on a conducting circular cylinder is studied. Eigenfunction expansions are used and boundary conditions are enforced to obtain a set of simultaneous equations. A fast convergent series formulation is obtained and numerical results are shown. Our theory provides a viable model for dipole radiation from a circumferential slot array on a conducting circular cylinder.
Discrete Microdomains with High Concentration of cAMP in Stimulated Rat Neonatal Cardiac Myocytes

The second messenger cyclic adenosine monophosphate (cAMP) is the most important modulator of sympathetic control over cardiac contractility. In cardiac myocytes and many other cell types, however, cAMP transduces the signal generated upon stimulation of various receptors and activates different cellular functions, raising the issue of how specificity can be achieved. In the general field of signal transduction, the view is emerging that specificity is guaranteed by tight localization of signaling events. Here, we show that in neonatal rat cardiac myocytes, β-adrenergic stimulation generates multiple microdomains with increased concentration of cAMP in correspondence with the region of the transverse tubule/junctional sarcoplasmic reticulum membrane. The restricted pools of cAMP show a range of action as small as approximately 1 micrometer, and free diffusion of the second messenger is limited by the activity of phosphodiesterases. Furthermore, we demonstrate that such gradients of cAMP specifically activate a subset of protein kinase A molecules anchored in proximity to the T tubule.
Atheroma Progression in Hyporesponders to Statin Therapy

Objective— Lowering low-density lipoprotein cholesterol (LDL-C) with statins has been demonstrated to slow plaque progression. This antiatherosclerotic effect in patients with minimal LDL-C lowering has not been investigated. Approach and Results— Six hundred forty-seven patients with angiographic coronary artery disease who were commenced on statin therapy underwent serial imaging with intravascular ultrasound. Responders were defined as a percentage reduction in LDL-C of <15%. Disease progression was compared in responders (n=517) and hyporesponders (n=130) to statin therapy. Twenty percentage of patients demonstrated minimal changes in LDL-C, despite commencement of statin therapy. Statin hyporesponders were younger (55 versus 57 years; P=0.01), more likely to be male (79% versus 66%; P=0.005), and obese (body mass index, 31.5±6.1 versus 30.3±5.9 kg/m2; P=0.04) and less likely to have a history of dyslipidemia (50% versus 66%; P<0.001). Baseline levels of systolic blood pressure (127±15 versus 132±17 mm Hg; P=0.01) and LDL-C (2.5±0.6 versus 3.4±0.8 mmol/L; P<0.001) were lower in statin hyporesponders. Baseline percent atheroma volume was similar between statin hyporesponders and responders (36.9±9.8% versus 38.3±9.2%; P=0.13). On serial evaluation, greater progression of percent atheroma volume (1.19±0.48% versus 0.09±0.43%; P=0.003) was observed in statin hyporesponders. After adjusting for baseline clinical characteristics and measures of plaque burden, statin hyporesponders still exhibited greater atheroma progression (+0.83±0.58% versus −0.21±0.52%; P=0.006). Conclusions— A substantial proportion of patients with coronary artery disease fail to achieve effective reductions in LDL-C, despite prescription of statin therapy. Greater progression of atherosclerosis is observed in these patients. Our current study underscores monitoring LDL-C level after the commencement of statin to ensure adequate response to statin therapy.
The TME Trial After a Median Follow-up of 6 Years: Increased Local Control But No Survival Benefit in Irradiated Patients With Resectable Rectal Carcinoma

Objective:To investigate the efficacy of preoperative short-term radiotherapy in patients with mobile rectal cancer undergoing total mesorectal excision (TME) surgery. Summary Background Data:Local recurrence is a major problem in rectal cancer treatment. Preoperative short-term radiotherapy has shown to improve local control and survival in combination with conventional surgery. The TME trial investigated the value of this regimen in combination with total mesorectal excision. Long-term results are reported after a median follow-up of 6 years. Methods:One thousand eight hundred and sixty-one patients with resectable rectal cancer were randomized between TME preceded by 5 × 5 Gy or TME alone. No chemotherapy was allowed. There was no age limit. Surgery, radiotherapy, and pathologic examination were standardized. Primary endpoint was local control. Results:Median follow-up of surviving patients was 6.1 year. Five-year local recurrence risk of patients undergoing a macroscopically complete local resection was 5.6% in case of preoperative radiotherapy compared with 10.9% in patients undergoing TME alone (P < 0.001). Overall survival at 5 years was 64.2% and 63.5%, respectively (P = 0.902). Subgroup analyses showed significant effect of radiotherapy in reducing local recurrence risk for patients with nodal involvement, for patients with lesions between 5 and 10 cm from the anal verge, and for patients with uninvolved circumferential resection margins. Conclusions:With increasing follow-up, there is a persisting overall effect of preoperative short-term radiotherapy on local control in patients with clinically resectable rectal cancer. However, there is no effect on overall survival. Since survival is mainly determined by distant metastases, efforts should be directed towards preventing systemic disease.