Nucleation and phase selection in undercooled melts: Magnetic alloys of industrial relevance (MAGNEPHAS)

Studies of phase selection and microstructure evolution in high-performance magnetic materials are an urgent need for optimization of production routes. Containerless solidification experiments by electromagnetic levitation and drop tube solidification were conducted in undercooled melts of Fe-Co, Fe-Ni soft magnetic, and Nd-Fe-B hard magnetic alloys. Melt undercooling under microgravity was achieved in the TEMPUS facility during parabolic flight campaigns. For Fe-Co and Fe-Ni alloys significant effects of microgravity on metastable phase formation were discovered. Microstructure modifications as well as metastable phase formation as function of undercooling and melt flow were elucidated in Nd-Fe-B. Modeling of solidification processes, fluid flow and heat transfer provide predictive tools for microstructure engineering from the melt. They were developed as a link between undercooling experiments under terrestrial and microgravity conditions and the production routes of magnetic materials

Depression and anxiety in acute ischemic stroke involving the anterior but not paramedian or inferolateral thalamus

Background and objectives: Emotional and cognitive deficits are prevalent in strokes involving the thalamus. In contrast to cognitive deficits, emotional deficits have not been studied prospectively in isolated thalamic stroke. Methods: In 37 ischemic thalamic stroke patients (57.0 [50.0; 69.5] years [median (Q1; Q3)], 21 males, 5 anterior, 12 paramedian, 20 inferolateral vascular territory), and 37 non-stroke control patients matched for age and sex, we prospectively examined depression, anxiety, activities of daily living, and quality of life at 1, 6, 12, and 24 months post-stroke using the Hospital-Anxiety-and-Depression Scale (HADS), Nürnberger-Alters-Alltagsaktivitäten scale (NAA), and Short Form-36 (SF36) questionnaire. Voxel-based lesion-symptom mapping (VLSM) and lesion-subtraction analyzes were performed to determine associations between questionnaire scores and thalamic stroke topography. Results: At 1 month post-stroke, anterior thalamic stroke patients had higher depression scores [8.0 (7.5; 10.5)] than paramedian [4.5 (1.0; 5.8)] and inferolateral [4.0 (1.0; 7.0)] thalamic stroke patients. Furthermore, anterior thalamic stroke patients had higher anxiety scores [11.0 (8.0; 14.5)] than their matched controls [2.5 (2.0; 2.5)], paramedian [4.5 (1.0; 5.8)] and inferior [4.0 (1.0; 7.0)] thalamic stroke patients. Depression and anxiety scores in anterior thalamic stroke patients remained high across the follow-up [depression: 9.0 (3.5; 13,8); anxiety:10.05 (2.8, 14.5)]. Physical health assessed by SF36 was intact in anterior [1 month post-stroke: T-score = 55.9 (37.0; 57.6)] but reduced in inferolateral [44.5(32.4; 53.1)] thalamic stroke, whereas mental health was reduced in anterior thalamic stroke [32.0 (29.8; 47.3)]. VLSM confirmed that voxels in the anterior thalamus around Montreal Neurological Institute (MNI) coordinates X = −8, Y = −12, Z = 2 were more often affected by the stroke in depressed (HADS-score ≥ 8) than non-depressed (HADS-score < 8) patients and voxels around coordinates X = −10, Y = −12, Z = 2 were more often affected in anxious (HADS-score ≥ 8) than non-anxious (HADS-score < 8) patients. Conclusion: Anterior, but not paramedian or inferolateral thalamic stroke was associated with depression and anxiety. Even though our results are mostly significant in the left thalamus, this observation on stroke laterality might be confounded by the fact that the right hemisphere was underrepresented in our study

Electric Stimulation of Neurogenesis Improves Behavioral Recovery After Focal Ischemia in Aged Rats

© Copyright © 2020 Balseanu, Grigore, Pinosanu, Slevin, Hermann, Glavan and Popa-Wagner. The major aim of stroke therapies is to stimulate brain repair and to improve behavioral recuperation after cerebral ischemia. Despite remarkable advances in cell therapy for stroke, stem cell-based tissue replacement has not been achieved yet stimulating the search for alternative strategies for brain self-repair using the neurogenic zones of the brain, the dentate gyrus and the subventricular zone (SVZ). However, during aging, the potential of the hippocampus and the SVZ to generate new neuronal precursors, declines. We hypothesized that electrically stimulation of endogenous neurogenesis in aged rats could increase the odds of brain self-repair and improve behavioral recuperation after focal ischemia. Following stroke in aged animals, the rats were subjected to two sessions of electrical non-convulsive stimulation using ear-clip electrodes, at 7- and 24 days after MCAO. Animal were sacrificed after 48 days. We report that electrical stimulation (ES) stimulation of post-stroke aged rats led to an improved functional recovery of spatial long-term memory (T-maze) but not on the rotating pole or the inclined plane, both tests requiring complex sensorimotor skills. Surprisingly, ES had a detrimental effect on the asymmetric sensorimotor deficit. Histologically, there was a robust increase in the number of doublecortin-positive cells in the dentate gyrus and SVZ of the infarcted hemisphere and the presence of a considerable number of neurons expressing tubulin beta III in the infarcted area. Among the gene that were unique to ES, we noted increases in the expression of seizure related 6 homolog like which is one of the physiological substrate of the β-secretase BACE1 involved in the pathophysiology of the Alzheimer’s disease and Igfbp3 and BDNF receptor mRNAs which has been shown to have a neuroprotective effect after cerebral ischemia. However, ES was associated with a long-term down regulation of cortical gene expression after stroke in aged rats suggesting that gene expression in the peri-infarcted cortical area may not be related to electrical stimulation induced-neurogenesis in the subventricular zone and hippocampus

Peptide exchange on MHC-I by TAPBPR is driven by a negative allostery release cycle.

Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex

Compromised Hippocampal Neuroplasticity in the Interferon-α and Toll-like Receptor-3 Activation-Induced Mouse Depression Model.

Disrupted neuronal plasticity due to subtle inflammation is considered to play a fundamental role in the pathogenesis of major depressive disorder. Interferon-α (IFN-α) potentiates immune responses against viral pathogens that induce toll-like receptor-3 (TLR3) activation but evokes severe major depressive disorder in humans by mechanisms that remain insufficiently described. By using a previously established mouse model of depression induced by combined delivery of IFN-α and polyinosinic:polycytidylic acid (poly(I:C)), a TLR3 agonist, we provide evidence that IFN-α and poly(I:C) reduce apical dendritic spine density in the hippocampal CA1 area ex vivo via mechanisms involving decreased TrkB signaling. In vitro, IFN-α and poly(I:C) treatments required neuronal activity to reduce dendritic spine density and TrkB signaling. The levels of presynaptic protein vesicular glutamate transporter (VGLUT)-1 and postsynaptic protein postsynaptic density-95 (PSD95) were specifically decreased, whereas the expression of both synaptic and extrasynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1 (AMPAR1) was increased by IFN-α and poly(I:C) delivery. Patch clamp recordings in primary hippocampal neurons revealed that morphological changes at the synapse induced by IFN-α and poly(I:C) costimulation were accompanied by an increased action potential threshold and action potential frequency, indicative of impaired neuronal excitability. Taken together, IFN-α and poly(I:C) delivery leads to structural and functional alterations at the synapse indicating that compromised neuroplasticity may play an integral role in the pathogenesis of immune response-induced depression

Clustering of antibiotic resistance of E. coli in couples: suggestion for a major role of conjugal transmission

BACKGROUND: Spread of antibiotic resistance in hospitals is a well-known problem, but studies investigating the importance of factors potentially related to the spread of resistant bacteria in outpatients are sparse. METHODS: Stool samples were obtained from 206 healthy couples in a community setting in Southern Germany in 2002–2003. E. coli was cultured and minimal inhibition concentrations were tested. Prevalences of E. coli resistance to commonly prescribed antibiotics according to potential risk factors were ascertained. RESULTS: Prevalences of ampicillin resistance were 15.7% and 19.4% for women and men, respectively. About ten percent and 15% of all isolates were resistant to cotrimoxazole and doxycycline, respectively. A partner carrying resistance was the main risk factor for being colonized with resistant E. coli. Odds ratios (95% CI) for ampicillin and cotrimoxazole resistance given carriage of resistant isolates by the partner were 6.9 (3.1–15.5) and 3.3 (1.5–18.0), respectively. CONCLUSION: Our data suggest that conjugal transmission may be more important for the spread of antibiotic resistance in the community setting than commonly suspected risk factors such as previous antibiotic intake or hospital contacts

Epidemiological analysis of tongue cancer in South Australia for the 24-year period, 1977-2001

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.Background: Tongue cancer (141 ICD-9) is the most common intra-oral malignancy in Western countries. In recent decades, reported tongue cancer incidence and mortality rates have increased both in Europe and in the United States, whilst survival has not improved. This study aimed to determine the epidemiology and survival trends of tongue cancer in South Australia over the 24-year period from 1977 to 2001. Methods: Population-based data for tongue cancer were provided by the Central Cancer Registry Unit of the Epidemiology Branch of the South Australian Department of Health. Age-standardized incidence and mortality rates for males and females were calculated. Kaplan-Meier survival analysis was conducted according to time periods, age, sex and tongue sub-sites. Cox regression analysis was used to determine factors that influenced survival. Results: During this 24-year period, 611 cases of tongue cancer (398 males, 213 females) were reported, the majority of which were squamous cell carcinomas. The most common age of diagnosis was 65–69 years in males and 60–64 years in females. Fifty cases (8.18 per cent of all tongue cancer cases) occurred in patients 40 years or younger. The most common cancer sub-sites reported were ‘unspecified site’ (48.45 per cent), lateral border (25.53 per cent) and base (18.49 per cent) of the tongue. The agestandardized incidence and mortality rates for males and females in South Australia were relatively low and stable, and there was no significant improvement in survival of tongue cancer over this period. Significant predictors for survival were sex, age and tongue sub-sites, with male, advanced age and base of tongue associated with poorer survival. Conclusions: Tongue cancer is an important health issue associated with poor survival. Early detection and diagnosis is important in order to improve survival rate for this malignancy.L Lam, RM Logan and C Luk

Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3'-Deoxy-3'-[18^{18}F]Fluorothymidine in Preclinical Models of Lung Cancer

3'-Deoxy-3'-[$^{18}$F]fluorothymidine positron emission tomography ([$^{18}$F]FLT-PET) and diffusion-weighted MRI (DW-MRI) are promising approaches to monitor tumor therapy response. Here, we employed these two imaging modalities to evaluate the response of lung carcinoma xenografts in mice after gemcitabine therapy. Caliper measurements revealed that H1975 xenografts responded to gemcitabine treatment, whereas A549 growth was not affected. In both tumor models, uptake of [$^{18}$F]FLT was significantly reduced 6 hours after drug administration. On the basis of the gemcitabine concentration and [$^{18}$F]FLT excretion measured, this was presumably related to a direct competition of gemcitabine with the radiotracer for cellular uptake. On day 1 after therapy, [$^{18}$F]FLT uptake was increased in both models, which was correlated with thymidine kinase 1 (TK1) expression. Two and 3 days after drug administration, [$^{18}$F]FLT uptake as well as TK1 and Ki67 expression were unchanged. A reduction in [$^{18}$F]FLT in the responsive H1975 xenografts could only be noted on day 5 of therapy. Changes in ADC$_{mean}$ in A549 xenografts 1 or 2 days after gemcitabine did not seem to be of therapy-related biological relevance as they were not related to cell death (assessed by caspase-3 IHC and cellular density) or tumor therapy response. Taken together, in these models, early changes of [$^{18}$F]FLT uptake in tumors reflected mechanisms, such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition, and only reflected growth-inhibitory effects at a later time point. Hence, the time point for [$^{18}$F]FLT-PET imaging of tumor response to gemcitabine is of crucial importance.The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement number 115151, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. This work was also supported by the Deutsche Forschungsgemeinschaft (DFG), Cells-in-Motion Cluster of Excellence (EXC1003 – CiM), University of Munster (Münster, Germany)

Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3'-Deoxy-3'-[18^{18}F]Fluorothymidine in Preclinical Models of Lung Cancer

3'-Deoxy-3'-[$^{18}$F]fluorothymidine positron emission tomography ([$^{18}$F]FLT-PET) and diffusion-weighted MRI (DW-MRI) are promising approaches to monitor tumor therapy response. Here, we employed these two imaging modalities to evaluate the response of lung carcinoma xenografts in mice after gemcitabine therapy. Caliper measurements revealed that H1975 xenografts responded to gemcitabine treatment, whereas A549 growth was not affected. In both tumor models, uptake of [$^{18}$F]FLT was significantly reduced 6 hours after drug administration. On the basis of the gemcitabine concentration and [$^{18}$F]FLT excretion measured, this was presumably related to a direct competition of gemcitabine with the radiotracer for cellular uptake. On day 1 after therapy, [$^{18}$F]FLT uptake was increased in both models, which was correlated with thymidine kinase 1 (TK1) expression. Two and 3 days after drug administration, [$^{18}$F]FLT uptake as well as TK1 and Ki67 expression were unchanged. A reduction in [$^{18}$F]FLT in the responsive H1975 xenografts could only be noted on day 5 of therapy. Changes in ADC$_{mean}$ in A549 xenografts 1 or 2 days after gemcitabine did not seem to be of therapy-related biological relevance as they were not related to cell death (assessed by caspase-3 IHC and cellular density) or tumor therapy response. Taken together, in these models, early changes of [$^{18}$F]FLT uptake in tumors reflected mechanisms, such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition, and only reflected growth-inhibitory effects at a later time point. Hence, the time point for [$^{18}$F]FLT-PET imaging of tumor response to gemcitabine is of crucial importance.The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement number 115151, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. This work was also supported by the Deutsche Forschungsgemeinschaft (DFG), Cells-in-Motion Cluster of Excellence (EXC1003 – CiM), University of Munster (Münster, Germany)