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Supplementary Figure Legend from Appearance of the Novel Activating F1174S ALK Mutation in Neuroblastoma Correlates with Aggressive Tumor Progression and Unresponsiveness to Therapy

Both polyesters and polycarbonates have been proposed as alternatives to polyethers as host materials for future polymer electrolytes for solid-state lithium-ion batteries. While being comparatively similar functional groups, the electron density on the coordinating carbonyl oxygen is different, thereby rendering different coordinating strength towards lithium ions. In this study, the transport properties of poly(ε-caprolactone) and poly(trimethylene carbonate) as well as random copolymers of systematically varied composition of the two have been investigated, in order to better elucidate the role of the coordination strength. The cationic transference number, a property well-connected with the complexing ability of the polymer, was shown to depend almost linearly on the ester content of the copolymer, increasing from 0.49 for the pure poly(ε-caprolactone) to 0.83 for pure poly(trimethylene carbonate). Contradictory to the transference number measurements that suggest a stronger lithium-to-ester coordination, DFT calculations showed that the carbonyl oxygen in the carbonate coordinates more strongly to the lithium ion than that of the ester. FT-IR measurements showed the coordination number to be higher in the polyester system, resulting in a higher total coordination strength and thereby resolving the paradox. This likely originates in properties that are specific of polymeric solvent systems, e.g. steric properties and chain dynamics, which influence the coordination chemistry. These results highlight the complexity in polymeric systems and their ion transport properties in comparison to low-molecular-weight analogues, and how polymer structure and steric effects together affect the coordination strength and transport properties., A linear dependence of the lithium transference number and the composition of the polyester–polycarbonate copolymer electrolyte host material was discovered, and the coordination properties causing the trend were investigated with DFT calculations.

This study illuminates professionals in key positions and their lived experience of measuring results in social services. Human service organizations were chosen as a focus area since the social se...

Background It is crucial to provide care based on individual needs. Swedish health care is obliged to give care on equal conditions for the entire population. The person with the greatest need should be given the most care, and the health care system should strive to be cost-efficient. Medical and technical advances have been significant during the last decades and the recent Covid-19 pandemic has caused a shift in health care, from in-person visits to virtual visits. The majority of pregnant women with a low risk assessment have an uncomplicated antenatal course without adverse events. These women probably receive excessive and unnecessary antenatal care. This study will investigate if an antenatal care program for healthy pregnant women with a low risk for adverse outcomes could be safely monitored with fewer in-person visits to a midwife, and with some of them replaced by virtual visits. Methods This is a non-inferiority trial where a stepped wedge cluster randomized controlled design will be used. Data collection includes register data and questionnaires that concern antenatal, obstetric and neonatal outcomes, patient- and caregiver-reported experiences, healthcare-economy, and implementation aspects. The modified antenatal care (MAC) study is performed in parts of the southeast of Sweden, which has approximately 8200 childbirths annually. At the start of the study, all antenatal care centers included in the study will use the same standard antenatal care (SAC) program. In the MAC program the in-person visits to a midwife will be reduced to four instead of eight, with two additional virtual meetings compared with the SAC program. Discussion This presented study protocol is informed by research knowledge. The protocol is expected to provide a good structure for future studies on changed antenatal care programs that introduce virtual visits for healthy pregnant women with a low risk for adverse outcomes, without risking quality, safety, and increased costs. Trial registration The study is registered the 21th of April 2021 in the ISRCTN registry with trial ID: ISRCTN14422582, retrospectively registered.

It has previously been shown that nanoparticle additives can, in a simple way, significantly improve the ionic conductivity in solid polymer electrolyte systems with the semi-crystalline poly(ethyl ...

Increasing the ionic conductivity has for decades been an overriding goal in the development of solid polymer electrolytes. According to fundamental theories on ion transport mechanisms in polymers, the ionic conductivity is strongly correlated to free volume and segmental mobility of the polymer for the conventional transport processes. Therefore, incorporating plasticizing side chains onto the main chain of the polymer host often appears as a clear-cut strategy to improve the ionic conductivity of the system through lowering of the glass transition temperature (T-g) This intended correlation between Tg and ionic conductivity is, however, not consistently observed in practice. The aim of this study is therefore to elucidate this interplay between segmental mobility and polymer structure in polymer electrolyte systems comprising plasticizing side chains. To this end, we utilize the synthetic versatility of the ion-conductive poly(trimethylene carbonate) (PTMC) platform. Two types of host polymers with side chains added to a PTMC backbone are employed, and the resulting electrolytes are investigated together with the side chain-free analogue both by experiment and with molecular dynamics (MD) simulations. The results show that while added side chains do indeed lead to a lower Tg, the total ionic conductivity is highest in the host matrix without side chains. It was seen in the MD simulations that while side chains promote ionic mobility associated with the polymer chain, the more efficient interchain hopping transport mechanism occurs with a higher probability in the system without side chains. This is connected to a significantly higher solvation site diversity for the Li+ ions in the side-chain-free system, providing better conduction paths. These results strongly indicate that the side chains in fact restrict the mobility of the Li+ ions in the polymer hosts.

Background: Organ donation has an obvious establishment in health care. When the patient hasn’t expressed his or hers stand for donation, relatives will be placed in a decision-making position which may seem daunting and complex. Purpose: The purpose was to elucidate relative’s experiences in connection with the donation process. Method: A qualitative literature study based on 20 caring science articles. Result: Three themes were created. When life fades is dealing with feelings of denial to a critical condition, uncertainty about death and the feeling of losing the footing. The importance of getting your own needs satisfied highlights confirmed and neglected needs. To make sense of death is about giving life as a gift to someone in need of transplantation and find meaning by the experience that the deceased lives on in someone else. Conclusion: For relatives’ life turns up and down when a critically ill next of kin passes. Not having your needs confirmed can lead to further suffering. By a consideration about the occurrence of deficiencies and about what is perceived as satisfactory to relatives during the organ donation process, the intensive care nurse can pay better attention to requests.

Large carnivores have historically been decreasing worldwide, often as a result of human-carnivore conflicts. However, large carnivores are recovering throughout Europe, and European management scenarios can provide important insights into broad issues related to human-large carnivore existence. After becoming almost extinct in Sweden during the mid-19th century the Swedish grey wolf (Canis lupus) population has now recovered. Current national wolf management aims to promote distribution shifts from the current areas in central Sweden, potentially also into a previously exempt reindeer husbandry area. Prior wolf re-introductions have highlighted the necessity of pro-active management for colonization success. Identification of likely range expansion areas could therefore be paramount for a successful Swedish wolf management. We characterized the demographic and spatial progression of Swedish wolves during 2001–2015 and used a MaxEnt approach to species distribution models to identify potential range expansion areas. The Swedish wolf population had expanded from 10 to almost 60 reproductions or territorial pairs, and increased in both range size and density. Our distribution models suggested that Swedish wolf management may face trade-offs between costs of hosting wolves in densely populated areas in southern Sweden with cattle and sheep and the costs of allowing wolves to expand into reindeer husbandry areas with associated cultural and economic consequences. Spatially explicit data on the economic, social and cultural factors associated with wolf conflict and acceptance may be paramount for developing optimal management strategies in the face of such a trade-off.

In design phases of large and complex infrastructure projects, a main challenge is to coordinate numerous technical specialists. Heuristics, or cognitive rules of thumb, is one factor that may influence the development of organisational structures and routines, especially if project management discretion is high: A longitudinal case study, comprising non-participant observation over three years, was carried out of the early design phase of a major railway tunnel project. Availability and familiarity heuristics were found important, as well as coordination neglect a general tendency to focus more on partitioning tasks than on coordination needs. Satisficing, meaning that the first acceptable organising solution is selected and retained, was found to be strong in temporary, transitory contexts. Shared heuristics were manifest as short catchphrases, or mantras. Clients should develop meta-routines and meta-functions to support adaptation within, and learning between, projects.

In large infrastructure projects, important decisions are made in early design phases. For a client, a key issue is how to stimulate innovative joint performance within the design team. This paper investigates the process of designing and implementing bonuses for cooperation and innovation in a large urban railway tunnel project. Data were collected through non-participatory observations, documents, interviews and a survey. Previous research has shown that incentives influence performance positively or negatively depending on task contents and perceived intentions, but also that people tend to underestimate this complexity and over-emphasize the power of incentives. Based on case observations, effects of bonuses for engineering consultants are discussed in relation to client awareness and management resources. The case results suggest that there are low risks for negative effects on task motivation of design consultants if incentives are low-stakes and not tied to specified performance. However, for low-stake incentives to add value, symbolic roles and the communication processes generated by the incentive scheme need to be strategically and purposefully managed. We conclude that research is needed to guide clients in considering a wider range of measures for enabling innovation and collaboration in design teams.

Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.

This study utilized pharmacological manipulations to analyze the role of direct and indirect activation of 5-HT 7 receptors (5-HT 7 Rs) in passive avoidance learning by assessing emotional memory in male C57BL/6J mice. Additionally, 5-HT 7 R binding affinity and 5-HT 7 R-mediated protein phosphorylation of downstream signaling targets were determined. Elevation of 5-HT by the selective serotonin reuptake inhibitor (SSRI) fluoxetine had no effect by itself, but facilitated emotional memory performance when combined with the 5-HT 1A R antagonist NAD-299. This facilitation was blocked by the selective 5-HT 7 R antagonist SB269970, revealing excitatory effects of the SSRI via 5-HT 7 Rs. The enhanced memory retention by NAD-299 was blocked by SB269970, indicating that reduced activation of 5-HT 1A Rs results in enhanced 5-HT stimulation of 5-HT 7 Rs. The putative 5-HT 7 R agonists LP-44 when administered systemically and AS19 when administered both systemically and into the dorsal hippocampus failed to facilitate memory. This finding is consistent with the low efficacy of LP-44 and AS19 to stimulate protein phosphorylation of 5-HT 7 R-activated signaling cascades. In contrast, increasing doses of the dual 5-HT 1A R/5-HT 7 R agonist 8-OH-DPAT impaired memory, while co-administration with NAD-299 facilitated of emotional memory in a dose-dependent manner. This facilitation was blocked by SB269970 indicating 5-HT 7 R activation by 8-OH-DPAT. Dorsohippocampal infusion of 8-OH-DPAT impaired passive avoidance retention through hippocampal 5-HT 1A R activation, while 5-HT 7 Rs appear to facilitate memory processes in a broader cortico-limbic network and not the hippocampus alone.

Mutations in the kinase domain of ALK (anaplastic lymphoma kinase) have recently been shown to be important for the progression of the childhood tumour neuroblastoma. In the present study we investigate six of the putative reported constitutively active ALK mutations, in positions G1128A, I1171N, F1174L, R1192P, F1245C and R1275Q. Our analyses were performed in cell-culture-based systems with both mouse and human ALK mutant variants and subsequently in a Drosophila melanogaster model system. Our investigation addressed the transforming potential of the putative gain-of-function ALK mutations as well as their signalling potential and the ability of two ATP-competitive inhibitors, Crizotinib (PF-02341066) and NVP-TAE684, to abrogate the activity of ALK. The results of the present study indicate that all mutations tested are of an activating nature and thus are implicated in tumour initiation or progression of neuroblastoma. Importantly for neuroblastoma patients, all ALK mutations used in the present study can be blocked by the inhibitors, although some mutants exhibited higher levels of drug sensitivity than others.

Activating mutations in the kinase domain of anaplastic lymphoma kinase (ALK) have recently been shown to be an important determinant in the genetics of the childhood tumor neuroblastoma. Here we discuss an in-depth analysis of one of the reported gain-of-function ALK mutations-ALK(I1250T)-identified in the germ line DNA of one patient. Our analyses were performed in cell culture-based systems and subsequently confirmed in a Drosophila model. The results presented here indicate that the germ line ALK(I1250T) mutation is most probably not a determinant for tumor initiation or progression and, in contrast, seems to generate a kinase-dead mutation in the ALK receptor tyrosine kinase (RTK). Consistent with this, stimulation with agonist ALK antibodies fails to lead to stimulation of ALK(I1250T) and we were unable to detect tyrosine phosphorylation under any circumstances. In agreement, ALK(I1250T) is unable to activate downstream signaling pathways or to mediate neurite outgrowth, in contrast to the activated wild-type ALK receptor or the activating ALK(F1174S) mutant. Identical results were obtained when the ALK(I1250T) mutant was expressed in a Drosophila model, confirming the lack of activity of this mutant ALK RTK. We suggest that the ALK(I1250T) mutation leads to a kinase-dead ALK RTK, in stark contrast to assumed gain-of-function status, with significant implications for patients reported to carry this particular ALK mutation.

The epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph (mceph/mceph) is homozygous for a spontaneous mutation truncating the Shaker-like voltage gated potassium channel, Kv1.1 (Kcna1). The mceph/mceph mice are asymptomatic at birth, but develop from 3 weeks of age epileptic seizures, overgrowth and neuronal hyperplasia of the hippocampus. Hippocampal cognitive function of the mice was examined by investigating emotional memory using the aversive Passive Avoidance (PA) task combined with studies of explorative behavior using the non-aversive Novel Cage test (NCT). The behavioural results were examined by multivariate analysis. Compared to wild type and heterozygous mice, the mceph/mceph mice displayed lower exploratory and safety assessment behavior in the NCT and impairment in PA retention 24 hours after training, indicating an impairment in cognitive functions. In conclusion, the epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph, with chronic epilepsy related to potassium-channelopathy, display a behavioural phenotype characterized by impairments in emotional memory and defensive motivational responses probably related to hippocampal dysfunctions.

Background. Stress-related ill health, e.g. burnout, is of great concern worldwide. Effective rehabilitation programs need to be developed and their therapeutic aspects understood. Purpose. To explore and describe how women with stress-related ill health who are on sick leave experience the rehabilitation process in a therapeutic garden and how these experiences connect to their everyday lives. Methods. This longitudinal study used methods from grounded theory. Five women completed three semi-structured interviews at three weekly intervals during rehabilitation and one interview three months after. Data were analyzed using a constant comparative approach. Findings. A secure environment facilitated engagement in activities that provided feelings of enjoyment. These experiences inspired participants to add enjoyable activities in their everyday lives, contributing to occupational balance, despite worries of not be able to continue performing enjoyable activities. Implications. Effective rehabilitation programs need to focus on enjoyable activities in a protective environment to support achievement of occupational balance.

Adenovirus type 37 (Ad37) is a leading cause of epidemic keratoconjunctivitis (EKC), a severe and highly contagious ocular disease. Whereas most other adenoviruses infect cells by engaging CD46 or the coxsackie and adenovirus receptor (CAR), Ad37 binds previously unknown sialic acid-containing cell surface molecules. By glycan array screening, we show here that the receptor-recognizing knob domain of the Ad37 fiber protein specifically binds a branched hexasaccharide that is present in the GD1a ganglioside and that features two terminal sialic acids. Soluble GD1a glycan and GD1a-binding antibodies efficiently prevented Ad37 virions from binding and infecting corneal cells. Unexpectedly, the receptor is constituted by one or more glycoproteins containing the GD1a glycan motif rather than the ganglioside itself, as shown by binding, infection and flow cytometry experiments. Molecular modeling, nuclear magnetic resonance and X-ray crystallography reveal that the two terminal sialic acids dock into two of three previously established sialic acid-binding sites in the trimeric Ad37 knob. Surface plasmon resonance analysis shows that the knob-GD1a glycan interaction has high affinity. Our findings therefore form a basis for the design and development of sialic acid-containing antiviral drugs for topical treatment of EKC.

Cholinergic and GABAergic neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) projecting to the hippocampus, constitute the septohippocampal projection, which is important for hippocampal-dependent learning and memory. There is also evidence for an extrinsic as well as an intrinsic glutamatergic network within the MS/vDB. GABAergic and cholinergic septohippocampal neurons express the serotonergic 5-HT(1A) receptor and most likely also glutamatergic NMDA receptors. The aim of the present study was to examine whether septal 5-HT(1A) receptors are important for hippocampal-dependent long-term memory and whether these receptors interact with glutamatergic NMDA receptor transmission in a manner important for hippocampal-dependent spatial memory. Intraseptal infusion of the 5-HT(1A) receptor agonist (R)-8-OH-DPAT (1 or 4 microg/rat) did not affect spatial learning in the water maze task but impaired emotional memory in the passive avoidance task at the higher dose tested (4 microg/rat). While intraseptal administration of (R)-8-OH-DPAT (4 microg) combined with a subthreshold dose of the NMDA receptor antagonist D-AP5 (1 microg) only marginally affected spatial acquisition, it produced a profound impairment in spatial memory. In conclusion, septal 5-HT(1A) receptors appears to play a more prominent role in emotional than in spatial memory. Importantly, septal 5-HT(1A) and NMDA receptors appear to interact in a manner, which is particularly critical for the expression or retrieval of hippocampal-dependent long-term spatial memory. It is proposed that NMDA receptor hypofunction in the septal area may unmask a negative effect of 5-HT(1A) receptor activation on memory, which may be clinically relevant.

Caffeine is believed to exert its stimulant effects by blocking A2A and A1 adenosine receptors (A2AR and A1R). Although a genetic knockout of A2AR eliminates effects of caffeine, the phenotype of the knockout animal does not resemble that of caffeine treatment. In this study we explored the possibility that a mere reduction of the number of A1Rs and A2ARs, achieved by deleting one of the two copies of the A1R and A2AR genes, would mimic some aspects of long-term caffeine ingestion. The A1R and A2AR double heterozygous (A1R-A2AR dHz) mice indeed had approximately one-half the number of A1R and A2AR, and there were little compensatory changes in A2B or A3 adenosine receptor (A2BR or A3R) expression. The ability of a stable adenosine analog to activate receptors was shifted to the right by caffeine and in A1R-A2AR dHz tissue. Caffeine (0.3 g/l in drinking water for 7–10 days) and A1R-A2AR dHz genotype increased locomotor activity (LA) and decreased heart rate without significantly influencing body temperature. The acute stimulatory effect of a single injection of caffeine was reduced in A1R-A2AR dHz mice and in mice treated long term with oral caffeine. Thus at least some aspects of long-term caffeine use can be mimicked by genetic manipulation of the A1R and A2AR.

5-HT 1A receptors are implicated in the modulation of cognitive processes including encoding of fear learning. However, their exact role has remained unclear due to contrasting contributions of pre- vs. postsynaptic 5-HT 1A receptors. Therefore, their role in fear conditioning was studied in mice using the selective ligand S15535, which fully activates 5-HT 1A autoreceptors, yet only weakly stimulates their postsynaptic counterparts. The effects of S15535 were compared to those of the full agonist 8-OH-DPAT and the selective antagonist NAD-299. 8-OH-DPAT dose-dependently (0.01–0.5 mg/kg) and markedly impaired both context- and tone-dependent fear conditioning, as determined by complementary measures of inactivity and freezing. 8-OH-DPAT-mediated impairments were blocked by pre-injection of the selective 5-HT 1A antagonist WAY100635. S15535 (0.01–5.0 mg/kg) mimicked 8-OH-DPAT in predominantly impairing conditioned contextual fear, though with smaller effect size than 8-OH-DPAT, consistent with lower efficacy at postsynaptic 5-HT 1A receptors. Furthermore, S15535 (1.0 mg/kg) tended to attenuate the impairment of fear conditioning by 8-OH-DPAT (0.3 mg/kg). In contrast, NAD-299 (0.3 and 1 mg/kg) facilitated contextual freezing. WAY100635 (0.3 mg/kg) prevented the impairment of contextual fear by S15535 (1 and 5 mg/kg), underpinning the role of 5-HT 1A receptors in the actions of S15535. Collectively, these data indicate that 5-HT 1A receptor ligands modulate fear conditioning in a bidirectional manner: activation of postsynaptic 5-HT 1A sites exerts an inhibitory influence, whereas their blockade promote facilitation of fear conditioning. The results with S15535 underscore the importance of ligand efficacy in determining the actions of 5-HT 1A receptor ligands in fear conditioning and other models of cognitive function.

The principal 5-HT(1A) receptor agonist 8-Hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) impairs several different types of learning. Besides 5-HT(1A) receptors, 8-OH-DPAT stimulates 5-HT(7) receptors, but it is not known whether 5-HT(7) receptors contribute to the impairments. The 5-HT(7) receptor antagonist (2R)-1-[(3-Hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl] pyrrolidine (SB-269970) was combined with 8-OH-DPAT to dissociate 5-HT(1A) from 5-HT(7) receptor-mediated effects, in the passive avoidance task for emotional learning. SB-269970 intensified impairments caused by 8-OH-DPAT. SB-269970 alone had no effect on memory performance, but moderately decreased retention under suboptimal learning conditions. These findings indicate that 5-HT(7) receptor stimulation by 8-OH-DPAT counteracts 5-HT(1A) receptor-mediated impairments in hippocampal-dependent contextual learning.

A new compound, Mn3Pd20P6, has been synthesized and the crystal and magnetic structures have been determined by neutron powder diffraction. The crystal structure is cubic, with a = 11.9563 ( 2 ) A , space group Fm 3 ¯ m, and is isostructural to Mn3Ni20P6, a ternary ordering variant of the Cr23C6-type structure. The magnetic properties of Mn3Pd20P6 and Mn3Ni20P6 were studied by magnetization measurements. For Mn3Pd20P6 a transition, suggested to be of first order, to a ferromagnetic structure takes place at 110 K, whereas the saturation magnetization shows unusual temperature dependence. Magnetization vs. field loops show very weak coercivity, and the magnitude of the saturation magnetization agrees well with parallel Mn magnetic moments on two different sublattices of 4.24(8) μB, and 2.88(8) μB, respectively, found by neutron powder diffraction at 10 K. Magnetization vs. temperature measurements for Mn3Ni20P6 do not show a well-defined transition temperature, but show signatures of magnetic order with small excess magnetic moments aligned by the applied field below about 240 K. Further, signatures of a spin reorientation process at around 30 K are noted.

A new ternary phase, Mn4Ir7−xMnxGe6 (0x1.3), was studied by X-ray and neutron powder diffraction and SQUID magnetometry. The crystal structure is cubic, of the U4Re7Si6 type, space group , Z=2, with the lattice parameter at 295 K. Within the limited range of homogeneity small variations of the composition yield dramatic changes of the magnetic structure. For x=0 long-range antiferromagnetic order is formed below the transition temperature 228 K, with large magnetic moments on Mn, 4.11(9) μB at 10 K, in a magnetic unit cell , cM=2aC. In contrast, for x=1.3 spin glass behavior is observed below 90 K. The Mn atoms form an ideal cubic framework, on which geometric frustration of competing nearest and next nearest neighbor antiferromagnetic interactions is suggested to explain the composition sensitive magnetic properties. A TiNiSi-type phase, IrMnGe, is found in samples of 1:1:1 composition quenched from the melt.

The structural and magnetic properties of a new ternary Ir–Mn–Ge phase, Mn3IrGe, as well as the solid solution Mn3Ir(Si1−xGex), 0⩽x⩽1, have been investigated by means of X-ray and neutron powder diffraction, magnetization measurements and first principles calculations. The crystal structure is cubic, of the AlAu4-type (an ordered form of the β-Mn structure), Z=4, space group P213, and the unit-cell dimension varies linearly with the silicon content. For all compositions, antiferromagnetic ordering is found below a critical temperature of about 225 K. The magnetic structure is noncollinear, as a result of frustrated magnetic interactions on a triangular network of Mn atoms, on which the moments rotate 120° around the triangle axes. The magnitude of the magnetic moment at 10 K is 3.39(4) μB for Mn3IrGe. The theoretical calculations reproduce with very good accuracy the magnitudes as well as the directions of the experimentally observed magnetic moments.

The effect of the surface coating on the magnetic properties of superparamagnetic iron oxide nanoparticles (SPION) with 8 nm in size has been studied. Four different biocompatible coating layers are considered: poly L,L-lactic acid (PLLA), poly e-caprolactone (PCL), bovine serum albumin (BSA) and gold. The presence of coating layer on the surface of SPION is confirmed by FT-IR spectroscopy. Mossbauer spectroscopy and magnetic susceptibility measurements show that for uncoated SPION and Au@SPION the superparamagnetic fraction is retained. The formation of clusters in the case of BSA@SPION and chain-like structure for PCL@SPION and PLLA@SPION increase the inter-particle interactions resulting in hyperfine magnetic structure observed in the Mossbauer spectra at ambient temperature.

Midkine (MDK) and Pleiotrophin (PTN) are small heparin-binding cytokines with closely related structures. The Drosophila genome harbours two genes encoding members of the MDK/PTN family of proteins, known as miple1 and miple2. We have investigated the role of Miple proteins in vivo, in particular with regard to their proposed role as ligands for the Alk receptor tyrosine kinase (RTK). Here we show that Miple proteins are neither required to drive Alk signaling during Drosophila embryogenesis, nor are they essential for development in the fruit fly. Additionally we show that neither MDK nor PTN can activate hALK in vivo when ectopically co-expressed in the fly. In conclusion, our data suggest that Alk is not activated by MDK/PTN related growth factors Miple1 and Miple 2 in vivo.

Hepatoblastoma (HB) is a rare malignant embryonal liver tumor. Its pathogenesis has been associated with altered regulation of the IGF2 and H19 genes, and previous studies have suggested a correlation between abnormal methylation and altered expression of these genes in hepatoblastoma. Upregulation of the activity of the IGF2 promoter P3 has previously been shown to be tightly correlated with demethylation in hepatoblastoma. Here, we have used bisulfite genomic sequencing to characterize the methylation pattern of the IGF2 promoter P3 in the hepatoblastoma-derived cell line Hep T1, in the original tumor from which Hep T1 is derived, and in nude mouse xenografts of the Hep T1 cell line. The results show a clear difference in methylation pattern of the most proximal region of the IGF2 P3 promoter between the primary tumor, the cell line, and the xenografts. RNase protection and mRNA in situ hybridization revealed that variations in methylation patterns was paralleled by the levels of IGF2 P3 mRNA, which was detectable in the primary tumor and xenografts, but not in the cell line. Furthermore, it was demonstrated that H19 was reactivated and demethylated in the HepT1 cell line by 5-azaCytidine, in contrast to IGF2 P3, which was not demethylated or reactivated. We suggest that methylation of the proximal IGF2 P3 is important for its regulation.

Hepatoblastoma, a rare pediatric liver tumour, is a poorly understood disease. While expression studies for some members of the Insulin-like growth factor axis have been studied in hepatoblastoma, a systematic analysis of the IGF-axis has not been carried out. We have examined a series of hepatoblastomas with matched normal liver tissue for gene expression differences with emphasis on members of the insulin-like growth factor binding proteins. The expression profiles obtained reveal that the expression of these genes are altered in these tumors. The results indicate that the IGF-axis is seriously disturbed in the tumors.

Glomerular hyperfiltration is commonly observed in diabetics early after the onset of the disease and predicts the progression of nephropathy. Sustained hyperglycaemia is also closely associated with kidney hypertrophy and increased electrolyte and glucose reabsorption in the proximal tubule. In this study, we investigated the role of the increased tubular sodium/glucose cotransport for diabetes-induced glomerular hyperfiltration. To eliminate any potential confounding effect of the tubuloglomerular feedback (TGF) mechanism, we used adenosine A₁-receptor deficient (A1AR(-/-)) mice known to lack a functional TGF mechanism and compared the results to corresponding wild-type animals (A1AR(+/+)).Diabetes was induced by an intravenous bolus injection of alloxan. Glomerular filtration rate (GFR) was determined in conscious mice by a single bolus injection of inulin. The sodium/glucose cotransporters were inhibited by phlorizin 30 min prior to GFR measurements.Normoglycaemic animals had a similar GFR independent of genotype (A₁AR(+/+) 233 ± 11 vs. A₁AR(-/-) 241 ± 25 μL min(-1)), and induction of diabetes resulted in glomerular hyperfiltration in both groups (A₁AR(+/+) 380 ± 25 vs. A₁AR(-/-) 336 ± 35 μL min(-1); both P0.05). Phlorizin had no effect on GFR in normoglycaemic mice, whereas it reduced GFR in both genotypes during diabetes (A₁AR(+/+) 365 ± 18 to 295 ± 19, A₁AR(-/-) 354 ± 38 to 199 ± 15 μL min(-1); both P0.05). Notably, the reduction was more pronounced in the A₁AR(-/-) (P0.05).This study demonstrates that increased tubular sodium/glucose reabsorption is important for diabetes-induced hyperfiltration, and that the TGF mechanism is not involved in these alterations, but rather functions to reduce any deviations from a new set-point.

A new phase in the ternary Ir–Mn–Si system has been synthesised. From powder neutron diffraction data the crystal structure was determined to be of the AlAu4 type and to be described in the cubic space group P213 with the unit cell a=6.4973(3) A. Susceptibility measurements using a SQUID-magnetometer showed a transition typical of antiferromagnetism, with TN=210 K. Low temperature antiferromagnetic order is confirmed by extra peaks in neutron diffractograms recorded at 10 and 80 K.

To describe and compare how occupational gaps were reported in everyday occupations in a rehabilitation group of people with musculoskeletal pain or stress-related ill health and in a reference group from the Swedish population.Seventy-two persons with musculoskeletal pain or stress-related ill health and 261 people from the Swedish population were included. The Occupational Gaps Questionnaire, measuring to what extent individuals perceive a discrepancy between what they want to do and what they actually do, was completed by the participants. Descriptive statistics were used to analyse the data.Occupational gaps were reported more often in the rehabilitation group. Leisure activities were the gaps reported most often. The occupational repertoire seemed to decrease over time as the number of activities was decreasing, particularly leisure and work-related activities. Instrumental ADL were more desirable as the length of sick leave extended.Being on sick leave appears to start a process towards occupational deprivation where the areas that remain in the occupational repertoire become more important. Our study highlights the need to emphasize the whole occupational repertoire in rehabilitation and to facilitate engagement in valued activities to create a sound base for the process of returning to work.

Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT₄R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies.

Mutations in the kinase domain of the ALK kinase have emerged recently as important players in the genetics of the childhood tumor neuroblastoma. Here, we report the appearance of a novel ALK mutation in neuroblastoma, correlating with aggressive tumor behavior. Analyses of genomic DNA from biopsy samples initially showed ALK sequence to be wild type. However, during disease progression, mutation of amino acid F1174 to a serine within the ALK kinase domain was observed, which correlated with aggressive neuroblastoma progression in the patient. We show that mutation of F1174 to serine generates a potent gain-of-function mutant, as observed in 2 independent systems. First, PC12 cell lines expressing ALKF1174S display ligand-independent activation of ALK and further downstream signaling activation. Second, analysis of ALKF1174S in Drosophila models confirms that the mutation mediates a strong, rough eye phenotype upon expression in the developing eye. Thus, we report a novel ALKF1174S mutation that displays ligand-independent activity in vivo, correlating with rapid and treatment-resistant tumor growth. The study also shows that initial screening in the first tumor biopsy of a patient may not be sufficient and that further molecular analysis, in particular in tumor progression and/or tumor relapse, is warranted for better understanding of the treatment of neuroblastoma patients. Cancer Res; 71(1); 98–105. ©2011 AACR.

Despite much progress in the study and treatment of depression, the mechanisms underlying this debilitating disease are still unclear. Altered activity of several major neurotransmitters in the brain including serotonin is involved, but pinpointing the parts of the brain affected in depression has proved challenging. Alexander and colleagues now implicate a brain region called the nucleus accumbens and a protein called p11 expressed in this region as important mediators of depression in humans and mice. The authors were alerted to the potential importance of p11 in depression because mice that lack this protein show depressive-like behavior. This protein is involved in the activation of two receptors for serotonin, 5-HT1B and 5-HT4. Alexander et al . decided to down-regulate expression of p11 specifically in the nucleus accumbens by injecting a viral vector containing a small interfering RNA against p11 directly into this brain region in healthy mice. They then tested the treated mice to see if they exhibited depressive-like behaviors in response to two stress tests (suspension by the tail and swimming in a water tank). In both tests, treated mice showed greater immobility compared with control animals, a sign of depressive-like behavior. To show that these depressive symptoms were indeed caused by loss of p11 in the nucleus accumbens, the investigators overexpressed p11 in the nucleus accumbens of mice that completely lacked this protein. They demonstrated restoration of normal immobility times on the two stress tests and an increased desire to sip sucrose solution (a treat that rodents normally enjoy but depressed animals do not). They also showed increased activity of 5-HT1B serotonin receptors expressed by striatal neurons in the nucleus accumbens of mice overexpressing p11. But do these results have any relevance to depression in humans? Alexander and colleagues tackled this question by comparing postmortem nucleus accumbens brain tissue from individuals with and without depression at the time of death. They discovered that expression of p11 was much lower in the nucleus accumbens of depressed individuals compared with healthy persons. These new findings pinpoint the nucleus accumbens and the p11 protein as important mediators of depression and provide new therapeutic targets for drug development.

The aim was to describe how former clients with stress-related disorders and rehabilitation team members experience the rehabilitation process, and to describe how experiences from the rehabilitation have been integrated into the former clients' everyday lives. A qualitative grounded theory approach was used. The sample consisted of seven team members working at a vocational rehabilitation clinic and eight former clients who were interviewed. The participants were involved in four different rehabilitation programmes, all of which used cognitive approaches. In addition, two of the programmes offered activities in a therapeutic garden. The result highlighted experiences that might have contributed to changes in the former clients' self-image, development of conscious strategies for handling stressful situations, and changes in values attached to everyday occupations. In addition, two different modes of integrating experiences from rehabilitation into the former clients' everyday lives were identified: changing approaches to handling stressful situations in everyday life and changing occupational repertoire in everyday life. Important implications might be that activities which promote relaxation and enjoyment should be included in the rehabilitation of people with stress-related disorders since experiences from these activities seemed to facilitate occupational balance in everyday life.

Serotonergic (5-HT) neurotransmission plays a role in learning and memory processes, but the physiological role of various receptor subtypes is not well characterised. Among these, 5-HT1B receptors are located as autoreceptors on 5-HT axons and heteroreceptors on non-serotonergic terminals. This study examined the role of the 5-HT1B receptor in one-trial aversive contextual learning using the passive avoidance (PA) task in NMRI mice. Subcutaneous administration of the 5-HT1B receptor agonist anpirtoline (0.1–1.0 mg/kg) before PA training impaired retention performance 24 h later. Combined administration of anpirtoline with the selective 5-HT1B receptor antagonist NAS-181 (0.1–1.0 mg/kg) fully blocked the impairments. Administration of NAS-181 alone dose-dependently improved PA retention performance. This facilitatory effect was blocked by subthreshold doses of both the muscarinic antagonist scopolamine (0.03 mg/kg) and the NMDA receptor antagonist MK-801 (0.03 mg/kg). NAS-181 also fully blocked the PA impairments induced by an amnesic dose of scopolamine (0.1 mg/kg), when administered prior to, but not after, scopolamine. In addition, NAS-181 attenuated PA impairments induced by MK-801 (0.3 mg/kg). These findings indicate that 5-HT1B receptors are activated at basal levels of 5-HT transmission. The facilitatory effect of NAS-181 involved alleviation of an inhibitory 5-HT tone mediated via 5-HT1B receptors on cholinergic and glutamatergic transmission. This disinhibition is expected to occur in neuronal circuits involved in contextual learning including the hippocampus and interconnected cortico-limbic regions. Blockade of brain 5-HT1B heteroreceptors may represent a novel therapeutic strategy for restoration of deficient cholinergic and glutamatergic neurotransmission contributing to memory disorders.

The ascending serotonin (5-HT) neurons innervate the cerebral cortex, hippocampus, septum and amygdala, all representing brain regions associated with various domains of cognition. The 5-HT innervation is diffuse and extensively arborized with few synaptic contacts, which indicates that 5-HT can affect a large number of neurons in a paracrine mode. Serotonin signaling is mediated by 14 receptor subtypes with different functional and transductional properties. The 5-HT(1A) subtype is of particular interest, since it is one of the main mediators of the action of 5-HT. Moreover, the 5-HT(1A) receptor regulates the activity of 5-HT neurons via autoreceptors, and it regulates the function of several neurotransmitter systems via postsynaptic receptors (heteroreceptors). This review assesses the pharmacological and genetic evidence that implicates the 5-HT(1A) receptor in learning and memory. The 5-HT(1A) receptors are in the position to influence the activity of glutamatergic, cholinergic and possibly GABAergic neurons in the cerebral cortex, hippocampus and in the septohippocampal projection, thereby affecting declarative and non-declarative memory functions. Moreover, the 5-HT(1A) receptor regulates several transduction mechanisms such as kinases and immediate early genes implicated in memory formation. Based on studies in rodents the stimulation of 5-HT(1A) receptors generally produces learning impairments by interfering with memory-encoding mechanisms. In contrast, antagonists of 5-HT(1A) receptors facilitate certain types of memory by enhancing hippocampal/cortical cholinergic and/or glutamatergic neurotransmission. Some data also support a potential role for the 5-HT(1A) receptor in memory consolidation. Available results also implicate the 5-HT(1A) receptor in the retrieval of aversive or emotional memories, supporting an involvement in reconsolidation. The contribution of 5-HT(1A) receptors in cognitive impairments in various psychiatric disorders is still unclear. However, there is evidence that 5-HT(1A) receptors may play differential roles in normal brain function and in psychopathological states. Taken together, the evidence indicates that the 5-HT(1A) receptor is a target for novel therapeutic advances in several neuropsychiatric disorders characterized by various cognitive deficits.

We have examined behavioral consequences of genetic deletion of the adenosine A3 receptors in mice. The open field behavior of A3 adenosine receptor knock-out (A3R KO) mice was investigated both under basal conditions and after stimulation with psychostimulants. Adolescent (21 day-old) and adult A3R KO males showed an increase in overall motor activity compared to wild type (WT) males, but the type of activity differed. The motor activity, especially rearing, was also higher in A3R KO compared to WT adult females. A3 receptors have a low affinity for caffeine and it was therefore surprising to find a decreased response to stimulation with either caffeine or amphetamine in A3R KO as compared to WT mice in males as well as females. Telemetry recordings also showed a significantly smaller increase in activity upon darkness in A3R KO. There were no compensatory changes in the mRNA expression of any other adenosine receptor subtypes (A1, A2A and A2B) or any changes in dopamine D1 and D2 receptor binding in A3R KO brains. Challenge with the developmental toxicant methylmercury (1 microM in drinking water) during pregnancy and lactation did not cause any behavioral alterations in adolescent and adult WT female offspring. In contrast, the A3R KO female offspring displayed changes in locomotion indicating an interaction between perinatal methylmercury and adenosine A3 receptors. In conclusion, despite low expression of A3 receptors in wild type mouse brain we observed several behavioral consequences of genetic elimination of the adenosine A3 receptors. The possibility that this is due to a role of A3 receptors in development is discussed.

The Drosophila Alk receptor tyrosine kinase (RTK) drives founder cell specification in the developing visceral mesoderm and is crucial for the formation of the fly gut. Activation of Alk occurs in response to the secreted ligand Jelly Belly. No homologues of Jelly Belly are described in vertebrates, therefore we have approached the question of the evolutionary conservation of the Jeb-Alk interaction by asking whether vertebrate ALK is able to function in Drosophila. Here we show that the mouse ALK RTK is unable to rescue a Drosophila Alk mutant, indicating that mouse ALK is unable to recognise and respond to the Drosophila Jeb molecule. Furthermore, the overexpression of a dominant-negative Drosophila Alk transgene is able to block the visceral muscle fusion event, which an identically designed dominant-negative construct for the mouse ALK is not. Using PC12 cells as a model for neurite outgrowth, we show here for the first time that activation of dAlk by Jeb results in neurite extension. However, the mouse Alk receptor is unable to respond in any way to the Drosophila Jeb protein in the PC12 system. In conclusion, we find that the mammalian ALK receptor is unable to respond to the Jeb ligand in vivo or in vitro. These results suggest that either (i) mouse ALK and "mouse Jeb" have co-evolved to the extent that mALK can no longer recognise the Drosophila Jeb ligand or (ii) that the mALK RTK has evolved such that it is no longer activated by a Jeb-like molecule in vertebrates.

A new compound, Mn8Pd15Si7, is reported to crystallize in a face centered cubic unit cell of dimension a = 12.0141(2) A, space group F m 3 ¯ m , and can thus be classified as a G-phase. The crystal structure was studied by single crystal X-ray diffraction, X-ray and neutron powder diffraction and electron diffraction. A filled Mg6Cu16Si7 type structure was found, corresponding to the Sc11Ir4 type structure. The magnetic properties were investigated by magnetization measurements and Reverse Monte Carlo modeling of low temperature magnetic short-range order (SRO). Dominating near neighbor antiferromagnetic correlations were found between the Mn atoms and geometric frustration in combination with random magnetic interactions via metal sites with partial Mn occupancy were suggested to hinder formation of long-range magnetic order.

Two compounds, ${\mathrm{Mn}}_{3}\mathrm{CoSi}$ and ${\mathrm{Mn}}_{3}\mathrm{CoGe}$ have been synthesized and found to crystallize in the ${\mathrm{AlAu}}_{4}$ type structure, an ordered form of the $\ensuremath{\beta}\ensuremath{-}\mathrm{Mn}$ structure. The magnetic structure and properties have been studied by magnetometry and neutron powder diffraction and the theoretical work is based on first principles total energy calculations. Comparison is made with the magnetic properties of the isostructural compounds ${\mathrm{Mn}}_{3}\mathrm{IrGe}$ and ${\mathrm{Mn}}_{3}\mathrm{IrSi}$. The solid solutions ${\mathrm{Mn}}_{3}{\mathrm{Ir}}_{1\ensuremath{-}y}{\mathrm{Co}}_{y}\mathrm{Si}$ $(0\ensuremath{\leqslant}y\ensuremath{\leqslant}1)$ and ${\mathrm{Mn}}_{3}{\mathrm{CoSi}}_{1\ensuremath{-}x}{\mathrm{Ge}}_{x}$ $(0\ensuremath{\leqslant}x\ensuremath{\leqslant}1)$ are also studied. A noncollinear antiferromagnetic structure is experimentally observed for $y=0.20$ as well as for $x=0.50$ and 1.0, similar to that of ${\mathrm{Mn}}_{3}\mathrm{IrSi}$ and ${\mathrm{Mn}}_{3}\mathrm{IrGe}$, with 120\ifmmode^\circ\else\textdegree\fi{} angles between magnetic moments on a triangular network of Mn atoms, and this finding is corroborated by theoretical calculations. For $y=0.80\text{--}1.0$ a transformation to a new type of magnetic structure takes place. The magnetic transition temperature decreases on decreasing unit cell dimension, with good qualitative agreement with the decay of the calculated interatomic exchange energy. Both theory and experiments find the magnitude of the Mn magnetic moment to decrease on decreasing unit cell volume, the same trend is found in calculations for $\ensuremath{\beta}\ensuremath{-}\mathrm{Mn}$.

HBV-DNA quantitation, the HBe antigen status and the appearance of mutations in the core promoter, precore and polymerase regions are important elements in the management of chronic HBV infection.We performed a technical evaluation of 3 new kits, affigene HBV VL, affigene HBV mutant VL and affigene HBV DE/3TC assays (Sangtec Molecular Diagnostics) in comparison with the Amplicor HBV Monitor assay (Manual Test, Roche), direct sequencing and direct sequencing/Inno-LIPA HBV DR (Innogenetics), respectively. We evaluated the clinical application of these tests in the management of patients with chronic (HBeAg positive) hepatitis B. Serial sera of 11 chronic HBeAg positive patients were studied before, during and after lamivudine/interferon treatment.HBV-DNA quantitation detected with affigene HBV VL showed a high correlation with the Amplicor HBV Monitor test (r=0.85). affigene HBV mutant VL (positions G1764A, G1896A) and affigene HBV DE/3TC (positions rtL180M, rtM204V/I) were able to detect a low presence of mutants in a mixed population (wild type and mutant) compared to direct sequencing and Inno-LIPA HBV DR, which identified only the dominant population.These three sensitive assays, performed with the same DNA extraction, give clinicians useful information for the management of chronic hepatitis B and for timing treatment.

A new compound, IrMnSi, has been synthesized, and its crystal structure and magnetic properties have been investigated by means of neutron powder diffraction, magnetization measurements, and first-principles theory. The crystal structure is found to be of the TiNiSi type (ordered Co2P, space group Pnma). The Mn-projected electronic states are situated at the Fermi level, giving rise to metallic binding, whereas a certain degree of covalent character is observed for the chemical bond between the It and Si atoms. A cycloidal, i.e., noncollinear, magnetic structure was observed below 460 K, with the propagation vector q=[0,0,0.4530(5)] at 10 K. The magnetism is dominated by large moments on the Mn sites, 3.8 mu(B)/atom from neutron diffraction. First-principles theory reproduces the propagation vector of the experimental magnetic structure as well as the angles between the Mn moments. The calculations further result in a magnetic moment of 3.21 mu(B) for the Mn atoms, whereas the Ir and Si moments are negligible, in agreement with observations. A calculation that more directly incorporates electron-electron interactions improves the agreement between the theoretical and experimental magnetic moments. A band mechanism is suggested to explain the observed magnetic order.

Drug-resistant malaria is spreading in Africa. The few available drugs might be safeguarded if combined with an artemisinin derivative. We investigated the efficacy, safety, and tolerability of 2 combinations of artesunate with sulfadoxine-pyrimethamine (SP) in a mesoendemic region in Uganda with SP resistance, from September 1999 to June 2000. In a randomized, double-blind, placebo-controlled trial, 420 children aged 6-59 months with uncomplicated Plasmodium falciparum malaria were assigned SP alone (25 mg/kg sulfadoxine, 1.25 mg/kg pyrimethamine) or combined with artesunate (AS; 4 mg/kg/d) for either 1 d (SPAS1) or 3 d (SPAS3). Children were followed-up for 28 d. Day 14 cure rates were 84.6% (99/117) with SPAS3 and 61.9% (73/118) with SPAS1 compared with 55.8% (86/154) with SP. Corresponding day 28 results were 74.4% (87/117) and 45.2% (52/115) compared with 40.5% (62/153). A significant improvement was obtained with the addition of 3 d, but not 1 d, of artesunate (risk ratio [RR] = 1.5, 95% CI 1.3-1.8 at 14 d and RR = 1.8, 95% CI 1.5-2.3 at 28 d). Both AS regimens achieved significantly faster parasite clearance and lower gametocyte carriage. All drug regimens were well tolerated, but SP alone was ineffective. Treatment efficacy improved with SPAS3 but the cure rate at day 28 was modest. The combinations were well tolerated and safe. In areas where SP resistance is prevalent other combinations should be considered.