Orthogonal beta-beta motifs in proteins

A super-secondary structural motif comprising two orthogonally oriented beta-strands connected by short linking segments of <5 residues has been identified from a data set of 65 independent protein crystal structures. Of the 42 examples from 14 proteins, a vast majority have only a single residue as the linking element. Analysis of the conformational angles at the junction reveals that the recently described type VIII beta-turn occurs frequently at the connecting hinge, while the type II beta-turn is also fairly common.

Gene therapy: Principles, practice, problems and prospects

The remarkable advances made in recombinant DNA technology over the last two decades have paved way for the use of gene transfer to treat human diseases. Several protocols have been developed for the introduction and expression of genes in humans, but the clinical efficacy has not been conclusively demonstrated in any of them. The eventual success of gene therapy for genetic and acquired disorders depends on the development of better gene transfer vectors for sustained, long term expression of foreign genes as well as a better understanding of the pathophysiology of human diseases, it is heartening to note that some of the gene therapy protocols have found other applications such as the genetic immunization or DNA vaccines, which is being heralded as the third vaccine revolution, Gene therapy is yet to become a dream come true, but the light is seen at the end of the tunnel.

Identification and functional characterization of a cis-acting positive DNA element regulating CYP 2B1/B2 gene transcription in rat liver

A positive cis-acting DNA element in the near 5'-upstream region of the CYP2B1/B2 genes in rat liver was found to play an important role in the transcription of these genes. An oligonucleotide covering -69 to -98 nt mimicked the gel mobility shift pattern given by the fragment -179 to +29 nt, which was earlier found adequate to confer the regulatory features of this gene. Two major complexes were seen, of which the slower and faster moving complexes became intense under uninduced and Phenobarbitone-induced conditions respectively. Minigene cloned DNA plasmid covering -179 to +181 nt in pUC 19 and Bal 31 mutants derived from this parent were transcribed in whole nuclei and cell free transcription extracts and mutants containing only upto -75 nt of the upstream were poorly transcribed. Transcription extracts from phenobarbitone-injected rat liver nuclei were significantly more active than extracts from uninduced rats in transcribing the minigene constructs. Addition of the oligonucleotide (-69 to -98nt) specifically inhibited the transcription of the minigene construct (-179 to +181 nt) in the cell free transcription system. It is therefore, concluded that the region -69 to -98 nt acts as a positive cis-acting element in the transcription of the CYP2B1/B2 genes and in mediating the inductive effects of phenobarbitone.

Bustle behind the scenes of action : nemosis as a model for fibroblast inflammatory activation

Wound healing is a complex process that requires an interplay between several cell types. Classically, fibroblasts have been viewed as producers of extracellular matrix, but more recently they have been recognized as orchestrators of the healing response, promoting and directing, inflammation and neovascularization processes. Compared to those from healthy tissue, inflammation-associated fibroblasts display a dramatically altered phenotype and have been described as sentinel cells, able to switch to an immunoregulatory profile on cue. However, the activation mechanism still remains largely uncharacterized. Nemosis is a model for stromal fibroblast activation. When normal human primary fibroblasts are deprived of growth support they cluster, forming multicellular spheroids. Clustering results in upregulation of proinflammatory markers such as cyclooxygenase-2 and secretion of prostaglandins, proteinases, cytokines, and growth factors. Fibroblasts in nemosis induce wound healing and tumorigenic responses in many cell types found in inflammatory and tumor microenvironments. This study investigated the effect of nemotic fibroblasts on two components of the vascular system, leukocytes and endothelium, and characterized the inflammation-promoting responses that arose in these cell types. Fibroblasts in nemosis were found to secrete an array of chemotactic cytokines and attract leukocytes, as well as promote their adhesion to the endothelium. Nuclear factor-kB, the master regulator of many inflammatory responses, is activated in nemotic fibroblasts. Nemotic fibroblasts are known to produce large amounts of hepatocyte growth factor, a motogenic and angiogenic factor. Also, as shown in this study, they produce vascular endothelial growth factor. These two factors induced migratory and sprouting responses in endothelial cells, both required for neovascularization. Nemotic fibroblasts also caused a decrease in the expression of adherens and tight junction components on the surface of endothelial cells. The results allow the conclusion that fibroblasts in nemosis share many similarities with inflammation-associated fibroblasts. Both inflammation and stromal fibroblasts are known to be involved in tumorigenesis and tumor progression. Nemosis may be viewed as a model for stromal fibroblast activation, or it may correlate with cell-cell interactions between adjacent fibroblasts in vivo. Nevertheless, due to nemosis-derived production of proinflammatory cytokines and growth factors, fibroblast nemosis may have therapeutic potential as an inducer of controlled tissue repair. Knowledge of stromal fibroblast activation gained through studies of nemosis, could provide new strategies to control unwanted inflammation and tumor progression.

Molecular epidemiology of human rhinoviruses

The first part of this work investigates the molecular epidemiology of a human enterovirus (HEV), echovirus 30 (E-30). This project is part of a series of studies performed in our research team analyzing the molecular epidemiology of HEV-B viruses. A total of 129 virus strains had been isolated in different parts of Europe. The sequence analysis was performed in three different genomic regions: 420 nucleotides (nt) in the VP4/VP2 capsid protein coding region, the entire VP1 capsid protein coding gene of 876 nt, and 150 nt in the VP1/2A junction region. The analysis revealed a succession of dominant sublineages within a major genotype. The temporally earlier genotypes had been replaced by a genetically homogenous lineage that has been circulating in Europe since the late 1970s. The same genotype was found by other research groups in North America and Australia. Globally, other cocirculating genetic lineages also exist. The prevalence of a dominant genotype makes E-30 different from other previously studied HEVs, such as polioviruses and coxsackieviruses B4 and B5, for which several coexisting genetic lineages have been reported. The second part of this work deals with molecular epidemiology of human rhinoviruses (HRVs). A total of 61 field isolates were studied in the 420-nt stretch in the capsid coding region of VP4/VP2. The isolates were collected from children under two years of age in Tampere, Finland. Sequences from the clinical isolates clustered in the two previously known phylogenetic clades. Seasonal clustering was found. Also, several distinct serotype-like clusters were found to co-circulate during the same epidemic season. Reappearance of a cluster after disappearing for a season was observed. The molecular epidemiology of the analyzed strains turned out to be complex, and we decided to continue our studies of HRV. Only five previously published complete genome sequences of HRV prototype strains were available for analysis. Therefore, all designated HRV prototype strains (n=102) were sequenced in the VP4/VP2 region, and the possibility of genetic typing of HRV was evaluated. Seventy-six of the 102 prototype strains clustered in HRV genetic group A (HRV-A) and 25 in group B (HRV-B). Serotype 87 clustered separately from other HRVs with HEV species D. The field strains of HRV represented as many as 19 different genotypes, as judged with an approximate demarcation of a 20% nt difference in the VP4/VP2 region. The interserotypic differences of HRV were generally similar to those reported between different HEV serotypes (i.e. about 20%), but smaller differences, less than 10%, were also observed. Because some HRV serotypes are genetically so closely related, we suggest that the genetic typing be performed using the criterion "the closest prototype strain". This study is the first systematic genetic characterization of all known HRV prototype strains, providing a further taxonomic proposal for classification of HRV. We proposed to divide the genus Human rhinoviruses into HRV-A and HRV-B. The final part of the work comprises a phylogenetic analysis of a subset (48) of HRV prototype strains and field isolates (12) in the nonstructural part of the genome coding for the RNA-dependent RNA polymerase (3D). The proposed division of the HRV strains in the species HRV-A and HRV-B was also supported by 3D region. HRV-B clustered closer to HEV species B, C, and also to polioviruses than to HRV-A. Intraspecies variation within both HRV-A and HRV-B was greater in the 3D coding region than in the VP4/VP2 coding region, in contrast to HEV. Moreover, the diversity of HRV in 3D exceeded that of HEV. One group of HRV-A, designated HRV-A', formed a separate cluster outside other HRV-A in the 3D region. It formed a cluster also in the capsid region, but located within HRV-A. This may reflect a different evolutionary history of distinct genomic regions among HRV-A. Furthermore, the tree topology within HRV-A in the 3D region differed from that in the VP4/VP2, suggesting possible recombination events in the evolution of the strains. No conflicting phylogenies were observed in any of the 12 field isolates. Possible recombination was further studied using the Similarity and Bootscanning analyses of the complete genome sequences of HRV available in public databases. Evidence for recombination among HRV-A was found, as HRV2 and HRV39 showed higher similarity in the nonstructural part of the genome. Whether HRV2 and HRV39 strains - and perhaps also some other HRV-A strains not yet completely sequenced - are recombinants remains to be determined.

Reducing luminance contrast on the window wall and users’ interventions in an office room

High luminance contrast between windows and surrounding surfaces could cause discomfort glare, which could reduce office workers’ productivity. It might also increase energy usage of buildings due to occupants’ interventions in lighting conditions to improve indoor visual quality. It is presumed that increasing the luminance of the areas surrounding the windows using a supplementary system, such Light Emitting Diodes (LEDs), could reduce discomfort glare. This paper reports on the results of a pilot study in a conventional office in Brisbane, Australia. The outcomes of this study indicated that a supplementary LED system could reduce the luminance contrast on the window wall from values in the order of 24:1 to 12:1. The results suggest that this reduction could significantly reduce discomfort glare from windows, as well as diminishing the likelihood of users’ intention to turn on the ceiling lights and/ or to move the blind down.

Diffusion and Creep in Silica-Doped Tetragonal Zirconia

Silica segregation at two grain junctions or in amorphous triple junction pockets can influence creep by altering the grain-boundary diffusion coefficient. Although the addition of silica to superplastic yttria-stabilized tetragonal zirconia enhances ductility, differences in reported creep parameters have limited critical identification of rate controlling mechanisms. The present study on a pure 3 mol% yttria-stabilized tetragonal zirconia (3YTZ) and 3YTZ with 0.39 or 3.9 wt% silica involved a detailed characterization of creep over a wide range of experimental conditions and also tracer diffusion measurements. The data broadly show transitions in creep stress exponents from n∼1 to ∼2 to ∼3 with a decrease in the stress. The data at high stresses are consistent with Coble diffusion creep, and creep at lower stresses is attributed to interface-controlled diffusion creep. Measurements indicated that silica does not have any significant influence on grain boundary or lattice diffusion, and this is consistent with the observation that 3YTZ and 3YTZ with 0.39% or 3.9% silica exhibit essentially identical creep behavior in the Coble creep regime. Silica influences the interface control process so that the transitions in stress exponents are pushed to lower stresses with an increase in silica content.

Evaluation of regional and distant metastases in head and neck squamous cell carcinoma patients with special reference to the assessment of regional lymph nodes in oral cancer

For optimal treatment planning, a thorough assessment of the metastatic status of mucosal squamous cell carcinoma of the head and neck (HNSCC) is required. Current imaging methods do not allow the recognition of all patients with metastatic disease. Therefore, elective treatment of the cervical lymph nodes is usually given to patients in whom the risk of subclinical metastasis is estimated to exceed 15-20%. The objective of this study was to improve the pre-treatment evaluation of patients diagnosed with HNSCC. Particularly, we aimed at improving the identification of patients who will benefit from elective neck treatment. Computed tomography (CT) of the chest and abdomen was performed prospectively for 100 patients diagnosed with HNSCC. The findings were analysed to clarify the indications for this examination in this patient group. CT of the chest influenced the treatment approach in 3% of patients, while CT of the abdomen did not reveal any significant findings. Our results suggest that CT of the chest and abdomen is not indicated routinely for patients with newly diagnosed HNSCC but can be considered in selected cases. Retrospective analysis of 80 patients treated for early stage squamous cell carcinoma of the oral tongue was performed to investigate the potential benefits of elective neck treatment and to examine whether histopathological features of the primary tumour could be used in the prediction of occult metastases, local recurrence, or/and poor survival. Patients who had received elective neck treatment had significantly fewer cervical recurrences during the follow-up when compared to those who only had close observation of the cervical lymph nodes. Elective neck treatment did not result in survival benefit, however. Of the histopathological parameters examined, depth of infiltration and pT-category (representing tumour diameter) predicted occult cervical metastasis, but only the pT-category predicted local recurrence. Depth of infiltration can be used in the identification of at risk patients but no clear cut-off value separating high-risk and low-risk patients was found. None of the histopathological parameters examined predicted survival. Sentinel lymph node (SLN) biopsy was studied as a means of diagnosing patients with subclinical cervical metastases. SLN biopsy was applied to 46 patients who underwent elective neck dissection for oral squamous cell carcinoma. In addition, SLN biopsy was applied to 13 patients with small oral cavity tumours who were not intended to undergo elective neck dissection because of low risk of occult metastasis. The sensitivity of SLN biopsy for finding subclinical cervical metastases was found to be 67%, when SLN status was compared to the metastatic status of the rest of the neck dissection specimen. Of the patients not planned to have elective neck dissection, SLN biopsy revealed cervical metastasis in 15% of the patients. Our results suggest that SLN biopsy can not yet entirely replace elective neck dissection in the treatment of oral cancer, but it seems beneficial for patients with low risk of metastasis who are not intended for elective neck treatment according to current treatment protocols.

Prevalence of foot disease and risk factors in general inpatient populations: A systematic review and meta-analysis

Objective: To systematically review studies reporting the prevalence in general adult inpatient populations of foot disease disorders (foot wounds, foot infections, collective ‘foot disease’) and risk factors (peripheral arterial disease (PAD), peripheral neuropathy (PN), foot deformity). Methods: A systematic review of studies published between 1980 and 2013 was undertaken using electronic databases (MEDLINE, EMBASE and CINAHL). Keywords and synonyms relating to prevalence, inpatients, foot disease disorders and risk factors were used. Studies reporting foot disease or risk factor prevalence data in general inpatient populations were included. Included study's reference lists and citations were searched and experts consulted to identify additional relevant studies. 2 authors, blinded to each other, assessed the methodological quality of included studies. Applicable data were extracted by 1 author and checked by a second author. Prevalence proportions and SEs were calculated for all included studies. Pooled prevalence estimates were calculated using random-effects models where 3 eligible studies were available. Results: Of the 4972 studies initially identified, 78 studies reporting 84 different cohorts (total 60 231 517 participants) were included. Foot disease prevalence included: foot wounds 0.01–13.5% (70 cohorts), foot infections 0.05–6.4% (7 cohorts), collective foot disease 0.2–11.9% (12 cohorts). Risk factor prevalence included: PAD 0.01–36.0% (10 cohorts), PN 0.003–2.8% (6 cohorts), foot deformity was not reported. Pooled prevalence estimates were only able to be calculated for pressure ulcer-related foot wounds 4.6% (95% CI 3.7% to 5.4%)), diabetes-related foot wounds 2.4% (1.5% to 3.4%), diabetes-related foot infections 3.4% (0.2% to 6.5%), diabetes-related foot disease 4.7% (0.3% to 9.2%). Heterogeneity was high in all pooled estimates (I2=94.2–97.8%, p<0.001). Conclusions: This review found high heterogeneity, yet suggests foot disease was present in 1 in every 20 inpatients and a major risk factor in 1 in 3 inpatients. These findings are likely an underestimate and more robust studies are required to provide more precise estimates.

How many inpatients in our hospitals have foot complications? The foot disease in inpatients study

Background Foot complications have been found to affect large proportions of hospital in patients with diabetes. However, no studies have investigated the proportion of foot complications affecting all people in general inpatient populations. The aims of this cross-sectional study were to investigate the point-prevalence of different foot complications in general inpatient populations, analyse differences in diabetes and non-diabetes sub-groups, and examine characteristics of people primarily admitted for a foot complication. Methods Eligible participants were all adults admitted overnight, for any reason, into five diverse hospitals on one day; excluding maternity, mental health and cognitively impaired patients. All participants underwent a physical foot examination, by trained podiatrists using validated measures, to clinically diagnose different foot complications; including foot wounds, infections, deformity, peripheral arterial disease (PAD) and peripheral neuropathy (PN). Data were also collected on participants' primary reason for admission and a range of demographic, social determinant, medical history, foot complication history, self-care and footwear risk factors. Results Overall, 733 participants consented (83% of eligible participants); mean(±SD) age 62(±19) years, 480 (55.8%) male and 172 (23.5%) had diabetes. Foot complication prevalence included: wounds 9.0% (95% CI) (5.1-8.7), infections 3.3% (2.2-4.9), deformity 22.4% (19.5-26.7), PAD 21.0% (18.2-24.1) and PN 22.0% (19.1-25.1). Diabetes populations had significantly more foot complications than non-diabetes (p < 0.01); wounds (15.7% vs 7.0%), infections (7.1% vs 2.2%), deformity (30.5% vs 19.9%), PAD (35.1% vs 16.7%) and PN (43.3% vs 15.4%). Foot complications were the primary reason for admission in 7.4% (95% CI) (5.7-9.5) of all participants. In a backwards stepwise multivariate analysis having a foot complication as the primary reason for admission was independently associated (OR (95% CI) with foot wounds (18.9 (7.3-48.7)), foot infections (6.0 (1.6-22.4)), history of amputation (4.7 (1.3-17.0) and PAD (2.9 (1.3-6.6)). Conclusions Findings of this study indicate one in every ten hospital inpatients had an active foot wound or infection. In patients with diabetes had significantly higher proportions of foot complications than non-diabetes inpatients. Remarkably one in every thirteen inpatients in this study were primarily hospitalised for a foot complication. Further research and policy is required to tackle this seemingly large inpatient foot complication burden.

Neuromagnetic studies on cortical somatosensory functions in infants and children : Normal development and effect of early brain lesions

Until recently, objective investigation of the functional development of the human brain in vivo was challenged by the lack of noninvasive research methods. Consequently, fairly little is known about cortical processing of sensory information even in healthy infants and children. Furthermore, mechanisms by which early brain insults affect brain development and function are poorly understood. In this thesis, we used magnetoencephalography (MEG) to investigate development of cortical somatosensory functions in healthy infants, very premature infants at risk for neurological disorders, and adolescents with hemiplegic cerebral palsy (CP). In newborns, stimulation of the hand activated both the contralateral primary (SIc) and secondary somatosensory cortices (SIIc). The activation patterns differed from those of adults, however. Some of the earliest SIc responses, constantly present in adults, were completely lacking in newborns and the effect of sleep stage on SIIc responses differed. These discrepancies between newborns and adults reflect the still developmental stage of the newborns’ somatosensory system. Its further maturation was demonstrated by a systematic transformation of the SIc response pattern with age. The main early adult­like components were present by age two. In very preterm infants, at term age, the SIc and SIIc were activated at similar latencies as in healthy fullterm newborns, but the SIc activity was weaker in the preterm group. The SIIc response was absent in four out of the six infants with brain lesions of the underlying hemisphere. Determining the prognostic value of this finding remains a subject for future studies, however. In the CP adolescents with pure subcortical lesions, contrasting their unilateral symptoms, the SIc responses of both hemispheres differed from those of controls: For example the distance between SIc representation areas for digits II and V was shorter bilaterally. In four of the five CP patients with cortico­subcortical brain lesions, no normal early SIc responses were evoked by stimulation of the palsied hand. The varying differences in neuronal functions, underlying the common clinical symptoms, call for investigation of more precisely designed rehabilitation strategies resting on knowledge about individual functional alterations in the sensorimotor networks.

Highly efficient spin-conversion effect leading to energy up-converted electroluminescence in singlet fission photovoltaics

Free charge generation in donor-acceptor (D-A) based organic photovoltaic diodes (OPV) progresses through formation of charge-transfer (CT) and charge-separated (CS) states and excitation decay to the triplet level is considered as a terminal loss. On the other hand a direct excitation decay to the triplet state is beneficial for multiexciton harvesting in singlet fission photovoltaics (SF-PV) and the formation of CT-state is considered as a limiting factor for multiple triplet harvesting. These two extremes when present in a D-A system are expected to provide important insights into the mechanism of free charge generation and spin-character of bimolecular recombination in OPVs. Herein, we present the complete cycle of events linked to spin conversion in the model OPV system of rubrene/C60. By tracking the spectral evolution of photocurrent generation at short-circuit and close to open-circuit conditions we are able to capture spectral changes to photocurrent that reveal the triplet character of CT-state. Furthermore, we unveil an energy up-conversion effect that sets in as a consequence of triplet population build-up where triplet-triplet annihilation (TTA) process effectively regenerates the singlet excitation. This detailed balance is shown to enable a rare event of photon emission just above the open-circuit voltage (VOC) in OPVs.

Tuning the Conductance of Dirac Fermions on the Surface of a Topological Insulator

We study the transport properties of the Dirac fermions with a Fermi velocity v(F) on the surface of a topological insulator across a ferromagnetic strip providing an exchange field J over a region of width d. We show that the conductance of such a junction, in the clean limit and at low temperature, changes from oscillatory to a monotonically decreasing function of d beyond a critical J. This leads to the possible realization of a magnetic switch using these junctions. We also study the conductance of these Dirac fermions across a potential barrier of width d and potential V-0 in the presence of such a ferromagnetic strip and show that beyond a critical J, the criteria of conductance maxima changes from chi = eV(0)d/(h) over barv(F) = n pi to chi = (n + 1/2)pi for integer n. We point out that these novel phenomena have no analogs in graphene and suggest experiments which can probe them.

Shift of peak in summer monsoon rainfall over Korea and its association with El Nino-Southern Oscillation

The annual cycle of rainfall over the Korean Peninsula is marked by two peaks: one during July and the other during August. Since the mid-1970s, the maximum rainfall over the Korean Peninsula has shifted from July to August. This shift in rainfall peak was caused by a significant increase of August rainfall after the mid-1970s. The basic reason for this shift has been traced to a change in teleconnection between El Nino-Southern Oscillation (ENSO) and August rainfall. The relationship between August rainfall over Korea and ENSO changed from 1954-1975 (PI) to 1976-2002 (PII). The variability of August rainfall was significantly associated with sea surface temperature (SST) variation over the eastern equatorial Pacific during PI, but this relationship is absent during the PII period. In El Nino years during PI, low-level westerly and southerly wind anomalies are dominant around the East China Sea, which relates to strong August rainfall. In La Nina years during PI, easterly and northerly wind anomalies are dominant. During the PII period, however, westerly and southerly wind anomalies around the East China Sea were responsible for the high August rainfall over the East Asian region, even though La Nina SST conditions were in effect over the eastern Pacific.

Power dissipation for systems with junctions of multiple quantum wires

We study power dissipation for systems of multiple quantum wires meeting at a junction, in terms of a current splitting matrix (M) describing the junction. We present a unified framework for studying dissipation for wires with either interacting electrons (i.e., Tomonaga-Luttinger liquid wires with Fermi-liquid leads) or noninteracting electrons. We show that for a given matrix M, the eigenvalues of (MM)-M-T characterize the dissipation, and the eigenvectors identify the combinations of bias voltages which need to be applied to the different wires in order to maximize the dissipation associated with the junction. We use our analysis to propose and study some microscopic models of a dissipative junction which employ the edge states of a quantum Hall liquid. These models realize some specific forms of the M matrix whose entries depends on the tunneling amplitudes between the different edges.