Regulation of nuclear import and export of negative cofactor 2.
The negative cofactor 2 (NC2) is a protein complex composed of two subunits, NC2alpha and NC2beta, and plays a key role in transcription regulation. Here we investigate whether each subunit contains a nuclear localization signal (NLS) that permits individual crossing of the nuclear membrane or whether nuclear import of NC2alpha and NC2beta depends on heterodimerization. Our results from in vitro binding studies and transfection experiments in cultured cells show that each subunit contains a classical NLS (cNLS) that is recognized by the importin alpha/beta heterodimer. Regardless of the individual cNLSs the two NC2 subunits are translocated as a preassembled complex as co-transfection experiments with wild-type and cNLS-deficient NC2 subunits demonstrate. Ran-dependent binding of the nuclear export receptor Crm1/exportin 1 confirmed the presence of a leucine-rich nuclear export signal (NES) in NC2beta. In contrast, NC2alpha does not exhibit a NES. Our results from interspecies heterokaryon assays suggest that heterodimerization with NC2alpha masks the NES in NC2beta, which prevents nuclear export of the NC2 complex. A mutation in either one of the two cNLSs decreases the extent of importin alpha/beta-mediated nuclear import of the NC2 complex. In addition, the NC2 complex can enter the nucleus via a second pathway, facilitated by importin 13. Because importin 13 binds exclusively to the NC2 complex but not to the individual subunits this alternative import pathway depends on sequence elements distributed among the two subunits.


Vitamin D and retinoids in parathyroid glands (review).
Vitamin D and retinoids are important regulators of differentiation and proliferation in a number of tissues, and have been implicated as chemopreventive agents in several different tumors. While vitamin D is known to be important for regulation of parathyroid function and proliferation, it has recently been established that parathyroid cells also are targets for retinoids. Hyperparathyroidism (HPT) is a common disorder, and evaluation of the disease has indicated high prevalence of subclinical disease, as well as clear benefits of offering treatment for the disease. This review summarizes the data so far gathered concerning parathyroid cells, vitamin D and retinoids, with clear implication on prospects of possible medical treatment of hyperparathyroidism.


2D-pattern matching image and video compression: theory, algorithms, and experiments.
In this paper, we propose a lossy data compression framework based on an approximate two-dimensional (2D) pattern matching (2D-PMC) extension of the Lempel-Ziv (1977, 1978) lossless scheme. This framework forms the basis upon which higher level schemes relying on differential coding, frequency domain techniques, prediction, and other methods can be built. We apply our pattern matching framework to image and video compression and report on theoretical and experimental results. Theoretically, we show that the fixed database model used for video compression leads to suboptimal but computationally efficient performance. The compression ratio of this model is shown to tend to the generalized entropy. For image compression, we use a growing database model for which we provide an approximate analysis. The implementation of 2D-PMC is a challenging problem from the algorithmic point of view. We use a range of techniques and data structures such as k-d trees, generalized run length coding, adaptive arithmetic coding, and variable and adaptive maximum distortion level to achieve good compression ratios at high compression speeds. We demonstrate bit rates in the range of 0.25-0.5 bpp for high-quality images and data rates in the range of 0.15-0.5 Mbps for a baseline video compression scheme that does not use any prediction or interpolation. We also demonstrate that this asymmetric compression scheme is capable of extremely fast decompression making it particularly suitable for networked multimedia applications.


Population genetic structure of Taenia solium from Madagascar and Mexico: implications for clinical profile diversity and immunological technology.
Taenia solium is a cestode parasitic of humans and pigs that strongly impacts on public health in developing countries. Its larvae (cysticercus) lodge in the brain, causing neurocysticercosis, and in other tissues, like skeletal muscle and subcutaneous space, causing extraneuronal cysticercosis. Prevalences of these two clinical manifestations vary greatly among continents. Also, neurocysticercosis may be clinically heterogeneous, ranging from asymptomatic forms to severely incapacitating and even fatal presentation. Further, vaccine design and diagnosis technology have met with difficulties in sensitivity, specificity and reproducibility. Parasite diversity underlying clinical heterogeneity and technological difficulties is little explored. Here, T. solium genetic population structure and diversity was studied by way of random amplified polymorphic DNA in individual cysticerci collected from pigs in Madagascar and two regions in Mexico. The amplification profiles of T. solium were also compared with those of the murine cysticercus Taenia crassiceps (ORF strain). We show significant genetic differentiation between Madagascar and Mexico and between regions in Mexico, but less so between cysticerci from different localities in Mexico and none between cysticerci from different tissues from the same pig. We also found restricted genetic variability within populations and gene flow was estimated to be low between populations. Thus, genetic differentiation of T. solium suggests that different evolutionary paths have been taken and provides support for its involvement in the differential tissue distribution of cysticerci and varying degrees of severity of the disease. It may also explain difficulties in the development of vaccines and tools for immunodiagnosis.


Arterial stiffness in children with and without probable developmental coordination disorder.
Children with cardiovascular disease risk factors demonstrate adverse arterial alterations that are predictive of cardiovascular morbidity and mortality in adults. Children with developmental coordination disorder (DCD) are at cardiovascular risk as they are more likely to be obese and inactive. The purpose of this study was to assess arterial structure and function in children with and without probable DCD (p-DCD). A cross-sectional study of 33 children with p-DCD (22 male) and 53 without (30 male). The Movement Assessment Battery for Children was used to classify those with p-DCD. Adiposity was assessed using the BOD POD. Compliance, distensibility, and intima-media thickness were measured at the common carotid artery (CCA). ECG R-wave-to-toe pulse wave velocity (PWV) was also measured. Compared to controls, males with p-DCD had lower CCA distensibility (p=0.034) and higher PWV (p=0.001). No differences were evident in females. Body fat percent was a significant predictor of CCA distensibility and removed the effect of p-DCD on PWV in males. The present study demonstrates augmented arterial stiffness in males with p-DCD, likely attributed to body fat. These findings underscore the importance of targeted interventions in children with p-DCD, specifically males, in order to prevent future cardiovascular risk.


Myofibroblast involvement in glycosaminoglycan synthesis and lipid retention during coronary repair.
Myofibroblasts of adventitial origin have been linked to neointimal formation and remodeling after coronary injury. Accordingly, the goal of this study was to examine whether myofibroblasts contribute to focal accumulation of glycosaminoglycans (GAGs) and lipids during coronary repair. GAG synthesis was assessed by ex vivo labeling of balloon-injured porcine coronary arteries with (14)C-glucosamine. The synthesis of total GAGs transiently increased at 8 days in the normolipemic model (a 2.2-fold increase over baseline, p < 0.05). The majority of newly synthesized GAGs were sensitive to chondroitin ABC lyase (chondroitin/dermatan sulfate GAGs). Versican was localized to myofibroblast-rich regions in the adventitia and neointima [positive for alpha-smooth muscle (SM) actin, negative for h-caldesmon and SM myosin heavy chain]. In contrast, the adjacent SM-rich media showed no increase in versican expression. The association between injury-induced GAG accumulation and lipid retention was examined at 2 weeks after coronary injury in the hyperlipemic model. Lipid (Oil Red O) accumulated in the neointima and adventitia, but not in the adjacent media. Coronary repair under hyperlipemic conditions was associated with macrophage infiltration (19 +/- 5 vs. 3 +/- 2% of neointimal cells in normolipemic animals, p < 0.001) and increased neointimal formation (1.8 +/- 0.5 vs. 1.0 +/- 0.3 mm(2) in normolipemic animals, p < 0.01). In conclusion, this study demonstrated a transient increase in GAG synthesis following coronary injury. Chondroitin sulfate proteoglycans (e.g., versican) were rapidly synthesized by activated adventitial and neointimal cells which could contribute to early lipid retention in injured vessels.


GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction.
Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30-80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory-inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1(neo-/-) mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABA(B)-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.


Impulsive behavior and nicotinic acetylcholine receptors.
Higher impulsivity is thought to be a risk factor for drug addiction, criminal involvement, and suicide. Excessive levels of impulsivity are often observed in several psychiatric disorders including attention-deficit/hyperactivity disorder and schizophrenia. Previous studies have demonstrated that nicotinic acetylcholine receptors (nAChRs) are involved in impulsive behavior. Here, we introduce recent advances in this field and describe the role of the following nAChR-related brain mechanisms in modulating impulsive behavior: dopamine release in the ventral striatum; α4β2 nAChRs in the infralimbic cortex, which is a ventral part of the medial prefrontal cortex (mPFC); and dopamine release in the mPFC. We also suggest several potential therapeutic drugs to address these mechanisms in impulsivity-related disorders and explore future directions to further elucidate the roles of central nAChRs in impulsive behavior.


Nocardiopsis flavescens sp. nov., an actinomycete isolated from marine sediment.
A Gram-positive, aerobic bacterium, strain SA6(T), was isolated from marine sediment taken at a depth of 20 cm on the seashore of Lianyungang, Jiangsu Province, China. Strain SA6(T) contained meso-diaminopimelic acid, no diagnostic sugars, type PIII phospholipids, and MK-10(H(2)) and MK-10(H(4)) as the predominant menaquinones. The organism showed a range of chemical and morphological properties consistent with its classification in the genus Nocardiopsis. The almost-complete 16S rRNA gene sequence of strain SA6(T) was aligned with corresponding sequences of representatives of the genus Nocardiopsis and related taxa by using two tree-making algorithms. Strain SA6(T) formed a distinct phyletic line within the evolutionary radiation occupied by the genus Nocardiopsis and was related most closely to the type strain of Nocardiopsis lucentensis. Strain SA6(T) could be distinguished from its nearest phylogenetic relatives in the genus Nocardiopsis based on DNA-DNA relatedness data and a combination of phenotypic properties. Strain SA6(T) should therefore be assigned to the genus Nocardiopsis as a representative of a novel species, for which the name Nocardiopsis flavescens sp. nov. is proposed. The type strain is SA6(T) ( = CGMCC 4.5723(T) = JCM 17424(T)).


Exercise Enhances the Behavioral Responses to Acute Stress in an Animal Model of PTSD.
This study examined the effects of endurance exercise on the behavioral response to stress and patterns of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), and δ-opioid receptor (phospho-DOR) expression in the hippocampus. Animals ran on a treadmill at 15 m·min, 5 min·d gradually increasing to 20 min·d, 5 d·wk for 6 wk. After training, one group of animals was exposed to a predator scent stress (PSS) protocol for 10 min. Outcome measurements included behavior in an elevated plus-maze (EPM) and acoustic startle response (ASR) 7 d after exposure to stress. Immunohistochemical technique was used to detect the expression of the BDNF, NPY, and phospho-DOR in the hippocampus 8 d after exposure. Sedentary animals exposed to PSS were observed to have a greater incidence of extreme behavior responses including higher anxiety, less total activity in the EPM, and greater amplitude in the ASR than unexposed and/or trained animals. Exercise-trained animals exposed to PSS developed a resiliency to the stress, reflected by significantly greater total activity in the EPM, reduced anxiety, and reduced ASR compared to the sedentary, exposed animals. Exercise in the absence of stress significantly elevated the expression of BDNF and phospho-DOR, whereas exposure to PSS resulted in a significant decline in the expression of NPY, BDNF, and phospho-DOR. Trained animals that were exposed maintained expression of BDNF, NPY, and phospho-DOR in most subregions of the hippocampus. Results indicated that endurance training provided a mechanism to promote resilience and/or recovery from stress. In addition, exercise increased expression of BDNF, NPY, and DOR signaling in the hippocampus that was associated with the greater resiliency seen in the trained animals.


Markers of Atherosclerosis, Clinical Characteristics, and Treatment Patterns in Heart Failure: A Case-Control Study of Middle-Aged Adult Heart Failure Patients in Rural Kenya.
Although risk factors for heart failure are increasingly common worldwide, the contribution of atherosclerosis to heart failure in sub-Saharan Africa is largely unknown. This study assessed the association between atherosclerotic risk factors and heart failure in a developing country. We performed a case-control study of heart failure in rural Kenya. We assessed the risk factors for heart failure by using international criteria based on electrocardiogram (ECG), echocardiogram, physical examination findings, and laboratory testing. Atherosclerotic risk factors were determined by ECG, echocardiogram, ankle-brachial index (ABI), and lipid testing. We described the relationship of wall motion abnormalities on echocardiogram, ABI <0.9, and ischemic pattern on ECG with the presence of heart failure with multivariable logistic regression adjusting for age and sex and using adjusted odds ratios (AORs) and 95% confidence intervals (CIs). There were 125 cases and 191 controls (n = 316); 49% were male. The mean age was 60 (SD = 13) years. Most patients had hypertension (53%), and 16% had human immunodeficiency virus infection. Lipids were in the normal range for all. Cases were older than controls (62 years vs. 58 years, respectively). The most common abnormality associated with heart failure was dilated cardiomyopathy. Ischemic heart failure was the second most common cause in men. Cases were more likely to have an ABI <0.9 (46% vs. 31%; AOR: 1.99; 95% CI: 1.19 to 3.32), ischemia or infarct on ECG (68% vs. 43%; AOR: 3.01; 95% CI: 1.43 to 6.34), and wall motion abnormalities on echocardiogram (54% vs. 15%; AOR: 7.00; 95% CI: 3.95 to 12.39). Ischemic heart failure is more common in Kenya than previously recognized. Noninvasive markers of atherosclerosis are routinely found among patients with heart failure. Treatment and prevention of heart failure in sub-Saharan Africa must consider many causes including those related to atherosclerosis.


Surgical education and adult learning: Integrating theory into practice.
Surgical education continues to evolve from the master-apprentice model. Newer methods of the process need to be used to manage the dual challenges of educating while providing safe surgical care. This requires integrating adult learning concepts into delivery of practical training and education in busy clinical environments. A narrative review aimed at outlining and integrating adult learning and surgical education theory was undertaken. Additionally, this information was used to relate the practical delivery of surgical training and education in day-to-day surgical practice. Concepts were sourced from reference material. Additional material was found using a PubMed search of the words: 'surgical education theory' and 'adult learning theory medical'. This yielded 1351 abstracts, of which 43 articles with a focus on key concepts in adult education theory were used. Key papers were used to formulate structure and additional cross-referenced papers were included where appropriate. Current concepts within adult learning have a lot to offer when considering how to better deliver surgical education and training. Better integration of adult learning theory can be fruitful. Individual teaching surgical units need to rethink their paradigms and consider how each individual can contribute to the education experience. Up skilling courses for trainers can do much to improve the delivery of surgical education. Understanding adult learning concepts and integrating these into day-to-day teaching can be valuable.


Sight and switch off: Nerve density visualization for interventions targeting nerves in prostate cancer.
Nerve density is associated with prostate cancer (PCa) aggressiveness and prognosis. Thus far, no visualization methods have been developed to assess nerve density of PCa in vivo. We compounded propranolol-conjugated superparamagnetic iron oxide nerve peptide nanoparticles (PSN NPs), which achieved the nerve density visualization of PCa with high sensitivity and high specificity, and facilitated assessment of nerve density and aggressiveness of PCa using magnetic resonance imaging and magnetic particle imaging. Moreover, PSN NPs facilitated targeted therapy for PCa. PSN NPs increased the survival rate of mice with orthotopic PCa to 83.3% and decreased nerve densities and proliferation indexes by more than twofold compared with the control groups. The present study, thus, developed a technology to visualize the nerve density of PCa and facilitate targeted neural drug delivery to tumors to efficiently inhibit PCa progression. Our study provides a potential basis for clinical imaging and therapeutic interventions targeting nerves in PCa.


[Suspected autoimmune coagulation factor IX deficiency difficult to diagnose due to concurrent lupus anticoagulant].
A woman in her 70s who was undergoing treatment for an overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis developed persistent genital bleeding. Coagulation tests revealed a longer activated partial thromboplastin time, a 7% decrease in coagulation factor IX activity (FIX:C) and a FIX inhibitor (of 3 BU/ml). Lupus anticoagulant (LA), anticardiolipin antibody, and anti-β2 glycoprotein I antibody were positive, and the activated partial thromboplastin time cross-mixing test suggested the presence of LA. Additionally, all intrinsic coagulation factors decreased, but activity of all factors except FIX showed dilution linearity, which suggested a false decrease in activity due to LA. Although definitive diagnosis was difficult due to concurrent LA, this case was strongly suspected to be autoimmune coagulation FIX deficiency complicated by LA. Bypass therapy was not performed because the patient had no anemia and was positive for LA, and immunosuppressive therapy with prednisolone was initiated immediately. Eleven weeks after diagnosis, FIX:C was 41% and zFIX inhibitor was less than 1 BU/ml, leading to remission.


Putative tyrosine kinases expressed in K-562 human leukemia cells.
Tyrosine phosphorylation is important in the transmission of growth and differentiation signals; known tyrosine kinases include several oncoproteins and growth factor receptors. Interestingly, some differentiated cell types, such as erythrocytes and platelets contain high amounts of phosphotyrosine. We analyzed tyrosine kinases expressed in the K-562 chronic myelogenous leukemia cell line, which has a bipotential erythroid and megakaryoblastoid differentiation capacity. Analysis of 359 polymerase chain reaction-amplified cDNA clones led to the identification of 14 different tyrosine kinase-related sequences (JTK1-14). Two of the clones (JTK2 and JTK4) represent unusual members of the fibroblast growth factor receptor gene family, and the clones JTK5, JTK11, and JTK14 may also belong to the family of receptor tyrosine kinases but lack a close relationship to any known tyrosine kinase. Each of these different genes has its own characteristic expression pattern in K-562 cells and several other human tumor cell lines. In addition, the JTK11 and JTK14 mRNAs are induced during the megakaryoblastoid differentiation of K-562 cells. These tyrosine kinases may have a role in the differentiation of megakaryoblasts or in the physiology of platelets.


R-spondin 3 regulates dorsoventral and anteroposterior patterning by antagonizing Wnt/β-catenin signaling in zebrafish embryos.
The Wnt/β-catenin or canonical Wnt signaling pathway plays fundamental roles in early development and in maintaining adult tissue homeostasis. R-spondin 3 (Rspo3) is a secreted protein that has been implicated in activating the Wnt/β-catenin signaling in amphibians and mammals. Here we report that zebrafish Rspo3 plays a negative role in regulating the zygotic Wnt/β-catenin signaling. Zebrafish Rspo3 has a unique domain structure. It contains a third furin-like (FU3) domain. This FU3 is present in other four ray-finned fish species studied but not in elephant shark. In zebrafish, rspo3 mRNA is maternally deposited and has a ubiquitous expression in early embryonic stages. After 12 hpf, its expression becomes tissue-specific. Forced expression of rspo3 promotes dorsoanterior patterning and increases the expression of dorsal and anterior marker genes. Knockdown of rspo3 increases ventral-posterior development and stimulates ventral and posterior marker genes expression. Forced expression of rspo3 abolishes exogenous Wnt3a action and reduces the endogenous Wnt signaling activity. Knockdown of rspo3 results in increased Wnt/β-catenin signaling activity. Further analyses indicate that Rspo3 does not promote maternal Wnt signaling. Human RSPO3 has similar action when tested in zebrafish embryos. These results suggest that Rspo3 regulates dorsoventral and anteroposterior patterning by negatively regulating the zygotic Wnt/β-catenin signaling in zebrafish embryos.


Differential Regulation of Human Surfactant Protein A Genes, SFTPA1 and SFTPA2, and Their Corresponding Variants.
The human SFTPA1 and SFTPA2 genes encode the surfactant protein A1 (SP-A1) and SP-A2, respectively, and they have been identified with significant genetic and epigenetic variability including sequence, deletion/insertions, and splice variants. The surfactant proteins, SP-A1 and SP-A2, and their corresponding variants play important roles in several processes of innate immunity as well in surfactant-related functions as reviewed elsewhere [1]. The levels of SP-A have been shown to differ among individuals both under baseline conditions and in response to various agents or disease states. Moreover, a number of agents have been shown to differentially regulate SFTPA1 and SFTPA2 transcripts. The focus in this review is on the differential regulation of SFTPA1 and SFTPA2 with primary focus on the role of 5' and 3' untranslated regions (UTRs) and flanking sequences on this differential regulation as well molecules that may mediate the differential regulation.


Calcium requirements for Asian children and adolescents.
Calcium is important for bone health. Over the last 15 years, reference calcium intakes in Western countries have been revised upwards for maximizing bone mass at skeletal maturity and for prevention of osteoporotic fractures. Some of these reference figures have also been adopted for use in Asian countries. However, the scientific data based on for revising reference calcium intakes in the West was largely based on Caucasians. Limited human studies relating to calcium requirements and bone mineralization have been conducted in Asians in Asia. In children and adolescents, a trial has confirmed no effects of calcium supplementation on bone gains in adolescent girls after 7 years. A meta-analysis has also revealed that calcium supplementation has little beneficial effects on bone gain. Given that genetic factors, hormonal status, body size, bone structure, diets, physical activity, vitamin D status and adaptation could modify calcium retention and bone integrity, these factors need to be considered collectively to promote bone health in Asian populations. Furthermore, studies to identify indigenous foods rich in calcium and high in bioavailability are needed to widen sources of dietary calcium. Ethnic differences in calcium retention, hormonal status, bone structure, bone mineral accretion and peak bone mass are evident among Asians, Caucasians and Blacks in USA. Hence, reference calcium intakes for Asians are likely to be unique and different from those of Caucasians. More research has to be conducted in Asian populations in order to develop appropriate reference calcium intakes for the region.


Development of a Questionnaire to Determine Incidence and Attitudes to "Voluntary Stopping of Eating and Drinking".
"Voluntary stopping of eating and drinking" (VSED) is an option to hasten death at the end of life. There are no data available about incidence of either the explicit VSED or implicit (V)SED nor information about experiences and attitudes of health professionals about VSED in Switzerland. To develop, test, and translate a standardized questionnaire that measures the incidence of VSED, and physicians' and nurses' experiences about explicit VSED and implicit (V)SED. The development of the questionnaire was based on a systematic search, which were updated in 2016. The questionnaire was tested by palliative care specialists using standard pretest and content validity index (CVI). Subsequently, a forward/backward translation was made. The questionnaire includes 38 items. Feedback of 15 participants in the standard pretest were positive in terms of intelligibility with an average time of 28 minutes. After adjustment, 27 experts validated the items in two rounds. The questionnaire achieves excellent item-CVI values between 0.91 and 1.00 and scale-CVI values of 0.97. The forward/backward translations were each carried out by two independent translators with subsequent building of a consensus through a consultant. A mulitlingual questionnaire has been developed, which measures the incidence of explicit VSED and implicit (V)SED. This questionnaire is the basis for a Swiss-wide census of all physicians and nurses of outpatient and long-term care.


Decline in Antigenicity of Tumor Markers by Storage Time Using Pathology Sections Cut From Tissue Microarrays.
Sectioning a whole tissue microarrray (TMA block) and storing the sections maximizes the number of sections obtained, but may impair the antigenicity of the stored sections. We have investigated the impact of TMA section storage on antigenicity. First, we reexamined existing TMA data to determine whether antigenicity in stored sections changes over time. Component scores for each marker, based on cellular compartment of staining and score-type, were evaluated separately. Residual components scores adjusted for grade, tumor size, and node positivity, were regressed on the number of days storage to evaluate the effect of storage time. Storage time ranged from 2 to 1897 days, and the mean change in antigenicity per year ranged from -0.88 (95% confidence interval, -1.11 to -0.65) to 0.035 (95% confidence interval, 0.016-0.054). Further analysis showed no significant improvement in the fit of survival models if storage time adjusted scores were included in the models rather than unadjusted scores. We then compared 3 ways of processing TMA sections after cutting-immediate staining, staining after 1 year, and staining after 1 year coated in wax-on the immunohistochemistry results for: progesterone receptor, a routinely used, robust antibody, and MKI67, which is generally considered less robust. The progesterone receptor scores for stored sections were similar to those for unstored sections, whereas the MKI67 scores for stored sections were substantially different to those for unstored sections. Wax coating made little difference to the results. Biomarker antigenicity shows a small decline over time that is unlikely to have an important effect on studies of prognostic biomarkers.


Tamper-Resistant Mobile Health Using Blockchain Technology.
Digital health technologies, including telemedicine, mobile health (mHealth), and remote monitoring, are playing a greater role in medical practice. Safe and accurate management of medical information leads to the advancement of digital health, which in turn results in a number of beneficial effects. Furthermore, mHealth can help lower costs by facilitating the delivery of care and connecting people to their health care providers. Mobile apps help empower patients and health care providers to proactively address medical conditions through near real-time monitoring and treatment, regardless of the location of the patient or the health care provider. Additionally, mHealth data are stored in servers, and consequently, data management that prevents all forms of manipulation is crucial for both medical practice and clinical trials. The aim of this study was to develop and evaluate a tamper-resistant mHealth system using blockchain technology, which enables trusted and auditable computing using a decentralized network. We developed an mHealth system for cognitive behavioral therapy for insomnia using a smartphone app. The volunteer data collected with the app were stored in JavaScript Object Notation format and sent to the blockchain network. Thereafter, we evaluated the tamper resistance of the data against the inconsistencies caused by artificial faults. Electronic medical records collected using smartphones were successfully sent to a private Hyperledger Fabric blockchain network. We verified the data update process under conditions where all the validating peers were running normally. The mHealth data were successfully updated under network faults. We further ensured that any electronic health record registered to the blockchain network was resistant to tampering and revision. The mHealth data update was compatible with tamper resistance in the blockchain network. Blockchain serves as a tamperproof system for mHealth. Combining mHealth with blockchain technology may provide a novel solution that enables both accessibility and data transparency without a third party such as a contract research organization.


Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values.
Liver stiffness measurement (LSM) frequently overestimates the severity of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Controlled attenuation parameter (CAP) is a new parameter provided by the same machine used for LSM and associated with both steatosis and body mass index, the two factors mostly affecting LSM performance in NAFLD. We aimed to determine whether prediction of liver fibrosis by LSM in NAFLD patients is affected by CAP values. Patients (n = 324) were assessed by clinical and histological (Kleiner score) features. LSM and CAP were performed using the M probe. CAP values were grouped by tertiles (lower 132-298, middle 299-338, higher 339-400 dB/m). Among patients with F0-F2 fibrosis, mean LSM values, expressed in kilopascals, increased according to CAP tertiles (6.8 versus 8.6 versus 9.4, P = 0.001), and along this line the area under the curve of LSM for the diagnosis of F3-F4 fibrosis was progressively reduced from lower to middle and further to higher CAP tertiles (0.915, 0.848-0.982; 0.830, 0.753-0.908; 0.806, 0.723-0.890). As a consequence, in subjects with F0-F2 fibrosis, the rates of false-positive LSM results for F3-F4 fibrosis increased according to CAP tertiles (7.2% in lower versus 16.6% in middle versus 18.1% in higher). Consistent with this, a decisional flowchart for predicting fibrosis was suggested by combining both LSM and CAP values. In patients with NAFLD, CAP values should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography. (Hepatology 2017;65:1145-1155).


Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.


Mutations in K-ras and epidermal growth factor receptor expression in Korean patients with stages III and IV colorectal cancer.
K-Ras somatic mutations in advanced colorectal cancer (CRC) can predict resistance to mAbs that target the epidermal growth factor receptor (EGFR). The relationships between K-ras mutations and the EGFR status have not yet been examined, especially in Korean patients. A total of 82 colorectal tumors (stage III-IV) were analyzed. K-Ras mutations at codons 12 and 13 were detected by polymerase chain reaction-single strand conformational polymorphism. The EGFR expressions were examined by immunohistochemistry, and these were graded according to a modified EGFR expression scoring system. The relationships between the patients' characteristics and the survival time and the gene mutation status were analyzed. The EGFR expression was positive in 69 patients (84.1%) and negative in 13 patients (15.9%). The K-ras mutation rate was 35.4%. In all, 20 (68.9%) cases were mutated at codon 12 and 9 (31.1%) cases were mutated at codon 13. No relationship was observed between the EGFR status and K-ras mutation. The median overall survival (OS) was 68.1 months. There was no difference between the K-ras mutant group and the wild type group for overall survival (30.3% vs 21.0%, respectively, at 36 months, P = .777). K-ras mutation and the EGFR status were not independent prognostic factors for OS (P = .105 and P = .499, respectively). For the Korean patients with CRC, the rate of an EGFR protein expression was greater than that for the patients in Western countries, and the rate of K-ras mutations was lower than that for patients in Western countries. This study found no correlation between the EGFR status and K-ras mutations in colorectal tumors.


Secretion of lysosomal enzymes induced by immune complexes and complement.
Immune complexes react with neutrophils and macrophages by way of surface membrane Fc receptors. Alternatively, after fixation of complement, interaction may be with membrane C3b receptors. As a result, phagocytosis is induced. A consequence of this process is the liberation to the extracellular medium of lysosomal constituents. In neutrophils, fusion of granules with phagocytic vacuoles liberates the contents to the outside because some of the vacuoles, for various reasons, are inefficiently closed off. Alternatively, reaction of neutrophils in vitro or in vivo with immune complexes and/or activated complement components (C3b, C3a, C5a, C567) on surfaces too large to be phagocytosed, induces direct exocytosis of granules with consequent release of constituents. In both cases the liberation of lysosomal constituents is a secretory process, does not involve cell lysis, and resembles closely the secretory reactions of other widely differing cell types.


The chiropractic consultation: a stressful experience?
Psychosocial stress has been linked to compromised health status. Prolonged exposure to minor problems has been found to have an equal or greater impact on health status than exposure to isolated major events. Stress is, however, determined by the reaction of the individual to a stimulus; stress responses can be managed, and ill health outcomes can be minimized. This paper explores the stress level associated with the chiropractic consultation. A case study using closed questions. Purposive sampling of chiropractors by the researcher and convenience sampling of patients by participating chiropractors was undertaken. Chiropractors and patients completed closed questions on the level of stress they believed patients associated with the chiropractic consultation. A case study of 25 chiropractors and 137 patients found that although the chiropractic consultation was not regarded as stressful by most patients, some patients found adjustment stressful. Chiropractors assessment of perceived stress varied according to the patient. The trend was for practitioners to overestimate the stress felt by the patient. Chiropractors demonstrated the personalized nature of their care by the specificity of their responses to each patient. The importance of explaining the adjustment and the sensations that patients are likely to experience, particularly in new patients, is confirmed. The desirability of scrutinizing the patient for evidence of stress and of using diverse strategies for minimizing the stress response are discussed. Although the chiropractic consultation is not generally regarded as a stress-provoking experience, chiropractors should actively screen their patients for evidence of stress and take steps to enhance their patients' perceptions of the chiropractic consultation as a stress-free experience.


Nutritional evaluation of low glucosinolate mustard meals (Brassica juncea) in broiler diets.
Experiments were conducted to evaluate the nutritional value of meal derived from low glucosinolate cultivars of mustard (Brassica juncea) in comparison to samples of canola meal (Brassica napus, Brassica rapa). Samples of Brassica seed (four B. juncea, one B. napus, and one B. rapa) were processed using laboratory procedures to produce oil-extracted meals, which were examined for composition (DM basis), and nutritional value for broiler chickens as judged by nutrient retention (AMEn, ileal protein digestibility) and performance. Meals derived from B. juncea contained more CP and less total dietary fiber (TDF) on a dry basis than either B. napus or B. rapa, 45.9 vs 44.6 and 43.1% CP and 27.22 vs 29.47 and 29.67% TDF, respectively. Acid detergent fiber (ADF) and neutral detergent fiber (NDF) levels for B. juncea and B. rapa meals were similar to each other, but lower than those of B. napus, 12.79 and 13.20 vs 20.6% ADF, and 21.15 and 19.58 vs 29.47% NDF, respectively. Brassica juncea meals contained more glucosinolates than B. napus and B. rapa, 34.3 vs 21.8 and 25.5 mumol/g total glucosinolates, respectively. Brassica juncea meals were equal or superior to B. napus and B. rapa meals for AMEn and apparent ileal protein digestibility. Similarly, broilers fed B. juncea meals grew as quickly and converted feed to BW gain as efficiently to 21 d of age as those birds fed B. napus and B. rapa meals. Feeding meal from B. rapa reduced growth rate and gain to feed ratio. In conclusion, the nutritional value of meal from low glucosinolate mustard was equal or superior to that of canola meal samples derived from B. napus and B. rapa cultivars.


HMG protein family members stimulate human immunodeficiency virus type 1 and avian sarcoma virus concerted DNA integration in vitro.
We have reconstituted concerted human immunodeficiency virus type 1 (HIV-1) integration in vitro with specially designed mini-donor HIV-1 DNA, a supercoiled plasmid acceptor, purified bacterium-derived HIV-1 integrase (IN), and host HMG protein family members. This system is comparable to one previously described for avian sarcoma virus (ASV) (A. Aiyar et al., J. Virol. 70:3571-3580, 1996) that was stimulated by the presence of HMG-1. Sequence analyses of individual HIV-1 integrants showed loss of 2 bp from the ends of the donor DNA and almost exclusive 5-bp duplications of the acceptor DNA at the site of integration. All of the integrants sequenced were inserted into different sites in the acceptor. These are the features associated with integration of viral DNA in vivo. We have used the ASV and HIV-1 reconstituted systems to compare the mechanism of concerted DNA integration and examine the role of different HMG proteins in the reaction. Of the three HMG proteins examined, HMG-1, HMG-2, and HMG-I(Y), the products formed in the presence of HMG-I(Y) for both systems most closely match those observed in vivo. Further analysis of HMG-I(Y) mutants demonstrates that the stimulation of integration requires an HMG-I(Y) domain involved in DNA binding. While complexes containing HMG-I(Y), ASV IN, and donor DNA can be detected in gel shift experiments, coprecipitation experiments failed to demonstrate stable interactions between HMG-I(Y) and ASV IN or between HMG-I(Y) and HIV-1 IN.


Neural crest stem cells from hair follicles and boundary cap have different effects on pancreatic islets in vitro.
Neural crest stem cells derived from the boundary cap (bNCSCs), markedly promote survival, proliferation and function of insulin producing β-cells in vitro and in vivo after coculture/transplantation with pancreatic islets [ 1, 2 ]. Recently, we have shown that beneficial effects on β-cells require cadherin contacts between bNCSCs and β-cells [ 3, 4 ]. Here we investigated whether hair follicle (HF) NCSCs, a potential source for human allogeneic transplantation, exert similar positive effects on β-cells. We established cocultures of HF-NCSCs or bNCSCs from mice expressing enhanced green fluorescent protein together with pancreatic islets from DxRed expressing mice or NMRI mice and compared their migration towards islet cells and effect on proliferation of β-cells as well as intracellular relations between NCSCs and islets using qRT-PCR analysis and immunohistochemistry. Whereas both types of NCSCs migrated extensively in the presence of islets, only bNCSCs demonstrated directed migration toward islets, induced β-cell proliferation and increased the presence of cadherin at the junctions between bNCSCs and β-cells. Even in direct contact between β-cells and HF-NCSCs, no cadherin expression was detected. These observations indicate that HF-NCSCs do not confer the same positive effect on β-cells as demonstrated for bNCSCs. Furthermore, these data suggest that induction of cadherin expression by HF-NCSCs may be useful for their ability to support β-cells in coculture and after transplantation.


Chondrosarcomas of the skull base and temporal bone.
To evaluate the clinical presentation and outcomes of treatment for patients with chondrosarcomas involving the skull base and temporal bone. Retrospective review. Tertiary medical centre. Cases of histologically confirmed chondrosarcoma involving the skull base and temporal bones. Surgery. Demographic features of presenting patients; presenting symptoms and signs; surgical approach employed; use of post-operative radiation therapy; histological grade of tumour; and interval of post-operative follow up. Twelve patients were identified with chondrosarcomas involving the skull base, with post-operative follow up ranging from three to 33 years. The average age at presentation was 42 years. The most common presenting symptoms were diplopia, decreased visual acuity and headaches. Five of the 12 patients required multiple surgical procedures. Patients with chondrosarcoma involving the skull base and temporal bone may present in a variety of ways. Surgical resection, even subtotal, in combination with radiation therapy, can often provide good tumour control over many years for these rare tumours.


Shock Thyroid in a Patient with Septic Shock: A Case Report and Literature Review.
Shock thyroid is a rare manifestation of the CT hypotension complex and can be diagnosed when thyroid and perithyroidal edemas are observed on CT during the onset of shock. Shock thyroid can be a useful CT sign for decompensated shock. This condition is reversible and recovers rapidly with adequate treatment. We present the case of an 84-year-old female with septic shock, exhibiting CT features consistent with a shock thyroid. We also reviewed the clinical and radiological findings reported in the literature. The present case emphasizes that shock thyroid can be an early indicator of impending hemodynamic instability and has important prognostic and therapeutic implications.


The potential of Asparagus-P to inactivate reactive oxygen radicals.
Asparagus-P is a traditional herbal medicinal product consisting of a combination of asparagus roots and parsley leaves in equal shares. It is used to support aquaretic kidney function. The present study was undertaken to shed light on the antioxidative effects of both main ingredients and their combination as in Asparagus-P. For that purpose, differentiated promyelocytic HL60 cells (functional neutrophils) capable of generating superoxide radicals upon stimulation, were used. Parsley leaves and, hence, also Asparagus-P had a marked dose-dependent antioxidant effect, whereas asparagus roots had only a minor efficacy in this respect. In conclusion, Asparagus-P does not only support kidney function, but is also able to inactivate reactive oxygen radicals which might occur by a metabolic or exogenous overload (oxidative stress) or in the course of inflammatory processes. This antioxidant efficacy is primarily related to the content of parsley leaves; asparagus roots seem to enhance this efficacy by promoting the potential of parsley leaves, thus generating a synergistic effect in the combination product Asparagus-P.


Safety assessment of the calcium-binding protein, apoaequorin, expressed by Escherichia coli.
Calcium-binding proteins are ubiquitous modulators of cellular activity and function. Cells possess numerous calcium-binding proteins that regulate calcium concentration in the cytosol by buffering excess free calcium ion. Disturbances in intracellular calcium homeostasis are at the heart of many age-related conditions making these proteins targets for therapeutic intervention. A calcium-binding protein, apoaequorin, has shown potential utility in a broad spectrum of applications for human health and well-being. Large-scale recombinant production of the protein has been successful; enabling further research and development and commercialization efforts. Previous work reported a 90-day subchronic toxicity test that demonstrated this protein has no toxicity by oral exposure in Sprague-Dawley rodents. The current study assesses the allergenic potential of the purified protein using bioinformatic analysis and simulated gastric digestion. The results from the bioinformatics searches with the apoaequorin sequence show the protein is not a known allergen and not likely to cross-react with known allergens. Apoaequorin is easily digested by pepsin, a characteristic commonly exhibited by many non-allergenic dietary proteins. From these data, there is no added concern of safety due to unusual stability of the protein by ingestion.


Distribution of Prevalent and Incident Vertebral Fractures and Their Association with Bone Mineral Density in Postmenopausal Women in the Teriparatide Versus Risedronate VERO Clinical Trial.
Vertebral fractures (VFx) occur most frequently in the mid-thoracic and thoraco-lumbar regions, which experience the highest mechanical loading along the spine. The prevalence and incidence of VFx by their location and severity, and their relationship with bone mineral density (BMD), are seldom reported in randomized clinical trial cohorts. The VERO trial randomized 1360 postmenopausal women with at least two moderate or one severe VFx to receive either teriparatide or risedronate for up to 24 months. In this post hoc analysis, we describe the centrally read distribution and severity of prevalent and incident VFx, and the association of their location with the baseline BMD. At baseline, 21.4% of all evaluable vertebral bodies had a prevalent VFx; most commonly at L1, T12, L2 and T11 (38.5%, 37.4%, 25.3% and 23.5% of patients, respectively). Patients with prevalent VFx only at T12/L1 showed a higher baseline BMD compared to patients with VFx at other levels. At month 24, 100 patients had 126 incident VFx (teriparatide: 35; risedronate: 91). The most frequent incident VFx occurred at T12 (n = 17, 1.6% of patients), followed by L1 and T11 (n = 14, 1.3% both). The frequency of incident VFx was lower at all vertebral levels in patients given teriparatide. These results confirm prior reports that VFx occurs more frequently at mid-thoracic and thoraco-lumbar regions of the spine. Patients with these VFx locations have higher BMD than those who fracture at other sites, suggesting a role for mechanical stress in the etiology of VFx. Teriparatide is superior to risedronate in the prevention of VFx at these common fracture locations.Trial registration ClinicalTrials.gov Identifier: NCT01709110.


Laparoscopic cholecystectomy for biliary dyskinesia in children provides durable symptom relief.
The purpose of this study was to determine the effectiveness of laparoscopic cholecystectomy in children with biliary dyskinesia. Reports of children with an abnormal cholecystokinin (CCK)-stimulated HIDA scan between January 2001 and July 2006 who underwent laparoscopic cholecystectomy were reviewed. Postoperatively, a 23-item Likert scale, symptom questionnaire was administered to parents. Sixty-four children with chronic abdominal pain and no gallstones on ultrasound had an abnormal CCK-HIDA scan. Twenty-three children (median age, 14 years; 16 girls), with mean (SD) ejection fraction of 17% (8), underwent laparoscopic cholecystectomy and were further analyzed. Preoperatively, these children had right upper quadrant/epigastric pain (78%), nausea (52%), vomiting (43%), and generalized abdominal pain (22%) lasting for a median of 3 months (range, 1 month to 2.5 years). Median postoperative follow-up was 2.7 years. Sixteen (70%) parents completed the questionnaire. Of those who responded, 63% indicated that their children had no abdominal pain, 87% had no vomiting, and 69% had no nausea in the month preceding the questionnaire. Overall, 67% of parents indicated that their children's symptoms were completely relieved after cholecystectomy, whereas 7% indicated that the symptoms were not relieved. Laparoscopic cholecystectomy is effective in providing both short-term and long-term improvement of symptoms in children with biliary dyskinesia.


The role of arachidonic acid metabolism in the activities of interleukin 1 and 2.
Several investigations have suggested that products of arachidonic acid metabolism have modulatory effects on the development of cellular immunity. In this report we have studied the role of arachidonic acid metabolism in the specific effects of interleukin 1 (IL 1) induction of interleukin 2 (IL 2), and also IL 2 stimulation of proliferation and interferon-gamma (IFN-gamma) production. Utilizing cell lines that are specifically responsive to IL 1 or IL 2, it was found that both interleukins stimulate lipoxygenation of arachidonic acid in their respective target cell. The ability of each interleukin to induce monohydroxyeicosatetraenoic acid (HETE) correlated with the induction of secondary lymphokine secretion. Utilizing selective and partially selective pharmacologic inhibitors of arachidonic acid metabolism, the data suggest that the participation of lipoxygenase activity is required for both IL 1 induction of IL 2 production and IL 2 regulation of proliferation and IFN-gamma secretion. The same requirement for lipoxygenase activity was seen when phorbol myristate acetate (PMA) was used as a secretory stimulant, suggesting a similar mode of action for stimulation-secretory activity between PMA and interleukins. Studies performed with an endogenous inhibitor of 5-lipoxygenase (15-HETE) demonstrated the requirement of this enzyme system for IL 2-dependent proliferation and IFN-gamma production. Although leukotrienes could replace IL 2 for IFN-gamma secretion, they had no effect on IL 2 growth promotion. The results suggest that both IL 1 and IL 2, and PMA, may share the lipoxygenase pathway of arachidonic acid metabolism which is a component of the intracellular signal transduction process that regulates secretory activity and/or cellular proliferation.


Criminal multilation of the human body in Sweden--a thirty-year medico-legal and forensic psychiatric study.
During the 30-year period 1961-1990, a total of 22 deaths with criminal multilation/dismemberment of the human body were registered in Sweden. The multilations occurred in time clusters, mostly during the summer and winter periods, and increased during the three decades, with incidence rates of 0.05, 0.1, and 0.125 per million inhabitants and year, respectively. Multilation was noted 6.6 times more often in large urban areas than in the rest of Sweden. Defensive mutilation, in order to get rid of the corpse or make its identity more difficult, was noted in ten instances, aggressive mutilation following outrageous overkilling in four, offensive mutilation (lust murder) in seven, and necromanic multilation in one instance. In the last-mentioned case the cause of death was natural, while all deaths in the first three groups were homicidal, or homicide was strongly suspected. All perpetrators were males, in six instances assisted by other persons. In more than half of the cases the perpetrator's occupation was associated with application of anatomical knowledge, e.g., butcher, physician, veterinary assistant, or hunter. The perpetrators of the defensive and aggressive mutilations were mostly disorganized, i.e., alcoholics or drug users with previous psychiatric contacts and criminal histories, while the lust murderers were mostly organized, with a history of violent crimes (including the "serial killing" type), drug abuse and mental disorders with anxiety and schizophrenia, in that order to a diminishing degree. There were differences in mode of mutilation, depending on whether the mutilation was carried out by a layman, a butcher, or a physician. In only one case was the perpetrator convicted for the mutilation act itself; in the remaining instances the manslaughter, as a more serious crime, assimilated the mutilation. When the mutilation made it impossible to establish the cause of death, the perpetrators, despite strong circumstantial evidence indicating murder, were acquitted.


Clinico-microbiological Efficacy of Indocyanine Green as a Novel Photosensitizer for Photodynamic Therapy among Patients with Chronic Periodontitis: A Split-mouth Randomized Controlled Clinical Trial.
Conventional nonsurgical periodontal therapy, i.e., scaling and root planing (SRP), is not sufficient to completely eradicate the microorganisms present in dental plaque biofilm due to the incapability of instruments to reach the inaccessible areas of a tooth with anatomical variations. Hence, to increase the effectiveness of SRP, many adjunctive treatment strategies are proposed, including photodynamic therapy (PDT). Therefore, the purpose of this study was to determine the clinical and microbiological efficacy of PDT using Indocyanine green (ICG) as a novel photosensitizer for the treatment of chronic periodontitis. Twenty individuals who fulfilled the eligibility criteria were enrolled for this randomized controlled clinical trial using split-mouth design. Treatment sites from each individual were randomly allocated into two groups: SRP was done for the sites of the control group and an additional session of PDT using ICG was performed for the sites of the test group. Subgingival plaque samples were collected from both the sites and sent for quantitative analysis of Treponema denticola, Porphyromonas gingivalis, and Tannerella forsythia using real-time polymerase chain reaction (RT-PCR) technique. Probing pocket depth (PD), clinical attachment loss (CAL), and count of all the three microorganisms were assessed at baseline and after 3 months. After 3 months, PD and CAL showed statistically significant improvement in the test sites (P < 0.001) compared to the control sites. However, the differences in the microbiological parameters were statistically nonsignificant between the groups. ICG as a photosensitizer may enhance the outcomes of SRP and can be used for PDT for the nonsurgical management of periodontal diseases.


[Nerve growth factor auto-antibodies in children with various forms of mental dysontogenesis and in schizophrenia high risk group].
The level of autoantibodies (AAb) to nerve growth factor was evaluated in blood serum of 163 children with different forms of mental dysontogenesis of endogenic, residual-organic, psychogenic and deprivative origin. Significant elevation of the level of AAb was found in all forms of psychic dysontogenesis. The most significant elevation of the level of AAb (p < 0.01), as compared with the controls (45 children), was characteristic for endogenic forms of dysontogenesis (schizophrenia, early children's autism, schizotypic diathesis). The level of AAb was also found as an indicator of the acuteness of the pathologic state. Besides, its elevation was observed 1-2 weeks prior to the onset of the clinical exacerbation. Elevation of AAb level was also found in psychic dysontogenesis of residual-organic nature (children with perinatal encephalopathy), but it was not so significant as compared with the controls (p < 0.05%). The analysis in the age dynamics of children from this group revealed, that AAb level may serve as some prognostic index of the severity of psychic dysontogenesis. The level of AAb differs some states in schizotypic diathesis and deprivative dysontogenesis, which are clinically quite similar. The method for the estimation of serum AAb level may be proposed as screening in prophylactic medical examination of children from the first year of life under conditions of pediatric outpatient service for identification of risk-groups by psychic dysontogenesis to perform early special psychoprophylaxis.


Influence of increased adiposity on mitochondrial-associated proteins of the rat colon: a proteomic and transcriptomic analysis.
Epidemiological studies report obesity to be an important risk factor influencing colon pathologies, yet mechanism(s) are unknown. Recent studies have shown significant elevation of insulin, leptin and triglycerides associated with increased adipose tissue. In situ hybridisation studies have located insulin, leptin and adiponectin receptor expression in the colon epithelia. The influence of increased adiposity and associated deregulation of insulin and adipokines on regulation of the colon epithelium is unknown. Altered adipokine and insulin signalling associated with obesity has an impact on mitochondrial function and mitochondrial dysfunction is increasingly recognised as a contributing factor in many diseases. Proteomics and transcriptomics are potentially powerful methods useful in elucidating the mechanisms whereby obesity increases risk of colon diseases as observed epidemiologically. This study investigated colon mitochondrial-associated protein profiles and corresponding gene expression in colon in response to increased adiposity in a rat model of diet induced obesity. Increased adiposity in diet-induced obese sensitive rats was found to be associated with altered protein expression of 69 mitochondrial-associated proteins involved in processes associated with calcium binding, protein folding, energy metabolism, electron transport chain, structural proteins, protein synthesis and degradation, redox regulation, and transport. The changes in these mitochondrial protein profiles were not correlated with changes at the gene expression level assessed using real-time PCR arrays.


Beat perception ability and instructions to synchronize influence gait when walking to music-based auditory cues.
Synchronizing gait to music-based auditory cues (rhythmic auditory stimulation) is a strategy used to manage gait impairments in a variety of neurological conditions, including Parkinson's disease. However, knowledge of how to individually optimize music-based cues is limited. The purpose of this study was to investigate how instructions to synchronize with auditory cues influences gait outcomes among healthy young adults with either good or poor beat perception ability. 65 healthy adults walked to metronome and musical stimuli with high and low levels of perceived groove (how much it induces desire to move) and familiarity at a tempo equivalent to their self-selected walking pace. Participants were randomized to instruction conditions: (i) synchronized: match footsteps with the beat, or (ii) free-walking: walk comfortably. Participants were classified as good or poor beat perceivers using the Beat Alignment Test. In this study, poor beat perceivers show better balance-related parameters (stride width and double-limb support time) when they are not instructed to synchronize their gait with cues (versus when synchronization was required). Good beat perceivers, in contrast, were better when instructed to synchronize gait (versus when no synchronization was required). Changes in stride length and velocity were influenced by musical properties, in particular the perceived 'groove' (greater stride length and velocity with high- versus low-groove cues) and, in some cases, this interacted with beat perception ability. The results indicate that beat perception ability and instructions to synchronize indeed influence spatiotemporal gait parameters when walking to music- and metronome-based rhythmic auditory stimuli. Importantly, these results suggest that both low groove cues and instructing poor beat perceivers to synchronize may interfere with performance while walking, thus potentially impacting both empirical and clinical outcomes.


New technologies in robotic surgery: the Korean experience.
The development of the robotic systems has made surgery an increasingly technology-driven field. Since the introduction of the first robotic platform in 2005, surgical practice in South Korea has also been caught up in the global robotic revolution. Consequently, a market focused on improving the robotic systems was created and Korea has emerged as one of its frontrunners. This article reviews the Korean experience in developing various robotic technologies and then Korea's most recent contributions to the development of new technologies in robotic surgery. The goal of new technologies in the field of robotic surgery has been to improve on the current platforms by eliminating their disadvantages. The pressing goal is to develop a platform that is less bulky, more ergonomic, and capable of providing force feedback to the surgeon. In Korea, the Lapabot and two new robotic systems for single-port laparoscopic surgery are the most recent advances that have been reported. Robotic surgery is rapidly evolving and Korea has stayed in the forefront of its development. These new advancements in technology will eventually produce better robotic platforms that will greatly improve the manner in which surgical care is delivered.


[Local hemostasis in surgical practice].
Results of experimental and clinical investigations of a new local highly effective hemostatic drug " Gelplastan " are presented. Gelplastan was found to increase blood coagulation, to have strong adhesive and prolonged antibacterial properties. It is well resolved in the tissues, is biologically intact, has no side effects.


Stress response of Chlorella pyrenoidosa to nitro-aromatic compounds.
Handling of two nitro-aromatic compounds, 4-nitroaniline (4NA) and 4-nitrophenol (4NP), simultaneously by Chlorella pyrenoidosa was investigated. Algae would secrete or degrade nitro-aromatic compounds depending on different environmental conditions, in which the mode of handling was determined by the relative formation and degradation rate of the compound. Repeated intermittent trigger with externally added 4NA would induce the continuous secretion of 4NA by algae. Simultaneous exposure of both 4NA and 4NP to algae at normal condition would induce the algae to secrete both compounds. An increase in 4NA exposure concentration would elevate both 4NA and 4NP secretion, and that would be inhibited by the stress conditions of starving or lack of oxygen. Increased 4NA degradation per production rate induced by starving or lack of oxygen might explain the subsequent decrease in 4NA secretion in the presence of 4NP in algae. For 4NP in the presence of 4NA, secretion at normal condition was completely stopped and turned to degradation mode in stress conditions. The decreased formation and increased degradation of 4NP during starving for replenishing energy would explain the net degradation of 4NP in starving condition. The condition of lack of oxygen would inhibit the 4NP formation from 4NA via oxidative deamination, while the degradation of 4NP might not be significantly affected because alternative pathway of degradation via nitro-reduction was available. It may lead to the degradation rate exceeding the formation and explain the net degradation of 4NP in the condition of lack of oxygen.


Finding the Sweet Spot: Measurement, Modification, and Application of Sweet Hedonics in Humans.
Sweetness is a sensation that contributes to the palatability of foods, which is the primary driver of food choice. Thus, understanding how to measure the appeal (hedonics) of sweetness and how to modify it are key to effecting dietary change for health. Sweet hedonics is multidimensional so can only be captured by multiple approaches including assessment of elements such as liking, preference, and consumption intent. There are both innate and learned components to the appeal of sweet foods and beverages. These are responsive to various behavioral and biological factors, suggesting the opportunity to modify intake. Given the high amount of added sugar intake in the United States and recommendations from many groups to reduce this, further exploration of current hypothesized approaches to moderate sugar intake (e.g., induced hedonic shift, use of low-calorie sweeteners) is warranted.


Copalyl Diphosphate Synthase Mutation Improved Salt Tolerance in Maize (Zea mays. L) via Enhancing Vacuolar Na+ Sequestration and Maintaining ROS Homeostasis.
Salinity stress impairs plant growth and causes crops to yield losses worldwide. Reduction of in vivo gibberellin acid (GA) level is known to repress plant size but is beneficial to plant salt tolerance. However, the mechanisms of in vivo GA deficiency-enhanced salt tolerance in maize are still ambiguous. In this study, we generated two independent maize knockout mutant lines of ent-copalyl diphosphate synthase (one of the key enzymes for early steps of GA biosynthesis), zmcps-1 and zmcps-7, to explore the role of GA in maize salt tolerance. The typical dwarf phenotype with lower GA content and delayed leaf senescence under salinity was observed in the mutant plants. The leaf water potential and cell turgor potential were significantly higher in zmcps-1 and zmcps-7 than in the wild type (WT) under salt stress. The mutant plants exhibited a lower superoxide anion production rate in leaves and also a downregulated relative expression level of NAPDH oxidase ZmRbohA-C than the WT maize under salt stress. Also, the mutant plants had higher enzymatic activities of superoxide dismutase (SOD) and catalase (CAT) and higher content of soluble sugars and proline under salt stress. The Na+/K+ ratio was not significantly different between the mutant maize plants and WT plants under salt stress conditions, but the Na+ and K+ content was increased in zmcps-1 and zmcps-7 leaves and shoots. Na+ fluorescent dye staining showed that the mutant leaves have significantly higher vacuolar Na+ intensity than the WT maize. The expression level of vacuolar Na+/H+ exchanger gene ZmNHX1 and vacuolar proton pump genes ZmVP1-1 and ZmVP2 were upregulated in the zmcps-1 and zmcps-7 plants under salinity, further proving that in vivo GA deficiency enhanced vacuolar Na+ sequestration in zmcps-1 and zmcps-7 leaves cells to avoid Na+ cytotoxicity. Together, our results suggested that maintaining ROS homeostasis and enhancing vacuolar Na+ sequestration could be involved in GA deficiency-improved maize salt tolerance.


Amelioration of the premature ageing-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-23.
Genetic ablation of fibroblast growth factor 23 from mice (Fgf-23(-/-)) results in a short lifespan with numerous abnormal biochemical and morphological features. Such features include kyphosis, hypogonadism and associated infertility, osteopenia, pulmonary emphysema, severe vascular and soft tissue calcifications, and generalized atrophy of various tissues. To determine whether these widespread anomalies in Fgf-23(-/-) mice can be ameliorated by genetically restoring the systemic actions of FGF-23, we generated Fgf-23(-/-) mice expressing the human FGF-23 transgene in osteoblasts under the control of the 2.3 kb alpha1(I) collagen promoter (Fgf-23(-/-) /hFGF-23-Tg double mutants). This novel mouse model is completely void of all endogenous Fgf-23 activity, but produces human FGF-23 in bone cells that is subsequently released into the circulation. Our results suggest that lack of Fgf-23 activities results in extensive premature ageing-like features and early mortality of Fgf-23(-/-) mice, while restoring the systemic effects of FGF-23 significantly ameliorates these phenotypes, with the resultant effect being improved growth, restored fertility, and significantly prolonged survival of double mutants. With regard to their serum biochemistry, double mutants reversed the severe hyperphosphataemia, hypercalcaemia, and hypervitaminosis D found in Fgf-23(-/-) littermates; rather, double mutants show hypophosphataemia and normal serum 1,25-dihydroxyvitamin D(3) levels similar to pure FGF-23 Tg mice. These changes were associated with reduced renal expression of NaPi2a and 1 alpha-hydroxylase, compared to Fgf-23(-/-) mice. FGF-23 acts to prevent widespread abnormal features by acting systemically to regulate phosphate homeostasis and vitamin D metabolism. This novel mouse model provides us with an in vivo tool to study the systemic effects of FGF-23 in regulating mineral ion metabolism and preventing multiple abnormal phenotypes without the interference of native Fgf-23.


Recovery after an Ironman triathlon: sustained inflammatory responses and muscular stress.
Ultra-endurance exercise, such as an Ironman triathlon, induces muscle damage and a systemic inflammatory response. As the resolution of recovery in these parameters is poorly documented, we investigated indices of muscle damage and systemic inflammation in response to an Ironman triathlon and monitored these parameters 19 days into recovery. Blood was sampled from 42 well-trained male triathletes 2 days before, immediately after, and 1, 5 and 19 days after an Ironman triathlon. Blood samples were analyzed for hematological profile, and plasma values of myeloperoxidase (MPO), polymorphonuclear (PMN) elastase, cortisol, testosterone, creatine kinase (CK) activity, myoglobin, interleukin (IL)-6, IL-10 and high-sensitive C-reactive protein (hs-CRP). Immediately post-race there were significant (P < 0.001) increases in total leukocyte counts, MPO, PMN elastase, cortisol, CK activity, myoglobin, IL-6, IL-10 and hs-CRP, while testosterone significantly (P < 0.001) decreased compared to prerace. With the exception of cortisol, which decreased below prerace values (P < 0.001), these alterations persisted 1 day post-race (P < 0.001; P < 0.01 for IL-10). Five days post-race CK activity, myoglobin, IL-6 and hs-CRP had decreased, but were still significantly (P < 0.001) elevated. Nineteen days post-race most parameters had returned to prerace values, except for MPO and PMN elastase, which had both significantly (P < 0.001) decreased below prerace concentrations, and myoglobin and hs-CRP, which were slightly, but significantly higher than prerace. Furthermore, significant relationships between leukocyte dynamics, cortisol, markers of muscle damage, cytokines and hs-CRP after the Ironman triathlon were noted. This study indicates that the pronounced initial systemic inflammatory response induced by an Ironman triathlon declines rapidly. However, a low-grade systemic inflammation persisted until at least 5 days post-race, possibly reflecting incomplete muscle recovery.


Coccidioidomycosis among persons undergoing lung transplantation in the coccidioidal endemic region.
Coccidioidomycosis, an endemic fungal infection, is more likely to be symptomatic and severe among those receiving allogeneic transplants. While several case series have been published for various transplanted organs, none has described the incidence and outcomes in those receiving lung transplants within the coccidioidal endemic region. Patients receiving a heart-lung, single-lung, or bilateral-lung transplantation at the University of Arizona between 1985 and 2009 were retrospectively reviewed. Coccidioidomycosis occurred post transplantation in 11 (5.8%) of 189 patients. All but one patient was diagnosed with pulmonary coccidioidomycosis and only one had a history of prior coccidioidomycosis. Two patients received transplants from donors found to have coccidioidomycosis at the time of transplantation and one death was directly attributed to coccidioidomycosis. The risk of developing active coccidioidomycosis was significantly higher if the patient did not receive some type of antifungal therapy post transplantation (P<.001). Within the coccidioidal endemic region, post-transplantation coccidioidomycosis was a definable risk among lung transplant recipients. Use of antifungals appeared to reduce this incidence of disease. Almost all cases resulted in pulmonary disease, suggesting that the lung is the primary site of infection.


IL-17 Aggravates Pseudomonas aeruginosa Airway Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease.
Pseudomonas aeruginosa airway infection increases risks of exacerbations and mortality in chronic obstructive pulmonary disease (COPD). We aimed to elucidate the role of IL-17 in the pathogenesis. We examined the expression and influences of IL-23/IL-17A in patients with stable COPD (n = 33) or acute COPD exacerbations with P. aeruginosa infection (n = 34). A mouse model of COPD (C57BL/6) was used to investigate the role of IL-17A in host inflammatory responses against P. aeruginosa infection through the application of IL-17A-neutralizing antibody or recombinant IL-17A. We found that P. aeruginosa infection increased IL-23/17A signaling in lungs of both COPD patients and COPD mouse models. When COPD mouse models were treated with neutralizing antibody targeting IL-17A, P. aeruginosa induced a significantly less polymorphonuclear leukocyte infiltration and less bacterial burden in their lungs compared to those of untreated counterparts. The lung function was also improved by neutralizing antibody. Furthermore, IL-17A-signaling blockade significantly reduced the expression of pro-inflammatory cytokine IL-1β, IL-18, TNF-α, CXCL1, CXCL15 and MMP-9, and increased the expression of anti-inflammatory cytokine IL-10 and IL-1Ra. The application of mouse recombinant IL-17A exacerbated P. aeruginosa-mediated inflammatory responses and pulmonary dysfunction in COPD mouse models. A cytokine protein array revealed that the expression of retinol binding protein 4 (RBP4) was down-regulated by IL-17A, and exogenous RBP4-recombinant protein resulted in a decrease in the severity of P. aeruginosa-induced airway dysfunction. Concurrent application of IL-17A-neutralizing antibody and ciprofloxacin attenuated airway inflammation and ventilation after inoculation of P. aeruginosa in COPD mouse models. Our results revealed that IL-17 plays a detrimental role in the pathogenesis of P. aeruginosa airway infection during acute exacerbations of COPD. Targeting IL-17A is a potential therapeutic strategy in controlling the outcomes of P. aeruginosa infection in COPD patients.


Moving Beyond Correlations in Assessing the Consequences of Poverty.
In the United States, does growing up in a poor household cause negative developmental outcomes for children? Hundreds of studies have documented statistical associations between family income in childhood and a host of outcomes in childhood, adolescence, and adulthood. Many of these studies have used correlational evidence to draw policy conclusions regarding the benefits of added family income for children, in particular children in families with incomes below the poverty line. Are these conclusions warranted? After a review of possible mechanisms linking poverty to negative childhood outcomes, we summarize the evidence for income's effects on children, paying particular attention to the strength of the evidence and the timing of economic deprivation. We demonstrate that, in contrast to the nearly universal associations between poverty and children's outcomes in the correlational literature, impacts estimated from social experiments and quasi-experiments are more selective. In particular, these stronger studies have linked increases in family income to increased school achievement in middle childhood and to greater educational attainment in adolescence and early adulthood. There is no experimental or quasi-experimental evidence in the United States that links child outcomes to economic deprivation in the first several years of life. Understanding the nature of socioeconomic influences, as well as their potential use in evidence-based policy recommendations, requires greater attention to identifying causal effects.


Determination of serum and plasma sclerostin concentrations by enzyme-linked immunoassays.
Sclerostin alters bone formation. The precise and reproducible measurement of sclerostin concentrations in biological samples is important for assessment of metabolic bone disease. We determined sclerostin concentrations in serum and plasma using two commercially available ELISA. We measured sclerostin concentrations in serum or heparin-plasma obtained from 25 normal human subjects using two commercial ELISA available from Biomedica Medizinprodukte GmbH and TECOmedical AG. With the Biomedica assay, serum sclerostin concentrations were 0.99 ± 0.12 ng/ml (mean ± sem), and plasma concentrations were 1.47 ± 0.13 ng/ml (paired t test, P < 0.001). With the TECO assay, serum sclerostin levels were 0.71 ± 0.05 ng/ml, and plasma sclerostin concentrations were 0.80 ± 0.06 ng/ml (paired t test, P < 0.001). Serum and plasma sclerostin concentrations were significantly different when determined by the two assays (serum, P = 0.015; plasma, P < 0.001). Recovery of added recombinant sclerostin to serum was less than expected with both Biomedica and TECO assays (P < 0.001, paired t test). The concentrations of sclerostin in serum and plasma are different when determined by the two assays. Serum or plasma sclerostin concentrations with current assays should be interpreted with caution. The data suggest that the same assay should be used for comparing groups of patients or patients being followed longitudinally. Standardization of sclerostin assays is required before being introduced into general clinical laboratory use.


Increases in waist circumference and weight as predictors of type 2 diabetes in individuals with impaired fasting glucose: influence of baseline BMI: data from the DESIR study.
To evaluate in impaired fasting glucose (IFG) the relative importance of increases in waist circumference and weight on progression to type 2 diabetes. The 9-year incidence of diabetes was studied in 979 men and women with baseline IFG, from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. Increases in both waist circumference and weight were significantly associated with diabetes incidence. Standardized odds ratios (95% CI) were 1.79 (1.45-2.21) and 1.86 (1.51-2.30), respectively, after controlling for baseline risk factors. The impact of waist circumference increase was greater for BMI <25 kg/m(2) (2.40 [1.63-3.52]) than for BMI >or=25 kg/m(2) (1.66 [1.28-2.16]) and persisted after adjusting for concurrent changes in either insulinemia or the homeostasis model assessment of insulin resistance index. Weight change had a similar impact in both BMI groups. In individuals with IFG, it is important to monitor and prevent increases in waist circumference, in particular for those with BMI <25 kg/m(2).


Rapid Identification of Neutralizing Antibodies against SARS-CoV-2 Variants by mRNA Display.
The increasing prevalence of SARS-CoV-2 variants with the ability to escape existing humoral protection conferred by previous infection and/or immunization necessitates the discovery of broadly-reactive neutralizing antibodies (nAbs). Utilizing mRNA display, we identified a set of antibodies against SARS-CoV-2 spike (S) proteins and characterized the structures of nAbs that recognized epitopes in the S1 subunit of the S glycoprotein. These structural studies revealed distinct binding modes for several antibodies, including targeting of rare cryptic epitopes in the receptor-binding domain (RBD) of S that interacts with angiotensin- converting enzyme 2 (ACE2) to initiate infection, as well as the S1 subdomain 1. A potent ACE2-blocking nAb was further engineered to sustain binding to S RBD with the E484K and L452R substitutions found in multiple SARS-CoV-2 variants. We demonstrate that mRNA display is a promising approach for the rapid identification of nAbs that can be used in combination to combat emerging SARS-CoV-2 variants.


GW433908/ritonavir once daily in antiretroviral therapy-naive HIV-infected patients: absence of protease resistance at 48 weeks.
To investigate the emergence of resistance to GW433908 (908), a protease inhibitor (PI) with demonstrated antiviral efficacy, safety and tolerability, when administered once daily (q.d.) with low dose ritonavir (908/r). A 48-week Phase III open-label study (SOLO, APV30002) in which antiretroviral therapy-naive patients (n = 649) were treated with 908/r, (1400 mg/200 mg, q.d.) or nelfinavir [1250 mg, twice daily (b.i.d.)] with two nucleoside reverse transcriptase inhibitors (NRTI), abacavir (300 mg, b.i.d.) and lamivudine (150 mg, b.i.d.). Viral genotype and phenotype were analysed at baseline and on treatment up to 48 weeks and beyond. Emergence of genotypic resistance was significantly different between the 908/r q.d. and the nelfinavir b.i.d. treatment arms for both PIs (0 versus 50%; P < 0.001) and the NRTI (13% versus 69%; P < 0.001) received. In the nelfinavir arm the key protease mutations D30N and/or L90M were frequently observed. The absence of protease resistance mutations and reduced incidence of NRTI resistance mutations in the 908/r q.d. arm was confirmed by phenotyping, which showed a lack of PI cross-resistance. The absence of resistance to 908 or cross-resistance to other PIs, and reduced NRTI resistance, following a 908/r q.d. regimen supports the use of this boosted PI early in therapy.


Probability and delay discounting of erotic stimuli.
Adult undergraduate men (n=38) and women (n=33) were categorized as erotica "users" (n=34) and "non-users" (n=37) based on their responses to screening questions and completed computerized delay and probability discounting tasks concerning hypothetical money and erotica. Erotica users discounted the value of erotica similarly to money on three of the four erotica tasks; erotica non-users discounted the value of money consistent with erotica users, but not the value of erotica. Erotica users were disproportionately male, scored higher on several psychometric measures of sexuality-related constructs, and exhibited more impulsive choice patterns on the delay discounting for money task than erotica non-users did. These findings suggest that discounting processes generalize to erotic outcomes for some individuals.


Sex determination in Madagascar geckos of the genus Paroedura (Squamata: Gekkonidae): are differentiated sex chromosomes indeed so evolutionary stable?
Among amniote vertebrates, geckos represent a clade with exceptional variability in sex determination; however, only a minority of species of this highly diverse group has been studied in this respect. Here, we describe for the first time a female heterogamety in the genus Paroedura, the group radiated in Madagascar and adjacent islands. We identified homomorphic ZZ/ZW sex chromosomes with a highly heterochromatic W chromosome in Paroedura masobe, Paroedura oviceps, Paroedura karstophila, Paroedura stumpffi, and Paroedura lohatsara. Comparative genomic hybridization (CGH) revealed that female-specific sequences are greatly amplified in the W chromosome of P. lohatsara and that P. gracilis seems to possess a derived system of multiple sex chromosomes. Contrastingly, neither CGH nor heterochromatin visualization revealed differentiated sex chromosomes in the members of the Paroedura picta-Paroedura bastardi-Paroedura ibityensis clade, which is phylogenetically nested within lineages with a heterochromatic W chromosome. As a sex ratio consistent with genotypic sex determination has been reported in P. picta, it appears that the members of the P. picta-P. bastardi-P. ibityensis clade possess homomorphic, poorly differentiated sex chromosomes and may represent a rare example of evolutionary loss of highly differentiated sex chromosomes. Fluorescent in situ hybridization (FISH) with a telomeric probe revealed a telomere-typical pattern in all species and an accumulation of telomeric sequences in the centromeric region of autosomes in P. stumpffi and P. bastardi. Our study adds important information for the greater understanding of the variability and evolution of sex determination in geckos and demonstrates how the geckos of the genus Paroedura provide an interesting model for studying the evolution of the sex chromosomes.


Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice.
ATP-binding cassette A3 (ABCA3) is a lipid transport protein required for synthesis and storage of pulmonary surfactant in type II cells in the alveoli. Abca3 was conditionally deleted in respiratory epithelial cells (Abca3(Δ/Δ)) in vivo. The majority of mice in which Abca3 was deleted in alveolar type II cells died shortly after birth from respiratory distress related to surfactant deficiency. Approximately 30% of the Abca3(Δ/Δ) mice survived after birth. Surviving Abca3(Δ/Δ) mice developed emphysema in the absence of significant pulmonary inflammation. Staining of lung tissue and mRNA isolated from alveolar type II cells demonstrated that ∼50% of alveolar type II cells lacked ABCA3. Phospholipid content and composition were altered in lung tissue, lamellar bodies, and bronchoalveolar lavage fluid from adult Abca3(Δ/Δ) mice. In adult Abca3(Δ/Δ) mice, cells lacking ABCA3 had decreased expression of mRNAs associated with lipid synthesis and transport. FOXA2 and CCAAT enhancer-binding protein-α, transcription factors known to regulate genes regulating lung lipid metabolism, were markedly decreased in cells lacking ABCA3. Deletion of Abca3 disrupted surfactant lipid synthesis in a cell-autonomous manner. Compensatory surfactant synthesis was initiated in ABCA3-sufficient type II cells, indicating that surfactant homeostasis is a highly regulated process that includes sensing and coregulation among alveolar type II cells.


Curcumin inhibits hepatitis B virus infection by down-regulating cccDNA-bound histone acetylation.
To investigate the potential effect of curcumin on hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and the underlying mechanism. A HepG2.2.15 cell line stably transfected with HBV was treated with curcumin, and HBV surface antigen (HBsAg) and e antigen (HBeAg) expression levels were assessed by ELISA. Intracellular HBV DNA replication intermediates and cccDNA were detected by Southern blot and real-time PCR, respectively. The acetylation levels of histones H3 and H4 were measured by Western blot. H3/H4-bound cccDNA was detected by chromatin immunoprecipitation (ChIP) assays. The deacetylase inhibitors trichostatin A and sodium butyrate were used to study the mechanism of action for curcumin. Additionally, short interfering RNAs (siRNAs) targeting HBV were tested along with curcumin. Curcumin treatment led to time- and dose-dependent reductions in HBsAg and HBeAg expression and significant reductions in intracellular HBV DNA replication intermediates and HBV cccDNA. After treatment with 20 μmol/L curcumin for 2 d, HBsAg and cccDNA levels in HepG2.2.15 cells were reduced by up to 57.7% (P < 0.01) and 75.5% (P < 0.01), respectively, compared with levels in non-treated cells. Meanwhile, time- and dose-dependent reductions in the histone H3 acetylation levels were also detected upon treatment with curcumin, accompanied by reductions in H3- and H4-bound cccDNA. Furthermore, the deacetylase inhibitors trichostatin A and sodium butyrate could block the effects of curcumin. Additionally, transfection of siRNAs targeting HBV enhanced the inhibitory effects of curcumin. Curcumin inhibits HBV gene replication via down-regulation of cccDNA-bound histone acetylation and has the potential to be developed as a cccDNA-targeting antiviral agent for hepatitis B.


Removal of the cecum, including the ileocecocolic junction, and its effects on digestibility in cattle.
The cecum and ileocecocolic junction in each of five 7-month-old Holstein steers were removed. Two steers of the same breed and age were sham-operated. All steers survived and were subjected to a digestibility experiment for 16 weeks. Digestibility of dry matter, neutral-detergent fiber, acid-detergent fiber, and cellulose decreased (P less than 0.05) during postsurgical weeks (PSW) 1 to 4, but not during PSW 16. However, digestibility of protein and hemicellulose was not significantly (P less than 0.07) influenced by the operation. Digestibility of the previously described components was not significantly different from that in 2 sham-operated steers. The mean daily weight gain of the cecectomized steers decreased during PSW 1 to 4; however, it started to increase at PSW 8 so that at PSW 16 it approached preoperative values. The mean daily weight gain of the sham-operated steers also decreased during PSW 1 to 4, but was higher than the preoperative values at PSW 14. The difference in mean daily weight gains between the cecectomized and sham-operated steers was insignificant. The consistency of the feces of the cecectomized steers was loose to watery for a period of about 4 weeks after surgery. At PSW 16, the feces were firm, but not of normal consistency. Feces of the sham-operated steers were loose after surgery, but returned to normal consistency after approximately 7 days. Adhesions developed at the surgical site and involved the ileum, the proximal loop of the ascending colon, and the adjacent mesentery and greater omentum.(ABSTRACT TRUNCATED AT 250 WORDS)


Metabolic oligosaccharide engineering: perspectives, applications, and future directions.
Many adhesion and signaling molecules critical for development, as well as surface markers implicated in diseases ranging from cancer to influenza, contain oligosaccharides that modify their functions. Inside a cell, complex glycosylation pathways assemble these oligosaccharides and attach them to proteins and lipids as they traffic to the cell surface. Until recently, practical technologies to manipulate glycosylation have lagged unlike the molecular biologic and genetic methods available to intervene in nucleic acid and protein biochemistry; now, metabolic oligosaccharide engineering shows promise for manipulating glycosylation. In this methodology, exogenously-supplied non-natural sugars intercept biosynthetic pathways and exploit the remarkable ability of many of the enzymes involved in glycosylation to process metabolites with slightly altered chemical structures. To date, non-natural forms of sialic acid, GalNAc, GlcNAc, and fucose have been incorporated into glycoconjugates that appear on the cell surface; in addition O-GlcNAc protein modification involved in intracellular signaling has been tagged with modified forms of this sugar. Reactive functional groups, including ketones, azides, and thiols, have been incorporated into glycoconjugates and thereby provide chemical 'tags' that can be used for diverse purposes ranging from drug delivery to new modes of carbohydrate-based cell adhesion that can be used to control stem cell destiny. Finally, strategies for further engineering non-natural sugars to improve their pharmacological properties and provide complementary biological activities, such as addition of short chain fatty acids, are discussed in this article.


Torque-dense photomechanical actuation.
Contactless actuation powered using light is shown to generate torque densities approaching 10 N m kg-1 at angular velocities ∼102 rad s-1: metrics that compare favorably against tethered electromechanical systems. This is possible even though the extinction of actinic light limits the characteristic thickness of photoresponse in polymers to tens of μm. Confinement of molecularly patterned developable shells fabricated from azobenzene-functionalized liquid crystalline polymers encodes torque-dense photoactuation. Photostrain gradients from unstructured irradiation segment this geometry into two oppositely curved regions connected by a curved crease. A monolithic curved shell spontaneously bifurcates into a jointed, arm-like mechanism that generates flexure over sweep angles exceeding a radian. Strain focusing at the crease is hierarchical: an integral crease nucleates at smaller magnitudes of the prebiased curvature, while a crease decorated with point-like defects emerges at larger curvatures. The phase-space of morphogenesis is traceable to the competition between stretch and bending energies and is parameterizable as a function of the geometry. The framework for generating repetitive torque-dense actuation from slender light-powered actuators holds broader implications for the design of soft, remotely operated machines. Here, it is harnessed in illustrative mechanisms including levers, lifters and grabbers that are powered and regulated exclusively using light.