Cancer-associated fibroblasts promote proliferation of endometrial cancer cells.
Endometrial cancer is the most commonly diagnosed gynecologic malignancy worldwide; yet the tumor microenvironment, especially the fibroblast cells surrounding the cancer cells, is poorly understood. We established four primary cultures of fibroblasts from human endometrial cancer tissues (cancer-associated fibroblasts, CAFs) using antibody-conjugated magnetic bead isolation. These relatively homogenous fibroblast cultures expressed fibroblast markers (CD90, vimentin and alpha-smooth muscle actin) and hormonal (estrogen and progesterone) receptors. Conditioned media collected from CAFs induced a dose-dependent proliferation of both primary cultures and cell lines of endometrial cancer in vitro (175%) when compared to non-treated cells, in contrast to those from normal endometrial fibroblast cell line (51%) (P<0.0001). These effects were not observed in fibroblast culture derived from benign endometrial hyperplasia tissues, indicating the specificity of CAFs in affecting endometrial cancer cell proliferation. To determine the mechanism underlying the differential fibroblast effects, we compared the activation of PI3K/Akt and MAPK/Erk pathways in endometrial cancer cells following treatment with normal fibroblasts- and CAFs-conditioned media. Western blot analysis showed that the expression of both phosphorylated forms of Akt and Erk were significantly down-regulated in normal fibroblasts-treated cells, but were up-regulated/maintained in CAFs-treated cells. Treatment with specific inhibitors LY294002 and U0126 reversed the CAFs-mediated cell proliferation (P<0.0001), suggesting for a role of these pathways in modulating endometrial cancer cell proliferation. Rapamycin, which targets a downstream molecule in PI3K pathway (mTOR), also suppressed CAFs-induced cell proliferation by inducing apoptosis. Cytokine profiling analysis revealed that CAFs secrete higher levels of macrophage chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-8, RANTES and vascular endothelial growth factor (VEGF) than normal fibroblasts. Our data suggests that in contrast to normal fibroblasts, CAFs may exhibit a pro-tumorigenic effect in the progression of endometrial cancer, and PI3K/Akt and MAPK/Erk signaling may represent critical regulators in how endometrial cancer cells respond to their microenvironment.


Predictors of emotional and physical dating violence in a sample of serious juvenile offenders.
We estimate group-based dating violence trajectories and identify the adolescent risk factors that explain membership in each trajectory group. Using longitudinal data from the Pathways to Desistance Study, which follows a sample of 1354 serious juvenile offenders from Philadelphia, Pennsylvania and Phoenix, Arizona between mid-adolescence and early adulthood, we estimate group-based trajectory models of both emotional dating violence and physical dating violence over a span of five years in young adulthood. We then estimate multinomial logistic regression models to identify theoretically motivated risk factors that predict membership in these groups. We identified three developmental patterns of emotional dating violence: none (33%), low-level (59%) and high-level decreasing (8%). The best-fitting model for physical dating violence also had three groups: none (73%), low-level (24%) and high-level (3%). Race/ethnicity, family and psychosocial variables were among the strongest predictors of both emotional and physical dating violence. In addition, delinquency history variables predicted emotional dating violence and relationship variables predicted physical dating violence. Dating violence is quite prevalent in young adulthood among serious juvenile offenders. Numerous predictors distinguish between chronic dating violence perpetrators and other groups. These may suggest points of intervention for reducing future violence. Copyright © 2016 John Wiley & Sons, Ltd.


Cariology Clinical Trials: What Are We-and What Should We Be-Looking At?
Randomized control trial (RCT) methodology has compared interventions for the prevention and management of dental caries since the late 1960s. Despite almost 50 years and evidence of significant wastage within the wider biomedical research field, there has been little investigation into what works well and where weaknesses lie. This paper aims to draw attention to areas for improvement within cariology clinical trial methodology by summarizing systematic reviews on interventions and outcomes, and using examples to illustrate some challenges with intervention delivery fidelity, outcome analyses, and intervention co-production. Trial design stage choices are critical to ensure that optimum information is obtained when testing interventions. Intervention choice, outcome choice, and analyses are particularly important, and cariology trials have specific issues associated with them. A systematic search and review of cariology RCTs found 650 RCT reports. Social Network Analysis of interventions revealed a high degree of separation between prevention and management trials, gaps in clinically important comparisons, and a tendency for there to be comparisons within groups; e.g., comparison of interventions within the same, rather than different, levels of invasiveness. Outcomes measured for the same trial reports show: a focus on restoration performance and individual/population caries burden; the growing use of carious lesion activity and economic-related outcomes; and sparse, although an increase in the use of, patient-reported/patient-centered outcomes. Fidelity of adherence to complex interventions can be challenging to measure but is important in interpreting trial findings. Involving target populations in intervention design, delivery, and relating it to the planned rollout, are opportunities to ensure intervention relevance and improved uptake. Outcomes analyses should consider the minimum clinically important differences and outcome relevance measures for the target population. Factors underlying trialists' comparator and outcome choices need to be identified, and there is a need to ensure that a minimum dataset of outcomes allow for combination and comparisons of trial data for systematic review.


A novel stem cell source for vasculogenesis in ischemia: subfraction of side population cells from dental pulp.
Cell therapy with stem cells and endothelial progenitor cells (EPCs) to stimulate vasculogenesis as a potential treatment for ischemic disease is an exciting area of research in regenerative medicine. EPCs are present in bone marrow, peripheral blood, and adipose tissue. Autologous EPCs, however, are obtained by invasive biopsy, a potentially painful procedure. An alternative approach is proposed in this investigation. Permanent and deciduous pulp tissue is easily available from teeth after extraction without ethical issues and has potential for clinical use. We isolated a highly vasculogenic subfraction of side population (SP) cells based on CD31 and CD146, from dental pulp. The CD31(-);CD146(-) SP cells, demonstrating CD34+ and vascular endothelial growth factor-2 (VEGFR2)/Flk1+, were similar to EPCs. These cells were distinct from the hematopoietic lineage as CD11b, CD14, and CD45 mRNA were not expressed. They showed high proliferation and migration activities and multilineage differentiation potential including vasculogenic potential. In models of mouse hind limb ischemia, local transplantation of this subfraction of SP cells resulted in successful engraftment and an increase in the blood flow including high density of capillary formation. The transplanted cells were in proximity of the newly formed vasculature and expressed several proangiogenic factors, such as VEGF-A, G-CSF, GM-CSF, and MMP3. Conditioned medium from this subfraction showed the mitogenic and antiapoptotic activity on human umbilical vein endothelial cells. In conclusion, subfraction of SP cells from dental pulp is a new stem cell source for cell-based therapy to stimulate angiogenesis/vasculogenesis during tissue regeneration.


Intensive versus conventional glycaemic control for treating diabetic foot ulcers.
The estimated likelihood of lower limb amputation is 10 to 30 times higher amongst people with diabetes compared to those without diabetes. Of all non-traumatic amputations in people with diabetes, 85% are preceded by a foot ulcer. Foot ulceration associated with diabetes (diabetic foot ulcers) is caused by the interplay of several factors, most notably diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD) and changes in foot structure. These factors have been linked to chronic hyperglycaemia (high levels of glucose in the blood) and the altered metabolic state of diabetes. Control of hyperglycaemia may be important in the healing of ulcers. To assess the effects of intensive glycaemic control compared to conventional control on the outcome of foot ulcers in people with type 1 and type 2 diabetes. In December 2015 we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; EBSCO CINAHL; Elsevier SCOPUS; ISI Web of Knowledge Web of Science; BioMed Central and LILACS. We also searched clinical trial databases, pharmaceutical trial databases and current international and national clinical guidelines on diabetes foot management for relevant published, non-published, ongoing and terminated clinical trials. There were no restrictions based on language or date of publication or study setting. Published, unpublished and ongoing randomised controlled trials (RCTs) were considered for inclusion where they investigated the effects of intensive glycaemic control on the outcome of active foot ulcers in people with diabetes. Non randomised and quasi-randomised trials were excluded. In order to be included the trial had to have: 1) attempted to maintain or control blood glucose levels and measured changes in markers of glycaemic control (HbA1c or fasting, random, mean, home capillary or urine glucose), and 2) documented the effect of these interventions on active foot ulcer outcomes. Glycaemic interventions included subcutaneous insulin administration, continuous insulin infusion, oral anti-diabetes agents, lifestyle interventions or a combination of these interventions. The definition of the interventional (intensive) group was that it should have a lower glycaemic target than the comparison (conventional) group. All review authors independently evaluated the papers identified by the search strategy against the inclusion criteria. Two review authors then independently reviewed all potential full-text articles and trials registry results for inclusion. We only identified one trial that met the inclusion criteria but this trial did not have any results so we could not perform the planned subgroup and sensitivity analyses in the absence of data. Two ongoing trials were identified which may provide data for analyses in a later version of this review. The completion date of these trials is currently unknown. The current review failed to find any completed randomised clinical trials with results. Therefore we are unable to conclude whether intensive glycaemic control when compared to conventional glycaemic control has a positive or detrimental effect on the treatment of foot ulcers in people with diabetes. Previous evidence has however highlighted a reduction in risk of limb amputation (from various causes) in people with type 2 diabetes with intensive glycaemic control. Whether this applies to people with foot ulcers in particular is unknown. The exact role that intensive glycaemic control has in treating foot ulcers in multidisciplinary care (alongside other interventions targeted at treating foot ulcers) requires further investigation.


Density-dependent facilitation cascades determine epifaunal community structure in temperate Australian mangroves.
Co-occurring foundation species can determine biological community structure via facilitation cascades. We examined the density dependencies of facilitation cascades, including how the density of a basal foundation species influences the density of secondary foundation species, and how the density of secondary foundation species influences community structure. The system in which we assessed density dependencies was a temperate mangrove forest in which pneumatophores trap the fucoid alga Hormosira banksii and provide substrate for the oyster, Saccostrea glomerata. The alga and oyster in turn determine benthic community structure. In the field, algal biomass was positively correlated with pneumatophore density. Oysters, by contrast, were highly over-dispersed and correlated with the presence/absence of pneumatophores. Epifaunal abundance and species richness were positively correlated with algal and oyster abundance, but their effects were independent. The positive effect of pneumatophore density on epifauna was primarily an indirect effect of trapping more algae. Pneumatophores did not directly influence invertebrate communities. Experiments revealed that, at very low pneumatophore densities, algal retention was insufficient to facilitate epifauna above that found on pneumatophores alone. At higher densities, however, increasing the density of pneumatophores increased algal retention, and the density and diversity of associated invertebrates. Shading by the mangrove canopy reduced algal biomass but did not modify the density-dependent nature of the cascade. Our results extend facilitation theory by showing that the density of both basal and secondary foundation species can be critical in triggering facilitation cascades. Our study also reveals that, where foundation species co-occur, multiple, independent cascades may arise from a single basal facilitator. These findings enhance our understanding of the role of density-dependent facilitation cascades in community assembly.


Human monocyte-derived dendritic cells pulsed with wild-type p53 protein efficiently induce CTLs against p53 overexpressing human cancer cells.
Dendritic cells are the most potent antigen-presenting cells for initiating cellular immune responses. Dendritic cells are attractive immunoregulatory cells for cancer immunotherapy, and their efficacy has been investigated in clinical trials. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and p53-based immunization is an attractive approach to cancer immunotherapy because of the accumulation of p53 protein in malignant but not in normal cells. It has been shown that dendritic cells transduced with an adenoviral wild-type p53 (wt-p53) construct mediate the antitumor immune responses against p53-overexpressing tumor cells. We examined whether monocyte-derived human dendritic cells pulsed with the purified full-length wt-p53 protein were also capable of inducing the specific antitumor responses against p53-overexpressing tumors in vitro. Immature dendritic cells generated in the presence of interleukin-4 and granulocyte/macrophage colony-stimulating factor from monocytes of HLA-A2- or HLA-A24-positive healthy individuals were pulsed with the purified p53 protein. Uptake of p53 protein by human dendritic cells was assessed by Western blotting and immunohistochemical staining using anti-p53 antibody. Induction of p53-specific CTL response was also evaluated by the cytotoxic assay against p53-overexpressing human tumor cells. Both Western blot and immunohistochemical analysis showed the accumulation of p53 protein in human immature dendritic cells. T cells obtained from HLA-A2- or HLA-A24-positive healthy donors were stimulated twice with p53 protein-pulsed dendritic cells and then applied to the cytotoxicity assay against p53-overexpressing target cells. The CTL activity was specific for p53-overexpressing tumor cells and MHC class I restricted. Moreover, the CTL activity generated by p53 protein-pulsed dendritic cells was nearly identical with that induced by adenoviral wt-p53-transduced dendritic cells. Our results indicate that monocyte-derived human dendritic cells pulsed with the wt-p53 protein could induce the specific antitumor effect against p53-overexpressing tumors and that this in vitro model offers a new and more simple approach to the development of p53-based immunotherapy.


Sources of erroneous sequences and artifact chimeric reads in next generation sequencing of genomic DNA from formalin-fixed paraffin-embedded samples.
Tissues used in pathology laboratories are typically stored in the form of formalin-fixed, paraffin-embedded (FFPE) samples. One important consideration in repurposing FFPE material for next generation sequencing (NGS) analysis is the sequencing artifacts that can arise from the significant damage to nucleic acids due to treatment with formalin, storage at room temperature and extraction. One such class of artifacts consists of chimeric reads that appear to be derived from non-contiguous portions of the genome. Here, we show that a major proportion of such chimeric reads align to both the 'Watson' and 'Crick' strands of the reference genome. We refer to these as strand-split artifact reads (SSARs). This study provides a conceptual framework for the mechanistic basis of the genesis of SSARs and other chimeric artifacts along with supporting experimental evidence, which have led to approaches to reduce the levels of such artifacts. We demonstrate that one of these approaches, involving S1 nuclease-mediated removal of single-stranded fragments and overhangs, also reduces sequence bias, base error rates, and false positive detection of copy number and single nucleotide variants. Finally, we describe an analytical approach for quantifying SSARs from NGS data.


Genomic approaches to improve the clinical diagnosis and management of patients with congenital hydrocephalus.
Congenital hydrocephalus (CH), characterized by incomplete clearance of CSF and subsequent enlargement of brain ventricles, is the most common congenital brain disorder. The lack of curative strategies for CH reflects a poor understanding of the underlying pathogenesis. Herein, the authors present an overview of recent findings in the pathogenesis of CH from human genetic studies and discuss the implications of these findings for treatment of CH. Findings from these omics data have the potential to reclassify CH according to a molecular nomenclature that may increase precision for genetic counseling, outcome prognostication, and treatment stratification. Beyond the immediate patient benefits, genomic data may also inform future clinical trials and catalyze the development of nonsurgical, molecularly targeted therapies. Therefore, the authors advocate for further application of genomic sequencing in clinical practice by the neurosurgical community as a diagnostic adjunct in the evaluation and management of patients diagnosed with CH.


Traceless Silylation of β-C(sp3)-H Bonds of Alcohols via Perfluorinated Acetals.
We report the silylation of primary C-H bonds located β to secondary and tertiary alcohols by exploiting perfluorinated esters as traceless directing groups. The conversion of a secondary or tertiary alcohol to a perfluoroalkyl ester and conversion of the ester to the corresponding silyl acetals by hydrosilylation allows for selective β-C(sp3)-H silylation catalyzed by the combination of [Ir(cod)OMe]2 and Me4Phen (3,4,7,8-tetramethyl-1,10-phenanthroline) to form 6-membered dioxasilinane. Tamao-Fleming oxidation of these dioxasilinane leads to 1,2 diols. The developed sequence was applied to a series of natural products containing hydroxyl groups.


Does vitamin D deficiency increase the severity of COVID-19?
The severity of coronavirus 2019 infection (COVID-19) is determined by the presence of pneumonia, severe acute respiratory distress syndrome (SARS-CoV-2), myocarditis, microvascular thrombosis and/or cytokine storms, all of which involve underlying inflammation. A principal defence against uncontrolled inflammation, and against viral infection in general, is provided by T regulatory lymphocytes (Tregs). Treg levels have been reported to be low in many COVID-19 patients and can be increased by vitamin D supplementation. Low vitamin D levels have been associated with an increase in inflammatory cytokines and a significantly increased risk of pneumonia and viral upper respiratory tract infections. Vitamin D deficiency is associated with an increase in thrombotic episodes, which are frequently observed in COVID-19. Vitamin D deficiency has been found to occur more frequently in patients with obesity and diabetes. These conditions are reported to carry a higher mortality in COVID-19. If vitamin D does in fact reduce the severity of COVID-19 in regard to pneumonia/ARDS, inflammation, inflammatory cytokines and thrombosis, it is our opinion that supplements would offer a relatively easy option to decrease the impact of the pandemic.


Outcome after microsurgery in 14 patients with spinal cavernomas and review of the literature.
Spinal cavernomas are rare, but can cause significant neurological deficits due to mass effect and extralesional hemorrhage. The authors present their results of microsurgical treatment of 14 consecutive patients with spinal cavernoma, and review the literature. Of the 376 patients with cavernomas of the CNS treated at Helsinki University Central Hospital (a catchment area close to 2 million inhabitants) between January 1980 and June 2009, 14 (4%) had a spinal cavernoma. The authors reexamined and analyzed the patient files and images retrospectively. Median patient age at presentation was 45 years (range 20–57 years). The female/male ratio was equal. Median duration of symptoms before admission to the department was 12 months (range 0.1–168 months). Patients suffered from sensorimotor paresis, radicular pain, or neurogenic micturition disorders in different combinations or separately. Hemorrhage had occurred in 7 patients (50%) before surgery. In 9 patients (64%) the cavernoma was intramedullary, in 4 (29%) extradural, and in 1 intradural extramedullary. On MR imaging, 6 patients (43%) had a cavernoma in the cervical region, 7 (50%) in the thoracic region, and 1 (7%) in the lumbar region. Postoperatively, patients were followed up for a median of 3 years (range 1–10 years). At follow-up, 13 patients (93%) experienced significant improvement in motor ability after surgery, and all patients were able to walk with or without aid. Ten of the 11 patients with pain syndrome (91%) showed significant pain relief without recurrence. Micturition disorder was noted in 6 patients (43%) at follow-up, but in 5 the condition had existed before surgery. No patient improved in bladder function after surgery, and 1 patient developed micturition dysfunction postoperatively. Microsurgical removal of spinal cavernomas alleviates sensorimotor deficits and pain caused by mass effect and hemorrhage. However, bladder dysfunction remains unchanged after surgery.


Is a fatty pancreas a banal lesion?
So far, a fatty pancreas has been related to obesity and the ageing processes in the body. The current list of pathogenetic factors of the condition is clearly extended with genetically conditioned diseases (cystic fibrosis, Shwachman-Diamond syndrome and Johanson-Blizzard syndrome), pancreatitis, especially hereditary and obstructive, metabolic and hormonal disorders (hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hypercortisolemia), alcohol overuse, taking some medicines (especially adrenal cortex hormones), disease of the liver and visceral adiposis. As regards lipomatosis of that organ resulting mainly from dyslipidemia and hyperglycemia, the term "nonalcoholic fatty pancreas disease" was introduced. Experimental studies on animals and histological preparations of the pancreatic fragments show that the lipotoxicity of the collected adipocytes collected ion the organ release a cascade of proinflammatory phenomena, and even induces the processes of carcinogenesis. Pancreas adiposis is best defined in Computed Tomography and Magnetic Resonance Imaging. However, a series of works proved the usefulness in the diagnostics of that pathology of transabdominal and endoscopic ultrasonography. In that method, the degree of adiposis was based on the comparison of echogenicity of the pancreas and the liver, renal parenchyma, spleen and/or retroperitoneal adipose. Recently, the evaluation was expanded by the evaluation of the degree of pancreatic adipose with the pancreas-to-liver index, utilizing to that end a special computer program. According to our experience, the simplest solution is the method utilized by us. On one crosssection of the body of the pancreas, its echogenicity is assessed in comparison to retroperitoneal adipose and the visibility of the splenic vein, pancreatic duct and the major retroperitoneal vessels. Depending on the visualization of these structures, it is possible to determine the degree of pancreas adiposis. Such a study applies to 250 people, in whom the adiposis was detected in 16.5%, which is close to other cohort US examinations results.


Phylogenomic analyses of more than 4000 nuclear loci resolve the origin of snakes among lizard families.
Squamate reptiles (lizards and snakes) are the most diverse group of terrestrial vertebrates, with more than 10 000 species. Despite considerable effort to resolve relationships among major squamates clades, some branches have remained difficult. Among the most vexing has been the placement of snakes among lizard families, with most studies yielding only weak support for the position of snakes. Furthermore, the placement of iguanian lizards has remained controversial. Here we used targeted sequence capture to obtain data from 4178 nuclear loci from ultraconserved elements from 32 squamate taxa (and five outgroups) including representatives of all major squamate groups. Using both concatenated and species-tree methods, we recover strong support for a sister relationship between iguanian and anguimorph lizards, with snakes strongly supported as the sister group of these two clades. These analyses strongly resolve the difficult placement of snakes within squamates and show overwhelming support for the contentious position of iguanians. More generally, we provide a strongly supported hypothesis of higher-level relationships in the most species-rich tetrapod clade using coalescent-based species-tree methods and approximately 100 times more loci than previous estimates.


First Report of Grapevine leafroll-associated virus 7 in Two Native Grape Varieties in China.
Grapevine leafroll disease (GLD) is one of the most economically important diseases of cultivated grapevines (Vitis vinifera), causing decrease in yield, as well as decreasing the sugar levels and increasing the acidity of the berries (1). There are currently at least 10 serologically distinct viruses, referred to as grapevine leafroll-associated viruses (GLRaVs), from the family Closteroviridae that are associated with leafroll disease (4). China is one of the world's leading grape producers, and nearly 75% of the vineyards in China are located in Xinjiang Uygur Autonomous Region, and Hebei, Shandong, Gansu, Ningxia, and Yunnan provinces. Grapevine leafroll-associated virus 7 (GLRaV-7) isolates have been reported so far in Liaoning (GQ849392, GQ849393, and JF927943) and Henan (EF093187) provinces in China (3). The four Chinese isolates were isolated respectively from grape varieties, Cabernet Sauvignon (GQ849392, GQ849393), Centennial Seedless (JF927943), and Semillon (EF093187), and these grape varieties are introduced from abroad. Cow's Nipple and Dragon's Eye are old grape varieties native to China. Cow's nipple is extensively cultivated in Xinjiang Uygur Autonomous Region, while Dragon's Eye is widely planted in Heibei Province. To determine if GLRaV-7 was present in these two varieties, six samples (three per variety) were collected from six individual grapevines showing GLD-like symptoms in two vineyards in Xinjiang Uygur Autonomous Region and Hebei Province, respectively, in September 2011. Total RNA extracts obtained from phloem scrapings of samples using the RNeasy plant mini kit (QIAGEN) were tested by reverse transcription (RT)-PCR with primers F1 (5'-TATATCCCAACGGAGATGGC-3') and R1 (5'-ATGTTCCTCCACCAAAATCG-3') (2) specific to the heat shock protein 70 homologue (HSP-70 gene) of GLRaV-7. All samples produced a single band of the expected size of 502 bp. One GLRaV-7-specific amplicon per variety was cloned into pMD 18-T simple vector (TaKaRa). Plasmid DNA was purified using Column Plasmid DNAOUT (TIANDZ, Beijing, China) from three individual clones and sequenced from both directions. The sequence of the two isolates (GenBank Accession Nos. JX494722 and JX494723) shared 97.81% identity at the nucleotide level and 100% identity at the amino acid level. A pairwise comparison of HSP-70 sequences of the two isolates from this report with nine corresponding sequences of GLRaV-7 isolates (including four previously reported Chinese isolates) showed nucleotide sequence identities ranging from 91.24% (EF093187) to 98.80% (GQ849392). These samples were further analyzed by double antibody sandwich (DAS)-ELISA using antibody specific to GLRaV-7 (NEOGEN Europe, Ayr, Scotland) according to the manufacturer's instructions, and the results confirmed the presence of the virus in these samples that were positive by RT-PCR. To our knowledge, this is the first report of GLRaV-7 occurring in native grape varieties in China. These results could be helpful in developing sound diagnostic systems for implementing efficient disease management strategies. References: (1) B. Akbas et al. Hort. Sci. 36:97, 2009. (2) E. Engel et al. Plant Dis. 92:1252, 2008. (3) X. Fan et al. Acta Hortic. Sinica 39:949, 2012. (4) G. P. Martelli. Extended Abstr. 16th Meet. International Council for the Study of Virus and Virus-like Diseases of Grapevines (ICVG). 15-23, 2009.


A fluorescent, shape-persistent dendritic host with photoswitchable guest encapsulation and intramolecular energy transfer.
A fluorescent and photoresponsive host based on rigid polyphenylene dendrimers (PPDs) has been synthesized. The key building block for the divergent dendrimer buildup is a complex tetracyclone 12 containing azobenzenyl, pyridyl, and ethynyl entities. The rigidity of polyphenylenes is of crucial importance for a site-specific placement of different functions: eight azobenzene (AB) moieties into the rigid scaffold, a fluorescent perylenetetracarboxdiimide (PDI) into the core, and eight pyridin functions into the interior cavities. AB moieties of host-1 undergo reversible cis-trans photoisomerization and are photostable, as confirmed by various techniques: UV-vis, (1)H NMR, size exclusion chromatography, and fluorescence correlation (FCS). In this system, AB moieties act as photoswitchable hinges and enable control over (i) molecular size, (ii) intramolecular energy transfer between AB and PDI, and (iii) encapsulation and release of guest molecules. The presence of PDI allows not only following the effect of cis-trans photoisomerization on molecular size with highly sensitive FCS but also monitoring the efficiency of the intramolecular energy transfer process (from AB to PDI) by time-resolved optical spectroscopy. Pyridyl functions were incorporated to facilitate guest uptake via hydrogen bonds between the host and guests. Also, we have demonstrated that the photoswitchability of the host can be utilized to actively encapsulate guest molecules into its interior cavities. This novel, light-driven encapsulation mechanism could enable the design of new drug delivery systems.


Adsorption of heavy metals on kaolinite and montmorillonite: a review.
The process of adsorption is considered to be one of the best water treatment technologies around the world. Different heavy metals, due to their toxic and hazardous nature, are possibly the most widespread groundwater contaminants imposing a serious threat to human health. In this review, an attempt has been made to discuss the use of two common clay materials, namely kaolinite and montmorillonite, along with their modified forms for heavy metal removal on the basis of published reports (2008 onwards). The modifications of clays have been attempted by the process of pillaring, intercalation, acid/base activation, functionalization, etc. The adsorption of toxic metals, viz., As, Cd, Cr, Co, Cu, Fe, Pb, Mn, Ni, Zn, etc., has been studied predominantly. Montmorillonite and its modified forms have much higher metal adsorption capacity compared to that of kaolinite as well as modified-kaolinite. The modification often boosted the adsorption capacities of the clays, however, reverse trends are also reported in some cases.


Evidence from Y-chromosome analysis for a late exclusively eastern expansion of the Bantu-speaking people.
The expansion of the Bantu-speaking people (EBSP) during the past 3000-5000 years is an event of great importance in the history of humanity. Anthropology, archaeology, linguistics and, in recent decades, genetics have been used to elucidate some of the events and processes involved. Although it is generally accepted that the EBSP has its origin in the so-called Bantu Homeland situated in the area of the border between Nigeria and the Grassfields of Cameroon, and that it followed both western and eastern routes, much less is known about the number and dates of those expansions, if more than one. Mitochondrial, Y-chromosome and autosomal DNA analyses have been carried out in attempts to understand the demographic events that have taken place. There is an increasing evidence that the expansion was a more complex process than originally thought and that neither a single demographic event nor an early split between western and eastern groups occurred. In this study, we analysed unique event polymorphism and short tandem repeat variation in non-recombining Y-chromosome haplogroups contained within the E1b1a haplogroup, which is exclusive to individuals of recent African ancestry, in a large, geographically widely distributed, set of sub-Saharan Africans (groups=43, n=2757), all of whom, except one Nilo-Saharan-speaking group, spoke a Niger-Congo language and most a Bantu tongue. Analysis of diversity and rough estimates of times to the most recent common ancestors of haplogroups provide evidence of multiple expansions along eastern and western routes and a late, exclusively eastern route, expansion.


Preliminary study comparing the effects of locally and systemically applied L-carnitine on the healing of full-thickness skin defects.
L-carnitine as an endogenous cofactor has a role in the regulation of energy flow between different oxidative sources. The purpose of this study is to investigate that the clinical and histopathologic effects of L-carnitine locally and systemically on secondary healing in wounds of full thickness defects. We also measured the effects of L-carnitine on wound tensile strength as mechanical. sixty adult male Sprague-Dawley rats were divided into three groups randomly; group 1 (control group, n = 20), group 2 (local experimental group, n = 20), group 3 (systemic experimental group, n = 20). Group 1 was not given any pharmacologic agents. L-carnitine was administered locally in the group 2, and systemically in group 3 for a total of 14 days. The healing days of all groups were recorded. On the 7th, 10th,14th and 21st postoperative days, biopsy specimens, including tissue samples both from healing wound sites and sur-rounding healthy skin were evaluated for neovascularization, inflammation, the amount of collagen deposit, fibroblast migration and re-epithelization. Tensile strength was measured in the samples which completed healing on the 30th day. The results were evaluated by nonparametric Kruskall-Wallis test followed by Mann Whitney-U test. the mean clinical healing days were 18.25 days, 16.5 days, 15 days for the control group, local experimental and systemic group, respectively. The differences between groups were statistically significant (p < 0.005). Mean tensile strength values were 762.10 centinewton (cN), 801.69 cN and 786.13 cN for the control group, local experimental group and systemic experimental group, respectively. There were no statistically significant differences between groups (p > 0.05). There was no statistically significant difference in the histopathologic ex-amination on the 7th, 10th, 14th and 21st days in the neovascularization, inflammation and fibroblast migration. Collagen deposit was most prevalent in the systemic experimental group and was least in the control group. Complete wound closure rate was observed on the 7th day in the systemic administration group, on the 10th day in local administration group and on the 14th day in the control group. Re-epithelization thickness in the systemic carnitine group was more than the other groups. L-carnitine administered locally or systemically has positive effects on wound healing rate and tensile strength in rats.


Randomized Comparison of a Biodegradable Polymer Ultrathin Strut Sirolimus-Eluting Stent With a Biodegradable Polymer Biolimus-Eluting Stent in Patients Treated With Percutaneous Coronary Intervention: The SORT OUT VII Trial.
Coronary drug-eluting stents with biodegradable polymers have been designed to improve safety and efficacy. The Scandinavian Organization for Randomized Trials With Clinical Outcome (SORT OUT) VII trial-a large-scale registry-based randomized, multicenter, single-blind, 2-arm, noninferiority trial-compared 2 biodegradable polymer drug-eluting stents: the thin-strut cobalt-chromium sirolimus-eluting Orsiro stent and the stainless steel biolimus-eluting Nobori stent in an all-comer patient population. The primary end point target lesion failure was a composite of cardiac death, myocardial infarction (not related to other than index lesion), or target lesion revascularization within 1 year, analyzed by intention to treat (noninferiority margin of 3.0%). Clinically driven event detection based on Danish registries was used. A total of 1261 patients were assigned to receive the sirolimus-eluting stent (1590 lesions) and 1264 patients to the biolimus-eluting stent (1588 lesions). At 1 year, the composite end point target lesion failure occurred in 48 patients (3.8%) in the sirolimus-eluting group and in 58 patients (4.6%) in the biolimus-eluting group (absolute risk difference, -0.78% [upper limit of 1-sided 95% confidence interval, 0.61%]; P<0.0001). Rates of definite stent thrombosis occurred in 5 (0.4%) of the sirolimus-eluting group compared with 15 (1.2%) biolimus-eluting stent-treated patients (rate ratio, 0.33; 95% confidence interval, 0.12-0.92; P=0.034), which largely was attributable to a lower risk of subacute definite stent thrombosis: 0.1% versus 0.6% (rate ratio, 0.12; 95% confidence interval, 0.02-1.00; P=0.05). The thin-strut sirolimus-eluting Orsiro stent was noninferior to the biolimus-eluting Nobori stent in unselected patients for target lesion failure at 1 year. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01879358.


Feature Binding of Common Everyday Items Is Not Affected by Age.
There is a surge of studies confirming that old age spares the ability to bind in visual working memory (VWM) multiple features within singular object representations. Furthermore, it has been suggested that such ability may also be independent of the cultural background of the assessed individual. However, this evidence has been gathered with tasks that use arbitrary bindings of unfamiliar features. Whether age spares memory binding functions when the memoranda are features of everyday life objects remains less well explored. The present study investigated the influence of age, memory delay, and education, on conjunctive binding functions responsible for representing everyday items in VWM. We asked 32 healthy young and 41 healthy older adults to perform a memory binding task. During the task, participants saw visual arrays of objects, colours, or coloured objects presented for 6 s. Immediately after they were asked either to select the objects or the colours that were presented during the study display from larger sets of objects or colours, or to recombine them by selecting from such sets the objects and their corresponding colours. This procedure was repeated immediately after but this time providing a 30 s unfiled delay. We manipulated familiarity by presenting congruent and incongruent object-colour pairings. The results showed that the ability to bind intrinsic features in VWM does not decline with age even when these features belong to everyday items and form novel or well-known associations. Such preserved memory binding abilities held across memory delays. The impact of feature congruency on item-recognition appears to be greater in older than in younger adults. This suggests that long-term memory (LTM) supports binding functions carried out in VWM for familiar everyday items and older adults still benefit from this LTM support. We have expanded the evidence supporting the lack of age effects on VWM binding functions to new feature and object domains (i.e., everyday items). We have confirmed that education does not negatively impact on such ability at old age. Such results have important implications for the selection of culturally unbiased tests to screen for abnormal ageing trajectories.


Ensemble coding of vocal control in birdsong.
Zebra finch song is represented in the high-level motor control nucleus high vocal center (HVC) (Reiner et al., 2004) as a sparse sequence of spike bursts. In contrast, the vocal organ is driven continuously by smoothly varying muscle control signals. To investigate how the sparse HVC code is transformed into continuous vocal patterns, we recorded in the singing zebra finch from populations of neurons in the robust nucleus of arcopallium (RA), a premotor area intermediate between HVC and the motor neurons. We found that highly similar song elements are typically produced by different RA ensembles. Furthermore, although the song is modulated on a wide range of time scales (10-100 ms), patterns of neural activity in RA change only on a short time scale (5-10 ms). We suggest that song is driven by a dynamic circuit that operates on a single underlying clock, and that the large convergence of RA neurons to vocal control muscles results in a many-to-one mapping of RA activity to song structure. This permits rapidly changing RA ensembles to drive both fast and slow acoustic modulations, thereby transforming the sparse HVC code into a continuous vocal pattern.


Mapping atomic motions with ultrabright electrons: towards fundamental limits in space-time resolution.
The long held objective of directly observing atomic motions during the defining moments of chemistry has been achieved based on ultrabright electron sources that have given rise to a new field of atomically resolved structural dynamics. This class of experiments requires not only simultaneous sub-atomic spatial resolution with temporal resolution on the 100 femtosecond time scale but also has brightness requirements approaching single shot atomic resolution conditions. The brightness condition is in recognition that chemistry leads generally to irreversible changes in structure during the experimental conditions and that the nanoscale thin samples needed for electron structural probes pose upper limits to the available sample or "film" for atomic movies. Even in the case of reversible systems, the degree of excitation and thermal effects require the brightest sources possible for a given space-time resolution to observe the structural changes above background. Further progress in the field, particularly to the study of biological systems and solution reaction chemistry, requires increased brightness and spatial coherence, as well as an ability to tune the electron scattering cross-section to meet sample constraints. The electron bunch density or intensity depends directly on the magnitude of the extraction field for photoemitted electron sources and electron energy distribution in the transverse and longitudinal planes of electron propagation. This work examines the fundamental limits to optimizing these parameters based on relativistic electron sources using re-bunching cavity concepts that are now capable of achieving 10 femtosecond time scale resolution to capture the fastest nuclear motions. This analysis is given for both diffraction and real space imaging of structural dynamics in which there are several orders of magnitude higher space-time resolution with diffraction methods. The first experimental results from the Relativistic Electron Gun for Atomic Exploration (REGAE) are given that show the significantly reduced multiple electron scattering problem in this regime, which opens up micron scale systems, notably solution phase chemistry, to atomically resolved structural dynamics.


A Presence-Only Model of Suitable Roosting Habitat for the Endangered Indiana Bat in the Southern Appalachians.
We know little about how forest bats, which are cryptic and mobile, use roosts on a landscape scale. For widely distributed species like the endangered Indiana bat Myotis sodalis, identifying landscape-scale roost habitat associations will be important for managing the species in different regions where it occurs. For example, in the southern Appalachian Mountains, USA, M. sodalis roosts are scattered across a heavily forested landscape, which makes protecting individual roosts impractical during large-scale management activities. We created a predictive spatial model of summer roosting habitat to identify important predictors using the presence-only modeling program MaxEnt and an information theoretic approach for model comparison. Two of 26 candidate models together accounted for >0.93 of AICc weights. Elevation and forest type were top predictors of presence; aspect north/south and distance-to-ridge were also important. The final average best model indicated that 5% of the study area was suitable habitat and 0.5% was optimal. This model matched our field observations that, in the southern Appalachian Mountains, optimal roosting habitat for M. sodalis is near the ridge top in south-facing mixed pine-hardwood forests at elevations from 260-575 m. Our findings, coupled with data from other studies, suggest M. sodalis is flexible in roost habitat selection across different ecoregions with varying topography and land use patterns. We caution that, while mature pine-hardwood forests are important now, specific areas of suitable and optimal habitat will change over time. Combining the information theoretic approach with presence-only models makes it possible to develop landscape-scale habitat suitability maps for forest bats.


Real-time quantitative PCR of telomere length.
Telomeres cap the ends of chromosomes and are essential for the protection of chromosomes, as well as restricting the replicative potential of a cell. These functions are achieved by the regulation of telomeric repeat length, making the measurement of telomere length a useful aid in the elucidation of the replicative history and potential of cells. Previously published techniques employed either hybridization or flow cytometry methods, which are technically demanding and time-consuming. In 2002, R. M. Cawthon published a real-time polymerase chain reaction (PCR)-based method for telomere length measurement using the Applied Biosystems Prism 7700 sequence detection system. The technique measures the factor by which the ratio of telomere repeat copy number to single-gene copy number differs between a sample and that of a reference deoxyribonucleic acid sample. In many laboratories worldwide, including ours, real-time PCR is carried out using the Roche LightCycler, as opposed to the AB Prism 7700 system. This benchmark details the modifications to Cawthon's method and describes the parameters and reagents required to measure telomere length using the Roche LightCycler.


Bridging the gap between physiology and behavior: evidence from the sSoTS model of human visual attention.
We present the case for a role of biologically plausible neural network modeling in bridging the gap between physiology and behavior. We argue that spiking-level networks can allow "vertical" translation between physiological properties of neural systems and emergent "whole-system" performance-enabling psychological results to be simulated from implemented networks and also inferences to be made from simulations concerning processing at a neural level. These models also emphasize particular factors (e.g., the dynamics of performance in relation to real-time neuronal processing) that are not highlighted in other approaches and that can be tested empirically. We illustrate our argument from neural-level models that select stimuli by biased competition. We show that a model with biased competition dynamics can simulate data ranging from physiological studies of single-cell activity (Study 1) to whole-system behavior in human visual search (Study 2), while also capturing effects at an intermediate level, including performance breakdown after neural lesion (Study 3) and data from brain imaging (Study 4). We also show that, at each level of analysis, novel predictions can be derived from the biologically plausible parameters adopted, which we proceed to test (Study 5). We argue that, at least for studying the dynamics of visual attention, the approach productively links single-cell to psychological data.


Premature Progesterone Elevation Does Not Affect Pregnancy Outcome in High-Responder Patients Undergoing Short-Interval Coasting in IVF Cycles.
BACKGROUND We aimed to present the relationship between premature progesterone elevation (PPE) and clinical outcomes in high-responder patients who had a coasting period of <4 days in length due to their high risk of developing ovarian hyperstimulation syndrome (OHSS) and who were treated with a long-acting gonadotropin-releasing hormone agonist (GnRH-agonist) protocol in in vitro fertilization-embryo transfer (IVF-ET) cycles. MATERIAL AND METHODS This retrospective study was conducted at the University Hospital Assisted Reproductive Technology Center. The outcomes of 101 patients undergoing IVF- intracytoplasmic sperm injection (ICSI) cycles who showed a high response to COH (estradiol >4000 pg/ml and/or >20 follicles each ≥10 mm in diameter and at least 20% ≥15 mm) and who were coasted for <4 days were evaluated. Number of oocytes, 2 pronuclei (PN) embryos, implantation rate, and live birth rate were measured. RESULTS The incidence of PPE was 32.6%. Compared with those without PPE, patients with PPE had a higher number of oocytes retrieved. Total mature and fertilized oocytes and the mean number of embryos transferred were not significantly different between groups. Live birth rates (41.9% vs. 38.7%) and implantation rates (26.5% vs. 23%) were also not significantly divergent in the PPE and non-PPE groups, respectively. CONCLUSIONS P concentrations ≥1.3 ng/ml on the day of human chorionic gonadotropin (hCG) administration, designated in this study as PPE, does not appear to be related to adverse effects in terms of clinical outcomes in high-responder patients undergoing coasting <4 days due to their high risk of developing OHSS treated with a long-acting GnRH-a protocol in IVF-embryo transfer cycles.


Genetic mosaics in strangler fig trees: implications for tropical conservation.
Single trees of six species of strangler figs (Ficus spp., Moraceae) in Panama were found to be made up of multiple genotypes, presumably formed by the fusion of different individuals. The phenomenon is frequent enough that strangler fig populations will contain considerably more genetic variation than would be expected from the number of trees. How this cryptic variation affects populations depends on the flowering phonology of composite trees. If the genetically different portions of trees flower asynchronously, populations of pollinating wasps may be more resistant to low host population sizes than previously thought. If different portions flower synchronously, attempts to infer mating-system parameters from the parentage of fruit crops will be misleading. The fruiting of figs, which are considered a keystone species in tropical forests, is important for maintaining biodiversity but is also particularly susceptible to failure at small population sizes. It is therefore important to know both the number of trees and the number of genotypes in a population.


A stochastic optimization approach for integrated urban water resource planning.
Urban water is facing the challenges of both scarcity and water quality deterioration. Consideration of nonconventional water resources has increasingly become essential over the last decade in urban water resource planning. In addition, rapid urbanization and economic development has led to an increasing uncertain water demand and fragile water infrastructures. Planning of urban water resources is thus in need of not only an integrated consideration of both conventional and nonconventional urban water resources including reclaimed wastewater and harvested rainwater, but also the ability to design under gross future uncertainties for better reliability. This paper developed an integrated nonlinear stochastic optimization model for urban water resource evaluation and planning in order to optimize urban water flows. It accounted for not only water quantity but also water quality from different sources and for different uses with different costs. The model successfully applied to a case study in Beijing, which is facing a significant water shortage. The results reveal how various urban water resources could be cost-effectively allocated by different planning alternatives and how their reliabilities would change.


Gene expression profile in rat hippocampus with and without memory deficit.
The cholinergic neuronal system, through its projections to the hippocampus, plays an important role in learning and memory. The aim of the study was to identify genes and networks in rat hippocampus with and without memory deficit. Genome-scale screening was used to analyze gene expression changes in rats submitted or not to intraparenchymal injection of 192 IgG-saporin and trained in spatial/object novelty tasks. Results showed learning processes were associated with significant expression of genes that could be grouped into several clusters of similar expression profiles and that are involved in biological functions, namely lipid metabolism, signal transduction, protein metabolism and modification, and transcription regulation. Memory loss following hippocampal cholinergic deafferentation was associated with significant expression of genes that did not show similar cluster organization. Only one cluster of genes could be identified; it included genes that would be involved in tissue remodeling. More important, most of the genes significantly altered in lesioned rats were down-regulated.


Defect engineering on electrocatalysts for gas-evolving reactions.
The hydrogen evolution reaction (HER) and oxygen redox reaction, including the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) are the core processes used for water splitting and in metal-air batteries. Thus, the design of electro-catalysts for use in the oxygen redox reaction and HER have received a lot attention around the world. Many strategies have been developed to improve these catalysts, including increasing the surface area, creating unique facet structures, enhancing the conductivities and so on. Among these improvements defect engineering on catalysts has been proven to be an effective and feasible way to accelerate the reaction rate. Herein, a short overview of the recent advances in defect engineering on electro-catalysts for ORR, OER and HER is presented, and the outlook for the defect engineering field is also summarized.


Lactobacillus paracasei SD1, a novel probiotic, reduces mutans streptococci in human volunteers: a randomized placebo-controlled trial.
The present study investigates the effect of an oral Lactobacillus paracasei SD1 isolate on a number of salivary mutans streptococci, lactobacilli, and yeasts and to examine whether the strain could persist in the oral cavity after a short period of consumption. The potential side effect of the probiotic was also evaluated. After informed consent, 40 healthy young adults were recruited and randomly assigned to either the test (A) or placebo (B) groups. Group A received milk powder contained L. paracasei SD1, and group B received standard milk powder once daily for 4 weeks. Salivary mutans streptococci, lactobacilli, and yeasts were enumerated using quantitative differential culture at the baseline and then once a week for 4 weeks after the administration period. The persistence of L. paracasei SD1 was also investigated using AP-PCR for the DNA fingerprinting. A statistically significant reduction in mutans streptococci counts occurred within group A compared to the baseline B (P < 0.05) along with a non-statistically significant reduction in yeast counts. A significant increase in lactobacilli numbers occurred in group A (P < 0.05), and the probiotic strain could be detected up to 4 weeks following cessation of dosing. Our results demonstrate that short-term daily ingestion of the human-derived probiotic L. paracasei SD1 reduces the number of oral mutans streptococci. L. paracasei SD1 may help to decrease the risk of dental caries, and this organism may be a useful probiotic organism for dairy products.


Climate change and children's health--a call for research on what works to protect children.
Climate change is affecting and will increasingly influence human health and wellbeing. Children are particularly vulnerable to the impact of climate change. An extensive literature review regarding the impact of climate change on children's health was conducted in April 2012 by searching electronic databases PubMed, Scopus, ProQuest, ScienceDirect, and Web of Science, as well as relevant websites, such as IPCC and WHO. Climate change affects children's health through increased air pollution, more weather-related disasters, more frequent and intense heat waves, decreased water quality and quantity, food shortage and greater exposure to toxicants. As a result, children experience greater risk of mental disorders, malnutrition, infectious diseases, allergic diseases and respiratory diseases. Mitigation measures like reducing carbon pollution emissions, and adaptation measures such as early warning systems and post-disaster counseling are strongly needed. Future health research directions should focus on: (1) identifying whether climate change impacts on children will be modified by gender, age and socioeconomic status; (2) refining outcome measures of children's vulnerability to climate change; (3) projecting children's disease burden under climate change scenarios; (4) exploring children's disease burden related to climate change in low-income countries; and (5) identifying the most cost-effective mitigation and adaptation actions from a children's health perspective.


Isolated leptomeningeal carcinomatosis and possible fungal meningitis as late sequelae of oesophageal adenocarcinoma.
We describe a case of a 67-year-old man with known chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, osteoarthritis, previous history of excess alcohol intake, and oesophagectomy 3 years earlier for T3N0 adenocarcinoma, referred by his general practitioner with confusion, weight loss and several recent falls. CT of the chest, abdomen and pelvis revealed a right middle-lobe pulmonary embolism, while CT of the head revealed a communicating hydrocephalus. Lumbar puncture was performed, and empirical treatment for tuberculous and fungal meningitis was commenced. Unfortunately, he suffered a rapid neurological deterioration with markedly elevated cerebrospinal fluid (CSF) pressures, leading to an external ventricular drain. Cytological analysis of a CSF sample revealed a cellular infiltrate consistent with leptomeningeal carcinomatosis (adenocarcinoma), with the previous oesophageal malignancy the likely primary. He passed away 17 days after hospital admission. Prolonged culture of CSF later produced evidence of two distinct phaeomycotic moulds (Cladosporium sp and Exophiala sp), suggesting that fungal meningitis may also have contributed to the clinical picture.


Spontaneous dwarf rat: a novel model for aging research.
Dwarf animal models can provide new models for aging research. For the spontaneous dwarf rat (SDR), a dwarf strain derived from the Sprague-Dawley (SD) rat, no data relevant to aging research are available. The present study aimed to examine its growth, hormonal background, lifespan and age-related diseases. Male SDR and SD rats were used for growth comparison and for immunohistochemistry and plasma hormonal analysis. SDR of each sex were maintained until natural death and then inspected pathologically. SDR showed an apparent dwarfism in their youth. Immunohistochemistry indicated that the development of growth hormone (GH)-positive cells in the pituitary was insufficient in SDR. In SDR, plasma GH levels were lower than in SD rats. Moreover, both insulin-like growth factor-1 (IGF-1) and insulin levels were decreased compared to levels in SD rats. Male and female SDR showed a mean lifespan of 29.3 +/- 3.3 and 26.8 +/- 5.3 months, respectively. The main neoplastic lesions in SDR were pituitary and mammary tumors. Major non-neoplastic lesions were incisor malocclusion, heart disease, chronic nephropathy (male) and cerebral hemorrhage (female). Most cases of chronic nephropathy were mild. Compared with longevity data and pathological data reported for SD rats, the lifespan in SDR was increased by 20-40% in males and 10-20% in females, and SDR had characteristic decreases in pituitary and mammary tumors as well as in severe chronic nephropathy. The SDR, differing in endocrinology, longevity and pathology from the SD rat, is potentially a new animal model for aging research.


Impact of Risk-Benefit Perception and Trust on Medical Technology Acceptance in Relation to Drug and Device Lag: A Tripartite Cross-Sectional Survey.
New drug and medical device introduction in Japan usually lags behind that in the West. Many reports indicate that in Japan, the associated risks are considered greater than the benefits recognized in other countries. This study aimed to compare the relationship between risk-benefit perception and acceptance of medical technologies in 3 leading markets. A tripartite cross-sectional survey of the general public was used. In total, 3345 adults in the United Kingdom, the United States, and Japan participated, and sexes and age groups were equally represented. Questions about the perception of risk, benefit, and acceptance of medical and other scientific technologies, and trust of medical product providers or regulatory authorities were included. Five-step Likert coding for risk/benefit/acceptance of 4 medical items (x-rays, antibiotics, vaccines, and cardiac pacemakers) and 6 general items (such as automobiles and airplanes) were collected. Relationships between benefit perception and acceptance were linear for 4 medical technologies. The relationship had a similar slope but was shifted downward in Japan compared with the UK and US ( P < .01), suggesting a lower acceptance in Japan for all benefit perceptions. The trend was the same between risk perception and acceptance, except for slopes that were negative. Correspondence analysis showed a strong correlation among acceptance of medical technologies, benefits of medical technologies, trust in doctors, and trust in the Department of Health. The UK and US attributes were clustered with positive responses such as "useful," "acceptable," and "trustworthy," whereas Japan was clustered with intermediate to negative responses such as "neither" and "untrustworthy." Acceptance of medical technologies was low in Japan because of significant differences in trust for doctors and authorities compared with that in the UK and US. This is a possible basis for delays of 24 to 60 months for medical product approval in Japan.


Fungal morphogenesis.
Morphogenesis in fungi is often induced by extracellular factors and executed by fungal genetic factors. Cell surface changes and alterations of the microenvironment often accompany morphogenetic changes in fungi. In this review, we will first discuss the general traits of yeast and hyphal morphotypes and how morphogenesis affects development and adaptation by fungi to their native niches, including host niches. Then we will focus on the molecular machinery responsible for the two most fundamental growth forms, yeast and hyphae. Last, we will describe how fungi incorporate exogenous environmental and host signals together with genetic factors to determine their morphotype and how morphogenesis, in turn, shapes the fungal microenvironment.


Why Do Kestrels Soar?
Individuals allocate considerable amounts of energy to movement, which ultimately affects their ability to survive and reproduce. Birds fly by flapping their wings, which is dependent on the chemical energy produced by muscle work, or use soaring-gliding flight, in which chemical energy is replaced with energy harvested from moving air masses, such as thermals. Flapping flight requires more energy than soaring-gliding flight, and this difference in the use of energy increases with body mass. However, soaring-gliding results in lower speeds than flapping, especially for small species. Birds therefore face a trade-off between energy and time costs when deciding which flight strategy to use. Raptors are a group of large birds that typically soar. As relatively light weight raptors, falcons can either soar on weak thermals or fly by flapping with low energy costs. In this paper, we study the flight behavior of the insectivorous lesser kestrel (Falco naumanni) during foraging trips and the influence of solar radiation, which we have adopted as a proxy for thermal formation, on kestrel flight variables. We tracked 35 individuals from two colonies using high frequency GPS-dataloggers over four consecutive breeding seasons. Contrary to expectations, kestrels relied heavily on thermal soaring when foraging, especially during periods of high solar radiation. This produced a circadian pattern in the kestrel flight strategy that led to a spatial segregation of foraging areas. Kestrels flapped towards foraging areas close to the colony when thermals were not available. However, as soon as thermals were formed, they soared on them towards foraging areas far from the colony, especially when they were surrounded by poor foraging habitats. This reduced the chick provisioning rate at the colony. Given that lesser kestrels have a preference for feeding on large insects, and considering the average distance they cover to capture them during foraging trips, to commute using flapping flight would result in a negative energy balance for the family group. Our results show that lesser kestrels prioritize saving energy when foraging, suggesting that kestrels are more energy than time-constrained during the breeding season.


Evaluation of environmental monitoring strategies.
In environmental monitoring, it is important that the monitoring system should emit early warnings when undesired events occur. These events may be sudden or of a more subtle nature. In the design of such monitoring systems, a proper balance between cost and risk must be achieved. There are 2 classic types of risk connected with early warning systems, namely the risk of not detecting significant changes and the risk of false alarms. The purpose of this paper is to describe a method for comparing the performance of different monitoring systems, considering the classic types of risk and cost. The method is applied to the monitoring of the lichen cover as a test case. The expected utility has been used as a measure of performance. When estimating the probabilities of the events, spatial microsimulation and Monte-Carlo simulation techniques have been used. The monitoring programs studied are based on satellite images, aerial photos, field samples, and land-cover maps. The major conclusions of this study are that standardized quality measures are extremely useful for evaluating the usability of environmental monitoring methods. In addition, when estimating gains and costs, spatial microsimulation techniques are useful. To improve the method, however, macroconstraints should also be used for aligning the simulation model.


Physiological migration of hematopoietic stem and progenitor cells.
Hematopoietic stem cells (HSCs) reside predominantly in bone marrow, but low numbers of HSCs are also found in peripheral blood. We examined the fate of blood-borne HSCs using genetically marked parabiotic mice, which are surgically conjoined and share a common circulation. Parabionts rapidly established stable, functional cross engraftment of partner-derived HSCs and maintained partner-derived hematopoiesis after surgical separation. Determination of the residence time of injected blood-borne progenitor cells suggests that circulating HSCs/progenitors are cleared quickly from the blood. These data demonstrate that HSCs rapidly and constitutively migrate through the blood and play a physiological role in, at least, the functional reengraftment of unconditioned bone marrow.


MMPI disability profile is associated with degree of opioid use in chronic work-related musculoskeletal disorders.
To examine the relationship between level of opioid use and Minnesota Multiphasic Personality Inventory (MMPI) findings among chronic pain patients who were about to begin a functional restoration program. A prospective cohort study of patients with chronic disabling occupational musculoskeletal disorders. A total of 768 consecutive patients with valid MMPI were divided into 2 groups: 398 patients who reported no opioid use upon admission (No); and 370 patients who reported opioid use upon admission (Yes). Average daily opioid doses (in morphine equivalents) could be determined for 287 of 370 patients, who were further divided into 4 opioid subgroups: Low (>0 to 30 mg, n=148); Medium (>30 to 60 mg, n=57); High (>60 to 120 mg, n=47); and Very High (>120 mg, n=35). Seventy-five percent of the patients who produced valid MMPI profiles could be classified into 1 of the 4 MMPI profiles. Of those patients who could be classified, approximately 7% showed a Normal profile, 15% showed a Conversion V, 9% showed a Neurotic Triad, and 69% showed the Disability Profile. Although the Disability Profile accounted for the majority of patients in all opioid subgroups, the proportions did increase with pretreatment opioid dose, as expected, indicating a relationship between degree of psychopathology and level of pretreatment opioid use. Patients who did not take pretreatment opioids showed the highest proportions of Conversion V and Normal profiles, which indicate a lesser degree or absence of psychopathology, respectively. Patients who took pretreatment opioids were more than one-and-a-half times as likely as patients who did not take pretreatment opioids to produce the Disability Profile, whereas patients taking very high doses of pretreatment opioids were nearly 3 times as likely to produce this profile as patients who took no pretreatment opioids. The results of this study support the hypothesis that increasing levels of pretreatment opioid use is associated with less desirable MMPI profiles, specifically the Disability Profile and, thus, greater levels of pretreatment psychopathology.


Effect of agricultural management regime on Burkholderia community structure in soil.
The main objective of this study was to determine the Burkholderia community structure associated with areas under different agricultural management and to evaluate to which extent this community structure is affected by changes in agricultural management. Two fields with distinct soil history (arable land and permanent grassland) were exposed to three agricultural management regimes (crop rotation, maize monoculture, and grassland). By using a culture-independent approach, based on a Burkholderia-specific polymerase chain reaction-denaturing gradient gel electrophoresis system, it was possible to observe the conversion of Burkholderia communities typical for permanent grassland to those of arable land after four consecutive years. However, the time needed to achieve the reverse transition, i.e., converting the Burkholderia community associated with arable land to that of grassland, was beyond the duration of the field experiment. In addition, by applying principal response curves, the direction and extent of the conversion from grassland to arable land (maize monoculture and to crop rotation) were determined. Hence, the results suggested that agricultural practices, such as fertilization and tillage, were more effective in changing the Burkholderia community structure than agricultural management regime. To determine the effect of agricultural management on the Burkholderia population with biocontrol abilities, the culturable fraction of the Burkholderia community was assessed. The areas under permanent grassland and grassland converted to maize monoculture had the highest percentages of Burkholderia strains with antagonistic activity against Rhizoctonia solani AG-3, mainly Burkholderia pyrrocinia and Burkholderia sp. LMG 22929. The isolation frequency of antagonistic isolates from arable land was extremely low. Our results indicate that (changes in) agricultural management, mainly crop rotation, affect the frequency of isolation of antagonistic Burkholderia strains and that grassland represents a reservoir of Burkholderia species with great potential for agricultural applications.


Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone.
Leptin, the product of the ob gene, is thought to play a key role in the regulation of body fat mass. Beyond this function, it appears to be an integral component of various hypothalamo-pituitary-endocrine feedback loops. Because childhood and puberty are periods of major metabolic and endocrine changes, leptin levels and various hormonal parameters were investigated in a large cohort of healthy children and adolescents (312 males, 401 females, age 5.8-19.9 yr). For this purpose, a specific and sensitive RIA was developed that allowed the accurate measurement of low leptin levels in young lean children. With this assay, leptin proved to be a comparatively stable protein under common conditions of blood sampling and storage. Leptin levels increased in girls with age (r = 0.47, P < 0.0001), but decreased in boys (r = -0.34, P < 0.0001). An analysis according to pubertal stage showed a steady increase in girls between 2.51 micrograms/L (median) at Tanner stage 1 to 6.24 micrograms/L at Tanner stage 5. In boys, leptin levels were highest at Tanner stage 2 (2.19 micrograms/L) and declined thereafter to 0.71 microgram/L at Tanner stage 5. A strong exponential relationship was observed for leptin levels with body mass index (BMI) and percentage body fat as determined by bioelectric impedance measurements in a subgroup of subjects. This relationship was similar between boys and girls at Tanner stages 1 and 2. In boys, there was a significant decline of leptin at a given BMI with further progression of puberty that was much less pronounced in girls. Although the relative increase of leptin with BMI and percent body fat was the same in both genders, the absolute values at a given BMI or percent body fat were significantly lower in boys in late puberty and in adolescents. In boys, but not in girls, there was an inverse correlation with testosterone concentrations (r = -0.43, P < 0.0001), which explained 10.5% of the variation of leptin levels in a multiple regression model. Since BMI proved to be the major influencing variable, reference ranges were constructed using a best-fit regression line of the form leptin = a*e(b*BMI) and stratifying ranges according to gender and pubertal stage. In conclusion, these data suggest that 1) plasma leptin levels increase in girls and decrease in boys after Tanner stage 2 as the pubertal development proceeds; 2) they show a significant gender difference especially in late puberty and adolescence, even after adjustment for BMI or percent body fat; 3) the lower levels in males may be explained at least in part by a suppressive effect of androgens; 4) reference ranges with BMI as the independent variable should be stratified according to gender and pubertal stage.


Trends in the contraceptive method mix in low- and middle-income countries: analysis using a new "average deviation" measure.
The method mix of contraceptive use is severely unbalanced in many countries, with over half of all use provided by just 1 or 2 methods. That tends to limit the range of user options and constrains the total prevalence of use, leading to unplanned pregnancies and births or abortions. Previous analyses of method mix distortions focused on countries where a single method accounted for more than half of all use (the 50% rule). We introduce a new measure that uses the average deviation (AD) of method shares around their own mean and apply that to a secondary analysis of method mix data for 8 contraceptive methods from 666 national surveys in 123 countries. A high AD value indicates a skewed method mix while a low AD value indicates a more uniform pattern across methods; the values can range from 0 to 21.9. Most AD values ranged from 6 to 19, with an interquartile range of 8.6 to 12.2. Using the AD measure, we identified 15 countries where the method mix has evolved from a distorted one to a better balanced one, with AD values declining, on average, by 35% over time. Countries show disparate paths in method gains and losses toward a balanced mix, but 4 patterns are suggested: (1) rise of one method partially offset by changes in other methods, (2) replacement of traditional with modern methods, (3) continued but declining domination by a single method, and (4) declines in dominant methods with increases in other methods toward a balanced mix. Regions differ markedly in their method mix profiles and preferences, raising the question of whether programmatic resources are best devoted to better provision of the well-accepted methods or to deploying neglected or new ones, or to a combination of both approaches.


Effect of resource availability on biparental care, and offspring neural and behavioral development in the California mouse (Peromyscus californicus).
Maternal care influences cognitive function in humans, primates and rodents; however, little is known about the effect of biparental care. Environmental factors such as resource availability play an important role in modulating parental investment strategies with subsequent effects on the offspring. Thus, we examined the interaction between foraging demand and biparental care on hippocampal development and novel object recognition in the monogamous, biparental California mouse. We characterized biparental behavior for 15 days in families exposed to either control (ad libitum feeding) or a high-foraging demand across the weaning period. Adult male offspring were then tested in the open field, and for novel object and place recognition, as well as for hippocampal synaptic density and the expression of genes encoding for subunits of the N-methyl-D-aspartate (NMDA) receptor complex, and the postsynaptic density (PSD)-95 scaffolding protein. Under high-foraging demand, the mothers' body weight was decreased at weaning and fathers spent significantly less time in contact with pups. Offspring reared under high-foraging demand weighed less at weaning and, as adults, were more fearful in the open field and showed profound deficits in both novel object and place recognition. While synaptic density and NR1 mRNA expression were unaffected, offspring reared under high-foraging demand showed increased NR2A and decreased NR2B mRNA expression. Further, PSD-95 protein expression was decreased in mice reared under high-foraging demand. Together, the results suggest that resource availability affects biparental investment strategies, with subsequent effects on hippocampal development and novel object recognition in the offspring.


DALIX: optimal DALI protein structure alignment.
We present a mathematical model and exact algorithm for optimally aligning protein structures using the DALI scoring model. This scoring model is based on comparing the interresidue distance matrices of proteins and is used in the popular DALI software tool, a heuristic method for protein structure alignment. Our model and algorithm extend an integer linear programming approach that has been previously applied for the related, but simpler, contact map overlap problem. To this end, we introduce a novel type of constraint that handles negative score values and relax it in a Lagrangian fashion. The new algorithm, which we call DALIX, is applicable to any distance matrix-based scoring scheme. We also review options that allow to consider fewer pairs of interresidue distances explicitly because their large number hinders the optimization process. Using four known data sets of varying structural similarity, we compute many provably score-optimal DALI alignments. This allowed, for the first time, to evaluate the DALI heuristic in sound mathematical terms. The results indicate that DALI usually computes optimal or close to optimal alignments. However, we detect a subset of small proteins for which DALI fails to generate any significant alignment, although such alignments do exist.


A consensus approach to electrolytes and blood pressure. Could we all be right?
This commentary sets forth the hypothesis that the putative beneficial or detrimental effects of specific electrolytes on blood pressure regulation in fact reflect highly integrated responses to interactions among these cationic and anionic species. In this paradigm, the impact of any given intake of an electrolyte on arterial pressure will be influenced by the concurrent consumption of other electrolytes. Thus, the heterogeneous blood pressure response in humans to isolated manipulations of nutrients such as sodium, calcium, and potassium may be determined, in part, by the adequacy of the dietary intake of other mineral elements. If this hypothesis is validated by continued research in this area, we would have new strategies available to improve blood pressure control in humans. For example, treatment of "NaCl sensitivity" in some humans might be more effectively approached by correcting dietary deficiencies of either potassium or calcium than by restricting dietary NaCl.


Conjugated thiophene-containing oligoacenes through photocyclization: bent acenedithiophenes and a thiahelicene.
The preparation of bent anthradithiophenes (BADTs) using an oxidative photocyclization-based synthetic strategy is reported. The optical properties of the new compounds were characterized by UV-vis and fluorescence spectroscopies, and the redox properties were probed by cyclic voltammetry. Structural studies using single crystal X-ray crystallography show that the unsubstituted BADT adopts a slipped cofacial stacking arrangement in the solid state with pi-pi interactions along the intermolecular stacking axis. The dialkylated derivatives adopt similar packing motifs with varying degrees of slipping along their long and short molecular axes while the diphenyl derivative packs into an edge-to-face herringbone arrangement. Powder diffraction data show that in thin films prepared by vacuum evaporation, molecules of the unsubstituted BADT are oriented nearly perpendicular to the substrate surface whereas the dialkylated derivatives adopt either multiple phases or new polymorphs. A thiahelicene prepared from the oxidative photocyclization of two isomers of 2,5-dithienyl-1,4-distyrylbenzene is described and the crystal structure reported.


Nomogram-based prediction of survival in patients with advanced oesophagogastric adenocarcinoma receiving first-line chemotherapy: a multicenter prospective study in the era of trastuzumab.
To develop and validate a nomogram and web-based calculator to predict overall survival (OS) in Caucasian-advanced oesophagogastric adenocarcinoma (AOA) patients undergoing first-line combination chemotherapy. Nine hundred twenty-four AOA patients treated at 28 Spanish teaching hospitals from January 2008 to September 2014 were used as derivation cohort. The result of an adjusted-Cox proportional hazards regression was represented as a nomogram and web-based calculator. The model was validated in 502 prospectively recruited patients treated between October 2014 and December 2016. Harrell's c-index was used to evaluate discrimination. The nomogram includes seven predictors associated with OS: HER2-positive tumours treated with trastuzumab, Eastern Cooperative Oncology Group performance status, number of metastatic sites, bone metastases, ascites, histological grade, and neutrophil-to-lymphocyte ratio. Median OS was 5.8 (95% confidence interval (CI), 4.5-6.6), 9.4 (95% CI, 8.5-10.6), and 14 months (95% CI, 11.8-16) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the derivation set and 4.6 (95% CI, 3.3-8.1), 12.7 (95% CI, 11.3-14.3), and 18.3 months (95% CI, 14.6-24.2) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the validation set. The nomogram is well-calibrated and reveals acceptable discriminatory capacity, with optimism-corrected c-indices of 0.618 (95% CI, 0.591-0.631) and 0.673 (95% CI, 0.636-0.709) in derivation and validation groups, respectively. The AGAMENON nomogram outperformed the Royal Marsden Hospital (c-index=0.583; P=0.00046) and Japan Clinical Oncology Group prognostic indices (c-index=0.611; P=0.03351). We developed and validated a straightforward model to predict survival in Caucasian AOA patients initiating first-line polychemotherapy. This model can contribute to inform clinical decision-making and optimise clinical trial design.


Receptor-like cytoplasmic kinase MARIS functions downstream of CrRLK1L-dependent signaling during tip growth.
Growing plant cells need to rigorously coordinate external signals with internal processes. For instance, the maintenance of cell wall (CW) integrity requires the coordination of CW sensing with CW remodeling and biosynthesis to avoid growth arrest or integrity loss. Despite the involvement of receptor-like kinases (RLKs) of the Catharanthus roseus RLK1-like (CrRLK1L) subfamily and the reactive oxygen species-producing NADPH oxidases, it remains largely unknown how this coordination is achieved. ANXUR1 (ANX1) and ANX2, two redundant members of the CrRLK1L subfamily, are required for tip growth of the pollen tube (PT), and their closest homolog, FERONIA, controls root-hair tip growth. Previously, we showed that ANX1 overexpression mildly inhibits PT growth by oversecretion of CW material, whereas pollen tubes of anx1 anx2 double mutants burst spontaneously after germination. Here, we report the identification of suppressor mutants with improved fertility caused by the rescue of anx1 anx2 pollen tube bursting. Mapping of one these mutants revealed an R240C nonsynonymous substitution in the activation loop of a receptor-like cytoplasmic kinase (RLCK), which we named MARIS (MRI). We show that MRI is a plasma membrane-localized member of the RLCK-VIII subfamily and is preferentially expressed in both PTs and root hairs. Interestingly, mri-knockout mutants display spontaneous PT and root-hair bursting. Moreover, expression of the MRI(R240C) mutant, but not its wild-type form, partially rescues the bursting phenotypes of anx1 anx2 PTs and fer root hairs but strongly inhibits wild-type tip growth. Thus, our findings identify a novel positive component of the CrRLK1L-dependent signaling cascade that coordinates CW integrity and tip growth.


Wrist-ankle acupuncture for the treatment of pain symptoms: a systematic review and meta-analysis.
Routine acupuncture incorporates wrist-ankle acupuncture (WAA) for its analgesic effect, but WAA is not widely used in clinics due to incomplete knowledge of its effectiveness and concerns about less clinical research and because less people know it. This study aimed to assess the efficacy and possible adverse effects of WAA or WAA adjuvants in the treatment of pain symptoms. This study compared WAA or WAA adjuvant with the following therapies: western medication (WM), sham acupuncture (SA), or body acupuncture (BA). Randomized controlled trials (RCTs) were searched systematically in related electronic databases by two independent reviewers. 33 RCTs were finally included, in which 7 RCTs were selected for meta-analysis. It was found that WAA or WAA adjuvant was significantly more effective than WM, SA, or BA in pain relief. There was nothing different between WAA and SA in adverse events, but WAA was marginally significantly safer than WM. Although both WAA and WAA adjuvant appeared to be more effective than WM, SA, or BA in the treatment of pain symptoms with few side effects, further studies with better and more rigorously designed are still necessary to ensure the efficacy and safety issue of WAA due to the poor methodology and small sample size of previous studies.


Crystallographic analysis of Staphylococcus aureus LcpA, the primary wall teichoic acid ligase.
Gram-positive bacteria, including major clinical pathogens such as Staphylococcus aureus, are becoming increasingly drug-resistant. Their cell walls are composed of a thick layer of peptidoglycan (PG) modified by the attachment of wall teichoic acid (WTA), an anionic glycopolymer that is linked to pathogenicity and regulation of cell division and PG synthesis. The transfer of WTA from lipid carriers to PG, catalyzed by the LytR-CpsA-Psr (LCP) enzyme family, offers a unique extracellular target for the development of new anti-infective agents. Inhibitors of LCP enzymes have the potential to manage a wide range of bacterial infections because the target enzymes are implicated in the assembly of many other bacterial cell wall polymers, including capsular polysaccharide of streptococcal species and arabinogalactan of mycobacterial species. In this study, we present the first crystal structure of S. aureus LcpA with bound substrate at 1.9 Å resolution and those of Bacillus subtilis LCP enzymes, TagT, TagU, and TagV, in the apo form at 1.6-2.8 Å resolution. The structures of these WTA transferases provide new insight into the binding of lipid-linked WTA and enable assignment of the catalytic roles of conserved active-site residues. Furthermore, we identified potential subsites for binding the saccharide core of PG using computational docking experiments, and multiangle light-scattering experiments disclosed novel oligomeric states of the LCP enzymes. The crystal structures and modeled substrate-bound complexes of the LCP enzymes reported here provide insights into key features linked to substrate binding and catalysis and may aid the structure-guided design of specific LCP inhibitors.


Racial disparities in length of stay in hospice care by tumor stage in a large elderly cohort with non-small cell lung cancer.
This study examined whether there are racial disparities for length of stay in hospice for patients with non-small cell lung cancer (NSCLC).We studied 53,626 deceased patients aged ≥66 years diagnosed with American Joint Committee on Cancer stages I-IV NSCLC identified from the Surveillance, Epidemiology, and End Results-Medicare linked data who used hospice services in the last six months before death, and died between 1 January 1991 and 31 December 2005. Median time (days) and percent length of stay in hospice, and multivariate incidence rate ratios (IRRs) with 95% confidence intervals (CIs) using zero-truncated negative binomial regression described relationships. In 2000-2005, most patients (64.1%) had <30 days, including those (30.2%) with <7 days length of stay in hospice care. After adjusting for confounders, the IRR for length of stay in hospice compared to whites was 38% increased for blacks (IRR = 1.38; 95% CI: 1.01-1.89), and almost three-fold increased for Hispanics (IRR = 2.91;95% CI: 1.15-7.37) at stages I-II. However, blacks at stages III-IV had slightly decreased use of hospice services (IRR = 0.91; 95% CI: 0.85-0.97). Length of stay decreased slightly among blacks diagnosed with late stage (III-IV) NSCLC in 2000-2005.The gap in disparity for length of stay in hospice has narrowed for ethnic minorities compared to whites, while some ethnic minorities had greater length of stay at early disease stage.


Tunable nonlinear optical properties in nanocrystalline Si/SiO2 multilayers under femtosecond excitation.
The nonlinear optical properties of nanocrystalline-Si/SiO2 (nc-Si/SiO2) multilayers have been investigated through Z-scan technique by using a Ti-sapphire laser with 50-fs pulse duration at 800 nm as a pump laser. It is interesting to note that with increasing the annealing temperature to make the sample change from amorphous phase to nanocrystalline state, the nonlinear absorption turns the reverse saturation absorption into saturation absorption while the nonlinear optical refraction is also changed simultaneously from self-defocusing to self-focusing. We propose that the localized states at the nc-Si/SiO2 interfaces play the key role in the observed switching behaviors. Our results demonstrate that the tunable optical nonlinearities can be achieved by controlling the microstructures of nc-Si, which can be used as engineering different nonlinear optical devices.


Coherent gigahertz phonons in Ge₂Sb₂Te₅ phase-change materials.
Using ≈40 fs ultrashort laser pulses, we investigate the picosecond acoustic response from a prototypical phase change material, thin Ge2Sb2Te5 (GST) films with various thicknesses. After excitation with a 1.53 eV-energy pulse with a fluence of ≈5 mJ cm(-2), the time-resolved reflectivity change exhibits transient electronic response, followed by a combination of exponential-like strain and coherent acoustic phonons in the gigahertz (GHz) frequency range. The time-domain shape of the coherent acoustic pulse is well reproduced by the use of the strain model by Thomsen et al 1986 (Phys. Rev. B 34 4129). We found that the decay rate (the inverse of the relaxation time) of the acoustic phonon both in the amorphous and in the crystalline phases decreases as the film thickness increases. The thickness dependence of the acoustic phonon decay is well modeled based on both phonon-defect scattering and acoustic phonon attenuation at the GST/Si interface, and it is revealed that those scattering and attenuation are larger in crystalline GST films than those in amorphous GST films.


Genetic polymorphisms of dsRNA ligating pattern recognition receptors TLR3, MDA5, and RIG-I. Association with systemic lupus erythematosus and clinical phenotypes.
This study aimed to demonstrate possible associations between genetic polymorphisms in Toll-like receptor 3, interferon induced with helicase C domain 1 (IFIH1) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 and systemic lupus erythematosus (SLE), including the phenotypes lupus nephritis and malar rash, as well as the presence of autoantibodies against nucleic acid-containing complexes. Genotyping was carried out in two Danish cohorts [Copenhagen (CPH) and Odense (ODE)] totaling 344 patients and was compared with 641 previously genotyped healthy controls. In the ODE cohort, the patients were only genotyped for the rs1990760 polymorphism of IFIH1. Single nucleotide polymorphisms (SNPs) were determined by a multiplex bead-based assay (CPH cohort) or real-time PCR (ODE cohort). Associations were investigated using the Cochran-Armitage trend test. The odds ratio (OR) for minor allele homozygotes versus major allele homozygotes suggested a protective effect of the IFIH1 rs1990760 SNP for SLE in the ODE cohort [OR 0.52, 95 % confidence intervals (95 % CI) 0.31-0.88, Pcorr. = 0.05] but not in the CPH cohort, although the OR suggested a trend in the same direction, and when combining the two patient cohorts, ORs were 0.57, 95 % CI 0.37-0.88. None of the other investigated polymorphisms showed any association with SLE. Regarding phenotypes, we found a statistically significant association between rs1990760 and malar rash in the CPH cohort, with ORs suggesting a protective effect (OR 0.28, 95 % CI 0.13-0.62 for heterozygotes and OR 0.11, 95 % CI 0.03-0.41 for homozygotes, Pcorr. = 0.0001). There were no significant associations between rs1990760 and presence of anti-dsDNA, anti-U1RNP, or anti-Smith antibodies. Our study supports previous findings of an association between the rs1990760 polymorphism of IFIH1 and SLE and indicates that this SNP may also be associated with malar rash in SLE patients although this finding needs confirmation.


The Secretome Engages STAT3 to Favor a Cytokine-rich Microenvironment in Mediating Acquired Resistance to FGFR Inhibitors.
Acquired resistance severely hinders the application of small-molecule inhibitors. Our understanding of acquired resistance related to FGFRs is limited. Here, to explore the underlying mechanism of acquired resistance in FGFR-aberrant cancer cells, we generated cells resistant to multiple FGFR inhibitors (FGFRi) and investigated the potential mechanisms underlying acquired resistance. We discovered that reprogramming of the secretome is closely associated with acquired resistance to FGFRi. The secretome drives acquired resistance by activating the transcription factor STAT3 via its cognate receptors. Moreover, macrophages and fibroblasts could interact with cancer cells to enhance acquired resistance by promoting exaggerated and dynamic cytokine secretion, as well as STAT3 activation. We also found that Hsp90 and HDAC inhibitors could substantially and simultaneously suppress the proliferation of resistant cells, the secretion of multiple cytokines, and the activation of STAT3. Our study offers translational insights concerning the poor efficacy observed in patients with macrophage- and fibroblast-rich lung cancers and breast tumors after treatment with FGFRi in clinical trials.