An explicit strategy prevails when the cerebellum fails to compute movement errors.
In sensorimotor adaptation, explicit cognitive strategies are thought to be unnecessary because the motor system implicitly corrects performance throughout training. This seemingly automatic process involves computing an error between the planned movement and actual feedback of the movement. When explicitly provided with an effective strategy to overcome an experimentally induced visual perturbation, people are immediately successful and regain good task performance. However, as training continues, their accuracy gets worse over time. This counterintuitive result has been attributed to the independence of implicit motor processes and explicit cognitive strategies. The cerebellum has been hypothesized to be critical for the computation of the motor error signals that are necessary for implicit adaptation. We explored this hypothesis by testing patients with cerebellar degeneration on a motor learning task that puts the explicit and implicit systems in conflict. Given this, we predicted that the patients would be better than controls in maintaining an effective strategy assuming strategic and adaptive processes are functionally and neurally independent. Consistent with this prediction, the patients were easily able to implement an explicit cognitive strategy and showed minimal interference from undesirable motor adaptation throughout training. These results further reveal the critical role of the cerebellum in an implicit adaptive process based on movement errors and suggest an asymmetrical interaction of implicit and explicit processes.


Effect of cadmium on cytosine hydroxymethylation in gastropod hepatopancreas.
5-Hydroxymethylcytosine (5hmC) is an important, yet poorly understood epigenetic DNA modification, especially in invertebrates. Aberrant genome-wide 5hmC levels have been associated with cadmium (Cd) exposure in humans, but such information is lacking for invertebrate bioindicators. Here, we aimed to determine whether this epigenetic mark is present in DNA of the hepatopancreas of the land snail Cantareus aspersus and is responsive to Cd exposure. Adult snails were reared under laboratory conditions and exposed to graded amounts of dietary cadmium for 14 days. Weight gain was used as a sublethal endpoint, whereas survival as a lethal endpoint. Our results are the first to provide evidence for the presence of 5hmC in DNA of terrestrial mollusks; 5hmC levels are generally low with the measured values falling below 0.03%. This is also the first study to investigate the interplay of Cd with DNA hydroxymethylation levels in a non-human animal study system. Cadmium retention in the hepatopancreas of C. aspersus increased from a dietary Cd dose of 1 milligram per kilogram dry weight (mg/kg d. wt). For the same treatment, we identified the only significant elevation in percentage of samples with detectable 5hmC levels despite the lack of significant mortalities and changes in weight gain among treatment groups. These findings indicate that 5hmC is an epigenetic mark that may be responsive to Cd exposure, thereby opening a new aspect to invertebrate environmental epigenetics.


Cloning of human thymic subcapsular cortex epithelial cells with T-lymphocyte binding sites and hemopoietic growth factor activity.
The thymic microenvironment involves complex cell interactions among different types of epithelial cells, macrophages, tissue histiocytes, and immature and maturing T cells. We describe the isolation of a subset of thymic epithelial cells by selective primary culture followed by cotransfection with a simian virus 40 replication-origin-defective mutant and pSV2neo plasmid. The cloned cells have the composite immunophenotype that is unique to thymic subcapsular epithelial cells, suggesting that they may provide a model system in vitro for analyzing the earliest steps in T-cell differentiation. This possibility is supported by the finding that these epithelial cells express LFA-3-associated binding sites for T cells, secrete a macrophage hemopoietic growth factor, and synergize with macrophages in the production of interleukin 1.


When Caregiving Ends: The Experiences of Former Family Caregivers of People With Dementia.
Numerous adverse physiological and psychological effects of family caregiving are documented in the literature. However, there is little knowledge about family caregivers after caregiving ends. The purpose of this study is to examine the health of former family caregivers and describe their experiences following the death of a care recipient with dementia. Eight former family caregivers were recruited using convenience sampling. Each caregiver participated in one semi-structured interview ranging from 45 minutes to 3 hours in length. The interviews were audio recorded and transcribed for qualitative content analysis. Three overarching themes emerged from the data: (a) sleep disturbances, (b) changes in health status, and (c) learning to live again. Despite relief from caregiving duties, sleep disturbances in former family caregivers persisted for as long as 10 years post-caregiving. Caregivers reported changes in health such as acute health crises, ongoing illness, or a cascade of nonacute illnesses. Caregivers illustrated post-caregiving as a process of learning to live again, characterized by initial uncertainty about how to proceed in life and a reluctance to relinquish caregiving after years of identifying with the caregiver role. The results of this study suggest that there may be long-term effects of caregiving on health that persist well beyond the first year post-caregiving. Former caregivers would benefit from further research on the physical and psychological health of former caregivers after the first year of post-caregiving, the role of triggering events during post-caregiving, and interventions to meet the needs of former caregivers.


XP BOND in self-curing mode used for luting porcelain restorations. Part A: Microtensile test.
To assess the bond strength to dentin of an experimental adhesive and the proprietary resin cement used in different curing modes to lute ceramic disks of different thicknesses. Empress II disks (Ivoclar-Vivadent) were luted to dentin using XP BOND (Dentsply [XP]) in combination with the proprietary self-curing activator (SCA) and cement Calibra (Dentsply [C]). Curing of the adhesive was induced either by mixing with the activator (activator, groups 3 to 6) or by light irradiation for 20 s (group 2). The cement was either light cured for 40 s through the ceramic onlay (groups 1 to 5) or cured chemically (groups 6 and 7). Groups 2 and 4 were compared with group 1, in which Prime & Bond NT (Dentsply DeTrey) was tested as control. In groups 3 and 6, 2-mm-thick onlays were luted with XP+SCA, and the cement was light cured for 40 s or autocured for 5 min, respectively. These groups were compared with group 7, in which Syntac (Ivoclar Vivadent) was applied with C and, in order to reproduce the handling procedures of group 6 (although contrary to manufacturer's instructions), no light irradiation was provided for the adhesive or the cement. The influence of onlay thickness (2, 3, 4 mm) on the bond strength developed by XP+SCA/C was assessed by comparing groups 3, 4, 5. In these groups, C was light cured for 40 s through the onlay. Microtensile beams were obtained from the luted teeth. Bond strengths not including pretest failures (in parentheses: value including pretest failures as 0 MPa) were 21.0 (17.5) MPa in group 1, 24.9 (21.2) MPa in group 2, 23.7 (21.3) MPa in group 3, 29.9 (26.7) MPa in group 4, 30.3 (24.6) MPa in group 5, 28.6 (24.6) MPa in group 6, and 17.1 (9.2) MPa in group 7. Statistically significant differences were found between groups 1 and 4, groups 3 and 5, and groups 6 and 7. The bonding potential of XP BOND used with the activator or light cured in combination with Calibra in self- or dual-curing mode outperformed that of a control adhesive-cement system. The bond strength of XP+ SCA + Calibra was not negatively affected by the onlay thickness.


Robotic-assisted laparoscopic "salvage" rectopexy for recurrent ileoanal J-pouch prolapse.
Total restorative proctocolectomy with ileal pouch-anal anastomosis (RP/IPAA) has become the standard of care for the surgical treatment of ulcerative colitis. Despite its correlation with an excellent quality of life and favorable long-term outcomes, RP/IPAA has been associated with several complications. Prolapse of the ileoanal pouch is a rare and debilitating complication that should be considered in the differential diagnosis of pouch failure. Limited data exist regarding the prevalence and treatment of pouch prolapse. We present the case of a recurrent J-pouch prolapse treated with a novel minimally invasive "salvage" approach involving a robotic-assisted laparoscopic rectopexy with mesh.


The Faculty of Medical Sciences, St Augustine, and its contribution to human resource development in the Caribbean.
The University of the West Indies (UWI), Faculty of Medical Sciences (FMS), St Augustine campus, began teaching its undergraduate programme in October 1989, in three Schools: Medicine, Dentistry and Veterinary Medicine. The first batch of students graduated in 1994. A four-year Pharmacy Programme commenced in 1995, producing its first graduates in 1999 and ten years later an accelerated Bachelor of Science in Nursing was started and saw its first graduates in 2006. In its twenty years of existence, the FMS has graduated 2380 students from its undergraduate programmes. The facuhy has thus strengthened the human resource capacity in the health sector of most of the contributing territories of the Caribbean region and the vast majority of the undergraduates have been from Trinidad and Tobago. To present a longitudinal study of the number of graduates from 1994 to 2008, and to highlight the number of doctors, dentists, veterinarians, pharmacists and nurses in the region and beyond, who have graduated from the programmes of the FMS. The FMS, St Augustine, plays an important role in producing qualified health personnel. The study is a compilation of graduates from the UWI, FMS, St Augustine from 1994 to 2008. The first batch, which started in 1989, graduated in 1994. No other compilation of this type exists for other faculties. Data were obtained by harvesting the names of graduates from the graduation booklets, and by cross-checking administration records of the Faculty's Office. The study shows that fifteen of the sixteen contributing Caribbean territories have had graduates from the FMS, St Augustine, with Anguilla the one exception. Other graduates have come from beyond the region, including 16 developed and developing nations. The FMS, St Augustine, serves a key role in providing health professionals for the region.


A Novel Strategy for Decoding and Validating the Combination Principles of Huanglian Jiedu Decoction From Multi-Scale Perspective.
Traditional Chinese medicine (TCM) formulas treat complex diseases through combined botanical drugs which follow specific compatibility rules to reduce toxicity and increase efficiency. "Jun, Chen, Zuo and Shi" is one of most used compatibility rules in the combination of botanical drugs. However, due to the deficiency of traditional research methods, the quantified theoretical basis of herbal compatibility including principles of "Jun, Chen, Zuo and Shi" are still unclear. Network pharmacology is a new strategy based on system biology and multi-disciplines, which can systematically and comprehensively observe the intervention of drugs on disease networks, and is especially suitable for the research of TCM in the treatment of complex diseases. In this study, we systematically decoded the "Jun, Chen, Zuo and Shi" rules of Huanglian Jiedu Decoction (HJD) in the treatment of diseases for the first time. This interpretation method considered three levels of data. The data in the first level mainly depicts the characteristics of each component in single botanical drug of HJD, include the physical and chemical properties of component, ADME properties and functional enrichment analysis of component targets. The second level data is the characterization of component-target-protein (C-T-P) network in the whole protein-protein interaction (PPI) network, mainly include the characterization of degree and key communities in C-T-P network. The third level data is the characterization of intervention propagation properties of HJD in the treatment of different complex diseases, mainly include target coverage of pathogenic genes and propagation coefficient of intervention effect between target proteins and pathogenic genes. Finally, our method was validated by metabolic data, which could be used to detect the components absorbed into blood. This research shows the scientific basis of "Jun-Chen-Zuo-Shi" from a multi-dimensional perspective, and provides a good methodological reference for the subsequent interpretation of key components and speculation mechanism of the formula.


A crucial role for T-bet in selectin ligand expression in T helper 1 (Th1) cells.
Proinflammatory T helper 1 (Th1) cells express high levels of carbohydrate ligands for the endothelial selectins, but the molecular basis for this phenotype is incompletely understood. We document here a significant role in selectin ligand formation for the recently described Th1 transcription factor T-bet. Th1 cells generated from T-bet-/- mice showed significantly lower levels of ligands for both E-selectin and P-selectin, compared with wild-type (WT) Th1 cells. Enforced expression of T-bet in WT Th0 cells only modestly up-regulated P-selectin ligands and had no effect on E-selectin ligands. To define a mechanism for the defects observed in T-bet-/- mice, we examined expression of glycosyltransferases involved in selectin ligand biosynthesis. T-bet-/- Th1 cells expressed significantly lower levels of core 2 beta1,6 N-acetylglucosaminyltransferase I (C2GlcNAcT-I), but no differences in levels of alpha 2,3-sialyltransferase IV (ST3Gal-IV). Further, we show that T-bet is responsible for the signal transducer and activator of transcription 4 (Stat4)-independent increase in Th1 cells of fucosyltransferase VII (FucT-VII). We also identify ST3Gal-VI, which is thought to play an important role in E- and P-selectin ligand formation, as an interleukin 12 (IL-12)-regulated, T-bet-dependent gene. These data show that T-bet controls selectin ligand formation in Th1 cells via control of expression of multiple key enzymes in response to IL-12 signaling and establishes an independent transcriptional pathway for control of Th1 cell traffic.


Beta2-agonists for acute bronchitis.
There are no clearly effective treatments for the cough of acute bronchitis. Beta2-agonists are often prescribed, perhaps because clinicians suspect many patients also have reversible airflow restriction contributing to the symptoms. To determine whether beta2-agonists improve acute bronchitis symptoms in patients with no underlying pulmonary disease. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2011, issue 1 which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (January 1966 to February week 1, 2011) and EMBASE (1974 to February 2011). Randomised controlled trials (RCTs) in which patients (adults, or children over two years of age) with acute bronchitis or acute cough and without known pulmonary disease were allocated to beta2-agonist versus placebo, no treatment or alternative treatment. Three review authors independently selected outcomes and extracted data while blinded to study results. Two review authors independently assessed each trial for risk of bias. We analysed trials in children and adults separately. Two trials in children (n = 109) with no evidence of airway obstruction did not find any benefits from oral beta2-agonists. Five trials in adults (n = 418) had mixed results but overall summary statistics did not reveal any significant benefits from oral (three trials) nor inhaled (two trials) beta2-agonists. There were no significant differences in daily cough scores nor in the percentage of adults still coughing after seven days (control group 73%; risk ratio (RR) 0.77, 95% confidence interval (CI) 0.54 to 1.09). in one trial, subgroups with evidence of airflow limitation had lower symptom scores if given beta2-agonists. The trials that noted quicker resolution of cough with beta2-agonists were those with a higher proportion of wheezing patients at baseline. Adults given beta2-agonists were more likely to report tremor, shakiness or nervousness (RR 7.94, 95% CI 1.17 to 53.94; number needed to treat to harm (NNTH) 2.3). There is no evidence to support the use of beta2-agonists in children with acute cough who do not have evidence of airflow obstruction. There is also little evidence that the routine use of beta2-agonists is helpful for adults with acute cough. These agents may reduce symptoms, including cough, in people with evidence of airflow obstruction. However, this potential benefit is not well-supported by the available data and must be weighed against the adverse effects associated with their use.


Computational immuno-biology for organ transplantation and regenerative medicine.
Organ transplantation and regenerative medicine are adopted platforms that provide replacement tissues and organs from natural or engineered sources. Acceptance, tolerance and rejection depend greatly on the proper control of the immune response against graft antigens, motivating the development of immunological and genetical therapies that prevent organ failure. They rely on a complete, or partial, understanding of the immune system. Ultimately, they are innovative technologies that ensure permanent graft tolerance and indefinite graft survival through the modulation of the immune system. Computational immunology has arisen as a tool towards a mechanistic understanding of the biological and physicochemical processes surrounding an immune response. It comprehends theoretical and computational frameworks that simulate immuno-biological systems. The challenge is centered on the multi-scale character of the immune system that spans from atomistic scales, during peptide-epitope and protein interactions, to macroscopic scales, for lymph transport and organ-organ reactions. In this paper, we discuss, from an engineering perspective, the biological processes that are involved during the immune response of organ transplantation. Previous computational efforts, including their characteristics and visible limitations, are described. Finally, future perspectives and challenges are listed to motivate further developments.


Femorotibial cartilage morphology: reproducibility of different metrics and femoral regions, and sensitivity to change in disease.
This study was designed to characterize the reproducibility and sensitivity to change of magnetic resonance imaging-based cartilage morphology metrics and femoral regions of interest (ROIs), in order to provide preferable outcome measures in longitudinal studies of cartilage morphology. Test-retest acquisitions were obtained at 3 tesla (T) in 33 subjects with and without radiographic signs of osteoarthritis (OA) (reproducibility study) as well as baseline and 2-year follow-up acquisitions in 28 subjects with radiographic signs of advanced OA (sensitivity study). Cartilage was segmented in the tibia and two distinct anatomical femoral ROIs, a 'long' ROI extending 60% from the trochlear notch to the posterior end of the condyles, and a 'short' ROI extending to the intercondylar bone bridge. Coefficients of variation (reproducibility study) and standardized response means (SRMs, sensitivity study) were obtained for different morphology metrics and anatomical regions. The subchondral bone area of the long ROI was 20% greater and less variable than that of the short ROI; cartilage morphology metrics were generally more reproducible in the long ROI. Normalized cartilage volume (VCtAB) and mean cartilage thickness (over the entire subchondral bone area; ThCtAB.Me) tended to be more reproducible and more sensitive to change (SRM up to -0.62) than cartilage volume (SRM up to -0.44), cartilage thickness over the cartilaginous area (ThCcAB; SRM up to -0.48) or maximum cartilage thickness (ThCtAB; SRM up to -0.35). The long femoral cartilage ROI provided more reproducible measurements than the short one. VCtAB and ThCtAB.Me may be preferable metrics in longitudinal studies of articular cartilage adaptation or OA.


Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis.
A major obstacle to developing small interfering RNAs (siRNAs) as cancer drugs is their intracellular delivery to disseminated cancer cells. Fusion proteins of single-chain fragmented antibodies (ScFvs) and positively charged peptides deliver siRNAs into specific target cells. However, the therapeutic potential of ScFv-mediated siRNA delivery has not been evaluated in cancer. Here, we tested whether Polo-like kinase 1 (PLK1) siRNAs complexed with a Her2-ScFv-protamine peptide fusion protein (F5-P) could suppress Her2(+) breast cancer cell lines and primary human cancers in orthotopic breast cancer models. PLK1-siRNAs transferred by F5-P inhibited target gene expression, reduced proliferation, and induced apoptosis of Her2(+) breast cancer cell lines and primary human cancer cells in vitro without triggering an interferon response. Intravenously injected F5-P/PLK1-siRNA complexes concentrated in orthotopic Her2(+) breast cancer xenografts and persisted for at least 72 hours, leading to suppressed PLK1 gene expression and tumor cell apoptosis. The intravenously injected siRNA complexes retarded Her2(+) breast tumor growth, reduced metastasis, and prolonged survival without evident toxicity. F5-P-mediated delivery of a cocktail of PLK1, CCND1, and AKT siRNAs was more effective than an equivalent dose of PLK1-siRNAs alone. These data suggest that F5-P could be used to deliver siRNAs to treat Her2(+) breast cancer.


Kinetics of immune responses to the AZD1222/Covishield vaccine with varying dose intervals in Sri Lankan individuals.
To understand the kinetics of immune responses with different dosing gaps of the AZD1222 vaccine, we compared antibody and T cell responses in two cohorts with two different dosing gaps. Antibodies to the SARS-CoV-2 virus were assessed in 297 individuals with a dosing gap of 12 weeks, sampled at 12 weeks post second dose (cohort 1) and in 77 individuals with a median dosing gap of 21.4 weeks (cohort 2) sampled 6 weeks post second dose. ACE2 receptor blocking antibodies (ACE2R-Abs), antibodies to the receptor binding domain (RBD) of the virus and variants of concern (VOC) and ex vivo T cell responses were assessed in a sub cohort. All individuals (100%) had SARS-CoV-2 specific total antibodies and 94.2% of cohort 1 and 97.1% of cohort 2 had ACE2R-blocking Abs. There was no difference in antibody titres or positivity rates in different age groups in both cohorts. The ACE2R-blocking Abs (p<0.0001) and antibodies to the RBD of the VOCs were significantly higher in cohort 2, compared to cohort 1. 41.2% to 65.8% of different age groups gave a positive response by the haemagglutination assay to the RBD of the ancestral virus and VOCs in cohort 1, while 53.6% to 90% gave a positive response in cohort 2. 17/57 (29.8%) of cohort 1 and 17/29 (58.6%) of cohort 2 had ex vivo IFNγ ELISpot responses above the positive threshold. The ACE2R-blocking antibodies and ex vivo IFNγ ELISpot responses at 12 weeks post-first dose, significantly correlated with levels 12 weeks post second dose (Spearman's r=0.46, p=0.008) and (Spearman's r=0.71, p<0.0001) respectively. Both dosing schedules resulted in high levels of antibody and T cell responses post vaccination, although those with a longer dosing gap had a higher magnitude of responses, possibly as immune responses were measured 6 weeks post second dose compared to 12 weeks post second dose.


Cdt1 and Geminin in cancer: markers or triggers of malignant transformation?
Cdt1 and its inhibitor Geminin are important regulators of replication licensing. In normal cells, a critical balance between these two proteins ensures that firing of each origin along the genome will take place only once per cell cycle. Cdt1 overexpression in cell lines and animals leads to aberrant replication, activates DNA damage checkpoints and predisposes for malignant transformation. Geminin inactivation mimics the effects of Cdt1 overexpression in cells and generates mitotic defects and abnormal chromosome segregation. Aberrant expression of Cdt1 and Geminin is thus linked to DNA replication defects, aneuploidy and genomic instability. These traits are considered integral to precancerous states and essential elements for malignant transformation. Moreover, Cdt1 and Geminin expression is deregulated in human tumor specimens and Cdt1 and Geminin may represent novel markers useful for cancer diagnosis and prognosis.


Mutant p53 is a transcriptional co-factor that binds to G-rich regulatory regions of active genes and generates transcriptional plasticity.
The molecular mechanisms underlying mutant p53 (mutp53) "gain-of-function" (GOF) are still insufficiently understood, but there is evidence that mutp53 is a transcriptional regulator that is recruited by specialized transcription factors. Here we analyzed the binding sites of mutp53 and the epigenetic status of mutp53-regulated genes that had been identified by global expression profiling upon depletion of endogenous mutp53 (R273H) expression in U251 glioblastoma cells. We found that mutp53 preferentially and autonomously binds to G/C-rich DNA around transcription start sites (TSS) of many genes characterized by active chromatin marks (H3K4me3) and frequently associated with transcription-competent RNA polymerase II. Mutp53-bound regions overlap predominantly with CpG islands and are enriched in G4-motifs that are prone to form G-quadruplex structures. In line, mutp53 binds and stabilizes a well-characterized G-quadruplex structure in vitro. Hence, we assume that binding of mutp53 to G/C-rich DNA regions associated with a large set of cancer-relevant genes is an initial step in their regulation by mutp53. Using GAS1 and HTR2A as model genes, we show that mutp53 affects several parameters of active transcription. Finally, we discuss a dual mode model of mutp53 GOF, which includes both stochastic and deterministic components.


Regular consumption of vitamin D-fortified yogurt drink (Doogh) improved endothelial biomarkers in subjects with type 2 diabetes: a randomized double-blind clinical trial.
Endothelial dysfunction has been proposed as the underlying cause of diabetic angiopathy that eventually leads to cardiovascular disease, the major cause of death in diabetes. We recently demonstrated the ameliorating effect of regular vitamin D intake on the glycemic status of patients with type 2 diabetes (T2D). In this study, the effects of improvement of vitamin D status on glycemic status, lipid profile and endothelial biomarkers in T2D subjects were investigated. Subjects with T2D were randomly allocated to one of the two groups to receive either plain yogurt drink (PYD; containing 170 mg calcium and no vitamin D/250 mL, n1 = 50) or vitamin D3-fortified yogurt drink (FYD; containing 170 mg calcium and 500 IU/250 mL, n2 = 50) twice a day for 12 weeks. Anthropometric measures, glycemic status, lipid profile, body fat mass (FM) and endothelial biomarkers including serum endothelin-1, E-selectin and matrix metalloproteinase (MMP)-9 were evaluated at the beginning and after the 12-week intervention period. The intervention resulted in a significant improvement in fasting glucose, the Quantitative Insulin Check Index (QUICKI), glycated hemoglobin (HbA1c), triacylglycerols, high-density lipoprotein cholesterol (HDL-C), endothelin-1, E-selectin and MMP-9 in FYD compared to PYD (P < 0.05, for all). Interestingly, difference in changes of endothelin-1, E-selectin and MMP-9 concentrations in FYD compared to PYD (-0.35 ± 0.63 versus -0.03 ± 0.55, P = 0.028; -3.8 ± 7.3 versus 0.95 ± 8.3, P = 0.003 and -2.3 ± 3.7 versus 0.44 ± 7.1 ng/mL, respectively, P < 0.05 for all), even after controlling for changes of QUICKI, FM and waist circumference, remained significant for endothelin-1 and MMP-9 (P = 0.009 and P = 0.005, respectively) but disappeared for E-selectin (P = 0.092). On the contrary, after controlling for serum 25(OH)D, the differences disappeared for endothelin-1(P = 0.066) and MMP-9 (P = 0.277) but still remained significant for E-selectin (P = 0.011). Ameliorated vitamin D status was accompanied by improved glycemic status, lipid profile and endothelial biomarkers in T2D subjects. Our findings suggest both direct and indirect ameliorating effects of vitamin D on the endothelial biomarkers. ClinicalTrials.gov: NCT01236846.


Experience sampling research in individuals with mental illness: reflections and guidance.
The experience sampling method (ESM) represents a valuable way of assessing clinical phenomena in real world settings and across time. Despite its theoretical advantages, using this methodology in psychiatric populations is challenging. This paper acts as a guide to researchers wishing to employ this approach when investigating mental illness. The contents represent the opinions of researchers around the United Kingdom and the Netherlands who are experienced at using the ESM. In ESM studies, participants are required to fill in questions about their current thoughts, feelings and experiences when prompted by an electronic device (e.g. a wristwatch, PDA). Entries are typically made at fixed or random intervals over 6 days. This article outlines how to design and validate an ESM diary. We then discuss which sampling procedure to use and how to increase compliance through effective briefing and telephone sessions. Debriefing, data management and analytical issues are considered, before suggestions for future clinical uses of the ESM are made. The last decade has seen an increase in the number of studies employing the ESM in clinical research. Further research is needed to examine the optimal equipment and procedure for different clinical groups.


Femoral antetorsion: comparing asymptomatic volunteers and patients with femoroacetabular impingement.
To assess the range of femoral antetorsion with magnetic resonance (MR) imaging in asymptomatic volunteers and patients with different subtypes of femoroacetabular impingement (FAI) because abnormal femoral antetorsion might be a contributing factor in the development of FAI. This study was institutional review board approved; all individuals provided signed informed consent. Sixty-three asymptomatic volunteers and 63 patients with symptomatic FAI between age 20 and 50 years were matched for age and sex. They underwent standard MR imaging with two additional rapid transverse sequences over the proximal and distal femur for antetorsion measurement. Twenty volunteers underwent a second MR imaging examination in the same leg. Two readers independently measured femoral antetorsion. The time for the additional sequences was tabulated. Interobserver agreement was calculated; differences in antetorsion were assessed by using analysis of variance and the unpaired t test. Femoral antetorsion can be assessed with MR imaging in about 80 seconds, with high interobserver agreement (intraclass correlation coefficient [ICC] = 0.967) and high agreement between different MR examinations (ICC = 0.966). Women had a significantly larger antetorsion than men (P < .001 for both readers), and antetorsion of the left femur was significantly larger than that of the right femur (P = .01 for reader 1, P = .02 for reader 2). Overall, antetorsion was similar in volunteers and in patients for reader 1 (12.7° ± 10.0 [standard deviation] vs 12.6° ± 9.8, respectively; P = .9) and reader 2 (12.8° ± 10.1 vs 13.5° ± 9.8, respectively; P = .7). Femoral antetorsion was significantly higher in patients with pincer-type FAI than in those with cam-type FAI for reader 1 (18.3° ± 9.8 vs 10.0° ± 9.1, P = .02) and reader 2 (18.7° ± 10.5 vs 11.6° ± 8.8, P = .04). Femoral antetorsion can be measured rapidly and with good reproducibility with MR imaging. Patients with pincer-type FAI had a significantly larger femoral antetorsion than patients with cam-type FAI.


Suicide risk and associated factors in healthcare workers seeking psychological support during COVID-19: a cross-sectional study.
Healthcare workers have been one of the groups most severely affected by the COVID-19 pandemic, leaving them with serious psychological effects. Some of these effects have not been treated promptly, leading to further psychological symptoms. The objective of this study was to evaluate suicide risk in healthcare workers seeking psychological help during the COVID-19 pandemic, and factors associated with this risk on participants that were searching for treatment during the COVID-19 pandemic. This is a cross-sectional study analyzing data from 626 Mexican healthcare workers seeking psychological help due to the COVID-19 pandemic through the www.personalcovid.com platform. Before they entered treatment, the Plutchik Suicide Risk Scale, the Depression Scale of the Center for Epidemiologic Studies, the Pittsburgh Sleep Quality Index, and the Professional Quality of Life Measure, were administered. Results: 49.4% (n = 308) presented suicide risk. The most severely affected groups were nurses (62%, n = 98) and physicians (52.7%, n = 96). Predictors of suicide risk in healthcare workers were secondary traumatic stress, high depressive affect, low positive affect, emotional insecurity and interpersonal problems, and medication use. Conclusions: The suicidal risk detected was high, found mostly in nurses and doctors. This study suggests the presence of psychological effects on healthcare workers, despite the time that has elapsed since the onset of the pandemic.


IL-12 directly enhances in vitro murine erythropoiesis in combination with IL-4 and stem cell factor.
It has been demonstrated recently that in vivo administration of murine IL-12 to mice enhances the activity of cytotoxic NK cells and lymphocyte-activated killer cells, and that it has antitumor and antimetastatic activity. However, one side effect observed in response to systemic IL-12 treatment is anemia. In the present study, we examined for the first time the ability of IL-12 to affect directly the growth of murine erythroid progenitor cells in vitro. Whereas IL-12 alone or in combination with Erythropoietin (Epo) showed no stimulatory effect on erythroid progenitors, IL-12 potently enhanced the number of erythroid burst-forming unit (BFU-E) colonies formed in response to Epo+IL-4 by 63% and Epo+stem cell factor by 80%. The stimulatory effect of IL-12 occurred in a concentration-dependent fashion, with maximum enhancing effect observed at 50 ng/ml. Furthermore, single cell experiments suggested that the stimulatory effect of IL-12 on erythroid colony formation was directly mediated. Thus, IL-12 can directly enhance murine erythropoiesis in vitro, suggesting that IL-12-induced anemia is mediated through an indirect mechanism.


Flow cytometry study of blood cell subtypes reflects autoimmune and inflammatory processes in autoimmune polyendocrine syndrome type I.
Autoimmune polyendocrine syndrome type I (APS I) is a recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. AIRE is expressed in medullary epithelial cells where it activates transcription of organ-specific proteins in thymus, thereby regulating autoimmunity. Patients with APS I have, in addition to autoimmune manifestations in endocrine organs, also often ectodermal dystrophies and chronic mucocutaneous candidiasis. The aim of this study was to characterize immune cell subpopulations in patients with APS I and their close relatives. Extensive blood mononuclear cell immunophenotyping was carried out on 19 patients with APS I, 18 first grade relatives and corresponding sex- and age-matched healthy controls using flow cytometry. We found a significant relative reduction in T helper cells coexpressing CCR6 and CXCR3 in patients with APS I compared to controls (mean = 4.10% versus 5.94% respectively, P = 0.035). The pools of CD16(+) monocytes and regulatory T cells (Tregs) were also lower in patients compared with healthy individuals (mean = 15.75% versus 26.78%, P = 0.028 and mean = 4.12% versus 6.73%, P = 0.029, respectively). This is the first report describing reduced numbers of CCR6(+)CXCR3(+) T helper cells and CD16(+) monocytes in patients with APS I We further confirm previous findings of reduced numbers of Tregs in these patients.


Orientation discrimination performance is predicted by GABA concentration and gamma oscillation frequency in human primary visual cortex.
Neuronal orientation selectivity has been shown in animal models to require corticocortical network cooperation and to be dependent on the presence of GABAergic inhibition. However, it is not known whether variability in these fundamental neurophysiological parameters leads to variability in behavioral performance. Here, using a combination of magnetic resonance spectroscopy, magnetoencephalography, and visual psychophysics, we show that individual performance on a visual orientation discrimination task is correlated with both the resting concentration of GABA and the frequency of stimulus-induced gamma oscillations in human visual cortex. Behaviorally, a strong oblique effect was found, with the mean angular threshold for oblique discrimination being five times higher than that for vertically oriented stimuli. Similarly, we found an oblique effect for the dependency of performance on neurophysiological parameters. Orientation detection thresholds were significantly negatively correlated with visual cortex GABA concentration for obliquely oriented patterns (r = -0.65, p < 0.015) but did not reach significance for vertically oriented stimuli (r = -0.39, p = 0.2). Similarly, thresholds for obliquely oriented stimuli were negatively correlated with gamma oscillation frequency (r = -0.65, p < 0.017), but thresholds for vertical orientations were not (r = -0.02, p = 0.9). Gamma oscillation frequency was positively correlated with GABA concentration in primary visual cortex (r = 0.67, p < 0.013). These results confirm the importance of GABAergic inhibition in orientation selectivity and demonstrate, for the first time, that interindividual performance on a simple visual task is linked to neurotransmitter concentration. The results also suggest a key role for GABAergic gamma oscillations in visual discrimination tasks.


Ethnic differences in the link between physical discipline and later adolescent externalizing behaviors.
Parents' use of physical discipline has generated controversy related to concerns that its use is associated with adjustment problems such as aggression and delinquency in children. However, recent evidence suggests that there are ethnic differences in associations between physical discipline and children's adjustment. This study examined race as a moderator of the link between physical discipline and adolescent externalizing behavior problems, extending previous research beyond childhood into adolescence and considering physical discipline at multiple points in time. A representative community sample of 585 children was followed from pre-kindergarten (age 5) through grade 11 (age 16). Mothers reported on their use of physical discipline in the child's first five years of life and again during grades 6 (age 11) and 8 (age 13). Mothers and adolescents reported on a variety of externalizing behaviors in grade 11 including aggression, violence, and trouble at school and with the police. A series of hierarchical linear regressions controlling for parents' marital status, socioeconomic status, and child temperament revealed significant interactions between physical discipline during the child's first five years of life and race in the prediction of 3 of the 7 adolescent externalizing outcomes assessed and significant interactions between physical discipline during grades 6 and 8 and race in the prediction of all 7 adolescent externalizing outcomes. Regression slopes showed that the experience of physical discipline at each time point was related to higher levels of subsequent externalizing behaviors for European American adolescents but lower levels of externalizing behaviors for African American adolescents. There are race differences in long-term effects of physical discipline on externalizing behaviors problems. Different ecological niches may affect the manner in which parents use physical discipline, the meaning that children attach to the experience of physical discipline, and its effects on the adjustment of children and adolescents.


Benefits and resource implications of family meetings for hospitalized palliative care patients: research protocol.
Palliative care focuses on supporting patients diagnosed with advanced, incurable disease; it is 'family centered', with the patient and their family (the unit of care) being core to all its endeavours. However, approximately 30-50% of carers experience psychological distress which is typically under recognised and consequently not addressed. Family meetings (FM) are recommended as a means whereby health professionals, together with family carers and patients discuss psychosocial issues and plan care; however there is minimal empirical research to determine the net effect of these meetings and the resources required to implement them systematically. The aims of this study were to evaluate: (1) if family carers of hospitalised patients with advanced disease (referred to a specialist palliative care in-patient setting or palliative care consultancy service) who receive a FM report significantly lower psychological distress (primary outcome), fewer unmet needs, increased quality of life and feel more prepared for the caregiving role; (2) if patients who receive the FM experience appropriate quality of end-of-life care, as demonstrated by fewer hospital admissions, fewer emergency department presentations, fewer intensive care unit hours, less chemotherapy treatment (in last 30 days of life), and higher likelihood of death in the place of their choice and access to supportive care services; (3) the optimal time point to deliver FM and; (4) to determine the cost-benefit and resource implications of implementing FM meetings into routine practice. Cluster type trial design with two way randomization for aims 1-3 and health economic modeling and qualitative interviews with health for professionals for aim 4. The research will determine whether FMs have positive practical and psychological impacts on the family, impacts on health service usage, and financial benefits to the health care sector. This study will also provide clear guidance on appropriate timing in the disease/care trajectory to provide a family meeting. Australian New Zealand Clinical Trials Registry ACTRN12615000200583.


Molecular recognition of PTS-1 cargo proteins by Pex5p: implications for protein mistargeting in primary hyperoxaluria.
Peroxisomal biogenesis and function critically depends on the import of cytosolic proteins carrying a PTS1 sequence into this organelle upon interaction with the peroxin Pex5p. Recent structural studies have provided important insights into the molecular recognition of cargo proteins by Pex5p. Peroxisomal import is a key feature in the pathogenesis of primary hyperoxaluria type 1 (PH1), where alanine:glyoxylate aminotransferase (AGT) undergoes mitochondrial mistargeting in about a third of patients. Here, we study the molecular recognition of PTS1 cargo proteins by Pex5p using oligopeptides and AGT variants bearing different natural PTS1 sequences, and employing an array of biophysical, computational and cell biology techniques. Changes in affinity for Pex5p (spanning over 3-4 orders of magnitude) reflect different thermodynamic signatures, but overall bury similar amounts of molecular surface. Structure/energetic analyses provide information on the contribution of ancillary regions and the conformational changes induced in Pex5p and the PTS1 cargo upon complex formation. Pex5p stability in vitro is enhanced upon cargo binding according to their binding affinities. Moreover, we provide evidence that the rational modulation of the AGT: Pex5p binding affinity might be useful tools to investigate mistargeting and misfolding in PH1 by pulling the folding equilibria towards the native and peroxisomal import competent state.


[Comparison of denatured and non-denatured PAGE-silver-staining detection of PCR product of microsatellites].
The genomic DNAs from six chicken breeds in China were amplified using two microsatellite primers. The PCR products were detected by non-denatured and denatured PAGE gels respectively, and the gels were dyed by silver. There were distinct differences between the two kinds of gel. In non-denatured gels. There were many nonspecific bands while clear purposed bands were showed in denatured gels.


Towards public health decision support: a systematic review of bidirectional communication approaches.
To summarize the literature describing computer-based interventions aimed at improving bidirectional communication between clinical and public health. A systematic review of English articles using MEDLINE and Google Scholar. Search terms included public health, epidemiology, electronic health records, decision support, expert systems, and decision-making. Only articles that described the communication of information regarding emerging health threats from public health agencies to clinicians or provider organizations were included. Each article was independently reviewed by two authors. Ten peer-reviewed articles highlight a nascent but promising area of research and practice related to alerting clinicians about emerging threats. Current literature suggests that additional research and development in bidirectional communication infrastructure should focus on defining a coherent architecture, improving interoperability, establishing clear governance, and creating usable systems that will effectively deliver targeted, specific information to clinicians in support of patient and population decision-making. Increasingly available clinical information systems make it possible to deliver timely, relevant knowledge to frontline clinicians in support of population health. Future work should focus on developing a flexible, interoperable infrastructure for bidirectional communications capable of integrating public health knowledge into clinical systems and workflows.


Solid cellulose nanofiber based foams - Towards facile design of sustained drug delivery systems.
Control of drug action through formulation is a vital and very challenging topic within pharmaceutical sciences. Cellulose nanofibers (CNF) are an excipient candidate in pharmaceutical formulations that could be used to easily optimize drug delivery rates. CNF has interesting physico-chemical properties that, when combined with surfactants, can be used to create very stable air bubbles and dry foams. Utilizing this inherent property, it is possible to modify the release kinetics of the model drug riboflavin in a facile way. Wet foams were prepared using cationic CNF and a pharmaceutically acceptable surfactant (lauric acid sodium salt). The drug was suspended in the wet-stable foams followed by a drying step to obtain dry foams. Flexible cellular solid materials of different thicknesses, shapes and drug loadings (up to 50wt%) could successfully be prepared. The drug was released from the solid foams in a diffusion-controlled, sustained manner due to the presence of intact air bubbles which imparted a tortuous diffusion path. The diffusion coefficient was assessed using Franz cells and shown to be more than one order of magnitude smaller for the cellular solids compared to the bubble-free films in the wet state. By changing the dimensions of dry foams while keeping drug load and total weight constant, the drug release kinetics could be modified, e.g. a rectangular box-shaped foam of 8mm thickness released only 59% of the drug after 24h whereas a thinner foam sample (0.6mm) released 78% of its drug content within 8h. In comparison, the drug release from films (0.009mm, with the same total mass and an outer surface area comparable to the thinner foam) was much faster, amounting to 72% of the drug within 1h. The entrapped air bubbles in the foam also induced positive buoyancy, which is interesting from the perspective of gastroretentive drug-delivery.


Psychometric properties of the TACQOL-asthma, a disease-specific measure of health related quality-of-life for children with asthma and their parents.
The disease-specific-TACQOL-asthma questionnaire measures health-status and appraisal of health-status. The TACQOL-asthma evaluates the personal feelings about problems in the domains, 'complaints, situations, emotions, treatment and medication'. The TACQOL-asthma can be used alone or in combination with the generic TACQOL. Our objective was to study the psychometric properties of the TACQOL-asthma-questionnaire. Responses of 298 parents and children with asthma (age eight to 16 years) in four paediatric practices in the northern part of The Netherlands were studied. The factor-analysis and item-domain correlation analysis show a moderate to strong correlation between the different items and their hypothesised domains. For all items, the correlation of the separate item with the hypothesized domain is stronger than with any other domain. The internal consistency (Cronbach's alpha) of the domains is moderate to good. Concurrent correlation with the Paediatric-Asthma-Quality-of-Life-Questionnaire-(PAQLQ) was significant. Effect sizes of differences between asthma-severity classes in TACQOL-asthma and PAQLQ-scores were similar and of clinical importance. This study validates the TACQOL-asthma as a new disease-specific questionnaire. The TACQOL-asthma ensures a measurement of health status as well as appraisal of health problems. The TACQOL-asthma has good reliability and validity properties to serve as an evaluative and discriminate disease-specific health-related-quality-of-life questionnaire.


Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal, mammosphere growth, and drug resistance.
Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in >40% of breast cancers, where it is associated with poor prognosis, disease recurrence, and drug resistance. We questioned whether this may be linked to the ability of YB-1 to induce the expression of genes linked to cancer stem cells such as CD44 and CD49f. Herein, we report that YB-1 binds the CD44 and CD49f promoters to transcriptionally upregulate their expressions. The introduction of wild-type (WT) YB-1 or activated P-YB-1(S102) stimulated the production of CD44 and CD49f in MDA-MB-231 and SUM 149 breast cancer cell lines. YB-1-transfected cells also bound to the CD44 ligand hyaluronan more than the control cells. Similarly, YB-1 was induced in immortalized breast epithelial cells and upregulated CD44. Conversely, silencing YB-1 decreased CD44 expression as well as reporter activity in SUM 149 cells. In mice, expression of YB-1 in the mammary gland induces CD44 and CD49f with associated hyperplasia. Further, activated mutant YB-1(S102D) enhances self-renewal, primary and secondary mammosphere growth, and soft-agar colony growth, which were reversible via loss of CD44 or CD49f. We next addressed the consequence of this system on therapeutic responsiveness. Here, we show that paclitaxel induces P-YB-1(S102) expression, nuclear localization of activated YB-1, and CD44 expression. The overexpression of WT YB-1 promotes mammosphere growth in the presence of paclitaxel. Importantly, targeting YB-1 sensitized the CD44(High)/CD24(Low) cells to paclitaxel. In conclusion, YB-1 promotes cancer cell growth and drug resistance through its induction of CD44 and CD49f.


Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort.
Fatigue is the commonest symptom described by patients in most populations with the autoimmune liver disease primary biliary cirrhosis (PBC), and appears to be unrelated to liver disease severity. At present, it is unclear how the fatigue experienced by patients (only characterised to date in cross sectional studies) evolves over time. In this study, we set out to address how fatigue had changed over four years of follow up in a geographically defined cohort of PBC patients who participated in an earlier cross sectional study of fatigue impact. Participants in the original 2000 study who were still alive in 2004 were asked to complete the same fatigue assessment tool (fatigue impact score, FIS). In those who had died between 2000 and 2004, medical notes, death certificates, and primary care records were reviewed. A total of 108 of the original cohort of 136 patients were alive at the time of the follow up study, 99 of whom (92%) participated in the follow up study. With the exception of four patients who underwent transplantation between 2000 and 2004, all of whom showed significant improvement in fatigue severity as assessed by FIS, fatigue severity was unchanged over four years of follow up. Among the 28 patients who died during the follow up period, survival was significantly lower in patients who were fatigued at the 2000 baseline (FIS above the median for the whole PBC population (40/160); log rank test, p = 0.006 v non-fatigued patients at baseline). Increased fatigue severity was independently associated with decreased survival on multivariate analysis. Fatigued PBC subjects were significantly more likely to have suffered a cardiac death than non-fatigued patients. The fatigue phenotype appears to be highly stable in PBC. The presence of fatigue in PBC is independently associated with a significantly increased risk of death in general, and cardiac death in particular. Factors underpinning fatigue in PBC, and the mechanisms whereby fatigue is associated with increased mortality, warrant further study.


Impact of admission screening for methicillin-resistant Staphylococcus aureus on the length of stay in an emergency department.
Preventing and controlling methicillin-resistant Staphylococcus aureus (MRSA) includes early detection and isolation. In the emergency department (ED), such measures have to be balanced with the requirement to treat patients urgently and transfer quickly to an acute hospital bed. We assessed, in a busy and overcrowded ED, the contribution made to a patient's stay by previous MRSA risk group identification and by selective rescreening of those patients who were previously documented in the research hospital as being MRSA positive. Patients with a previous diagnosis of MRSA colonisation were flagged automatically as 'risk group' (RG) on their arrival in the ED and were compared with 'non-risk group' (NRG), i.e. not previously demonstrated in the research hospital to be infected or colonised with MRSA. Over an 18 month period, there were 16 456 admissions via the ED, of which 985 (6%) were RG patients. The expected median times to be admitted following a request for a ward bed for NRG and RG patients were 10.4 and 12.9h, respectively. Female sex, age >65 years, and RG status all independently predicted a statistically significantly longer stay in the ED following a request for a hospital bed. We consider that national and local policies for MRSA need to balance the welfare of patients in the ED with the need to comply with best practice, when there are inadequate ED and inpatient isolation facilities. Patients with MRSA requiring emergency admission must have a bed available for them.


Amazon river dolphins (Inia geoffrensis) modify biosonar output level and directivity during prey interception in the wild.
Toothed whales have evolved to live in extremely different habitats and yet they all rely strongly on echolocation for finding and catching prey. Such biosonar-based foraging involves distinct phases of searching for, approaching and capturing prey, where echolocating animals gradually adjust sonar output to actively shape the flow of sensory information. Measuring those outputs in absolute levels requires hydrophone arrays centred on the biosonar beam axis, but this has never been done for wild toothed whales approaching and capturing prey. Rather, field studies make the assumption that toothed whales will adjust their biosonar in the same manner to arrays as they will when approaching prey. To test this assumption, we recorded wild botos (Inia geoffrensis) as they approached and captured dead fish tethered to a hydrophone in front of a star-shaped seven-hydrophone array. We demonstrate that botos gradually decrease interclick intervals and output levels during prey approaches, using stronger adjustment magnitudes than predicted from previous boto array data. Prey interceptions are characterised by high click rates, but although botos buzz during prey capture, they do so at lower click rates than marine toothed whales, resulting in a much more gradual transition from approach phase to buzzing. We also demonstrate for the first time that wild toothed whales broaden biosonar beamwidth when closing in on prey, as is also seen in captive toothed whales and bats, thus resulting in a larger ensonified volume around the prey, probably aiding prey tracking by decreasing the risk of prey evading ensonification.


Community analysis of the bacterial assemblages in the winter cover and pelagic layers of a high mountain lake by in situ hybridization.
The bacterial community structure in the winter cover and pelagic zone of a high mountain lake was analyzed by in situ hybridization with fluorescently labeled rRNA-targeted oligonucleotide probes. Cells fixed on membrane filters were hybridized with a probe specific for the domain Bacteria as well as with probes for the alpha, beta, and gamma subclasses of the class Proteobacteria and the Cytophaga-Flavobacterium group. The fraction of bacteria detectable after hybridization with the bacterial probe EUB ranged from 40 to 81% of 4(prm1),6-diamidino-2-phenylindole (DAPI) counts. The bacterial assemblage varied considerably between and within different habitats (snow, slush, and lake water) but was in most cases dominated by members of the beta subclass (6.5 to 116% of bacteria detectable with probe EUB). The sum of bacteria hybridizing with group-specific probes was usually lower than the fraction detectable with probe EUB. Image analysis was used to characterize morphology and the size-specific biomass distribution of bacterial assemblages, which clearly separated the three habitats. Although the measured secondary production parameters and the fraction of 2-(p-iodophenyl)-3-(p-nitrophenyl)-5-phenyltetrazolium chloride-reducing bacteria varied by more than an order of magnitude in the different slush and pelagic layers, detectability with the fluorescent probe EUB was constantly high. Physiological strategies of bacteria under nutrient limitation and at low temperatures are discussed in the context of the ribosome content of single cells. This study confirms the suitability of fluorescently labeled rRNA-targeted probes for the characterization of bacterial population structures even in oligotrophic habitats.


Household Wealth in China.
With new nationwide longitudinal survey data now available from the China Family Panel Studies (CFPS), we study the level, distribution, and composition of household wealth in contemporary China. We find that the wealth Gini coefficient of China was 0.73 in 2012. The richest 1 percent owned more than one-third of the total national household wealth, while the poorest 25 percent owned less than 2 percent. Housing assets, which accounted for over 70 percent, were the largest component of household wealth. Finally, the urban-rural divide and regional disparities played important roles in household wealth distribution, and institutional factors significantly affected household wealth holdings, wealth growth rate, and wealth mobility.


A self-limiting switch based on translational control regulates the transition from proliferation to differentiation in an adult stem cell lineage.
In adult stem cell lineages, progenitor cells commonly undergo mitotic transit amplifying (TA) divisions before terminal differentiation, allowing production of many differentiated progeny per stem cell division. Mechanisms that limit TA divisions and trigger the switch to differentiation may protect against cancer by preventing accumulation of oncogenic mutations in the proliferating population. Here we show that the switch from TA proliferation to differentiation in the Drosophila male germline stem cell lineage is mediated by translational control. The TRIM-NHL tumor suppressor homolog Mei-P26 facilitates accumulation of the differentiation regulator Bam in TA cells. In turn, Bam and its partner Bgcn bind the mei-P26 3' untranslated region and repress translation of mei-P26 in late TA cells. Thus, germ cells progress through distinct, sequential regulatory states, from Mei-P26 on/Bam off to Bam on/Mei-P26 off. TRIM-NHL homologs across species facilitate the switch from proliferation to differentiation, suggesting a conserved developmentally programmed tumor suppressor mechanism.


Regulation of episomal gene expression by KRAB/KAP1-mediated histone modifications.
KAP1 is an essential cofactor of KRAB zinc finger proteins, a family of vertebrate-specific epigenetic repressors of largely unknown functions encoded in the hundreds by the mouse and human genomes. So far, KRAB/KAP1-mediated gene regulation has been studied within the environment of chromosomal DNA. Here we demonstrate that KRAB/KAP1 regulation is fully functional within the context of episomal DNA, such as adeno-associated viral and nonintegrated lentiviral vectors, and is correlated with histone modifications typically associated with this epigenetic regulator.


Ligand recognition and G-protein coupling of trace amine receptor TAAR1.
Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis1. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways2,3. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders4,5. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HT1AR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.


Does declining carbon-use efficiency explain thermal acclimation of soil respiration with warming?
Enhanced soil respiration in response to global warming may substantially increase atmospheric CO2 concentrations above the anthropogenic contribution, depending on the mechanisms underlying the temperature sensitivity of soil respiration. Here, we compared short-term and seasonal responses of soil respiration to a shifting thermal environment and variable substrate availability via laboratory incubations. To analyze the data from incubations, we implemented a novel process-based model of soil respiration in a hierarchical Bayesian framework. Our process model combined a Michaelis-Menten-type equation of substrate availability and microbial biomass with an Arrhenius-type nonlinear temperature response function. We tested the competing hypotheses that apparent thermal acclimation of soil respiration can be explained by depletion of labile substrates in warmed soils, or that physiological acclimation reduces respiration rates. We demonstrated that short-term apparent acclimation can be induced by substrate depletion, but that decreasing microbial biomass carbon (MBC) is also important, and lower MBC at warmer temperatures is likely due to decreased carbon-use efficiency (CUE). Observed seasonal acclimation of soil respiration was associated with higher CUE and lower basal respiration for summer- vs. winter-collected soils. Whether the observed short-term decrease in CUE or the seasonal acclimation of CUE with increased temperatures dominates the response to long-term warming will have important consequences for soil organic carbon storage.


Early routine endoscopic retrograde cholangiopancreatography strategy versus early conservative management strategy in acute gallstone pancreatitis.
The role and timing of endoscopic retrograde cholangiopancreatography (ERCP) in acute gallstone pancreatitis remains controversial. A number of clinical trials and meta-analyses have provided conflicting evidence. To systematically review evidence from randomized controlled trials (RCTs) assessing the clinical effectiveness and safety of the early routine ERCP strategy compared to the early conservative management with or without selective use of ERCP strategy, based on all important, clinically relevant and standardized outcomes including mortality, local and systemic complications as defined by the Atlanta Classification (Bradley 1993) and by authors of the primary study, and ERCP-related complications in unselected patients with acute gallstone pancreatitis. We searched the CENTRAL (The Cochrane Library), MEDLINE, EMBASE, and LILACS databases and major conference proceedings up to January 2012, using the Cochrane Upper Gastrointestinal and Pancreatic Diseases model with no language restrictions. RCTs comparing the early routine ERCP strategy versus the early conservative management with or without selective use of ERCP strategy in patients with suspected acute gallstone pancreatitis. We included studies in which the population with acute gallstone pancreatitis was a subgroup within a larger group of patients. We only included studies involving only a selected subgroup of patients with acute gallstone pancreatitis (actual severe pancreatitis) in subgroup analyses. Two review authors conducted study selection, data extraction, and methodological quality assessment independently. Using intention-to-treat analysis with random-effects models, we combined dichotomous data to obtain risk ratios (RR) with 95% confidence intervals (CI). We assessed heterogeneity using the Chi² test and I² statistic. To explore sources of heterogeneity, we conducted a priori subgroup analyses according to predicted severity of pancreatitis, cholangitis, biliary obstruction, time to ERCP in routine ERCP strategy, use of selective ERCP in conservative management strategy, and risk of bias. To assess the robustness of our results, we carried out sensitivity analyses using different summary statistics (RR versus odds ratio (OR)) and meta-analytic models (fixed versus random-effects), and per-protocol analysis. We performed influence analysis by exclusion of each study. Five RCTs comprising 644 participants were included in the main analyses. Two additional RCTs, comprising only patients with actual severe acute gallstone pancreatitis, were included only in subgroup analyses. There was statistical heterogeneity among trials for mortality, but not for other outcomes. In unselected patients with acute gallstone pancreatitis, there were no statistically significant differences between the two strategies in mortality (RR 0.74, 95% CI 0.18 to 3.03), local and systemic complications as defined by the Atlanta Classification (RR 0.86, 95% CI 0.52 to 1.43; and RR 0.59, 95% CI 0.31 to 1.11 respectively) and by authors of the primary study (RR 0.80, 95% CI 0.51 to 1.26; and RR 0.76, 95% CI 0.53 to 1.09 respectively). The results were robust to sensitivity and influence analyses except for systemic complications as defined by the Atlanta Classification. There was no evidence to suggest that the results were dependent on predicted severity of pancreatitis. Among trials that included patients with cholangitis, the early routine ERCP strategy significantly reduced mortality (RR 0.20, 95% CI 0.06 to 0.68), local and systemic complications as defined by the Atlanta Classification (RR 0.45, 95% CI 0.20 to 0.99; and RR 0.37, 95% CI 0.18 to 0.78 respectively) and by authors of the primary study (RR 0.50, 95% CI 0.29 to 0.87; and RR 0.41, 95% CI 0.21 to 0.82 respectively). Among trials that included patients with biliary obstruction, the early routine ERCP strategy was associated with a significant reduction in local complications as defined by authors of the primary study (RR 0.54, 95% CI 0.32 to 0.91), and a non-significant trend towards reduction of local and systemic complications as defined by the Atlanta Classification (RR 0.53, 95% CI 0.26 to 1.07; and RR 0.56, 95% CI 0.30 to 1.02 respectively) and systemic complications as defined by authors of the primary study (RR 0.59, 95% CI 0.35 to 1.01). ERCP complications were infrequent. In patients with acute gallstone pancreatitis, there is no evidence that early routine ERCP significantly affects mortality, and local or systemic complications of pancreatitis, regardless of predicted severity. Our results, however, provide support for current recommendations that early ERCP should be considered in patients with co-existing cholangitis or biliary obstruction.


Efficacy and Effectiveness of Lithium in the Long-Term Treatment of Bipolar Disorders: An Update 2018.
For more than 40 years, lithium has been the gold standard in the long-term treatment of bipolar disorders. In the course of the last 15 years, other drugs have been approved in this indication and are widely used in clinical practice at the expense of lithium. New research from the last few years, however, indicates that lithium is still the first-line treatment in this indication. Against this background and lithium's proven acute antimanic efficacy, we should perhaps be using lithium more regularly (in combination with an atypical antipsychotic, if necessary) right from the start for the acute treatment of a manic episode and, once remission has been achieved and euthymia maintained during continuation treatment, to regularly taper off the atypical antipsychotic, if possible, and continue with lithium as monotherapy for prophylactic treatment. This might lead to lithium being used more consistently with the scientific evidence in the long-term treatment of bipolar disorders. It remains uncertain, however, to predict who will respond to and tolerate lithium prophylactically, and more research is needed to deliver the best possible individualized care to our patients.


Divergence dates for Malagasy lemurs estimated from multiple gene loci: geological and evolutionary context.
The lemurs of Madagascar are a unique radiation of primates that show an extraordinary diversity of lifestyles, morphologies and behaviours. However, very little is known about the relative antiquity of lemuriform clades due to the lack of terrestrial fossils for the Tertiary of Madagascar. Here, we employ a Bayesian method to estimate divergence dates within the lemuriform radiation using several unlinked gene loci and multiple fossil calibrations outside the lemuriform clade. Two mitochondrial genes (cytochrome oxidase II and cytochrome b), two nuclear introns (transthyretin intron 1 and von Willebrand factor gene intron 11) and one nuclear exon (interphotoreceptor retinoid binding protein, exon 1) are used in separate and combined analyses. The genes differ in taxon sampling and evolutionary characteristics but produce congruent date estimates. Credibility intervals narrow considerably in combined analyses relative to separate analyses due to the increased amount of data. We also test the relative effects of multiple vs. single calibration points, finding that, when only single calibration points are employed, divergence dates are systematically underestimated. For the mitochondrial DNA data set, we investigate the effects of sampling density within the mouse lemur radiation (genus Microcebus). When only two representative species are included, estimated dates throughout the phylogeny are more recent than with the complete-species sample, with basal nodes less affected than recent nodes. The difference appears to be due to the manner in which priors on node ages are constructed in the two analyses. In nearly all analyses, the age of the lemuriform clade is estimated to be approximately 62-65 Ma, with initial radiation of mouse lemurs and true lemurs (genus Eulemur) occurring approximately 8-12 Ma. The antiquity of the mouse lemur radiation is surprising given the near uniform morphology among species. Moreover, the observation that mouse lemurs and true lemurs are of similar ages suggests discrepancies in rates of morphological, behavioural and physiological evolution in the two clades, particularly with regard to characteristics of sexual signalling. These differences appear to correlate with the nocturnal vs. diurnal lifestyles, respectively, of these two primate groups.


Prophylactic glutamine protects the intestinal mucosa from radiation injury.
Glutamine may be an essential dietary component, especially for the support of intestinal mucosal growth and function. This study evaluated the effects of a glutamine-enriched elemental diet, administered before whole-abdominal radiation on gut glutamine metabolism, mucosal morphometrics, and bacterial translocation. Rats were randomized to receive a nutritionally complete elemental diet that was glutamine-enriched or glutamine-free for 4 days. The animals were then subjected to a single dose of 1000 cGy x-radiation to the abdomen. After irradiation, all animals received the glutamine-free diet. Four days later the animals underwent laparotomy for sampling of arterial and portal venous blood, culture of mesenteric lymph nodes, and removal of the small intestine for microscopic examination. There was no difference in arterial glutamine or gut glutamine extraction between the two groups, but body weight loss was significantly diminished in the glutamine-fed rats. Rats receiving the glutamine-enriched elemental diet before radiation had a significant increase in jejunal villous number, villous height, and number of metaphase mitoses per crypt. Scanning electron microscopy confirmed the presence of an intact gut epithelium in eight of eight rats receiving prophylactic glutamine compared to one of eight animals in the glutamine-free group. Three of eight rats fed glutamine had culture positive mesenteric lymph nodes compared with five of seven rats receiving the glutamine-free diet. Glutamine exerts a protective effect on the small bowel mucosa by supporting crypt cell proliferation effect on accelerate healing of the acutely radiated bowel.


The socio-economic impact of multidrug-resistant nosocomial infections: a qualitative study.
The burden of healthcare-associated infections (HCAIs) has traditionally been measured using clinical and economic outcomes. We conducted semi-structured interviews with 18 patients or their caregivers affected by HCAI caused by multidrug-resistant organisms to better understand the human impact of HCAI. Most patients had misconceptions about HCAI and antimicrobial resistance, leading to strong negative feelings towards HCAIs despite positive views of their healthcare providers. Communication issues across power imbalances need to be addressed to help deal with trauma of HCAIs. A holistic approach to HCAIs incorporating patient perspectives will likely help guide policymakers developing solutions to improve patient outcomes.


Inventory of PCBs in Chicago and Opportunities for Reduction in Airborne Emissions and Human Exposure.
Urban areas are important regional sources of airborne polychlorinated biphenyls (PCBs) and population-scale airborne exposure, yet a comprehensive bottom-up source inventory of PCB emissions has never been quantified at urban scales in the United States. Here we report a comprehensive parcel level inventory of PCB stocks and emissions for Chicago, Illinois, developed with a transferable method from publicly available data. Chicago's legacy stocks hold 276 ± 147 tonnes ∑PCBs, with 0.2 tonnes added annually. Transformers and building sealants represent the largest legacy categories at 250 and 20 tonnes, respectively. From these stocks, annual emissions rates of 203 kg for ∑PCBs and 3 kg for PCB 11 explain observed concentrations in Chicago air. Sewage sludge drying contributes 25% to emissions, soils 31%, and transformers 21%. Known contaminated sites account for <1% of stocks and 17% of emissions to air. Paint is responsible for 0.00001% of stocks but up to 7% of ∑PCBs emissions. Stocks and emissions are highly concentrated and not correlated with population density or demographics at the neighborhood scale. Results suggest that strategies to further reduce exposure and ecosystem deposition must focus on the largest emissions sources rather than the most contaminated sites or the largest closed source legacy stocks.


Sensitivity and specificity of a nested polymerase chain reaction for detection of lentivirus infection in lions (Panthera leo).
Feline immunodeficiency virus (FIV) is a lentivirus in the Retroviridae family that causes lifelong infection in domestic cats. The lentivirus of African lions (Panthera leo), referred to as FIVple, is endemic in certain lion populations in eastern and southern Africa. Lentivirus infection leads to immunologic dysfunction and immunosuppressive disease in domestic cats; however, little is known about the pathogenic effects of infection in lions, nor about the epidemiologic impact on free-ranging and captive populations. Whole blood and serum samples were collected opportunistically from free-ranging lions in Kruger National Park, Republic of South Africa (RSA). Whole blood and serum samples were also collected from captive wild lions in the RSA. A nested polymerase chain reaction (PCR) assay for detection of FIV was performed on all whole blood samples. In addition, serum samples were tested for cross-reactive antibodies to domestic feline lentivirus antigens and puma lentivirus synthetic envelope peptide antigen. The PCR assay successfully amplified the lion lentivirus from African lions. The relative sensitivity and relative specificity were 79% and 100%, respectively, and the positive and negative predictive values were 100% and 67%, respectively. This research represents the first study to compare genetic material with antibody-based methods of lentivirus detection on lions in RSA. Using PCR as an additional diagnostic test for FIV in lions will increase screening sensitivity and will allow viral characterization among circulating isolates and monitoring of changes in the viral epidemiology within geographic regions and populations over time.


Obesity: a perfect storm for carcinogenesis.
Obesity-related cancers account for 40% of the cancer cases observed in the USA and obesity is overtaking smoking as the most widespread modifiable risk factor for carcinogenesis. Here, we use the hallmarks of cancer framework to delineate how obesity might influence the carcinogenic hallmarks in somatic cells. We discuss the effects of obesity on (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) resisting cell death; (d) enabling replicative immortality; (e) inducing angiogenesis; (f) activating invasion and metastasis; (g) reprogramming energy metabolism; and (h) avoiding immune destruction, together with its effects on genome instability and tumour-promoting inflammation. We present the current understanding and controversies in this evolving field, and highlight some areas in need of further cross-disciplinary focus. For instance, the relative importance of the many potentially causative obesity-related factors is unclear for each type of malignancy. Even within a single tumour type, it is currently unknown whether one obesity-related factor consistently plays a predominant role, or if this varies between patients or, even in a single patient with time. Clarifying how the hallmarks are affected by obesity may lead to novel prevention and treatment strategies for the increasingly obese population.


Effects of hetastarch 130/0.4 on plasma osmolality, colloid osmotic pressure and total protein in horses anaesthetised for elective surgical procedures.
Effects of lactated Ringer's solution (LRS) and hetastarch 130/0.4 (HES) on colloid osmotic pressure (COP), plasma osmolality (OSM) and total protein (TP) were investigated in 18 inhalational-anaesthetised healthy horses. Horses received 4-6 ml/kg LRS (LRS; n=9) or HES (HES; n=9) from anaesthesia induction through 60 min, after which all were administered LRS. COP, TP and OSM were measured before premedication (baseline), postinduction and 30 (n=18), 60 (n=18), 90 (n=18) and 120 (n=12) minutes. Baseline COP, OSM and TP were not different between groups. TP decreased in both groups at all time points after induction. OSM increased from baseline in HES at 30, 60, 90 and 120 minutes. COP decreased at 30-120 minutes in LRS, and at 90 and 120 minutes in HES. Mean COP was higher in HES than LRS at 30 (18.8±0.5 vs 16.3±0.4 mmHg (P=0.001)), 60 (19.1±0.5 vs 15.9±0.4 mmHg (P<0.0001)) and 90 (17.4±0.5 vs 15.4±0.5 mmHg (P=0.005)) minutes. Sixty minutes of HES infusion increases OSM and transiently maintains COP compared with an equal volume of LRS in anaesthetised horses.


Recent advances in childhood diabetes mellitus.
Diabetes mellitus (DM) is a syndrome characterized by disturbed metabolism of carbohydrate, protein, and fat. It is a chronic metabolic disorder caused by an absolute or relative deficiency of insulin. It presents with very different medical and psychosocial issues in children. Epidemiological studies indicate that there is gradual but steady increase in the incidence of both type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in both developed and developing countries. The manifestations, therapy goals, clinical course, susceptibility to complications of diabetes differ among childhood cases. T1DM accounts for the majority of cases of diabetes in children. Diabetic ketoacidosis may be the initial presentation of T1DM in many children particularly in Africa probably due to low level of awareness. The focus of this review on T1DM is to provide an overview of the major advances in the aetiology, pathogenesis, and clinical management of newly diagnosed children and their subsequent management with the aim of ensuring optimal growth and development as well as preventing acute and chronic complications. The advances in insulin therapy and regimens and the presentation and management of diabetic ketoacidosis are discussed. The prospects for the cure of the disease are also highlighted in this review.


The nucleus basalis in Alzheimer's disease: cell counts and cortical biochemistry.
The cell density in the Nucleus Basalis in six patients with clinical and histological evidence of Alzheimer's disease and reduced choline acetyltransferase activity in frontal and temporal cortex was found to be in approximately 50% of the cell count in five control subjects.


VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema.
Although lymphedema is a common clinical condition, treatment for this disabling condition remains limited and largely ineffective. Recently, it has been reported that overexpression of VEGF-C correlates with increased lymphatic vessel growth (lymphangiogenesis). However, the effect of VEGF-C-induced lymphangiogenesis on lymphedema has yet to be demonstrated. Here we investigated the impact of local transfer of naked plasmid DNA encoding human VEGF-C (phVEGF-C) on two animal models of lymphedema: one in the rabbit ear and the other in the mouse tail. In a rabbit model, following local phVEGF-C gene transfer, VEGFR-3 expression was significantly increased. This gene transfer led to a decrease in thickness and volume of lymphedema, improvement of lymphatic function demonstrated by serial lymphoscintigraphy, and finally, attenuation of the fibrofatty changes of the skin, the final consequences of lymphedema. The favorable effect of phVEGF-C on lymphedema was reconfirmed in a mouse tail model. Immunohistochemical analysis using lymphatic-specific markers: VEGFR-3, lymphatic endothelial hyaluronan receptor-1, together with the proliferation marker Ki-67 Ab revealed that phVEGF-C transfection potently induced new lymphatic vessel growth. This study, we believe for the first time, documents that gene transfer of phVEGF-C resolves lymphedema through direct augmentation of lymphangiogenesis. This novel therapeutic strategy may merit clinical investigation in patients with lymphedema.


Transcriptional changes induced by candidate malaria vaccines and correlation with protection against malaria in a human challenge model.
The complexity of immunity to malaria is well known, and clear correlates of protection against malaria have not been established. A better understanding of immune markers induced by candidate malaria vaccines would greatly enhance vaccine development, immunogenicity monitoring and estimation of vaccine efficacy in the field. We have previously reported complete or partial efficacy against experimental sporozoite challenge by several vaccine regimens in healthy malaria-naïve subjects in Oxford. These include a prime-boost regimen with RTS,S/AS02A and modified vaccinia virus Ankara (MVA) expressing the CSP antigen, and a DNA-prime, MVA-boost regimen expressing the ME TRAP antigens. Using samples from these trials we performed transcriptional profiling, allowing a global assessment of responses to vaccination. We used Human RefSeq8 Bead Chips from Illumina to examine gene expression using PBMC (peripheral blood mononuclear cells) from 16 human volunteers. To focus on antigen-specific changes, comparisons were made between PBMC stimulated with CSP or TRAP peptide pools and unstimulated PBMC post vaccination. We then correlated gene expression with protection against malaria in a human Plasmodium falciparum malaria challenge model. Differentially expressed genes induced by both vaccine regimens were predominantly in the IFN-γ pathway. Gene set enrichment analysis revealed antigen-specific effects on genes associated with IFN induction and proteasome modules after vaccination. Genes associated with IFN induction and antigen presentation modules were positively enriched in subjects with complete protection from malaria challenge, while genes associated with haemopoietic stem cells, regulatory monocytes and the myeloid lineage modules were negatively enriched in protected subjects. These results represent novel insights into the immune repertoires involved in malaria vaccination.


Ensiling of wheat straw decreases the required temperature in hydrothermal pretreatment.
Ensiling is a well-known method for preserving green biomasses through anaerobic production of organic acids by lactic acid bacteria. In this study, wheat straw is subjected to ensiling in combination with hydrothermal treatment as a combined pretreatment method, taking advantage of the produced organic acids. Ensiling for 4 weeks was accomplished in a vacuum bag system after addition of an inoculum of Lactobacillus buchneri and 7% w/w xylose to wheat straw biomass at 35% final dry matter. Both glucan and xylan were preserved, and the DM loss after ensiling was less than 0.5%. When comparing hydrothermally treated wheat straw (170, 180 and 190°C) with hydrothermally treated ensiled wheat straw (same temperatures), several positive effects of ensiling were revealed. Glucan was up-concentrated in the solid fraction and the solubilisation of hemicellulose was significantly increased. Subsequent enzymatic hydrolysis of the solid fractions showed that ensiling significantly improved the effect of pretreatment, especially at the lower temperatures of 170 and 180°C. The overall glucose yields after pretreatments of ensiled wheat straw were higher than for non-ensiled wheat straw hydrothermally treated at 190°C, namely 74-81% of the theoretical maximum glucose in the raw material, which was ~1.8 times better than the corresponding yields for the non-ensiled straw pretreated at 170 or 180°C. The highest overall conversion of combined glucose and xylose was achieved for ensiled wheat straw hydrothermally treated at 180°C, with overall glucose yield of 78% and overall conversion yield of xylose of 87%. Ensiling of wheat straw is shown to be an effective pre-step to hydrothermal treatment, and can give rise to a welcomed decrease of process temperature in hydrothermal treatments, thereby potentially having a positive effect on large scale pretreatment costs.


Rare peripheral T cells migrate to and persist in normal mouse thymus.
The traffic of T cells between the thymus and peripheral lymphoid organs is generally thought to be unidirectional. Using a technique of lymphocyte transfer between Thy-1 congenic mice, we demonstrate here the entry of rare peripheral lymph node T cells into the normal mouse thymus. At time points from 3 h to 24 wk after transfer, donor peripheral T cells were present in the host thymus, mainly as scattered single cells confined to the medulla. At 2 wk after transfer, donor T cells constituted 0.2% of the medullary thymocytes (compared with 11% of the peripheral lymph node T cells). As a population, these cells exhibited a stable mature immunophenotype (Ly-1hi, PNAlo, and mixed L3T4- and Lyt-2+). A minority of the donor T cells expressed high levels of the MEL-14 "homing receptor". The thymic medulla thus exhibits features of a peripheral lymphoid organ but differs in its low rate of turnover of recirculating T cells.


Chemical mutation of enzyme active sites.
New active sites can be introduced into naturally occurring enzymes by the chemical modification of specific amino acid residues with the use of appropriately designed coenzyme analogs. The resultant semisynthetic enzymes can have catalytic activities very different from those of the corresponding native enzymes. For example, papain has been converted into a highly effective oxidoreductase by covalent modification of the sulfhydryl group of the active site cysteine residue (Cys25) with flavins such as 8-bromoacetyl-10-methylisoalloxazine. Thus, it is now possible to enhance the catalytic versatility of existing enzymes through the process of "chemical mutation" of the active site.


IgE Cross-Reactivity of Cashew Nut Allergens.
Allergic sensitisation towards cashew nut often happens without a clear history of eating cashew nut. IgE cross-reactivity between cashew and pistachio nut is well described; however, the ability of cashew nut-specific IgE to cross-react to common tree nut species and other Anacardiaceae, like mango, pink peppercorn, or sumac is largely unknown. Cashew nut allergic individuals may cross-react to foods that are phylogenetically related to cashew. We aimed to determine IgE cross-sensitisation and cross-reactivity profiles in cashew nut-sensitised subjects, towards botanically related proteins of other Anacardiaceae family members and related tree nut species. Sera from children with a suspected cashew nut allergy (n = 56) were assessed for IgE sensitisation to common tree nuts, mango, pink peppercorn, and sumac using dot blot technique. Allergen cross-reactivity patterns between Anacardiaceae species were subsequently examined by SDS-PAGE and immunoblot inhibition, and IgE-reactive allergens were identified by LC-MS/MS. From the 56 subjects analysed, 36 were positive on dot blot for cashew nut (63%). Of these, 50% were mono-sensitised to cashew nuts, 19% were co-sensitised to Anacardiaceae species, and 31% were co-sensitised to tree nuts. Subjects co-sensitised to Anacardiaceae species displayed a different allergen recognition pattern than subjects sensitised to common tree nuts. In pink peppercorn, putative albumin- and legumin-type seed storage proteins were found to cross-react with serum of cashew nut-sensitised subjects in vitro. In addition, a putative luminal binding protein was identified, which, among others, may be involved in cross-reactivity between several Anacardiaceae species. Results demonstrate the in vitro presence of IgE cross-sensitisation in children towards multiple Anacardiaceae species. In this study, putative novel allergens were identified in cashew, pistachio, and pink peppercorn, which may pose factors that underlie the observed cross-sensitivity to these species. The clinical relevance of this widespread cross-sensitisation is unknown.


Comparison of the relationships between lidar integrated backscattered light and accumulated depolarization ratios for linear and circular polarization for water droplets, fog oil, and dust.
Recently, an empirical relationship between the layer integrated backscattered light and the layer accumulated depolarization ratio has been established for linear polarization for the case of water droplet clouds. This is a powerful relation, allowing calibration of space lidar and correction of the lidar signal for multiple scattering effects. The relationship is strongly based on Monte Carlo simulations with some experimental evidence. We support the empirical relationship with strong experimental data and then show experimentally and via second order scattering theoretical calculations that a modified relationship can be obtained for circular polarization. Also, we demonstrate that other empirical relationships exist between the layer accumulated linear and circular depolarization ratios and the layer integrated backscattered light for submicrometer particles and nonspherical particles.


Acculturation differences in communicating information about child mental health between Latino parents and primary care providers.
Significant Latino-white disparities in youth mental health care access and quality exist yet little is known about Latino parents' communication with providers about youth mental health and the role of acculturation in influencing this communication. We estimated regression models to assess the association between time in the US and the number of psychosocial issues discussed with the medical assistant (MA) and doctor, adjusting for child and parent mental health and sociodemographics. Other proxies of acculturation were also investigated including measures of Spanish and English language proficiency and nativity. Parent's length of time in the US was positively associated with their communication of: their child's psychosocial problems with their child's MA, stress in their own life with their child's MA, and their child's school problems with their child's doctor. These differences were especially apparent for parents living in the US for >10 years. Parent-child language discordance, parent and child nativity were also significantly associated with communication of psychosocial problems. Greater provider and MA awareness of variation in resistance to communicating psychosocial issues could improve communication, and improve the prevention, diagnosis and treatment of youth mental illness.


Antibiotic resistomes of healthy pig faecal metagenomes.
Antibiotic resistance reservoirs within food-producing animals are thought to be a risk to animal and human health. This study describes the minimum natural resistome of pig faeces as the bacteria are under no direct antibiotic selective pressure. The faecal resistome of 257 different genes comprised 56 core and 201 accessory resistance genes. The genes present at the highest relative abundances across all samples were tetW, tetQ, tet44, tet37, tet40, mefA, aadE, ant(9)-1, ermB and cfxA2. This study characterized the baseline resistome, the microbiome composition and the metabolic components described by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in healthy pig faeces, without antibiotic selective pressures. The microbiome hierarchical analysis resulted in a cluster tree with a highly similar pattern to that of the accessory resistome cluster tree. Functional capacity profiling identified genes associated with horizontal gene transfer. We identified a statistically significant positive correlation between the total antibiotic resistome and suggested indicator genes, which agree with using these genes as indicators of the total resistomes. The correlation between total resistome and total microbiome in this study was positive and statistically significant. Therefore, the microbiome composition influenced the resistome composition. This study identified a core and accessory resistome present in a cohort of healthy pigs, in the same conditions without antibiotics. It highlights the presence of antibiotic resistance in the absence of antibiotic selective pressure and the variability between animals even under the same housing, food and living conditions. Antibiotic resistance will remain in the healthy pig gut even when antibiotics are not used. Therefore, the risk of antibiotic resistance transfer from animal faeces to human pathogens or the environment will remain in the absence of antibiotics.