Varicella zoster virus infection of highly pure terminally differentiated human neurons.
In vitro analyses of varicella zoster virus (VZV) reactivation from latency in human ganglia have been hampered by the inability to isolate virus by explantation or cocultivation techniques. Furthermore, attempts to study interaction of VZV with neurons in experimentally infected ganglion cells in vitro have been impaired by the presence of nonneuronal cells, which become productively infected and destroy the cultures. We have developed an in vitro model of VZV infection in which highly pure (>95 %) terminally differentiated human neurons derived from pluripotent stem cells were infected with VZV. At 2 weeks post-infection, infected neurons appeared healthy compared to VZV-infected human fetal lung fibroblasts (HFLs), which developed a cytopathic effect (CPE) within 1 week. Tissue culture medium from VZV-infected neurons did not produce a CPE in uninfected HFLs and did not contain PCR-amplifiable VZV DNA, but cocultivation of infected neurons with uninfected HFLs did produce a CPE. The nonproductively infected neurons contained multiple regions of the VZV genome, as well as transcripts and proteins corresponding to VZV immediate-early, early, and late genes. No markers of the apoptotic caspase cascade were detected in healthy-appearing VZV-infected neurons. VZV infection of highly pure terminally differentiated human neurons provides a unique in vitro system to study the VZV-neuronal relationship and the potential to investigate mechanisms of VZV reactivation.


Sequence specificity analysis of the SETD2 protein lysine methyltransferase and discovery of a SETD2 super-substrate.
SETD2 catalyzes methylation at lysine 36 of histone H3 and it has many disease connections. We investigated the substrate sequence specificity of SETD2 and identified nine additional peptide and one protein (FBN1) substrates. Our data showed that SETD2 strongly prefers amino acids different from those in the H3K36 sequence at several positions of its specificity profile. Based on this, we designed an optimized super-substrate containing four amino acid exchanges and show by quantitative methylation assays with SETD2 that the super-substrate peptide is methylated about 290-fold more efficiently than the H3K36 peptide. Protein methylation studies confirmed very strong SETD2 methylation of the super-substrate in vitro and in cells. We solved the structure of SETD2 with bound super-substrate peptide containing a target lysine to methionine mutation, which revealed better interactions involving three of the substituted residues. Our data illustrate that substrate sequence design can strongly increase the activity of protein lysine methyltransferases.


Common variants at 1p36 are associated with superior frontal gyrus volume.
The superior frontal gyrus (SFG), an area of the brain frequently found to have reduced gray matter in patients with schizophrenia, is involved in self-awareness and emotion, which are impaired in schizophrenia. However, no genome-wide association studies of SFG volume have investigated in patients with schizophrenia. To identify single-nucleotide polymorphisms (SNPs) associated with SFG volumes, we demonstrated a genome-wide association study (GWAS) of gray matter volumes in the right or left SFG of 158 patients with schizophrenia and 378 healthy subjects. We attempted to bioinformatically ascertain the potential effects of the top hit polymorphism on the expression levels of genes at the genome-wide region. We found associations between five variants on 1p36.12 and the right SFG volume at a widely used benchmark for genome-wide significance (P<5.0 × 10(-8)). The strongest association was observed at rs4654899, an intronic SNP in the eukaryotic translation initiation factor 4 gamma, 3 (EIF4G3) gene on 1p36.12 (P=7.5 × 10(-9)). No SNP with genome-wide significance was found in the volume of the left SFG (P>5.0 × 10(-8)); however, the rs4654899 polymorphism was identified as the locus with the second strongest association with the volume of the left SFG (P=1.5 × 10(-6)). In silico analyses revealed a proxy SNP of rs4654899 had effect on gene expression of two genes, HP1BP3 lying 3' to EIF4G3 (P=7.8 × 10(-6)) and CAPN14 at 2p (P=6.3 × 10(-6)), which are expressed in moderate-to-high levels throughout the adult human SFG. These results contribute to understand genetic architecture of a brain structure possibly linked to the pathophysiology of schizophrenia.


The momentum of human behavior in a natural setting.
Adults with mental retardation in a group home received popcorn or coffee reinforcers for sorting plastic dinnerware. In Part 1 of the experiment, reinforcers were dispensed according to a variable-interval 60-s schedule for sorting dinnerware of one color and according to a variable-interval 240-s schedule for sorting dinnerware of a different color in successive components of a multiple schedule. Sorting rates were similar in baseline, but when a video program was shown concurrently, sorting of dinnerware was more resistant to distraction when correlated with a higher rate of reinforcement. In Part 2 of the experiment, popcorn or coffee reinforcers were contingent upon sorting both colors of dinnerware according to variable-interval 60-s schedules, but additional reinforcers were given independently of sorting according to a variable-time 30-s schedule during one dinnerware-color component. Baseline sorting rate was lower but resistance to distraction by the video program was greater in the component with additional variable-time reinforcers. These results demonstrate that resistance to distraction depends on the rate of reinforcers obtained in the presence of component stimuli but is independent of baseline response rates and response-reinforcer contingencies. Moreover, these results are similar to those obtained in laboratory studies with pigeons, demonstrating that the determination of resistance to change by stimulus-reinforcer relations is not confined to controlled laboratory settings or unique to the pigeon.


Patient and impatient punishers of free-riders.
Costly punishment of cheaters who contribute little or nothing to a cooperating group has been extensively studied, as an effective means to enforce cooperation. The prevailing view is that individuals use punishment to retaliate against transgressions of moral standards such as fairness or equity. However, there is much debate regarding the psychological underpinnings of costly punishment. Some authors suggest that costly punishment must be a product of humans' capacity for reasoning, self-control and long-term planning, whereas others argue that it is the result of an impulsive, present-oriented emotional drive. Here, we explore the inter-temporal preferences of punishers in a multilateral cooperation game and show that both interpretations might be right, as we can identify two different types of punishment: punishment of free-riders by cooperators, which is predicted by patience (future orientation); and free-riders' punishment of other free-riders, which is predicted by impatience (present orientation). Therefore, the picture is more complex as punishment by free-riders probably comes not from a reaction against a moral transgression, but instead from a competitive, spiteful drive. Thus, punishment grounded on morals may be related to lasting or delayed psychological incentives, whereas punishment triggered by competitive desires may be linked to short-run aspirations. These results indicate that the individual's time horizon is relevant for the type of social behaviour she opts for. Integrating such differences in inter-temporal preferences and the social behaviour of agents might help to achieve a better understanding of how human cooperation and punishment behaviour has evolved.


Daily Coffee Drinking Is Associated with Lower Risks of Cardiovascular and Total Mortality in a General Italian Population: Results from the Moli-sani Study.
An inverse relationship between coffee intake and mortality has been observed in several population cohorts, but rarely within Mediterranean countries. Moreover, the biological pathways mediating such an association remain unclear. We assessed the associations between coffee consumption and total and cause-specific mortality and examined the mediating roles of N-terminal pro B-type natriuretic peptide (NTproBNP), high-sensitivity Troponin I, blood glucose, lipid metabolism, and selected biomarkers of inflammation and renal function. We longitudinally analyzed data on 20,487 men and women (35-94 years old at baseline) in the Moli-sani Study, a prospective cohort established in 2005-2010. Individuals were free from cardiovascular disease (CVD) and cancer and were followed-up for a median of 8.3 years. Dietary data were collected by a 188-item semi-quantitative FFQ. Coffee intake was standardized to a 30-mL Italian espresso cup size. HRs with 95% CIs were calculated by multivariable Cox regression. In comparison with no/rare coffee consumption (up to 1 cup/d), HRs for all-cause mortality across categories of coffee consumption (>1 to ≤2, >2 to ≤3, >3 to ≤4 and >4 cups/d) were 0.79 (95% CI, 0.65-0.95), 0.84 (95% CI, 0.69-1.03), 0.72 (95% CI, 0.57-0.92), and 0.85 (95% CI, 0.62-1.12), respectively. For CVD mortality, a nonlinear (P for non-linearity = 0.021) J-shaped association was found (magnitude of the relative reduction = 37%; nadir at 3-4 cups/d). Circulating levels of NTproBNP explained up to 26.4% of the association between coffee and all-cause mortality, while systolic blood pressure was likely to be on the pathway between coffee and CVD mortality, although to a lesser extent. In this large cohort of Italian adults, moderate consumption (3-4 cups/d) of Italian-style coffee was associated with lower risks of all-cause and, specifically, of CVD mortality. Among the known biomarkers investigated here, NTproBNP likely mediates the relationship between coffee intake and all-cause mortality.


Well-done meat consumption, NAT1 and NAT2 acetylator genotypes and prostate cancer risk: the multiethnic cohort study.
Prostate cancer (PC) is the most common male malignancy in the United States and disparities in risk exist among ethnic/racial groups. A high intake of well-done meat and the presence of the rapid NAT1 and slow NAT2 acetylator genotypes, as modifiers of the carcinogenic effect of heterocyclic amines, were hypothesized to increase PC risk and possibly explain these ethnic differences in risk. This study examined the associations between well-done (red) meat consumption, NAT1 and NAT2 acetylator genotypes, and PC risk among five ethnicities (African American, Native Hawaiian, Japanese American, Latino, and Caucasian) in a case-control study of PC nested within the Multiethnic Cohort study. Cases (n = 2,106) and controls (n = 2,063) were genotyped for eight single nucleotide polymorphisms in NAT1 and seven single nucleotide polymorphisms in NAT2 that characterized all common alleles for these genes. Well-done meat intake was computed based on responses to a detailed food frequency questionnaire including a question on meat preference. Conditional logistic regression was used in the analysis. There was no evidence of an increased risk associated with preference for well-done meat, intake of well-done meat, and NAT1 or NAT2 genotypes (jointly or separately). These results do not support the hypothesis that exposure to heterocyclic amines is associated with risk of PC. However, additional studies with more precise exposure measures are needed.


Stochastic model of template-directed elongation processes in biology.
We present a novel modular, stochastic model for biological template-based linear chain elongation processes. In this model, elongation complexes (ECs; DNA polymerase, RNA polymerase, or ribosomes associated with nascent chains) that span a finite number of template units step along the template, one after another, with semaphore constructs preventing overtaking. The central elongation module is readily extended with modules that represent initiation and termination processes. The model was used to explore the effect of EC span on motor velocity and dispersion, and the effect of initiation activator and repressor binding kinetics on the overall elongation dynamics. The results demonstrate that (1) motors that move smoothly are able to travel at a greater velocity and closer together than motors that move more erratically, and (2) the rate at which completed chains are released is proportional to the occupancy or vacancy of activator or repressor binding sites only when initiation or activator/repressor dissociation is slow in comparison with elongation.


Engineered allosteric activation of kinases in living cells.
Studies of cellular and tissue dynamics benefit greatly from tools that can control protein activity with specificity and precise timing in living systems. Here we describe an approach to confer allosteric regulation specifically on the catalytic activity of protein kinases. A highly conserved portion of the kinase catalytic domain is modified with a small protein insert that inactivates catalytic activity but does not affect other protein functions (Fig. 1a). Catalytic activity is restored by addition of rapamycin or non-immunosuppresive rapamycin analogs. Molecular modeling and mutagenesis indicate that the protein insert reduces activity by increasing the flexibility of the catalytic domain. Drug binding restores activity by increasing rigidity. We demonstrate the approach by specifically activating focal adhesion kinase (FAK) within minutes in living cells and show that FAK is involved in the regulation of membrane dynamics. Successful regulation of Src and p38 by insertion of the rapamycin-responsive element at the same conserved site used in FAK suggests that our strategy will be applicable to other kinases.


Social Reward Questionnaire-Adolescent Version and its association with callous-unemotional traits.
During adolescence, social interactions are a potent source of reward. However, no measure of social reward value exists for this age group. In this study, we adapted the adult Social Reward Questionnaire, which we had previously developed and validated, for use with adolescents. Participants aged 11-16 (n = 568; 50% male) completed the Social Reward Questionnaire-Adolescent Version (SRQ-A), alongside measures of personality traits-five-factor model (FFM) and callous-unemotional (CU) traits-for construct validity purposes. A confirmatory factor analysis of the SRQ-A supported a five-factor structure (Comparative Fit Index = 0.90; Root Mean Square Error of Approximation = 0.07), equating to five questionnaire subscales: enjoyment of Admiration, Negative Social Potency, Passivity, Prosocial Interactions and Sociability. Associations with FFM and CU traits were in line with what is seen for adult samples, providing support for the meaning of SRQ-A subscales in adolescents. In particular, adolescents with high levels of CU traits showed an 'inverted' pattern of social reward, in which being cruel is enjoyable and being kind is not. Gender invariance was also assessed and was partially supported. The SRQ-A is a valid, reliable measure of individual differences in social reward in adolescents.


Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells.
Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreER(T2)/R26R-YFP/Notch1(loxP/loxP) [Notch1inducible knock-out (iKO)] mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFP+ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild-type (WT) mice (nestin-CreER(T2)/R26R-YFP/Notch1(w/w)) after tamoxifen (post-TAM), producing adult-generated YFP+ dentate gyrus neurons. Compared with WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFP+ cells 13 and 30 d post-TAM but had significantly fewer SGZ YFP+ cells 60 and 90 d post-TAM. Significantly fewer YFP+ Type-1 NSCs and transiently amplifying progenitors (TAPs) resulted in generation of fewer YFP+ granule neurons in Notch1 iKO mice. Strikingly, 30 d of running rescued this deficit, as the total YFP+ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch- and Type-1 NSC-independent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli.


Self-stimulation alters human sensory brain responses.
Human electrocortical potentials evoked by self-administered auditory and visual stimuli manifest much smaller amplitude and faster poststimulus timing than do average brain responses evoked by identical machine-delivered stimuli. Auditory evoked potentials show this "self-stimulation effect" to a greater degree than do visual responses. For visual evoked potentials, the effect appears greater at the vertex association area than over the occipital cortex. Individual differences in the magnitude of the "self-stimutlation effect" relate to level of intelligence.


A mutation in Arabidopsis seedling plastid development1 affects plastid differentiation in embryo-derived tissues during seedling growth.
Oilseed plants like Arabidopsis (Arabidopsis thaliana) develop green photosynthetically active embryos. Upon seed maturation, the embryonic chloroplasts degenerate into a highly reduced plastid type called the eoplast. Upon germination, eoplasts redifferentiate into chloroplasts and other plastid types. Here, we describe seedling plastid development1 (spd1), an Arabidopsis seedling albino mutant capable of producing normal green vegetative tissues. Mutant seedlings also display defects in etioplast and amyloplast development. Precocious germination of spd1 embryos showed that the albino seedling phenotype of spd1 was dependent on the passage of developing embryos through the degreening and dehydration stages of seed maturation, suggesting that SPD1 is critical during eoplast development or early stages of eoplast redifferentiation. The SPD1 gene was found to encode a protein containing a putative chloroplast-targeting sequence in its amino terminus and also domains common to P-loop ATPases. Chloroplast localization of the SPD1 protein was confirmed by targeting assays in vivo and in vitro. Although the exact function of SPD1 remains to be defined, our findings reveal aspects of plastid development unique to embryo-derived cells.


Use of tolvaptan in patients hospitalized for worsening chronic heart failure with severe hyponatremia: The initial experience at a single-center in Turkey.
The aim of the present study was to assess the efficacy and safety of tolvaptan for severe hyponatremia (SH) in hypervolemic heart failure (HF) patients within daily clinical practice. We restrospectively reviewed our database on tolvaptan as an add-on treatment in hypervolemic patients admitted to our clinic due to deterioration of HF and having hyponatremia resistant to standard therapy. Severe hyponatremia was defined as serum sodium concentration ≤125 mEq/L. The database included demographic, clinical, laboratory, and echocardiographic findings on admission, and numerous outcome measures for oral tolvaptan treatment were used to assess its efficacy and safety. The study group consisted of 56 hypervolemic HF patients with severe hyponatremia (25 female and 31 male) with mean age of 66 years. All patients received a single dose of tolvaptan 15 mg daily for an average of 3.2 days due to severe hyponatremia. Sodium and potassium concentrations, fluid intake, and urine volume increased (p<0.0001, p=0.037, p<0.0001, and p<0.0001, respectively), whereas furosemide dosage, body weight, heart rate, systolic and diastolic blood pressure, and New York Heart Association class decreased significantly in response to tolvaptan treatment, without a rise in serum creatinine or urea concentrations (p<0.0001, p<0.0001, p=0.001, p<0.049, p<0.009 ve p=0.001, respectively). In this retrospective, single-centered study conducted in a small group of Turkish patients, short-term treatment with low-dose tolvaptan added to standard therapy of hypervolemic HF patients with severe hyponatremia was well tolerated with a low rate of major side effects and was effective in correcting severe hyponatremia.


The sympathetic nervous system stimulates anti-inflammatory B cells in collagen-type II-induced arthritis.
As previously shown, the sympathetic nervous system (SNS) shows proinflammatory activity during initiation of arthritis but is anti-inflammatory in established collagen-induced arthritis (CIA). Interleukin 10 (IL-10)-producing B cells suppress arthritis and are a potential target of the SNS because (1) B cells express functional β(2)-adrenoceptors (β(2)ARs) and (2) IL-10, at least in monocytes/macrophages, is regulated in a cAMP/PKA/CREB-dependent manner. To test the hypothesis that anti-inflammatory effects of the SNS in CIA are mediated by stimulating IL-10-producing anti-inflammatory B cells. Collagen-induced arthritis in DBA/1 mice, sympathectomy, adoptive B cell transfer, in vitro B cell culture, and assessment of B cell IL-10 production. Mice treated with B cells from SNS-intact mice showed less severe arthritis than mice treated with B cells from sympathectomised mice. This anti-inflammatory action of B cells from SNS-intact mice correlated with increased IL-10 produced by B cells, which was mediated by norepinephrine (NE), in a β(2)AR, PKA-dependent manner. However, an NE-mediated increase in IL-10 was seen only in B cells from immunised but not naive mice, explaining in part the anti-inflammatory properties of the SNS in the late phase of arthritis. Finally, animals treated with B cells isolated from immunised mice and activated in vitro in the presence of a β(2)AR stimulus showed a decrease in arthritis severity in comparison with controls, an approach that might be used for future cellular treatment strategies.


3 Different types of strength training in older women.
The objective of the present study was to evaluate and compare the neuromuscular, morphological and functional adaptations of older women subjected to 3 different types of strength training. 58, healthy women (67 ± 5 year) were randomized to experimental (EG, n=41) and control groups (CG, n=17) during the first 6 weeks when the EG group performed traditional resistance exercise for the lower extremity. Afterwards, EG was divided into three specific strength training groups; a traditional group (TG, n=14), a power group (PG, n=13) that performed the concentric phase of contraction at high speed and a rapid strength group (RG, n=14) that performed a lateral box jump exercise emphasizing the stretch-shortening-cycle (SSC). Subjects trained 2 days per week through the entire 12 weeks. Following 6 weeks of generalized strength training, significant improvements occurred in EG for knee extension one-repetition (1RM) maximum strength (+19%), knee extensor muscle thickness (MT, +15%), maximal muscle activation (+44% average) and onset latency ( -31% average) for vastus lateralis (VL), vastus medialis (VM) and rectus femoris (RF) compared to CG (p<0.05). Following 6 more weeks of specific strength training, the 1RM increased significantly and similarly between groups (average of +21%), as did muscle thickness of the VL (+25%), and activation of VL (+44%) and VM (+26%). The onset latency of RF (TG=285 ± 109 ms, PG=252 ± 76 ms, RG=203 ± 43 ms), reaction time (TG=366 ± 99 ms, PG=274 ± 76 ms, RG=201 ± 41 ms), 30-s chair stand (TG=18 ± 3, PG=18 ± 1, RG=21 ± 2) and counter movement jump (TG=8 ± 2 cm, PG=10 ± 3 cm, RG=13 ± 2 cm) was significantly improved only in RG (p<0.05). At the end of training, the rate of force development (RFD) over 150 ms (TG=2.3 ± 9.8 N·s(-1), PG=3.3 ± 3.2 N·s(-1), RG=3.8 ± 6.8 N·s(-1), CG=2.3 ± 7.0 N·s(-1)) was significantly greater in RG and PG than in TG and CG (p<0.05). In conclusion, rapid strength training is more effective for the development of rapid force production of muscle than other specific types of strength training and by consequence, better develops the functional capabilities of older women.


Genetic and familial environmental effects on suicide attempts: a study of Danish adoptees and their biological and adoptive siblings.
Genetic factors have been found to influence the risk of suicide. It is less clear if this also applies to attempted suicide. We have investigated genetic and familial environmental factors by studying the occurrence of suicide attempts in biological and adoptive siblings of adoptees who attempted suicide compared to siblings of adoptees with no suicide attempts. We used a random sample of 1933 adoptees from the Danish Adoption Register, a register of non-familial adoptions of Danish children, i.e. the adoptive parents are biologically unrelated to the adoptee. Analyses were conducted on incidence rates of attempted suicide in biological and adoptive siblings given occurrence of attempted suicide in the adoptees while also taking into account psychiatric disorders. Information about suicidal attempt and history of psychiatric disorder was based on hospital admissions. The rate of attempted suicide in full siblings of adoptees who attempted suicide before age 60 years was higher than in full siblings of adoptees who had not attempted suicide (incidence rate ratios (IRR)=3.45; 95% confidence interval [CI]=0.94-12.7). After adjustment for history of psychiatric admission of siblings the increased rate was statistically significant (IRR=3.88; 95% CI-1.42-10.6). Information on attempted suicide and psychiatric history was limited to that which involved hospitalisation. Genetic factors influence risk of suicide attempts.


Treatment Patterns, Health Care Resource Utilization, and Spending in Medicaid Beneficiaries Initiating Second-generation Long-acting Injectable Agents Versus Oral Atypical Antipsychotics.
Second-generation long-acting injectable therapies (SGA-LAIs) may reduce health care resource utilization (HRU) and health care costs compared with daily oral atypical antipsychotics (OAAs) in patients with schizophrenia due to reduced dosing frequency, delivery/monitoring by a health care provider, and improved adherence. The aim of the present study was to compare treatment patterns, HRU, and Medicaid spending in patients with schizophrenia initiated on SGA-LAIs (overall and according to agent) versus OAAs. Medicaid claims data (2010-2015) from 6 states were used to identify adult schizophrenia patients initiated on SGA-LAIs or OAAs. Treatment patterns (proportion of days covered [PDC] ≥80% and persistence [no gap ≥30, 60, or 90 days] to index treatment), HRU, and costs were evaluated over 12 months and compared by using multivariable logistic, Poisson, and ordinary least squares regression models, respectively. P values for HRU and cost outcomes were obtained from a nonparametric bootstrap procedure. Costs (2015 US dollars) reflect the Medicaid payer's perspective before any rebate. Overall, 3307 and 21,355 patients initiated SGA-LAIs and OAAs, respectively (paliperidone palmitate LAI [PP-LAI; n = 2182], risperidone LAI [n = 968], aripiprazole LAI [n = 108], and olanzapine LAI [n = 49]). During follow-up and compared with OAA patients, SGA-LAI patients were more likely to reach PDC ≥80% (odds ratio [OR], 1.28; P < 0.001) and be persistent (eg, no gap ≥60 days; OR, 1.45; P < 0.001) to the index treatment. Relative to OAA patients, SGA-LAI patients had fewer long-term care days (incidence rate ratio [IRR], 0.75; P < 0.001) and home care visits (IRR, 0.75; P < 0.001) but more mental health institute (IRR, 1.16; P < 0.001) and 1-day mental health institute (IRR, 1.16; P < 0.001) admissions. Moreover, PP-LAI patients had fewer inpatient days (IRR, 0.78; P = 0.004) versus OAA patients. SGA-LAI patients had lower medical costs (mean monthly cost difference [MMCD], -$168; P < 0.001) than OAA patients, offsetting more than one half of the higher pharmacy costs (MMCD, $271; P < 0.001). Compared with OAAs, only PP-LAI was associated with significant medical cost savings (MMCD, -$225; P < 0.001). Medicaid beneficiaries with schizophrenia initiated on SGA-LAIs had better adherence and persistence to therapy over 12 months than patients initiated on OAAs. SGA-LAIs, particularly PP-LAI, were associated with lower medical costs that successfully offset more than one half of the higher pharmacy costs relative to OAA.


Counseling about medication-induced birth defects with clinical decision support in primary care.
We evaluated how computerized clinical decision support (CDS) affects the counseling women receive when primary care physicians (PCPs) prescribe potential teratogens and how this counseling affects women's behavior. Between October 2008 and April 2010, all women aged 18-50 years visiting one of three community-based family practice clinics or an academic general internal medicine clinic were invited to complete a survey 5-30 days after their clinic visit. Women who received prescriptions were asked if they were counseled about teratogenic risks or contraception and if they used contraception at last intercourse. Eight hundred one women completed surveys; 27% received a prescription for a potential teratogen. With or without CDS, women prescribed potential teratogens were more likely than women prescribed safer medications to report counseling about teratogenic risks. However, even with CDS 43% of women prescribed potential teratogens reported no counseling. In multivariable models, women were more likely to report counseling if they saw a female PCP (odds ratio: 1.97; 95% confidence interval: 1.26-3.09). Women were least likely to report counseling if they received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Women who were pregnant or trying to conceive were not more likely to report counseling. Nonetheless, women who received counseling about contraception or teratogenic risks were more likely to use contraception after being prescribed potential teratogens than women who received no counseling. Physician counseling can reduce risk of medication-induced birth defects. However, efforts are needed to ensure that PCPs consistently inform women of teratogenic risks and provide access to highly effective contraception.


A positive Real-Time Elastography (RTE) combined with a Prostate Cancer Gene 3 (PCA3) score above 35 convey a high probability of intermediate- or high-risk prostate cancer in patient admitted for primary prostate biopsy.
The standard of care in patients with suspected prostate cancer (PCa) is systematic prostate biopsies. This approach leads to unnecessary biopsies in patients without PCa and also to the detection of clinical insignificant PCa. Better tools are wanted. We have evaluated the performance of real-time elastography (RTE) combined with prostate cancer gene 3 (PCA3) in an initial biopsy setting with the goal of better identifying patients in need of prostate biopsies. 127 patients were included in this study; three were excluded because of not measureable PCA3 score leading to 124 evaluable patients. A cut-off value of 35 was used for PCA3. All patients were examined with a Hitachi Preirus with an endfire probe for RTE, a maximum of five targeted biopsies were obtained from suspicious lesions detected by RTE. All patients then had a 10-core systematic biopsy performed by another urologist unaware of the RTE results. The study includes follow-up data for a minimum of three years; all available histopathological data are included in the analysis. There was a significant difference in PCA3 score: 26.6 for benign disease, 73.6 for cancer patients (p < 0.001). 70 patients (56 %) were diagnosed with prostate cancer in the study period, 21 (30 %) low-risk, 32 (46 %) intermediate-risk and 17 (24 %) high-risk. RTE and PCA3 were significant markers for predicting intermediate- and high-risk PCa (p = 0.001). The combination of RTE and PCA3 had a sensitivity of 96 % and a negative predictive value (NPV) of 90 % for the group of intermediate- and high-risk PCa together and a NPV for high-risk PCa of 100 %. If both parameters are positive there is a high probability of detecting intermediate- or high-risk PCa, if both parameters are negative there is only a small chance of missing prostate cancer with documented treatment benefit. RTE and PCA3 may be used as pre-biopsy examinations to reduce the number of prostate biopsies.


Immunoliposomes for Targeted Delivery of an Antifibrotic Drug.
Excessive extracellular matrix formation in organs and tissues arises from an imbalance between the synthesis and degradation of matrix proteins, especially collagen. This condition interferes with proper wound healing and regeneration, and to date, no specific treatment is available. In the present study, we propose a targeted drug delivery system consisting of cell-specific immunoliposomes (ILs) loaded with deferoxamine (DFO) as an antifibrotic drug. ILs were functionalized with polyethylene glycol (PEG) to improve the steric stability and prolong their half-life. In addition, a single-chain Fv (scFv) antibody fragment that specifically targets fibroblast activation protein (FAP) was incorporated. An in vitro fibrosis model was employed to test this construct. This model consisted of highly activated pro-fibrotic fibroblasts with 2- to 6-fold induction of selected fibrosis markers: cell/matrix deposited collagen I, total soluble collagen, and α smooth muscle actin. The activation was accompanied by a significant and cell-specific elevation of FAP expression and activity, thereby confirming that FAP is an adequate target for antifibrotic drug delivery. Purified anti-FAP scFv was shown to bind specifically to these cells without influencing the FAP enzymatic activity. DFO was demonstrated to have a dose-dependent antifibrotic activity as quantified by collagen deposition. Specific binding and intracellular uptake of DiI-labeled ILs into the activated fibroblasts were shown by flow cytometry and microscopy. Finally, DFO-loaded ILs targeted to FAP caused a significant reduction in the collagen deposition, whereas no effect was observed using liposomes that lacked the targeting antibody fragment. These results suggest that the FAP-specific scFv-conjugated liposomes have considerable potential for cell-specific targeting applicable as a therapy for excessive collagen deposition during fibrosis. In general, through liposome encapsulation, bioactive molecules, such as DFO, that have broad effects and poor cell penetration can be converted into cell-specific composites for targeted drug delivery.


Generation and decay of the immune response to a progressive fibrosarcoma. I. Ly-1+2- suppressor T cells down-regulate the generation of Ly-1-2+ effector T cells.
It was shown that the progressive growth of the immunogenic meth A fibrosarcoma in its semisyngeneic host results in the generation of concomitant immunity to the growth of a tumor implant. The generation of immunity occurred between days 6 and 9 of tumor growth and was associated with the generation of sensitized T cells that were capable, on passive transfer, of causing regression of a 3-d tumor in gamma-irradiated recipients. After day 9 of tumor growth, concomitant immunity and the T cells able to passively transfer it were progressively lost, and this was associated with the generation of splenic suppressor T cells able to suppress the expression of adoptive immunity against an established tumor in T cell-deficient ( TXB ) recipients. The T cells that passively transferred concomitant immunity were shown to be of the Ly-1-2+ phenotype, in contrast to the T cells that transferred suppression, which were shown with the same reagents to be Ly-1+2-. The results are consistent with the hypothesis that the progressive growth of an immunogenic tumor results in the generation of Ly-1-2+-sensitized effector T cells that fail to reach a number sufficient to destroy the tumor because their generation is down-regulated by tumor-induced Ly-1+2- suppressor T cells.


The fusiform face area: a module in human extrastriate cortex specialized for face perception.
Using functional magnetic resonance imaging (fMRI), we found an area in the fusiform gyrus in 12 of the 15 subjects tested that was significantly more active when the subjects viewed faces than when they viewed assorted common objects. This face activation was used to define a specific region of interest individually for each subject, within which several new tests of face specificity were run. In each of five subjects tested, the predefined candidate "face area" also responded significantly more strongly to passive viewing of (1) intact than scrambled two-tone faces, (2) full front-view face photos than front-view photos of houses, and (in a different set of five subjects) (3) three-quarter-view face photos (with hair concealed) than photos of human hands; it also responded more strongly during (4) a consecutive matching task performed on three-quarter-view faces versus hands. Our technique of running multiple tests applied to the same region defined functionally within individual subjects provides a solution to two common problems in functional imaging: (1) the requirement to correct for multiple statistical comparisons and (2) the inevitable ambiguity in the interpretation of any study in which only two or three conditions are compared. Our data allow us to reject alternative accounts of the function of the fusiform face area (area "FF") that appeal to visual attention, subordinate-level classification, or general processing of any animate or human forms, demonstrating that this region is selectively involved in the perception of faces.


Biochemical evidence of the interactions of membrane type-1 matrix metalloproteinase (MT1-MMP) with adenine nucleotide translocator (ANT): potential implications linking proteolysis with energy metabolism in cancer cells.
Invasion-promoting MT1-MMP (membrane type-1 matrix metalloproteinase) is a key element in cell migration processes. To identify the proteins that interact and therefore co-precipitate with this proteinase from cancer cells, we used the proteolytically active WT (wild-type), the catalytically inert E240A and the C-end truncated (tailless; DeltaCT) MT1-MMP-FLAG constructs as baits. The identity of the pulled-down proteins was determined by LC-MS/MS (liquid chromatography tandem MS) and then confirmed by Western blotting using specific antibodies. We determined that, in breast carcinoma MCF cells (MCF-7 cells), ANT (adenine nucleotide translocator) efficiently interacted with the WT, E240A and DeltaCT constructs. The WT and E240A constructs also interacted with alpha-tubulin, an essential component of clathrin-mediated endocytosis. In turn, tubulin did not co-precipitate with the DeltaCT construct because of the inefficient endocytosis of the latter, thus suggesting a high level of selectivity of our test system. To corroborate these results, we then successfully used the ANT2-FLAG construct as a bait to pull-down MT1-MMP, which was naturally produced by fibrosarcoma HT1080 cells. We determined that the presence of the functionally inert catalytic domain alone was sufficient to cause the proteinase to interact with ANT2, thus indicating that there is a non-proteolytic mode of these interactions. Overall, it is tempting to hypothesize that by interacting with pro-invasive MT1-MMP, ANT plays a yet to be identified role in a coupling mechanism between energy metabolism and pericellular proteolysis in migrating cancer cells.


Gestational caffeine exposure acts as a fetal thyroid-cytokine disruptor by activating caspase-3/BAX/Bcl-2/Cox2/NF-κB at ED 20.
The objective of this examination was to explore the impact of gestational caffeine (1,3,7-trimethylxanthine) exposure on the maternofetal thyroid axis and fetal thyroid-cytokine communications during gestation. Pregnant rats (Rattus norvegicus) were intraperitoneally administered caffeine (120 or 150 mg kg-1) from gestation day (GD) 1 to 20. Both doses of caffeine resulted in maternal hyperthyroidism, whereas the elevation in the concentration of serum free triiodothyronine (FT3) and free thyroxine (FT4) was related to a depletion in the level of TSH at GD 20. Maternal body weight gain and food consumption were markedly increased, while fetal body weight was significantly reduced. These alterations caused fetal hypothyroidism and several pathological lesions in the fetal thyroid gland including a vacuolar colloid, destructive degeneration, atrophy and hyperplasia at embryonic day (ED) 20. The abnormalities in the fetal thyroid gland seemed to depend on the activation of caspase-3, Bcl-2, BAX, Cox2, and NF-κB mRNA expression. Both maternal caffeine doses caused a marked attenuation in the values of fetal serum GH, IGF-II, VEGF, TGF-β, TNF-α, IL-1β, IL-6, leptin and MCP-1, and a noticeable elevation in the value of fetal serum adiponectin at ED 20. Thus, gestational caffeine exposure might disrupt the fetal thyroid-cytokine axis.


[Autoimmune hepatitis and membranous glomerulonephritis under immune therapy in chronic hepatitis C].
A 63-year-old patient is evaluated for an unclear weight loss with general malaise and fatigue for several months. Serological examination reveales the first diagnosis of a hepatitis-C-virus-genotype-1b-infection with an initial viral load of 980 000 IU / ml. The duration of the infection is suggested to be more than 6 months. Because of the initially elevated anti-nuclear-antibodies (ANA) the diagnosis of an autoimmune hepatitis needs to be excluded. All other liver related autoantibodies and the immunoglobulins (Ig) IgG, IgA and IgM are normal. A liver biopsy is conducted. After a short test with non-pegylated interferon (IFN) liver enzymes remain stable and treatment with pegylated IFN-alfa-2a and ribavirin (RBV) is initiated. The patient is a "rapid viral responder" and his viral load is found under the detection limit within 4 weeks under therapy. On the 16th week, liver enzymes increase rapidly. ANA's and IgG-immunoglobulins are positive. A second lever biopsy does not confirm the diagnosis of autoimmune hepatitis and the treatment is continued under careful observation of all relevant liver parameters. 21 weeks after the initiation of the treatment, massive peripheral edema, hypoproteinemia and proteinuria are observed. The renal biopsy reveales membranous glomerulonephritis. Because of the preserved renal function, no acute immunosuppression is initiated and the treatment gets completed after overall 24 weeks. Liver and renal parameters return quickly back to normal after treatment discharge. This is the first report of a combined autoimmune reaction with development of autoimmune hepatitis and glomerulonephritis under INF and RBV antiviral therapy for a chronic hepatitis-C-infection. The occurrence of autoimmune manifestations should especially be considered in genetically susceptible individuals or those with positive autoimmunity markers. The initiation of INF for the treatment of chronic hepatitis-C-infection has to be critically evaluated since nowadays alternative, INF-free therapeutic regimens are available.


Psychosis associated to Parkinson's disease in the early stages: relevance of cognitive decline and depression.
To evaluate the prevalence of psychosis associated with Parkinson's disease (PSY-PD) in its early stages, its incidence over a 24 month follow-up period and the association with motor and non-motor clinical features. PRIAMO is a 2 year longitudinal observational study that has enrolled patients with parkinsonism in 55 Italian centres. A cohort of 495 patients with early disease stage PD (baseline Hoehn and Yahr score ≤ 2, disease's duration (median) 3.4 years) were followed for 2 years. PSY-PD was evaluated by means of a clinician rated questionnaire and defined as the presence of at least one of the following symptoms occurring for at least 1 month: illusions, hallucinations, jealousy ideas and persecutory ideas. Patients with and without PSY-PD were compared on several clinical variables, encompassing motor and non-motor features. The prevalence of PSY-PD at baseline was 3%; the incidences at 12 and 24 months were 5.2% and 7.7%, respectively. Longer disease duration and prescription of dopamine agonists at baseline were associated with the development of PSY-PD over the 24 month period. At this follow-up time, worse disease severity, decline in cognitive performances, presence of depressive symptoms and anxiety were more frequently observed in PSY-PD. Psychotic type symptoms may occur in the early stages of PD although less frequently than in later stages. Beyond dopaminergic treatment, there are disease related factors, such as disease severity and the occurrence of cognitive and depressive symptoms, which may underlie the onset of psychotic type symptoms from the earliest stages.


Color obsessions and phobias in autism spectrum disorders: the case of J.G.
The current study is the first investigation of color 'obsessions' and 'phobias' in ASD. We investigate the color perception and cognition of J.G., a boy with ASD who has a strong obsession with blue, and a strong phobia of other colors. J.G.'s performance on a series of color tasks (color-entity association; chromatic discrimination; color classification) is compared to 13 children with and without autism who do not have color obsessions or phobias. The findings lead to the formalization of two hypotheses: (i) color obsessions and phobias in individuals with ASD are related to an unusually strong ability to associate colors with entities; (ii) color obsessions are related to hyposensitivity, and color phobias to hypersensitivity, in the affected regions of color space.


A cohort study of serum bilirubin levels and incident non-alcoholic fatty liver disease in middle aged Korean workers.
Serum bilirubin may have potent antioxidant and cytoprotective effects. Serum bilirubin levels are inversely associated with several cardiovascular and metabolic endpoints, but their association with nonalcoholic fatty liver disease (NAFLD) has not been investigated except for a single cross-sectional study in a pediatric population. We assessed the prospective association between serum bilirubin concentrations (total, direct, and indirect) and the risk for NAFLD. We performed a cohort study in 5,900 Korean men, 30 to 59 years of age, with no evidence of liver disease and no major risk factors for liver disease at baseline. Study participants were followed in annual or biennial health examinations between 2002 and 2009. The presence of fatty liver was determined at each visit by ultrasonography. We observed 1,938 incident cases of NAFLD during 28,101.8 person-years of follow-up. Increasing levels of serum direct bilirubin were progressively associated with a decreasing incidence of NAFLD. In age-adjusted models, the hazard ratio for NAFLD comparing the highest to the lowest quartile of serum direct bilirubin levels was 0.61 (95% CI 0.54-0.68). The association persisted after adjusting for multiple metabolic parameters (hazard ratio comparing the highest to the lowest quartile 0.86, 95% CI 0.76-0.98; P trend = 0.039). Neither serum total nor indirect bilirubin levels were significantly associated with the incidence of NAFLD. In this large prospective study, higher serum direct bilirubin levels were significantly associated with a lower risk of developing NAFLD, even adjusting for a variety of metabolic parameters. Further research is needed to elucidate the mechanisms underlying this association and to establish the role of serum direct bilirubin as a marker for NAFLD risk.


Paclitaxel-Loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy.
Peritoneal carcinomatosis is present in more than 60% of gastric cancer, 40% of ovarian cancer, and 35% of colon cancer patients. It is the second most common cause of cancer-related mortality, with a median survival of 1 to 3 months. Cytoreductive surgery combined with intraperitoneal chemotherapy is the current clinical treatment, but achieving curative drug accumulation and penetration in peritoneal carcinomatosis lesions remains an unresolved challenge. Here, we used flexible and pH-sensitive polymersomes for payload delivery to peritoneal gastric (MKN-45P) and colon (CT26) carcinoma in mice. Polymersomes were loaded with paclitaxel and in vitro drug release was studied as a function of pH and time. Paclitaxel-loaded polymersomes remained stable in aqueous solution at neutral pH for up to 4 months. In cell viability assay on cultured cancer cell lines (MKN-45P, SKOV3, CT26), paclitaxel-loaded polymersomes were more toxic than free drug or albumin-bound paclitaxel (Abraxane). Intraperitoneally administered fluorescent polymersomes accumulated in malignant lesions, and immunofluorescence revealed an intense signal inside tumors with no detectable signal in control organs. A dual targeting of tumors was observed: direct (circulation-independent) penetration, and systemic, blood vessel-associated accumulation. Finally, we evaluated preclinical antitumor efficacy of paclitaxel-polymersomes in the treatment of MKN-45P disseminated gastric carcinoma using a total dose of 7 mg/kg. Experimental therapy with paclitaxel-polymersomes improved the therapeutic index of drug over free paclitaxel and Abraxane, as evaluated by intraperitoneal tumor burden and number of metastatic nodules. Our findings underline the potential utility of the polymersome platform for delivery of drugs and imaging agents to peritoneal carcinomatosis lesions. Mol Cancer Ther; 15(4); 670-9. ©2016 AACR.


Food security: the challenge of feeding 9 billion people.
Continuing population and consumption growth will mean that the global demand for food will increase for at least another 40 years. Growing competition for land, water, and energy, in addition to the overexploitation of fisheries, will affect our ability to produce food, as will the urgent requirement to reduce the impact of the food system on the environment. The effects of climate change are a further threat. But the world can produce more food and can ensure that it is used more efficiently and equitably. A multifaceted and linked global strategy is needed to ensure sustainable and equitable food security, different components of which are explored here.


Acquired hypogammaglobulinemia in HIV-positive subjects after liver transplantation.
As more solid organ transplantations are performed in patients infected with human immunodeficiency virus (HIV), post-transplant complications in this population are becoming better defined. Using serum samples from the Solid Organ Transplantation in HIV: Multi-Site Study, we studied the epidemiology of acquired hypogammaglobulinemia (HGG) after liver transplantation (LT) in 79 HIV-infected individuals with a median CD4 count at enrollment of 288 (interquartile range 200-423) cells/μL. Quantitative immunoglobulin G (IgG) levels before and after LT were measured, with moderate and severe HGG defined as IgG 350-500 mg/dL and <350 mg/dL, respectively. Incidence, risk factors, and associated outcomes of moderate or worse HGG were evaluated using Kaplan-Meier estimator and proportional hazards (PH) models. The 1-year cumulative incidence of moderate or worse HGG was 12% (95% confidence interval [CI]: 6-22%); no new cases were observed between years 1 and 2. In a multivariate PH model, higher pre-transplant model for end-stage liver disease score (P = 0.04) and treated acute rejection (P = 0.04) were both identified as significant predictors of moderate or worse HGG. There was a strong association of IgG levels <500 mg/dL with non-opportunistic serious infection (hazard ratio [95% CI]: 3.5 [1.1-10.6]; P = 0.03) and mortality (3.2 [1.1-9.4]; P = 0.04). These associations held after adjustment for important determinants of infection and survival among the entire cohort. These results suggest that a proportion of HIV-positive LT recipients will develop clinically significant HGG after transplantation.


The Effect of Prophylactic Antibiotics on Post Laparoscopic Cholecystectomy Infectious Complications: A Double-Blinded Clinical Trial.
Laparoscopic cholecystectomy (LC) is one of the most common surgeries in laparoscopic surgery. Although, it is believed that LC has low-risk for post-operative infectious complications, the use of a prophylactic antibiotic is still controversial in elective LC. To determine the impact of prophylactic antibiotics on postoperative infection complications in elective laparoscopic cholecystectomy. In this double-blind, placebo-controlled, randomized, clinical trial, patients who were candidates for elective LC, from March 2012 to 2015, in four hospitals in Babol, Iran, were studied. Patients were allocated randomly to two groups, i.e., group C: Cefazolin (n = 182) and group P: placebo (n = 247). Group C received 1 g of Cefazolin 30 minutes before anesthesia and and then, six and 12 hours after anesthesia. Group P patients received 10 ml of isotonic sodium chloride solution. Age, gender, type of gallbladder diseases (stone, polyp, or hydrops), the length of post-operative hospitalization, frequency of gallbladder rupture, the duration of surgery, and the kinds of complications associated with infections were collected for each patient in the two groups. The data were analyzed by IBM-SPSS version 20, using the t-test and the chi-squared test, and a p-value < 0.05 was considered as significant. There were no significant differences between the two groups in terms of gender (C versus P: 18 (9.9%) male versus 22 (9%); p = 0.74), age (C versus P: 43.75 + 13.30 years versus 40.91 + 13.05; p = 0.20), and duration of surgery (C versus P: 34.97 ± 8.25 min versus 34.11 ± 8.39; p = 0.71). There were no significant differences between the two groups in the incidences of post-operative infection (C versus P: 3 (1.7%) versus 5 (2%); p = 0.99) and rupture of the gallbladder (C versus P: 14 (7.8%) versus 17 (6.8%); p = 0.85). No other post-operative systemic infectious complications (e.g., sepsis, pneumonia, or urinary tract infection) were found in either group. For patients who underwent laparoscopic cholecystectomy (LC), prophylactic antibiotics had no important role in the prevention of infections; so these antibiotics apparently are not necessary in treatment, and they are not recommended for patients with laparoscopic cholecystectomy as low-risk selective antibiotics. The trial was registered at the Iranian Clinical Trial Registry (http://www.irct.ir) with the IRCT identification number IRCT2013070413865N1. This research was supported financially by the Research Council of Babol University of Medical Sciences.


Pre-clinical Pharmacokinetic and Metabolomic Analyses of Isorhapontigenin, a Dietary Resveratrol Derivative.
Background: Isorhapontigenin (trans-3,5,4'-trihydroxy-3'-methoxystilbene, ISO), a dietary resveratrol (trans-3,5,4'-trihydroxystilbene) derivative, possesses various health-promoting activities. To further evaluate its medicinal potentials, the pharmacokinetic and metabolomic profiles of ISO were examined in Sprague-Dawley rats. Methods: The plasma pharmacokinetics and metabolomics were monitored by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS), respectively. Results: Upon intravenous injection (90 μmol/kg), ISO exhibited a fairly rapid clearance (CL) and short mean residence time (MRT). After a single oral administration (100 μmol/kg), ISO was rapidly absorbed and showed a long residence in the systemic circulation. Dose escalation to 200 μmol/kg resulted in higher dose-normalized maximal plasma concentrations (Cmax/Dose), dose-normalized plasma exposures (AUC/Dose), and oral bioavailability (F). One-week repeated daily dosing of ISO did not alter its major oral pharmacokinetic parameters. Pharmacokinetic comparisons clearly indicated that ISO displayed pharmacokinetic profiles superior to resveratrol as its Cmax/Dose, AUC/Dose, and F were approximately two to three folds greater than resveratrol. Metabolomic investigation revealed that 1-week ISO administration significantly reduced plasma concentrations of arachidonic acid, cholesterol, fructose, allantoin, and cadaverine but increased tryptamine levels, indicating its impact on metabolic pathways related to health-promoting effects. Conclusion: ISO displayed favorable pharmacokinetic profiles and may be a promising nutraceutical in view of its health-promoting properties.


Role of recording geometry in the performance of spectral diversity filters with spherical beam volume holograms.
We present experimental demonstrations of spectral diversity filters with spherical beam volume holograms for multimodal multiplex spectroscopy. Major properties of filters under diffuse-light illumination are discussed. The comparisons of spectral diversity between the transmission geometry holograms and the reflection geometry holograms are also studied. The results show that there is a trade-off between the degree of the spatial coherence of the source and the spectral diversity of the filter. We also conclude that the reflection geometry holograms have better spectral diversity and less sensitivity to the spatial coherence of the source.


Phenolic ethers in the organic polymer of the murchison meteorite.
Seven phenolic acids and many nonphenolic organic acids, including large amounts of meta-hydroxy (3-hydroxy) benzoic acid and 3-hydroxy-1,5-benzene-dicarboxylic acid, were obtained from the organic polymer of the Murchison C2 chondrite upon oxidation with alkaline cupric oxide. The phenolic acids apparently were derived from phenolic ethers in the polymer, which in turn probably were formed from carbon monoxide and hydrogen by catalytic Fischer-Tropsch type reactions in the solar nebula. In contrast, terrestrial polymers such as lignin, humic acid, and coal yield mainly para-hydroxy (4-hydroxy) benzene derivatives by the same oxidation procedure.


The gut microbiome as mediator between diet and its impact on immune function.
Dietary habits may affect inflammatory status in humans. Here we explore this interaction as well as the potential mediating role of the gut microbiome (GM), given that the GM is both involved in processing of dietary components and influences the immune system. A cross-sectional analysis of a sample of 482 healthy participants (207 males and 275 females) was performed. Dietary intake was assessed by a semiquantitative food questionnaire. Adipokines and soluble inflammatory mediators were assayed with multiple immunoassays and ELISA. Microbial DNA was extracted from frozen stool samples of 471 participants. Polychoric correlation analysis was used to establish dietary patterns, and joint multivariate associations between these dietary patterns and immune biomarkers were studied using regression analyses with adjustment for sex, age, BMI, smoking, education levels and physical exercise and other dietary patterns. Non-parametric entropy mediation was applied to investigate whether diet-immune relationships are mediated by abundance of microbial species. In this cohort, we identified three dietary patterns, characterized as "high-meat" (meat and sweetened drink), "prudent diet" (fish, fruit, legumes and vegetables) and "high alcohol" (higher alcohol consumption). Higher adherence to prudent diet was associated with a higher adiponectin level. The high alcohol pattern was associated with high concentrations of circulating concentrations of pro-inflammatory markers (CRP, IL-6, VEGF). Dialister invisus was found to mediate the relationship between a prudent dietary pattern and adiponectin, AAT, CRP, IL-6, and VEGF. In conclusion, a meat-based diet and a diet with high alcohol consumption were associated with high concentrations of biomarkers of chronic low-grade inflammation, and conversely, a prudent diet was associated with anti-inflammatory biomarkers. Diet-inflammation regulation may differ between sexes. Mediation analyses revealed that the association between prudent diet and immune function was partially mediated by the GM. The study adds to our understanding of the associations between diet, the immune system and the GM in a healthy population.


Regulation of phycobilisome rod proteins and mRNA at different light intensities in the cyanobacterium Synechococcus 6301.
The regulation of the light-harvesting antennae, the phycobilisome (Pbs), and the cpcB1A1-cpcH-cpcI-cpcD operon encoding the structural proteins of the Pbs rod, was studied in the cyanobacterium, Synechococcus sp. PCC 6301, when grown at different light intensities (li). Pbs were purified and their linker protein (LP) profiles analyzed on SDS-polyacrylamide gels. At increasing li, the amount of the distal 30-kDa LP decreased prior to any change in the amount of the proximal 33-kDa LP, indicating a sequential increase in the Pbs rod length. While the amount of LP in the rod decreased with increasing li, the levels of the LP mRNAs increased. Post-transcriptional regulation of the expression of the polycistronic cpcB1A1-cpcH-cpcI-cpcD mRNA was inferred from these observations. The half-life of the mRNAs studied was typically found to be 7 min with four exceptions: (1 and 2) the half-lives for the 3.4- and 3.7-kb polycistronic LP mRNAs were 16 and 1 min at the low (lli) and high li (hli), respectively; (3) the half-life of the 1.4-kb cpcB1A1 mRNA was 2 min at lli; and (4) the 1.3-kb cpcB1A1 transcript had a half-life of 10 min at lli. At hli, it was found that the 1.3-kb cpcB1A1 transcript did not start to disappear until the amount of the 1.4-kb cpcB1A1 transcript had reached the level equal to that of the 1.3-kb mRNA, implying that the 1.4-kb transcript might be processed to the 1.3-kb form.


Heterogeneity of response to antipsychotics from multiple disorders in the schizophrenia spectrum.
Antipsychotic response after the initiation of neuroleptic treatment shows wide variation in schizophrenic patient populations. In this overview, the authors suggest that the variance in antipsychotic drug response within schizophrenia can be reduced by resolving the schizophrenias into several discrete "endophenotypes," each with different etiologic underpinnings. Studies relating differences in the relative speed or completeness of antipsychotic response to differences in distribution of 2 biological markers with possible etiologic significance are reviewed. Such studies had assessed recently hospitalized, neuroleptic-free patients undergoing exacerbation of nonaffective psychotic disorders. Prior to initiation of neuroleptic, the cohort of patients had been assessed for the quantity of the dopamine metabolite homovanillic acid in plasma (pHVA) and had undergone the first of 2 magnetic resonance imaging (MRI) studies for analyses of ventricle volumes. A second MRI was subsequently performed during a period of (partial) remission to determine within-patient stability of ventricular volumes. These selected studies assessed the distribution of pHVA and distribution of rates of ventricular change, with non-normal distributions resolved by K-means clustering. The speed and completeness of neuroleptic-induced antipsychotic response were related to 3 clusters of patients delineated by modal distributions of pHVA and of apparent rates of ventricular change. At least 3 unique "endophenotypes" of the "group of the schizophrenias" can be defined with respect to speed and completeness of antipsychotic response. Each endophenotype appears to show at least one unique biological feature that differentiates it from a normal comparison group. A rapidly responsive psychosis was associated with excessive production of dopamine, as identifiable by elevation of pHVA and a "good-prognosis" course. A delayed-response psychosis had low-to-normal pHVA, clinically demonstrated persistent negative symptoms, and was associated with an excessive rate of change in ventricle volume between exacerbations of psychosis and (partial) remissions. Finally, a nonresponsive psychosis could be characterized as having both low-to-normal pHVA and rate of change of ventricle volumes similar to that of controls. Additional studies revealed that each of the endophenotypes had high rates of the psychoses in family members. The good-prognosis course of the rapidly responsive group of studied patients was also found in their family members who had psychotic disorders. Similarly, the prominent negative symptoms of the delayed-response probands were reflected as a prominent trait in their family members also afflicted with psychosis. The endophenotypes tended to "breed true" in terms of prognosis and negative symptoms. Major differences in antipsychotic response patterns appear to be associated with patient and family characteristics that may be related to differences in the etiology and consequent pathophysiology of illness.


Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2).
Ataxia is a symptom that is often associated with syndromic inherited diseases. We previously reported the linkage of a novel syndrome, ataxia with blindness and deafness (SCAR3/SCABD, OMIM# 271250), to chromosome 6p21-p23 by linkage mapping of an Arab Israeli consanguineous family. We have now identified by whole-exome sequencing a homozygous missense mutation in the Arab Israeli family in the SLC52A2 gene located in 8qter, therefore excluding linkage of this family to 6p. We confirmed the involvement of SLC52A2 by the identification of a second mutation in an independent family with an identical syndromic presentation, which we suggest to name SCABD2. SCABD2 is therefore allelic to Brown-Vialleto-Van Laere syndrome type 2 defined by prominent motoneuronopathy and deafness, and also caused by SLC52A2 mutations. In the course of this project, we identified a clinically similar family with a homozygous missense mutation in PEX6, which is located in 6p21. Therefore, despite false linkage in the initial family, SCABD1/SCAR3 is located in 6p21 and is caused by PEX6 mutations. Both SLC52A2 and PEX6 should be included in screening panels for the diagnosis of syndromic inherited ataxias, particularly as patients with mutations in SLC52A2 can be ameliorated by riboflavin supplementation.


Alkylphenolic compounds and bisphenol A contamination within a heavily urbanized area: case study of Paris.
This study evaluates the influence of a heavily urbanized area (Paris Metropolitan area), on receiving water contamination by both bisphenol A (BPA) and alkylphenol ethoxylate (APE) biodegradation product. The study began by investigating concentrations within urban sources. In addition to the more commonly studied wastewater treatment plant effluent, wet weather urban sources (including combined sewer overflows, urban runoff, and total atmospheric fallout) were considered. The initial results highlight a significant contamination of all urban sources (from a few nanograms per liter in atmospheric fallout to several micrograms per liter in the other sources) with clearly distinguishable distribution patterns. Secondly, concentration changes along the Seine River from upstream of the Paris Metropolitan area to downstream were investigated. While the concentrations of BPA and nonylphenoxy acetic acid (NP₁EC) increase substantially due to urban sources, the 4-nonylphenol concentrations remain homogeneous along the Seine. These results suggest a broad dissemination of 4-nonylphenol at the scale of the Seine River basin. Moreover, the relationship between pollutant concentrations and Seine River flow was assessed both upstream and downstream of the Paris conurbation. Consequently, a sharp decrease in dissolved NP1EC concentrations relative to Seine River flow underscores the influence of single-point urban pollution on Seine River contamination. Conversely, dissolved 4-nonylphenol concentrations serve to reinforce the hypothesis of its widespread presence at the Seine River basin scale.


Dissolution of radioactive, cesium-rich microparticles released from the Fukushima Daiichi Nuclear Power Plant in simulated lung fluid, pure-water, and seawater.
To understand the chemical durability of highly radioactive cesium-rich microparticles (CsMPs) released from the Fukushima Daiichi Nuclear Power Plant in March 2011, we have, for the first time, performed systematic dissolution experiments with CsMPs isolated from Fukushima soils (one sample with 108 Bq and one sample with 57.8 Bq of 137Cs) using three types of solutions: simulated lung fluid, ultrapure water, and artificial sea water, at 25 and 37 °C for 1-63 days. The 137Cs was released rapidly within three days and then steady-state dissolution was achieved for each solution type. The steady-state 137Cs release rate at 25 °C was determined to be 4.7 × 103, 1.3 × 103, and 1. 3 × 103 Bq·m-2 s-1 for simulated lung fluid, ultrapure water, and artificial sea water, respectively. This indicates that the simulated lung fluid promotes the dissolution of CsMPs. The dissolution of CsMPs is similar to that of Si-based glass and is affected by the surface moisture conditions. In addition, the Cs release from the CsMPs is constrained by the rate-limiting dissolution of silicate matrix. Based on our results, CsMPs with ∼2 Bq, which can be potentially inhaled and deposited in the alveolar region, are completely dissolved after >35 years. Further, CsMPs could remain in the environment for several decades; as such, CsMPs are important factors contributing to the long-term impacts of radioactive Cs in the environment.


Androgens predict parasitism in female meerkats: a new perspective on a classic trade-off.
The immunocompetence handicap hypothesis posits that androgens in males can be a 'double-edged sword', actively promoting reproductive success, while also negatively impacting health. Because there can be both substantial androgen concentrations in females and significant androgenic variation among them, particularly in species portraying female social dominance over males or intense female-female competition, androgens might also play a role in mediating female health and fitness. We examined this hypothesis in the meerkat (Suricata suricatta), a cooperatively breeding, social carnivoran characterized by aggressively mediated female social dominance and extreme rank-related reproductive skew. Dominant females also have greater androgen concentrations and harbour greater parasite loads than their subordinate counterparts, but the relationship between concurrent androgen concentrations and parasite burdens is unknown. We found that a female's faecal androgen concentrations reliably predicted her concurrent state of endoparasitism irrespective of her social status: parasite species richness and infection by Spirurida nematodes, Oxynema suricattae, Pseudandrya suricattae and coccidia were greater with greater androgen concentrations. Based on gastrointestinal parasite burdens, females appear to experience the same trade-off in the costs and benefits of raised androgens as do the males of many species. This trade-off presumably represents a health cost of sexual selection operating in females.


Dietary supplement use among elderly, long-term cancer survivors.
The purpose of the present study was to assess dietary supplement use and its association with micronutrient intakes and diet quality among older (>or=65 years), long-term survivors (>or=5 years post-diagnosis) of female breast, prostate, and colorectal cancer. The sample included 753 survivors who participated in telephone screening interviews to determine eligibility for a randomized diet and physical activity intervention trial entitled RENEW: Reach-out to ENhancE Wellness in Older Cancer Survivors. Telephone surveys included two 24-hour dietary recalls and items regarding supplement use (type, dose, and duration). Nutrient intakes were compared to Dietary Reference Intakes (DRIs). Diet quality was assessed using the revised Healthy Eating Index (HEI). Descriptive statistics and multivariate logistic regression were used in this cross-sectional study. A majority of survivors (74%) reported taking supplements, with multivitamins (60%), calcium/vitamin D (37%), and antioxidants (30%) as the most prevalent. Overall proportions of the total sample with dietary intakes below Estimated Average Requirements (EARs) were substantial, although supplement users had more favorable mean HEI scores (P < 0.01) and nutrient intakes for 12 of the 13 vitamins and minerals investigated (P values < 0.05). Supplement use was positively associated with older age (>or=70 years) (odds ratio (OR)=1.70; 95% confidence interval (95% CI)=1.17, 2.46) and female gender (OR=1.49; 95% CI=1.04, 2.13), and negatively associated with current smoking (OR=0.40, 95% CI=0.21, 0.76). Individuals scoring higher on the Total Fruit (OR=1.12, 95% CI=1.01, 1.23), Whole Grain (OR=1.14, 95% CI=1.04, 1.25), and Oil (OR=1.10, 95% CI=1.01, 1.11) components of the HEI were significantly more likely to take supplements, while those scoring higher on the Meat and Beans category (OR=0.81, 95% CI=0.71, 0.93) were significantly less likely to take supplements. Compared to those with less than a high school education, survivors with a professional or graduate degree were significantly more likely to use supplements (OR=2.18, 95% CI=1.13, 4.23). Demographic, disease, and health-related correlates of supplement use follow similar trends observed in the general population as well as previous reports from other cancer survivor populations. Supplement use may reduce the prevalence of nutrient inadequacies in this population, though survivors who use supplements are the least likely to need them. Supplement use may be an effective means for many survivors to achieve adequate nutrient intakes; however, open communication between healthcare providers and survivors is needed to ensure potential concerns are addressed as supplement use may not always be beneficial.


Clonality and antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus at the University Hospital Zurich, Switzerland between 2012 and 2014.
Methicillin-resistant Staphylococcus aureus (MRSA) is a global epidemic threat. The aim of this study was to determine which globally known MRSA lineages are currently present at our tertiary care hospital in Switzerland, a hospital with low MRSA prevalence. In light of the increasing prevalence of multi drug resistance including vancomycin resistance we also assessed antibiotic susceptibilities. The 146 MRSA strains collected over two years (March 2012 until February 2014) at the University Hospital Zurich, Switzerland, were analyzed by PFGE analysis of SmaI digests in combination with spa-typing. In addition, representative isolates were analyzed by multi locus sequence typing (MLST). Susceptibilities to eight antibiotics were assessed using the Kirby-Bauer disc diffusion method. Isolates showed resistance to erythromycin (48%), ciprofloxacin (43%), clindamycin (31%), tetracycline (22%), and gentamicin (16%). All isolates were susceptible to vancomycin, 95% were susceptible to sulfamethoxazole/trimethoprim and rifampicin, respectively. PFGE analysis revealed 22 different patterns, with four major patterns that accounted for 53.4% of all MRSA isolates, and seven sporadic patterns. Spa typing revealed 50 different spa types with the predominant types being t008 (14%), t002 (10%), and t127 (9%). 82% of the MRSA isolates could be assigned to six clonal complexes (CCs) namely CC1 (10%), CC5 (23%), CC8 (18%), CC22 (17%), CC30 (11%), and CC45 (3%) based on spa-types, PFGE patterns, and MLST. Two isolates could not be typed by either PFGE analysis or spa-typing and three isolates had spa-types that have not yet been described. The combination of the two typing methods was more discriminatory as compared to the use of a single method. Several of the lineages that are predominant in Europe are present in our hospital. Resistances to antibiotics have decreased in comparison to a study conducted between 2004 and 2006.


Complex effects of temperature on mosquito immune function.
Over the last 20 years, ecological immunology has provided much insight into how environmental factors shape host immunity and host-parasite interactions. Currently, the application of this thinking to the study of mosquito immunology has been limited. Mechanistic investigations are nearly always conducted under one set of conditions, yet vectors and parasites associate in a variable world. We highlight how environmental temperature shapes cellular and humoral immune responses (melanization, phagocytosis and transcription of immune genes) in the malaria vector, Anopheles stephensi. Nitric oxide synthase expression peaked at 30°C, cecropin expression showed no main effect of temperature and humoral melanization, and phagocytosis and defensin expression peaked around 18°C. Further, immune responses did not simply scale with temperature, but showed complex interactions between temperature, time and nature of immune challenge. Thus, immune patterns observed under one set of conditions provide little basis for predicting patterns under even marginally different conditions. These quantitative and qualitative effects of temperature have largely been overlooked in vector biology but have significant implications for extrapolating natural/transgenic resistance mechanisms from laboratory to field and for the efficacy of various vector control tools.


Vitamin D level after allogeneic hematopoietic stem cell transplant.
Vitamin D (VD) deficiency can cause osteomalacia, bone pain, muscle weakness, fatigue, and increased risk of fracture, and may precipitate or exacerbate osteopenia and osteoporosis. Patients receiving treatment for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) may have limited exposure to sunlight and often experience gastrointestinal side effects that may decrease their ability to maintain an adequate VD level. We hypothesized that patients with AML and ALL would have a low VD level after allogeneic hematopoietic cell transplant (HCT), and that these patients would have a high incidence of osteoporosis/osteopenia. We therefore studied the incidence of low VD level and low bone mineral density after HCT. Of 289 patients with AML or ALL undergoing HCT between January 1, 2000, and January 31, 2009, at the Cleveland Clinic, 58 (20.1%) patients had VD testing after HCT. Of these, 52 (89.7%) patients had a low VD level, and 6 (10.3%) had a normal level. Most patients with VD testing had graft-versus-host disease (GVHD) and were taking corticosteroids (94.8% and 98.3%, respectively). Of the 49 patients with VD testing who also had bone mineral density testing, 65% had abnormal (low bone density) results. Only 21% of patients with VD testing were taking VD supplements prior to testing, and 65% had an elevated parathyroid hormone level. We found that most patients did not have VD testing after HCT, but those that did were very likely to have a low level and have low bone mineral density. Those with a low VD level were likely to have received corticosteroids, have GVHD, and have an elevated parathyroid hormone (PTH) level. Given the potential morbidity of low VD level, VD deficiency should be considered after HCT. Prospective study of VD level and its impact on morbidity and mortality after HCT is warranted.


Microtubule assembly dynamics: an attractive target for anticancer drugs.
Microtubules, composed of alphabeta tubulin dimers, are dynamic polymers of eukaryotic cells. They play important roles in various cellular functions including mitosis. Microtubules exhibit differential dynamic behaviors during different phases of the cell cycle. Inhibition of the microtubule assembly dynamics causes cell cycle arrest leading to apoptosis; thus, qualifying them as important drug targets for treating several diseases including cancer, neuronal, fungal, and parasitic diseases. Although several microtubule-targeted drugs are successfully being used in cancer chemotherapy, the development of resistance against these drugs and their inherent toxicities warrant the development of new agents with improved efficacy. Several antimicrotubule agents are currently being evaluated for their possible uses in cancer chemotherapy. Benomyl, griseofulvin, and sulfonamides have been used as antifungal and antibacterial drugs. Recent reports have shown that these drugs have potent antitumor potential. These agents are shown to inhibit proliferation of different types of tumor cells and induce apoptosis by targeting microtubule assembly dynamics. However, unlike vincas and taxanes, which inhibit cancer cell proliferation in nanomolar concentration range, these agents act in micromolar range and are considered to have limited toxicities. Here, we suggest that these drugs may have a significant use in cancer chemotherapy when used in combination with other anticancer drugs.


Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD18.
Complement component C3 has a potential role in thrombotic pathologies. It is transformed, without proteolytic cleavage, into C3(H2O) upon binding to the surface of activated platelets. We hypothesise that C3(H2O) bound to activated platelets and to platelet-derived microparticles (PMPs) contributes to platelet-PMN complex (PPC) formation and to the binding of PMPs to PMNs. PAR-1 activation of platelets in human whole blood from normal individuals induced the formation of CD16+/CD42a+ PPC. The complement inhibitor compstatin and a C5a receptor antagonist inhibited PPC formation by 50 %, while monoclonal antibodies to C3(H2O) or anti-CD11b inhibited PPC formation by 75-100 %. Using plasma protein-depleted blood and blood from a C3-deficient patient, we corroborated the dependence on C3, obtaining similar results after reconstitution with purified C3. By analogy with platelets, PMPs isolated from human serum were found to expose C3(H2O) and bind to PMNs. This interaction was also blocked by the anti-C3(H2O) and anti-CD11b monoclonal antibodies, indicating that C3(H2O) and CD11b are involved in tethering PMPs to PMNs. We confirmed the direct interaction between C3(H2O) and CD11b by quartz crystal microbalance analysis using purified native C3 and recombinant CD11b/CD18 and by flow cytometry using PMP and recombinant CD11b. Transfectants expressing CD11b/CD18 were also shown to specifically adhere to surface-bound C3(H2O). We have identified contact-activated C3(H2O) as a novel ligand for CD11b/CD18 that mediates PPC formation and the binding of PMPs to PMNs. Given the various roles of C3 in thrombotic reactions, this finding is likely to have important pathophysiological implications.


Tenofovir nephrotoxicity among Asians living with HIV: review of the literature.
Tenofovir disoproxil fumarate (TDF), prodrug of tenofovir (TFV), is one of the most widely used nucleotide reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infection in resource-rich and resource-limited settings with proven efficacy and safety, and also for the treatment of hepatitis B infections. However, TDF can cause renal proximal tubular dysfunction and also reduces estimated glomerular filtration rate (eGFR) more than other NRTIs. To date, TDF-associated renal dysfunction is generally regarded as mild and tolerable. However, it is notable that low body weight is one of the risk factors for TFV nephrotoxicity and that Asians are generally of smaller body stature and can be susceptible to such nephrotoxicity, as shown in several cohort studies. Until tenofovir alafenamide (TAF), another prodrug of TFV with minimal renal toxicity, becomes widely accessible for people living with HIV and replaces TDF, it is warranted that physicians who prescribe TDF have a good understanding of TFV nephrotoxicity. This paper reviews recent literature on TFV nephrotoxicity among people living with HIV especially focusing on Asians who might be susceptible to TFV nephrotoxicity due to their lower body weight and discusses implications for clinical care and future directions.


Collagen of Dupuytren's disease.
1. In contrast to collagen from the aponeurosis of normal adult subjects, the nodules, contractures and apparently unaffected aponeurosis from patients with Dupuytren's disease contained substantial amounts of type III collagen. 2. The presence of type III collagen supports the previous proposal that the initial response to injury is the synthesis of an increased proportion of this form of collagen. The increased amounts in the apparently unaffected aponeurosis indicate the disease is not strictly focal but more systemic than is usually considered.


A quantum pulse gate based on spectrally engineered sum frequency generation.
We introduce the concept of a quantum pulse gate (QPG), a method for accessing the intrinsic broadband spectral mode structure of ultrafast quantum states of light. This mode structure can now be harnessed for applications in quantum information processing. We propose an implementation in a PPLN waveguide, based on spectrally engineered sum frequency generation (SFG). It allows us to pick well-defined spectral broadband modes from an ultrafast multi-mode state for interconversion to a broadband mode at another frequency. By pulse-shaping the bright SFG pump beam, different orthogonal broadband modes can be addressed individually and extracted with high fidelity.


Interactions between MUC1 and p120 catenin regulate dynamic features of cell adhesion, motility, and metastasis.
The mechanisms by which MUC1 and p120 catenin contribute to progression of cancers from early transformation to metastasis are poorly understood. Here we show that p120 catenin ARM domains 1, 3-5, and 8 mediate interactions between p120 catenin and MUC1, and that these interactions modulate dynamic properties of cell adhesion, motility, and metastasis of pancreatic cancer cells. We also show that different isoforms of p120 catenin, when coexpressed with MUC1, create cells that exhibit distinct patterns of motility in culture (motility independent of cell adhesion, motility within a monolayer while exchanging contacts with other cells, and unified motility while maintaining static epithelial contacts) and patterns of metastasis. The results provide new insight into the dynamic interplay between cell adhesion and motility and the relationship of these to the metastatic process.


Indigeneity and Likelihood of Discharge to Psychiatric Hospital in an Australian Deliberate Self-Poisoning Hospital-Treated Cohort.
Hospital-treated self-harm rates for Aboriginal and Torres Strait Islander (Indigenous) people are at least double those for other Australians. Despite this, limited research has explored the relationship between Indigeneity and the clinical management of hospital-treated deliberate self-harm. A retrospective clinical cohort study (2003-2012) at a regional referral centre (NSW) for deliberate self-poisoning was used to explore the magnitude and direction of the relationship between Indigeneity and discharge destination (psychiatric hospital vs. other) using a series of logistic regressions. There were 149 (4%) Indigenous and 3697 (96%) non-Indigenous deliberate self-poisoning admissions during the study period. One-third (31%) were referred to the psychiatric hospital at discharge; Indigenous 21% (n = 32) vs. non-Indigenous 32% (n = 1175). Those who identified as Indigenous were less likely to be discharged to the psychiatric hospital, OR 0.59 (0.40-0.87) at the univariate level, with little change after sequential adjustment; and AOR 0.34 (0.21-0.73) in the fully adjusted model. The Indigenous cohort had a lower likelihood of psychiatric hospital discharge even after adjustment for variables associated with discharge to the psychiatric hospital highlighting the need for further investigation of the reasons accounting for this differential pattern of clinical management and the effectiveness of differential after-care allocation.


Stereospecificity of Corynebacterium glutamicum 2,3-butanediol dehydrogenase and implications for the stereochemical purity of bioproduced 2,3-butanediol.
The stereochemistry of 2,3-butanediol (2,3-BD) synthesis in microbial fermentations is important for many applications. In this work, we showed that Corynebacterium glutamicum endowed with the Lactococcus lactis genes encoding α-acetolactate synthase and decarboxylase activities produced meso-2,3-BD as the major end product, meaning that (R)-acetoin is a substrate for endogenous 2,3-butanediol dehydrogenase (BDH) activity. This is curious in view of the reported absolute stereospecificity of C. glutamicum BDH for (S)-acetoin (Takusagawa et al. Biosc Biotechnol Biochem 65:1876-1878, 2001). To resolve this discrepancy, the enzyme encoded by butA Cg was produced in Escherichia coli and purified, and the stereospecific properties of the pure protein were examined. Activity assays monitored online by 1H-NMR using racemic acetoin and an excess of NADH showed an initial, fast production of (2S,3S)-2,3-BD, followed by a slow (∼20-fold lower apparent rate) formation of meso-2,3-BD. Kinetic parameters for (S)-acetoin, (R)-acetoin, meso-2,3-BD and (2S,3S)-BD were determined by spectrophotometric assays. V max values for (S)-acetoin and (R)-acetoin were 119 ± 15 and 5.23 ± 0.06 μmol min-1 mg protein-1, and K m values were 0.23 ± 0.02 and 1.49 ± 0.07 mM, respectively. We conclude that C. glutamicum BDH is not absolutely specific for (S)-acetoin, though this is the preferred substrate. Importantly, the low activity of BDH with (R)-acetoin was sufficient to support high yields of meso-2,3-BD in the engineered strain C. glutamicum ΔaceEΔpqoΔldhA(pEKEx2-als,aldB,butA Cg ). Additionally, we found that the BDH activity was nearly abolished upon inactivation of butA Cg (from 0.30 ± 0.03 to 0.004 ± 0.001 μmol min-1 mg protein-1), indicating that C. glutamicum expresses a single BDH under the experimental conditions examined.


Associating pregnancy with partner violence against Chinese women.
The present study discusses if pregnancy is a risk factor for intimate partner violence using a large, representative sample containing detailed information on partner violence including physical and sexual abuse as well as perpetrator-related risk factors. Data from a representative sample of 2,225 men were analyzed. The self-reported prevalence of men's violence against their female partners was computed and compared in terms of demographic, behavioral, and relationship characteristics. The preceding-year prevalence of physical assault, sexual violence, and "any violence or injury" among the group whose partners were pregnant was 11.9%, 9.1%, and 18.8%, respectively. This is significantly higher than the nonpregnant group. Pregnancy was significantly associated with increased odds of violence, including physical assault, sexual violence, and "any violence or injury" (ORs = 2.42, 2.42, and 2.60, respectively). Having controlled for relationship characteristics including social desirability, social support, in-law conflict, dominance, and jealousy of male perpetrators, pregnancy was significantly associated with "any violence or injury." Demographic and behavioral variables accounted for pregnant women's significantly higher odds of having been abused in the year preceding the data collection. This study provides preliminary findings on the association between pregnancy and partner violence. Our findings underscore the need to screen for violence among pregnant women in clinical health care settings as well as in communities. Perpetrator-related risk factors should be included in the assessment of risk for partner violence against pregnant women. For the prevention of intimate partner violence, family-based intervention is needed to work with victims as well as perpetrators.


Stress-induced perinatal and transgenerational epigenetic programming of brain development and mental health.
Research efforts during the past decades have provided intriguing evidence suggesting that stressful experiences during pregnancy exert long-term consequences on the future mental wellbeing of both the mother and her baby. Recent human epidemiological and animal studies indicate that stressful experiences in utero or during early life may increase the risk of neurological and psychiatric disorders, arguably via altered epigenetic regulation. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications are prone to changes in response to stressful experiences and hostile environmental factors. Altered epigenetic regulation may potentially influence fetal endocrine programming and brain development across several generations. Only recently, however, more attention has been paid to possible transgenerational effects of stress. In this review we discuss the evidence of transgenerational epigenetic inheritance of stress exposure in human studies and animal models. We highlight the complex interplay between prenatal stress exposure, associated changes in miRNA expression and DNA methylation in placenta and brain and possible links to greater risks of schizophrenia, attention deficit hyperactivity disorder, autism, anxiety- or depression-related disorders later in life. Based on existing evidence, we propose that prenatal stress, through the generation of epigenetic alterations, becomes one of the most powerful influences on mental health in later life. The consideration of ancestral and prenatal stress effects on lifetime health trajectories is critical for improving strategies that support healthy development and successful aging.


Personalized Exposure Control Using Adaptive Metering and Reinforcement Learning.
We propose a reinforcement learning approach for real-time exposure control of a mobile camera that is personalizable. Our approach is based on Markov Decision Process (MDP). In the camera viewfinder or live preview mode, given the current frame, our system predicts the change in exposure so as to optimize the trade-off among image quality, fast convergence, and minimal temporal oscillation. We model the exposure prediction function as a fully convolutional neural network that can be trained through Gaussian policy gradient in an end-to-end fashion. As a result, our system can associate scene semantics with exposure values; it can also be extended to personalize the exposure adjustments for a user and device. We improve the learning performance by incorporating an adaptive metering module that links semantics with exposure. This adaptive metering module generalizes the conventional spot or matrix metering techniques. We validate our system using the MIT FiveK [1] and our own datasets captured using iPhone 7 and Google Pixel. Experimental results show that our system exhibits stable real-time behavior while improving visual quality compared to what is achieved through native camera control.


Multifunctional hydroxyapatite and poly(D,L-lactide-co-glycolide) nanoparticles for the local delivery of cholecalciferol.
Cholecalciferol, vitamin D3, plays an important role in bonemetabolism by regulating extracellular levels of calcium. Presented here is a study on the effects of the local delivery of cholecalciferol (D3) using nanoparticulate carriers composed of hydroxyapatite (HAp) and poly(D,L-lactide-co-glycolide) (PLGA). Multifunctional nanoparticulate HAp-based powders were prepared for the purpose of: (a) either fast or sustained, local delivery of cholecalciferol, and (b) the secondary, osteoconductive and defect-filling effect of the carrier itself. Two types of HAp-based powders with particles of narrowly dispersed sizes in the nano range were prepared and tested in this study: HAp nanoparticles as direct cholecalciferol delivery agents and HAp nanoparticles coated with cholecalciferol-loaded poly(D,L)-lactide-co-glycolide (HAp/D3/PLGA). Satisfying biocompatibility of particulate systems, when incubated in contact with MC3T3-E1 osteoblastic cells in vitro, was observed for HAp/D3/PLGA and pure HAp. In contrast, an extensively fast release of cholecalciferol from the system comprising HAp nanoparticles coated with cholecalciferol (HAp/D3) triggered necrosis of the osteoblastic cells in vitro. Artificial defects induced in the osteoporotic bone of the rat mandible were successfully reconstructed following implantation of cholecalciferol-coated HAp nanoparticles as well as those comprising HAp nanoparticles coated with cholecalciferol-loaded PLGA (HAp/D3/PLGA). The greatest levels of enhanced angiogenesis, vascularization, osteogenesis and bone structure differentiation were achieved upon the implementation of HAp/D3/PLGA systems.


Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis.
Bronchus-associated lymphoid tissue (BALT) was originally described as a mucosal lymphoid organ in the lungs of some species. However, while the lungs of naive mice and humans typically lack BALT, pulmonary infection in mice leads to the development of inducible BALT (iBALT), which is located in peribronchial, perivascular, and interstitial areas throughout the lung. Here we investigated whether iBALT forms in patients with a variety of interstitial lung diseases. We show that while iBALT can be found in the lungs of patients suffering from multiple diseases, well-developed iBALT is most prevalent in patients with pulmonary complications of RA and Sjögren syndrome. In these patients, iBALT consisted of numerous B cell follicles containing germinal centers and follicular dendritic cells. A loosely defined T cell area surrounded the B cell follicles while lymphatics and high endothelial venules were found at the B cell/T cell interface. Increased expression of lymphoid-organizing chemokines, such as CXCL13 and CCL21, as well as molecules involved in the immunopathology of RA, such as B cell-activating factor of the TNF family (BAFF), ICOS ligand, and lymphotoxin, correlated with more well-developed iBALT. Finally, the presence of iBALT correlated with tissue damage in the lungs of RA patients, suggesting that iBALT participates in local RA pathogenesis.