Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons.
Parkinson's disease is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). DA neurons in the ventral tegmental area are more resistant to this degeneration than those in the SNc, though the mechanisms for selective resistance or vulnerability remain poorly understood. A key to elucidating these processes may lie within the subset of DA neurons that corelease glutamate and express the vesicular glutamate transporter VGLUT2. Here, we addressed the potential relationship between VGLUT expression and DA neuronal vulnerability by overexpressing VGLUT in DA neurons of flies and mice. In Drosophila, VGLUT overexpression led to loss of select DA neuron populations. Similarly, expression of VGLUT2 specifically in murine SNc DA neurons led to neuronal loss and Parkinsonian behaviors. Other neuronal cell types showed no such sensitivity, suggesting that DA neurons are distinctively vulnerable to VGLUT2 expression. Additionally, most DA neurons expressed VGLUT2 during development, and coexpression of VGLUT2 with DA markers increased following injury in the adult. Finally, conditional deletion of VGLUT2 made DA neurons more susceptible to Parkinsonian neurotoxins. These data suggest that the balance of VGLUT2 expression is a crucial determinant of DA neuron survival. Ultimately, manipulation of this VGLUT2-dependent process may represent an avenue for therapeutic development.


The relationship between parental religiosity and mental health of pre-adolescents in a community sample: the TRAILS study.
The purpose of this study is to examine the relationship between parental religiosity, parental harmony on the subject of religiosity, and the mental health of pre-adolescents. In a community-based sample of 2,230 pre-adolescents (10-12 years), mental health problems were assessed using self-report (Youth Self-Report, YSR), parental report (Child Behavior Checklist, CBCL) as well as teacher report (Teacher Checklist for Psychopathology, TCP). Information about the religiosity of mother, the religiosity of father and religious harmony between the parents was obtained by parent report. The influence of maternal religiosity on internalizing symptoms depended on the religious harmony between parents. This was particularly apparent on the CBCL. Higher levels of internalizing symptoms were associated with parental religious disharmony when combined with passive maternal religiosity. Boys scored themselves as having more externalizing symptoms in case of religiously disharmonious parents. The levels of internalizing and externalizing symptoms in pre-adolescents were not influenced by parental religiosity. Religious disharmony between parents is a risk factor for internalizing problems when the mother is passive religious. Religious disharmony is a risk factor on its own for externalizing problems amongst boys. Parental religious activity and parental harmony play a role in the mental health of pre-adolescents.


Patient cost-sharing for ambulatory neuropsychiatric services in Abu Dhabi, UAE.
Neuropsychiatric disorders are of high concern and burden of disease in the United Arab Emirates (UAE). The aim of this study is to describe patient cost-sharing patterns, insurance coverage of ambulatory neuropsychiatric disorders, and utilization of neuropsychiatric services in Abu Dhabi. The study utilized the data published by Health Authority-Abu Dhabi (HAAD) and the American Center for Psychiatry and Neurology (ACPN) records in Abu Dhabi. The data were collected from the ACPN to describe patterns of insurance coverage and patient cost-sharing. The data included information on patient visits to the ACPN from January 1, 2010 till May 16, 2013. The data also included insurance coverage, total cost of treatment for each patient and the amount of coinsurances and deductibles paid by each patient. Additionally, the study utilized data published by HAAD on health services utilization, and health insurance plans in 2014. The percentage of total costs paid by patients and insurance were calculated by insurance groups and health service. Insurance plans with different patient cost-sharing arrangements for mental health treatment benefits were divided into three groups. ANOVA and MANOVA analyses were performed to test for differences among three categories of neuropsychiatric services (neurology, psychiatry and psychotherapy) in terms of the total costs and patient cost-sharing. The data were analysed using STATA version 12. About 36 % of the total costs on ambulatory neuropsychiatric services was paid directly by patients; 1 % of total costs was covered by patients as co-insurances and deductibles, and 63 % of total costs was covered by insurance providers. The average cost per visit was about 485 AED ($132), including 304 AED ($83) paid by insurance and 181 AED ($49) paid by patient. About 44 % of total costs was related to psychiatry services, 28 % of total costs was related to neurology services, and 28 % of total costs was related to psychotherapy services. Using ANOVA analyses, statistical differences were found among three categories of neuropsychiatric services in terms of the total costs and patient cost-sharing. These findings provide hint on some degree of association between patient cost-sharing and neuropsychiatry services utilization. The determination of parities in the coverage and finance between neuropsychiatric and physical health services will help policymakers make informed decisions on regulations of health insurance plans. Given the level of unmet need for neuropsychiatric services in Abu Dhabi, there is a need to fully include neuropsychiatric services in all basic and enhanced insurance plans. The study provided a description of patient cost-sharing and coverage of neuropsychiatric services in order for policymakers to recognize the disparities of the coverage and the degree of economic burden on households.


Predictors of actual turnover in a national sample of newly licensed registered nurses employed in hospitals.
This paper is a report of a study of factors that affect turnover of newly licensed registered nurses in United States hospitals. There is a large body of research related to nursing retention; however, there is little information specific to newly licensed registered nurse turnover. Incidence rates of turnover among new nurses are unknown because most turnover data are not from nationally representative samples of nurses. This study used a longitudinal panel design to obtain data from 1653 registered nurses who were recently licensed by examination for the first time. We mailed surveys to a nationally representative sample of hospital registered nurses 1 year apart. The analytic sample consisted of 1653 nurses who responded to both survey mailings in January of 2006 and 2007. Full-time employment and more sprains and strains (including back injuries) result in more turnover. Higher intent to stay and hours of voluntary overtime and more than one job for pay reduces turnover. When we omitted intent to stay from the probit model, less job satisfaction and organizational commitment led to more turnover, confirming their importance to turnover. Magnet Recognition Award(®) hospitals and several other work attributes had no effect on turnover. Turnover problems are complex, which means that there is no one solution to decreasing turnover. Multiple points of intervention exist. One specific approach that may improve turnover rates is hospital policies that reduce strains and sprains.


Microarray analysis of differentially expressed microRNAs in non-regressed and regressed bovine corpus luteum tissue; microRNA-378 may suppress luteal cell apoptosis by targeting the interferon gamma receptor 1 gene.
MicroRNAs (miRNAs) are small non-coding endogenous RNA molecules that down-regulate the expression of target genes in a sequence-dependent manner. Recent studies indicated that miRNAs are mechanistically involved in the regulation of the mammalian corpus luteum (CL). However, few studies have profiled the different miRNA expression patterns in bovine non-regressed and regressed CL. In this study, miRNA microarray was employed to investigate the different miRNA expression patterns in bovine CL. Among the 13 differentially expressed miRNAs, seven were preferentially expressed in non-regressed CL, while six miRNAs were more highly expressed in regressed CL. Real-time RT-PCR was used to validate the microarray results. Mir-378 miRNA, known to be associated with apoptosis, was 8.54-fold (P < 0.01) up-regulated in non-regressed CL, and the interferon gamma receptor 1 (IFNGR1) gene, which potentially plays a role in apoptosis of the luteal cell, was predicted to be the target of mir-378. The results of real-time RT-PCR of mir-378 and western blot analysis of the IFNGR1 protein at different stages of CL development showed that mir-378 decreased the expression of IFNGR1 protein but not IFNGR1 mRNA. Taken together, our data support a direct role for miRNA in apoptosis of bovine CL.


Effects of melatonin on testicular tissue nitric oxide level and antioxidant enzyme activities in experimentally induced left varicocele.
The pathophysiology of the testicular damage in varicocele have not been completely understood. There are several studies concerning the effects of increased seminal reactive oxygen species (ROS) and the role of nitric oxide (NO) in infertile patients with varicocele and antioxidants have been used successfully to decrease oxidative stress in testis. In this study, we determined the effects of melatonin on testicular NO and antioxidant enzyme levels and investigated whether melatonin can prevent or diminish testicular damage in adult rats with experimentally induced unilateral varicocele. Thirty adult male Wistar rats were randomly divided into three groups. In group I, using midline incision left renal vein was exposed but not tied. In group II, left renal vein was partially ligated to create varicocele. In group III, after creation of varicocele, daily and fresh-prepared melatonin was administered intraperitoneally for 4 weeks. Histopathological examination was performed and tissue malondialdehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and tissue NO levels were determined. In group II, there were severe degenerative changes of the germinal epithelium and atrophy of the seminiferous tubules in left testis. In group III, in which rats received melatonin intraperitoneally, there were focal areas showing decrease in spermatogenesis and some degenerative changes. Similarly, the levels of ROS and NO were significantly increased in testicular tissue of rats in group II, whereas group III rat testes in which melatonin was administered, showed increased antioxidant enzyme activity and decreased NO levels. Infertility related to varicocele has multiple pathophysiological mechanisms and the effect of ROS, NO and antioxidant defense system are contributing factors in the disease state. Melatonin, a potent free radical scavenger, administration might be helpful in the prevention or at least, in the delay of the severe effects of varicocele on testicular tissue.


Degradation of T cell receptor (TCR)-CD3-zeta complexes after antigenic stimulation.
T cell activation by specific antigen results in a rapid and long-lasting downregulation of triggered T cell receptors (TCRs). In this work, we investigated the fate of downregulated TCR- CD3-zeta complexes. T cells stimulated by peptide-pulsed antigen-presenting cells (APCs) undergo an antigen dose-dependent decrease of the total cellular content of TCR-beta, CD3-epsilon, and zeta chains, as detected by FACS(R) analysis on fixed and permeabilized T-APC conjugates and by Western blot analysis on cell lysates. The time course of CD3-zeta chain consumption overlaps with that of TCR downregulation, indicating that internalized TCR-CD3 complexes are promptly degraded. Inhibitors of lysosomal function (bafilomycin A1, folimycin) markedly reduced zeta chain degradation, leading to the accumulation of zeta chain in large Lamp1(+) vesicles. These results indicate that in T cell-APC conjugates, triggered TCRs are rapidly removed from the cell surface and are degraded in the lysosomal compartment.


Pandemic risk: how large are the expected losses?
There is an unmet need for greater investment in preparedness against major epidemics and pandemics. The arguments in favour of such investment have been largely based on estimates of the losses in national incomes that might occur as the result of a major epidemic or pandemic. Recently, we extended the estimate to include the valuation of the lives lost as a result of pandemic-related increases in mortality. This produced markedly higher estimates of the full value of loss that might occur as the result of a future pandemic. We parametrized an exceedance probability function for a global influenza pandemic and estimated that the expected number of influenza-pandemic-related deaths is about 720 000 per year. We calculated that the expected annual losses from pandemic risk to be about 500 billion United States dollars - or 0.6% of global income - per year. This estimate falls within - but towards the lower end of - the Intergovernmental Panel on Climate Change's estimates of the value of the losses from global warming, which range from 0.2% to 2% of global income. The estimated percentage of annual national income represented by the expected value of losses varied by country income grouping: from a little over 0.3% in high-income countries to 1.6% in lower-middle-income countries. Most of the losses from influenza pandemics come from rare, severe events.


Bead size has a greater effect on in vitro elution from antimicrobial-impregnated calcium sulfate beads than drug concentration.
To compare the elution characteristics of amikacin-impregnated calcium sulfate (CaSO4) beads based on different drug concentrations and bead size configurations. Six groups of amikacin-impregnated CaSO4 beads and one negative control group. Amikacin-impregnated CaSO4 beads were formed with either 500 mg (low-concentration) or 1 g (high-concentration) of amikacin per 15 g CaSO4 hemihydrate powder. The number of beads necessary to approximate 150 mg of amikacin for each of the 3 bead sizes (3 mm, 5 mm, and 7 mm) at both low and high concentrations were placed in 6 mL of phosphate-buffered saline. The saline was sampled at 14 time points over 28 days. Amikacin concentrations were determined using liquid chromatography-mass spectrometry. Smaller beads reached higher mean peak concentrations than larger beads (P < .0006). Peak concentrations for the low- and high-concentration groups were 20.5 mg/mL and 27.4 mg/mL, 13.1 mg/mL and 14.0 mg/mL, and 8.85 mg/mL and 6.75 mg/mL for the 3 mm, 5 mm, and 7 mm beads, respectively. Bead size also affected the length of therapeutic duration, lasting 6 days for the 3 mm and 5 mm beads and 9 days for the 7 mm beads. However, this was only statistically evident among the high-concentration beads (P < .044). Antimicrobial concentration within the same bead sizes did not affect elution. Amikacin-impregnated CaSO4 beads achieved extreme supratherapeutic eluent concentrations. While additional studies are needed, bead size significantly affected elution with smaller beads reaching higher peak concentrations and 7 mm, high-concentration beads demonstrating a longer therapeutic duration than smaller beads.


Cord blood stem cell-mediated induction of apoptosis in glioma downregulates X-linked inhibitor of apoptosis protein (XIAP).
XIAP (X-linked inhibitor of apoptosis protein) is one of the most important members of the apoptosis inhibitor family. XIAP is upregulated in various malignancies, including human glioblastoma. It promotes invasion, metastasis, growth and survival of malignant cells. We hypothesized that downregulation of XIAP by human umbilical cord blood mesenchymal stem cells (hUCBSC) in glioma cells would cause them to undergo apoptotic death. We observed the effect of hUCBSC on two malignant glioma cell lines (SNB19 and U251) and two glioma xenograft cell lines (4910 and 5310). In co-cultures of glioma cells with hUCBSC, proliferation of glioma cells was significantly inhibited. This is associated with increased cytotoxicity of glioma cells, which led to glioma cell death. Stem cells induced apoptosis in glioma cells, which was evaluated by TUNEL assay, FACS analyses and immunoblotting. The induction of apoptosis is associated with inhibition of XIAP in co-cultures of hUCBSC. Similar results were obtained by the treatment of glioma cells with shRNA to downregulate XIAP (siXIAP). Downregulation of XIAP resulted in activation of caspase-3 and caspase-9 to trigger apoptosis in glioma cells. Apoptosis is characterized by the loss of mitochondrial membrane potential and upregulation of mitochondrial apoptotic proteins Bax and Bad. Cell death of glioma cells was marked by downregulation of Akt and phospho-Akt molecules. We observed similar results under in vivo conditions in U251- and 5310-injected nude mice brains, which were treated with hUCBSC. Under in vivo conditions, Smac/DIABLO was found to be colocalized in the nucleus, showing that hUCBSC induced apoptosis is mediated by inhibition of XIAP and activation of Smac/DIABLO. Our results indicate that downregulation of XIAP by hUCBSC treatment induces apoptosis, which led to the death of the glioma cells and xenograft cells. This study demonstrates the therapeutic potential of XIAP and hUCBSC to treat malignant gliomas.


METAL: fast and efficient meta-analysis of genomewide association scans.
METAL provides a computationally efficient tool for meta-analysis of genome-wide association scans, which is a commonly used approach for improving power complex traits gene mapping studies. METAL provides a rich scripting interface and implements efficient memory management to allow analyses of very large data sets and to support a variety of input file formats. METAL, including source code, documentation, examples, and executables, is available at http://www.sph.umich.edu/csg/abecasis/metal/.


Supply chain management and accessibility to point-of-care testing in resource-limited settings: a systematic scoping review.
World Health Organization (WHO) has created an essential list of in-vitro diagnostics. Supply chain management (SCM) is said to be the vehicle that ensures that developed point-of-care (POC) tests reach their targeted settings for use. We therefore, mapped evidence on SCM of and accessibility to POC testing (availability and use of POC tests) in low- and middle-income countries (LMICs). We conducted a systematic scoping review using Arksey and O'Malley's framework as a guide. We searched PubMed; CINAHL; MEDLINE; WEB of Science; Science Direct; and Google Scholar databases for studies that focused on POC diagnostic tests and SCM. The review included studies that were undertaken in 140 countries defined by the World Bank as LMICs published up to August 2017. Two reviewers independently screened the abstracts and full articles against the eligibility criteria. The study used the mixed methods appraisal tool version 2011 to assess the risk of bias for the included studies. NVivo version 11 was employed to extract themes from all included studies and results presented using a narrative approach. Of 292 studies identified in this review, only 15 published between 2009 and 2017 included evidence on POC diagnostics and SCM. Of the 15 studies, three were conducted in Zambia, one each in Mozambique, Uganda, Guatemala; South Africa, one in Burkina Faso, Zimbabwe, and one multi-country study (Tanzania, Uganda, China, Peru and Zambia and Brazil). Six studies were not country specific since they were not primary studies. Majority of the studies reported stock-outs of HIV, syphilis, and malaria POC tests. There was a moderate to substantial level of agreement between the reviewers' responses at full article screening stage (Kappa statistic = 0.80, p < 0.01). Nine studies underwent methodological quality appraisal and all, scored between 90 and 100%. The results demonstrated limited published research on SCM of and accessibility to POC testing in LMICs. Further studies aimed at investigating SCM of POC tests in resource-limited settings to identify the barriers/challenges and provide a context-specific evidence-based solutions for policy/decision makers, implementers, and POC developers, funders, and development partners would be essential. CRD42016043711.


[Depression and dementia: perspectives from clinical studies].
In this review, we present an overview of clinical studies that addressed the relationship between depression and dementia or cognitive decline. Cross-sectional studies and meta-analyses have repeatedly shown an association between late-life depression (LLD) and dementia, particularly Alzheimer's disease (AD) and vascular dementia; however, the findings of cohort studies have been inconsistent. Furthermore, studies on the association between depression with a younger age of onset and dementia have yielded inconsistent results. Regarding cognitive decline associated with LLD, several studies have reported an association between LLD and mild cognitive impairment, suggesting that depression itself can cause persistent cognitive impairment. Other studies have compared the cognitive profile between LLD and depression with a younger age of onset, but their results have been inconclusive, especially regarding the association between memory impairment and the age of onset of depression. LLD is associated with vascular change and white matter degeneration of the brain, as shown by magnetic resonance imaging (MRI). Recently, several studies reported an association between gray matter change and LLD. Studies currently in progress employ functional brain imaging methods such as single-photon emission computed tomography, functional MRI, and positron emission tomography. Clinically, it is important to understand how subtypes of depression can be defined in terms of risk of developing dementia, and to devise effective treatments. One paper explored the possibility of detecting depression associated with AD by measuring the blood Aβ40/Aβ42 levels, and other studies have suggested that symptoms of apathy and loss of interest are associated with conversion of depression to AD. Unfortunately, current antidepressants may have limited efficacy on depression with dementia; therefore, further investigation for devising methods of predicting conversion of depression to dementia and subsequent treatment is required.


Greensporone C, a Freshwater Fungal Secondary Metabolite Induces Mitochondrial-Mediated Apoptotic Cell Death in Leukemic Cell Lines.
Therapeutic agents used in the treatment of cancer are known to develop resistance against cancer cells. Hence, there is a continuing need to investigate novel agents for the treatment and management of cancer. Antitumor activity of greensporone C (GC), a new resorcylic acid lactone isolated from an organic extract of a culture of a Halenospora sp. freshwater fungus, was subjected for screening against a panel of leukemic cell lines (K562, U937, and AR320). In all the three cell lines, cell proliferation was inhibited in dose-dependent fashion. GC further arrested the cells in SubG0 phase in dose-dependent manner. Annexin V/PI dual staining data confirmed apoptotic death of treated K562 and U937 leukemic cells. Treatment with GC suppressed constitutively phosphorylated AKT and downregulated expression of inhibitor of apoptotic proteins XIAP, cIAP-1, and cIAP-2. In summation to this, GC-treated leukemic cells upregulated protein expression of pro-apoptotic proteins, Bax with concomitant decrease in expression of anti-apoptotic proteins including Bcl-2 and Bcl-xL. Upregulation of Bax was associated with cytochrome c release which was confirmed from the collapse of mitochondrial membrane. Released cytochrome c further activated caspase cascade which in turn initiated apoptosis process. Anticancer activity of this isolated fungal compound GC was potentiated via stimulating production of reactive oxygen species (ROS) along with depletion of reduced glutathione (GSH) levels in K562 and U937 leukemic cells. Pretreatment of these cells with N-acetyl cysteine prevented GC-induced depletion of reduced GSH level and mitochondrial-caspase-induced apoptosis. Altogether, our data show that GC modulates the apoptotic response of human leukemic cells and raises the possibility of its use as a novel therapeutic strategy for hematological malignancies.


Development of new strategies for early diagnosis of mucormycosis from bench to bedside.
Early diagnosis and initiation of amphotericin B (AmB) for treatment of mucormycosis increases survival from approximately 40% to 80%. The central objective of a new study of the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) Zygomycosis Working Group is to improve the clinical and laboratory diagnosis of mucormycosis. The diagnostic tools generated from this study may help to significantly improve survival from mucormycosis worldwide. The study has three major objectives: to conduct a prospective international registration of patients with mucormycosis using a well-established global network of centres; to construct a predictive risk model for patients at risk for mucormycosis; and to establish an international archive of specimens of tissues, fluids, and organisms linked from the patients enrolled into the registry that will be used for development of leading edge molecular, proteomic, metabolic and antigenic systems for mucormycosis.


A Tale of Specialization in 2 Professions: Comparing the Development of Radiology in Chiropractic and Medicine.
The purpose of this article is to describe the development of radiology as a specialty in chiropractic with a comparison to the development of the specialty of radiology in medicine. Specialization in medicine has been notably successful, with advanced training and enhanced capabilities in specialized skills leading to better outcomes for patients and increased prestige for practitioners. However, with chiropractic, as with other complementary and alternative medicine professions, no specialization has been recognized within it. Specialist radiology training in chiropractic bears a resemblance to that of medicine, with competitive entry for residencies, certification exams, and the creation of a journal and specialist professional organizations. To facilitate the comparison, I have divided the development of radiology into 4 phases from the chiropractic perspective. Phase 1 started with the discovery of x-rays in 1895, in which medicine adopted them but chiropractic did not. Phase 2 began in 1910 when B. J. Palmer introduced radiography to show chiropractic subluxations. Phase 3 started in 1942 when Waldo Poehner advocated for the mainstream diagnostic use of radiography in addition to subluxation analysis. Phase 4 started in 1957 when an examining board for certification in diagnostic radiology was assembled and many chiropractors began to embrace the mainstream medical use of radiography. In this tale of 2 professions, radiology gained official specialty designation in the field of medicine. The medical profession had a monopoly on health care, and thus had few internal and external barriers to overcome. Chiropractic was oppressed by organized medicine, which helped to create the unofficial specialty of chiropractic radiology but which also later helped to limit the specialty. Chiropractic radiology has maintained its independence and autonomy, but also remains on the fringe of mainstream health care.


Uterine contractility patterns after an episode of preterm labor.
Uterine contractility patterns were studied in an attempt to identify those women on tocolytic therapy at risk for preterm delivery. One hundred sixteen women treated successfully after an episode of preterm labor were followed with an ambulatory tocodynamometer system. Contractions were monitored twice daily for 1 hour until delivery or until 36 completed weeks of gestation. In this group, 52 women (45%) delivered preterm and 64 (55%) delivered at term. The analysis revealed that 1) from 24-29 weeks' gestation, there was no significant difference in the uterine activity between the two groups; and 2) beginning at 30 weeks' gestation and continuing until the end of the 36th week of gestation, uterine activity was significantly greater in women destined to deliver preterm. These observations suggest that the patterns of daily uterine contractility observed in patients after an episode of preterm labor can identify those at greater risk for a preterm delivery.


Gastric pull-up reconstruction for the hypopharyngeal and cervical esophageal carcinoma in small thoracic unit.
The objective of this article is to review results of one surgical team for gastric pull-up reconstruction for carcinoma of the hypopharynx and cervical esophagus after pharyngolaryngo-esophagectomy in small thoracic unit. Between July, 2004 and December 2005, four patients underwent pharyngolaryngo-esophagectomy and gastric pull-up reconstruction for carcinoma of hypopharynx and esophagus. There were three female and one male patient with average age at the time of surgery 47 years. The study analyzed complications and mortality in early postoperative period after resections of the carcinoma. Squamous cell cancer in all patients was confirmed. There was no in-hospital mortality and non-fatal complications were occurred in 3 patients. It was recorded two year survival for two patients. Pharyngolaryngo-esophagectomy and gastric pull-up reconstruction can be performed for the patients with carcinoma of the hypopharynx and cervical esophagus with an acceptable operative mortality and morbidity rate even in small thoracic unit. Long term survival despite good early postoperative results still remains poor.


Taking Orders from Light: Photo-Switchable Working/Inactive Smart Surfaces for Protein and Cell Adhesion.
Photoresponsive smart surfaces are promising candidates for a variety of applications in optoelectronics and sensing devices. The use of light as an order signal provides advantages of remote and noninvasive control with high temporal and spatial resolutions. Modification of the photoswitches with target biomacromolecules, such as peptides, DNA, and small molecules including folic acid derivatives and sugars, has recently become a popular strategy to empower the smart surfaces with an improved detection efficiency and specificity. Herein, we report the construction of photoswitchable self-assembled monolayers (SAMs) based on sugar (galactose/mannose)-decorated azobenzene derivatives and determine their photoswitchable, selective protein/cell adhesion performances via electrochemistry. Under alternate UV/vis irradiation, interconvertible high/low recognition and binding affinity toward selective lectins (proteins that recognize sugars) and cells that highly express sugar receptors are achieved. Furthermore, the cis-SAMs with a low binding affinity toward selective proteins and cells also exhibit minimal response toward unselective protein and cell samples, which offers the possibility in avoiding unwanted contamination and consumption of probes prior to functioning for practical applications. Besides, the electrochemical technique used facilitates the development of portable devices based on the smart surfaces for on-demand disease diagnosis.


Large-scale compensation of errors in pairwise-additive empirical force fields: comparison of AMBER intermolecular terms with rigorous DFT-SAPT calculations.
The intermolecular interaction energy components for several molecular complexes were calculated using force fields available in the AMBER suite of programs and compared with Density Functional Theory-Symmetry Adapted Perturbation Theory (DFT-SAPT) values. The extent to which such comparison is meaningful is discussed. The comparability is shown to depend strongly on the intermolecular distance, which means that comparisons made at one distance only are of limited value. At large distances the coulombic and van der Waals 1/r(6) empirical terms correspond fairly well with the DFT-SAPT electrostatics and dispersion terms, respectively. At the onset of electronic overlap the empirical values deviate from the reference values considerably. However, the errors in the force fields tend to cancel out in a systematic manner at equilibrium distances. Thus, the overall performance of the force fields displays errors an order of magnitude smaller than those of the individual interaction energy components. The repulsive 1/r(12) component of the van der Waals expression seems to be responsible for a significant part of the deviation of the force field results from the reference values. We suggest that further improvement of the force fields for intermolecular interactions would require replacement of the nonphysical 1/r(12) term by an exponential function. Dispersion anisotropy and its effects are discussed. Our analysis is intended to show that although comparing the empirical and non-empirical interaction energy components is in general problematic, it might bring insights useful for the construction of new force fields. Our results are relevant to often performed force-field-based interaction energy decompositions.


Comparison of uropathogens and antibiotic susceptibility patterns in catheterized ambulant middle-aged and elderly Nigerian patients with bladder outlet obstruction.
Advanced age is one of the notable risk factors for catheter-associated urinary tract infections (CAUTIs), and differences between middle aged and elderly men with CAUTIs is poorly understood. This study aimed at comparing the pattern of urinary pathogens and antibiotic susceptibility in ambulant catheterized middle-aged and elderly Nigerian men. One hundred and fifty-four patients catheterized for >48 hours had provided clean catch mid-stream urine samples for microscopic analysis, culture and sensitivity tests. Eighty-two men aged <65, and 72 men aged ≥65 years matched for age, level of education, occupation and marital status were compared. Prevalence of CAUTIs among middle-aged men was middle-aged men was higher than the elderly (90.2% and 80.6% respectively) but this was not statistically significant (p=0.086). CAUTIs in middle-aged men with suprapubic catheters were significantly more frequent than those with urethral catheters (p=0.000). The prevalence of CAUTIs in middle-aged men with urethral stricture was different from other causes of bladder outlet obstruction (p=0.004). Men with indwelling catheters longer than 2 weeks had higher CAUTIs (p=0.000). Escherichia coli was the commonest pathogen in both groups while nitrofurantoin was the most sensitive drug. There are differential rates of CAUTIs in both the middle-aged men and the elderly with bladder outlet obstruction in our environment. The knowledge of the common pathogens and the antibiotic susceptibility will prevent irrational antibiotic use. Middle-aged men had higher prevalence of CAUTIs when Proteus spp. was the infectious agent. However, E. coli was the commonest pathogen of CAUTIs in all men. Also, middle- aged men with suprapubic catheters had higher rates of CAUTIs. Nitrofurantoin was the best drug in all men with CAUTIs but elderly men had higher rates of multi-resistance.


How many Assertive Community Treatment Teams are Needed in Japan? Estimate from Need Survey in Sendai City.
Despite the increasing ACT teams in Japan, no research exists on the need of ACT within the Japanese mental health system. The aim of this study was to describe the needs and feasibility of ACT teams. Furthermore, we estimated the number of po-tential ACT users and ACT teams needed in Japan. This study consists of two cross-sectional surveys in Sendai city. The primary survey was a self-completed questionnaire on the need and feasibility of ACT. In the secondary survey, the number of patients eligible for ACT was estimated based on primary physicians' evaluations. In the primary survey, 17 of the 57 in-stitutions responded (response rate 29.8%). All respondents answered that ACT teams are needed in the city of Sendai and "Crisis response" was as the most needed role of ACT. Based on the results of the secondary survey, approximately 900 to 3,600 patients in Sendai are estimated to be eligible for ACT. This finding indicates that the estimated number of ACT teams needed for 100,000 populations is from 0.9 to 3.5 in Japan, a result that is in general agreement with data from other coun-tries.


A synthetic matrix with independently tunable biochemistry and mechanical properties to study epithelial morphogenesis and EMT in a lung adenocarcinoma model.
Better understanding of the biophysical and biochemical cues of the tumor extracellular matrix environment that influence metastasis may have important implications for new cancer therapeutics. Initial exploration into this question has used naturally derived protein matrices that suffer from variability, poor control over matrix biochemistry, and inability to modify the matrix biochemistry and mechanics. Here, we report the use of a synthetic polymer-based scaffold composed primarily of poly(ethylene glycol), or PEG, modified with bioactive peptides to study murine models of lung adenocarcinoma. In this study, we focus on matrix-derived influences on epithelial morphogenesis of a metastatic cell line (344SQ) that harbors mutations in Kras and p53 (trp53) and is prone to a microRNA-200 (miR-200)-dependent epithelial-mesenchymal transition (EMT) and metastasis. The modified PEG hydrogels feature biospecific cell adhesion and cell-mediated proteolytic degradation with independently adjustable matrix stiffness. 344SQ encapsulated in bioactive peptide-modified, matrix metalloproteinase-degradable PEG hydrogels formed lumenized epithelial spheres comparable to that seen with three-dimensional culture in Matrigel. Altering both matrix stiffness and the concentration of cell-adhesive ligand significantly influenced epithelial morphogenesis as manifest by differences in the extent of lumenization, in patterns of intrasphere apoptosis and proliferation, and in expression of epithelial polarity markers. Regardless of matrix composition, exposure to TGF-β induced a loss of epithelial morphologic features, shift in expression of EMT marker genes, and decrease in mir-200 levels consistent with EMT. Our findings help illuminate matrix-derived cues that influence epithelial morphogenesis and highlight the potential utility that this synthetic matrix-mimetic tool has for cancer biology.


ß-amylase1 mutant Arabidopsis plants show improved drought tolerance due to reduced starch breakdown in guard cells.
In plants, drought stress is a major growth limiting factor causing cell water loss through open stomata. In this study, guard cell-specific transcripts from drought-stressed Arabidopsis plants were analysed and a down-regulation of β-amylase 1 (BAM1) was found. In previous studies, BAM1 was shown to be involved in stomatal starch degradation under ambient conditions. Impaired starch breakdown of bam1 mutant plants was accompanied by decreased stomatal opening. Here, it is shown that drought tolerance of bam1 mutant plants is improved as compared with wild-type controls. Microarray analysis of stomata-specific transcripts from bam1 mutant plants revealed a significant down-regulation of genes encoding aquaporins, auxin- and ethylene-responsive factors, and cell-wall modifying enzymes. This expression pattern suggests that reduced water uptake and limited cell wall extension are associated with the closed state of stomata of bam1 mutant plants. Together these data suggest that regulation of stomata-specific starch turnover is important for adapting stomata opening to environmental needs and its breeding manipulation may result in drought tolerant crop plants.


Palliative Care Problem Severity Score: Reliability and acceptability in a national study.
The Palliative Care Problem Severity Score is a clinician-rated tool to assess problem severity in four palliative care domains (pain, other symptoms, psychological/spiritual, family/carer problems) using a 4-point categorical scale (absent, mild, moderate, severe). To test the reliability and acceptability of the Palliative Care Problem Severity Score. Multi-centre, cross-sectional study involving pairs of clinicians independently rating problem severity using the tool. Clinicians from 10 Australian palliative care services: 9 inpatient units and 1 mixed inpatient/community-based service. A total of 102 clinicians participated, with almost 600 paired assessments completed for each domain, involving 420 patients. A total of 91% of paired assessments were undertaken within 2 h. Strength of agreement for three of the four domains was moderate: pain (Kappa = 0.42, 95% confidence interval = 0.36 to 0.49); psychological/spiritual (Kappa = 0.48, 95% confidence interval = 0.42 to 0.54); family/carer (Kappa = 0.45, 95% confidence interval = 0.40 to 0.52). Strength of agreement for the remaining domain (other symptoms) was fair (Kappa = 0.38, 95% confidence interval = 0.32 to 0.45). The Palliative Care Problem Severity Score is an acceptable measure, with moderate reliability across three domains. Variability in inter-rater reliability across sites and participant feedback indicate that ongoing education is required to ensure that clinicians understand the purpose of the tool and each of its domains. Raters familiar with the patient they were assessing found it easier to assign problem severity, but this did not improve inter-rater reliability.


Distinctive genetic signatures in the Libyan Jews.
Unlinked autosomal microsatellites in six Jewish and two non-Jewish populations were genotyped, and the relationships among these populations were explored. Based on considerations of clustering, pairwise population differentiation, and genetic distance, we found that the Libyan Jewish group retains genetic signatures distinguishable from those of the other populations, in agreement with some historical records on the relative isolation of this community. Our methods also identified evidence of some similarity between Ethiopian and Yemenite Jews, reflecting possible migration in the Red Sea region. We suggest that high-resolution statistical methods that use individual multilocus genotypes may make it practical to distinguish related populations of extremely recent common ancestry.


Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss.
Secreted extracellular matrix components which regulate craniofacial development could be reactivated and play roles in adult wound healing. We report a patient with a loss-of-function of the secreted matricellular protein SMOC2 (SPARC related modular calcium binding 2) presenting severe oligodontia, microdontia, tooth root deficiencies, alveolar bone hypoplasia, and a range of skeletal malformations. Turning to a mouse model, Smoc2-GFP reporter expression indicates SMOC2 dynamically marks a range of dental and bone progenitors. While germline Smoc2 homozygous mutants are viable, tooth number anomalies, reduced tooth size, altered enamel prism patterning, and spontaneous age-induced periodontal bone and root loss are observed in this mouse model. Whole-genome RNA-sequencing analysis of embryonic day (E) 14.5 cap stage molars revealed reductions in early expressed enamel matrix components (Odontogenic ameloblast-associated protein) and dentin dysplasia targets (Dentin matrix acidic phosphoprotein 1). We tested if like other matricellular proteins SMOC2 was required for regenerative repair. We found that the Smoc2-GFP reporter was reactivated in adjacent periodontal tissues 4 days after tooth avulsion injury. Following maxillary tooth injury, Smoc2-/- mutants had increased osteoclast activity and bone resorption surrounding the extracted molar. Interestingly, a 10-day treatment with the cyclooxygenase 2 (COX2) inhibitor ibuprofen (30 mg/kg body weight) blocked tooth injury-induced bone loss in Smoc2-/- mutants, reducing matrix metalloprotease (Mmp)9. Collectively, our results indicate that endogenous SMOC2 blocks injury-induced jaw bone osteonecrosis and offsets age-induced periodontal decay.


Frequency of angiotensin II type 1 receptor gene polymorphism in Turkish acute stroke patients.
This study was performed in acute stroke patients in the Turkish population to determine the frequency of the A1166C polymorphism in the AT1 gene and to examine the role of this polymorphism in acute stroke development. In this study, 257 genomic DNA samples were analysed (from 206 acute stroke patients and 51 healthy individuals). Genomic DNA was prepared from peripheral blood using the salt-extraction method. The presence of the A1166C polymorphism in the AT1 gene was determined using the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. PCR products were separated by 2% agarose gel electrophoresis and visualized by a charge-coupled device (CCD) camera. In this study, the allele frequency at the A1166C position was 92% A and 8% C for control and 97% A and 3% C for patients. This difference in allele frequency between the control group and the patient group was not statistically significant. However, genotype and allele frequencies showed a significant difference (P < 0.001) in the control and the patient groups. The results of this study show no relationship between the A1166C polymorphism in the AT1 gene and acute stroke in the Turkish population.


Obtaining Lissamine Green 1% Solution for Clinical Use.
With new compounding pharmacy laws, the only economically feasible approach to using lissamine is through dye-impregnated strips. This research aims to determine the concentration of lissamine that can be obtained using a single commercially available lissamine strip. With the optimal vital staining requiring 1% concentration of lissamine, we sought to obtain this concentration using supplies in an ordinary ophthalmology clinic. A standard curve was generated using compounded lissamine green 1% solution. Serial dilutions were made with 3 different diluents and measured using a spectrophotometer at a wavelength of 633 μm. Combinations of the number of strips, amount of solvent, and absorption time were performed to obtain a 1% solution. Cost analyses were performed to select the most economical method. Single lissamine strips wetted with any of the diluents produced 0.17% ± 0.05% (95% confidence interval) lissamine solution, a 5-fold weaker concentration than the optimal for vital staining. Combinations of 4 strips in 200 μL (4 drops) for 1 minute and 2 strips in 200 μL for 5 minutes were found to reach concentrations of 1%. Cost analysis showed that the 2 strip/4 drops/5 minutes method costs $0.67 and the 4 strips/4 drops/1 minute method $1.27. Use of a single lissamine strip leads to suboptimal concentrations for vital staining. With only the addition of disposable microcentrifuge tubes to the clinical setting, ophthalmologists can make 1% solutions of lissamine. This solution is both more economical and in compliance with both state and national compounding laws.


Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1.
The Raf family of protein kinases display differences in their abilities to promote the entry of quiescent NIH 3T3 cells into the S phase of the cell cycle. Although conditional activation of deltaA-Raf:ER promoted cell cycle progression, activation of deltaRaf-1:ER and deltaB-Raf:ER elicited a G1 arrest that was not overcome by exogenously added growth factors. Activation of all three deltaRaf:ER kinases led to elevated expression of cyclin D1 and cyclin E and reduced expression of p27Kip1. However, activation of deltaB-Raf:ER and deltaRaf-1:ER induced the expression of p21Cip1, whereas activation of deltaA-Raf:ER did not. A catalytically potentiated form of deltaA-Raf:ER, generated by point mutation, strongly induced p21Cip1 expression and elicited cell cycle arrest similarly to deltaB-Raf:ER and deltaRaf-1:ER. These data suggested that the strength and duration of signaling by Raf kinases might influence the biological outcome of activation of this pathway. By titration of deltaB-Raf:ER activity we demonstrated that low levels of Raf activity led to activation of cyclin D1-cdk4 and cyclin E-cdk2 complexes and to cell cycle progression whereas higher Raf activity elicited cell cycle arrest correlating with p21Cip1 induction and inhibition of cyclin-cdk activity. Using green fluorescent protein-tagged forms of deltaRaf-1:ER in primary mouse embryo fibroblasts (MEFs) we demonstrated that p21Cip1 was induced by Raf in a p53-independent manner, leading to cell cycle arrest. By contrast, activation of Raf in p21Cip1(-/-) MEFs led to a robust mitogenic response that was similar to that observed in response to platelet-derived growth factor. These data indicate that, depending on the level of kinase activity, Raf can elicit either cell cycle progression or cell cycle arrest in mouse fibroblasts. The ability of Raf to elicit cell cycle arrest is strongly associated with its ability to induce the expression of the cyclin-dependent kinase inhibitor p21Cip1 in a manner that bears analogy to alpha-factor arrest in Saccharomyces cerevisiae. These data are consistent with a role for Raf kinases in both proliferation and differentiation of mammalian cells.


Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7.
The chromobox 7 (CBX7) protein of the polycomb repressive complex 1 (PRC1) functions to repress transcription of tumor suppressor p16 (INK4a) through long noncoding RNA, ANRIL (antisense noncoding RNA in the INK4 locus) directed chromodomain (ChD) binding to trimethylated lysine 27 of histone H3 (H3K27me3), resulting in chromatin compaction at the INK4a/ARF locus. In this study, we report structure-guided discovery of two distinct classes of small-molecule antagonists for the CBX7ChD. Our Class A compounds, a series including analogues of the previously reported MS452, inhibit CBX7ChD/methyl-lysine binding by occupying the H3K27me3 peptide binding site, whereas our Class B compound, the newly discovered MS351, appears to inhibit H3K27me3 binding when CBX7ChD is bound to RNA. Our crystal structure of the CBX7ChD/MS351 complex reveals the molecular details of ligand recognition by the aromatic cage residues that typically engage in methyl-lysine binding. We further demonstrate that MS351 effectively induces transcriptional derepression of CBX7 target genes, including p16 (INK4a) in mouse embryonic stem cells and human prostate cancer PC3 cells. Thus, MS351 represents a new class of ChD antagonists that selectively targets the biologically active form of CBX7 of the PRC1 in long noncoding RNA- and H3K27me3-directed gene transcriptional repression.


Italian deprivation index and dental caries in 12-year-old children: a multilevel Bayesian analysis.
Evidence from the literature has shown that people with a lower socioeconomic status enjoy less good health than people with a higher socioeconomic status. The Italian deprivation index (DI) was used with the aim to evaluate the association between the DMFT index and risk factors for dental caries, including city population and DI. The study included 4,305 12-year-old children living in 38 cities classified by demographic size as small, midsize and large. Zero-inflated negative binomial multilevel regression models were used to assess risk factors for DMFT and to address excess of zero DMFT and overdispersion through a Bayesian approach. The difference in the average level of DMFT among children living in cities with different DI quintile was not statistically significant (p = 0.578). The DI and ln(population), included as city-level fixed effects in the two-level variance components model, were not statistically significant. Consuming sweet drinks on average increased the mean DMFT of a susceptible child, while having a highly educated mother reduced it. Unobserved heterogeneity among cities was detected for the probability to be non-susceptible to caries (city-level variance = 0.26 with 95% credibility interval 0.09-0.57), while no territorial effect was found for the mean DMFT of the susceptible children. Our results suggest that the DI and city population did not play a role in explaining between-city variability. Interventions against social deprivation can be influential on the perception of oral health in Italian 12-year-old children to the extent that they can also affect individual level factors.


Configuration of the magnetosome chain: a natural magnetic nanoarchitecture.
Magnetospirillum gryphiswaldense is a microorganism with the ability to biomineralize magnetite nanoparticles, called magnetosomes, and arrange them into a chain that behaves like a magnetic compass. Rather than straight lines, magnetosome chains are slightly bent, as evidenced by electron cryotomography. Our experimental and theoretical results suggest that due to the competition between the magnetocrystalline and shape anisotropies, the effective magnetic moment of individual magnetosomes is tilted out of the [111] crystallographic easy axis of magnetite. This tilt does not affect the direction of the chain net magnetic moment, which remains along the [111] axis, but explains the arrangement of magnetosomes in helical-like shaped chains. Indeed, we demonstrate that the chain shape can be reproduced by considering an interplay between the magnetic dipolar interactions between magnetosomes, ruled by the orientation of the magnetosome magnetic moment, and a lipid/protein-based mechanism, modeled as an elastic recovery force exerted on the magnetosomes.


Genetic analysis of pathway regulation for enhancing branched-chain amino acid biosynthesis in plants.
The branched-chain amino acids (BCAAs) valine, leucine and isoleucine are essential amino acids that play critical roles in animal growth and development. Animals cannot synthesize these amino acids and must obtain them from their diet. Plants are the ultimate source of these essential nutrients, and they synthesize BCAAs through a conserved pathway that is inhibited by its end products. This feedback inhibition has prevented scientists from engineering plants that accumulate high levels of BCAAs by simply over-expressing the respective biosynthetic genes. To identify components critical for this feedback regulation, we performed a genetic screen for Arabidopsis mutants that exhibit enhanced resistance to BCAAs. Multiple dominant allelic mutations in the VALINE-TOLERANT 1 (VAT1) gene were identified that conferred plant resistance to valine inhibition. Map-based cloning revealed that VAT1 encodes a regulatory subunit of acetohydroxy acid synthase (AHAS), the first committed enzyme in the BCAA biosynthesis pathway. The VAT1 gene is highly expressed in young, rapidly growing tissues. When reconstituted with the catalytic subunit in vitro, the vat1 mutant-containing AHAS holoenzyme exhibits increased resistance to valine. Importantly, transgenic plants expressing the mutated vat1 gene exhibit valine tolerance and accumulate higher levels of BCAAs. Our studies not only uncovered regulatory characteristics of plant AHAS, but also identified a method to enhance BCAA accumulation in crop plants that will significantly enhance the nutritional value of food and feed.


Skeleton pruning by contour partitioning with discrete curve evolution.
In this paper, we introduce a new skeleton pruning method based on contour partitioning. Any contour partition can be used, but the partitions obtained by Discrete Curve Evolution (DCE) yield excellent results. The theoretical properties and the experiments presented demonstrate that obtained skeletons are in accord with human visual perception and stable, even in the presence of significant noise and shape variations, and have the same topology as the original skeletons. In particular, we have proven that the proposed approach never produces spurious branches, which are common when using the known skeleton pruning methods. Moreover, the proposed pruning method does not displace the skeleton points. Consequently, all skeleton points are centers of maximal disks. Again, many existing methods displace skeleton points in order to produces pruned skeletons.


Non-surgical interventions for late rectal problems (proctopathy) of radiotherapy in people who have received radiotherapy to the pelvis.
This is an update of a Cochrane review first published in 2002, and previously updated in 2007. Late radiation rectal problems (proctopathy) include bleeding, pain, faecal urgency, and incontinence and may develop after pelvic radiotherapy treatment for cancer. To assess the effectiveness and safety of non-surgical interventions for managing late radiation proctopathy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2015); MEDLINE (Ovid); EMBASE (Ovid); CANCERCD; Science Citation Index; and CINAHL from inception to November 2015. We included randomised controlled trials (RCTs) comparing non-surgical interventions for the management of late radiation proctopathy in people with cancer who have undergone pelvic radiotherapy for cancer. Primary outcomes considered were: episodes of bowel activity, bleeding, pain, tenesmus, urgency, and sphincter dysfunction. Study selection, 'Risk of bias' assessment, and data extraction were performed in duplicate, and any disagreements were resolved by involving a third review author. We identified 1221 unique references and 16 studies including 993 participants that met our inclusion criteria. One study found through the last update was moved to the 'Studies awaiting classification' section. We did not pool outcomes for a meta-analysis due to variation in study characteristics and endpoints across included studies.Since radiation proctopathy is a condition with various symptoms or combinations of symptoms, the studies were heterogeneous in their intended effect. Some studies investigated treatments targeted at bleeding only (group 1), some investigated treatments targeted at a combination of anorectal symptoms, but not a single treatment (group 2). The third group focused on the treatment of the collection of symptoms referred to as pelvic radiation disease. In order to enable some comparison of this heterogeneous collection of studies, we describe the effects in these three groups separately.Nine studies assessed treatments for rectal bleeding and were unclear or at high risk of bias. The only treatments that made a significant difference on primary outcomes were argon plasma coagulation (APC) followed by oral sucralfate versus APC with placebo (endoscopic score 6 to 9 in favour of APC with placebo, risk ratio (RR) 2.26, 95% confidence interval (CI) 1.12 to 4.55; 1 study, 122 participants, low- to moderate-quality evidence); formalin dab treatment (4%) versus sucralfate steroid retention enema (symptom score after treatment graded by the Radiation Proctopathy System Assessments Scale (RPSAS) and sigmoidoscopic score in favour of formalin (P = 0.001, effect not quantified, 1 study, 102 participants, very low- to low-quality evidence), and colonic irrigation plus ciprofloxacin and metronidazole versus formalin application (4%) (bleeding (P = 0.007, effect not quantified), urgency (P = 0.0004, effect not quantified), and diarrhoea (P = 0.007, effect not quantified) in favour of colonic irrigation (1 study, 50 participants, low-quality evidence).Three studies, of unclear and high risk of bias, assessed treatments targeted at something very localised but not a single pathology. We identified no significant differences on our primary outcomes. We graded all studies as very low-quality evidence due to unclear risk of bias and very serious imprecision.Four studies, of unclear and high risk of bias, assessed treatments targeted at more than one symptom yet confined to the anorectal region. Studies that demonstrated an effect on symptoms included: gastroenterologist-led algorithm-based treatment versus usual care (detailed self help booklet) (significant difference in favour of gastroenterologist-led algorithm-based treatment on change in Inflammatory Bowel Disease Questionnaire-Bowel (IBDQ-B) score at six months, mean difference (MD) 5.47, 95% CI 1.14 to 9.81) and nurse-led algorithm-based treatment versus usual care (significant difference in favour of the nurse-led algorithm-based treatment on change in IBDQ-B score at six months, MD 4.12, 95% CI 0.04 to 8.19) (1 study, 218 participants, low-quality evidence); hyperbaric oxygen therapy (at 2.0 atmospheres absolute) versus placebo (improvement of Subjective, Objective, Management, Analytic - Late Effects of Normal Tissue (SOMA-LENT) score in favour of hyperbaric oxygen therapy (HBOT), P = 0.0019) (1 study, 150 participants, moderate-quality evidence, retinol palmitate versus placebo (improvement in RPSAS in favour of retinol palmitate, P = 0.01) (1 study, 19 participants, low-quality evidence) and integrated Chinese traditional plus Western medicine versus Western medicine (grade 0 to 1 radio-proctopathy after treatment in favour of integrated Chinese traditional medicine, RR 2.55, 95% CI 1.30 to 5.02) (1 study, 58 participants, low-quality evidence).The level of evidence for the majority of outcomes was downgraded using GRADE to low or very low, mainly due to imprecision and study limitations. Although some interventions for late radiation proctopathy look promising (including rectal sucralfate, metronidazole added to an anti-inflammatory regimen, and hyperbaric oxygen therapy), single small studies provide limited evidence. Furthermore, outcomes important to people with cancer, including quality of life (QoL) and long-term effects, were not well recorded. The episodic and variable nature of late radiation proctopathy requires large multi-centre placebo-controlled trials (RCTs) to establish whether treatments are effective. Future studies should address the possibility of associated injury to other gastro-intestinal, urinary, or sexual organs, known as pelvic radiation disease. The interventions, as well as the outcome parameters, should be broader and include those important to people with cancer, such as QoL evaluations.


Metropolitan-level ethnic residential segregation, racial identity, and body mass index among U.S. Hispanic adults: a multilevel cross-sectional study.
The few studies that have examined whether metropolitan-level ethnic residential segregation is associated with obesity among Hispanics are mixed. The segmented assimilation theory, which suggests patterns of integration for immigrant groups varies by social factors, may provide an explanation for these mixed findings. In this study we examined whether one social factor, racial identity, modified the association between ethnic residential segregation and body mass index (BMI) among Hispanics. We used data on 22,901 male and 37,335 non-pregnant female Hispanic adult participants of the 2003-2008 U.S. Behavioral Risk Factor Surveillance System living in 227 metropolitan or micropolitan areas (MMSAs). Participants self-identified as White, Black, and 'some other race'. BMI was calculated using self-reported height and weight; the Hispanic isolation index was used to measure Hispanic residential segregation. Using multi-level linear regression models, we examined the association of Hispanic residential segregation with BMI, and we investigated whether this relationship varied by race. Among men, Hispanic segregation was unassociated with BMI after adjusting for age, race, MMSA-level poverty, and MMSA-level population size; there was no variation in this relationship by race. Among women, significant associations between Hispanic segregation and BMI in models adjusted for demographics and MMSA-level confounders became attenuated with further adjustment for education and language of exam. However, there was statistically significant variation by race (Pinteraction = 0.03 and 0.09 for Hispanic Blacks and Hispanics who identified as some other race, respectively, vs. Hispanic Whites). Specifically, higher segregation was associated with higher mean BMI among Hispanic Whites, but it was associated with lower mean BMI among Hispanic Blacks. Segregation was unassociated with BMI among Hispanic women identifying as some other race. This heterogeneity highlights the persistent influence of race on structural processes that can have downstream consequences on health. As Hispanics grow as a proportion of the U.S. population, especially across urban centers, understanding the health consequences of residence in segregated areas, and whether or not these impacts vary across different groups, will be important for the design of more comprehensive solutions to prevent adverse health outcomes.


Defining a standard set of patient-centered outcomes for men with localized prostate cancer.
Value-based health care has been proposed as a unifying force to drive improved outcomes and cost containment. To develop a standard set of multidimensional patient-centered health outcomes for tracking, comparing, and improving localized prostate cancer (PCa) treatment value. We convened an international working group of patients, registry experts, urologists, and radiation oncologists to review existing data and practices. The group defined a recommended standard set representing who should be tracked, what should be measured and at what time points, and what data are necessary to make meaningful comparisons. Using a modified Delphi method over a series of teleconferences, the group reached consensus for the Standard Set. We recommend that the Standard Set apply to men with newly diagnosed localized PCa treated with active surveillance, surgery, radiation, or other methods. The Standard Set includes acute toxicities occurring within 6 mo of treatment as well as patient-reported outcomes tracked regularly out to 10 yr. Patient-reported domains of urinary incontinence and irritation, bowel symptoms, sexual symptoms, and hormonal symptoms are included, and the recommended measurement tool is the Expanded Prostate Cancer Index Composite Short Form. Disease control outcomes include overall, cause-specific, metastasis-free, and biochemical relapse-free survival. Baseline clinical, pathologic, and comorbidity information is included to improve the interpretability of comparisons. We have defined a simple, easily implemented set of outcomes that we believe should be measured in all men with localized PCa as a crucial first step in improving the value of care. Measuring, reporting, and comparing identical outcomes across treatments and treatment centers will provide patients and providers with information to make informed treatment decisions. We defined a set of outcomes that we recommend being tracked for every man being treated for localized prostate cancer.


Confined crystallization of fenofibrate in nanoporous silica.
Producing stable nanocrystals confined to porous excipient media is a desirable way to increase the dissolution rate and improve the bioavailability of poorly water soluble pharmaceuticals. The poorly soluble pharmaceutical fenofibrate was crystallized in controlled pore glass (CPG) of 10 different pore sizes between 12 nm and 300 nm. High drug loadings of greater than 20 wt% were achieved across all pore sizes greater than 20 nm. Nanocrystalline fenofibrate was formed in pore sizes greater than 20 nm and showed characteristic melting point depressions following a Gibbs-Thomson relationship as well as enhanced dissolution rates. Solid-state Nuclear Magnetic Resonance (NMR) was employed to characterize the crystallinity of the confined molecules. These results help to advance the fundamental understanding of nanocrystallization in confined pores.


Child Maltreatment and Adult Sexual Assault Victimization: Genetic and Environmental Associations.
Despite the pervasiveness of adult sexual assault (ASA), evidence-based knowledge on the risk factors for sexual victimization is insufficient. Here, we investigated the etiology of ASA in a population-based Finnish twin sample. Specifically, we estimated the extent of the genetic and environmental influences on the risk of ASA, and we examined its phenotypic and genetic associations with five types of child maltreatment (CM). We found large unique environmental, but also small genetic influences on the risk of ASA, motivating further research on situational and behavioral conditions potentially exploited by sexually motivated perpetrators. The prevalence of ASA was highest among victims of severe child sexual abuse. However, when accounting for the co-occurrence of multiple types of CM, emotional abuse was the strongest predictor of ASA. We further examined, and could not entirely rule out, the possibility of common genetic and environmental pathways underlying CM and ASA. Lastly, we focused on sex differences. Emotional and physical abuse were the strongest predictors of ASA in women and men, respectively, and genetic influences on the risk of ASA were larger in women than men. However, such higher heritability did not reflect sex-limited genetic effects, but, rather, women's systematic exposure to environmental risk of ASA.


Immunosuppressive effects of human CTLA4Ig in a non-human primate model of allogeneic pancreatic islet transplantation.
Ag-specific T cell activation requires a CD28-mediated costimulatory interaction. This observation has suggested novel approaches to suppress donor-specific immunity, including the use of soluble CD28 antagonists, such as CTLA4Ig, which suppresses transplant rejection in small animal models. In this study, CTLA4Ig therapy was examined in a non-human primate model of allogeneic pancreatic islet transplantation. Two of five CTLA4Ig-treated monkeys showed prolonged graft survival, which correlated with donor-specific hyporesponsiveness in vitro. Humoral responses to the transplanted tissue were suppressed in all treated animals. These results suggest that CTLA4Ig is effective in suppressing both humoral and cellular immune responses in a non-human primate model of allogeneic transplantation.


Improvement in endothelial dysfunction in patients with systemic lupus erythematosus with N-acetylcysteine and atorvastatin.
To study the effects of N-acetylcysteine (NAC) and atorvastatin on endothelial dysfunction in patients with systemic lupus erythematosus (SLE). Thirty-two SLE patients and age, sex-matched 10 healthy control subjects were studied. The patients were between 17 and 65 years of age and positive for diagnostic tests, such as antinuclear antibodies (ANA). Photoplethysmogram (PPG) detects the changes in the amount of light absorbed by hemoglobin, which reflects changes in the blood volume. Pulse wave analysis was performed at rest, 30 s, 90 s after shear stress, and 10 min after 300 μm of salbutamol inhalation. Stiffness index (SI) of patients before the treatment was 8.46±2.78 cm/s and of controls was 6.07±1.4 cm/s (P = 0.002) and that of reflection index (RI) was 73±13 for patients and 65±7 for controls (P = 0.001). The percentage change in RI after salbutamol inhalation for controls and patients were -16±6 and -7±4 (P = 0.001), respectively, indicating the presence of endothelial dysfunction. The percentage decrease in RI after salbutamol inhalation was from -2.36±0.76 to ?7.92±1.46 in patients treated with N-acetylcysteine (NAC, P = 0.007). The percentage decrease in RI after salbutamol inhalation was from ?6.36΁1.21 to -9.92±1.21 in patients treated with atorvastatin (P = 0.05). This indicated the improvement in endothelial function. There was decrease in C-reactive protein (CRP) from 1.03±0.72 mg/dL to 0.52±0.22 mg/dL and that of malondialdehyde (MDA) from 11.20±4.07 nmol/mL to 8.81±2.79 nmol/mL with N-acetylcysteine treatment (P < 0.05). The CRP was decreased from 1.11±0.92 mg/dL to 0.440.16 mg/dL (P = 0.05) and that of MDA was decreased from 9.37±3.29 nmol/mL to 8.51±3.27 nmol/mL after treatment with atorvastatin. It showed improvement in oxidative stress with these treatments. The presence of arterial stiffness indicated endothelial dysfunction. There was reduction in RI and SI with treatment of N-acetylcysteine and atorvastatin suggesting improvement in endothelial dysfunction. There was decrease in CRP (a marker of inflammation) and MDA after treatment with N-acetylcysteine suggesting improvement in endothelial dysfunction. There was reduction in CRP after treatment with atorvastatin, suggesting improvement in endothelial function. Improvement in endothelial dysfunction is associated with decreased incidence of cardiovascular and cerebrovascular accidents.


A common genetic variant at 15q25 modifies the associations of maternal smoking during pregnancy with fetal growth: the generation R study.
Maternal smoking during pregnancy is associated with fetal growth retardation. We examined whether a common genetic variant at chromosome 15q25 (rs1051730), which is known to be involved in nicotine metabolism, modifies the associations of maternal smoking with fetal growth characteristics. This study was performed in 3,563 European mothers participating in a population-based prospective cohort study from early pregnancy onwards. Smoking was assessed by postal questionnaires and fetal growth characteristics were measured by ultrasound examinations in each trimester of pregnancy. Among mothers who did not smoke during pregnancy (82.9%), maternal rs1051730 was not consistently associated with any fetal growth characteristic. Among mothers who continued smoking during pregnancy (17.1%), maternal rs1051730 was not associated with head circumference. The T-allele of maternal rs1051730 was associated with a smaller second and third trimester fetal femur length [differences -0.23 mm (95%CI -0.45 to -0.00) and -0.41 mm (95%CI -0.69 to -0.13), respectively] and a smaller birth length [difference -2.61 mm (95%CI -5.32 to 0.11)]. The maternal T-allele of rs1051730 was associated with a lower third trimester estimated fetal weight [difference -33 grams (95%CI -55 to -10)], and tended to be associated with birth weight [difference -38 grams (95%CI -89 to 13)]. This association persisted after adjustment for smoking quantity. Our results suggest that maternal rs1051730 genotype modifies the associations of maternal smoking during pregnancy with impaired fetal growth in length and weight. These results should be considered as hypothesis generating and indicate the need for large-scale genome wide association studies focusing on gene--fetal smoke exposure interactions.


Diagenesis and clay mineral formation at Gale Crater, Mars.
The Mars Science Laboratory rover Curiosity found host rocks of basaltic composition and alteration assemblages containing clay minerals at Yellowknife Bay, Gale Crater. On the basis of the observed host rock and alteration minerals, we present results of equilibrium thermochemical modeling of the Sheepbed mudstones of Yellowknife Bay in order to constrain the formation conditions of its secondary mineral assemblage. Building on conclusions from sedimentary observations by the Mars Science Laboratory team, we assume diagenetic, in situ alteration. The modeling shows that the mineral assemblage formed by the reaction of a CO2-poor and oxidizing, dilute aqueous solution (Gale Portage Water) in an open system with the Fe-rich basaltic-composition sedimentary rocks at 10-50°C and water/rock ratio (mass of rock reacted with the starting fluid) of 100-1000, pH of ∽7.5-12. Model alteration assemblages predominantly contain phyllosilicates (Fe-smectite, chlorite), the bulk composition of a mixture of which is close to that of saponite inferred from Chemistry and Mineralogy data and to that of saponite observed in the nakhlite Martian meteorites and terrestrial analogues. To match the observed clay mineral chemistry, inhomogeneous dissolution dominated by the amorphous phase and olivine is required. We therefore deduce a dissolving composition of approximately 70% amorphous material, with 20% olivine, and 10% whole rock component.


Gas-phase stability of G-quadruplex DNA determined by electrospray ionization tandem mass spectrometry and molecular dynamics simulations.
The relative gas-phase stabilities of seven quadruplex DNA structures, [d(TG(4)T)](4), [d(T(2)G(3)T)](4), [d(G(4)T(4)G(4))](2), [d(T(2)AG(3))(2)](2), d(T(2)AG(3))(4), d(T(2)G(4))(4), and d(G(2)T(4))(4), were investigated using molecular dynamics simulations and electrospray ionization mass spectrometry (ESI-MS). MD simulations revealed that the G-quadruplexes maintained their structures in the gas phase although the G-quartets were distorted to some degree and ammonium ions, retained by [d(TG(4)T)](4) and [d(T(2)G(3)T)](4), played a key role in stabilizing the tetrad structure. Energy-variable collisional activated dissociation was used to assess the relative stabilities of each quadruplex based on E(1/2) values, and the resulting order of relative stabilities was found to be [d(TG(4)T)](4) >> d(T(2)AG(3))(4) approximately d(T(2)G(4))(4) > [d(T(2)G(3)T)](4) > [d(T(2)AG(3))(2)](2) approximately d(G(2)T(4))(4) approximately [d(G(4)T(4)G(4))](2.) The stabilities from the E(1/2) values generally paralleled the RMSD and relative free energies of the quadruplexes based on the MD energy analysis. One exception to the general agreement is [d(G(4)T(4)G(4))](2), which had the lowest E(1/2) value, but was determined to be the most stable quadruplex according to the free-energy analysis and ranked fourth based on the RMSD comparison. This discrepancy is attributed to differences in the fragmentation pathway of the quadruplex.


Walking and balance in children and adolescents with lower-limb amputation: A review of literature.
Children with lower limb loss face gait and balance limitations. Prosthetic rehabilitation is thus aimed at improving functional capacity and mobility throughout the developmental phases of the child amputee. This review of literature was conducted to determine the characteristics of prosthetic gait and balance among children and adolescents with lower-limb amputation or other limb loss. Both qualitative and quantitative studies were included in this review and data were organized by amputation etiology, age range and level of amputation. The findings indicated that the structural differences between children with lower-limb amputations and typically developing children lead to functional differences. Significant differences with respect to typically developing children were found in spatiotemporal, kinematic, and kinematic parameters and ground-reaction forces. Children with transtibial amputation place significantly larger load on their intact leg compared to the prosthetic leg during balance tasks. In more complex dynamic balance tests, they generally score lower than their typically developing peers. There is limited literature pertaining to improving physical therapy protocols, especially for different age groups, targeting gait and balance enhancements. Understanding gait and balance patterns of children with lower-limb amputation will benefit the design of prosthetic components and mobility rehabilitation protocols that improve long-term outcomes through adulthood.


Sirtuins: critical regulators at the crossroads between cancer and aging.
Sirtuins (SIRTs 1-7), or class III histone deacetylases (HDACs), are protein deacetylases/ADP ribosyltransferases that target a wide range of cellular proteins in the nucleus, cytoplasm, and mitochondria for post-translational modification by acetylation (SIRT1, -2, -3 and -5) or ADP ribosylation (SIRT4 and -6). The orthologs of sirtuins in lower organisms play a critical role in regulating lifespan. As cancer is a disease of aging, we discuss the growing implications of the sirtuins in protecting against cancer development. Sirtuins regulate the cellular responses to stress and ensure that damaged DNA is not propagated and that mutations do not accumulate. SIRT1 also promotes replicative senescence under conditions of chronic stress. By participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers. Here, we review the growing implications of sirtuins both in cancer prevention and as specific and novel cancer therapeutic targets.


Maternal Weaning Modulates Emotional Behavior and Regulates the Gut-Brain Axis.
Evidence shows that nutritional and environmental stress stimuli during postnatal period influence brain development and interactions between gut and brain. In this study we show that in rats, prevention of weaning from maternal milk results in depressive-like behavior, which is accompanied by changes in the gut bacteria and host metabolism. Depressive-like behavior was studied using the forced-swim test on postnatal day (PND) 25 in rats either weaned on PND 21, or left with their mother until PND 25 (non-weaned). Non-weaned rats showed an increased immobility time consistent with a depressive phenotype. Fluorescence in situ hybridization showed non-weaned rats to harbor significantly lowered Clostridium histolyticum bacterial groups but exhibit marked stress-induced increases. Metabonomic analysis of urine from these animals revealed significant differences in the metabolic profiles, with biochemical phenotypes indicative of depression in the non-weaned animals. In addition, non-weaned rats showed resistance to stress-induced modulation of oxytocin receptors in amygdala nuclei, which is indicative of passive stress-coping mechanism. We conclude that delaying weaning results in alterations to the gut microbiota and global metabolic profiles which may contribute to a depressive phenotype and raise the issue that mood disorders at early developmental ages may reflect interplay between mammalian host and resident bacteria.


The Legionella pneumophila LetA/LetS two-component system exhibits rheostat-like behavior.
When confronted with metabolic stress, replicative Legionella pneumophila bacteria convert to resilient, infectious cells equipped for transmission. Differentiation is promoted by the LetA/LetS two-component system, which belongs to a family of signal-transducing proteins that employ a four-step phosphorelay to regulate gene expression. Histidine 307 of LetS was essential to switch on the transmission profile, but a threonine substitution at position 311 (T311M) suggested a rheostat-like function. The letS(T311M) bacteria resembled the wild type (WT) for some traits and letS null mutants for others, whereas they displayed intermediate levels of infectivity, cytotoxicity, and lysosome evasion. Although only 30 to 50% of letS(T311M) mutants became motile, flow cytometry determined that every cell eventually activated the flagellin promoter to WT levels, but expression was delayed. Likewise, letS(T311M) mutants exhibited delayed induction of RsmY and RsmZ, regulatory RNAs that relieve CsrA repression of transmission traits. Transcriptional profile analysis revealed that letS(T311M) mutants expressed the flagellar regulon and multiple other transmissive-phase loci at a higher cell density than the WT. Accordingly, we postulate that the letS(T311M) mutant may relay phosphate less efficiently than the WT LetS sensor protein, leading to sluggish gene expression and a variety of phenotypic profiles. Thus, as first described for BvgA/BvgS, rather than acting as on/off switches, this family of two-component systems exhibit rheostat activity that likely confers versatility as microbes adapt to fluctuating environments.


Effects of the Fukushima Daiichi nuclear accident on goshawk reproduction.
Although the influence of nuclear accidents on the reproduction of top predators has not been investigated, it is important that we identify the effects of such accidents because humans are also top predators. We conducted field observation for 22 years and analysed the reproductive performance of the goshawk (Accipiter gentilis fujiyamae), a top avian predator in the North Kanto area of Japan, before and after the accidents at the Fukushima Daiichi nuclear power plant that occurred in 2011. The reproductive performance declined markedly compared with the pre-accident years and progressively decreased for the three post-accident study years. Moreover, it was suggested that these declines were primarily caused by an increase in the air dose rate of radio-active contaminants measured under the nests caused by the nuclear accidents, rather than by other factors. We consider the trends in the changes of the reproductive success rates and suggest that internal exposure may play an important role in the reproductive performance of the goshawk, as well as external exposure.


Highly Efficient F, Cu doped TiO2 anti-bacterial visible light active photocatalytic coatings to combat hospital-acquired infections.
Bacterial infections are a major threat to the health of patients in healthcare facilities including hospitals. One of the major causes of patient morbidity is infection with Staphylococcus aureus. One of the the most dominant nosocomial bacteria, Methicillin Resistant Staphylococcus aureus (MRSA) have been reported to survive on hospital surfaces (e.g. privacy window glasses) for up to 5 months. None of the current anti-bacterial technology is efficient in eliminating Staphylococcus aureus. A novel transparent, immobilised and superhydrophilic coating of titanium dioxide, co-doped with fluorine and copper has been prepared on float glass substrates. Antibacterial activity has demonstrated (by using Staphylococcus aureus), resulting from a combination of visible light activated (VLA) photocatalysis and copper ion toxicity. Co-doping with copper and fluorine has been shown to improve the performance of the coating, relative to a purely fluorine-doped VLA photocatalyst. Reductions in bacterial population of log10 = 4.2 under visible light irradiation and log10 = 1.8 in darkness have been achieved, compared with log10 = 1.8 under visible light irradiation and no activity, for a purely fluorine-doped titania. Generation of reactive oxygen species from the photocatalytic coatings is the major factor that significantly reduces the bacterial growth on the glass surfaces.


Properties of Daily Helium Fluxes.
We present the precision measurement of 2824 daily helium fluxes in cosmic rays from May 20, 2011 to October 29, 2019 in the rigidity interval from 1.71 to 100 GV based on 7.6×10^{8} helium nuclei collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The helium flux and the helium to proton flux ratio exhibit variations on multiple timescales. In nearly all the time intervals from 2014 to 2018, we observed recurrent helium flux variations with a period of 27 days. Shorter periods of 9 days and 13.5 days are observed in 2016. The strength of all three periodicities changes with time and rigidity. In the entire time period, we found that below ∼7 GV the helium flux exhibits larger time variations than the proton flux, and above ∼7 GV the helium to proton flux ratio is time independent. Remarkably, below 2.4 GV a hysteresis between the helium to proton flux ratio and the helium flux was observed at greater than the 7σ level. This shows that at low rigidity the modulation of the helium to proton flux ratio is different before and after the solar maximum in 2014.


Restrictive Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy.
Restrictive cardiomyopathy (RCM) is characterized by nondilated left or right ventricle with diastolic dysfunction. The restrictive cardiomyopathies are a heterogenous group of myocardial diseases that vary according to pathogenesis, clinical presentation, diagnostic evaluation and criteria, treatment, and prognosis. In this review, an overview of RCMs will be presented followed by a detailed discussion on 3 major causes of RCM, for which tailored interventions are available: cardiac amyloidosis, cardiac sarcoidosis, and cardiac hemochromatosis. Each of these 3 RCMs is challenging to diagnose, and recognition of each disease entity is frequently delayed. Clinical clues to promote recognition of cardiac amyloidosis, cardiac sarcoidosis, and cardiac hemochromatosis and imaging techniques used to facilitate diagnosis are discussed. Disease-specific therapies are reviewed. Early recognition remains a key barrier to improving survival in all RCMs.


NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease.
In humans, natural killer (NK) cell function is regulated by a series of receptors and coreceptors with either triggering or inhibitory activity. Here we describe a novel 60-kD glycoprotein, termed NTB-A, that is expressed by all human NK, T, and B lymphocytes. Monoclonal antibody (mAb)-mediated cross-linking of NTB-A results in the induction of NK-mediated cytotoxicity. Similar to 2B4 (CD244) functioning as a coreceptor in the NK cell activation, NTB-A also triggers cytolytic activity only in NK cells expressing high surface densities of natural cytotoxicity receptors. This suggests that also NTB-A may function as a coreceptor in the process of NK cell activation. Molecular cloning of the cDNA coding for NTB-A molecule revealed a novel member of the immunoglobulin superfamily belonging to the CD2 subfamily. NTB-A is characterized, in its extracellular portion, by a distal V-type and a proximal C2-type domain and by a cytoplasmic portion containing three tyrosine-based motifs. NTB-A undergoes tyrosine phosphorylation and associates with the Src homology 2 domain-containing protein (SH2D1A) as well as with SH2 domain-containing phosphatases (SHPs). Importantly, analysis of NK cells derived from patients with X-linked lymphoproliferative disease (XLP) showed that the lack of SH2D1A protein profoundly affects the function not only of 2B4 but also of NTB-A. Thus, in XLP-NK cells, NTB-A mediates inhibitory rather than activating signals. These inhibitory signals are induced by the interaction of NTB-A with still undefined ligands expressed on Epstein-Barr virus (EBV)-infected target cells. Moreover, mAb-mediated masking of NTB-A can partially revert this inhibitory effect while a maximal recovery of target cell lysis can be obtained when both 2B4 and NTB-A are simultaneously masked. Thus, the altered function of NTB-A appears to play an important role in the inability of XLP-NK cells to kill EBV-infected target cells.


Mitochondria and neurodegenerative diseases: Special issue of BMB Reports in 2020.
Mitochondria is essential to generate metabolic energy in eukaryotic cells as well as to regulate calcium buffering, cell signaling, the production of reactive oxygen species (ROS), and apoptosis. They mainly produce most of the cellular energy derived from the breakdown of carbohydrates and fatty acids, which is consequently converted to ATP via oxidative phosphorylation. Mitochondria are also distinctive among the cytoplasmic organelles in that they contain their own DNA, which encodes limited number of mitochondrial proteins, tRNAs, and rRNAs. Evidence has accumulated from many reports, indicating that mitochondrial abnormalities are involved in age-related neurodegenerative diseases (NDDs). Causal factors for most age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis are largely unknown. Although genetic defects are reported to cause a small number of NDDs, cellular, molecular, and pathological mechanisms of disease progression and selective neuronal cell death are not understood fully in these diseases. Especially, age-dependent and mitochondriagenerated ROS has been identified as an important factor that is responsible for disease progression and cell death, particularly in late-onset diseases. Based on the current hypothesis supported by many recent findings, this issue discusses the roles of mitochondria in the progression of age-related neurodegenerative diseases, the connection between mitochondrial abnormalities and NDD, and the drug development targeted to mitochondria in NDDs. [BMB Reports 2020; 53(1): 1-2].


Facial emotion recognition in adopted children.
Children adopted from public care are more likely to experience emotional and behavioural problems. We investigated two aspects of emotion recognition that may be associated with these outcomes, including discrimination accuracy of emotions and response bias, in a mixed-method, multi-informant study of 4-to-8-year old children adopted from local authority care in the UK (N = 42). We compared adopted children's emotion recognition performance to that of a comparison group of children living with their birth families, who were matched by age, sex, and teacher-rated total difficulties on the Strengths and Difficulties Questionnaire (SDQ, N = 42). We also examined relationships between adopted children's emotion recognition skills and their pre-adoptive histories of early adversity (indexed by cumulative adverse childhood experiences), their parent- and teacher-rated emotional and behavioural problems, and their parents' coded warmth during a Five Minute Speech Sample. Adopted children showed significantly worse facial emotion discrimination accuracy of sad and angry faces than non-adopted children. Adopted children's discrimination accuracy of scared and neutral faces was negatively associated with parent-reported behavioural problems, and discrimination accuracy of angry and scared faces was associated with parent- and teacher-reported emotional problems. Contrary to expectations, children who experienced more recorded pre-adoptive early adversity were more accurate in identifying negative emotions. Warm adoptive parenting was associated with fewer behavioural problems, and a lower tendency for children to incorrectly identify faces as angry. Study limitations and implications for intervention strategies to support adopted children's emotion recognition and psychological adjustment are discussed.


Orthogonally polarized dual-wavelength Nd:YAlO(3) laser at 1341 and 1339 nm and sum-frequency mixing for an emission at 670 nm.
We report a diode-pumped continuous wave (cw) orthogonally polarized dual-wavelength laser at 1339 and 1341 nm with a single b-cut Nd:YAlO(3) (Nd:YAP) crystal. By adjusting the tilt angle of the uncoated glass plate inserted in the laser cavity, we can control the cavity losses of two polarized directions. The output wavelengths are 1339 nm in a-axis polarization and 1341 nm in c-axis polarization, respectively, which are orthogonal to each other. At an incident pump power of 17.3 W, the cw output power obtained at 1339 and 1341 nm is 1.6 and 2.3 W, respectively. Furthermore, intracavity sum-frequency mixing at 1339 and 1341 nm was then realized in a KTiOPO(4) (KTP) crystal to reach the red range. To our knowledge, this is the first work realizing an orthogonally polarized dual-wavelength Nd:YAP laser based on the (4)F(3/2-)-(4)I(13/2) transition. Such a dual-wavelength laser would be especially valuable as a compact laser source to generate terahertz emission because the frequency difference between 1339 and 1341 nm is about 0.9 THz.


SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance.
To analyse the expression of SIRT1 in synovial tissues and cells of patients with rheumatoid arthritis (RA) and to study the function of SIRT1 in inflammation and apoptosis in RA. Levels of SIRT1 expression were analysed in synovial tissues and cells from patients with RA by real-time PCR and western blotting before and after stimulation with toll-like receptor ligands, tumour necrosis factor α (TNFα) and interleukin 1β (IL-1β). Immunohistochemistry was used to study the localisation of SIRT1. Fluorescence activated cell sorting analysis was performed to investigate the effect of SIRT1 on apoptosis. Peripheral blood monocytes and rheumatoid arthritis synovial fibroblasts (RASFs) were transfected with wild-type or enzymatically inactive SIRT1 expression vectors or with siRNA targeting SIRT1. Cytokine analysis of IL-6, IL-8 and TNFα were performed by ELISA to study the role of SIRT1 on proinflammatory mediators of RA. SIRT1 was found to be constitutively upregulated in synovial tissues and cells from patients with RA compared to osteoarthritis. TNFα stimulation of RASFs and monocytes resulted in further induced expression levels of SIRT1. Silencing of SIRT1 promoted apoptosis in RASFs, whereas SIRT1 overexpression protected cells from apoptosis. Inhibition of SIRT1 enzymatic activity by inhibitors, siRNA and overexpression of an enzymatically inactive form of SIRT1 reduced lipopolysaccharide-induced levels of TNFα in monocytes. Similarly, knockdown of SIRT1 resulted in a reduction of proinflammatory IL-6 and IL-8 in RASFs. The TNFα-induced overexpression of SIRT1 in RA synovial cells contributes to chronic inflammation by promoting proinflammatory cytokine production and inhibiting apoptosis.


Combining in silico prediction and ribosome profiling in a genome-wide search for novel putatively coding sORFs.
It was long assumed that proteins are at least 100 amino acids (AAs) long. Moreover, the detection of short translation products (e.g. coded from small Open Reading Frames, sORFs) is very difficult as the short length makes it hard to distinguish true coding ORFs from ORFs occurring by chance. Nevertheless, over the past few years many such non-canonical genes (with ORFs < 100 AAs) have been discovered in different organisms like Arabidopsis thaliana, Saccharomyces cerevisiae, and Drosophila melanogaster. Thanks to advances in sequencing, bioinformatics and computing power, it is now possible to scan the genome in unprecedented scrutiny, for example in a search of this type of small ORFs. Using bioinformatics methods, we performed a systematic search for putatively functional sORFs in the Mus musculus genome. A genome-wide scan detected all sORFs which were subsequently analyzed for their coding potential, based on evolutionary conservation at the AA level, and ranked using a Support Vector Machine (SVM) learning model. The ranked sORFs are finally overlapped with ribosome profiling data, hinting to sORF translation. All candidates are visually inspected using an in-house developed genome browser. In this way dozens of highly conserved sORFs, targeted by ribosomes were identified in the mouse genome, putatively encoding micropeptides. Our combined genome-wide approach leads to the prediction of a comprehensive but manageable set of putatively coding sORFs, a very important first step towards the identification of a new class of bioactive peptides, called micropeptides.